Advances in Carbohydrate Chemistry and Biochemistry, Volume 34

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Advances in Carbohydrate Chemistry and Biochemistry

Volume 34

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Advances in Carbohydrate Chemistry and Biochemistry Editors R. STUART TIPSON

DEREK HORTON

Board of Advisors LAURENSANDERSON ALLAN B. FOSTER DEXTERFRENCH BENGT LINDBERG

HANS PAULSEN W. WARD PIGMAN MAURICESTACEY ROY L. WHISTLEH

Volume 34

1977

ACADEMIC PRESS

New York

San Francisco London

A Subsidiary of Harcourt Brace Jovanovich, Publishers

COPYRIGHT @ 1911,BY ACADEMIC PRESS,INC. ALL RIGHTS RESERVED. NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

ACADEMIC PRESS, INC.

111 Fifth Avenue, New York, New York 10003

United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London NW1

LIBRARY OF CONGRESS CATALOG CARD NUMBER: 45- 1135 1 ISBN 0-12-007234-3 PRINTED IN THE UNITED STATES OF AMERICA

CONTENTS LIST OF CONTRIBUTORS. . . . . . . . . . . . . . . . . . . . . . . . . . PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

vii ix

Edward John Bourne (1922-1974) HELMUTWEIGEL Text

. . . . . . .

. . . .

1

1.6.Anhydro Derivatives of Aldohexoses

MILOSLAV CERNYAND

JAN

STANEK.JR .

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Formation and Preparation of 1,6.Anhydrohexopyranoses 111. General Properties of 1,6.Anhydrohexopyranoses . . . . . . . . . . IV . Reactions of 1.6.Anhydrohexopyranoses . . . . . . . . . . . . . . . V. 1.6.2,3. and 1.6.3.4.Dianhydrohexopyranoses . . . . . . . . . . . . VI . Nitrogen Derivatives of 1,6.Anhydrohexopyranoses . . . . . . . . . VII . Halogeno. Thio, and Deoxy Derivatives of 1,6.Anhydrohexopyranoses VIII . 1,6.Anhydrohexopyrariose and 1,6.Anhydrohexofuranose Analogs . . . IX . 1,6.Anhydrohexofuranoses . . . . . . . . . . . . . . . . . . . . . . X . 1,6.Anhydro Derivatives of Oligosaccharides . . . . . . . . . . . . XI . Tables of Properties of 1,6.Anhydrohexoses and Their Derivatives . .

. .

. . . . . .

.

24 26 50 63 107 121 131 146 151 157 164

Cyclic Acetals of the Aldoses and Aldosides ANTHONY N .

DE

BELDER

179 I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 I1. The Acetalation Reaction . . . . . . . . . . . . . . . . . . . . . . 111. Physical Methods for Structural Elucidation . . . . . . . . . . . . . . 192 198 IV . Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 V. General Features . . . . . . . . . . . . . . . . . . . . . . . . . . VI . Tables of Properties of Cyclic Acetals of the Aldoses and Aldosides . . 209

The Koenigs-Knorr Reaction KIKUO IGARASHI

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . I1. Synthesis of Glycopyranosides . . . . . . . . . . . . . . . 111. Synthesis of Glycosides Other Than Pyranosides . . . . . .

243 245 277

Metabolism of D-Fructose MINSHENCHEN AND ROY L . WHISTLER I . Iiitroductioii

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Metabolism of D-Fructose in Liver. Intestine. and Kidney . . . . . . . IV . Metabolism of D-Fructose in Adipose Tissue . . . . . . . . . . . . . I1. Assimilation from Intestine

v

286 287 291 297

vi

CONTENTS

V . Metabolism of DFructose in Blood and Muscle Cells . . . . . . . . . VI . Metabolism of &Fructose in Testes and Spermatozoa . . . . . . . . . VII . Inborn Errors of &Fructose Metabolism . . . . . . . . . . . . . . . VIII . Metabolism of DFructose in Micro-organisms . . . . . . . . . . . . . IX . Synthesis and Degradation of D-Fructatis . . . . . . . . . . . . . . . X . Effect of DFructose on Metabolism of Ethanol . . . . . . . . . . . . XI . Effect of &Fructose on the Nucleotide Pool in Liver . . . . . . . . . XI1 . Effect of D-Fructose on the Energy Metabolism of Intestinal, Epithelial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI11 . Effect of D-Fructose on Lipid Metabolism . . . . . . . . . . . . . . . XIV . Key Enzymes in Metabolism of &Fructose . . . . . . . . . . . . . . XV . Use of &Fructose . . . . . . . . . . . . . . . . . . . . . . . . . .

298 298 306 310 314 317 322 324 325 330 343

Bibliography of Crystal Structures of Carbohydrates. Nucleosides. and Nucleotides. 1975

GEORGEA . JEFFREYAND MUTTAIYASUNDARALINGAM 345 I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 I1 . Data for Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . 111. Data for Nucleosides and Nucleotides . . . . . . . . . . . . . . . . . 362 IV . Preliminary Communications . . . . . . . . . . . . . . . . . . . . . 371

AUTHORINDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUBJECTINDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

'379 415

LIST OF CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors’ contributions begin.

MILOSLAV ~ E R N PDepartment , of Organic Chemistry, Charles University, 128 40 Albertov 2030, Prugue 2, Czechoslovakia (23) MINSHENCHEN, Department of Biochemistry, Purdue Univemity, Lafayette, Indiana 47907 (285) ANTHONY N. DE BELDER, Resenrch Division, Pharmacia A B , S7.51 25 Uppsala 1 , Sweden (179)

KIKUO IGARASHI,Shionogi Research Laboratory, Shionogi iL Co., Ltd., Fukushimu-ku, Osaka 5.53,J a p a n (243) GEORGEA. JEFFREY,* Department of Chemistry, Brookhaven Nutional Laboratory, Upton, Long Island, New York 11973 (345) JAN

STANEK,JR., Laboratory of Monosaccharides, Institute of Chemical Technolog!/, 166 28 Prague 6, Czechoslovakin (23)

MUTTAIYASUNDARALINGAM, Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706 (345) HELMUT WEIGEL, Department of Chemistry, Royal Holloway College, Egham Hill, Egham, Surrey TW20 OEX, England (1) ROY L. WHISTLER, Department of Biochemistry, Purdue Unioersity, Lafayette, Indiana 47907 (285)

* Present address: I)epaitment of‘ Crystallography, Uiiiversity of Pittslmrgh, Pittsburgh, Pennsylvania 1.5260, vii

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PREFACE In this volume of Advunces, Cerny and Staiick, Jr. (Prague) contribute a comprehensive article on the 1,6-anhydro derivatives of aldohexoses. This class of anhydro sugars, earlier termed the hexosans, constitutes by far the largest class of sugar anhydrides to have been studied. The scope of the topic is now so extensive that the Editors, in view of their earlier practice of limiting chapter size in individual volumes ofAdvunces in the interest of diversification of subject material, were inclined to divide this chapter into two parts, to appear in successive volumes. However, as the latter practice has elicited some unfavorable reaction from readers on previous occasions, it was decided to present the article here in its entirety. The chapter complements previous ones on other classes of anhydro derivatives, in particular, recent ones on anhydrides of the oxirane (epoxide) and 2,5anhydro (oxolane) types. Although the cyclic acetals of aldoses and aldosides were the subject of an article by De Belder (Uppsala) as recently as Volume 20 (1965), the subject has been in a state of particularly active development in recent years, because of the exceptional synthetic utility of these derivatives and as a result of access to other types of cyclic acetals through the advent of new preparative methods and improvements in methods for the analysis of reaction mixtures. T o keep the subject up to date, De Belder has now contributed a new article that highlights the literature since his chapter in Volume 20, and he also provides a supplement to the tables of data featured with the original article. The Koenigs-Knorr reaction is one of the oldest reactions in the carbohydrate literature, yet the rational use of this synthesis for generating the mixed acetal group that links sugar residues in glycosides and oligosaccharides remains enigmatic and capricious; generalizations are difficult to make and the reaction continues to challenge modern investigators. In this issue, Igarashi (Osaka) has provided a detailed comparison of numerous efforts in this area, with particular emphasis on the relationship between anomeric ratios in the products and the conditions used for the reaction. With the advent of new, commercial procedures for production of D-fructose and high-fructose sweeteners, profound changes are taking place in the traditional sweetener industry, and human diet-patterns face substantial changes toward an increased, direct intake of D-fructose. The article by Chen and Whistler (Purdue) on metabolism of D-fructose is thus particularly timely, as it brings into detailed focus the frequently overlooked metabolic differences between the conventional dietary sugars and this ketose acting alone.

X

PREFACE

The 1975 literature of crystal structures of carbohydrates, nucleosides, and nucleotides has been summarized by Jeffrey (Upton, N. Y.) and Sundaralingam (Madison); following the procedure used by them in previous such bibliographies, the depictions have been re-drawn by means of computer graphics so as to present the structures in a format that is most readily comprehensible for organic chemists and biochemists. Corrections in the original data have been made where necessary, especially as regards specification of the correct enantiomer. The untimely death of our friend and colleague Edward J. Bourne was noted briefly in the previous volume; in this issue, Weigel (Egham) contributes a sensitive and personal account of Bourne’s life and scientific work. The editors note with regret the passing of our friends Sir Edmund Hirst on October 29, 1975, J. K. N. Jones on April 13,1977 and W. W. Pigman on September 30, 1977. The Subject Index was compiled by Dr. L. T. Capell. Kensington, Maryland Columbus, Ohio September, 1977

R. STUARTTPSON DEREKHORTON

Advances in Carbohydrate Chemistry and Biochemistry Volume 34

1922-1974

EDWARD JOHN BOURNE

1922-1974 Biographical Notes

Cannock Chase is the remnant of a vast forest that covered much of Staffordshire at the time of the Domesday survey. Once a hunting ground of the kings of Mercia, it is today an oasis of undulating forestland and heath, perched between two great industrial regions, known as the Potteries and the Black Country, where the population is found massed together in the neighborhood of two great coalfields. It received its name from the ancient manor of Chenet, and it was in the township of Cannock, to the south-west of the Chase that Edward John Bourne was born on Sunday, the 1st day of January 1922. Staffordshire remained poor up to the eighteenth century, despite its rich stores of mineral wealth, notably iron and coal. The lack of communication between this county and the rest of England was an obstacle to industrial and commercial development of Staffordshire. It was shut in on the north by tracts of moorland and limestone hills, with the wooded Cannock Chase on the south, and the Welsh mountains as a barrier in the western direction. The Trent, the main river in Staffordshire, rises in the north of the county, but only from the neighborhood of Burton-upon-Trent, on the eastern boundary of the county, was river navigation of any consequence. There was no way of reaching the western seaboard by water until the cutting of canals in the eighteenth century. The economic life of the county was transformed by the industrial revolution-in the south, by the emergence of a new, primary iron industry based on coal instead of charcoal, and in the north, by the rapid growth of the pottery industry. Essential to this change was the construction of the network of trunk and local canals. By 1777, the Staffordshire and Worcestershire Canal and the Grand Trunk Canal linked the three estuaries of Humber, Mersey, and Severn, and by the early nineteenth century, Staffordshire had become the pivot of England’s waterway system.

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Cannock began the nineteenth century with a tiny population of 1359, which, by 1851, had increased to only 2099. A coalfield characterized by shallow workings, limited local markets, and the activity of small enterprises (to use the local expression, “bucket pits”) could support no more. However, within a quarter of a century, this coalfield gave place to an extended area of deep winnings, supplying an extensive market. The transformation was made possible by the growing incapacity of Black Country collieries to meet demands, but, above all, by the advent of the railway and the development of the canal system. In fifty years, by 1901, the population of the township of Cannock had increased more than ten-fold, to 23,974. Ted Bourne was very conscious of where his roots lay, and, whenever he had an opportunity, he returned to his native Staffordshire. God gaoe all men all earth to looe, But since our hearts are small, Ordained f o r each one spot should prove Belooed m e r all.

The chronicles of the county contain numerous references to the name Bourne. As early as 1315, a John de la Bourne was chaplain to the Hospital of St. John the Baptist, Lichfield; in 1548, John and William Bourne jointly held the lease of the prebend of Congreve in the collegiate church of Penkridge. In 1654, Richard Bourne was established in Cannock by the Church Commissioners to preach the gospel at a salary of $100 per annum. Methodism made its most striking advances in the industrial towns, where the existing parochial organization was incapable of catering for the increasing population. Not surprisingly therefore, Primitive Methodism had its origins in the Potteries. One of the pioneers of this movement in the early nineteenth century was Hugh Bourne, a carpenter from Bemersly. Among the factors that contributed to the comparative success of Primitive Methodism among the urban working class was Hugh Bourne’s ability to appeal to his audiences in simple, unambiguous terms. Ted’s own, more-immediate ancestors lived in Stoke-on-Trent, where they are said to have owned a pottery business. Certainly, a John and Ralph Bourne were running a pottery in Fenton, on the outskirts of the city, in the late 1820’s.Ted’s father, Arthur John (Jack) Bourne, was born, one of nine children, in 1888 at Wolstanton in the Potteries. After the family had lost its interest in the pottery business, Arthur John’s father (Ted’s grandfather) moved to Hednesford, two miles to the north-east of Cannock, where he became foreman at the

OBITUARY-EDWARD

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3

local brickworks. Arthur John could not sing so well as his four sisters and four brothers, all of whom were members of the church choir in Hednesford, and one of whom, Joe, made occasional broadcasts, but Arthur John very proudly acted as organ blower. Gifted and intelligent, Arthur John Bourne would have liked to become a teacher, but the circumstances of the family did not permit this. On leaving school at the age of thirteen, he worked in a drapery business in Hednesford. At the end of a year, he moved to the nearby Littleton Colliery, where the pay and prospects were somewhat better. The sinking operations to establish the colliery had commenced in 1876. The main reserves of the colliery, which today produces general-purpose coal for the domestic and industrial market and for power stations, constitute a virgin area, the full extent of which is not yet proven. A scheme to reconstruct Littleton as a modern, long-life colliery was begun in 1947. Arthur John joined the staff of the winding house as a greaser, and rose to the position of winder. This job he held until he retired at the age of sixty-nine, having worked at the same colliery for 55 years. The steam-driven engines were then going to be replaced by electric winding gear, a prospect which he did not relish. To this day, many miners, either still at Littleton Colliery or now retired, remember kind Jack Bourne, on whom they relied to take them down to the coalface and bring them back safely into the daylight again. The vicissitudes of the mining industry in the United Kingdom in the 1920’s and 30’s are well known. The headlines of the Cannock Advertiser bear witness to the fact that the three-day working week was prevalent in the Cannock Chase coalfield. Even at such times, the pit shafts and ropes had to be examined daily, and, in the earlier days, the horses had to be fed. Consequently, compared with others, the job of a winder was relatively secure, and the winders worked seven days a week all year round. On many a Christmas morning, the Bourne children opened their presents when their father was at work. Arnold Price, for many years Jack Bourne’s work-mate, recalls that, for eleven consecutive years, he worked on Christmas Day. Ted’s father was a quiet man. He did not frequent the workingmen’s clubs which were, and still are, such an important feature of the social life of that district. He had no hobbies, but was very dextrous, and enjoyed mending anything which was in need of repair, from bicycles to watches. His generosity brought coal, which he received as part of his wages, into many a home, and the ambitions he once held for himself he saw realized in his own four children, three of whom became school teachers; the other, Edward John, became

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Professor of Chemistry in the Royal Holloway College of the University of London. Ted Bourne’s mother, Florence Handley, came from a family of edge-tool makers. This trade had developed in South Staffordshire, where the valleys of the Tame and the Stour provided early manufacturers with stone suitable for grinding, and water power for setting the grinding stones in motion. Her father worked for the firm of Cornelius Whitehouse and Sons of Bridgtown, Cannock, which made the specialized edge-tools used by the local collieries; he gave his spare time to the Salvation Army, in which he was a Bandmaster. As a schoolgirl, Florence is said to have been always at the top of her class. The earliest anecdote about Ted is told about the toddler. One day he was missing. His parents, fearing the worst, searched the neighborhood and found him in a kennel, playing with the most ferocious dog in Cannock. Did this foreshadow the friendliness and diplomacy of the man he was to become? Ted Bourne started his education at the local Church of England infant school, and, at the age of six, moved to Walhouse School, founded in 1828 by Mrs. Walhouse of Hatherton Hall; her family, particularly the 3rd Lord Hatherton, was deeply involved in the development of Littleton Colliery. In the scholarship examination, Ted passed out as the top boy in all Staffordshire, receiving the Graham Balfour prize, and this set the pattern for the entire period of his education at school and university. Rugeley Grammar School, which Ted Bourne entered in 1932, was a small school with a friendly atmosphere. It had a very successful hockey team, and many boys later played for the internationally known Cannock Hockey Club. The geography master once challenged the boys to swim across the river Trent, a challenge which was taken up and won by Ted. Those who knew Bourne only as a professor, may be surprised to learn that, as a schoolboy, Ted was also an outstanding sportsman and athlete. He played football, cricket, and hockey and obtained colours for all these games. In his last year at Rugeley, he won the school cross-country race, and was Victor Ludorum, beating the previous year’s Victor, who had stayed on at school and again competed. Ted was a fast bowler, and in one cricket match against Brewood Grammar School, he took all ten wickets, a feat for which he was awarded a Jack Hobbs bat by the News Chronicle. He treasured that bat for many years. At home, the Bourne family lived a quiet life. The greatest excitement for the two boys was on fine summer mornings to meet their

OBITUARY-EDWARD

JOHN B O U R N E

5

father at the colliery, when he came off the night shift, and to cycle home with him across the Chase. Ted was only a schoolboy of sixteen when he first met Kathleen Joyce Cryer, who had then just become a Sunday School teacher. Their friendship grew, and they were married in 1947 at St. Luke’s Church, Cannock, where they had met. Academic achievement came natural to Ted Bourne, and he must have received a Form Prize every year he was at school. His particular interest in chemistry was fostered by his chemistry master, Tom W. Kirkwood, better known as Twink, who was a much-loved character.” The stimulus on a schoolboy in a place like Cannock to turn to the physical sciences, especially chemistry, probably came not so much from the proximity of coal-mining and iron-founding as from the ceramics of the Potteries and the chemical and heavy engineering industries of the Black Country. Although he was successful in all subjects except art, Bourne was as unassuming, and consequently as popular, then as he was to be when he had risen to an influential position later in life. Bourne’s first intention was to become a teacher, but, having won a County Major Scholarship at the age of seventeen, he had the opportunity to study chemistry at the University of Birmingham. He found lodgings close to the laboratories. At that time, the head of the Chemistry Department was Nobel Laureate Professor W. N. Haworth (later Sir Norman). The Second World War was only a month old when Bourne began to read for a degree in chemistry. Among his teachers were such eminent chemists as Stanley Peat, Fred Smith, Maurice Stacey, and Don (L. F.) Wiggins. It was a strange time to be an undergraduate student. Games and sports gave way to war efforts. One night in five, Private Bourne, Birmingham University Home Guard, Wanvickshire Regiment, could be found on fire-watching duty on the top of “Joe,” the University clock-tower; but the Private reported that the only shot he heard fired was when Roy Heath accidentally pulled the trigger of his rifle and a bullet passed through the roof of the Great Hall of the University. Many of the younger members of the staff having been called up to serve in the forces, Ted Bourne and his contemporaries received no formal teaching in their final year, but instead were assigned projects. It was at this time that he first worked closely under Maurice Stacey, who was studying the preparation, purification, and estimation of uranium compounds, a project which was guided by Haworth, and which contributed in no small measure to the production of the atomic bomb. Many of these substances must have been dark powders, and some were pyrophoric; and Ted’s mother, un“

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aware of the nature of the work her son was engaged in, complained frequently that his lab-coats were “sooty.” Bourne graduated with a First Class Honours B.Sc. degree in Chemistry in 1942. As the best chemistry student of the year, he was awarded the Frankland Medal, and he took root in the university. He was made a lecturer at the age of twenty-two (1944), was awarded the Ph.D. degree in 1945, was appointed Senior Lecturer in Organic Chemistry in 1950, awarded the degree of D.Sc. in 1952, and appointed Reader in 1955. He was only 34 years old when the University of London appointed him, in 1956, to its Chair of Chemistry and to be Head of the Department of Chemistry in the Royal Holloway College. Bourne began his researches in Haworth’s school, and his supervisor in his postgraduate studies was Stanley Peat. Although their formal association lasted only until 1948, when Peat left Birmingham to take up his appointment to the Chair of Chemistry at the University College of North Wales, Bangor, they developed a deep and lasting friendship. Their many consultations on a wide range of academic) matters, when each was master in his own house, bear witness to the respect they had for each other’s judgment. The contribution to chemistry made by E. J. Bourne is substantial, and the true range of his activities was formidable, as the Bibliography shows, but in his thirty-two years of research, he was always attracted to certain fields. He once wrote of himself: “I and my colleagues, with pupils of many nations, have found challenge and satisfaction in techniques, syntheses and reaction mechanisms, whilst at the same time helping to unravel the intricate processes of Nature and so strengthen the scientific basis of medicine and agriculture.” The continuing interest of Bourne in the chemistry of polysaccharides and associated enzymes originated from the work of Haworth and Peat directed towards the enzymic synthesis and degradation of starch. The impetus for this work was given by the discovery, made by C . S. Hanes in 1940, that a phosphorylase isolated from the potato and pea effects the synthesis, from D-glucosyl phosphate, of starch, later shown (by Haworth, Heath, and Peat) to be amylose. In his first paper (with Haworth and Peat) in 1944, Bourne described the isolation of the Q-enzyme which, in conjunction with phosphorylase, effects the conversion of D-glucosyl phosphate into the major component of whole starch, namely, amylopectin. He had discovered the Q-enzyme in a fraction discarded by previous workers. Already, the quintessence of his mind was revealed in this work: meticulous attention to detail, and perception of essentials. Bill (William J.) Whelan, three years Bourne’s junior (and now Pro-

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7

fessor and Chairman of the Department of Biochemistry, School of‘ Medicine, University of Miami), recalls those early days: “I came to know Ted well from the fact that we both enjoyed working long hours in the laboratory. Evening work was not a popular pastime, so that often there would only be the two of us. There was the added handicap that Sir Norman had banned work after normal hours, for reasons of safety. Ted was always a very law-abiding person, and this is the only instance when I recall him as being in breach of the rules. We used to enter and leave the laboratory via a window deliberately left open, often leaving in a hurry when the night watchman, aware of Haworth’s rule, would try to apprehend us. . . . Ted’s quite outstanding abilities led to his appointment, while still a research student, to the teaching staff of the Department. In his new role, Ted should probably have owed more loyalty to the University than to the younger and rebellious research students, but it never happened that he broke the confidences we shared with him. His own deep respect for law and order would not permit him to join in some of the escapades, but he took a vicarious pleasure in the recounting of them, which ranged from the manufacture of explosives with which we hoped to break the banks of a local canal, to the use of other reagents to provide liquid refreshments for the celebration of the end of the Second World War. . . . The strongest impression that Ted left on me was the confidence with which he approached his research work. Everything was meticulously planned, and recorded in his notebook with equal precision. To a tyro in the research laboratory, it was as if Ted could control the outcome of the experiments, but that was only the logical progression of the careful thought that had gone into their planning and execution. His work was a model of efficiency for the way in which it went to the heart of the matter and achieved its goal by the most direct path.” Maurice Stacey, then Professor in Charge of Organic and Biological Chemistry, appointed Ted Bourne the leader of what was to become a vigorous research team, the activities of which were later transferred to the Royal Holloway College. The range of substances investigated was widened, and included the saccharides of Polytomella coeca, Neisseria perjlava, Escherichia coli, and Aspergillus niger, bacterial cellulose, the various dextrans which have found medicinal and industrial applications, heparinoid anticoagulants, human-liver glycogens, pectins from tobacco plants, and the polysaccharides that occur in seaweeds. In most cases, the associated enzymes were investigated in detail from all possible angles; for example, the glycosyltransferases of the aforementioned organisms, glucoamylases, dextransucrases, and dextranases of vari-

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ous origins, to name but a few. A colleague once remarked that Bourne seemed to feel personally responsible for just about everything around him. This is exemplified by his work on the effects of antibiotics on the enzymic synthesis and degradation of carbohydrates at a time when antibiotics were about to become more widely used. More recently, he extended this work to hormones. In a review on the enzymic synthesis and degradation of polysaccharides he stated, in the early ~ O ’ S ,that “the subject is really only just emerging from its infancy.” The counterpart, published in the ~ O ’ S ,detailed, with characteristic lucidity, areas where further development should be encouraged. In one of his scientific papers, Bourne likened the chemistry of polysaccharides to Tennyson’s “Brook”: “men may come and men may go, but it goes on for ever.” Studies on trifluoroacetic acid gave Ted Bourne an opportunity to collaborate with his cousin, J. Colin Tatlow, initially under the guidance of Professor M. Stacey. Tatlow, another Rugeley Grammar School boy (now Professor and Head of the Department of Chemistry, Birmingham University), was himself investigating organofluoro compounds. Together they showed the potentials of the reagent in organic synthesis; for example, in the formation of carboxylic esters, ketones, sulfonates, sulfones, nitro compounds, and diazonium salts. Once ensconced at Royal Holloway, Bourne also effectively used the new reagent in the synthesis of selectively substituted sugars and alditols. Selective ring-opening of cyclic acetals led to a series of useful synthetic intermediates which were accessible only with difficulty by more-conventional methods. The consequence of these investigations was the synthesis of a linear polyester containing, in its repeating unit, residues of 2,4-O-methylene-D-glucitol and adipic acid. While still in Haworth’s laboratories, it was Don Wiggins who first introduced Bourne to the cyclic acetals of alditols. In the span of three decades, these derivatives were explored in great detail by applying every conceivable technique, and, today, much of our knowledge thereof stems from Bourne’s researches. Useful synthetic and degradative transformations were demonstrated; for example, the degradation of acetals by Lewis acids to give the parent alditols. A notable development was the use of boron trichloride to effect demethylation of methyl ethers of sugars, a method which has since become a routine practice. Pitting his brain against problems was what Ted Bourne enjoyed, whether in crossword puzzles, a book of which he always carried in his briefcase, or in chemistry.

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M y mind to me a kingdom i s , Such perfect joy therein I find, That it excels all other bliss That world uffords or grows by kind.

One day, in nearby Windsor, watching a barber pole as it slowly revolved, he observed to the writer: “The positions at which the red and white streams seemingly emerge from the bottom depend on the speed of their flow.” Back on Egham Hill, research workers and technicians were soon busy constructing an apparatus for continuous chromatography that incorporated a revolving drum of filter paper. Or again, he had received a sample of filter paper impregnated with a silicone, allowing the passage of organic solvents, but not of water. With characteristic grin and twinkling eyes, he remarked: “There must be a good use for this somewhere.” The “good use” turned out to be a countercurrent extraction apparatus employing semipermeable membranes, for which a patent application was filed. Bourne always emphasized that the successful outcome of many chemical investigations is dependent on simple and reliable methods by which compounds can be separated and identified. His Bibliography contains numerous papers on every conceivable type of chromatography and electrophoresis. Expanding facilities of infrared spectroscopy were boon employed for the characterization of sugars, and these methods remained in general use until the advent of more-advanced spectroscopic methods. However, he then gathered around him colleagues who could assist his researches with these newer techniques. Professor Bourne’s major concern was for the general advancement of chemical science, and he served on many committees of the learned societies, For some years, he was Chairman of the Downland Section of the Royal Institute of Chemistry, and he was a member of the British Carbohydrate Nomenclature Committee and of the Editorial Board of Carbohydrate Research. Inevitably, he became involved in the affairs of the University, where he was Chairman of the Board of Studies in Chemistry and Chemical Industries. He played a prominent part in setting up the University of London’s Intercollegiate Research Service. Especially, he became involved in the affairs of the Royal Holloway College, where he was for a time Vice-principal. Many innovations had their origin in his farsightedness, and came to fruition as a result of his power to inspire, and, above all, to convince. Scrupulously fair in all matters, he never took advantage of his own influential position. Whether he found himself in the company of university vice-chancellors or of students, he was always the same, cour-

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teous Ted Bourne. If proposals were made with which he disagreed, his misgivings and warnings were delivered clearly and firmly, but with a gentle considerateness rarely seen matched. In every situation, he brought common sense to bear. Whenever tempers became frayed, he would, in a few softly spoken words, suggest G solution that would avoid bruised feelings. This conciliatory approach did a great deal to sustain a sense of community and dignity within the College. The Royal Holloway College stands on the brow of Egham Hill, overlooking Runnymede, where, on the 15th June, 1215, King John of England sealed Magna Carta. The College was founded and endowed by Thomas Holloway in memory of his wife Jane, and was opened by Queen Victoria in 1886. Holloway, born in 1800, was a West Country man, and throughout his boyhood and youth, he lived humbly with his widowed mother, helping her in a little shop in Penzance. At the age of 28, he set off for London to seek his fortune. Having struggled for some years, he became a vender of pills and ointments in London’s dockland, whence he rose to control a large section of the field of proprietary medicines. “Holloway’s Pills” became a household name throughout the world, largely as a result of Holloway’s pioneering in commercial advertising. In 1842, he was already spending f5,000a year on publicity, and, by the end of his life, in 1884, the annual total therefor had risen to i40,OOO. Wanting to spend his accumulated wealth for the public good, Holloway built, on two adjacent hills, two great institutions, namely, Holloway Sanatorium, providing for the mentally ill, and the College, providing for the higher education of women. The College was designed to resemble the French Renaissance architecture of the Ch2teau de Chambord, with its spaciousness, its lavishness of ornament, and the splendor of its outlines. Soon after the University of London Act received the Royal Assent in 1898, establishing that University as a teaching university rather than a mere examining body, the College became one of the Schools of the University of London. The College has been fully co-educational since 1965, and has equipped itself with modem buildings, residences, and laboratories on triple the Founder’s original scale. Set in about 67 hectares of woodland, the College combines the advantages of spacious grounds and quiet surroundings with those of the nearby Capital. On his arrival at Royal Holloway, Bourne immediately embarked on a program of modernization of the existing laboratories. In the 1960’s, the opportunity arose to build new laboratories to cater for the increased student population, and Bourne set about this new, and to him unfamiliar, task with more than his usual zest and thorough-

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ness. He worked very closely with the architects, discussing in detail everything from the siting of the whole building to the positioning of taps on the benches; and the design of the building was greatly influenced by ideas which Bourne pressed on the architects, including the need to allow for unforeseen change and growth. The completed building, with 6,632 mz gross area, erected at a cost of f800,000, and now called The Bourne Laboratory, standing among the flowering shrubs he liked so much, has been acclaimed in journals of architecture and chemical education in many parts of the world. In recognition of his work, he was elected a Fellow of the Royal Society of Arts. The Chemical Society celebrated the opening of the building in 1971 by making it the setting for the first Haworth Memorial Lecture, which was given by Professor Maurice Stacey, C.B.E., F.R.S., entitled “The Consequences of Some Projects Initiated by Sir Norman Haworth.” In the undergraduate school, Professor Bourne regarded it as his own responsibility to introduce the first-year students to the principles of organic chemistry. He had an exceptionally quiet voice, and, on the rare occasion when it was raised in anger, the recipient was not to be envied. His lecture audiences were probably the quietest ever known, as “even a whisper from a neighbor might mean the loss of valuable examination data.” Once accustomed to the hushed delivery, and to his highly individual, microscopic handwriting which neatly covered the blackboard, the students discovered that they were listening to no ordinary man. Such teaching wcis un urt requiring cares And qualities peculiar to itself.

Everyone’s progress was keenly followed, and recorded. Those who encountered difficulties, or suffered stress, he took into his particular sympathetic care, whilst the gifted, of whom he demanded much, could rely on him for the furtherance of their careers. The structure of the new B.Sc. degree course in the University of London, a course-unit system, owes much to the suggestions made by Bourne. In his own Department, he laid emphasis on Industrial Chemistry and Management Science, and persuaded important companies to provide vacation courses. Ted did not read much outside his own subject, except for the literature of higher education in general. His library consisted almost solely of the usual classics and books on chemistry. He often confessed that he could raise no enthusiasm for the subjects taught by his colleagues in the Faculty of Arts. Nor could concert halls, theatres,

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and art galleries count him among their frequent patrons. He allowed himself no time for these things. However, his bald head, and slow, slightly rolling gait were known all over the College, and nowhere was he more visible than in his own Department, where he made a point of walking regularIy through the different parts of his domain, keeping in touch with all who worked there. This could be embarrassing at times. On one occasion, he penetrated behind the large permanent magnet in the n.m.r. lab. to discover a Bridge school in session. In the Department, E.J.B. was a stickler for obeying his own rules. During the energy crisis in the winter of 1973-1974, he drew up detailed plans for conserving electricity. A postgraduate student, finding himself in a long discussion with him, as evening drew in and no light was switched on, could pinpoint his Professor only by the steady glow of an Embassy cigarette from the far end of the room. All that Ted achieved rested on the foundation of a happy familylife, first in Cannock, and then with his wife Kath and son David. At “The Rowans” in Virginia Water, near the College, he became a keen gardener, and on the lawns, many a cricket match between father and son was fought out with the Jack Hobbs bat, whilst Kath became involved in the RHC Women’s Club. It is probably banal, yet true, to say that Ted was happiest in his Department and at home. He did not travel very much, and on one of the half dozen or so occasions when he did venture abroad, the writer had the pleasure of introducing him to his own family. Was it that he thought the benefits of travel are sometimes overstressed by the modern world, or did he find sufficient stimulus and variety in everyday life? If he thought the latter, he was in good company. Kant never passed beyond the gates of his native Konigsberg, and Johann Sebastian Bach remained in the narrow confines of Middle Germany with his organ, his many children, and his God. The picture of Ted Bourne as a serious-minded chemist, dedicated to his work, scrupulously fair with all those who worked with or under him, would be distorted if it did not portray his humor. He was wry, but never acerb; he was no wit, but he enjoyed the humor of a situation. Thus it was, having been unable to go to church for some time, he met a “pillar of the church” after morning service, and said: “I haven’t seen you here for some time!” Active sport, from which Ted Bourne derived so much pleasure as a schoolboy, he returned to in later years. He joined the Wentworth Club, and nothing could interfere on any Saturday morning with his enjoyment and relaxation on the golf links. Here, he added another sporting “trophy” to his collection. The visitor to his home

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would be shown a golf ball with the inscription: “12th, Wentworth East Course, Hole in One, Distance 158, Visibility 110, 30th December 1972”! On the morning of Saturday, the 30th day of November, 1974, Edward John Bourne was playing his customary round of golf at Wentworth when coronary thrombosis ended his life. Post loizga regrecli tandem exilia.

This, then, is the memorable journey b y a wise, gifted, and loving man who fulfilled himself and did good things for others in the world through which he travelled, and who found inspiration and joy in exploring and explaining some of the mysteries of the creation with its store of wonders untold. HELMUTWEIGEL

BIBLIOGRAPHY The following records the published works of E. J. Bourne, as well as the names of all his research associates. “Synthesis of Amylopectin,” W. N. Haworth, S. Peat, and E. J. Bourne, Nature, 154,236 (1944). “The Constitution of Trimethylene Sorbitol,” E. J. Bourne and L. F. Wiggins, 1. Chem. Soc., 517-521 (1944). “The Enzymic Synthesis and Degradation of Starch. Part I, The Synthesis of Amylopectin,” E. J. Bourne and S. Peat,]. Chem. Soc., 877-882 (1945). “The Enzymic Synthesis and Degradation of Starch. Part 11, The Amylolytic Function of the Q-Enzyme of the Potato,” E. J. Bourne, A. Macey, and S. Peat,]. Chem. S O C . , 882-888 (1945). “A New Indicator for Iodonietric Analysis,” S. Peat, E. J. Bourne, and R. D. Thrower, Nature, 159, 810 (1947). “The Amylolytic Degradation of Starch. A Revision of the Hypothesis of Sensitisation,” E. J. Bourne, Sir Norman Haworth, A. Macey, and S. Peat,]. Chem. SOC., 924930 (1948). “Enzymic Conversion of Amylose into Amylopectin,” S. Peat, E. J. Bourne, and S. A. Barker, Nature, 161, 127 (1948). “Starches of the Wrinkled and Smooth Pea,” S. Peat, E. J. Bourne, and M. J. Nicholls, Nature, 161,206 (1948). “Thymol and cycZoHexanol as Fractionating Agents for Starch,” E. J. Bourne, G . H. Donnison, Sir Norman Haworth, and S. Peat,]. Chem. SOC.,1687-1693 (1948). “Ethylidene Derivatives of Sorbitol,” E. J. Bourne and L. F. Wiggins,]. Chem. Soc., 1933-1936 (1948). “Photochemical Degradation of Starch,” S. Peat, E . J. Bourne, and W. J. Whelan, Nature, 161, 762 (1948). “The Fractionation of Potato Starch by Means of Aluminium Hydroxide,” E. J. Bourne, G. H. Donnison, S. Peat, and W. J. Whelan,]. Chem. Soc., 1-5 (1949).

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“The Amylose Component of Waxy Maize Starch,” E. 1. Bourne and S. Peat,]. Chem. Soc., 5-9 (1949). “A Modified Method for the End-group Assay of Amylose and Other Long-chain Starch Fractions,” E. J. Bourne, K. H. Fantes, and S. Peat,]. Chem. Soc., 1109-1113 (1949). “The Enzymic Synthesis and Degradation of Starch. Part 111, The Role of Carhohydrate Activators,” E. 1. Bourne, D. A. Sitch, and S. Peat, ]. Chem. Soc., 1448-1457 (1949). “The Enzymic Synthesis and Degradation of Starch. Part IV, The Purification and Storage of the Q-Enzyme of the Potato,” S. A. Barker, E. J. Bourne, and S. Peat, /. Chem. Soc., 1705-1711 (1949). “The Enzymic Synthesis and Degradation of Starch. Part V, The Action of Q-Enzyme on Starch and its Components,” S. A. Barker, E . J. Bourne, and S. Peat,]. Chem. Soc., 1712-1717 (1949). “A General Method of Esterification Using Trifluoroacetic Anhydride,” M. Stacey, E. J. Bourne, J. C. Tatlow, and 1. M. Tedder, Nature, 164, 705 (1949). “Studies of Trifluoroacetic Acid. Part I, Trifluoroacetic Anhydride as a Promoter of Ester Formation between Hydroxy-compounds and Carboxylic Acids,” E. J. Bourne, M. Stacey, J. C. Tatlow, and 1. M. Tedder,]. Chem. Soc., 2976-2979 (1949). “The Enzymic Synthesis and Degradation of Starch. Part VI, The Properties of Purified P- and Q-Enzymes,” S. A. Barker, E. 1. Bourne, I. A. Wilkinson, and S. Peat,]. Chern. Soc., 84-92 (1950). “The Enzymic Synthesis and Degradation of Starch. Part VII, The Mechanism of Q-Enzyme Action,” S. A. Barker, E. 1. Bourne, I. A. Wilkinson, and S. Peat, ]. Chem. SOC.,93-99 (1950). “cycloHexylidene Derivatives of Mannitol,” E. J. Bourne, W. M. Corbett, and D. Erilinne,]. Chem. Soc., 786-790 (1950). “Studies of Trifluorracetic Acid. Part 11, Preparation and Properties of Some Trifluoroacetyl Esters,” E. 1. Bourne, C. E. M. Tatlow, and 1. C. Tatlow,]. Chem. Soc., 1367-1369 (1950). “Mechanism of the Beta-Amylolysis of Amylose,” E. 1. Bourne and W. J. Whelan, Nature, 166,258 (1950). “The Composition of the Polysaccharide Synthesised by Polytomella coeca,” E. J. Bourne, M. Stacey, and I. A. Wilkinson,]. Chent. Soc., 2694-2698 (1950). “The Structure of the Starch-type Polysaccharide Synthesised from Sucrose by Neisseria perjazja,” S. A. Barker, E. J. Bourne, and M . Stacey, J. Chem. SOC.,28842887 (1950). “The Enzymic Synthesis and Degradation of Starch. Part VIII, The Use of Mixtures of P- and Q-Enzymes in the Synthesis of Starch-type Polysaccharides,” S. A. Barker, E. J. Bourne, S. Peat, and I. A. Wilkinson,]. Chem. Soc., 3022-3027 (1950). “The Enzymic Synthesis and Degradation of Starch. Part IX, Methylation and Endgroup Assay of Some Synthetic Polysaccharides,” S. A. Barker, E. J. Bourne, and I. A. Wilkinson,]. Chem. Soc., 3027-3030 (1950). “A Microbiological Method for the Preparation of l4 C-Labelled Starch from Sodium Acetate,” J. C. Bevington, E. J. Bourne, and I. A. Wilkinson, Chem. I n d . (Loitdor~), 691-692 (1950). “The Methyl Ethers of D-Glucose,” E. J. Bourne and S. Peat, Adc. Curbolaydr. Chem., 5, 145-190 (1950). “Studies of Trifluoroacetic Acid. Part 111, The Use of Trifluoroacetic Anhydride in the Synthesis of Aromatic Ketones and Sulphones,” E. 1. Bourne, M. Stacey, J. C. Tatlow, and 1. M. Tedder,]. Chern. Soc., 718-720 (1951).

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“Studies of Trifluoroacetic Acid. Part IV, Use of 4 : 6-Benzylidene Trifluoroacetyl Methyl-cu-D-glucopyraiioside in the Synthesis of 2- and 3-Substituted Glucoses,” E. J. Bourne, M. Stacey, C. E. M. Tatlow, and J . C. Tatlow,/. Chern. Soc., 826-833 (1951). “Trifluoroacetic Anhydride, A New Tool in Organic Chemistry,” E. J. Bourne, M. Stacey, and J. C. Tatlow, Ahstr. Znt. Congr. Pure A p p l . Chern., 12th, New York, 430 (1951). “Detection of Sugars by Paper Chromatography,” R. J. Bayly, E. J. Bourne, and M. Stacey, Nature, 168, 510 (1951). “Some Recent Developments in the Academic Fields of Starch Chemistry,” E. J. Bourne, Chern. Ind. (London),1047-1052 (1951). “A Correction,” E. J. Bourne, C h e m Ind. (London),216 (1952). “The Synthesis of Uronic Acids,” S. A. Barker, E. J. Bourne, and M. Stacey, Chern. Znd. (London),970 (1951). “Carbohydrate Primers for Q-Enzyme,” S. A. Barker, A. Bebbington, and E. J. Bourne, Nature, 168, 834 (1951). “The Oligosaccharides Synthesised by Escherichia coli from Maltose,” S. A. Barker and E. J. Bourne, Biochem. ]., 49, lxi (1951). “Properties and Reactions of Mixtures of Trifluoroacetic Anhydride and Oxy-acids,” E. J. Bourne, J. E. B. Randles, J. C. Tatlow, and J . M. Tedder, Nature, 168, 942 (1951). “Ethylidene Derivatives of hlannitol,” E. J. Bourne, G. T. Bruce, and L. F. Wiggins, J. Chem. Soc., 2708-2713 (1951). “The Oligosaccharides Synthesised from Maltose by Escherichia coli,” S. A. Barker and E. J. Bourne,]. Chem. Soc., 209-215 (1952). “The Q-Enzyme of Polytornella coeca,” A. Bebbington, E. J. Bourne, M. Stacey, and 1. A. Wilkinson,]. Chem. Soc., 240-245 (1952). “The Conversion of Amylose into Ainylopectin by the Q-Enzyme of Polytomella coeca,” A. Bebbington, E. J. Bourne, and I. A. Wilkinson,]. Chem. Soc., 246-253 (1952). “Favoured Ring Forms in Acetals of the Polyhydric Alcohols,” S. A. Barker and E. J. Bourne,]. Chent. Soc., 905-909 (1952). “isoPropylidene Derivatives of Sorbitol,” E. J. Bourne, G . P. McSweeney, M. Stacey, and L. F. Wiggins,]. Chem. Soc., 1408-1414 (1952). “Acetals and Ketals of the Tetritols, Pentitols and Hexitols,” S. A. Barker and E. J. Bourne. Adc. Cnrboh!/dr. Chetti., 7, 137-207 (1952). “Studies of Trifluoroacetic Acid. Part V, Trifluoroacetic Anhydride as a Condensing Agent in Reactions of Nitrous and Nitric Acids,” E. J. Bourne, M. Stacey, J. C. Tatlow, and J. bl. Tedder,]. Chem. Soc., 1695-1696 (1952). “Detection of Sugars by Paper Chromatography: The Glycosylamines,” R. J. Bayly, E. J. Bourne, and M. Stacey, Nature, 169,876 (1952). “The isoPropylidene Derivatives of Hexahydric Alcohols. Part 111, isopropylidene Derivatives of L-Iditol,” E. J. Bourne, 6. P. McSweeney, and L. F. Wiggins,]. Chem. Soc., 2ij42-2546 (1952). “2 : 4-3: 5-Diethylidene nlciehydo-L-Xylose and its Derivatives,” E. J. Bourne, W. M. Corbett, and M. Stacey,]. Chern. Soc., 2810-2812 (1952). “The 2 :3-4 : 5-Diisopropylideiie Derivatives of aldehydo-L-Xylose and L-Xylitol,” E. J. Bourne, G. P. McSweeney, and L. F. Wiggins,J. Chem. Soc., 3113-3114 (1952). “Stnicture of the Polyglucosan from Aspergillus niger (Strain 152),” S. A. Barker, E. J. Bourne, and M. Stacey, Chem. Znd. (London),756-757 (19.52). “An Explanation of the Preferential Formation of Certain Rings in Acetals of the Polyhydric Alcohols,” S. A. Barker, E . J. Bourne, and D. H . Whiffen, J. Chem. Soc., 3865-3870 (1952). “Studies of TriHuoroacetic Acid. Part VI, Trifluoroacetyl Derivatives of Amines,”

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E. J. Bourne, S. H. Henry, C . E. M. Tatlow, and J. C . Tatlow,]. Chem. Soc., 40144019 (1952). “Structure of a Novel Dextran Synthesised by a Betacoccus arabinosaceous,” S. A. Barker, E. J. Bourne, G . T. Bruce, and M. Stacey, Chem. Ind. (London),1156 (1952). “Macromolecules,” E. J. Bourne, Annu. Rep. Prog. Chem., 49, 235-251 (1952). “A New Method for the Paper Chromatography of Oligosaccharides,” R. J. Bayly and E. J. Bourne, Nature, 171,385 (1953). “Studies of Trifluoroacetic Acid. Part VII, The Synthesis of 2-Benzoyl4 : 6-Benzylidene Methyl-a-D-glucopyranoside and its Conversion into the Isomeric 3-Benzoate by an Acyl Migration,” E. J. Bourne, A. J. Huggard, and J. C. Tatlow,]. Chem. Soc., 735741 (1953). “Enzymic Synthesis of Polysaccharides,” S. A. Barker and E. J. Bourne, Q. Reo. Chem. Soc., 7, 56-83 (1953). “Infra-red Absorption Spectra of Dextran and Other Polyglucosans,” S. A. Barker, E. J. Bourne, M. Stacey, and D. H. Whiffen, Chem. Ind. (London),196-197 (1953). “Studies of Aspergillus niger. Part I, The Structure of the Polyglucosan Synthesised by Aspergillus niger 152,” S. A. Barker, E. J. Bourne, and M. Stacey, J . Cheni. Soc., 3084-3090 (1953). “The Biological Synthesis of Starch,” E. J. Bourne, Biochem. Soc. Symp., 11, 3-16 (1953). “The Mode of Action of the Q-Enzyme of Polytomella coeca,” S. A. Barker, A. Bebbington, and E. J. Bourne, J. Chem. Soc., 4051-4057 (1953). “The Synthesis of P-Linked Glucosaccharides by Aspergillus niger (Strain 152),” S. A. Barker, E. J. Bourne, and M. Stacey, Chem. Ind. (London),1287 (1953). “Chemical Degradation of 14C-Glucoseand its Application to I4C-Starch from Polytomella coeca,” J. C . Bevington, E. J. Bourne, and C . N. Turton, Chem. Ind. (London), 1390-1391 (1953). “Infra-red Spectra of Carbohydrates. Part I, Some Derivatives of D-Ghcopyranose,” S. A. Barker, E . J. Bourne, M. Stacey, and D. H. Whiffen,]. Chem. Soc., 171-176 (1954). “The Action of Lead Tetra-Acetate on Sugar Mercaptals,” E. J. Bourne, W. M. Corbett, M. Stacey, and R. Stephens, Chem. Znd. (London),106-107 (1954). “14C-Cellulosefrom Acetobacter acetigenum,” E. J. Bourne and H. Weigel, Chem. Ind. (London),132 (1954). “Structural Studies of the Cellulose Synthesised by Acetobacter acetigenum,” K. S. Barclay, E. J. Bourne, M. Stacey, and M. Webb,J. Chem. Soc., 1501-1505 (1854). “Studies of Trifluoroacetic Acid. Part XII, Acyl Trifluoroacetates and their Reactions,” E. J. Bourne, M. Stacey, J. C . Tatlow, and R. Worral1,J. Chem. Soc., 2006-2012 (1954). “Studies of Aspergillus niger. Part 111, The Structure of a Trisaccharide Synthesised from Sucrose,” S. A. Barker, E. J. Bourne, and T. R. Carrington,]. Chem. Soc., 21252129 (1954). “Immunopolysaccharides. Part 11, Structure of a Betacoccus arabinosaceous Dextran,” S. A. Barker, E. J. Bourne, G. T. Bruce, W. B. Neely, and M. Stacey,J. Chem. SOC.,2395-2399 (1954). “Studies of‘ Trifluoroacetic Acid. Part X, The Mechanisms of Syntheses Effected by Solutions of Oxyacids in Trifluoroacetic Anhydride,” E. J. Bourne, J. E. €3. Randles, M. Stacey, J. C. Tatlow, and J. M. Tedder,]. A m . Cheni. Soc., 76, 3206-3208 (1954). “Infra-red Spectra of Carbohydrates. Part 11, Anomeric Configuration of Some Hexoand Pento-pyranoses,” S. A. Barker, E. J . Bourne, R. Stephens, and D. H. Whiffen, J. Chem. Soc., 3468-3473 (1954).

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“A Descent of the Sugar Series Based on Ketose Mercaptols,” E. J. Bourne and R. Stephens,J. Chem. Soc., 4009-4013 (1954).

“Infra-red Spectra of Carbohydrates. Part V, Use of Potassium Bromide Films,” S. A. Barker, E. J. Bourne, W. B. Neely, and D. H. Whiffen, Chem. Ind. (London), 1418-1419 (1954). “Infrared Spectra of Carbohydrates. Part 111, Characterisation of Deoxy-compounds,’’ S. A. Barker, E. J. Bourne, R. Stephens, and D. H. Whiffen,]. Chem. Soc., 42114215 (1954). “Effect of Streptomycin on Various Enzymes Responsible for Syntheses and Degradations of Higher Saccharides,” S. A. Barker, E. J. Bourne, M. Stacey, and R. B. Ward, Nature, 175,203 (1955). “Use of Furanosides in Separations of Carbohydrates on Charcoal Columns,” S. A. Barker, E. J. Bourne, and D. M. O’Mant, Chem. Ind. (London), 425 (1955). “Immunopolysaccharides. Part V, Structure of a Modified Betacoccus arabinosaceous Dextran,” S . A. Barker, E. J. Bourne, A. E. James, W. B. Neely, and M. Stacey, J . Chem. Soc., 2096-2099 (1955). “Studies ofAspergiZZus niger. Part IV, The Synthesis of P-Linked Glucosaccharides,” S. A. Barker, E . J. Bourne, G. C. Hewitt, and M. Stacey,]. Chem. Soc., 3734-3740 (1955). “Synthesis of Oligosaccharides by Growing Cultures of Betacoccus arabinosaceous,” H. W. Bailey, S. A. Barker, E . J. Bourne, and M. Stacey, Nature, 175, 635 (1955). “Separations of Carbohydrates on Charcoal Columns in the Presence of Borate,” S. A. Barker, E. J. Bourne, and 0. Theander,J. Chem. Soc., 42764280 (1955). “Enzymic Synthesis of a ‘Branched’ Trisaccharide,” R. W. Bailey, S. A. Barker, E. J. Bourne, and M .Stacey, Nature, 176, 1164-1165 (1955). “Use of Infrared Analysis in the Determination of Carbohydrate Structure,” S. A. Bnrker, E. J. Bourne, and D. H. Whiffen, Methods Biochem. Anal., 3,213-245 (1956). “Infrared Spectra of Carbohydrates. Part VI, Avoidance of Spectral Changes with Potassium Bromide Films,” S. A. Barker, E. J. Bourne, H. Weigel, and D. H. Whiffen, Chem. Znd. (London), 318 (1956). “Radiation as a Tool in the Synthesis of Organic Compounds,” E. J. Bourne, M. Stacey, and G. Vaughan, Chem. Ind. (London),1372-1376 (1956). “The Action of Gamma-Radiation on Dilute Aqueous Solutions of Amylose,” E. J. Bourne, M. Stacey, and G. Vaughan, Chem. Znd. (London),573-574 (1956). “Ionophoresis of Oligosaccharides as N-Benzylglycosylammonium Ions,” S. A. Barker, E. J. Bourne, P. M. Grant, and M. Stacey, Nature, 177, 1125 (1956). “Chemistry of Carbohydrates,” E. J. Bourne and R. Stephens, Annu. Reu. Biochem., 25, 79-100 (1956). “Ionophoresis of Carbohydrates. Part IV, Separations of Carbohydrates on Fibreglass Sheets,” E. J. Bourne, A. B. Foster, and P. M. Grant,J. Chem. Soc., 4311-4314 (1956). “Enzymic and Chemical Synthesis of the Alpha-I : 2-Glucosidic Linkage,” S. A. Barker, E. J. Bourne, P. M. Grant, M. Stacey, S. Haq, and W. J. Whelan, Nature, 178, 1221-1223 (1956). “Studies of Trifluoroacetic Acid. Part XIII, Cryoscopic Measurements on Trifluoroacetic Anhydride-Acetic Acid Systems,” E. J. Bourne, J. C. Tatlow, and R. Wowall, J . Chem. Soc., 315-318 (1957). “Separations of Carbohydrates on Charcoal Columns in the Presence of Molvbdate.” S. A. Barker, E. J. Bourne, A. B. Foster, and R. B. Ward, Nature, 179, 262-263 (1957). “Significance of Oligosaccharide Intermediates i n Dextran Synthesis,” R. W. Bailey,

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S. A. Barker, E. J. Bourne, M. Stacey, aiid 0. Theander, Nature, 179, 310 (1957). “Studies ofAspergillusniger. Part V, The Enzymic Synthesis of a New Trisaccharide,” S. A. Barker, E. J . Bourne, and 0. Theander,]. Chem. Soc., 2064-2067 (1957). “The Separation of Reducing Carbohydrates as their N-Substituted Glycosylammonium Ions,” S. A. Barker, E. J. Bourne, P. M. Grant, and M. Stacey,]. Chetn. Soc., 2067-2071 (1957). “Studies of Aspergillus niger. Part VI, The Separation and Structures of 0ligos;iccharides from Nigeran,” S. A. Barker, E. J. Bourne, D. M. O’Mant, and M. Stacey,]. Chetn. SOC.,2448-2454 (1957). “The Effect of Streptomycin on the Enzymic Synthesis and Degradation of Carbohydrates,” S. A. Barker, E. J. Bourne, M. Stacey, and R. B. Ward,.\. Chem. Soc., 2994-2998 (1957). “Immunopolysaccharides. Part VI, The Isolation and Properties ofthe Dextransucrase ofBetacoccus arabinosaceous,” R. W. Bailey, S. A. Barker, E. J. Bourne, and 34. Stacey, J . Chem. SOC.,3530-3536 (1957). “Immunopolysaccharides. Part VII, The Transglucosylase Action of Betococcus arubinosaceous Dextransucrase,” R. W. Bailey, S. A. Barker, E. J. Bourne, and M. Stacey, J . Chem. Soc., 3536-3541 (1957). “Studies of Aspergillus niger. Part VII, The Enzymic Synthesis of 3-0-/3-~-Glucopyrdnosyl-D-xylOSe,” S. A. Barker, E. J. Bourne, G. C. Hewitt, and M. Stacey,]. Chetn. SOC.,3541-3544 (1957). “Studies on Aspergillus niger. Part IX, The Mechanism of Glucamylase Action,” S. A. Barker, E. J. Bourne, and J. G. Fleetwood,/. Chem. Soc., 48654871 (1957). “Immunopolysaccharides. Part VIII, Enzymic Synthesis of 6-O-ol-~-Glucop).ranosyl3-0-methyl-D-glucose by Betacoccus arabinosaceous,” S. A. Barker, E. J. Bourne, P. M . Grant, and M. Stacey,]. Chem. Soc., 601-604 (1958). “The Polyhydric Alcohols; Acyclic Polyhydric Alcohols,” E. J. Bourne, in “Handbuch der Pflanzenphysiologie,” W. Ruhland, ed., Springer Verlag, Berlin, 1958, pp. 345-362. “Studies of Trifluoroacetic Acid. Part XIV, Reaction of Acyl Trifluoroacetates with 1:6-Di-0-benzoyl-2 :4-3 : 5-di-0-methylene-D-glucitol,” E. J. Bourne, J. Burdon. and J. C. Tatlow,]. Chem. Soc., 1274-1279 (1958). “Immunopolysaccharides. Part IX, The Enzymic Synthesis of Trisaccharides Containing the a-l:2-Glucosidic Linkage,” R. W. Bailey, S. A. Barker, E. J. Bourne, P. M. Grant, and M. Stacey, J. Chem. SOC.,1895-1902 (1958). “Infrared Spectra of Carbohydrates. Differentiation of y- and &Lactones of Aldonic Acids,” S. A. Barker, E. J. Bourne, R. M. Pinkard, and D. H. Whiffen, Chem. Ind. ( L o t ~ d o n658-659 ), (1958). “Some Paper Chromatographic Studies with Aspergillus niger ‘152’ Transfnictosylase,” S. A. Barker, E. J. Bourne, M. Stacey, and R. B. Ward, Biochem. J., 69, 60-62 (1958). “Boron Trichloride as a Degradative Reagent for Carbohydrates and Their Derivatives,” S. Allen, T. G. Bonner, E. J. Bourne, and N. M. Saville, Chetn. I n d . (London), 630 (1958). “The Stereoisomers of2:4-Dimethyl-l:3-dioxalan,” S. A. Barker, E. J. Bourne, R. M. Pinkard, M. Stacey, and D. H. Whiffen,]. Chem. Soc., 3232 (1958). “Studies of Trifluoroacetic Acid. Part XV, Further Investigations on the Reactions of Acyl Trifluoroacetates with Hydroxy-compounds,” E. J. Bourne, M. Stace?;, J. G. Tatlow, and R. Worrall,]. Chem. S O C . , 3268-3282 (1958). “Studies of Trifluoroacetic Acid. Part XVI, The Use of 1:3-2: 4-Di-O-ethylitlene-60-trifluoroacetyl-D-glucitol in the Synthesis of Some 5- and 6-Substituted u-Clucitols,” E. J. Bourne, C. E. M. Tatlow, J. C . Tatlow, aiid R. Worral1,J. Chem. S O C . , 3945-3950 ( 1958).

OBITUARY-EDWARD

JOHN BOURNE

19

“Catalytic Oxidation of Carbohydrates. Some Properties of Potassium a - ~ - G l u c o pyranuronate 1-(Dipotassium Phosphate),” S. A. Barker, E. J. Bourne, J. G. Fleetwood, and M. Stacey,]. Chem. Soc., 41284132 (1958). “Immunopolysaccharides. Part XI, Structure of an Acetobacter capsulatum Dextran,” S . A. Barker, E. J. Bourne, G. T. Bruce, and M. Stacey,J. Chem. Soc., 4414-4416 (1958). “Production of Mannitol by aLactobacillus Causing Ropiness in Cider,” S. A. Barker, E. J. Bourne, E. Salt, and M. Stacey,]. Chem. Soc., 2736-2740 (1958). “Ketose-Polyol Interconversions by a Ropy-cider Organism,” S. A. Barker, E. J. Bourne, E. Salt, and M. Stacey,]. Chem. SOC.,593-598 (1959). “Spectra of Acetals. Part I, The Infrared and Raman Spectra of 1: 3-Dioxolan,” S. A. Barker, E. J. Bourne, R. M. Pinkard, and D. H. Whiffen,]. Chem. Soc., 802-806 (1959). “Spectra of Acetals. Part 11, The Infrared and Raman Spectra of Substituted 1:3-Dioxolans,” S. A. Barker, E. J . Bourne, R. M. Pinkard, and D. H. Whiffen,]. Chem. Soc., 807-813 (1959). “Steric Effects in the Ionophoresis of Carbohydrates,” S. A. Barker, E. J. Bourne, A. B. Foster, and R. M. Pinkard, Chem. Ind. (London),226-227 (1959). “Studies of TriHuoroacetic Acid. Part XVII, Reaction of Acyl Trifluoroacetates with PC-, /3-, and a-Acetals of D-Glucitol,” E. J. Bourne, J. Burdon, and J. C. Tatlow,]. Chem. Soc., 1864-1870 (1959). “Paper Chromatography of Ferrocene and its Derivatives,” A. N. de Belder, E. J. Bourne, and J. B. Pridham, Chern. Ind. (London),996-997 (1959). “Metal Chelates of Polyhydroxy Compounds,” E. J. Bourne, R. Nery, and H. Weigel, Chem. Ind. (London),998-999 (1959). “Interaction of Sucrose Stearate with Starch,” E. J. Bourne, A. I. Tiffin, and H. Weigel, Nature, 184, 110-111 (1959). “Mechanism of the Enzymic Synthesis of a Branched Trisaccharide Containing the a-1:2-Glucosidic Linkage,” E. J. Bourne, J. Hartigan, and H. Weigel, J . Chem. Soc., 2332-2337 (1959). “Paper Ionophoresis of Carbohydrates in Molybdate Solution,” E. J. Bourne, D. H. Hutson, and H. Weigel, Chem. Ind. (London), 1047-1048 (1959). “Interaction of Anti-Staling Agents with Starch,” E . J. Bourne, A. I. Tiffin, and H. Weigel, Nature, 184, 547 (1959). “Formation of Leucrose in Dextran-producing Cultures of Streptococcus hoois,” R. W. Bailey and E. J. Bourne, Nature, 184, 904-905 (1959). “The Iodine-catalysed Conversion of Sucrose into 5-Hydroxymethylfurfuraldehyde,” T. G. Bonner, E. J. Bourne, and M. Ruszkiewicz, J . Chem. Soc., 787-791 (1960). “Some Infrared Studies on the Use of Deuterium in the Carbohydrate Group,” M. Stacey, R. H. Moore, S. A. Barker, H. Weigel, E. J. Bourne, and D. H. Whiffen, Proc. U . N . Znt. Conf., Peaceful Uses A t . E n e r g y , Znd,Geneva, 1958,20,251-256 (1960). “Interaction of Starch with Sucrose Stearates and Other Antistaling Agents,” E. J. Bourne, A. I. Tiffin, and H. Weige1,J. Sci. Food Agric., 101-109 (1960). “Trifluoroisopropylidene Derivatives of Mannitol,” E. J. Bourne, A. J. Huggard, M. Stacey, and J. C. Tatlow,J. Chem. Soc., 2716-2720 (1960). “Ring Scission of Cyclic Acetals. Part I, The Formation of a Linear Polyester from 1,3 :2 , 4 : 5,6-Tri-O-methylene-~-glucitol,Adipic Acid, and Trifluoroacetic Anhydride,” T. G. Bonner, E. J. Bourne, and N. M. Saville,]. Chem. Soc., 2914-2917 (1960). “Ring Scission of Cyclic Acetals. Part 11, The Reactions of Di-O-methylenepentaerythritol with Carboxylic Acids and TriHuoroacetic Anhydride,” T. G. Bonner, E. J. Bourne, and N. M. Saville,J. Chern. Soc., 2917-2921 (1960). “Dealkylation and Deacylation of Carbohydrate Derivatives with Boron Trichloride and Boron Tribromide,” T. G. Bonner, E. J. Bourne, and S. McNally, J . Chem. Soc., 2929-2934 (1960).

20

HELMUT WEICEL

“Paper Ionophoresis of Glucopyranosyl-fructoses and Other Substituted Fructoses,” E. J. Bourne, D. H. Hutson, and H. Weigel, Chem. Ind. (London), 1111-1112 (1960). “Colour Reactions Given by Sugars and Diphenylamine-Aniline Spray Reagents on Paper Chromatograms,” R. W. Bailey and E. J. Bourne, J . Chromatogr., 4, 206-213 (1960). “Paper Ionophoresis of Sugars and other Cyclic Polyhydroxy-compounds in Molybdate Solution,” E. J . Bourne, D. H. Hutson, and H. Weige1,J. Chem. Soc., 42524256 (1960). “Self-decomposition of [‘4C]Clucose,” E. J. Bourne, D. H. Hutson, and H. Weigel, J . Chem. Soc., 5153-5159 (1960). “Complexes Between Molybdate and Acyclic Polyhydroxy-compounds,” E. J. Bourne, D. H. Hutson, and H. Weige1,J. Chem. Soc., 35-38 (1961). “Biosynthesis of a-D-Glucopyranosyl DGalactofuranoside and other D-Galactosecontaining Saccharides by Betacoccus arubinosaceous,” E. J. Bourne, J. Hartigan, and H. Weigel,]. Chem. Soc., 1088-1092 (1961). “Clucosyl Derivatives of Cyclopentadiene and Cyclopentane,” A. N . de Belder, E. J. Bourne, and J. B. Pridham, Chem. Ind. (London), 432 (1961). “Studies of Trifluoroacetic Acid. Part XVIII, Reaction of N-Aroylglycines with Perfluoro-carboxylic Anhydrides,” E. J. Bourne, J. Burdon, V. C. R. McLoughlin, and J. C. Tatlow,J. Chem. Soc., 1771-1775 (1961). “Oligosaccharides in Dextran-producing Cultures of Streptococcus bocis,” E. J. Bourne, D. H. Hutson, and H. Weigel, Biochem. I. 79, ,549-553 (1961). “Intracellular Glycosidases of Dextran-producing Bacteria,” R. W. Bailey and E. J. Bourne, Nature, 191, 277-278 (1961). “Pentaerythrose,” T. G. Bonner, E. J. Bourne, and J. Butler, Chem. Ind. (London), 750-751 (1961). “P-Glucopyranosides of Hydroxymethyl- and Hydroxyethyl-ferrocene,” A. N. de Belder, E. J. Bourne, and J. B. Pridham,J. Chem. Soc., 4464-4467 (1961). “The Biosynthesis of Galactosylsucrose Derivatives,” E. J. Bourne, J. 8.Pridham, and M. W. Walter, Biochem. J., 8 2 , 4 4 ~(1962). “The Reactivity of the Methyl a-D-Glucoside-Boron Trichloride Reagent,” T. G. Bonner, E. J. Bourne, and S. McNally,J. Chem. Soc., 761-767 (1962). “Studies on Dextrans and Dextranases. The Action of Mould Dextranases on Modified Isomaltodextrins and the Effect of Anomalous Linkages on Dextran Hydrolysis,” E. J. Bourne, D. H. Hutson, and H. Weigel, Biochem. J., 85, 158-163 (1962). “Obituary Notice-Alexander Graham Foster, 1906-1962,” E. J. Bourne, Proc. CAenL. Soc., 3 9 9 4 0 0 (1962). “Carbon-Oxygen Bond Scissions with Boron Trichloride,” T. G. Bonner and E. J. Bourne, Methods Curbohydr. Chem., 2,206-207 (1963). “But-2-enylidene Derivatives of Glucitol,” T. G. Bonner, E. J. Bourne, and D. Lewis, J . Chem. Soc., 3375-3381 (1963). “Studies on Dextrans and Dextranases. 3, Structures of Oligosaccharides from Leuconostoc mesenteroides (Birmingham) Dextran,” E. J. Bourne, D. H. Hutson, and H. Weigel, Biochem. J., 86, 555-562 (1963). “Paper Chromatography of Carbohydrates and Related Compounds in the Presence of Benzeneboronic Acid,” E. J. Bourne, E. M. Lees, and H. Weigel, J . Chromutogr., 11, 253-257 (1963). “The Identification of Naturally Occurring Cinnamic Acid Derivatives,” E. J. Bourne, N. J. Macleod, and J. B. Pridham, Phytochemistry, 2, 225-230 (1963). “Complexes Between Polyhydroxy-compounds and Inorganic Oxy-acids. Tungstate Complexes of Sugars and Other Cyclic Polyhydroxy-compounds,” H. J. F. Angus, E. J.

OBITUARY-EDWARD

JOHN BOURNE

21

Bourne, F. Searle, and H. Weigel, Tetrahedron Lett., 55-60 (1964). “The Synthesis of Pentaerythrose,” C. A. Armour, T. G. Bonner, E. J. Bourne, and J. Butler,]. Chem. Soc., 301-304 (1964). “Studies with Glycogens from the Livers of Human Foetuses and Young Children,” E. J. Bourne, A. McLean, and J. B. Pridham, Abstr. Meet. Fed. Eur. Biochem. Soc. Ist, A81 (1964). “Synthesis of Sucrose Labelled with Carbon-14 in the Fructose Part,” E. J. Bourne, J. Peters, and H. Weigel,]. Chem. Soc., 4605-4607 (1964). “The Condensation of Ferrocenealdehyde with D-Glucitol and DMannitol,” A. N. de Belder, E. J. Bourne, and J. B. Pridham,]. Chem. Soc., 5486-5488 (1964). “Complexes Between Polyhydroxy-compounds and Inorganic Oxy-acids. Part V, Tungstate Complexes ofAcyclic Polyhydroxy-compounds,” H. J. F. Angus, E. J. Bourne, and H. Weigel,]. Chem. Soc., 21-26 (1965). “Butylidene Derivatives of Glucitol,” T. G. Bonner, E. J. Bourne, S. E. Harwood, and D. Lewis, J. Chem. SOC., 121-126 (1965). “Phenylboronates of Acyclic Polyhydroxy-compounds,” E . J. Bourne, E. M. Lees, and H. Weigel,]. Chem. Soc., 3798-3802 (1965). “The Biosynthesis of Raffinose,” E. J. Bourne, M. W. Walter, and J. B. Pridham, Biochem. J., 97,802-806 (1965). “The 4,6-O-Butylidene Acetals of D-Glucose and D-Glucitol,” T. G. Bonner, E. J. Bourne, and D. Lewis, J. Chem. Soc., 7453-7458 (1965). “The Structure and Deposition of Human-liver Glycogens,” E. J. Bourne, A. McLean, and J. B. Pridham, Biochem. J., 98,678-681 (1966). “Studies on Dextrans and Dextranases. Part VIII, Size and Distribution of Branches in Some Dextrans,” D. Abbott, E. J. Bourne, and H. Weigel,]. Chem. Soc., C, 827-831 (1966). “A New Mono-0-butylidene-~-glucitol,”T. G. Bonner, E. J. Bourne, P. J. V. Cleare, and D. Lewis, Chem. I n d . (London), 1268-1269 (1966). “Furfurylidene Derivatives of Glucitol,” T. G. Bonner, E. J. Bourne, S. E . Harwood, and D. Lewis, J. Chem. Soc., A, 2229-2233 (1966). “2,4 :3,5-Di-O-Benzylidene-D-Glucitol,” T. G. Bonner, E. J. Bourne, and D. Lewis, Carbohydr. Res., 2,421-425 (1966). “Studies on tert-Butyl Derivatives of D-Glucose,” A. N. de Belder, E. J. Bourne, and H. Weigel, Carbohydr. Res., 3, 1-6 (1966). “Pectic Substances in Cured and Uncured Tobacco,” E. J. Bourne, J. B. Pridham, and H. G. J. Worth, Phytochemisiry, 6 , 4 2 3 4 3 1 (1967). “Professor T. S. Moore-Obituary,” E. J. Bourne, Nature, 214, 1063 (1967). “Ring Scission of Cyclic Acetals. Part 111, Reaction of Acetyl Trifluoroacetate with 1,3:2,5 :4,6Tri-O-methylene-~-mannitol,” T. G. Bonner, E. J. Bourne, and D. Lewis, J . Chem. Soc., C , 2321-2336 (1967). “The Formation, under Kinetic Control, of a New Monoacetal (2,3-O-Butylidene-~Glucitol) from D-Glucitol and n-Butyraldehyde,” T. G. Bonner, E. J. Bourne, P. J. V. Cleare, and D. Lewis,./. Chem. Soc., B , 822-827 (1968). “Kinetic and Thermodynamic Control in the Formation of Monoacetals from Aldehydes and DGlucitol,” T. G. Bonner, E. J. Bourne, P. J. V. Cleare, and D. Lewis,]. Chem. Soc., B , 827-830 (1968). “The Active Carbohydrate Metabolites of Fucus oesiculosus,” E. Percival, E. J. Bourne, and P. Brush, Int. Seaweed S y m p . , 6th, Santiago de Compostela, 575-577 (1968). “The Active Carbohydrate Metabolites of the Brown Seaweed, Fucus uesiculosus,” E. J. Bourne, P. Brush, and E. Percival, Carbohydr. Res., 9,415-422 (1969).

22

HELMUT WEIGEL

“Butylidene Acetals of D-Mannitol and Their N.M.R. Spectra,” T. G. Bonner, E. J. Bourne, D. G. Gillies, and D. Lewis, Carbohydr. Res., 9 , 4 6 3 4 7 0 (1969). “a-Amylase Activity in Sugar Cane (Saccharum officinarum) Chloroplasts,” E. J. Bourne, D. R. Davies, and J. B. Pridham, Phytochemistry, 9,345-348 (1970). “Polysaccharides-Enzymic Synthesis and Degradation,” E. J. Bourne and P. Finch, R. I n s t . Chem. Reo., 3,45-60 (1970). “The Water-soluble Polysaccharides of Cladophora rupestris. Part IV, Autohydrolysis, Methylation of the Partly Desulphated Material, and Correlation with the Results from Smith Degradation,” E. J. Bourne, P. G. Johnson, and E. Perciva1,J. Chem. Soc., C, 1561-1569 (1970). “Studies on Type I1 Glycogenosis. Effects of Cortisone Derivatives on Acid a-Glucosidase,” E. J. Bourne, K. Clarke, J. B. Pridham, and J. J. M. Rowe, Biochem. J . , 121, 663-666 (1971). “Complexes Between Polyhydroxy Compounds and Copper-I1 Ions,” E. J. Bourne, F. Searle, and H. Weigel, Carbohydr. Res., 16, 185-187 (1971). “Acid-catalysed Formation of Monoacetals from n-Butyraldehyde and Certain D-GIUcitol Derivatives,” T. G . Bonner, E. J. Bourne, P. J. V. Cleare, R. F. J. Cole, and D. Lewis, J . Chem. SOC.,B , 957-962 (1971). “A Detailed Investigation of the Acid-catalysed Formation of Acetals from Acetone and D-Glucitol,” T. G. Bonner, E. J. Bourne, R. F. J. Cole, and D. Lewis, Carbohydr. Res., 21, 29-35 (1972). “Studies on Dextrans and Dextranases. Part X, Types and Percentages of Secondary Linkages in the Dextrans Elaborated by Leuconostoc mesenteroides NRRL B-1299,” E. J. Bourne, R. L. Sidebotham, and H. Weigel, Carbohydr. Res., 22, 13-22 (1972). “Carbohydrates ofAcetabularia Species. Part I, A. crenulata,” E. J. Bourne, E. PerciVal, and B. Smestad, Carhohydr. Res., 22,75-82 (1972). “The Synthesis and Hydrolytic Stability of 1-Glucopyranosylimidazoles,” E. J. Bourne, P. Finch, and A. G. Nagpurkar, 1. Chem. Soc. Perkin Trans. 1 , 2202-2205 ( 1972). “The Maintenance of Federalism,” E. J. Bourne, Times Higher Education Supplement, 1st December 1972, p. 14. “A Convenient Method for the Synthesis of 6-O-Methyl-D-glucose,” E. J. Bourne, I. R. McKinley, and H. Weigel, Carbohydr. Res., 25, 516-517 (1972). “Further Observations on the Activation of Lysosomal Acid a-Glucosidase by Cortisone Derivatives,” E. J. Bourne, K. Clarke, J. B. Pridham, and J. J. M. Rowe, Biochern. /., 132,435438 (1973). “The Enzyme-inhibitory Properties of 1-a- and 1-P-D-Glucopyranosylimidazoles,” E. J. Bourne, P. Finch, and A. G. Nagpurkar, Carbohydr. Res., 29,492-496 (1973). “Butylidene Acetals of Galactitol,” T. G. Bonner, E. J. Bourne, D. Lewis, and L. Yuceer, Carbohydr. Res., 33, 1-8 (1974). “Carbohydrates Metabolised by the Green Seaweed Urospora Penicilliformis,” E. J. Bourne, M. L. Megarry, ancl E. Percival, J . Carhohydr. Nucleos. Nucleot., 1, 235-264 (1974). “Studies on Dextrans and Dextranases. Part XI, The Structure of a Dextran Elaborated by Leuconostoc mesenteroides NRRL B-1299,’’ E. J. Bourne, R. L. Sidebotham, and H. Weigel, Carbohydr. Res., 34, 279-288 (1974). “The Structure of the Benzeneboronate of Pentane-1,3,5-triol,” E. J. Bourne, I. R. McKinley, and H. Weigel, Carbohydr. Res., 35, 141-149 (1974).

1,gANHYDRO DERIVATIVES OF ALDOHEXOSES BY

MILOSLAV CEFWY

AND JAN STANEK, JR.

Department of Organic Chemistry, Charles Uniuersity, 128 40 Prague 2; Laboratory of Monosaccharides, Institute of Chemical Technology, 166 28 Prague 6, Czechoslovakia

................... . . 24 xopyranoses . . . . . . . . . . . . . . . . 26 ............................ 26

I. Introduction . . . . . . . . . . . . . . . . 11. Formation and Preparat

1. Cleavage of Glycosid 2. Cyclization of Hexop Containing Reactive Substituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Cyclization of 6C-Substituted Hexopyranoses . . . . . . . . . . . 4. Action of Acids on Hexoses and Their Derivatives . . . . . . . . . . . . . . . . . . . 5. Thermal Degradation of Polysaccharides, Oligosaccharides, and ..................... Hexoses . . . . . . . . . . . . . . . . . ........... 6. Miscellaneous Methods . . . . . . . . . . . . . . 7. Total Synthesis from Acrolein ....................................... 111. General Properties of 1,6-Anhydrohexopyranoses ........................ IV. Reactions of 1,6-Anhydrohexopyranoses. . 1. Cleavage of 1,6-Anhydride Bonds ....................................

34 38 46 48 50

..................... 4. Nucleophilic Replacement of Sulfonic Esters ......................... ............................... 5. Acyloxonium Ions

85 87

2. General Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Reactions Involving Cleavage of the Oxirane Ring .................... VI. Nitrogen Derivatives of 1,6-Anhydrohexopyranoses

112 115

. . . . . . . . . 146

23

24

MILOSLAV CERNY AND JAN STANEK, JR.

1. Formation and Preparation ............................. 151 ............................................ 2. General Properties . . 153 3. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X. 1,6-Anhydro Derivatives of 1. Preparation . . . . . . . . . . . . . 2. Properties and Reactions XI. Tables of Properties of 1,6-Anhydrohexoses and Their Derivatives . . . . . . . . 164

I. INTRODUCTION* The 1,6-anhydroaldohexopyranoses(for reviews, see Refs. 1 and 2) and 1,6-anhydroaldohexofuranoses(for a review, see Ref. 3 ) are aIdohexose derivatives that can be formed from free hexoses by dehydration in such a way that intramolecular glycosides containing a glycosidically linked, primary hydroxyl group are formed. According to whether the D-hexose adopts the pyranoid or furanoid form, two analogous, bicyclic systems are formed, namely, 1,6-anhydro-/3-~-aldohexopyranoses (1= la) having a 6,8-dioxabicyclo[3.2.l]octane skeleton from the former, and 1,6-anhydro-/3-~-aldohexofuranoses (2 = 2a) having a 2,8-dioxabicyclo[3.2.lloctane skeleton from the latter. In their chemical properties, both these types of compound resemble to a certain degree the methyl P-D-aldopyranosides or the methyl a- or p-D-aldofuranosides. They do not have reducing properties, and are relatively stable in alkaline media, but are hydrolyzed by acids to the free hexoses. A characteristic feature of these compounds is their steric rigidity: in the crystalline state,4 as well as in s ~ l u t i o nthe , ~ 1,6-anhydro-p-~hexopyranoses adopt exclusively the 'C,(D) conformation (la),whereas the corresponding D-hexoses and their glycosides generally occur in the '(D) conformation. These different conformations determine the chemical and physical properties of the 1,6-anhydro-P-~-hexopyranoses. A similar situation exists with the 1,6-anhydroaldohexofuranoses. * Throughout the text, such shortened names as 1,6-anhydrohexopyranoses, 1,6-anhydrohexoses, or, sometimes, hexosans will be used for 1,6-anhydroaldohexopyranoses, and 1,6-anhydrohexofuranosesor 1,6-anhydrofuranoses for 1,6-anhydroaldohexofuranoses, respectively. (1) S. Peat,Ado. Carbohydr. Chem., 2, 37-77 (1946). (2) hI. Cern? and J. Stan&, Fortschr. Chem. Forsch., 14, 526-555 (1970). (3) R. J. Dimler, Ado. Carbohydr. Chem., 7, 37-52 (1952). (4) Y. J. Park, H. S. Kim, and G. A. Jeffrey, Acta Crystallogr., Sect. B , 27,220-227 (1971). (5) K. Heyns and J. Weyer,Justus Liebigs A n n . Chem., 718,224-237 (1968).

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

25

0

HOHO

OH

1,6-Anhydro-p-~-aldohexopyranose la

1

OH

1,6-Anhydro-p-o-aldohexofuranose 2

2a

During the past ten years, the 1,6-anhydro-p-~-hexopyranoses have found wide application in the synthesis of hexoses and their derivatives, and of oligosaccharides, and for polymerization to polysaccharides. They can be used as model compounds in studying the physical and chemical properties of monosaccharides, as has been shown, for example, by nuclear magnetic resonance (n.m.r.) studies, and also by studies of ( a ) their chiroptical properties, ( b )the partial reactivity of hydroxyl groups, and (c) their ability to form complexes. The most readily available and longest known compound of this series is 1,6-anhydro-~-~-glucopyranose, also called levoglucosan; it was first prepared as a well defined compound by Tanret6 in 1894. It is a very useful starting-material in syntheses, and approximates in its importance to methyl P-D-glucopyranoside. It can be prepared in the laboratory in kilogram q u a n t i t i e ~by ~ , pyrolysis ~ of starch under diminished pressure; a continuous procedure has also been developed, with (6) C . Tanret, Compt.,Rcrnd.,119, 158-161 (1894).

(7) G. Zemple'n and A. Gerecs, Ber., 64,1545-1554 (1931). (8) R. B. Ward, Methods Carbohydr. Chern., 2, 394-396 (1963). It is recommended that the pyrolysis be performed under diminished pressure (water pump) and that the crude distillate be treated with active carbon (present authors' comments).

26

MILOSLAV &RNY

AND JAN STANEK, JR.

promising possibilities for technological productionY-13(see also, Refs. 14 and 15). However, the practical utilization of levoglucosan in chemical industry is at present rather limited.16*17 Neither the 1,6-anhydrohexopyranosesnor the corresponding furanoses occur naturally; as they have been isolated from natural sources, however, they must have been formed as secondary products from hexoses or their derivatives during the isolation process. 1,6-Anhydro-2,3,4-trideoxyhexopyranoses are structurally similar to among natural dialkyl-substituted 6,8-dioxabicyclo[3.2.1]0ctanes,~*-~~ which the 1,5-dimethyl18and exo-7-ethyl-5-methyl derivativeslS occur in the aggregation pheromones of the western-pine bark-beetle. Levoglucosan as the degradation product of cellulose and celluloselike materials is at least partially responsible for flaming combustion, which may be important in the spreading of firesz2(for a review, see Ref. 23). Therefore, its formation is indirectly associated with the development of human culture and its environment. 11. FORMATION AND

PREPARATION OF

1,6-ANHYDROHEXOPYFiANOSES

1. Cleavage of Glycosides with Bases As early as 1881, SchiffZ4(see also, Refs. 25 and 26) prepared a glassy, levorotatory material having the empirical forniula C,H,,O, by thermal (9) Arch. No. 27199. Giprogum, Leningrad, 1960; see Ref. 11. I. S. Sorokin and D. V. Tishchenko, Gidroliz. Lesoklzim. Prom., 15 (3),8-9 (1962); Chem. Abstr., 57, 6186 (1962). S. V. Chepigo and G. S. Barysheva, Gidroliz. Lesokhim. Prom., 15 (3), 9-11 (1962); Chem. Ahstr., 57, 7538 (1962). C. M. Lakshmanan, B. Gal-Or, and H. E. Hoelscher, Znd. Eng. Chem. Prod. Res. Dev., 8, 261-267 (1969). C . M . Lakshmanan, B. Gal-Or, and H. E. Hoelscher, Staerke, 22,221-227 (1970). J. Sarasin, Arch. Sci. Phys. Nut., [4] 46, 5-32 (1918); Chem. Zentralbl., 11, 528 (1918). A. Pictet, German Pat. 326,316 (1920); Chem. Zentrulbl., 11,34 (1921). 0. P. Golova, U s p . Khim., 44, 1454-1474 (1975). F. Meyer, Brit. Pat. 519,661 (April 2, 19440); Chem. Ahstr., 36, 98 (1942). G. W. Kinzer, A. F. Fentiman, Jr., T. F. Page, Jr., R. L. Foltz, J. P. Vite, and G . €3. Pitman, Nature (London), 221,477-478 (1969). R. M. Silverstein, R. G. Brownlee, T. E. Bellas, D. L. Wood, and L. E. Browne, Science, 159,889-891 (1968). Y. Naya and M. Kotake, Tetrahedron Lett., 2459-2460 (1967). W. E. Gore, G. T. Pearce, and R. M. Silverstein, ]. Org. Chem., 40, 1705-1708 (1975). J. E. Hendrix, 6. L. Drake, Jr., and R. H. Barker,]. AppZ. Polym. Sci., 16,41-59 ( 1972).

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

27

degradation of the aromatic D-ghcosides esculin, phlorizin, and salicin. Thirteen years later, this compound, 1,6-anhydro-P-~-glucopyranose (levoglucosan, P-glucosan) (6) was obtained by T a n r e P 7 in crystalline state by heating such P-D-glucosides as picein, salicin, and coniferin with barium hydroxide. This reaction was then successfully applied in different modifications (-10% aqueous potassium hydroxide is mostly used), especially on the phenyl glycosides of a l d o h e x o p y r a n o ~ e s and ~ ~ - ~of~the corresponding oligosaccharides (see Sect. X,l,a), and still remains one of the methods frequently used for the preparation of 1,6-anhydro-p-~(for g l u c o p y r a n ~ s e(6) ~~ ~ ~example, ~ ~ ~ ~ specifically labelled with carbon-14; see Ref. 44) and of 1 , 6 - a n h y d r o - ~ - ~ - g a l a c t o p y r a n o s e . ~ ~ ~ ~ ~ If the aglycon has a more complicated structure, involving, for example, a heterocyclic ring of the pyridine, pyrimidine, purine, or F. Shafizadeh, Ado. Carbohydr. Chem., 23,419474 (1968). H. Schiff, Ber., 14,302-304 (1881). J. Habermann, Monatsh. Chem., 4, 753-786 (1883). A. Pictet and H. Goudet, Helu. Chim.Acta, 2, 698-703 (1919). C. Tanret, Bull. SOC. Chim. Fr., 11, 949-955 (1894). E. Vongerichten and F. Muller, Ber., 39, 241-245 (1906). E. M. Montgomery, N. K. Richtmyer, and C. S. Hudson, J. Am. Chem. SOC., 64, 1483-1484 (1942). E. M. Montgomery, N. K. Richtmyer, and C. S. Hudson,]. Am. Chem. Soc., 65, 3-7 (1943). G. H. Coleman, C. M. McCloskey, and R. Kirby, Ind. Eng. Chem., 36,1040-I041 (1944). C. M. McCloskey and G. H. Coleman,]. Org. Chenz., 10, 184-193 (1945). E. M. Montogmery, N. K. Richtmyer, and C. S. Hudson,]. Org. Chem., 10, 194198 (1945). L. H. Koehler and C. S. Hudson,]. Am. Chem. Soc., 72, 981-983 (1950). A. Dyfverman and B. Lindberg, Acta Chem. Scand., 4, 878-884 (1950). F. Micheel and G. Baum, Chem. Ber.. 88.479481 (1955). A. Fernez and P. J. Stoffyn, Tetrahedron, 6, 139-142 (1959). (38) R. W. Jeanloz, A. M. C. Rapin, and S.-I. Hakomori,/. Org. Chenz., 26,3939-3946 (1961). (39) E. Zissis and N. K. Richtmyer,]. Org. Chem., 26, 5244-5245 (1961). (40) G. H. Coleman, Methods Carbohydr. Chem., 2,397-399 (1963). (41) J . Tnkhly and S. Bauer, Chem. Zuesti, 19, 650-654 (1965); Chem Abstr., 63, 14,951 (1965). (42) M. Sozmen, Commun. Fac. Sci. Uniz;. Ankara, Ser. 23, 19,99-103 (1972);Chem. Abstr., 80, 96,236 (1974). (43)R. C . Gasman and D. C. Johnson,J.Org. Chem., 31, 1830-1838 (1966). (44) F. Shafizadeh and Y. 2. Lai,]. Org. Chem., 37,278-284 (1972). (45) T. Uryu, H. Libert, J. Zachoval, and C. Schuerch, Macromolecules, 3, 345-349 (1970). (454 P. A. Gent, R. Gigg, and A. A. E. Penglis,J. Chem. SOC.Perkin Trans. I, 13951404 (1976). ,

,

28

MILOSLAV

ERN';' A N D JAN STANEK, JR.

coumarin type, or if it contains a number of strongly electronegative groups in the aromatic nucleus, or a grouping of such kinds as enolic, allylic, or y-carbonyl, 1,6-anhydrohexoses are not formed on treatment with bases, and instead, reducing hexoses are liberated (for reviews, see Refs. 46 and 47). yield substituted 1,6Phenyl 3- or 4-0-a~kyl-P-~-glucopyranosides anhydro-~-D-glucopyranoses,3z~48-"2 whereas 2-0-alkyl derivatives do not react under those ~ o n d i t i o n s . ~ ' The , ~ ~ ,phenyl ~~,~~ glycosides of 2-, 3-, or 4-deoxyhexoses behave similarly (see Sect. VII,3). Under the action of an alkali, 1,6-anhydrohexopyranosesare also formed from phenyl l-thio-P-~-glucopyranoside,3~~~~ from the corresponding p-tolyl sulfones4(for a controversial view, see Ref. 55) and from phenyl l-se~eno-~-~-g~ycosides,~~ but not from s u l f o x i d e ~They .~~ are also obtained in very small proportion from aliphatic hexopyranoand hexofuranosides60;nevertheless, vinyl P-D-glucopyranoside yields 50% of levoglucosan61(6). The kinetics and mechanism of the formation of the 1,6-anhydride ring during the alkaline cleavage of aromatic glycosides depend on both the nature of the glycosidic bond and the substitution of the aglycon.32~3s~43~46~5s~s9~62-65 Provided that steric conditions enable the (46) C. E. Ballou, Adu. Carbohydr. Chem., 9,59-95 (1954). (47) G. Wagner and P. Nuhn, Pharmazie, 21,205-214 (1966). (48) R. E. Reeves,J. Am. Chem. Soc., 71,2116-2119 (1949). (49) M. P. Bardolph and G. H. Coleman,J. Org. Chem., 15, 169-173 (1950). (50) P. A. Seib, Carbohydr. Res., 8, 101-109 (1968). (51) D. Shapiro, Y. Rabinsohn, A. J. Acher, and A. Diver-Haber,J. Org. Chenz., 35, 1464-1467 (1970). (52) P. C. Wollwage and P. A. Seib,]. Chem. Soc., C , 3143-3155 (1971). (53) G. Wagner and P. Nuhn, Arch. Pharm. (Weinheim, Ger.),298, 686-692 (1965). (54) A. L. Clingman and N. K. Richtmyer,J. Org. Chem., 29, 1782-1787 (1964). (55) G . Wagner and M. Wagler, Arch. Phumi. (Weinheim, G e r . ) ,297,358-362 (1964). (56) B. Lindberg, Suen. Papperstidn., 59, 531-534 (1956); Chern. Abstr., 52, 4983 ( 1958). (57) E. Dryselius, B. Lindberg, and 0. Theander, Acta Chem. Scarad., 11, 663-667 (1957). (58) E. Dryselius, B. Lindberg, and 0. Theander, Acta Chern. Scand., 12, 340-342 (1958). (59) J. Janson and B. Lindberg, Acta Chem. Scand., 13, 138-143 (1959). (60) J. Janson and B. Lindberg, Acta Chern. Scand., 14,2051-2053 (1960). (61) T. D. Perrine, C. P. J. Glaudemans, R. K. Ness, J . Kyle, and H. G. Fletcher, Jr., /. Org. Chem., 32,664-669 (1967). (62) B. N. Stepanenko and 0. G. Serdyuk, Dokl. Akud. Nauk S S S R , 154, 877-880 (1964). (63) C. S. Tsai and C. Reyes-Zamora,J. Org. Chern., 37,2725-2729 (1972). (64)R. U. Lemieux, Ado. Carbohydr. Chem., 9, 1-57 (1954). (65) G. Wagner and H . Frenzel, Pharmazie, 22,415-420 (1967).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

29

formation of 1,2-anhydro-a-~-hexopyranose, for example, 4, through the participation of a hydroxyl group at C-2, cyclization proceeds rapidly and with a high yield by way of this intermediate. This fact agrees with the observation that Brigl’s anhydride ( 5 ) yields levoglucosan (6) in alkaline media35a4g,66 (see also, Ref. 67; and compare Ref. 68). Such a suitable, steric arrangement for the formation of the 1,6-anhy(3) (and in the dride ring is found in phenyl P-D-gluc~pyranoside~~ corresponding P - ~ - g a l a c t o s i d eand ~ ~ P - ~ - a l l o s i d ehaving ~~) trans substituents on C-1 and C-2; the formation and the cleavage of the oxirane ring can then proceed through the ‘C,(D) conformation (3a).

L

3

3a

OH 6

RO 4 R = H 5 R=Ac

If, for steric reasons, such a reaction path is impossible, as with phenyl a-D-glucopyran~side,~~ a- and P - ~ - m a n n o p y r a n o s i d e ,a-D~~*~~ a l l o p y r a n ~ s i d eor , ~ a-D-galactopyranoside,3° ~ formation of the 1,6-anhydride ring is strongly impeded, and, sometimes, even degradation occurs. Nevertheless, the formation of the 1,6-anhydride ring can pro~ ~ has , ~ ~not ~ ~yet ~ been ceed b y way of an alternative r n e c h a n i ~ mthat completely elucidated, possibly ( a ) through a 1,4-anhydro derivative (66) R. U. Lernieux and C. Brice, Can. /. Chem., 30, 295-310 (1952). (67) I. V. Balanina, G. M. Zaiubinskii, and S. N. Danilov, Zh. Ohshch. Khim., 43,447 (1973). (68) R. U. Lemieux, Can. /. Chem., 31, 949-951 (1953). (69) B. Capon, Chem. Rec., 69,407-498 (1969); see p. 429 thereof. (70) R. U. Lemieux, in “Molecular Rearrangements,” P. de Mayo, ed., Wiley-Interscience, New York, 1964, Vol. 11, pp. 761-672.

30

MILOSLAV CERNY A N D JAN STANEK, JR.

8, with participation of the 4-hydroxyl group, as with phenyl p-D-mannopyranoside (7), (b) with participation of the 6-hydroxyl group, as with phenyl a-D-galactopyranoside (9), or ( c ) ,conceivably, through a

7

9

0

10

carbonium ion (10).This is supported by the quite different behavior of the phenyl glycopyranosides: in aqueous alkali hydroxides under reflux, the a-D-allopyranoside decompose~,3~ the a-D-mannopyranoside yields only -5% of the l,fi-anhydro derivative, together with unidentified products,30and the a-D-glucopyranoside does not react at On the other hand, the a-~-galactopyranoside~~ and P-D-mannopyr a n o ~ i d react, e~~~ although ~~ very slowly, with yields of 85 and 57%, respectively. The behavior of the phenyl glycosides of the D - U ~ O , D - t a b , and ~ - i d oconfigurations, which might contribute to knowledge of the reaction mechanism, has not yet been studied. When the aromatic nucleus in a phenyl P-D-glucopyranoside contains one, or, particularly, several, strongly electronegative groups, for example a nitro group, nucleophilic substitution of the aromatic

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

31

ring by hydroxide or methoxide ion proceeds under 0-phenyl bond cleavage at the expense of the formation of l e v o g l ~ c o s a (compare, n~~~~~ Ref. 53). Similar behavior has been observed with some glycosides of electronegatively substituted, heterocyclic a g l y ~ o n s . ~ ~ , ~ ~ 2. Cyclization of Hexopyranosyl Derivatives Containing Reactive Substituents Those aldohexopyranosyl derivatives that have on C-1 a reactive group which displays a trend to elimination as an anion yield 1,6-anhydrohexopyranoses on treatment with alkoxides or aqueous alkali hydroxides, or anion-exchange resins .36,71-76 The m e c h a n i ~ mof~ this ~,~~ reaction is obviously analogous to that of the alkaline cleavage of phenyl glycosides (see Sect. II,l), and it is controlled by the same steric effects. Naturally, if the reactive group on C-1 is a better leavinggroup than a phenoxide ion, the cyclization takes place under milder conditions compared to that of phenyl glycosides. This method has also been employed for the preparation of 2-amino2-deoxy derivatives of levoglucosan (see Sect. VI,l,a).

a. Halides.-Of the glycopyranosyl halides studied by Micheel and Klemer (for a review, see Ref. 76), the best starting-compounds were the fluorides; among them, the fluorides having the ~ g 1 u c o ~ ~ , ~ ~ , ~ and ~ g u l u c t oconfigurations, ~~,~~ but not the fluorides of the ~ r n u n n o ' ~ configuration, yielded 176-anhydrides.As expected, the anomers differ markedly in their reactivities. Thus, P-D-ghcopyranosyl fluoride reacts more readily, and gives a higher yield of levoglucosan (6),than a-D-ghcopyranosyl f l ~ o r i d e . ~Moreover, ~ , ~ ~ , ~ at ~ higher hydroxide or methoxide concentration, the yield is significantly pH-dependent, and hexosans preponderate considerably, whereas, at low concentration of base, the normal hydrolysis products, or the methyl glycosides, res ~ 1 t . ~ On ~ *the ~ ~other , ~ hand, ~ , ~ the ~ reaction of a-D-mannopyranosyl fluoride with sodium methoxide leads to methyl a-D-mannopyrano(71) F. Micheel and A. Klemer, Chem. Ber., 85, 187-188 (1952). (72) F. Micheel, A. Klemer, G. Baum, P. RistiE, and F. Zumbiilte, Chem. Ber., 88, 475479 (1955). (73) F. Micheel and G. Baum, Chem. Ber., 88,2020-2025 (1955). (74) F. Micheel, A. Klemer, and R. Flitsch, Chem. Ber., 91, 663-667 (1958). (75) J. E. G. Barnett, Carbohydr. Res., 9, 21-31 (1969). (76) F. Micheel and A. Klemer, Ado. Curboh!&. Chem., 16,85-I03 (1961). (77) F. Micheel and D. Bomnann, Chem. Ber., 93, 1143-1147 (1960). (78) F. Micheel and A. Klemer,Ado. Curbohydr. Chem., 16,85-103 (1961); see p. 92 thereof.

32

MILOSLAV CERNY AND JAN STANEK, JR.

probably through the intermediary 1,2-anhydro-p-~-mannopyranose (compare Ref. 30). Under the action of sodium hydroxide, the 2-0-alkyl derivatives of D-glucopyranosyl fluorides react to afford 1,6-anhydrohexose~~~; however, treatment with sodium methoxide yields methyl g l u c o ~ i d e s . ~ ~ Levoglucosan (6) or its triacetate are also formed when 2,3,4-tri0-acetyl-a-D-ghcopyranosyl bromide is treated with alkalisoor silver oxide.81,82 Under similar conditions, they respectively result, as a byproduct,s3 from the corresponding tetra-0-acetyl bromide during the preparation of phenyl P-D-ghcopyranoside, and from 2,3,4-tri-0acetyl-6-O-tert-butyl-/?-~-ghcopyranosylchloride by the action of mercuric cyanide in nitromethanes4 (compare Sect. 11,6).

b. Ammonium and Sulfonium Salts.-For the synthesis of 1,6-anhydro derivatives, the ammonium salts originating from the reaction of 2,3,4,6-tetra-O-acetyl-a-D-glucoand -galacto-pyranosyl bromide with trimethylamine have also been ~ s e d . *This ~ , ~reaction ~ fails with D-rnanno~e.*~**~ 1,6-Anhydro-2,3,4-tri-O-benzyl-~-~-glucopyranose was obtained as a minor product from benzyl 2,3,4-tri-O-benzyl-l-thio-~-~-glucopyranoside by reaction with methyl iodide; the intermediate was assumed to be a sulfonium salt.89 c. Various Derivatives.- 1,6-Anhydrohexoses are similarly obtained from P-D-glucopyranosyl a ~ i d e , and ~ ~ ,from ~ ~ a-D-glucopyranosyl nitrate,90 as well as from the 1-mesitoic esters of p-D-glucose73’91 and P-D-galact~se.~~ These esters are cleaved by an 0-alkyl scission mechanism, because of steric hindrance, and behave, therefore, like glycosyl halides: only the P anomers yield 1,6-anhydrides; for example, ester 11 gives 1,6-anhydro-P-~-galactopyranose

(12). (79) F. Micheel, A. Klemer, and R. Flitsch, Chem Ber., 91, 194-197 (1958). (80) G. Zemplen, R. Bognir, and G. Pongor, Acta Chim. Acad. Sci. Hung., 19, 285293 (1959). (81) W. J. Whelan and S. Haq, Chem. I n d . (London),600 (1955). (82) S. Haq and W. J. Whelan,J. Chem. Soc., 4543-4549 (1956). (83) R. L. Whistler and P. A. Seib, Carbohydr. Res., 2,93-I03 (1966). (84) N. K. Kochetkov and E. M. Klimov, Carbohydr. Res., 44, 138-141 (1975). (85) P. Karrer and A. P. Smimoff, Helv. Chim. Actn, 4, 817-820 (1921). (86) F. Micheel, Ber., 62,687-693 (1929). (87) F. Micheel and H. Micheel, Ber., 63,386-393 (1930). (88) F. Micheel and H. Micheel, Ber., 63,2862-2866 (1930). (89) S. A. Holick, S.-H. L. Chiu, and L. Anderson, Carbohydr. Res., 50, 215-225 ( 1976). (90) E. K. Gladding and C. B. Purves,]. Am. Chem. Soc., 66,76-81 (1944). (91) H. B. Wood, Jr., and H. G. Fletcher, Jr.,]. Am. Chem. Soc., 78, 207-210 (1956).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

OH I

33

6H 11

12

The naturally occurring P-D-glucoside stevioside reacts similarly.s2

3. Cyclization of 6-C-Substituted Hexopyranoses The 1,6-anhydride ring can be produced by an intramolecular, nucleophilic displacement of any reactive substituent on C-6 (such as the p-tolylsulfonyloxy, iodo, or chloro group), with a hemiacetal hydroxyl group or its Levoglucosan (6)also appears as a minor product in the reaction mixture after alkaline hydrolysis of P-D-glucopyranose 6-phosphate .g6 The reaction proceeds through the ‘C,(D) conformation of the D-hexopyranose, and requires the axial orientation of the hemiacetal group, which, having adopted this position, reacts, rather than a syn-axial, 3-hydroxyl group which may be present in the molecule.s3 Consequently, 1,2,3,4-tetra-O-acety~-6-O-p-tolylsulfony~-~-D-glucopyranose (13) reacts with sodium methoxide to give 6 exclusively, even though 3,6-anhydro-~-glucose(15) might alternatively have been formed.s3 In contrast to 13, the 6-iodo (Y anomer (14) yields the 3,6-anhydro derivative (15); the acetylated 6-0-p-tolylsulfonyl derivatives of 2-amino-2-deoxy-~-glucosebehave similarlys5~s7; see also Sect. VI,l,a. In the D-gdacto series, analogous reactions do not take place.s3 It is assumed that this is probably due to an unfavorable interaction of the equally oriented dipoles of the 4-hydroxyl and leaving p-tolylsulfonyloxy groups in the transition state, which necessarily precedes the formation of the 1,6-anhydride bond. An alternative explanations3 of these results, based on the “passing interaction” effect, is not convincing. (92) H. B. Wood, Jr., R. Allerton, H. W. Diehl, and H. G. Fletcher, Jr.,J. Org. Chem., 20,875-883 (1955). (93) h4. Akagi, S. Tejima, and M. Haga, Chem. Pharm. Bull., 10,905-909 (1962). (94) H. J. Jennings and J. K. N. Jones, Can. J . Chem., 43,2372-2386 (1965). (95) K. Yamamoto, M. Haga, and S. Tejima, Chem. Pharm. Bull., 23,233-236 (1975). (96) C. A. Bunton and H . Chaimovich,J. Am. Chem. SOC., 88,40824089 (1966). (97) M. Akagi, S. Tejima, and M. Haga, Cheni. Pharm. Bull., 10, 1039-1042 (1962).

MILOSLAV CEKNY AND JAN STANEK, JR.

34

OH

/

'2

6

f!!!vmoA TsOCH,

I

AcO

CH,I

OAc

I

OAc

I

AcO

OAc

13

14

HON

15

O OH

H

The intermediate formation of a 1,6-anhydride bond was used to explain the course of reaction of methyl 2,3,4,6-tetra-O-(chlorosulfonyl)a-D-ghcopyranoside (16) with aluminum chloride.98The methoxyl group first anomerizes, and then moves from C-1 to C-6 by way of the cyclic oxonium ion 17, to give the 6-methyl ether (18).

4. Action of Acids on Hexoses and Their Derivatives Aldohexoses cyclize in aqueous, mineral acids to give mainly 1,6anhydrohexopyranoses; 1,6-anhydrohexofuranosesare simultaneously formed, but to a far lesser degree (see Sect. IX,l). An equilibrium is established for the 1,6-anhydrohexoses, whose composition can be calculated from thermodynamic data according to Angyal and DawesYg;

(98) C. F. Gibbs and H. J. Jennings, Can. J . Chem., 48, 2735-2739 (1970). (99) S. J. Angyal and K. Dawes, Aust. /. Chem., 21,2747-2760 (1968).

1,BANHYDRO DERIVATIVES OF ALDOHEXOSES

16 R = S O z C 1

35

17

/ c1 18

it is proportional to the difference between G o for the p anomer in the ‘C,(D) conformation and Go for the equilibrium mixture of the a and p anomers in the ‘C,(D) and ’C,(D) conformation^.^^ (The values Go for the a and fl anomers can be estimated by summation of instability factors derived on the basis of conformational analysis.loO) For the sake of simplification, it is assumed that the cyclization of the p anomer in the lC4 conformation, resulting in the formation of the 1,6-anhydride bridge, is accompanied by the same value of AGO, that is, -11.7 kJ, independent of the configuration of the h e ~ ~(see ~ Scheme e ~ ~1). ,

G o for the equilibrium

mixture of

01

and 6 anomers

G o for the 0 anomer in the ‘C,(D) conformation

Scheme 1

In other words, the fewer axial hydroxyl groups the 1,6-anhydrohexopyranose contains, the more of it is present in the equilibrium mixture102,103 (see also, Ref. 104). The axial 3-hydroxyl group (or another (100) S. J. Angyal, Aust. J . Chem., 21, 2737-2746 (1968). (101) E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, “Conformational Analysis,” Wiley, New York, 1965, pp. 415417. (102) R. E. Reeves,]. Am. Chem. SOC.,72, 1499-1506 (1950). (103) J. A. Mills, Ado. Carbohydr. Chem., 10, 1-53 (1955); see p. 50 thereof. (104) G . R. Barker and D. F. Shaw,]. Chem. Soc., 584-593 (1959).

~

~

~

MILOSLAV ~ E R N YAND JAN STANEK,JR.

36

bulky substituent) has a particularly large influence, as it diminishes the stability of the 1,6-anhydrohexose through 1,3-diaxial, steric, or polar, interactions The cyclization of hexoses has been studied from the analytical point of view (see Table I), and was also applied for the preparation of the .1053106

TABLE I Content of 1,6-Anhydro-~-~-hexopyranoses in the Equilibrium Mixture with D-Hexoses" 1,6-Anhydrohexoses Hexose

Found (%)

Calculated (%)

References

D-Glucose D-Mannose D-Galactose D-Talose DAllose D-Altrose D-&lose D-Idose

0.2 0.8 0.8 2.8 14.0 65.5 65.0 86.0

1.0 2.9 2.6 7.2 37.0 63.0 58.5 76.0

99,107-109 (cf.,Ref. l l O h ) 99,111-113 (cf.,Ref. 11ob) 99,114-116 (cf., Ref. 11ob) 99,104,116,117 99,118,119 99,120,121 99,122 99,123

" The values given in the Table were taken from the literatureg9for the following experimental conditions: 0.25-0.50% sugar solution in 0.25 M H,SO, at 100"; analysis of' the equilibrium mixture was performed by g.1.c. Anhydro sugars were not found. (105) J. W. Pratt and N. K. Richtmyer, J . Am. Chem. Soc., 79,2597-2600 (1957). (106) M. Cern?, M. Kollmann, J. Pachk, and M. BudGinsk?, Collect. Czech. Chem. Commun., 39,2507-2519 (1974). (107) A. Thompson, K. Anno, M. L. Wolfrom, and M. Inatome,]. Am. Chem. Soc., 76, 1309-1311 (1954). (108) L. D. Ough and R. G . Rohwer,]. Agric. Food Chem., 4,267-271 (1956). (109) S. Peat, W. J. Whelan, T. E. Edwards, and 0 . Owen, /. Chem. Soc., 586-592 (1958). (110) H. C. Silberman,/. Org. Chem., 26, 1967-1969 (1961). (111) E. Zissis, L. C. Stewart, and N . K. Richtmyer,]. Am. Chem. Soc., 79,2593-2597 (1957). (112) S. Peat, W. J. Whelan, and T. E. Edwards,J. Chem. Soc., 29-34 (1961). (113) K. Heyns, P. Ko11, and H. Paulsen, Chem. Ber., 104,830-836 (1971). (114) N. K. Richtmyer, Arch. Biochem. Biophys., 78, 376-385 (1958). (115) N. K. Richtmyer, A4ethod.s Carbohydr. Chem., 2,390-394 (1963). (116) P. Koll, Chem. Ber., 106,3559-3564 (1973). (117) J. W. Pratt and N. K. Richtmyer, unpublished results; see Ref. 114. (118) J. W. Pratt and N. K. Richtmyer,]. Am. Chem. Soc., 77, 1906-1908 (1955). (119) K. Heyns and P. Koll, Chem. Ber., 105,2228-2232 (1972). (120) N. K. Richtmyer and C. S. Hudson, J . Am. Chem. Soc., 57, 1716-1721 (1935). (121) K. Heyns, W.-D. Soldat, and P. Ko11, Chem. Ber., 104, 2063-2070 (1971). (122) L. C. Stewart and N. K. Richtmyer,]. Am. Chem. Soc., 77, 1021-1024 (1955). (123) E. Sorkin and T. Reichstein, Helv. Chim. Acta, 28, 1-17 (1945).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

37

1,6-anhydro derivatives of the altro 124~125guZo,122,126-128 allo118,119,129 and ido1233128,130,131 configurations. Equilibrium mixtures are formed not only from the free hexoses but also from all their derivatives that are readily hydrolyzed to the free hexoses in acid media, such as glyco~ i d e ~ , 1 2 2 , 1 2 3 , 1 2 5 ~ 1 2 R - 1 3 0 ~ 1 3 2 - l ~ 7oligosaccharides,120.'24 po~ysacch~rides,10R3 112,131,138,139 isopropylidene acetals,127,131,'40,141 and Others.142 Consequently, it may be assumed that a substantial proportion of the 1,6-anhydride will be present in all acid hydrolyzates of natural compounds containing altrose, gulose, or idose, as described in the 1iteratu1-e.'~~. 138~143-147 Similar cyclizations also proceed with hexose derivatives, such as 2 4 - , 3-0-, or 4_0-alky1,48,132,'48-150a deoXy,99,105,151-156C-alky1,106,157 amino,130,158-167 and halogen^^^^-'^^; they are controlled by steric and polar effects closely resembling those already described.

(124) N. K. Richtmyer and C. S. Hudson,/. Am. Chem. Soc., 62, 961-964 (1940). (125) A. G. Cottrell, E. Buncel, and J. K. N . Jones, Can.]. Chem.,44,1483-1491 (1966). (126) E. L. Hirst and D. A. Rees,/. Chem. Soc., 1182-1187 (1965). (127) G. J. F. Chittenden, Carbohydr. Res., 15, 101-109 (1970). (128) N. N. Shorygina and G. V. Davydova, Dokl. Akad. Nauk S S S R , 140, 617-619 ( 1961). (129) R. Ahluwahlia, S. J. Angyal, and M. H. Randall, Carbohydr. Res., 4, 478485 (1967). (130) L. F. Wiggins,J. Chem. Soc., 1590-1592 (1949). (131) P. J. Stoffyn and R. W. Jeanloz,]. Biol. Chem., 235,2507-2510 (1960). (132) G. J. Robertson and C. F. Griffith,J. Chem. Soc., 1193-1201 (1935). (133) E. Sorkin and T. Reichstein, Helo. Chim.Acta, 28, 662-664 (1945). (134) F. H. Newth and L. F. Wiggins,J. Chem. Soc., 1734-1737 (1950). (135) J. Lehmann, Angeu;. Chem., 77,863 (1965). (136) A. S. Perlin, B. Casu, G. R. Sanderson, and J. Tse, Carbohydr. Res., 21, 123-132 (1972). (137) J. M. Williams, Carbohydr. Res., 13, 281-287 (1970). (138) A. S. Perlin and G. R. Sanderson, Carbohydr. Res., 12, 183-192 (1970). (139) L. I. Larsson and 0. Samuelson, Soen. Pnpper.ytidn., 71, 432-435 (1968);Chem. Abstr., 69, 68,432 (1968). (140) J. A. Cifonelli, J. Ludowieg, and A. Dorfinan,J. Biol. Chem., 233,541-54s (1958). (141) G. J. F. Chittenden, Chem. Commun., 779-780 (1968). (142) J. C. Buchanan and E. M. Oakes, Carbohydr. Res., 1,242-253 (1965). (143) N. Cagnoli-Bellavita, P. Ceccherelli, R. Mariani, J. Polonsky, and 2. Baskevitch, Eur. J. Biochem., 15,356-359 (1970). (144) N. Cagnoli-Bellavita, P. Ceccherelli, M. Ribaldi, J. Polonsky, and Z. Baskevitch, Gazz. Chim.Itul., 99, 1354-1363 (1969);Chem. Abstr., 72, 133,141(1970). (145) P. Ceccherelli, N . Cagnoli-Bellavita, J . Polonsky, and 2. Baskevitch, Tetrahedron, 29,449-454 (1973). (146) E. L. Hirst, E. Percival, and J. K. Wold,/. Chem. Soc., 1493-1499 (1964). (147) H. E. Carter, A. Kisic, J. L. Koob, and J. A. Martin, Biochemistry, 8, 389-393 (1969). (148) N. Baggett and R. W. Jeanloz,J. Org. Chem., 28, 18451847 (1963). (149) N . Baggett, P. J . Stoffyn, and R. W. Jeanloz,]. Org. Clzetn., 28, 1041-1044 (1963).

38

MILOSLAV

CERNY A N D

JAN STANEK, JR.

5. Thermal Degradation of Polysaccharides, Oligosaccharides, and Hexoses

Levoglucosan (6)is one of the thermal-degradation products of cellulose, cellulose-like materials, wood, and polysaccharides containing Dglucose as a building unit. It is formed in various proportions, depending on the degradation conditions, including combustion. Consequently, very many studies dealing with fire retardation in these materials involve, directly or indirectly, the problem of levoglucosan formation. Because of the overall purpose of the present article, only those papers that may be of importance for levoglucosan preparation, or that concern some mechanistic aspects of its formation, will be mentioned. a. Po1ysaccharides.-The most useful method for the production of levoglucosan is the pyrolysis of starch, cellulose, or wood, which is also a prospective industrial p r ~ c e d u r e ~ - ~ ~(compare ~~~"-'* Ref. ~ 182). (150) L. F. Wiggins,]. Chem. Soc., 522-526 (1944); compare Ref. 133. (150a) J. Kiss and P. C. Wyss, Tetrahedron, 32, 1399-1402 (1976). (151) T. Golab and T. Reichstein, Helo. Chim. Acta, 44, 616-620 (1961). (152) H. W. H. Schmidt and H. Neukom, Tetrahedron Lett.,2063-2070 (1964). (153) H. W. H. Schmidt and H. Neukom, Carbohydr. Res., 10, 361-369 (1969). (154) A. F. Cook and W. G. Overend,J. Chem. Soc., C, 1549-1556 (1966). (155) P. A. Seib, J . Chem. Soc., C, 2552-2559 (1969). (156) J . M. Macleod, L. R. Schroeder, and P. A. Seib, Carhohydr. Res., 30, 337-347 ( 1973). (157) A. Rosenthal and C. M. Richards, Carbohydr. Res., 32, 53-65 (1974). (158) A. B. Foster, M. Stacey, and S. V. Vardheim, Acta Chern. Scand., 12, 1605-1610 ( 1958). (159) R. W. Jeanloz, 2. Tarasiejska-Glazer, and D. A. Jeanloz,]. Org. Chern., 26,532536 (1961). (160) R. W. Jeanloz and D. A. Jeanloz,J. Org. Chem., 26, 537-541 (1961). (161) B. Coxon and L. Hough,]. Chem. Soc., 1463-1469 (1961). (162) L. Goodman and J. E. Christensen, ]. Am. Chem. Soc., 83, 3823-3827 (1961). (163) L. F. Wiggins,J. Chem. Soc., 18-21 (1947). (164) E. E. van Tamelen, J. R. Dyer, H. E. Carter, J. V. Pierce, and E. E. Daniels,]. Am. Chern. Soc., 78,4817-4818 (1956). (165) A. B. Foster, M. Stacey, and S. V. Vardheim, Nature, 180, 247-248 (1957). (166) R. Kuhn and W. Bister,]ustzi.s Liehigs Ann. Chem., 617, 92-108 (1958). (167) J . S. Brimacombe, A. M. Mofti, and M. Stacey, Curboh!&. Res., 16, 303-308 (1971). (168) F. H. Newth, W. G. Overend, and L. F. Wiggins,]. Chem. Soc., 10-18 (1947). (169) I. Johansson and B. Lindberg, Carbohydr. Res., 1,467-473 (1966). (170) A. B. Foster, R. Hems, J. H. Westwood, and J. S. Brimacombe, Carbohydr. Res., 25,217-227 (1972). (171) C. M. Lakshmanan and H. E. Hoelscher, Ind. Eng. Chem. Prod. Res. Deu., 9, 57-59 (1970). (172) C . M. Lakshmanan and H. E. Hoelscher, Staerke, 22,261-264 (1970).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

39

In comparison with alternative methods, its advantage consists in the simplicity of thermal depolymerization of the polysaccharides under diminished pressure, and in easy separation of the levoglucosan by crystallization (after treatment with charcoal or an ion-exchange resin, r e s p e ~ t i v e l y l ~At ~ )present, ). the most important sources of levoglucosan are S~rc~7,8,12-14,~22,125,171.172,178,184-198 (for reviews, see Refs. 199 and 200) and ce~~u~osel4,l5,178-l80,l82,l84-186,188,191,196,201-218 (for reviews, see Refs. (173) A. v. Wacek and H. Wagner, Oesterr. Chem. Ztg., 40,401-419 (1937). (174) 0. P. Golova, Ya. V. Epshtein, V. N. Sergeeva, A. Kalnin’sh, P. Odintsov, N. S. Maksimenko, and V. G . Panasyuk, Girdoliz. Lesokhim. Prom., 14 (7),4-8 (1961); Chem. Abstr., 56, 7555 (1962). (175) W. Sandermann and H. Augustin, Holz Roh Werkst., 21,305-315 (1963);Chem. Abstr., 63, 11,847 (1965). (176) V. N. Sergeeva, 0. P. Golova, A. Kalnin’sh. N. S. Maksimenko, V. G. Panasyuk, P. N. Odintsov, and Ya. V. Epshtein, U.S.S.R. Pat. 115,665 (1958);Chem Abstr., 53, 12,675 (1959). (177) D. V. Tishchenko and I. S . Sorokin, U.S.S.R. Pat. 136,387 (1961);Chem. Abstr., 55,25,250 (1961). (178) L. J. Carlson, U. S. Pat. 3,235,541 (1966);Chem. Abstr., 64,16,122 (1966). (179) A. K. Esterer, U. S. Pat., 3,298,928 (1967);Chem. Abstr., 66, 56,886 (1967). (180) C. C. Heritage and A. K. Esterer, U. S . Pat., 3,309,355 (1967); Chem Abstr., 66, 106,076 (1967). (181) A. K. Esterer, U. S. Pat., 3,309,356 (1967);Chem. Abstr., 66, 106,072 (1967). (182) F. Shafizadeh, C. McIntyre, H. Lundstrom, and Yung-Lung Fu, Proc. Montana Acad. Sci., 33,65-96 (1973);Chem. Abstr., 81,41,104 (1974). (183) N. M. Merlis, 0. P. Golova, K. M. Saldadze, and I. I. Nikolaeva, Zzu. Akad. N a u k S S S R , Ser. Khim., 880-881 (1957). (184) A. Pictet and J. Sarasin, Compt. Rend., 166, 38-39 (1918). (185) A. Pictet and J. Sarasin, Helv. Chim.Acta, 1, 87-96 (1918). (186) A. Pictet and M. Cramer, Helu. Chim.Acta, 3, 640-644 (1920). (187) H. Pringsheim and K. Schmalz, Ber., 55,3001-3007 (1922). (188) J. C. Irvine and J. W. H. Oldham,J. Chem. Soc., 119,1744-1759 (1921). (189) D. J. Bryce and C. T. Greenwood, Staerke, 15,359-363 (1963). (190) J. S. Sawardeker, J. H. Sloneker, and R. J. Dimler, J . Chromatogr., 20,260-265 (1965). (191) D. J. Bryce and C. T. Greenwood, Staerke, 17,275-278 (1965). (192) I. A. Wolff, D. W. Olds, and G . E. Hilbert, Staerke, 20, 150-157 (1968). (193) D. F. Arseneau, Can.J. Chem., 49, 632-638 (1971). (194) F. Shafizadeh, G. D. McGinnis, and P. S. Chin, Carbohydr. Res., 18, 357-361 ( 1971). (195) Z. Csiiros, G. DeLk, and M. Haraszthy (Papp), Acta Chim. Acad. Sci. Hung., 21, 181-192 (1959). (196) D. Gardiner,/. Chem. Soc., C , 1473-1476 (1966). (197) M. Picon, Bull. SOC. Chim. Fr., 681-686 (1953). (198) H. Pringsheim and S. Kolodny, in Houben-Weyl, “Arbeitsmethoden der organischen Chemie,” 3rd. Edition, 1930. Vol. 3, p. 294. (199) C. T. Greenwood, Adu. Carbohydr. Chem., 22,483-515 (1967). (200) D. J. Bryce and C. T. Greenwood, Staerke, 15, 166-170 (1963). (201) H. J. P. Venn, J. Text. Znst., 1 5 , 4 1 4 4 1 8 ~ (1924).

40

MILOSLAV kERNY AND jAN STANEK, JR.

16 and 23); it has also been obtained from starch “ d e ~ t r i n s ” ’ ~ ~ ’ ~ ~ , ’ ~ ~ (compare Ref. 219), dextrans,lgOlichenan,220and from sources that may be of practical importance, namely, wood and cellulosic ~ a s t e ’ ~ ~ ’ ~ ~ 179,181,182,202,221-224 (for reviews, see Refs. 225 and 226). However, the contaminants present in the last-mentioned materials lessen their utilization; see, for example, Ref. 182. The yield of levoglucosan (6) depends on the reaction conditions and the kind and purity of the initial, raw materia1,7~12~172,178,182,187-’g2, (202) I. Mutti and A. Montalti, Ann. Chim. Appl., 17, 188-196 (1927); Chem. Abstr., 21,2381 (1927). (203) D. Tishchenko and T. Fedorishchev, Zh. PrikZ. Khim., 26,393-396 (1953). (204) R. F. Schwenker, Jr., and E. Pacsu, Chem. Eng. Data, Ser., 2,83-88 (1957);Chem. Abstr., 52, 3327 (1958). (205) 0. P. Golova and R. G. Krylova, Dokl. Akad. Nauk S S S R , 116,419421 (1957). (206) 0. P. Golova, A. M. Pakhomov, and E. A. Andrievskaya, Dokl. Akad. Nauk S S S R , 112,430-432 (1957). (207) S. L. Madorsky, V. E. Hart, and S. Straus,]. Res. Natl. Bur. Stand., 60, 343-349 (1958). (208) 0. P. Golova, N. M. Merlis, and Z. V. Volodina, Zzo. Akad. Nauk S S S R , Ser. Khim., 1127 (1958). (209) Ya. V. Epshtein, 0. P. Golova, and L. I. Durynina, Izv. Akad. Nauk S S S R , Ser. Khim., 1126-1 127 (1959). (210) T. V. Gatovskaya, 0. P. Golova, R. G. Krylova, and V. A. Kargin, Zh. Fiz. Khim., 33, 1418-1421 (1959); Chem. Abstr., 54,8212 (1960). (211) F. H. Holmes and C. J. G. Shaw,]. Appl. Chem., 11,210-216 (1961). (212) W. Sandermann and H. Augustin, HoZz Roh Werkst., 22,377-386 (1964); Chem. Abstr., 66, 11,994 (1967). (213) A. Broido, M. Evett, and C . C . Hodges, Carbohydr. Res., 44, 267-274 (1975). (214) G. A. Byrne, D. Gardiner, and F. H. Holmes,]. Appl. Chem., 16, 81-88 (1966). (215) S. Patai and Y. Halpem, Isr. ]. Chem., 8, 655-662 (1970). (216) 0. P. Golova, A. M. Pakhomov, E. A. Andrievskaya, and R. G. Krylova, Dokl. Akad. Nauk S S S R . , 115, 1122-1125 (1957). (217) 0. P. Golova, E. A. Andrievskaya, A. M. Pakhomov, and N. M. Merlis, Izv. Akad. Nauk S S S R , Ser. Khim., 389-391 (1957). (218) V. I. Ivanov, 0. P. Golova, and A. M. Pakhomov, Izv. Akad. Nauk S S S R , Ser. Khim., 1266-1267 (1956). (219) A. Thompson and M. L. Wolfrom,]. Am. Chem. Soc., 80, 6618-6620 (1958). (220) P. Karrer and M. Stauh, Helv. Chim.Acta, 7, 928-929 (1924). (221) N. V. Sergeeva and A. Kalnin’sh, Tr. Znst. Lesokhoz. Probl. Akad. Nauk Latv. SSR., 12, 183-189 (1957); Chem. Abstr. 52,21,070 (1958). (222) A. v. Wacek and H. Wagner, Oesterr. Chem. Ztg., 40, 387-391 (1937). (223) M. KoSik and V. Reiser, Holztechnologie, 14, 179-182 (1973); Chem. Abstr., 80, 72,233 (1974). (224) D. Tishchenko, K. Bardysheva, and N. Nosova, Zh. Prikl. Khim., 21, 976-984 (1948). (225) F. Shafizadeh,]. Polym. Sci., Part C , 21-51 (1971). (226) W. Sandermann and €3. Augustin, HoZz Roh Werkst., 21,256-265 (1963);Chem. Abstr., 63, 11,847 (196s).

1,6-ANHYDRO DERIVATIVES O F ALDOHEXOSES 201-203,206,207,209-216,2

18,227-232

41

such as starch 7,12,172,187,190-

192 and celluChanges suppressing the packingdensity and crystallinity of cellulose drastically decrease the yield.1sz, 210,215,216,227-229,232-234 The course of the pyrolysis of starch and cellulose is generally unfavorably influenced by the presence of organic or inorganic and a ~ m ~ x ~ r e s 1 7 1 , 1 8 2 , 2 0 1 ~ 2 1 1 ~ 2 1 3 - 2 1 6 , 2 2 3 , 2 3 0 , 2 3 1 , 2 3 5 - 2 4 8 . , the presence of ~ g l ~ ~ o (for s ea controversial ~ ~ ~ ~ view, ~ ~see~Ref. , ~ ~ ~ 191)and even traces of sodium ~ h l o r i d e ~ decreases ~ ~ , ~ ~the ~ yield , ~ ~ ~ , ~ ~ ~ of levoglucosan, whereas sodium hydrogensulfate improves it215(com~~~~~188,191,201~202~206~207,209--216~218~227~-232

(227) M. Lewin, A. Basch, and C. Roderig, Proc. Int. s y m p . Macromol., 225-250 (1974); Chem. Abstr., 83,44,916 (1975). (228) M. Koiik, V. Reiser, and I. Michlik, Zb. Vyzk. Pr. Odboru Pap. Celul., 18, v29v32 (1973);Chem. Abstr., 79, 67,973 (1973). (229) A. Basch and M . Lewin, J . Polym. Sci., Polym. Chem. Ed., 11,3095-3101 (1973); Chem. Abstr., 81, 26,126 (1974). (230) S. L. Madorsky, V. E. Hart, and S. Straus, J . Res. Natl. Bur. Stand., 56,343-354 ( 1956). (231) A. Basch and M. Lewin, J. Fire Flammability, 4 (April), 92-98 (1973); Chem. Abstr., 79, 80,504 (1973). (232) Y. Halpern and S. Patai, Isr. J . Chem., 7,673-683 (1969). (233) M. Lewin and A. Basch, Report 1972, NBS-GCR-4; Chem. Abstr., 79, 80,145 ( 1973). (234) M. KoSik, V. Luiikovi, and V. Reiser, Cellul. Chem. Technol., 6,589-597 (1972). (235) F. Shafizadeh and Y. L. Fu, Carbohydr. Res., 29, 113-122 (1973). (236) D. P. C. Fung, Y. Tsuchiya, and K. Sumi, Wood Sci., 5, 38-43 (1972); Chem. Abstr., 77, 103, 503 (1972). (237) A. Nunomura, H. Ito, A. Kasai, and K. Komazawa, Hokkaidoritsu Rinsan Shikenjo Kenkyu Hokoku, No. 57, 22-31 (1972); Chem. Abstr., 77, 128,357 (1972). (238) D. F. Arseneau and J. J. J. Stanwick, Proc. Int. Con.. Therm. Anal., 3rd, 1971, Basel, Switz., 3, 319-326 (1972),Chem. Abstr., 79, 32,810 (1973). (239) 0 . P. Golova, A. M. Pakhomov, and E. A. Andrievskaya, Izu. Akad. Nauk SSSR, Ser. Khim., 1499-1500 (1957). (240) 0 . P. Golova, Ya. V. Epshtein, and L. I. Durynina, Vysokomol. Soedin. Ser. A , 3, 536-540 (1961). (241) J . B. Berkowitz-Mattuck and T. Noguchi,J. A p p . P o l y m . Sci., 7,709-725 (1963). (242) R. G. Krylova, Thesis, Inst. Org. Khim. Akad. Nauk SSSR, 1962; See Ref. 16, p. 1469. (243) 0. P. Golova and R. G. Krylova, Dokl. Akad. Nauk S S S R , 135,1391-1394 (1960). (244) A. Basch and M. Lewin, Text. Res. J., 43,693-694 (1973);Chem. Abstr., 80,84,558 ( 1974). (245) Y. Halperii and S. Patai, Isr. /. Chem., 7, 685-690 (1969). (246) A. N. Kislitsyn, Z. M. Rodionova, V. I. Savinych, and A. V. Guseva, Zh. Prikl. Khim., 44,2518-2524 (1971). (247) 0 . P. Golova and R. G. Krylova, Vysokomol. Soedin., 1,1295-1304 (1959);Chem. Abstr., 54, 17,875 (1960). (248) 0. P. Golova, R. G. Krylova, and I. I. Nikolaeva, Vysokomol. Soedin., 1, 1305-

42

MILOSLAV

CERNY

AND JAN STANEK, JR.

pare Ref. 213). Preliminary washing with acetic treatment with sulfur dioxide,lS2and the presence of traces of calcium salts1s2 have been found to be favorable for starch pyrolysis. The optimum temperature for the vacuum pyrolysis of starch and cellulose lies around 350". At lower temperatures ( -ZOO0), dehydration, particularly in the presence of inorganic salts, and thermo-oxidation accompanied by partial depolymerization and progressive carbonization predominate; at temperatures above 500", ready carbonization and decomposition of the primary pyrolysis-products occur. Low pressures favor the formation of levoglucosan, which should be rapidly removed from the pyrolysis oven by a flow of an inert gas, preferably, superheated team.^^^^^^^^^^^^^^^^^^^^^^^^^^^ The pyrolysis may be conducted in ordinary, glass distillation equipment,7,' in various types of reactors having direct or dielectric heating, or in a continuous-pyrolysis r e a c t ~ r . ' ~Reproducible J~ yields attain 15 to 25% with a sample weight of -100 g, 44.5% with a 25-g sample of and -70% with a 5-g sample of c e l l u l ~ s e .Wheat7 ~ ~ ~ , or ~~~ corn' starch appear to be most advantageous for practical laboratory preparation.249 In addition to levoglucosan (6), some sugar by-products are formed during pyrolysis, including 1 , 6 - a n h y d r o - / 3 - ~ - g ~ u c o f u r a n o s e ~ ~ ~ ~ ~ (19) (for further references, see Sect. IX,l), 1,4:3,6-dianhydrohexoses,1s6,252,2s3 1,6-anhydro-3,4-dideoxy-~-~glycero-hex-3-enopyranos2-u10se213~2s4,255 (20, see also, Sect. IV,7,b), glycosulose 20 especially

I

OH 19

20

(249) If the crude levoglucosan crystallizes with difficulty, it is recommended that the aqueous solution of the tar obtained by pyrolysis be extracted with several portions of chloroform; cf., Ref. 10. (250) 0. P. Golova, N. M. Merlis, and Z. V. Volodina, Zh. Ohshch. Khim., 29,997-1000 (1959). (251) R. J. Dimler, H. A. Davis, and G . E. Hilbert,]. Am. Chem. Soc., 68, 1377-1380 (1946). (252) D. Tishchenko and N. Nosova, Zh. Obshch. Khim., 18, 1193-1197 (1948). (253) G. R. Bedford and D. Gardiner, Chem. Commun., 287-288 (1965). (254) Y. Halpern, R. Riffer, and A. Broido,]. Org. Chem., 38,204-209 (1973). 7,, 4 3 1 4 3 7 (1975). (255) A. Ohnishi, K. Kat6, and E. Takagi, P o l y m . I.

1.6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

43

being formed in the presence of acid admixtures (inorganic salts), and other carbonyl c o m p o ~ n d s(compare ~ ~ ~ , ~ Refs. ~ ~ 236, 257-260). More than 37 compounds of low molecular weight, such as %furaldehyde, furan, acetaldehyde, acetone, acrolein, formic acid, and acetic acid, are also formed (see Sect. IV,l,b). The mechanism of pyrolysis of starchIggand c e l l u l o ~ eis~very ~,~~~~~ complex; whether it is of heterolytic or radical nature has not yet been clarified, although the former alternative appears to be the more plausible. It has mainly been studied with cellulose182~193~196~205~213~z'4~ and can be described by the reactions given in Scheme 2. 2353241,2463261-270

1,Z-anhydro-a-Dglucopyranose (4) volatile degradation products

Cellulose

I

yur-auon

I

I charring

heterolytic Or

radical

\

1,6-anWro-P-Dglucopyranose (levoglucosan, 6 )

1,4-anhydro-a-~glucopyranose (21)

\

-

o l e o - and ~ 0 1 ~ saccharides

I

Scheme 2

(256) A. Ohnishi, E. Takagi, and K. Kat6, Chem. Lett., 1361-1362 (1974). (257) A. Ohnishi, E. Takagi, and K. Kato, Bull. Chem. Soc.]pn., 48,1959-1960 (1975). (258) Y. Tsuchiya and K. Sumi,]. Appl. Polym. Sci., 14, 2003-2013 (1970). (259) F. A. Wodley,]. Appl. Polym. Sci., 15,835-851 (1971). (260) A. E. Lipska and G. E . McCasland,]. Appl. Polym. Sci., 15,419-435 (1971). (261) F. J. Kilzer and A. Broido, Pyrodynamics, 2, 151-163 (1965). (262) P. K. Chatterjee and C. M. Conrad, Text. Res. J., 36, 487-4134 (1966); Chenz. Abstr., 65, 12,323 (1966). (263) G. A. Petropavlovskii, G. M. Mikhailov, and G. G. Vasil'eva, Cellul. Chenz. Technol., 6, 617-626 (1972). (264) P. C. Wollwage and P. A. Seib, Carbohydr. Res., 10, 589-594 (1969). (265) M. S. Bains, Carbohydr. Res., 34, 169-173 (1974). (266) A. E. Lipska and W. J. Parker,]. Appl. Polym. Sci., 10, 1439-1453 (1966). (267) S. Glassner and A. R. Pierce, 111, Anal. Chem., 37, 525-527 (1965). (268) R. Alger, Natl. Bur. Stand. ( U . S . ) Spec. Publ. No. 3.57, 171-183 (1972);Chem. Abstr., 78, 149,113 (1973). (269) K. Kate, T. Doihara, and F. Sakai, Nippon Nogei Kagaku Kaishi, 40, 443-448 (1966);Chem. Abstr., 66, 86,785 (1967). (270) N. G . Rafal'skii, L. V. Solov'eva, F. N. Kaputskii, S. S. Gusev, I. N. Ermolenko, and L. V. Vyacheslavova, Vestsi Akad. Nauuk BSSR, Ser. Khint. Nuuuk, 39-43 (1973);Chem. Abstr., 79, 32,806 (1973).

44

MILOSLAV

CERNY AND

JAN STANEK, JR.

The original proposal that the pyrolysis proceeds by way of free D-glucosel**has been abandoned.216-21*,271.272 Two important, alternative depolymerization mechanisms were suggested; one consists of heterolytic cleavage of ( 1+ 4)-glycosidic bonds by transglycosidation, possibly with participation of hydroxyl g r o ~ p s , ~ ~ , and ~ ~the ~ , ~ ~ ~ , other is based on radical cleavage16,212,246,273-277 (see critical comments in Refs. 44,225, and 235). Depolymerization of cellulose to levoglucosan is an endothermic reaction, requiring about 117 kJ (28 kcal) per molar equivalent of D-glucose residue265(see also, Ref. 278). It has been suggested that 6 is not itself a primary product of the pyrolysis, and that the principal mechanism of its formation must involve a volatile precursor that has not yet been identified.'13 Such a pyrolysis intermediate may be 1 , 2 - a n h y d r o - c r - ~ - g ~ u c o p y r a n o s e ~ ~ ~ ~ ~ (4) (the suggestion is opposed in Ref. 211, in relation to the smooth thermal degradation of 2-0-methylcellulose to yield 1,6-anhydro-2-0methyl-P-D-glucopyranoseZa; compare Ref. 279), or, more likely, 1,4anhydro-cr-~-glucopyranos (21) e ~ (compare ~ ~ ~ ~ ~ ~ ~Ref. ~ ~ ~280). However, compound 21 appears to be rather stable; attempts at its conversion into levoglucosan have not yet been made.281 CH,OH

4

21

Some other hexosans may also be obtained by pyrolysis of various polysaccharides; for example, 1,6-anhydro-/3-~-mannopyranose is formed in 5%yield from the mannans of ivory-nut kernels (Phytelephas (271) J. W. Liskowitz and €3. Carroll, Carbohydr. Res., 5, 245-255 (1967). (272) Y. Houminer and S. Patai, Isr. J . Chem., 7, 513-524 (1969). (273) A. N. Kislitsyn, Thesis, Lesokhim. Akud. im. Kirooa, Leningrad, 1974. (274) A. M. Pakhomov, Zzo. Akad. Nauk S S S R , Ser. Khim., 1497-1499 (1957). (275) K. Katd and N. Takahashi, Agric. Bid. Chem., 31, 519-524 (1967). (276) K. Katc?,Agric. B i d . Chem., 31, 657-663 (1967). (277) J. C. Arthur, Jr., and 0. Hinojosa, Text. Res. J., 36,385-387 (1966). (278) Y. Halpern and S. Patai, Isr. 1.Chem., 7, 691-696 (1969). (279) J. Heilly, Helo. Chim. Acta, 4, 616-621 (1921). (280) A. M. Pakhornov, 0. P. Golova, and I. I. Nikolaeva, Zzo. Akad. Nauk S S S R , Ser. Khim., 521-523 (1957). (281) F. Micheel, personal communication.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

45

~ u c ~ ~ c u ~ ~ u ) , 1 gand 6 ~ only zsz~ inz trace s 7 amounts from yeast or from

orchid roots286;similarly, 1,6-anhydro-/3-~-galactopyranose (12) has been prepared from agar.2x8

b. 0ligosaccharides.-The pyrolysis of l a ~ t o gives ~ ae ~ mixture of levoglucosan and 176-anhydro-/3-~-galactopyranose (12), from which, compound 12 can be separated as the 3,4-isopropylidene acetal; this method is of preparative ~ a 1 u e . ' Corresponding ~ ~ ~ ~ ~ ~ -1,6~ ~ ~ anhydrohexoses are also formed from cellobiose, cellotetraose, cellotriose, gentiobiose, maltose, maltotriose, melibiose, raffinose, sophorose, sucrose, and trehalose.185Jg1J9~1g7~zg1~2g2 c. Monosaccharides and Their Derivatives.- 1,6-Anhydro deriva~ x o s tives are also formed on pyrolysis of reducing ~ 2 1 2 ~ 2 1 6 ~ 2 1 7 ~ 2 7 1 ~ 2 7 2 ~ z g but 3 ~ 3 0 0generally in lower yields than from polysaccharides. The actual pyrolysis seems to be preceded by polycondensation to polysaccharides, followed by formation of anhydro derivatives by way of thermal d e p o l y m e r i z a t i ~ n ' ~at ~ *temperatures ~ ~ ~ ~ ~ ~ ~ ~ ~of~ ~ -260". The pyrolysis has been conducted with 217,271~272~293~296-300 (compare Ref. 212), ~ - f r u c t o s e , D-galactose,s6, ~~~ (282) G. Zemplkn, A. Gerecs, and T. Valatin, Ber., 73, 575-580 (1940). (283) A. E. Knauf, R. M. Hann, and C. S. Hudson, J. Am. Chem. Soc., 63, 14471451 (1941). (284) A. Wacek, W. Limontschew, and F. Leitinger, Monatsh. Chem., 88, 948-955 (1957). (285) G . 0. Aspinall and G. Zweifel,]. Chem. Soc., 2271-2278 (1957). (286) N. N. Shorygina and G . V. Davydova, I z v . Akad. Nauk SSSR, Ser. Khim., 20582062 (1962). (287) M. Sozmen, Middle East Tech. I3niv.J. Pure Appl. Sci., 4, 115-120 (1971);Chem. Abstr., 79, 32,197 (1973). (288) R. M. H a m and C. S. Hudson,]. Am. Chem. Soc., 63, 1484-1485 (1941). (289) R. M. Hann and C. S. Hudson,]. Am. Chenz. Soc., 64,2435-2438 (1942). (290) N. N. Shorygina and G . V. Davydova, Zzv. Akad. Nauk S S S R , Ser. Khim., 728 ( 1961).

(291) Y. Houminer and S. Patai, Isr. J . Chem., 7 , 535-546 (1969). (292) J. Reilly,/. Soc. Chem. Znd. London, Truns., 40, 249-251 (1921). (293) P. Karrer, Helv. Chim. Acta, 3, 258-260 (1920). (294) R. M. Hann and C. S. Hudson,]. Am. Chem. Soc., 63,2241-2242 (1941). (295) B. H. Alexander, R. J. Dimler, and C. L. Mehltretter,]. Am. Chem. Soc., 73,46584659 (1951). (296) N. M. Merlis, E. A. Andrievskaya, 2. V. Volodina, and 0.P. Golova, Zh. Obshch. Khim., 34,334-336 (1964). (297) H. Sugisawa and H. Edo, Chem. Ind. (London),892-893 (1964). (298) K. Heyns, R. Stute, and H. Paulsen, Carbohydr. Res., 2, 132-149 (1966). (299) Y. Houminer and S. Patai, Isr. J. Chem., 7, 525-534 (1969). (300) Y. Houminer, S. Hoz, and S. Patai, Isr. J . Chem., 7, 821-825 (1969).

~

~

s

46

1163294*295

MILOSLAV CERNY A N D JAN STANEK, JR.

and D-mann0~e.l'~1,6-Anhydro-~-hexofuranoses (see Sect.

IX,1) and 1,4: 3 , 6 - d i a n h y d r o h e x o s e are ~ ~ ~formed ~ ~ ~ ~ ~in~ ~small ~ ~ proportions as by-products. Levoglucosan is also formed by the caramelization of D - g l u c ~ s e , ~ ~ ~ by pyrolysis of glucosides, notably of aryl /3-~-glucopyranosides,~~~~~~ 182225,291,302-304 of 1,2 :5,6-di-O-isopropylidene-a-~-g~ucofuranose,~~~ and of D-glucose and sucrose in tobacco during ~ m o k i n g . ~ Low~~-~~' pressure distillation of crude 1,2:3,4-di-O-isopropylidene-a-~-galactopyranose yields a small proportion of 1,6-anhydro-3,4-0-isopropylidene-P-~-galactopyranose .308

6. Miscellaneous Methods

Levoglucosan triacetate is formed from 1,2,3,4-tetra-O-acetyl-p-Dglucopyranose on treatment with stannic chloride,66zinc ~ h l o r i d e , 3 ~ ~ , ~ ~ ~ or p-toluenesulfonic acid,310and from its 6-trityl ether (an analogous reaction affords the D-galact0 derivative3Og)on treatment with zinc chloride,3Og or ally1 p e r ~ h l o r a t e .Various ~~~ 1,6-anhydrohexoses are produced b y the reaction of per-0-acetyl or per-0-benzoyl derivatives of hexoses and their methyl a-glycosides with anhydrous hydrogen fl~oride.~~~,~~~ The presumed intermediate in all of the reactions mentioned is a ~ , ~ ~ at ~ 0-6, , ~ ~may ~ cyclic oxonium ion such as 22 ~ h i ~ h , 6if acylated

0 CH,0R3

RZO

q.J C

I

R' 22

R' = Me or Ph R2 = Ac or Bz RS = H, Ac, Bz, or Tr

H . Sugisawa and H. Edo,/. Food Sci., 31, 561-565 (1966). Y. Z. Lai and F. Shafizadeh, Carbohydr. Res., 38, 177-187 (1974). F. Shafizadeh, Y. Z. Lai, and R. A. Susott, Carbohydr. Res., 25,387-394 (1972). G. Domburgs, G. A. Rossinskaya, N. D . Pevzner, and I. Kirsbaums, Khim. Dreu., 15, 101-109 (1974);Chem. Abstr., 83, 62,157 (1975). F. L. Gager, Jr., J. W. Nedlock, and W. J. Martin, Carbohydr. Res., 17,327-333 (1971). A. Wenusch, Fachliche Mitt.Oesterr. Tabakregie, 4-5 (1938);Chem. Ahstr., 35, 4157 (1941). E. Molinari, Fachliche Mitt.Oesterr. Tubakregie, 10-11 (1938); Chem. Ahstr., 35,4157 (1941).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

47

isomerize, particularly in the presence of hydrogen fluoride, even before the cyclization takes place, to give the 1,6-anhydrides of D-altropyranose and D - m a n n o p y r a n o ~ e(see ~ ~ ~also, Refs. 313-315). The 2,3,4-tri-O-benzyl derivative (24)may be prepared in 76% yield by catalytic, azeotropic dehydration of D-glucose tribenzyl ether (23) with p-toluenesulfonic acid in benzene.316(The analogous trimethyl

23

24

ether i s formed on distillation of 2,3,4-tri-0-methyl-D-glu~ose.'~~) Under similar conditions, cyclization of methyl 2,3-di-O-p-tolylsulfonyl-a-D-glucopyranoside failed, apparently due to the steric effect of the 3-p-tolylsulfonyloxy group.317 2-0-Acetyl-1,6-anhydro-3,4-di-O-benzyl-~-~-glucopyranose results from the reaction of 3,4,6-tri-O-benzyl-1,2-0-( 1-ethoxyethy1idene)-aD-glucopyranose with mercuric chloride in nitromethane, and it may be formed as a by-product in the orthoester synthesis of oligosaccharides.318 1,6-Anhydrohexoses can be formed from the 2,3-unsaturated hexopyranosides319(see Sect. V1I73,a,i),from glycosides by chlorinolysis of the glycosidic and from 1,5-anhydro-2-deoxyhex-l-enitols (308) D. McCreath, F. Smith, E. G . Cox, and A. I. Wagstaff,J. Claern. Soc., 387-391 ( 1939). (309) H. Bredereck and G. Hoschele, Chem. Ber., 86, 1286-1294 (1953). (310) D. McGrath, E. E. Lee, and P. S. O'Colla, Carbohydr. Res., 11,453460 (1969). (311) V. A. Nesmeyanov, S. E. Zurabyan, and A. Ya. Khorlin, Tetrahedron Lett., 32133216 (1973). (312) K. Bock and C . Pedersen, Acta Chem. Scand., 27,2701-2709 (1973). (313) K. Rock and C. Pedersen, Actu Claem. Scand., Ser. B , 29, 181-184 (1975). (314) C . Pedersen, Acta Chem. Scand., 16, 1831-1836 (1962). (315) C . Pedersen, Acta Chern. Scand., 17, 673-677 (1963). (316) F. Micheel, 0.-E. Brodde, arid K. Reinking,Justus Leihigs Ann. Chern., 124-136 ( 1974). (317) H. Kuzuhara, H. Ohrui, and S. Emoto, Carbohydr. Res., 11, 9-16 (1969). (318) N. N. Malysheva, V. I. Torgov, E. M. Klimov, and N. K. Kochetkov, Zzu. Akad. Nauk SSSR, Ser. Khim., 2153-2155 (1974). (319) S. Dimitrijevich and N. F. Taylor, Carbohydr. Res., 20, 427-430 (1971). (320) R. L. Whistler, T. W. Mittag, and T. R. Ingle,]. Am. Chem. Soc., 87,42184219 (1965).

MILOSLAV CERNY AND JAN STANEK, JR.

48

(glycals) by addition of hypochlorous acid321followed by treatment of the intermediary chlorohydrins with a base. Levoglucosan has also been prepared from D-glucose, methyl a-D-glucopyranoside, or starch by the action of dimethyl s ~ l f o x i d at e ~160". ~~ As has already been mentioned, even 3,4,6-tri-O-acetyl-l,2-anhydro-a-D-glucopyranose (Brigl's anhydride, 5) may be exploited for the synthesis of levoglucosan (see Sect. II,l). Other methods, based on change of configuration of carbon atoms bearing hydroxyl groups, by nucleophilic displacement of sulfonic esters, oxidation-reduction processes, cleavage of the oxirane ring, or isomerization, are dealt with in Sections IV and V.

7. Total Synthesis from Acrolein Diels-Alder condensation of acrolein followed by reduction affords a fairly good yield of 3,4-dihydro-2H-pyran-2-methanol (25) which, in the presence of acid catalysts, cyclizes to racemic 6,8-dioxabicyclo[3.2.l]octane, that is, 1,6-anhydro-2,3,4-trideoxy-/3-~~-gZyceroh e x o p y r a n o ~ e ~(26). ~ ~ -On ~ ~reaction ~ of 26 with bromine in carbon tetrachloride, a mixture of 2-bromo derivatives (27) is formed325-327

Eir 25

26

27

which affords 1,6-anhydro-2,3,4-trideoxy-/3-~~-glycero-hex-2-enopyranose (28) and its isomer (29) on elimination of hydrogen bromide in the presence of b a ~ e(see ~ also ~ ~Sect. , ~VII,3,c). ~ ~ By a direct epoxidation of the double bond of 28 and 29, 2- or 4-deoxy dianhydrides of the DL-rib0 configuration were prepared, 6.Bakassian, F. Chizat, D. Sinou, and 6.Descotes, Bull. S O C . Chim. Fr., 621-623 (1969). M. H. Fischer, Carbohydr. Res., 8, 354-360 (1968). R. R. Whetstone, U. S. Pat. 2,511,890 (1950);Chem. Abstr., 44, 8961 (1950). E. L. Eliel, B. E. Nowak, R. A. Daignault, and V. G . Badding,]. Org. Chem., 30, 2441-2447 (1965). F. Sweet a n d R. K. Brown, Can. J . Chem., 46,2289-2298 (1968). T. P. Murray, C. S. Williams, and R. K. Brown,]. Org. Chem., 36, 1311-1314 (1971). R. M. Srivastava and R. K. Brown, Can. J . Chem., 48, 830-837 (1970).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

49

29

28

and further transformed into the remaining isomers having the DL-ZZJXO c o n f i g u r a t i ~ n .Treatment ~ ~ ~ ~ ~ ~of~ 1,6: , ~ ~2,3-dianhydro-4-deoxy-p-~~~ ribo-hexopyranose (30) with butyllithium resulted in ally1 derivative 31 which, on epoxidation with m-chloroperoxybenzoic acid, followed by alkaline hydrolysis of the epoxide 32, gave 1,6-anhydro-/3-~~-gluco(6); direct hydroxylation of 31 by use of osmium tetraoxide yielded332the 176-anhydrocompounds having the DL-UZZO (33) and DL-gUhCto (12) configuration. Other racemic 1,6-anhydrohexoses, as well as their deoxy and the corresponding dianhydro derivatives, can be synthesized in a similar way.325.327-329,331,333

30

32

31

Q0

HO Qo

HO

OH

OH

HO

33

12

OH 6

(328) T. P. Murray, U. P. Singh, and R. K. Brown, Can . J . Chem., 49,2132-2138 (1971). (329) K. Ranganayakulu, U. P. Singh, T. P. Murray, and R. K. Brown, Can. J . Chem., 52,988-992 (1974). (330) U. P. Singh and R. K. Brown, Can. J . Chem., 48, 1791-1792 (1970). (331) U. P. Singh and R. K. Brown, Can. J . Chem., 49,3342-3347 (1971). (332) U. P. Singh and R. K. Brown, Can. J . Chem., 49, 1179-1186 (1971). (333) K. Ranganayaknln and R. K. Brown, unpublished results.

50

MILOSLAV CERN? A N D JAN S T A N ~ ~JH K,

111. GENERALPROPERTIES

OF 1,6-ANHYDROHEXOPYRANOSES

1,6-Anhydrohexopyranoses (see Table V) readily crystallize, are very soluble in water, pyridine, and dimethyl sulfoxide, and, with heat, in the lower alcohols, 1,4-dioxane, and acetone. They dissolve to a very limited extent in ether, chloroform, and other less-polar solvents. All the 1,6-anhydro-P-~-hexopyranoses have a similar, unstriking taste, which can be described as b i t t e r - s ~ e e t , ~in. ~con~~,~~~ trast to the bitter taste of the related methyl @-D-glycopyranosides. The reason for the sweet taste is considered to lie in the possibility of hydrogen-bond interaction between the oxygen atom of the tetrahydropyran ring and the hydroxyl group on C-2 or C-4; elimination of the 2-hydroxyl group, or its substitution, suppresses the sweet, and strongly enhances the bitter, taste.334 ~ - " ~ Ref. 336), Levoglucosan (6) is not fermentable by y e a ~ t ~(compare and remains intact on treatment with e m u l ~ i n , ~amylases, , ~ ~ - ' ~ ~or maltase.ls5It does not influence the respiration qu0tient3~~; for its obscure role in diabetes, see Refs. 338 and 339. 1,6-Anhydro-P-o-galactopyranose (12) is neither a substrate for, nor an inhibitor of, the P-D-galactosidase from Eschcrichia ~ o l i . ~ ~ O 1,6-Anhydrohexopyranosesare relatively stable in aqueous alkalis, even on heating,56,57 and this property can be utilized in their separation from free sugars; they do not reduce Fehling solution. They are, however, readily hydrolyzed by mineral acids to reducing hexoses, especially when heated, and an equilibrium is established between the hexose and its 1,6-anhydro derivative (see Table I). The structure of some 1,6-anhydrohexopyranoseshas been demonstrated by classical, methylation a n a l y s i ~ , ' ~and ~ ,also ~ ~ follows ~ , ~ ~ ~from the results of their oxidation by per~o~a~e99,104.118,122-1124,283,288~289,341--344 or lead t e t r a a ~ e t a t e The . ~ ~ ~incorrect structures originally proposed for levoglucosan28~185~186~1ss~34fi~347 were later (334) C. K. Lee and 6. 6. Birch,]. Food Sci., 40, 784-787 (1975). (335) R. S. Shallenberger, Ado. Chem. Ser., 117,256-263 (1973); see p. 260 thereof. (336) W. Schuchardt, Ger. Pat. 738,962 (July 29, 1943);Chem. Abstr., 39, 5395 (1945). (337) K. Miyazaki and J. Abelin, Biochem. Z., 149, 109-135 (1924). (338) J. Kerb and E. Kerb-Etzdorf, Biochem. Z., 151,435-437 (1924). (339) J. Kerb and E. Kerb-Etzdorf, Biochem. Z., 144, 60-63 (1924). (340) G. S. Case, M. L. Sinnott, and J.-P. Tenu, Biochem. ]., 133, 99-104 (1973). (341) E. L. Jackson and C. S. Hudson,]. Am. Chem. Soc., 62, 958-961 (1940). (342) M. Viscontini and E. Hiirzeler-Jucker, Helo. Chim. Actu, 39, 1620-1631 (1956). (343) A. (R.) Jeanes and C. A. Wilham,]. Am. Chem. Soc., 72,2655-2657 (1950). (344) S. Hirano, T. Fukuda, and S. Kondo, Agric. Biol. Chem., 38, 1515-1520 (1974). (345) H. C. Hockett, M. T. Dienes, and H. E. Ramsden,]. Am. Chem. Soc., 65, 14741477 (1943). (346) P. Karrer and A. P. Smirnoff, H e l c . Chim.Acta, 5, 124-128 (1922).

1.6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

51

In solution and in the solid state, all unsubstituted 1,6-anhydro-pD-hexopyranoses adopt a conformation having the lC4(D) conformation of the pyranose and the E,, (E,) conformation of the 1,3-dioxolane ring, as was shown by studies of cupric complexes in ammonia solution48,349-352 (for a review, see Ref. 353), by n.m.r. spectroscopy5 (see later), and, for l e v o g l ~ c o s a n (compare ~ , ~ ~ ~ ~Ref. ~~~ 356) and its tri-0acetyl derivative,357by using X-ray crystal structure analysis. (For some elementary crystallographic data on levoglucosan (6), its triacetate, and 1,6-anhydro-P-~-galactopyranose (12),see Refs. 27, 107, and 308.) In the crystalline state, the pyranose ring of 6 is flattened4 to such an extent that the distance between the oxygen atoms of the hydroxyl groups on C-2 and C-4 increases from the usual value of 240 pm to 329.9 pm (compare Ref. 358), and the oxygen atom on C-3 recedes to a distance of 300 pm from C-6. No intramolecular hydrogen-bond was ob~erved.~ The second, possible conformation of the 1,6-anhydro-P-~-hexopyranoses is represented by the B,,(D) conformation, which is disfavored for steric reasons, even for the energetically rich levoglucosan, where the transition from the 'C4(D)to the B,,,(D) conformation might seem the most favorable, because of the reorientation involved of the three axial hydroxyl groups to equatorial ones. The energy difference between the two conformations (6 and 6a) of levoglucosan has been estimated by summation of the nonbonding interactions, and, according to the chosen procedure, has the values 4.62 and 2.94 kJ.mol-', re~pectively.~

(347) J. C. Irvine and J. W. H . Oldham,]. Chem. SOC.,127,2729-2735 (1925). (348) K. Josephson, Ber., 62,313-316 (1929). (349) R. E. Reeves,]. Am. Chem. SOC.,71, 1737-1739 (1949). (350) A. E. Reeves, J . Am. Chem. Soc., 73,957-959 (1951). (351) R. E. Reeves and J . R. Jung, Jr.,/. Am. Chem. SOC.,71,209-211 (1949). (352) R. E. Reeves and P. Bragg,]. Org. Chem., 26,3487-3489 (1961). (353) R. E. Reeves, Ado. Curbohydr. Chem., 6, 107-134 (1951). (354) K. B. Lindberg, Actu Chem. S c a d . Ser. A, 28, 1181-1182 (1974). (355) Y. J. Park, H. S. Kim, and G. A. Jeffrey,Actu Crystallogr., Sect. A, 25, S 197 (1969). (356) J. H. Noordik and G. A. Jeffrey, Actu Crystallogr., Sect. B , 33,403-408 (1977).

MILOSLAV ~ E H AND N ~ JAN S T A N ~ K ,JK.

52

For levoglucosan (6),the heat of combustion, AN:, was found to be -2,844.9 kJ.mo1-' (Refs. 212,265, and 359-362), the heat of formation AH,", -966.8 kJ.mo1-I (Refs. 265 and 363), of dehydration, AH",,,, -468.3 kJ.mo1-l (Ref. 265), and evaporation, AH:,,, +92.3, t3.6 kJ.mol-' (Ref. 364); for vapor-tension data, see Ref. 364. In contrast to their per-0-acetylated derivatives, free 1,6-anhydrohexopyranoses do not have sharp melting-points and, before melting, often sinter or display a tendency to sublime. Under diminished pressure, they distil or sublime without decomposition. ~ ~analog371 ~ ~ J ~ ~ ~ On heating 6 or its ~ t e r e o i ~ ~ m eorra thio to -looo, a solid-state transition takes place (observed by differential thermal analysis or differential scanning calorimetry) to give plastic, crystalline forms in which, due to their spherical shape, the molecules reorient around their centers without serious disruption of the crystal lattice. The transition is manifested by loss of anisotropy, and changes in the thermal capacity, X-ray diffraction, i.r. spectra, hardness, and vapor tension. consideration^^^^ supporting a conformational change of levoglucosan 6 from the 'C,(D) to the B 0 , 3 ( ~conformation ) at the transition temperature are not, however, convincing.367 As to the chiroptical properties of 1,6-anhydrohexopyranoses,their [MI, values can be calculated by summation of the molar, optical rotation values for the fundamental skeleton, that is, 1,6-anhydro-2,3,4trideoxy-P-Dglycero-hexopyranose (26), and, either the values of the partial, molar contributions of the hyclroxyl g r o ~ p s :(see ~ ~Scheme ~ . ~ ~3~) Rotational contributions: fundamental skeleton s = -127.3" hydroxyl groups (or amino or fluoro) a = 48.8" Q ' = 113.6' b = 6.8" c = 36.9" c' = 100.0" +C(+C')

@ O -c ( - c ' )

-a(-a') +a (+a')

The contributions n' and c' a r e used when the 3-hydroxyl (or 3-amino o r 3-fluoro) group adopts the equatorial position. For the anhydrodeoxyhexoses having the equatorial hydrogen atom on C-3, only the contributions a , b , and c a r e valid.

[MI, value

+

s a f b -c = -127.3' f 4 8 . 8 ' 6.8"+ = -108.6" for 1,6-anhydro-~-D-gulopyranose (46) = s a' -b + c' = -127.3"+ 113.6"+ = f79.5"

[MID value for 1,6-anhydro-P-o-glucopyranose (6) =

Scheme 3.

+

-

+

-36.9"

-6.8"f 100.OO

Calculations of [MID Values for 1,G-Anhydro-8-D- hexopyranoses and Their Aminodeoxy, Deoxyfluoro, and Deoxy Derivatives.

(357) F. Leung and R. H. Marchessault, Can. .I. Chem., 52,2516-2521 (1974). (358) For this reason, the phenylboronic ester of levoglucosan is unstable,'Y4and isopropylidene or benzylidene derivatives of levoglucosan have not yet been prepared.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

53

0

i

4)

0

0

Gauche (clockwise) positive rotational contribution

Gauche (counterclockwise) negative rotational contribution

Anti zero rotational contribution

Scheme 4

or, according to Horton and Wander,374,375 the values of pairwise 0/0 interactions in 0-C-C-0 groupings of the vicinal glycol type (see Scheme 4) with possible, supplemental consideration of 1,3-glycol contributions or other chiral elements .376,377 The applications of optical rotatory calculations described may be used not only for structural attributions for 1,6-anhydrohexopyranosesbut also for their aminodeoxy, deoxyfluoro, and deoxy derivatives.’06~’ss~’69~377-384 For 0-acyl and 0-alkyl derivatives, with the exception of the per acetate^,^^^ the aforementioned rules are of limited validity, and thus it is not yet possible to draw completely reliable conclusions from calculated values.

(359) International Critical Tubles, McGraw-Hill, New York, 1929, Vol. 5, p. 166. (360) P. Karrer, C. Nageli, 0. Hurwitz, and A. Wdti, Helo. Chim. Acta, 4 , 678-699 ( 1921). (361) P. Karrer and W. Fioroni, Rcr., 55, 2854-2863 (1922). (362) P. Karrer and W. Fioroni, Helo. Chini. Acta, 6 , 396-401 (1923). (363) D. R. Stull, E. F. Westnim, and G. C. Sinke, “The Chemical Thermodynamics of Organic Compounds,” Wiley, New York, 1969. (364) Ya. V. Epshtein, L. I. Durynina, and A. S. Pashinkin, Zh. Prikl. Khim. 37,25432545 (1964). (365) F. Shafizadeh, G . D. McCinnis, C. W. Philpot, and R. A. Susott, Carbohydr. Res., 13, 184-186 (1970). (366) V. N. Nikitin, I. Yu. Levdik, and M. A. Ivanov, Zh. Strukt. Khim., 9, 1011-1017 ( 1968). (367) F. Shafizadeh, G. D. McGinnis, R. A. Susott, and C. W. Philpot, Carbohydr. Res., 15, 165-178 (1970). (368) G . W. Smith and F. Shafizadeh,]. Cheni. SOC., B , 908-911 (1971). (369) F. Shafizadeh, C. W. Philpot, and N. Ostojic, Carbohydr. Res., 16,279-287 (1971). (370) F. Shafizadeh and R. A. Susott,/. Org. Chem., 38, 3710-3715 (1973). (371) F. Shafizadeh, R. A. Susott, and C. R. McIntyre, Carbohydr. Res., 41, 351-3.54 (1975). (372) M. C e r n j ~J. , Pacik, and J. Stanek, Chem. Ind. (London),1559-1560 (1966). (373) L. Dejniek, Thesis, Charles University, Prague, 1975. (374) D. Horton and J. D. Wander,/. Org. Chern., 32, 3780-3783 (1967).

54

MILOSLAV CERNY AND JAN STANEK, JR.

The influence of lyotropic compounds on the specific rotation of The 0.r.d spectrum levoglucosan (6) is completely negligible.385-387 of 6 is a simple, negative curve257(compare Ref. 388). 1,6-Anhydrohexopyranoseshaving a gauche 1,2-diol arrangement in their molecule form complexes with Cu(I1) ions in ammonia solution48,349-352 (for a review, see Ref. 353),displaying characteristic shifts of optical rotation values dependent on the absolute configuration: the clockwise orientation of glycol grouping causes negative shifts and the counterclockwise, positive shifts. Nevertheless, levoglucosan, and even its 3-methyl ether, although lacking a gauche-diol system, also form such c o m p l e ~ e s(compare ~ ~ , ~ ~ ~Refs. 385, 388, 389, and 390), apparently through the hydroxyl groups on C-2 and C-4. Some 1,6-anhydrohexopyranoses form complexes with Mn(II), and anionic comMn(III), and Mn(IV), as shown by p0larography,3~~ plexes with (a) sodium ~ t a n n a t e(1,6-anhydrides ~~~ of altrose, galactose, gulose, and mannose), ( b ) sodium m ~ l y b d a t e(1,6-anhydro-p~~~ (375) D. Horton and J . ,D. Wander, Carbohydr. Res., 14,83-94 (1970). (376) J. Pecka and M. Cemj., Collect. Czech. Chem. Commun., 38, 132-142 (1973). (377) J. Pecka, J. StanGk, Jr., and M. Cemj., Collect. Czech. Chem. Commun., 39, 1192-1209 (1974). (378) A. C. Richardson and H. 0. L. Fischer,]. Am. Chem. Soc., 83,1132-1139 (1961). (379) M. Cernj., T . Elbert, and J. Pacik, Collect. Czech. Chem. Commun., 39, 17521767 (1974). (380) J. Pacik, J. Podeiva, 2. ToGk, and M. Cernl, Collect. Czech Chem. Comnzun., 37,2589-2599 (1972). (381) J. Pacik, P. DraSar, D. Stropova, M. kernj., and M. Bud63insk9, Collect. Czech. Chem. Commun., 38,3936-3939 (1973). (382) J. Doleialovi, M. Cemj., T. Tmka, and J. Pacik, Collect. Czech. Chem. Commun., 41, 1944-1953 (1976). (383) M. Cernj., J. Stangk, Jr., and J. PacLk, Collect. Czech. Chem. Commun., 34,17501765 (1969). (384) J. Halbych, T. Tmka, and M. Cernl, Collect. Czech. Chem. Commun., 38,21512166 (1973). (385) K. Hess, W. Weltzien, and E. Messmer,Justus Liebigs Ann. Chem., 435, 1-144 (1924);see p. 41 thereof. (386) J. R. Katz and J. Seiberlich,]. Phys. Chem., 46,640-641 (1942). (387) J. A. Rendleman, Jr., Carbohydr. Res., 21,235-247 (1972). (388) W. Voelter, H . Bauer, and G . Kuhfittig, Chem. Ber., 107,3602-3615 (1974). (389) R. E. Reeves,]. B i d . Chem., 154,49-55 (1944). (390) T. Lieser and R. Ebert, Justus Liebigs Ann. Chem., 532, 89-94 (1937). (391) J. Doleial, E. Julkkovk, M. Cernj., and M. Kopanica, ]. Electroanal. Chena. Interfacial Electrochem., 52, 261-267 (1974); Chem. Abstr., 81, 20,162 (1974). (392) E. M. Lees and H. Weigel, unpublished results; see H. Weige1,Adu. Carbohydr. Chem., 18, 61-97 (1963),p. 86 thereof. (393) E. J. Bourne, D. H. Hutson, and H. Weige1,j. Chem. Soc., 4252-4256 (1960).

1,6-ANHYDRO DERIVATIVES O F A L D O H E X O S E S

55

D-mannopyranose), as demonstrated by paper electrophoresis, and ( c ) boric a ~ i d . ' ~ ~ Levoglucosan ,"~ (6) does not itself show any tendency to form either similar anionic ~ o r n p l e x e s or ~~ complexes ~ - ~ ~ ~ with boric acid and its derivatives 106,B01~394,396,397; nevertheless, complexes with methanolic sodium acetate and potassium398or sodium iodide,387and with alkali hydroxides have been described.397~399~400 A zinc-ferric , ~ complexes ~~~~~~ complex of levoglucosan of undefined s t r ~ c t u r eand of levoglucosan esters with Lewis acids, have been prepared. 1,6-Anhydro-P-~-allopyranose (33) in its 'C,(D) conformation manifests clear-cut complexing properties, because of the vicinal trio1 system with an ax-ey-ax (a-e-a) arrangement of the hydroxyl tridentate complex with g r o ~ p s . ~It ~forms ~ , ~a ~relatively ~ , ~ ~ stable, ~ periodic acid (34, X = 10,) whose formation precedes carbon-carbon bond c l e a ~ a g e . ' ~With ~ . ~ some ~ ~ lanthanides, the 1,6-anhydrides of P-D-allopyrar~ose$~~ 6-D-mannopyranose, and P - D - t a l o p y r a n o ~ e ~ ~ ~ ~ ~ ~ form complexes 34, 35, and 36 (for example, X = Eu3+ or P?'), having specific, contact interactions observed by lH-n.m.r. spectroscopy: other 1,6-anhydrohexopyranosesdo not form similar complexes406 (compare Ref. 404a).

(394) B. Lindberg and B. Swan, Acta Chem. Scand., 14, 1043-1050 (1960). (395) J. F. Angus and H. Weigel, unpublished results; see H. Weige1,Adu. Carbohydr. Chem., 18, 61-97 (1963), p. 86 thereof. (396) P. A. J. Gorin and M. Mazurek, Cnn. .I. Chem., 51, 3277-3286 (1973). (397) J. L. Frahn and J. A. Mills, Aust. J. Chem., 12, 65-89 (1959). (398) J. A. Rendleman, Jr.,]. Org. Chern., 31, 1839-1845 (1966). (399) J. A. Rendleman, Jr.,J. Org. Chern., 31, 1845-1851 (1966). (400) J. A. Rendleman, Jr., Adu. Carhohydr. Chem., 21, 209-271 (1966); see p. 266 thereof. (401) A. V. Babaeva, G. V. Derbisher, N. P. Filatova, 0.P. Golova, and K. I. Zhdanova, U. S. S. R. Pat. 277,763 (August 5, 1970); Chem. Abstr., 74, 64,378 (1971). (402) 0. P. Golova, K. I. Zhdanova, N. M. Merlis, A. V. Babaeva, and G. V. Derbisher, Fr. Detncinrle, 2,055,7:38 (June 4, 1971); Chetn. Alxtr., 76, 58,290 (1977). (403) S. J. Angyal, D. Greeves, and V. A. Pickles,]. Chem. Soc. Cheni. Comtnzrii., 589590 (1974). (404) G. R. Barker and D. F. Shaw, Proc. Client. Soc. (London),259-260 (1957).

56

MILOSLAV CERNY AND JAN STANEK, JR.

1.r. spectroscopic measurements on variously substituted derivatives in carbon tetrachloride revealed that, in the ‘C4(D)conformation, the axial hydroxyl group on C-3 and the equatorial hydroxyl group on C-2 can form a hydrogen bond with 0 - 6 , whereas the axial hydroxyl group on C-2 or C-4 can be bonded to 0-5 of the pyranose ring, apart from mutual interactions of hydroxyl groups. The frequency shift AvoH of bonded hydroxyl groups with reference to the free ones lies in the region 50-35 cm-’ (Refs. 52, 377, and 382; compare Ref. 407). Depending on the stereochemistry involved, hydrogen bonding probably influences the regioselective course of the partial acylation and (see Sect. IV,3,b). alkylation of 1,6-anhydrohexopyrano~es’~~~~~~ 1.r. spectroscopic data on levoglucosan,22~230~366.409.410 its triacetate,207,409,411 its tribenzoate,4I1 and their complexes with Lewis a ~ i d have ~ ~ been ~ reported. ~ - ~ ~ ~ The utility of ‘H-n.m.r. spectroscopy in structure elucidations here exceeds the customary scope of gross structure determinations; owing to the rigid ‘C4(D)conformation, it can be used to advantage for assigning to particular isomers their configuration. However, it should be noted that the similarity of the chemical shifts of ring protons, influenced, moreover, in half of the cases (allo, ido,gluco, and talo configurations) by a not negligible “symmetry” of the molecule, frequently causes, in 60-MHz, and even 100-MHz, spectra, incomplete resolution of the signals of some protons. Often, the selectively C-

(4044 S. J. Angyal, D. Greeves, L. Littlemore, and V. A. Pickles, Aust. 1. Chem., 29, 1231-1237 (1976). S. J. Angyal, Tetfuhedron, 30, 1695-1702 (1974). S. J. Angyal and R. J. Hickman, unpublished results; see Ref. 405. J . A. Rendleman, Jr., A h . Chem. Ser., 117, 51-69 (1973); see p. 58. The statement that the 3-hydroxyl group of levoglucosan cannot form an intramolecular hydrogen-bond is problematic (compare Ref. 377). 5. StanBk, Jr., J. JarL, and M. Cern);, Collect. Czech. Chem. Commun., to be published. L. P. Kuhn, Anal. Chem., 22, 276-283 (1950). R. G. Zhbankov, “Infrared Spectra of Cellulose and Its Derivatives,” Consultants Bureau, New York, 1966, p. 201. 2. Csiiros, G. DeLk, I. Gyurkovics, M. Haraszthy-Papp, and E. Zara-KacziHn, Acts Chim. Acad. Sci. Hung., 67, 93-107 (1971). L. Fenichel, G . Deik, S. Holly, P. Bak6, and Z. Csiiros, Actu Chim. Acud. Sci. Hung., 85, 299-311 (1975). G. Deak, E. Zara-Kaczian, and S. Holly, Actu Chim. Acad. Sci. H u n g . , 71, 105114 (1972). L. Fenichel, G . Deak, P. Bak6, S. Holly, and Z. Csiiriis, Actn Chim. Acc~d.Sci. H u n g . , 85, 313-326 (1975).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

57

deuterated derivatives have had to be ~ ~ e d , ~ and, , ~ in ~ ex, ~ ~ ~ , treme cases, not even they are of any use, and, even with the application of shift-reagents, have not given any interpretable results.418 Nevertheless, in the spectra of unsubstituted 1,6-anhydrohexopyranoses, it is always possible to identify the signal of H-1 resonating, due to the -I effect of neighboring oxygen atoms, at the lowest field. Its shift is almost independent of the configuration (for example, 6 5.24-5.42 for free 1,6-anhydrohe~opyranoses~~~~~~~~ in deuterium oxide). Regularities also appear in the shifts of other ring-protons, and may be correlated by empirical rules enabling the assignment of c~nfiguration,~ or, alternatively, of the position of O-methyl substitA special situation occurs with H-6ex0,4~Othe chemical shift uents.52,156 of which is almost independent not only of configuration but also of the type of substituents (for example, 6 3.55-3.78 for free hexosans in deuterium o ~ i d e ,and ~ , ~6 ~ 3.70-3.85 for triacetates in deuteriochloroform99~313,332,421-423; for further data on triacetates, see Refs. 50, 321, and 424-429a). The H-6exo multiplet usually appears at the highest field among the ring protons, -1 p.p.m. higher than H-5, and slightly higher than H-6endo. The H-5,H-Gendo,H-Gexo system has been studied very so that its identification (principally four-twofour lines) causes no difficulty. Inspection of a molecular model reveals that the formation of a C-6-0-6 bond is accompanied by a torsion of the methylene group along the C-5-C-6 bond of -30" from (415) D. Horton and J. S. Jewell, Carbohydr. Res., 3,255-257 (1966). (416) D. Horton, J. S. Jewell, E. K. Just, and J. D. Wander, Carbohydr. Res., 18,49-56 ( 1971). (417) K. Heyns, P. Koll, and H. Paulsen, Chem. Ber., 104, 2553-2566 (1971). (418) D. Horton, J. S. Jewell, E. K. Just, J. D. Wander, and R. L. Foltz, Biomed. Mass Spectrom., 1, 145-153 (1974). (419) K. Heyns, J. Weyer, and H. Paulsen, Chem. Ber., 100,2317-2334 (1967). (420) With regard to the non-uniformity in designating the protons of the methylene group of the 1,6-anhydride bond, we recommend strict use of the notation H-Gexo, H-6endo instead of the uninformative notation H-6 and H-6'. (421) P. L. Durette and H. Paulsen, Chem. Ber., 107, 937-950 (1974). (422) P. L. Durette and H. Paulsen, Chem. Ber., 107,951-965 (1974). (423) L. D. Hall, personal communication; see Ref. 99. (424) D. Horton and J. S. Jewell, Carbohydr. Res., 5, 149-160 (1967). (425) L. D. Hall and J. F. Manville, Carbohydr. Res., 4, 271-273 (1967). (426) L. D. Hall, J. F. Manville, and A. Tracey, Carbohydr. Res., 4, 514-515 (1967). (427) L. D. Hall and L. Hough, Proc. Chem. SOC. (London),382 (1962). (428) L. D. Hall and J. F. Manville, Carbohydr. Res., 8, 295-307 (1968). (429) L. D. Hall and J. F. Manville, Adv. Chem. Ser., 74, 228-253 (1968). (429a) H. Paulsen, H. Hohne, and P. L. Durette, Chem. Ber., 109, 597-604 (1976).

58

MILOSLAV CERNY AND JAN STANEK, JR.

the ideal, staggered orientation existing, for example, with 2,6anhydro analogs. Consequently, the torsion angle of H-5 and H-6exo drops to -30", and that of H-5 and H-6endo increases to -90" (compare 3,6-anhydrohexopyranosideshaving an analogous, steric arrangement430).The values of the coupling constants found are then as expected: J5,Bendo 0-1.5 Hz, J5,6exo 4.5-6.0 Hz; geminal JGexo,Gendo values vary in the range 7.0 to 8.5 Hz. The coupling constants J1,2, J 2 , 3 , J3,4, andJ,,, reflect the conformation of the ring protons and, consequently, the configuration of a 1,6anhydrohexopyranose (see Scheme 5). The antiperiplanar, a-u orientation of hydrogen atoms exists only for the derivatives having the H-6 exa.

Scheme 5

altro, gulo, and ido configurations, where J 2 , 3 or J3,4 may be observed126,313,317,422,429a in the range 9.0 to 9.9 Hz (for incomplete data on the ido configuration, see Refs. 5, 170, and 425429). For the remaining five configurations, having only the synclinal arrangement of H-1 to H-5 (H-1 and H-5 occupy equatorial positions), the analysis is facilitated by the flattening of the pyranoid chair, which is accompanied by an increase in the torsion angle of e-e oriented atoms and by the decrease in the a-e arrangement. This fact does not become evident forJl,2, where the -I effect lowers bothJl,2, to the range 1.5-2.5 Hz (see Refs. 5,50, 52,99,126, 155, 156,264,313,

317, 331, 332, 379, 421-424,428, and 431-439); however, it finds a (430) G. Birch, C. K. Lee, and A. C. Richardson, Carbohydr. Res., 16,235-238 (1971). (431) P. M. Collins and N. N. Oparaeche,J. Chem. S O C . Perkin Trans. 1 , 1695-1700 (1975). (432) L. Vegh and E. Hardegger, Helu. Chim. Acta, 56, 2020-2025 (1973). (433) W. Meyer zu Reckendorf, Chem. Ber., 103,2424-2427 (1970). (434) E. M. Bessell and J. H . Westwood, Carbohydr. Res., 25, 11-21 (1972). (435) E. Hardegger and W. Schiiep, Helo. Chim.Acta, 53, 951-959 (1970). (436) K. Heyns and P. Koll, Chem. Ber., 106,611-622 (1973). (437) M. PrystaS, H. Gustafsson, and F. Sorm, Collect. Czech. Chem. Commun., 36, 1487-1495 (1971). (438) T. Trnka, M. Cerny, M. BudGSinsky, and J. P a d k , Collect. Czech. Chem. Commun., 40,3038-3045 (1975). (439) A. K. Chatterjee, D. Horton, J. S. Jewell, and K. D . Philips, Carbohydr. Res., 7, 173-179 (1968).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

59

practical application in the case of J4,5; J 4 a , 5 lies in the range 3.45.0 HZ (Refs. 5, 99, 126, 156, 313, 423, 424, 428, 431, 436, 437, and 440), and exceptionally drops to 2.8 Hz (Refs. 313, 332, and 421), whereasJ4e,5has the range 1.5-2.5 Hz (Refs. 5, 52,317,332, 422, 428, 432,435,436, and 438). In the case ofJ2,3 andJ3.4,the differences are even more pronounced, the a-e arrangement having the range 4.25.8 Hz (Refs. 5, 99, 313, 317, 332, 379, 422-424, 428, 431, 433, 436, and 438-440), whereas, in the e-e system, the] value does not exceed 2.5 Hz (Refs. 5 , 52, 332, 379, 422, 428, 431, 437, 438, and 440). Values of vicinal coupling are practically unaffected by substitution (for methyl ethers, compare Refs. 52 and 441) if no change of the 'c4(D) to the B,,,(D) conformation (such as in, for example, 3-amino1,6-anhydro-3-deoxy-P-~-glucopyranose hydr~chloride~~') occurs. It seems likely that such a conformational interconversion may be the explanation of the atypical J values of some 2,4-disubstituted derivatives of l e v o g l ~ c o s a n(see ~ ~ ~also, * ~ ~Ref. ~ 443a). Otherwise, all 1,6anhydro-P-D-hexopyranoses having common substituents lacking significant dipolar interactions exist in the 'c4(D) conformation (see Ref. 444 for a misinterpretation). The aforementioned 'C,(D)= B,,,(D) equilibrium is then the only case438(compare Ref. 436) where the J values are substantially solvent-dependent. Certainly, the solvent-dependence of chemical shifts is more general, and, consequently, in order to obtain better resolution, dimethyl sulfoxide instead of water for unsubstituted 1 , 6 - a n h y d r o h e x o p y r a n o s e ~ , ~ ~ ~ ~ ~ ~ (compare Ref. 367) and benzene264*421s422,424 or trifluoroacetic instead of chloroform for substituted 1,6-anhydrohexopyranoses,are frequently used. The signals of ring protons of 1,6-anhydrohexopyranose derivatives are generally split b y long-range interactions5,52,106,155,264,325*3283 332,379,381,416,419,422,424-429,438,445,446 which are, as expected, the largest for (440) A printer's error can easily invalidate the n.m.r. data published. For example, ]4,5 = 7.7 Hz (Ref. 433) is correctly 3.7 H Z ; ] ~ = , ~ 2.5 Hz (Ref. 332) should read

5.2 Hz; (OH) at C-4 4.80 (Ref. 264) should be 5.20. ]J,6exo = 0.5 and J5,6enda = 9.1 (see Ref. 437) were interchanged, as well as ]Z,R and Js.., in Ref. 702. JR.6exo 1.2 Hz and some others in Ref. 367 are incorrect (cf. Ref. 438). In Ref. 376 (compound XVI), -2 Hz,JS,4ax = 2.2 Hz. (441) E. R. Ruckel and C. Schuerch,]. Org. Chern., 31,2233-2239 (1966). (442) M. Prystag and F. Sorm, Collect. Czech. Chern. Cornrnun., 36,1448-1471 (1971). (443) L. Vegh and E . Hardegger, Helu. Chim. Acta, 56, 1792-1799 (1973). (4434 J . Schraml, J. Pola, H . Jancke, G. Engelhardt, M. Cern);, and V. Chvalovsk);, Collect. Czech. Chern. Cornmun., 41, 360-367 (1976). (444) L. A. Mai and G. A. Fisher, Latv. PSR Zinat. Akad. Vestis Kim. Ser., 753-754 (1968). (445) €3. Coxon, Carhohydr. Res., 13,321-330 (1970).

60

SIILOSLAV C E R N ~ ’A N D JAN STANEK, JR.

the 1,3-diequatorial arrangement, varying from 1.1 to 1.5 Hz. 5 0.3 is usually -0.3 Hz, 4J4a,6exo -1 Hz, and Coupling Hz. Frequently, four-bond couplings across the ring-oxygen atoms are observed, their values also being influenced by the orientation of the electron pairs of the oxygen (4J1,6exo = 4Jl,6endo =0.2-0.,5 Hz, ==O-0.4 Hz; for the last-mentioned case, compare Refs. 5, 106, 264, 325, 381, 424,429, and 446). Even five-bond coupling-constants are significantly greater than zero, 0.5 Hz (Refs. 106,325, and 426; compare Ref. 446); thus, in levoglucosan triacetate (38), H-1 is coupled to all other ring-pr~tons.~’~ As a result, very complicated multiplets are often obtained in which the small J values can be deduced only from the changes of band widths effected by double-resonance experiments. Of similar, and possibly even greater, utility in structural analysis can be the long-range interactions 4JF,F in fluoro derivatives, in addition to the common 2JH,F and 3JH,F (Refs. 170, 380, 381, 447, and 448). Geminal 2JH,H couplings of deoxy derivatives are 12 to 16 Hz (Refs. 155,319,325,327-329,449, and 450). The rigid system also effects certain regularities in the chemical shifts of substituents. Among them, the differences between singlets of axially and equatorially, exo and endo oriented acetyl groups were formulated into useful r ~ l e(compare ~ ~ ~Ref., 452), ~ ~but,~ even though the correctness of the shift assignments was later sustained by study of selectively deuterated derivative^^^^,^^^,^^^ (see also, Ref. 50), the dependence of these chemical shifts on the presence of groups other than acetoxyl or acetamido s u b s t i t ~ e n t s ~greatly l , ~ ~ ~ restricts their general utility. The same is true for the chemical shifts of hydroxyl protons measured in dimethyl ~ ~ l f o ~ i d e . ~ ~ J ~ ~ , ~ ~ ~ ~ (446) J. C. Jochims, 6. Taigel, and W. Meyer zu Reckendorf, Tetrahedron Lett., 32273234 (1967). (447) A. D. Barford, A. B. Foster, J. H. Westwood, and L. D. Hall, Carbohydr. Res., 11, 287-288 (1969). (448) A. D. Barford, A. B. Foster, J. H. Westwood, L. D. Hall, and R. N. Johnson, Carbohydr. Res., 19,49-61(1971). (449) R. H . Bell, D. Horton, and D. M. Williams, Claem. Commun., 323-324 (1968); R. H. Bell, D. Horton, D. M. Williams, and E. Winter-Mihaly, Carhohydr. R e s . , in press. (450) M. CernL. J. Pacak, and J. Stanek, Carbohydr. Res., 15,379-389 (1970). (451) For the “anomaly” with galactosan triacetate, see data in Ref. 422; compare also, Ref. 454. (452) R. U. Lemieux, R. K. Kullnig, H. J. Bernstein, and W. G. Schneider,]. Am. Chem. SOC.,80,6098-6105 (1958). (4.53)P. L. Durette and H. Paulsen, Carbohydr. Res., 35, 221-233 (1974). (454) D. Shapiro, A. J. Acher, and E. S. Rachaman,]. Org. Chem., 32,3767-3771 (1967).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

61

The changes in multiplicities of signals H-1 to H-5 may be readily used for assigning the position of the carbonyl group455in keto derivatives. The chemical-shift values of 1,6-anhydro-p-~-hexopyranos-3uloses5,419,455 and their derivative^,^^',^^^ glycos-2-uloses, glycos-4and deoxy uloses and their isopropylidene derivatives,415~416~4is~436~457~45s and dideoxy k e t ~ n e ~are~ explained ~ ~ , ~ on ~ the ~ , basis ~ ~ of~ the anisotropy of the carbonyl group.5,377,450 The deviations of vicinal-coupling values from those of 1,6-anhydrohexopyranosesare not large (<1Hz), and correspond to a slight flattening of the ' c 4 ( D ) c ~ n f o n n a t i o n . ~ ~ ~ ~ " ' " ~ 450 Care must be taken in the interpretation of spectra of ketones having neighboring, free hydroxyl groups,419owing to ready formation of dimeric hemiacetals.417*436,460 Changes in multiplicity were also used for solving the structures of branched-chain sugars .106,461 Of special interest are the temperaturedependent, line-shape changes in 'H-n.m.r. spectra used for study. ~ ~13C-n.m.r. ~~~~~~~~~ ing molecular motions in solid l e v o g l u ~ o s a n The spectra of l e ~ ~ g l u ~ of~ other ~ a 1,6-anhydrohexopyran , ~ ~ ~ ~ ~ ~ ~ ~ o s ~ s and P ~of ~their ~ ,d e~r i~v a~t i ~v e ~ ~have ~ l ~ ,been ~ ~ ~ described. ~ Protons of 1,6-anhydrohexopyranoses having the a-e-a orientation of vicinal oxygen atoms (that is, the 1,6-anhydro-P-~-glycopyranoses of talose, mannose, and allose) exhibit lanthanide-induced shifts in 4 ~existence ~ ~ ~ ~of ~these ~ ~stereospecific ~ ~ ~ ~ ~ in~ ~ aqueous ~ o l u t i o n . The teractions was also confirmed by means of 13C-n.m.r.spectroscopy.462 The additional torsion along the C-2-C-3 (C-3-C-4) bond generated by the presence of the 1,3-dioxolane ring in isopropylidene acetals is connected with the further decrease of torsion angle of cis-oriented hydrogen atoms, and with its increase for the trans-e-e orientation. In conformity, J1,2a reaches the range 2.5-3.4 Hz in the 1,6-anhydro derivatives of P - D - i n a n n o p y r a n ~ s e ,P~-~D~-~t~a~ l~ o p y r a n ~ s e , ~ ~ ~ ~ ~ ~ 463-465 and P-D-altropyrano~e,4~~ andJ,,, increases even to 5.5 Hz (1,6and P-D-gul~pyranose~~~). anhydrides of~-D-ta~opyranose106~4163460~464~465 (455) K. Heyns, J. Weyer, and H. Paulsen, Chem. Ber., 98, 327-333 (1965). (456) K. Heyns, P. Koll, and H. Paulsen, Chem. Ber., 104,3096-3100 (1971). (457) D. Horton and J. S. Jewell, Carbohydr. Res., 2, 251-260 (1966). (458) D. Horton and E. K. Just, Chem. Commun., 1116-1117 (1969). (459) R.-W. Rennecke, K. Eberstein, and P. Koll, Chem. Ber., 108, 3652-3655 (1975). (460) K. Heyns and P. Ko11, Chem. Ber., 104,3835-3841 (1971). (461) D. Horton and E. K. Just, Carhohydr. Res., 18,81-94 (1971). (461a) H. Paulsen, V. Sinnwell, and W. Greve, Carbohydr. Res., 49, 27-35 (1976). (461b) R. G. S. Ritchie, N. Cyr, and A. S. Perlin, Cnn. J. Chem., 54,2301-2309 (1976). (462) P. A. J. Gorin, personal communication; see Ref. 405. (463) H. Paulsen, V . Sinnwell, and P. Stadler, Chem. Ber., 105, 1978-1988 (1972). (464) H. Paulsen and W. Greve, Chem. Ber., 106,2124-2139 (1973). (465) H. Paulsen, W. Greve, and H. Kuhne, Tetrahedron Lett., 2109-2112 (1971).

62

MILOSLAV CERNY AND JAN STANEK,JR.

In contrast, J e s s decreases to 0.7-1.4 Hz, and Jl,ze to 0-1.8 Hz (Refs. 106,417, and 436; see also, Ref. 466). Analogous changes may be observed forJ2,3 andJ3,4.Almost total flattening of the C-1 to C-5 part of the pyranoid chair occurs on introduction of the oxirane or aziridine ring, or of a double bond. The increase or decrease of J values of these compounds, compared to those of 1,6-anhydrohexopyranoses,agrees with the angular changes accompanying the approach to planarity.'55* 254,325,326,328,329,331,332,376,377,379,434,437,442,456,467-469

By using electron-impact (e.i.), mass spectrometry (ms.), the fragmentation of permethylated, per(trimethyIsiIyI)ated, peracetylated, and per(trifluoroacety1)ated 1,6-anhydrohexopyranoses, including those specifically de~terated,4~"-~'~ and also of 1,6 :2,3-dianhydro-pD - t a l ~ p y r a n o s eand ~ ~ ~2,3- or 3,4-isopropylidene acetals of 1,6-anhydro-P-D-talopyranose has been s t ~ d i e d .Fragmentation ~ ~ ~ , ~ ~ ~ processes furnishing the most abundant ions mle 101 and 88 of permethylated, and ions mle 157 and 144 of peracetylated 1,6-anhydrohexopyranoses can be interpreted on the basis of primary splitting of the C-1-C-2 bond, with eventual elimination of C-1 as HC02', followed by further elimination of oxygen fragments. In comparison to e.i.m.s., ions [M + NHJ+ and [MHI+ of very high intensities were observed, even with unsubstituted hexosans, by means of chemical ionization in ammonia or i ~ o b u t a n e . ~ ~ ~ , ~ ~ ~ Separation of 1,6-anhydrohexopyranosesand their derivatives from each other, and from mixtures with other sugars, can be achieved by using various types of chromatography, for example, on paper,55~96Jos~ 112,138,140,301,314,322 thin layerS,5l953,l13 co~Umns,82,99,138,140,297,301,310,453 and ion-exchange resins. 139,477,478 One of the most useful methods for quali(466) P. M. Collins and N. N. Oparaeche, Carbohydr. Res., 3 3 , 3 5 4 6 (1974). (467) K. Ranganayakulu and R. K. Brown,]. Org. Chem., 39,3941-3943 (1974). (468) D. Horton and E. K. Just, Carbohydr. Res., 9, 129-137 (1969). (469) K. Heyns, R.-W. Rennecke, and P. KO11, Chem. Ber., 108,3645-3651 (1975).

(470) K. Heyns and H. Scharmanii, Chem. Ber., 99, 3461-3476 (1966). (471) K. Heyns and H. Schamiann, Carbohldr. Res., 1, 371-392 (1966). (472) N. K. Kochetkov and 0. S. Chizhov, Ado. Carbohydr. Chem., 21, 39-93 (1966); see p. 81 thereof. (473) N. K. Kochetkov, 0. S. Chizhov, and B. M.Zolotarev, Khim. Prir. Soedin. Akad. Nauk U z . SSR, 2, 152-158 (1966). (474) K. Heyns, H. F. Griitzmacher, H. Scharmann, and D. Muller, Fortschr. Chem. Forsch., 5, 448-490 (1966). (475) D. Horton, E. K. Just, and J. D. Wander, Org. Mass Spectrom., 6, 1121-1129 ( 1972). (476) D. Horton, J . D . Wander, and R. L. Foltz, Carbohydr. Res., 36, 75-96 (1974). (477) E. Martinsson and 0. Samuelson, J . Chromatogr., 50,429-435 (1970). (478) 0. Samuelson, Methods Carbohydr. Chem., 6, 65-75 (1972). (479) T. Tmka and M. Gem?, Collect. Czech. Chem. Commun., 36,2216-2225 (1971).

1,6-ANHYDRO DERIVATIVES O F ALDOHEXOSES

63

tative and quantitative analysis is gas-liquid chromatography of the acet~tes799~113~116~119,121,14i~4i9,480 trimethylsilyl derivatives ,99,14i,190,194,196, 214,232,258,322,369,424,479-483 methyl ethers ,441,483,484 and free levoglucosan.485 The 1,6-anhydrohexosescan also be determined, after acid hydrolysis, as reducing sugars by the usual methods, provided that the compo-

sition of the equilibrium mixture of hexoses and anhydrohexoses (see Sect. II,4) is considered. In addition to the chromatographic methods already mentioned, the content of levoglucosan (for example in cellulose degradation-products) can be determined214,229,231 by i.r. spectroscopy from the ratio of intensity of bands at 1133 and 2900 cm-' (compare Refs. 211, 230, and 486), or o t h e n v i ~ e . ~ ~ ~ - ~ ~ ~ Iv. REACTIONS OF

1,6-ANHYDROHEXOPYFtANOSES

1. Cleavage of 1,8Anhydride Bonds a. Acid Cleavage.-The glycosidic bond of hexosans and their derivatives may be hydrolyzed under the catalysis of such mineral acids as hydrochloric or sulfuric acid, to yield aldoses, either free or substituted at C-2, C-3, or C-4. Practically no variations in experimental (480) T. Tmka and M. Gem$,]. Chromatogr., 78, D48-D49 (1973). (481) M. S. Kheiri and G. G . Birch, Cereal Chem., 46,400-405 (1969). (482) K. Turunen, A. Arvinen, and J. Turunen, Pap. Puu, 53, 189-194 (1971); Chem. Abstr., 75,22,791 (1971). (483) P. C. Wollwage and P. A. Seib,J. Polym. Sci., Part A-1, 9, 2877-2892 (1971). (484) D. A . Rces and J. W. B. S;untlcl,]. Chein. Soc., C, 2295-2298 (1967). (485) R. F. Schwenker, Jr., and L. R. Beck, Jr.,]. P ( J ~ ! / ISci., ? L , Put-t C , No. 2, 331-340 ( 1963). (486) A. Broido, Y. Houminer, and S. Patai,]. Chem. Soc., B , 4 1 1 4 1 4 (1966). (487) G. Zakis, I . Alsups, and B. Neiberte, Khim. Drew., (12) 107-114 (1972); Chem. Abstr., 79, 20,547 (1973). (488) I. Alsups, G. Zakis, and Z. Zh. Klyava, Khim. Dreu., (12) 115-118 (1972);Chem. Abstr., 79, 20,548 (1973). (489) I. Kirsbaums, I. Komburgs, and V. N. Sergeeva, Khirn. Dreu., (15) 159-160 (1974); Chem. Abstr., 81, 136,393 (1974). (490) G. Zemplin and G. Braun, Ber., 58,2566-2570 (1925). (491) K. Freudenberg, G. Bloniqvist, L. Ewald, and K. Soff, Ber., 69, 1258-1266 (1936). (492) T. H. Evans, I. Levi, W. L. Hawkins, and H. Hibbeit, Can.]. Res., 20B, 175-184 (1942). (493) W. T. Haskins, R. M. Hann, and C . S. Hudson,]. Am. Chem. Soc., 65,70-73 (1943). (494) B. Lindberg and B. Wickberg, Acta Chem. Scand., 8, 569-573 (1954). (495) M. L. Wolfrom, A. Thompson, and R. B. Ward,]. Am. Chem. Soc., 81, 46234625 (1959). (496) J. E. Hook and B. Lindberg, Acta Chem. Scand., 20,2363-2369 (1966). (497) N. A. Hughes, Carbohydr. Res., 7 , 4 7 4 4 7 9 (1968). (498) M. CernL, T. Tmka, P. Beran, and J. Pacik, Collect. Czech. Chem. Commun., 34,3377-3382 (1969).

64

MILOSLAV CERNY AND JAN STANEK, JR.

have been utilized for this rou-

pr~ce~ure27~28~50,264~283~285~308~448~483~490~499

tine reaction. The rate of hydrolysis is higher than with ordinary gly~ o s i d e s ~(compare ~ ~ , ~ ~Ref. ' 502); this difference, attributed to the ring strain (on the basis of studies conducted on 1,6-anhydro-2,3,4-trideoxy-P-DL-glycero-hexopyranose (26) and other bicyclic acetals503), plays an important role in the synthesis of disaccharides (see Section X). Naturally, the 2-deoxy derivatives are hydrolyzed more readily, and 2-0-substituted hexosans with greater difficulty, than the parent 1,6-anhydrohexopyranose.Especially difficult is the hydrolysis of 1,6-anhydrohexopyranosescarrying on C-2 an electronegative group such a s p-tolylsulfonyloxy,504~505 a f l ~ 0 r o , 3 ~an ~ acetamido, ,~~~-~~ or~a protonated amino group.439~505,509-513 For 1,6-anhydro-4-deoxy-3-0methyl-2-O-p-to~ylsulfonyl-~-D-glucopyranose, it is even possible to split off the methyl group without impairment of the anhydro bridge (by means of hydrogen bromide in acetic anhydride,514compare Ref. 515). In order to overcome this enhanced stability of the acetal grouping, 1% aqueous p-toluenesulfonic acid at 175" is used for 2-deoxy2-fluoro derivative^.^^^,^^^,^^^ Methanolic hydrogen chloride at elevated temperatures causes the conversion of 1,6-anhydrohexopyranosesinto mixtures of the corresponding methyl Ethyl 2,3,4-tri-O-benzyl- l-thioa-D-glucoside was similarly obtained on treatment of 24 with ethanethiol and zinc ~ h l o r i d e . ~The ~ ~ anhydro ,~'~ bridge of levoglucosan (6) (499) A. F. Bochkov and Ya. V. Voznyi, Carbohydr. Res., 32, 1-8 (1974). (500) K. Freudenberg, W. Kuhn, W. Dun, F. Bolz, and G. Steinbmnn, Ber., 63, 15101530 (1930). (501) K. Freudenberg and W. Nagai, Ber., €427-29 (1933). (502) K. Freudenberg, W. Durr, and H. von Hochstetter, Ber., 61, 1735-1743 (1928). (503) H. K. Hall, Jr., and F. DeBlauwe,]. Am. Chem. Soc., 97, 655-656 (1975). (504) M. Cernl., J. PacHk, and J. StanRk, Collect. Czech. Chem. Commun., 30, 11511157 (1965). (505) L. J. CarIson,J. (It-g. Chem., 30,3953-3955 (1965). (506) J. Pacik, Z. ToEik, and M. Cern?, Chem. Commun., 77 (1969). (507) J. PacHk, J. Podeha, and M. Cernj., Chem. Ind. (London),929 (1970). (508) J. Adamson, A. B. Foster, L. D. Hall, R. N. Johnson, and R. H. Hesse, Carbohydr. Res., 15,351-359 (1970). (509) S. P. James, F. Smith, M. Stacey, and L. F. Wiggins,]. Chem. Soc., 625-628 (1946). (510) R. W. Jeanloz, D. M. Schmid, and P. J. Stoffyn,]. Am. Chem. Soc., 79,2586-2590 ( 1957). (511) R. W. Jeanloz and P. J. Stoffyn,J. A m . Chem. Soc., 76,5682-5684 (1954). (512) R. W. Jeanloz,]. Am. Chem. Soc., 81, 1956-1960 (1959). (513) R. W. Jeanloz and A. M. C. Rapin,]. Org. Chem., 28,2978-2983 (1963). (514) M. Cernl. and J. Volf, unpuhlished results. (515) The more rapid methanolysis of the 1,Banhydride bond compared to that of the oxirane ring ofthe p-tolylsulfonyl epoxide (lll),as considered in Ref. 505, seems very improbable.

1,GANHYDRO DERIVATIVES OF ALDOHEXOSES

65

is also cleaved by the action of ~ h l o r a 1or~ acetone ~ ~ , ~ under ~ ~ acid conditions (see Sect. IV,6), to give c h l o r a l o ~ e or ,~~ 1,2 ~ :5,6-di-O-isopropylidene-a-D-gluco~e~~~ (compare Ref. 521), respectively. The action of concentrated hydrochloric acid on levoglucosan (6) yields (in addition to D-glucose) a broad spectrum of o l i g o s a ~ c h a r i d e s(compare ~~~,~~~ Refs. 524-527). Whereas the hydrolysis of derivatives having the Dgluco, Dmanno, Dgalacto, and Dtalo configurations proceeds in good yields, the results for the remaining isomers are greatly influenced by the final aldose equilibrium (see Sect. composition of the anhydrohexose 11,4); for the latter, substantially better results can be achieved by the action of acetic anhydride-sulfuric acid, which leads to a mixture of anomeric peracetates. H owever, acetolysis has also been applied to the first four 1,6-anhydrohexopyrano~es,~~~ variously substituted, particularly because such substituents as 0 - or Sbenzy1432,531-532c (compare Ref. 533),O - b e n z ~ y l ,O-aIly1,434N-phen~~~,~~~ y l ~ a r b a r n o y lN, ~-~a~~ e t y 1 ~(compare ~ ~ , ~ Ref. ~ ~ 509), , ~ ~ S~ - a ~ e t y l ,and ~~~,~~~

*

122,123~1333528,529

(516) S. Koto, T. Uchida, and S. Zen, Chem. Lett., 1049-1052 (1972). (517) S. Koto, T. Uchida, and S. Zen, Bull. Chem. Soc. J p n . , 46, 2520-2523 (1973). (518) A. Pictet and F. H. Reichel, Helu. Chim. Acta, 6, 621-627 (1923). (519) Present authors' comment. (520) M. CernL, V. Gut, and J . Pacik, Collect. Czech. Chem. Commun., 26,2542-2550 ( 1961). (521) E. Yu. Ponomarenko, V. L. Lapenko, and G. G. Markova, Tr. Voronezh. Gos. Uniu., 95, 72-74 (1972); Chem. Abstr., 78, 4437 (1973). (522) L. Reichel and H. Schiweck,Justus Liebigs Ann. Chem., 761, 182-188 (1972). (523) L. Reichel and H. Schiweck, Naturwissenschaften, 48,696 (1961). (524) H. Pringsheim and S. Kolodny, Ber., 59, 1135-1140 (1926). (525) H. Pringsheim and A. Beiser, Ber., 59,2241-2243 (1926). (526) L. Reichel and G. Erdos, Ber., 65, 1618-1623 (1932). (527) L. Reichel and F. Nagel, Ber., 74, 1742-1744 (1941). (528) N. K. Richtmyer and C . S. Hudson,J. Am. Chem. Soc., 63, 1727-1731 (1941). (529) P. Perchemlides, T. Osawa, E. A. Davidson, and R. W. Jeanloz, Carbohydr. Res., 3,463-477 (1967). (530) K. Freudenberg and K. Soff, Ber., 69, 1245-1251 (1936). (531) 6. Zempl&n,2. Csiiros, and S. J. Angyal, Ber., 70, 1848-1856 (1937). (532) J. M. J. Fr6chet and H. H. Baer, Can. /. Chem., 53, 670-679 (1975). (532a) N. Pravdii. and D. Keglevii., Tetrahedron, 21, 1897-1901 (1965). (532b) L. Kalvoda, M. PrystaS, and F. Sorm, Collect. Czech. Chem. Commun., 41,800815 (1976). (532c) M. PrystaS, L. Kalvoda, and F. Sorm, Collect. Czech. Chem. Commun., 41,14261447 (1976). (533) R. Allerton and H."G. Fletcher, Jr.,/. Am. Chem. Soc., 76, 1757-1760 (1954). (534) M: PrystaS and F. Sorm, Collect. Czech. Chem. Commun., 36, 1472-1481 (1971). (535) J. Smejkal andL. Kalvoda, Collect. Czech. Chem. Commun., 38,1981-1984 (1973). (536) R. Eby and C . Schuerch, Carhohqdr. Res., 27,63-72 (1973).

MILOSLAV C E R N Y AND JAN STANEK, JR.

66

aZido537-539 remain intact under the reaction conditions; see also, Refs. 51, 126,448, and 540.Instead of sulfuric acid, boron trifluoride etherate532b,532c,535,541,512 or perchloric have occasionally been employed. A combination of trifluoroacetic anhydride and sulfuric acid permits the preparation of hexose esters having their hydroxyl groups at C-1 and C-6 free, owing to the facile hydrolysis of trifluoroacetate~.~~~ Another kind of intervention in the anhydrohexose aldose equilibrium has been described for 1,6-anhydro-P-~-gulopyranose. The action of 40% aqueous hydrogen bromide and bromine at 80" causes simultaneous hydrolysis and oxidation to ~gulono-l,4-lactone.'22 Tri-0-acyl derivatives of levoglucosan yield the corresponding 6-~-acetyl-2,3,4-tri~-acy~-a-D-g~ucopyranosy~ bromides when treated with hydrogen bromide in acebc (see also-ef. 531); chloroform, usually used as a co-solvent, suppresses undesirable side-reacti on^.^^^ A similar reaction course is found with hydrogen bromide of other carboxylic in acetic a n h ~ d r i d e ,or ~~ in~anhydrides ,~~~ which give rise5= to various 6-0-acyl derivatives, such as, for example, 37. Fairly long action of neat, liquid hydrogen bromide346or (537) H. Paulsen, H. Koebernick, W. Stenzel, and P. Ko11, Tetrahedron Lett., 14931494 (1975). (538) H. Paulsen ayd W. Stenzel, Angew. Chem., 87,547-548 (1975). (539) H. Paulsen, C. Kolai, and W. Stenzel, Angew. Chem., 88,478 (1976). (540) L. Vegh and E. Hardegger, Helo. Chim. Acta, 56,2079-2082 (1973). (541) M. PrystaS, L. Kalvoda, and F. Sorm, Collect. Czech. Chein. Commun., 40,17751785 (1975). (542) L. Kalvoda, M. PrystaB, and F. Sorm, Collect. Czech. Chem. Commun., 41,788799 (1976). (543) M. Gernl, V. Piikrylova, and J. Pacak, Collect. Czech. Chem. Commun., 37,29782984 (1972). (544) M. Cernl, J . MQcovC,and J . Pacak, to be published. (545) J. Pacik, M. BraunovH, D. StropovQ, and M. Cernl, Collect. Czech. Chem. Commun., 42, 120-131 (1977). (546) 0. T. Schmidt and G. Klinger,justus Liebigs Ann. Chem., 609, 199-208 (1957). (547) H. Ohle and K. Spencker, Ber., 59, 1836-1848 (1926). (548) M. Bergmann and F. K. V. Koch, Ber., 62,311-313 (1929). (549) K. Josephson, Ber., 62,317-321 (1929). (550) A. (R.) Jeanes, C. A. Wilham, and G. E. HilbertJ. Am. Chem. SOC.,75,3667-3673 (1953).

(551) Z. Csuros, G. Deak, and M. Haraszthy-Papp, Acta Chim. Acad. Sci. Hung., 29, 227-235 (1961). (552) K. Freudenberg and K. Soff, Ber., 69, 1252-1257 (1936). (553) It should be noted that neat acetyl bromide is unable to split the 1,Ganhydride bond; however, traces of iron are sufficient to catalyze not only this reaction but also cleavage by some other acid bromides551;see also, Refs. 45a, 186, and 547.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

67

phosphorus ~ e n t a b r o m i d e ~on ~ ~levoglucosan , ~ ~ ~ , ~ ~ ~triacetate (38) yields 2,3,4-tri-O-acetyl-6-bromo-6-deoxy-c~-~-glucopyranosyl bromide (39).Analogous reaction with liquid hydrogen fluoride failed to give any fluoro derivative; only in the presence of acetic anhydride was a high yield of tetra-0-acetyl-a-D-ghcopyranosyl fluoride achieved.5556-Bromo-6-deoxy derivatives can also be obtained under the usual acetobrominolysis conditions; the prerequisite is the presence at C-2 of an electronegative group which, by its -I effect, stabilizes the C-1-0-6 bond, as described for 1,6-anhydro-2-deoxy-2-fluoro-~-D-g~ucopyrano~e.~~~ Fuming nitric acid and phosphorus pentaoxide in chloroform convert the trimethyl ether of levoglucosan into the 1,6-dinitrate.90*556 Similar reaction of 38 yields tri-0-acetyl-D-glucose 1,6-dinitrate.556 The 1,6-anhydro bridge of levoglucosan triacetate (38) can also be cleaved by the action of titanium t e t r a c h l ~ r i d e ~or, ~tetrabro~,~~~ mide7*8zin chloroform, to give 2,3,4-tri-0-acetyl-a-D-glucopyranosy~ chloride (40) and the corresponding bromide. Titanium tetrachloride but, with the D-manis also satisfactory for the D-galactose series,558*559 nose series, no evidence for such a course of cleavage could be found.282,560 Occasional failure of this reaction, even195,561,562 with triacetate 38, led to the conclusion that ethanol in the reaction mix~ - ~ ~ ~systematic studies ture is indispensable as a c o - c a t a l y ~ t . ' ~Further ~ - ~ ' ~that ~ ~at~least ~ * two ~ ~ ~ by Csuros, DeAk, and c ~ w o r k e r ~ ~ 'revealed moles of titanium tetrachloride per mole are needed for achieving a satisfactory course for this first-order reaction, ethoxytitanium trichloride being the real co-catalyst. Levoglucosan t r i p r ~ p i o n a t e ' ~ ~ , ~ ~ ~ or t r i b ~ t y r a t e lreact ~ ~ , ~similarly ~~ to 38; however, no reaction was observed with the t r i b e n z ~ a t e or ' ~the ~ ~t r~i ~ t~e a~r ~ a t~e ,~' ~obviously ~*~~~ due to steric hindrance of complex formation which involves 0 - 6 and (554) A. A. Gerasimenko, G. S . Tret'yakova, and E. B. Shaposhchnikova, Tekhnol. Smazki, 147-150 (1971); Chem. Abstr., 79, 115,791 (1973). (555) F. Micheel, A. Klemer, M. Nolte, H . Nordiek, L. Tork, and H. Westemann, Chem. Ber., 90,1612-1616 (1957). (556) J. W. H. Oldham,J. Chem. SOC., 127,2840-2845 (1925). (557) G . Zemple'n and Z. Csuros, Ber., 62,993-996 (1929). (558) G. Zemple'n, A. Gerecs, and H. Flesch, Ber., 71, 774-776 (1938). (559) A. Thompson, hl. L. Wolfrom, and M. Inatome,J. Am. Chem. Soc., 77,3160-3161 ( 1955). (560) Participation of the C-2 axial ester group cannot be excluded.519The stereospecific cleavage of 1,6-anhydro-3-azido-2-O-benzoyl-3,4-dideoxy-~-~-xylo-hexopyranose by antimony pentachloride, followed by the action of methanol, also supposedly proceeds by way of a 1,2-acyloxonium (561) C . D. Hurd and S. M. Cantor,J. Am. Chem. Soc., 60,2677-2687 (1938). (562) Z. Csuros, G. Deik, and M. Haraszthy, Period. Polytech., 3, 25-36 (1959).

MILOSLAV CEKNY AND JAN STANEK, JR.

68

the carbonyl group of the axially oriented acyl group195,411,562,563 on 0 - 3 . Levoglucosan trimethyl ether reacts only with Dichloromethyl methyl ether and zinc chloride cleave 38 to the 6-formate (41).With an excess of the reagent, the final product is 2,3,4tri-O-acety~-6-O-(dichloromethyl)-~-~-gl~copyran0sy~ ~hloride.~~~,~ D-GhcOSe per acetate

g glucose

0 II

k

OAc

OR

37R’=E/

368 R j == AH c CI,HCOMe, ZnC1,

CHCI,, EtOH

\

AcOQc,

39

NaH,PO,

0 FH,OH

OAc

H 150 H,F-P-ONa

II

H,FOCH

QCI

AcO OAc 40

OAc

41

OH 42

Unsubstituted 1,6-anhydrohexopyranoses react with boron tribromide or trichloride, the end products of this cleavage being unspecified oligosaccharides and free aldoses .126,567 Products having a C-6-P bond (for example, 42) are formed in the reaction of levoglucosan568~569 Z. Csuros, C . Deak, and L. Fenichel, Acta Chirn. Acad. Sci. Hung., 21, 169180 (1959). Z. Csiiriis, G . DeLk, and M. Haraszthy-Papp, Acta Chim. Accid. Sci. Hung., 21,193-203 (1959). R. Bognir, I. Farkas, M. Menyhart, H. Gross, and H. Paulsen, Carbohydr. Res., 6,404-413 (1968). I. Farkas, R. Bognar, I. F. Szabo, and M. Menyhirt, Kern. Kozl., 30, 297-304 (1968); Chern. Abstr., 70, 78,259 (1969). T. G. Bonner, E. J. Bourne, and S. McNally,J. Chern. Soc., 2929-2934 (1960). N. K. Kochetkov, E. E. Nifant’ev, and I. P. Gudkova, Zh. Obshch. Khirn., 37,277 (1967). E. E. Nifant’ev, I. P. Gudkova, and N. K. Kochetkov, Zh. Obshch. Khirn., 40,460463 (1970).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

69

(6) or 1,6-anhydro-/3-~-galactopyranose~~~ (12) with hypophosphorous acid and its sodium salt. It is possible that the cleavage of 6 with sodium hydrogensulfite at elevated temperature, the product of which is the sodium salt of D-g~ucose-6-su~fonic a ~ i d ,takes ~ ~ a~ similar , ~ ~ ~ course.

b. Pyrolytic Cleavage.-In addition to polymeric products and char (see Sect. IV,2), pyrolysis of levoglucosan (6) a variety of volatile prodUC~s~22,44,l93,2l2,2l3,225,Z~,259,Z65,Z67,269,Z76,3O3,369,57Z Depending on the conditions (temperature, inert atmosphere, low pressure), various reaction-paths may be followed. The products are essentially the same as those obtained by uncatalyzed, acid-catalyzed, or alkali-catalyzed thermal degradation, but differ significantly in their proportions. Addition of zinc chloride increases the formation of char, water, carbon dioxide, and 2-furaldehyde, whereas the addition of alkali promotes the formation of acetaldehyde, glyoxal, 2-butenal, and acrolein. This complex reaction has been studied by thermal degradation of [1-l4C1-,[2-l4C1-,and [6-'4C]-levoglucosan.44 c. Reductive Cleavage.-Hydrogenolysis of levoglucosan (6) over copper chromite leads to 1,5-anhydro-2-deoxy-~-arubino-he~ito1~~~ (compare Ref. 574),as a primary product of the reaction. Favored cleavage of the C-1-0-6 (compared to the C-1-03) bond was also observed on reduction of 26 with lithium aluminum hydride in the or' ~aluminum tripresence of such Lewis acids as boron t r i f l ~ o r i d e ~ Under ozonolysis conditions, this model acetal 26 is stable.576The lability of its acetal grouping under hydrogenolysis is substantially enhanced by the introduction of a double bond into 26 (see Sect. V I I , ~ , C ) . ~ ~ ~ 2. Polymerization The polymerization of 1,6-anhydro sugars has been the subject of several a r t i ~ l e s , ~ ~mainly * ~ ~ ~with - ~ *regard ~ to the development of fas(570) T. Matsui, Kogyo Kagaku Zasshi, 5 3 , 4 3 0 4 3 1 (1950). (571) T. Matsui, Kogyo Kagaku Zasshi, 54,72-83 (1951). (572) K. Heyns and M. Klier, Carbohydr. Res., 6,436-448 (1968). (573) P. A. J . Gorin,]. Org. Chem., 24,49-53 (1959). (574) G. S. Barysheva, N. A. Vasyunina, and S. V. Chepigo, Sb. Tr. Gos. NauchnoIssled. Inst. Gidroliz. Sul'jitno-Spirt. Prom., 11, 94-101 (1963); Chem. Abstr., 61,3285 (1964). (575) P. Clasper and R. K. Brown,J. Org. Chem., 37,3346-3347 (1972). (576) P. Deslongchamps, P. Atlani, D. Frthel, A. Malaval, and C. Moreau, Can. J. Chem., 52,3651-3664 (1974). (577) R. K. Brown, to be published. (578) I. J. Goldstein and T. L. Hullar, Ado. Carbohydr. Chem., 21,431-512 (1966).

70

MILOSLAV

CERNY AND

JAN STANEK, JR.

cinating possibilities in the synthesis of stereoregular, (1-+ 6)-linked polysaccharides starting from 2,3,4-tri-O-substituted 1,6-anhydrohexopyranoses. Unsubstituted levoglucosan (6) polymerizes either 4959582-585 or in the presence of such acid catalysts as zinc chloride,ls7, 586-589 monochloroacetic acid,483,585,5w and to yield oligoor poly-saccharides, their molecular weight being strongly dependent on the experimental conditions. No radical polymerization of 6 has been o b ~ e r v e d except , ~ ~ ~when ~ ~ ~maleic anhydride is present.595It appears that the polymerization starts by an attack on C-1 (compare Ref. 582) by the hydroxyl group on C-2 or C-4 of another hexosan molecule, with simultaneous opening of either a protonated or nonprotonated 1,6-anhydro bridge, so that the dimer formed, originally named588,589,596 “dilevoglucosan” corresponds to a mixture of 1,6-anhydro disaccharides, namely, products that may be termed maltosan, cellobiosan, kojibiosan, and s o p h o r o ~ a nThis . ~ ~ ~mechanism has been according to substantiated by the results of an exact kinetic which the dimer, once formed, reacts rapidly on thermal polymerization (compare Ref. 590) through its primary hydroxyl group, to give a

J. Klar, Chem. Z t g . , 87, 731-740 (1963). C. Schuerch, J. Zachoval, and B. Veruovi;, Chem. Listy, 66, 1124-1149 (1972). C . Schuerch, Acc. Chem. Res., 6, 184-191 (1973). M. L. Wolfrom, A. Thompson, R. B. Ward, D. Horton, and R. H. Moore,]. Org. Chem., 26,46174620 (1961). A. Pictet, HeZv. Chim.Acta, 1, 226-230 (1918). Y. Houminer and S. Patai, J. Polym. Sci., Part A-1, 7, 3005-3014 (1969). J. da Silva Carvalho, W. Prins, and C. Schuerch, J. Am. Chem. S O C . , 81, 40544058 (1959). A. Pictet and J . Pictet, H e h . Chirrt. Acta, 4, 788-795 (1921). A. Pictet and J. H. Ross, Compt. R e n d . , 174, 1113-1114 (1922). A. Pictet and J. H. Ross, Helu. Clzim. Acta, 5,876-883 (1922). J. C. Irvine and J. W. H. Oldhain, J. Chem. SOC., 127, 2903-2922 (1925). H . Abe and W. Prins, Makromol. Chem., 42,216-229 (1961). Yd. Ya. Makarov-Zemlyanskii and V. V. Gercev, Zlz. Obshch. Khim., 35,272-275 (1965). U. Stirna, R. Pernikis, J. Surna, and B. Apsite,Latc. P S R Zinut. Akad. Vestis Kim. Ser., 113-117 (1969). V. V. Korshak, 0. P. GoloVd, V. A. Sergeev, N. M. Merlis, and R. Ya. Shneer, Vysukoniol.Soeditl., 3, 477-485 (1961). Compare the mechanisms for the thermal depolymerization of polysaccharides, discussed in Sect. II,5. R. Pernikis, J. Surna, and A. Orbidane, Latv. PSR Zinut. Akad. Vestis K i m . Ser., 736-739 (1968). A. Georg and A. Pictet, Hela. Chitn. Actu, 9,612-625 (1926).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

71

(1-+ 6)-linkage next. In contrast, under acid catalysis (see Scheme 6), the propagation is slower than the dimerization step.483

H+ 6

-

fast

I

I

OH

OH

oo~'H o+o 6

fast

HO

1

fast

- HO

H

OH

OH

OH

OH

1

very slow

FH,OH

CH,OH

r--Q

OH

Scheme 6

The same is true for the polymerization of the 1,6-anhydrides of f i - ~ - m a n n o p y r a n o s and e ~ ~ ~@~ -~D ~~ - g a ~ a c t o p y r a n ~ sWhen e . ~ ~ ~co~~~~ polymerized with 6 under the catalysis of monochloroacetic acid, the latter compound gavesg9a galactoglucan having an almost 1: 1 ratio of Dgluco to Dgalacto residues. With this catalyst, the reactivity of various anhydro derivatives decreases in the order given in Table 11. The different tendency of monomers to polymerize corresponds to steric hindrance in the transition from the chair to the half-chair conformation of the appropriate cation (such as

(597) R. Robinson and I. J. Goldstein, Carbohydr. Res., 13,425-431 (1970). (598) A. Bhattacharya and C. Schuerch, J . Org. Chem., 26,3101-3104 (1961). (599) I. J. Goldstein and B. Lindberg, Acta Chem. Scand., 16, 387-391 (1962).

MILOSLAV CERNY AND JAN STANEK, JR

72

TABLE11 Relative Polymerization Rates (kR,) of 1,6-Anhydrohexopyranosesin a Melt at 115-120", under Catalysis" of Monochloroacetic ~~

1,6-Anhydro-P-~-pyranosederivative of 240 91 37 17 9.0 6.3 2.6 2.3 1.4 1.0

aruhino-Hexose, 2-deoxyMannose Glucose Galactose Cellobiose Glucose, 4-0-methylGlucose, 3-0-methylGalactose, 2-0-methylGlucose, 3,4-di-O-methylGlucose, 2-0-methyl~

~

~~

Molar ratio of 1,6-anhydrohexopyranose :acid so:1. "

=

Endeavors to achieve technical utilization led to co-polymerization of levoglucosan (6) with various alcohols600-602 and ether^.^^^,^^^-^^^ Even though the structures of the resins obtained are not exactly (600) B. Lazdina, R. Pemikis, J. Surna, and V. A. Sergeev, Latu. P S R Zinat.Akad. Vestis Kim. Ser., 476-480 (1968). (601) B. Lazdina, R. Pernikis, J. Surna, V. A. Sergeev, and B. Dzvinko, k t u . P S R Zinat. Akad. Vestis Kim. Ser., 740-743 (1968). (602) B. Lazdina, R. Pernikis, and J. Surna, Latu. P S R Zinat. Akud. Vestis Kim. Ser., 602-605 (1970). (603) R. Pernikis, V. V. Korshak, V. A. Sergeev, and J . Surna, Latu. P S R Zinut. Akad. Vestis Kim. Ser., 291-295 (1964). (604) U. Stima, R. Pemikis, B. Apsite, and J. Surna, Latv. P S R Zinut. Akad. Vestis Kim. Ser., 731-735 (1968). (605) U. Stirna, R. Pernikis, B. Apsite, J. Surna, and V. A. Sergeev, Latu. P S R Zinut. Akad. Vestis Kim. Ser., 118-122 (1969). (606) B. Apsite, R. Pernikis, and J. Surna, Latu. P S R Zinat. Akad. Vestis Kim. Ser., 721-725 (1969). (607) €3. Apsite, R. Pernikis, and J. Surna, Lutu. P S R Zinat. Akad. Vestis Kim. Ser., 233-235 (1970). (608) B. Apsite, R. Pemikis, and J. Surna, Latu. P S R Zinat. Akad. Vestis Kim. Ser., 600-603 (1971). (609) B. Apsite, H. Pemikis, and J. Surna, Latu. P S R Zinat. Akad. Vestis K i m . Ser., 706-710 (1971). (610) In the English abstracts of Russian papers, the terms ester and ether are often interchanged; see, for example, Refs. 595, 600,601, 604, and 645.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

73

known, their utilization in the preparation of adhesives and lacquers is promising. A simpler situation appears with 2,3,4-tri-O-substituted hexosans, where the ring-opening polymerization has proved most successful in producing practical yields of polysaccharides of high molecular weight. In general, the best results have been obtained with perbenzyl ethers and phosphorus pentafluoride as the catalyst at -55 to -75". The polymerization presumably involves an attack by 0-6 of a monomer on C-1 of another molecule of monomer, with simultaneous opening of the ring of the oxonium ion (see Scheme 7 ) .It is OCKPh

\

~

Rimer, etc.

24

OCH,Ph 24

Scheme 7

1,6possible to polymerize tribenzyl ethers of anhydro-/3-~-mannopyranose,~~~~~~~ and 1,6-anhydro-p-~-galactopyran0se45.fi14 specifically a , and to control the molecular weight within wide limits by appropriate choice of solvent, cationic initiator, temperature, and chain-transfer agent. 176-Anhydro-2,3,4-tri-O-benzyl-/3D-galactopyranose, as well as perbenzylated 1,6-anhydro disaccharides (see Section X) polymerize considerably more slowly than the benzyl ethers of levoglucosan and 1,6-anhydro-/3-~-mannopyranose614;this behavior manifests itself in co-polymerization experi(611) E. R. Ruckel and C. Schuerch,]. Am. Chem. SOC., 88,2605-2606 (1966). (612) E. R. Ruckel and C. Schuerch, Biopolymers, 5, 515-523 (1967). (613) J. Zachoval and C. Schuerch,]. Am. Chem. SOC., 91, 1165-1169 (1969). (614) J. W.-P. Lin and C. Schuerch,]. Polym. Sci., Part A-I, 10,2045-2060 (1972). (614a) C. Schuerch and T. Uryu, Macromol. Synth., 4, 151-155 (1972); Chem. Abstr., 84, 17,627 (1976). (615) J. Frechbt and C. Schuerch,]. Am. Chem. Soc., 91, 1161-1164 (1969).

74

MILOSLAV CERNi' AND JAN STANEK, JR.

ments .616*617High stereospecificity was also obtained on polymerization of 1,6-anhydro-2,3,4-tri-O-methyl-~-~-glucopyranose with various Lewis a ~ i d s ~ ~ (compare ~ , ~ ~ Ref. ~ ,622); ~ ~co-polymeriza~ ~ , ~ ~ ~ - ~ ~ tion of this compound with styrene has also been If esters instead of ethers are used, temperatures above -25" are needed in order to compensate for the decrease in the reactivity, and, consequently, the stereospecificity is lowered,j93,613,61j,""2."24.fi2j (see also, Refs. 309, 310, 441,and 614). Phosphorus pentafluoride also proved to be the best of the catalysts tested in the polymerization626-628 of the simplest model, namely, 26. The purity of the monomer is here the critical factor for obtaining products of high molecular

3. Etherification and Esterification The methods of preparation of ethers and esters of l,&anhydrohexopyranoses do not differ substantially from those commonly used for other glycosides. The same is true of the removal of alkyl or acyl groups introduced as protecting groups, where, however, the acid lability of hexosans may pose problems. In this regard, the benzyl group appears to be the most useful among ethers, because acid deb e n z y l a t i ~ n can ~ ~ ~be, ~obviated ~~ by catalytic hydrogenolysis over palladium-on-carbon.31y~380~479~498~fiz~-632 Hydrogenolysis can proceed (616) J. W.-P. Lin and C . Schuerch, Macromolecules, 6,320-324 (1973). (617) W. H. Lindenberger and C. Schuerch,]. Pol!/m. Sci. Pol!/ttt.Claem. Ed., 11, 12251235 (1973). (617a) V. V. Korshak, V. A. Sergeev, J. Surna, and R. Pernikis, Vysokomol. Soediti., 5, 1593-1596 (1963). (618) E . T . Reese and F. W. Parrish, Biopolymers, 4, 1043-1045 (1966). (619) C. C. Tu and C. Schuerch,J.Polym. Sci., Part B , 1, 163-165 (1963). (620) R. Pernikis, J. Surna, and B. Dzvinko, Latv. PSR Zinat. Akad. Vestis Kim. Ser., 501-504 (1970). (621) A. Klemer and C. Apostolides, Carbohydr. Res., 22, 432-435 (1972). (622) A. J, Mian, E. J. Quinn, and C. Schuerch,J. Org. Chem., 27, 1895-1896 (1962). (623) R. Pernikis, V. V. Korshak, V. A. Sergeev, and J. Surna, Latu. P S R Zinat. Akad. Vestis Kim.Ser., 297-302 (1964). (624) R. Pernikis, J. Surna, B. Apsite, and B. Dzvinko, Lato. P S R Zinat. Akad. V e s t i s Kim. Ser., 738 (1970). (625) R. Pemikis, B. Apsite, and J. Surna, Latv. PSR Zinat. Akad. Vestis Kim. Ser., 477-482 (1972). (626) H . Sumitomo, M. Okada, and Y. Hibino,J. Polym. Sci. Polym. Part €3, 10, 871876 (1972). (627) J. Kops, J . Polym. Sci., Part A-1, 10, 1275-1276 (1972). (628) H . K. Hall, Jr., and M. J. Steuck,]. Polym. Sci. Polym. Chem. Ed., 11, 1035-1042 (1973). (629) J. Pacik, P. Dragar, J. Nerudovi, and M. Cernq, Collect. Czech. Chem. Commun., 37,4120-4125 (1972).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

75

with unexpected selectivity, as was shown for the 4-O-benzyl group in 2-acetamido-1,6-anhydro-3,4-di-O-benzyl-2-deoxy-~-~-glucopyraDebenzylation with sodium in liquid or by oxidation to a benzoyl group followed by hydrolysis,319are rarely used. Markedly acid conditions, such as 80% trifluoroacetic acid for removing the tert-butyl group while maintaining the acetoxyl g r o ~ p (com~~5 pare Ref. 51),can be used only for those 1,6-anhydroderivatives having an electronegative substituent on C-2 (see Sect. VII,l,b). Catalytic hydrogenolysis is also advantageous for the removal of the versatile benzyloxycarbonyl group,52oeven though, for this group (as well as for acetyl and benzoyl groups), transesterification presents no difficulties. No selectivity was in the usual de-p-toluenesulfonylation with sodium amalgam,38J34*2s5 advantageously cond ~ ~ t e dat pH ~ ~6-8; ~ treatment j ~ ~ ~of, the ~ final ~ ~mixture with a s o h tion of chlorine in chloroform substantially simplifies the isolation of product^.^^^,^^^ Under carefully controlled conditions, the de-p-toluenesulfonylation of 1,6 : 3,4-dianhydro-2-O-p-to~ylsu~fo1iy~-/3-~-ga~actopyranose (111) proceeds even without epoxide (compare Ref. 448),as well as by the milder, photolytic de-p-toluene~ u l f o n y l a t i o n(compare ~~~,~~ Ref. ~ ~479). ~~~ Besides the groups already mentioned, some less-familiar O-substituents have been used in synthesis of 1,6-anhydrohexoses; for example, MeCH(C02H),638 -B(OR)2,591 -S02Cl,125 -S020Na,639 -NHCOPh,536.640*641 O - O ~ N C ~ H ~ C-O C -S,S~C~ U ~ , ~and ~ ~ the tetrahy-

(630) V. Soukupova, K. VereS, J. Benei, a i d M. Cemj., Radiopharm. Labelled Comp., 2,231-237 (1973). (631) V. Soukupovi, M. Cernj., and K. VereS, Rudiochem. Radioanal. Lett., 18, 107116 (1974). (632) N. M. Merlis, E. A. Andrievskaya, L. I . Kostelian, and 0. P. Golova, Zzv. Akad. Nauk S S S R , Ser. Khim., 139-142 (1975). (633) F. Schmitt and P. Sinay, Carbohydr. Res., 29,99-111 (1973). (634) G. V. Davydova, M. S. Dobrzhinskaya, and N . N. Shorygina, Izv. Akad. Nauk S S S R , Ser. Khim., 883-886 (1963). (635) Y. Rabinsohn, A. J. Acher, and D. Shapiro,J. Org. Chem., 38,202-204 (1973). (636) M. Cem?, L. Kalvoda, and J. Pacak, Collect. Czech. Chem. Commun., 33, 11431156 (1968). (637) A. D. Barford, A. B. Foster, and J. H. Westwood, Carbohydr. Res., 13, 189-190 (1970), (638) C. Merser and P. Sinay, Tetrahedron Lett., 1029-1032 (1973). (639) P. Karrer, H. Koenig, and E. Usteri, Helo. Chim. Acta, 26, 1296-1315 (1943). (640) I. A. Wolff and C. E. Rist,]. Am. Chem. SOC., 70,3961 (1948). (641) S. Hirase and K. Watanabe, Bull. Chem. Soc. Jpn., 45, 1569 (1972). (642) T. Lieser and W. Nage1,Justus Liebigs Ann. Chem., 495,235-249 (1932).

76

MILOSLAV CERNY AND JAN STANEK, JH

dropyranyl group."X".4Y6 DuringT the past several years, marked interest has developed610in glycidyl ethers of l e v o g l u ~ o s a n(see ~ ~ ~also, Ref. 644), and in miscellaneous products of its reaction with epichloroor propylene o ~ i d e . Their ~ ~ ~hardening,592,60s, , ~ ~ ~ hydrin,s92,605,64s-647 643,646,650 especially in the presence of 1,6-hexamethylene diisocyanate,"45,647,648,651 leads to resins having good physicomechanical properties. The same is true of polymers based on methacrylic esters of l e v o g l u c ~ s a n , adducts ~ ~ ~ - ~ of ~ ~levoglucosan with diisocyanate~,6~~ or polyurethans based on levoglucosan esters with adipic a ~ i d ,all~ ~ ~ , ~ of them seeming to be of practical use as coatings and foams (see also, Refs. 659 and 660). (643) L. G. Carlberg and F. Shafizadeh, U. S. Pat. 3,414,560 (1968); Chem. Abstr., 70, 58,227 (1969). (644) B. I. Mikhant'ev, V. L. Lapenko, E. Yu. Ponomarenko, an d N. L. Vasil'eva, Zh. Obshch. Khirn., 42, 190-193 (1972). (645) U. Stirna, R. Pemikis, J. Surna, B. Apsite, V. A. Sergeev, and M. V. Shashtaeva, USSR Pat. 298,608 (1971); Chem. Abstr., 76, 34,869 (1972). (646) U. Stirna, R. Pernikis, and J. Suma, USSR Pat. 372,236 (1973);Chetn. Abstr., 79, 54,309 (1973). (647) U. Stirna, R. Pernikis, and J. Suma, Lato. PSR Zinat. Akad. V e s t i s Kim. Ser., 726-731 (1969). (648) U. Stirna, B. Lazdina, R. Pemikis, J. Surna, and 0. N. Kuz'mina, Plasf. M u s s y , No. 1, 7-8 (1974). (649) B. Ladzina, R. Pernikis, and J. Suma, Lutu. PSR Zinut. Akad. Vestis Kim. Ser., 74-78 (1976). (650) U. Stima, R. Pernikis, and J. Surna, Lato. PSR Zinat. Akad. Vestis K i m . Ser., 606-609 ( 1974). (651) B. Lazdina, R. Pernikis, and J. Snrna, Latu. PSR Zinut. Akud. Vestis Kim. Ser., 349-353 (1975). (652) 0. P. Golova, N. M. Merlis, K. I. Zhdanova, S. P. Valueva, E . A. Andrievskaya, V. A. Kargin, and E. P. Cherneva, USSR Pat. 255,259 (1971); Chem. Abstr., 76, 59,975 (1972). (653)V. A. Kargin, Z. Ya. Beresneva, E. P. Cherneva, S . P. Valueva, 0. P. Golova, and K. I. Zhdanova, USSR Pat. 303,324 (1971); Chem. Abstr., 75, 152,334 (1971). (654) V. A. Kargin, S. P . Valueva, and E . P. Chemeva, Vysokomol. Soedin., Ser. B , 15, 157-159 (1973). (655) S. P. Valueva, A. B. Zezin, and V. A. Savin, Vysokomol. Soedin., Ser. A, 16,212216 (1974). (656) B. Lazdina, R. Pemikis, U . Stirna, and J. Surna, Lato. PSR Zinat. Akad. Vestis K i m . Ser., 711-716 (1971). (657) U. Stirna, R. Pernikis, J. Surna, and B. Apsite, Lata. PSR Zinat. Akud. Vestis Kim. Ser., 603-606 (1968). (658) U. Stirna, R. Pernikis, J. Surna, and B. Apsite, Latu. P S R Zinat. Akad. Vestis Kim. Ser., 618-621 (1972). (659) U. Stirna, R. Pernikis, and J. Surna, Latu. PSR Zinut. Akud. Vestis kin^ Ser., 696-700 (1971). (660) V. K. Matveev, L. S. Karmanova, K. V. Pazel'skaya, Ya. V. Epshtein, N.S. Maksimenko, and V. I. Minakova, USSR Pat. 192,328 (1967); Chem. Ahstr., 68, 79,074 ( 1968).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

77

a. Per-0-substituted 1,6-Anhydrohexopyranoses.-Even though the differences in the reactivity of secondary hydroxyl groups in acylations and alkylations are clear (see Sect. IV,3,b), especially in reactions with bulky and less reactive reagents, the per-0-substitution of poses no particular all eight possible 1,6-anhydro-p-~-hexopyranoses problem. The 2,3,4-tri-O-acyl or 2,3,4-tri-O-alkyl derivatives obtained now serve mainly for identification purposes; this is especially true of the complete series of triacetates (see Table V), and of per(trime~y~s~~y~)99,147,190,194,213,214,235,424,441,470,479,481-4483,661 and permethy149.67,90. 128,149,188,282,286,290,308,441,471,484,490,492,494,593,622,662,663 ethers, all of them useful ~c~99,113,116,119,12l,l47,l9O,l94,2l3,2l4,235,424,44l,47O,479,4Rl-4R4For most of the in configurational isomers, ~r~~~~~enzoy~,6,27~28,3R~9l~l22,l26,l3l,l46~l84~lS5~l95~2l7~ 222,283,289,292,437,520,563,662,664 tri-O-.p-tolylsulfonyl 38,118,122,156,283,289,520,622,665,666 , tri-O-(p-nitrobenzoyl),250,664tri-O-benzyl,45,287,316,444,531,533,613,615,fi16,634 hiO-(chlor~sulfonyl),~~~ and tri-O-(triflu~roacetyl)~~',~~~ derivatives have been further described. Some of these derivatives are known for the 1,6-anhydro-~-~-g~ycopyranoses from a110se,99,118,479,662 altr~se,'~~~~~ 479,664 ga~ac~ose,45,125,190,289,290,308,424,470,47l,479,483,616

g~Ucose,6,27,28,38,49,67,90,91,

125,156,184,185,188,190,194,195,213,214,2 17,222,235,250,292,316,424,441,470,479,481-483,490,492,494,520,

idose 7 125,128,131, and talose.424,479(The combination of configuration and type reference will enable the reader to find the compound in question.) For levoglucosan (6), the t r i - O - ~ t e a r o y l , ~tri-O-palmit0yl,6~~ ~~,~~~ trinitrate,622,668,669 tri-0-propi0 n y 1 , ~ ~~i -~O, -~b ~ i~t y r y l , ' ~tri-O-(methylsulfonyl),622 ~,~~O tri-O-ethy1,441, 521,644,671 t~i_O_al]y1,643,644 hi-0-viny1,52'*644and other derivatives536,616,617, have also been described. Their general properties are discussed in Section 111. An excess of sodium (-6 equiv.) in liquid ammonia converts the trimethyl ethers of 1,6-anhydrohexopyranosesinto pheno1128,286,290,672,fi73 531,533,563,593,613,622,634,661-663,665,666 147,149,471,479

guloSe,122,126,128,146,437,479,484

mannOse,282,283,286,2R7,424,471,479,483,615

639,640,6433644

(661) L. Birkofer, A. Ritter, and F. Bentz, Chem. Ber., 97, 2196-2201 (1964). (662) J . S. Brimacombe and L. C . N. Tucker, Carbohydr. Res., 40,387-390 (1975). (663) D. V. Tishchenko, Z h . PrikZ. Khim., 15, 970-976 (1942). (664) I. Johansson and N. K. Richtmyer, Carhohydr. Res., 10,322-324 (1969). (665) N. K. Richtmyer, personal communication; see Ref. 38. (666) E. Vis, Dissertation, Univ. Zurich, 1956; see Ref. 38. (667) P. Karrer, J. Peyer, and Z. Zega, Helw. Chim. Acta, 5, 853-863 (1922). (668) W. Will and F. Lenze, Ber., 31, 68-90 (1898). (669) L. P. Kuhn,J. Am. Chem. Soc., 68, 1761-1762 (1946). (670) I. A. Wolff,J. Am. Chem. SOC., 67, 1623-1624 (1945). (671) N. M. Merlis, 2 . V. Volodina, and 0. P. Colova, Zh. Obshch. Khim., 34, 38193821 (1964). (672) P. P. Shorygin and N. N. Makarova-Zemlyanskaya, Dokl. Akad. Nnuk SSSR, 23, 908-911 (1939). (673) N. N. Shorygina and G. V. Perfilova, Dokl. Akad. Nauk S S S R , 114, 1040-1042 ( 1957).

78

MILOSLAV ~ E R ~ X A Y N D JAN STANEK, JR.

together with -10% of a mixture of pyrocatechol, resorcinol, and resorcinol monomethyl ether.2S6,673j674 Under constant reaction-conditi on^,^*^*'^^ the yield of phenol from trimethyl ethers of the 1,6-anhydro-j+D-glycopyranoses from glucose, gulose, and idose is -50%, from that of galactose, -30%, and from that of mannose, 16%, as a consequence of structure-degradation mechanism relationships674 (see also, Ref. 675). If pyridine is used instead of ammonia, the major products are the bivalent phenol^."^ Levoglucosan triacetate (38), or the tribenzyl ether (24), produces no phenol under the conditions of the Shorygina reaction in ammonia634;the levoglucosan formed decomposes slowly in the presence of an excess of sodium. The persubstituted derivatives having two, or three, different substituents also serve mainly for identification purposes. Suitable selection of conditions needed for cleavage of the 1,6-anhydride bond permits transformation of most of the persubstituted 1,6-anhydrohexopyranoses into 2,3,4-tri-O-substituted derivatives of aldohexoses (see Sect. IV,l). Ring-opening polymerization of ethers and esters has been discussed in the previous Section. b. Partially Substituted 1,6-Anhydrohexopyranoses.-Even though the different reactivities of the hydroxyl groups often enable the direct preparation of partially esterified or etherified derivatives in high yield, indirect methods of synthesis have, so far, evidently been used more often. Many of these compounds were prepared from suitably substituted hexoses, glycosides, and polysaccharides, as described in Section 11. Among 1,6-anhydro compounds, the isopropylidene acetals are suitable (see Sect. IV,6) for the synthesis of 2- and 4-0-substituted 1,6anhydrohexopyranoses having cis-disposed, free hydroxyl groups (that is, among the 2-0-substituted compounds, only those of the d o , altro, galacto, and talo configurations). Isomers having trans-oriented, vicinal hydroxyl groups are then obtained from the mono-0substituted epoxy derivatives; however, this method is practically restricted (see Sect. V,3) to the synthesis of 2- and 4-0-substituted derivatives of levoglucosan, 4-0-substituted derivatives of 1,6-anhydro-6-D-galactopyranose, and 2-0-substituted derivatives of 1,6-anhydro-6-D-niannopyranose. (674) G . V . Davydovaand N. N. Shorygina,DokZ.Akad.h’nickSSSR,154,140-143( 1964). (675) G. V. Davydova, A. V. Lozanova, and N . N . Shorygina, in Khim. B i o k h i m . U g l e voclou, Muter. Vses. Konf., 4th, 81-83 (1967);N. K. Kochetkov, ed., Izd. “Nauka,” Moscow, USSR; Chem. A h t i - . , 73, 45,719 (1970). (676) G. V . Davydova, N. N. Shorygina, and A. V. Lozanova, Izv. Akod. Nuuk S S S R , Ser. Khim., 1870-1872 (1965).

1.6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

79

A suitable choice of the protecting group permits preparation, from these mono-0-substituted compounds, of the corresponding 2,3- or 3,4-di-O-substituted derivatives. The conversion5' of 1,6 :2,3-dianhydro-4-O-benzyl-/3-~-mannopyranose (116) into 1,6-anhydro-2,3-di-Omethyl-P-D-glucopyranose by way of 1,6-anhydro-4-O-benzyl-p-~glucopyranose serves as an example. In addition, the epoxide ring can be opened not only by hydrolysis but also by the action of alcohols or acids, to give further possible derivatives. The properties of esters and ethers of 1,6-anhydrohexopyranoseshaving one, or two, free hydroxyl group(s) are summarized in Table VI. Some partially esterified derivatives can also be obtained by using the decomposition of acyloxonium salts (see Section IV,5); as a result of a fair degree of stereospecificity, the preponderant isomer obtained is that having the axial hydroxyl group acylated and the equatorial one unsubstituted. An analogous regioselectivity is exhibited by the lithium aluminum hydride-aluminum chloride cleavage of 1,6-anhydro-2,3-O-benzylidene-~-~-mannopyranose or its 4-methyl ether, which yields the 3-0-benzyl derivative only.677 The number of partially substituted derivatives obtained directly from hexosans by way of partial esterification or etherification is still low, but has, however, grown rapidly in the past few years. This progress has been stimulated by developments in separation methods, especially by application of chromatography. Compared with common saccharides, the 1,6-anhydrohexopyranoses have the advantage of fixed equatorial or axial hydroxyl groups, these remaining unchanged in orientation in the course of even multi-stage acylation or alkylation. Moreover, the presence of the 1,6-anhydro bridge markedly influences the reactivity of the axial hydroxyl group on C-3. As a result, the overall differences in the reactivity of the hydroxyl groups are often so great that only one of the products possible is formed almost exclusively. Indeed, it was the use of partial esterification that enabled the great synthetic exploitation of levoglucosan (6), the most readily accessible 1,6-anhydrohexopyranose.The steric interaction of the axial 3-hydroxyl group with the 1,6-anhydro bridge is accentuated on reaction with the bulkier acid chlorides or anhydrides in pyridine in such a way that this hydroxyl group is esterified substantially more slowly than the other axially oriented ones. Consequently, the dimolar esterification of 6 with p-toluenesulfonic anhydride,lS6benzyloxycarbonyl chloride,520p-toluenesulfonyl chloride,38J06~156~505,520,636 benzoyl chlo(677) S. S. Bhattacharjee and P. A. J. Gorin, Can. J. Chenz., 47, 1207-1215 (1969).

80

MILOSLAV ~ E R N Y A N D JAN STANEK,JR.

ride,38,s2n*662 and benzoic anhydride38yields exclusively the 2,4-di-0substituted derivatives, with yields decreasing in the order in which the agents are mentioned (79, 74, 69%, etc.); p-toluenesulfonylation to give 43, followed by conversion into 1,6 :3,4-dianhydro-2-0-ptolylsulfonyl-P-D-galactopyranose (111) (see Sect. V, I), is generally the first step in a great majority of syntheses starting from levoglucosan (6).

6

43

In fact, p-toluenesulfonylation with p-toluenesulfonyl chloride in pyridine is the most thoroughly studied esterification for the group of 1,6-anhydrohexopyranoses.The readier esterification of the axial hydroxyl groups at C-2 and C-4 (compared with that on C-3) is also evident from the results of the monomolar p-toluenesulfonylation of various 2-or 4-O-substituted derivatives of 6 (Refs. 38, 155, 156, and 635), of the corresponding 2- and 4-deoxy derivatives,329and of the 2-fluor0,~~",~"~ 4-fluor0,4~~ and 2-(benzyloxycarbonylamino)678derivatives, where mostly those compounds having the 3-hydroxyl group free were obtained. Difficulties with the p-toluenesulfonylation of the axial, 3-hydroxyl group can be deduced, even from the conditions which had to be used for the preparation of 1,6-anhydro-2,3,4-tri-Op-to~y~sulfonyl-~-D-g~ucopyranose622 (compare also, total p-tolueneor 1,6sulfonylation of' 1,6-anhydro-4-O-benzyl-~-~-glucopyranose~~~ a i ~ h y d r o - 2 , 4 - d i - O - b e i i z o y l - ~ - ~ - g l u c o p y r ~ i i and ose~~ 1,6-anhydro~~~~) 2,3,4-tri-0-p-tolyls~lfonyl-~-D-a~~opyranose.'~~ The reactivities of the axial hydroxyl groups on C-2 and C-4 differ insignificantly; slightly more of the 2- than of the 4-O-.p-tolylsulfonylderivative was obtained ~ ~ ~also, ~ Ref. 448; and, on monomolar p - t o l u e n e s u l f o n y l a t i ~ nof~6~(see for the analogous benzoylation, see Ref. 680). No significant change M. Cerny, 0.JulCkova, and J. Pacik, Collect. Czech. Chem. Commun., 39, 13911396 (1974). M. Cerny, J. Standk, Jr., and J. Pacik, Collect. Czech. Chem. Commun., 34,849856 (1969). D. Shapiro, A. J. Acher, Y. Rabinsohn, and A. Diver-Haber,]. Org. Chem., 36, 832-834 (1971).

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

81

in the reactivity of the 4-hydroxyl group was observed when the free hydroxyl group on C-2 was replaced by a p-tolylsulfonyloxy group156 (compare Ref. 38). The equatorial hydroxyl groups on C-2 and C-3 are p-toluenesulfonylated more quickly than any one of the three axial groups already (44) (like its mentioned. Thus, 1,6-anhydro-p-~-mannopyranose 4-methyl ether) yields the corresponding 2-O-p-tolylsulfonyl derivativeZs5 (45); from 1,6-anhydro-2-O-benzoyl-~-~-altropyranose, the

HO

HO

45

44

3-O-p-tolylsulf~nylderivative was obtained.681In contrast to this, the equatorial hydroxyl group on C-4 is p-toluenesulfonylated with difficulty. The monomolar p-toluenesulfonylation of 1,6-anhydro-3deoxy-P-Dxylo-hexopyranoseyields the 2-p-toluenesulfonate as the major product; this was explained as resulting from the impossibility of the equatorial hydroxyl group on C-4 to be intramolecularly hydro1,6-anhydro-P-D-gulopyranose(46), the main g e n - b ~ n d e d . ' From ~~

OH 46

6TS 47

product of reaction (even with 6.3 equivalents of p-toluenesulfonyl chloride for 3 days) was found to be the 2,3-bis-p-toluenesulfonate1zz (47); also, the p-toluenesulfonylation of 1,6-anhydro-P-~-gulopyranose 2,3-phenylboronate proceeds, in contrast to such reactions of other isomeric 1,6-anhydrohexopyranose boronates, only with great diffic~1ty.l~~ However, as p-toluenesulfonylation of 48 readily gives 49 in a yield450of 71%, and as the main product of the p-toluenesul(681) F. H. Newth,J. Chem. SOC., 441-447 (1956).

82

MILOSLAV CERNY AND JAN STANEK, JR.

I OTs 40

I

OTs 49

fonylation of 1,6-anhydro-P-~-talopyranose is also the 2,4-bis-p-toluenesulfonate,682it may be supposed519that the nonreactivity of the 4-hydroxyl group of 46 is, at least partly, also due to the influence of the replacement of the vicinal hydroxyl group by the p-tolylsulfonyloxy group, which significantly retards further reaction in the e-e arrangement; the 2,3-diester (47)primarily formed does not react further to any appreciable extent. 1,6-Anhydro-/3-~-allopyranoseyields a rather complex mixture of p-toluenesulfonates .682 The effect of hydroxyl to p-tolylsulfonyloxy group exchange may also appear in otherp-toluenesulfonylations to the second or third stage previously mentioned, so that the conclusions reached on the basis of experiments carried to only one degree of substitution need not be entirely accurate. However, it seems probable5I9that the hydroxyl groups in 1,6-anhydrohexopyranosesreact with p-toluenesulfonyl chloride in pyridine in approximately the following order.683

OH-2e > OH-3e > OH-2u

OH-4a > OH-4e > OH-3a

The selectivity of esterification with benzoyl chloride in pyridine38,520,662,680 corresponds to that in the aforementioned p-toluenesulfonylations. Only 2-acetamido-l,6-anhydro-2-deoxy-/3-~-galactopyranose behaves “anomalously,” as benzoyl chloride or benzoic anhydride in pyridine gave512a greater proportion of axial 3-benzoate (48%) than 4-benzoate (38%). On methanesulfonylation, this conipound behaves “normally,” and gives mainly the 4 - s u l f 0 n a t e . ~The ~~ present authors conjecture that the possibility cannot be excluded that the result of benzoylation is influenced by the migration of ester groups during isolation, similar to that to be described for the acetates. (682) J. Doleialovii, unpublished results. (683) With such a sequence in mind, for a product (m.p. 70-71”, [c~],-63.8”)~*~ of the p-toluenesulfonylation of 1,6-anhydro-P-~-idopyranose, the structure of 1,6-anhydro-2-O-p-tolylsulfonyl-~-~-idopyranose may be proposed. The supposed structure of‘ 6-O-p-tolylsulfonyl-~-idosefor this compound123is, with respect to the optical rotation, improbable; the 1 , h n h y d r i d e bond should be stable under the conditions of p-toluenesulfonylation.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

83

The relevancy of steric interaction somehow decreases in esterifications with less bulky reagents; for example, the acetylation of 6 with 2.5 equivalents of acetic anhydride in pyridine gives the 2,3-, 3,4-, and 2,4-di-O-acetyl derivatives in almost the same yields.51 When compared with the result of the same reaction performed with the 2-acetamido analog 50, where the 4-0-acetyl derivative (51) is formed633almost exclusively, it is clear that the replacement of the 2-0-acetyl for the 2-acetamido group must very distinctly influence the reactivity relationships of the remaining axial hydroxyl groups in the molecule.

50

51

The course of the acetylation of 6 was examined kinetically.684The observed time-dependence of the total rate-constant was interpreted in the form of three independent, acetylation stages, for each of which the values of activation energies were determined; the energy of the second stage685is lower than those of the other two.686The rate constants for all six dideoxy derivatives of 1,6-anhydro-P-~-hexopyranoses during esterification with acetic anhydride in pyridine were estimated; because of the known difference in the behavior of carboxylic acid anhydrides and the corresponding acid chlorides during esterification in pyridine, the reaction with acetyl chloride was also studied.408The sequence of reactivities for acetic anhydride is OH-3e

- OH-4e > OH-2e > OH-4a > OH-& > O H - ~ U ,

(684) U. Stirna, R. Pernikis, and J. Surna, Latc. PSR Zinut. Akad. Vestis K i m . Ser., 479484 (1970). from d.s. 1 to d.s. 2 . (685) More (686) The interpretation of the experimental curve k-t in terms of three linear dependences seems very inadvisable, so that the values of the activation energies, E , , are highly questionable. We consider that the evaluation of the time dependency of the overall rate-constant cannot contribute substantially to the discussion of the complicated reaction system with 12 “partial” rate-constants.

84

MILOSLAV

CERNY AND

JAN STANEK, JR.

whereas the reactivities with acetyl chloride follow a quite different order, namely, OH-2e > OH-4a

3

OH-3e > OH-2a > OH-3a > OH-4e.

The results were interpreted by consideration of ( a ) steric interactions, such as that of the equatorial hydroxyl group on C-4 with the methylene group (retarding in both cases), ( b ) polar effects (the -I effect of the 5- and 6-oxygen atoms makes the reaction faster when acetic anhydride is used, but slower with acetyl chloride), and ( c ) stereopolar interactions that can be correlated with the existence and strength of intramolecular hydrogen-bonds (for AczO, retardation; for AcC1, acceleration; compare Refs. 52 and 156). From the background of quantitative evaluations of these effects, the results of the partial acetylation of several monodeoxy derivatives of 1,6-anhydrohexopyranoses were predicted.408The extension of the conclusions to unsubstituted 1,6-anhydrohexopyranosesis more complicated, owing to the different influence of the vicinal hydroxyl group and the acetoxyl group on the reactivity of the other hydroxyl groups. However, even in this case, it is possible to conclude from the sequence of reactivities that 1,6-anhydro-@-~-galactopyranose (12),or 2-0-acetyl-l,6-anhydroP-D-galactopyranose, should afford more 2,4-diacetate than 2,3-diacetate when acetylated with acetic anhydride and pyridine. Surprisingly, the experimental r e s ~ l t s ~of ” ,this ~ ~ reaction ~ were in contradiction with the previous conclusion; this “anomalous” acetylation was later explained b y the observation of migration of the acetyl group from 0-4 to 0 - 3 on silica gel during the chromatographic processing of the reaction mixture688(see also, Ref. 332); the acetylation itself results indeed in the expected 2,4-dia~etate.~’~ The selectivity of alkylation of 1,6-anhydrohexopyranosesis lower than that of acylations. The relative rate-constants for the three hy(6) during methyladroxyl groups in 1,6-anhydro-P-~-glucopyranose tion with dimethyl sulfate in 19% sodium hydroxide solution689are k, :k,: k, = 2.5: 1 : 1.8, so that the formation of pure monomethyl or dimethyl ethers of 6 by this method is of little preparative value (compare Refs. 224 and 671). 1,6-Anhydro-P-D-galactopyranose (12)affords mostly the 2,4-di-O-methyl derivative,6g0and 2-acetamido-l,6-anhydro-2-deoxy-P-~-galactopyranoseis mainly methylated at 0 - 4 by the (687) M. E. Chach-Fuertes and hd, Siartin-Lomas, An. @ii?n., to be pul~lished. (688) M. E. Chac6n-Fueites and M. Martin-Lomas, CarbohtJdr. Res., 42, c4-c5 (1975). (689) B. Norrman, Acta Chem. Scand., 22, 1623-1627 (1968). (690) J. Fellig, personal communication; see Ref. 510.

1,fi-ANHYDRO DERIVATI\’ES OF ALDOHEXOSES

85

action of dimethyl sulfate510;however, no methylation of the latter was observed when methyl iodide and silver oxide were used.510 Benzylation of 6 yields about 25% of the 2,4-di-O-benzyl derivative531,546*691; tritylation understandably proceeds more selectively, but with d i f f i c ~ l t y .The ~~~ use , ~of ~~ dipolar, aprotic solvents and, in connection with this, more moderate conditions, is evident in the benzylation of 50, where the 4- and 3-benzyl ethers are formed633in the ratio of 9: 2. Some selectivity of acylation or alkylation has been observed in several other cases; however, the structures of the products could not be unambiguously estimated.642~692*693 Low selectivity is characteristic of Koenigs-Knorr condensations of acetylated glycosyl halides with 1,6-anhydrohexopyranoses(see Sect. X,l,b).

4. Nucleophilic Replacement of Sulfonic Esters Nucleophilic substitutions without neighboring-group participation proceed with some difficulty for 1,6-anhydrohexopyranoses; owing to their rigid skeleton, they are restricted to only a few structural variants. For an equatorially attached sulfonyloxy group, only 52 undergoes513displacement with sodium azide to yield 53. Among

52

53

the axial sulfonyloxy groups, that on C-3 is readily displaced, provided that no axial, nonparticipating substituents are present on C-2 and C-4. Thus, 1,6-anhydro-4-deoxy-2,3-di-O-p-tolylsulfonyl-~-~Z~~~hexopyranose reacts with sodium benzoate in N,N-dimethylformaderivative having mide to give the 3-O-benzoyl-2-O-p-tolylsulfonyl Walcleii inversion also proceeds the p-Darabino coiifiguratioii.~R~ I. Angyal, Mag. Biol. Kutatdinti‘z. Munkai, 10, 449-451 (1938); Chem. Abstr., 33,4963 (1939). P. Karrer and H . R. Salomon, Helu. Chirn. Acta, 5, 108-123 (1922). N. M. Merlis, K. I. Zhdanova, A. K. Khomenkov, E. A. Andrievskap, L. I. Kostelian, and 0. P. Golova, USSR Pat. 321,100 (1972); Chem. Abstr., 78, 58,744 (1973).

MILOSLAV CEHNY A N D JAN STANEK, JR.

86

readily377for 219, and so the as-yet-undescribed 1,6-anhydro-2,3,4-tri0-p-tolylsulfonyl-fi-D-talopyranose would obviously react in the same way. On the other hand, the displacement of the axial hydroxyl group on C-3 of 1,6-anhydro-2-O-p-tolylsulfonyl-~-~-glucopyranose, or of 43, with triphenylphosphonium methiodide failed632;under these conditions, however, the axial hydroxyl group on C-4 in the former compound is replaced by iodine.632On C-2, no direct substitution of an axial sulfonyloxy group has been described, the effect of 0-6being clearly visible. Chloride anion displacements do not proceed for the tri(chlorosu1fate)s of 1,6-anhydro-P-~-gluco-,-galacto-, -ido-, and -altro-pyranoses,lZ5 even though, for the last, a reaction could be expected. The presence of the 1,3-dioxolane ring in isopropylidene acetals of 1,Fi-anhydro-2,4-di-O-benzoyl-3-O-(methyls~1lfonyl)-~-~-glucopyranfonyloxy groups completely i m p ~ s s i b l e . ~The ~ ~ axial -~~~ methylsulfonyloxy group in compound 54 reacts, however, with potassium fluoride dihydrate in methanol, but the reaction product is neither the 2-methyl ether695nor the 2-fluoro derivative of 1,6-anhydro-P-~-taloin~ , " ~ pyranose, but a mixture of methyl glycosides (55) ~ r i g i n a t i n g ~ ~ the intramolecular displacement from 0 - 6 (compare d e a m i n a t i ~ n , ~ ~ ' in Sect. VI).

KHF,

I

M

e

2

1

e

o

M

e

MeOH

0 I

OMS 54

55

Replacement, with neighboring-group participation, was used for the preparation of 1,6-anhydro-/3-~-allopyranose(33) by solvolysis of 1,6-anhydro-2,4-di-O-benzoy~-3-O-(methylsu~fony~)-~-~-g~ucopyr~~no s P 2 ; 1,6-anhydro-2-O-p-tolylsulfonyl-~-~-galactopyr~nose was prepared ~imilarly,"~ starting from 43.Often, the solvolysis of sulfonyloxy groups having an adjacent, trans, acetamido or benzamido group has (694) A. K. Chatterjee, D. Horton, and J. S. Jewell, Carbohydr. Res., 7,212-217 (1968). (69.5) P. W. Kent, D. \Y. A. Famier, a n d N. F. Taylor, Proc. Chem. Soc. (London), 187-

188 (1959). (fi96i N. A. Hughes,J. Chem. Soc., C , 2263-2266 (1969). (697) N. A. Hughes, Chem. Commun., 1072-1073 (1967). (6%) F. Micheel, W. Neier, and T. Riedel, Chem. Ber., 100, 2401-2409 (1967). (699) T. Trnka, Thesis, Charles University, Prague, 1972.

1.6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

87

been ~ s e d . ~This ~ reaction ~ , ~ with ~ ~sodium , ~ acetate ~ ~ ~ in aqueous ~ ~ ~ 2-methoxyethanol proceeds with Walden inversion, regardless of whether the groups are both axial or both equatorial. Similar reactions leading to epimines or epoxides are discussed in Sections V and VI, and eliminations are considered in Section VII,3.

5. Acyloxonium Ions The action of trifluoromethanesulfonic acid on cis, as well as trans, vicinal diacetates results in the formation of acetoxonium ions. On the other hand, only cis isomers are transformed by anhydrous hydrogen fluoride, whereas antimony pentachloride is the selective reagent for the trans isomers. Under these conditions, the reactions of 2,3,4-tri-O-acetyl-1,6-anhydrohexopyranosesare rather complicated, as the ions formed undergo isomerizations and ring-contractions; moreover, these are accompanied by decomposition. Such a reaction course may, however, be readily monitored by n.m.r. spectroscopy. Hydrolysis of acetoxonium ions in an aqueous solution of sodium hydrogencarbonate leads almost exclusively to cis opening, and the product having an axial ester group and an equatorial hydroxyl group preponderates. 1,6-Anhydro-P-~-altropyranose triacetate (56) and 1,6-anhydro-p-~mannopyranose triacetate (57) react with trifluoromethanesulfonic acid, with the formation of an equilibrium mixture of Daltro ion (58) and D-manno ion (59), the former significantly prevailing.422Similarly,

AcO 56

57

AcO OAc

Me 58

59

38

(700) A. C. Kichardson and H. 0.L. Fischer, Proc. Chein. Soc. (London), 341-342 (1960).

88

MILOSLAV

ERN+

AND JAN STANEK, JK.

an equilibrium mixture of D g d o (major) and ~ g a l a c t oions is obtained on reaction of the triacetates of 1,6-anhydro-P-~-gulopyranose or 1,6-anhydro-P-D-galactopyranose.""' For the latter, a trans pathway is also involved, with formation of the 2,3-D-talo ion. This pathway, involving the scission of the 2-acetoxyl group, is the only one that proceeds when levoglucosan triacetate (38) is here, the resulting in an no ion (59) is isomerized, as soon as it is formed, into the more stable 58. From 1,6-anhydro-p-~-allopyranose triacetate, a mixture of o is obtained422in which the 2,3-ion definitely prevails. both ~ a l l ions Both possible ~ t a l oions, in almost the same quantities, are formed triacetate.l% For a complex reacfrom 1,6-anhydro-p-~-talopyranose see Ref. 429a. tion of 2,3,4-tri-O-acety1-1,6-anhydro-P-~-idopyranose, Practically all reactions of tri-O-acetyl-1,6-anhydrohexopyranoses with trifluoromethanesuIfonic acid are connected with the formation of minor by-products, these either constituting derivatives having o D-gulo configurations (that is, from the truns-opening of the ~ - i d and oxonium ions) or belonging to the class of 1,6-anhydrohexofuranoses or 1,5-anhydrohexofuranosesformed by ring-contraction. The ringcontraction products are observed, markedly, in the D - ~ U Z O and D - u Z Z ~ series, where the 2,3-acetoxonium furanoid ions contain all three rings em-oriented and, therefore, are relatively the most stable.422,453 The presumed mechanism of the ring-contraction yielding a 1,6-anhydrohexofuranose with retention of configuration is presented, for the ~allo in Scheme 8.

he

Me

Me

I1

1.6-AN HY D R O DERIVATIVES OF A L D O H E X O S E S

89

The isomerization of the Drnanno ion (59) and Daltro ion ( 5 8 ) was also observed in hydrogen fluoride; here, the ions are generated from peracetates of D-glucose, D-mannose, and D-altrose, or from their methyl glycosides by way of the corresponding acetylated glycosyl f l ~ o r i d e s . ~An~ analogous ~ , ~ ~ ~ , reaction ~ ~ ~ with benzoyl derivatives is more convenient for preparation, as it allows the synthesis of 1,6anhydro-P-D-altropyranose in 45% yield, starting from per-0-benzoylP-D-gh~opyranose.”~ Methyl 2,3,6-tri-O-benzoyl-4-O-(p-nitrobenzoy1)-a-D-galactopyranoside (60) was similarly used3I3for a high-yield(46), isolated as the ing preparation of 1,6-anhydro-P-~-gulopyranose triacetate 61. CH,OBz

OBz

C,H,N%-P

OBZ

0

C,H,NO,-P

OBz

60

*“u r-9

’ (1) (2) H,O MeONa I”

*-20, C,H,N

0. +,,o

Y Ph

61

The reaction of 38 with antimony pentachloride is analogous to the reaction with trifluoromethanesulfonic acid, that is, the main products formed are those having the ~ a l t r oonf figuration.^^ The formation of benzoxoniuin or acetoxonium ions in the acidcatalyzed opening of the oxirane ring was used for the preparation of the 1,6-anhydrides of D-gulopyranose (46) and D - a l t r ~ p y r a n o s e ~ ~ ~ , ~ ~ ’ (see Sect. V,3).

6. Acetalation Those 1,6-anhydrohexopyranosesthat have two cis-disposed, vicinal, hydroxyl groups may readily be converted into the correspond-

90

MILOSLAV CERNY A N D JAN STANkK, JR.

ing monoisopropylidene acetals, by using acetone and anhydrous cupric s~~fa~e,30,37,86,l06,lll,ll3,ll6,~83,284,286,Z88-29O,294,295,464,465 or acetone in

the presence of sulfuric acid,"9~134,285,436~497~509~701~702 p-toluenesulfonic acid,4I8 ethyl o r t h o f ~ r m a t e or , ~ ~hydrogen ~ chloride with a trace of ~ a r a l d e h y d e .This ~ ~ ~ enables the isolation of the anhydrides concerned from complicated r e a c ~ ~ o n ~ m ~ x ~ u r e s , 3 0 ~ 3 7 . " ' . 1 1 3 . " ~ ~ l l 9 ~ ~ ~ ~ ~ ~ ~ ~ - ~ ~

especially as the isopropylidene group may easily be split off b y acid without cleavage of the l,6-anhydro ~ i n g . ~ ~ , ~ ~ ~ , ~ ~ 283-286,288-290,308,415,419,424,436,439,461,464,465,475,497,509,512,641,681,702-708 Owing to

290,294,2953701

the free hydroxyl group (either on C-2 or C-4), the isopropylidene derivatives are very good starting-materials for numerous syntheses. Thus, from 1,6-anhydro-2,3-0-isopropylidene-~-~-mannopyranose ,283-286,457 various ethers, esters, and disaccharides may be prepared (after the substitution of the free hydroxyl group at C-4) which yield, after removal of the isopropylidene group, the 4-O-substituted derivatives of 1,6-anhydro-p-~-mannopyranoseor D-mannose, respectively.48~283-2~5~493~705-707~709~710 Similarly, from 62 (Refs. 37, 86, 288-290, 294, and 308), the 2-O-substituted derivatives of 1,6-anhydro-p-~galactopyranose (for example, 63) or D-galactose may be obtainedPw. 48,289,308,509,512,641,703,704,708,708a,709 The use of a suitable protecting group (for example, the phenylcarbamoyl group) then also enables the synthesis641of the corresponding 3,4-di-O-substituted derivatives (for example, 64). 1,6-Anhydro-3,4-O-isopropylidene-~-~-altropyranose~~~~~~~~ and 1,6-anhydro-2,3-O-isopropylidene-~-~-gulopyranose,4~~ although slightly less accessible, are also suitable, synthetic intermediates. Both 1,6-anhydro-p-~-talopyranose (67) and the D-allose analog (33) have three cis-arranged hydroxyl groups, and, therefore, may always yield two isopropylidene acetals. From 67, the 2,3-acetal (68) is (701) J. S. Briinaconibe aiid P. A. Gent, Carbolqtir. Res., 12, 1-8 (1970). (702) L. N. Owen and P. L. Ragg,]. Chem. Soc., C, 1291-1296 (1966). (703) R. B. Duff,]. Chem. Soc., 1597-1600 (1949). (704) H. Masamune and S. Kamiyama, Tohoku j . E r p . hled., 66,43119 (1957). (705) W. T. Haskins, R. M. Hann, and C . S. Hudson,]. Am. Chem. Soc., 63,1724-1726 (1941). (706) R. M. Hann and C. S. Hudson,]. Am. Chem. Soc., 64,925-928 (1942). (707) W. T. Haskins, R. M. Hann, and C. S. Hudson,]. A m . Chem. Soc., 64,1852-1856 (1942). (708) R. M. Hann and C. S. Hudson,]. Am. Chem. Soc., 68, 1867 (1946). (708a) K. Igarashi, T. Honma, S. Mori, and J. Irisawa, Carbohydr. Res., 38, 312-315 (1974). (709) W. T. Haskins, R. M. Hann, and C. S. Hudson,]. Am. Chem. Soc., 70,1290 (1948). (710) D. Horton and H. S. Prihar, Carbohydr. Res., 4, 115-125 (1967).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

OH 12

91

OH 62

63 R' = H, RZ = alkyl or acyl

64 RZ = H, R1 = alkyl or acyl

0 65

66

67

mainly obtained by treatment with acetone containing sulfuric acid; the proportion of the 3,4-isopropylidene acetal (66) does not475,497 exceed 10%. The same equilibrium composition results directly from 66 when it is treated with acidified acetone497(compare Refs. 106, 464, and 465); acetal migration occurs even under the conditions of hydrolysis of 66, that is, where any recombination with acetone is highly improbable and, therefore, the reaction must have an intramolecular character.497In contrast, on isopropylidenation, 1,6-anhydro-P-D-allopyranose (33) yields436a greater proportion of the 3,4acetal than of the 2,3-acetal (69:70 = 2: 1). With 1,6-anhydro-3-Cmethyl-P-D-allopyranose, the proportion of the 3,4-isopropylidene acetal is still higher.lo6Here, no steric reasons can be deduced, and the greater proportion of 69 may be caused by the inductive effect of 0-6. As regards 1,6-anhydro-p-~-talopyranose (67), the suppressed formation of the 3,4-acetal was explained by an unfavorable steric interaction of the isopropylidene methyl group with the rnethylene group ofthe 1,6-anhydro ring497;however, the role ofthe arrangement of the oxygen atoms (a-e-a or e-a-e) cannot be ignored. The isopropylidene derivatives 66 (Refs. 418, 419, 424, and 497) and 68 (Refs. 415, 419, 424, and 497) are usually prepared from 62 or 1,6-anhydro-2,3-0-isopropylidene-~-~-mannopyranose by using an oxidation-reduction sequence, such as 62-65-66 or 78+68; on hydrolysis, the acetals yielded415,419*424,497 1,6-anhydro-p-~-talopyranose (67). This process also permits the preparation of various specifically deuterated 1,6-anhydro-O-isopropylidenehexopyranoses

MILOSLAV

92

r---P

CERNY AND

JAN STANEK, JR

r

P

69

0

66

70

useful for the interpretation of the mass and n.m.r. spectra of this tricyclic s y ~ t e m . ~ ~ Some ~ * other ~ ~ ~deuterated , ~ ~ ~ , isopropylidene ~ ~ ~ derivatives have been prepared directly from deuterated 1,6-anhydroh e x o p ~ r a n o s e s , 4and ~ ~ acetone-& has also been used.418All of the n.m.r. data reveal a considerable flattening of the pyranoid ring (see Sect. 111); this deformation has been proved711even for the crystalline state of 66. In the partially deformed 'C4(D) conformation, the nonbonding separations of H-6endo to 0-3 and to 0 - 4 are equal, namely, 260 pm. The change of the geometry as a result of formation of the 1,3-dioxolane ring influences the values of the optical rotations, and this has been used for structural determination^.'^^,^^^ The compact and rigid system of 1,6-anhydro-O-isopropylidene derivatives makes nucleophilic displacement of the corresponding sulfonic esters at C-2 and C-4 practically impossible; under forcing conditions, intramolecular rearrangements lead to significant structural changes of the bicyclic skeleton (see Sect. IV,4). However, replacement of the hydroxyl group by a hydrogen atom can be accomplished, either by p h o t o l y s i ~of~ ~ the ~ dirnethylthio~arbamate,~~~ or by way of the S-methyldithiocarbonate derivatives and subsequent reduction with (711) N. C . Panagiotopoulos, Acta Crystallogr. Sect. B, 30, 1402-1407 (1974). (712) G. Fodor and L. Otviis,Justus Liebigs Ann. Chem., 691, 205-211 (1966).

I,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

93

tributyltin hydride7I3 to give isopropylidene acetals of 1,6-anhydrodeoxyhexopyranoses (see also, Refs. 383 and 713a). Whereas vicinal, cis-hydroxyl groups readily form isopropylidene derivatives (see Table VII) or other466,677 alkylidene acetals containing a 1,3-dioxolane ring (even the stable spiro-acetals 76 and 77, having two isopropylidene groups on the bicyclic skeleton have been prepared417),the axially oriented 2- and 4-hydroxyl groups of 6 form a IJ-dioxane ring with neither acetone under various reaction condit i o n ~ , nor 2 benzaldehyde,"* ~ ~ ~ ~ ~ ~ ~ nor~chlora1518 ~ ~ (for formation of hemiacetals with the latter aldehyde, see Ref. 715). More-vigorous treatment leads to cleavage of the 1,6-anhydro ring of levoglucosan (6) with the formation of D-glucose derivatives.520In view of these facts, the present authors presume that the compound described5'l as 1,6-anhydro-2,4-O-isopropylidene-~-~-glucopyranose (prepared from 6 and acetone with catalysis by sulfuric acid) is, in fact, 1,2:5,6-di-O-isopropylidene-a-D-ghcofuranose; methylation of both compounds followed by hydrolysis would yield 3-O-methyl-D-glucose, so that the isolation of this compound provides no proof as to the structure of the supposed 2,4-acetal. The axial hydroxyl groups of 6 resist the formation of borate, diphenylborinate, and similar complexes (see Sect. 111),and even the 2,4-phenylb0ronate'~~is remarkably unstable, in contrast to the 2,3-phenylboronates of 1,6-anhydro-P-~-gulopyranose and 1,6-anhydro-P-D-mannopyranose,and to 3,4-phenylboronates of 1,6-anhydro-PD-galactopyranose and 1,6-anhydro-/3-~-altropyranose.~~~ The phenylboronic group can be used to protect even the pair of equatorial, transhydroxyl groups on this bicyclic skeleton; 1,6-anhydro-p-~-altropyranose yields, on treatment with phenylboronic acid, a mixture of 3,4- and 2,3-boronates in the ratio of 10: 1.From 1,6-anhydro-p-~-gulopyranose (46),however, the trans 3,4-boronate is not formed in observable amounts, obviously due to steric hindrance of the 4-hydroxyl group with the methylene group of the 1,6-anhydro ring.lg4

7. Preparation of Hexopyranosulose Derivatives In the 1,6-anhydrohexopyranose series, derivatives having a ketone group have been prepared either by partial oxidation of the unsubsti(713) D. H. R. Barton and S. W. McComhie,]. Clzeni. SOC.Perkin Trans. 1 , 1574-1585 ( 1975). (713a) P. Koll, R.-W. Rennecke, and K. Heyns, Chem. Ber., 109, 2537-2541 (1976). (714) H. Ohle and K. Spencker, Ber., 61,2387-2392 (1928). (715) R. Pernikis, B. Apsite, and J. Surna, Latc. PSR Zinat. Akad. Vestis Kim.Ser., 362365 (1975).

94

MILOSLAV C=ERNY AND JAN STANEK, JR.

tuted 1,6-anhydrohexopyranose or by oxidation of an “isolated” hydroxyl group of a suitable derivative, such as isopropylidene acetals, which can be used for the synthesis of glycos-2- or -4-uloses, or the 2,4-di-O-substituted derivatives, suitable for preparing the corresponding glycos-3-ulose derivatives. The ketones obtained are not stable in alkaline medium, and exhibit a tendency to form hydrates and hemiacetals. The reactions of 1,6-anhydrohexopyranosulosesproceed mostly with high selectivity, as a result of the rigid skeleton; this fact can be advantageously used for the preparation of otherwise inaccessible derivatives of 176-anhydrohexopyranoses, including those specifically labelled with deuterium.5,52,415*416*41s a. Partial Oxidation.-The axially oriented hydroxyl groups of the unsubstituted 1,6-anhydrohexopyranosesmore readily undergo catalytic oxidation with oxygen on platinum than the equatorial groups. Their reactivity decreases in the following ~ r d e r ~ ~ ~ , ~ ~ ~ : OH-3a > OH-4a > OH-% > OH-4e > OH-2e > OH-3e,

the yields of the monoketones isolated reaching as high as 55%. However, from the practical point of view, it is more convenient to use, for the preparation of glycos-2- or -4-uloses, the oxidation of the corresponding isopropylidene a c e t a l ~as , ~this ~ ~ protecting group can be removed by acid hydrolysis, with no adverse influence on the parent 1,6-anhydrohexopyranosulose.419~436~460 Among the other oxidation agents, only bromine exhibits a selectivity capable of practical use (ignoring the extremely long reaction-times) for the preparation of 3-keto derivatives of 1,6-anhydrohe~opyranoses.~~~~~~~ After a short reaction-time in the cold, no action of bromine or potassium permanganate on the 1,6-anhydrohexopyranoseshas been o b ~ e r ~ e d . ~ ~ . ~ ~ At higher temperatures, the oxidation of 6 by potassium permanganate results in the formation of an as-yet-unidentified diketone.ls6 The reduction of the ketone group of 1,6-anhydrohexopyranosuloses b y means of sodium borohydride, or hydrogen on platinum, favors formation of products having the exo-oriented hydroxyl group; in contrast, the more tedious reaction with sodium amalgam yields more of the products having the equatorial hydroxyl g r o ~ p .In~such ~ ~ a,way, ~ ~ ~ the 1,6-anhydro-P-~-pyranosesof glucose, mannose, or galactose have been converted by the redox sequence (by way of glycos-3-doses) into the corresponding allose, altrose, or gulose derivative^.^^^,^^^

(716) L. T. Crews, J. P. Hart, and M. R. Everett,]. Am. Chem. Soc., 62,491493 (19440). (717) N. K. Richtmyer and C. S. Hudson,J. Am. Chem. Soc., 61,214-215 (1939).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

OAc

73

74

95

Y

AcO 75

The 176-anhydrohexopyranosuloseshaving a free hydroxyl group next to the carbonyl group (as in 71) can be isolated under suitable conditions in the form of relatively stable, crystalline, dimeric hemiacetals containing either a 1,4-dioxane (as in 72), or 173-dioxolane connecting ring; unlike glycosuloses, they are almost insoluble in ~ a t e r . ~ 1,6-Anhydro-P-~1 ~ ~ , ~ ~ ~ yxo-hexopyranos-3-ulose , ~ ~ ~ (having both hydroxyl groups equatorially oriented) is the only such compound examined that shows no tendency to form a dimer417,4G0 (see also, the formation of h y d r a t e ~ ~ l this ~ . ~might ~ ~ ) ;be attributed to an unfavorable interaction of oxygen atoms of the hemiacetal grouping with vicinal substituents (the “A2 effect”), which is much greater than in other dimers.436,460 The dimers can be per(trimethylsily1)ated in pyridine solution with, ~ ~ ~ , ~attempts ~~; at acetylation resulted out d e c o m p o ~ i t i o n ~ ’ ~however, in the cleavage of the glycos-3-ulose dimers (with the exception of that having the Dribo configuration), with simultaneous elimination of acetic acid, so that the final products were the monomeric, enediol acetates.456As only derivatives having the Derythro configuration were isolated, the elimination clearly must involve, selectively, the axially oriented hydrogen atom in the vicinity of the masked carbonyl group; 72 yields only 73 (and not 74). Efforts to prepare the Dthreo isomers

96

MILOSLAV CERNY A N D JAN STANEK, JH.

(such as 74) from the monomeric 1,6-anhydro-P-~Zyxo-hexopyranos-2or -4-ulose failed; a low yield of 3-0-acetyl-1,6-anhydro-4-deoxy-P-Dglycero-hes-3-enopyranos-2-ulose(75) from the former, and of 2,4-diO-acetyl-1,6-anhydro-~-~-lyxo-hexopyranos-3-ulose (migration of the ketone group) from the latter, have been isolated456(compare Ref. 52). However, the isopropylidene derivatives of both glycosuloses yield compounds having the enediol grouping without d i f f i ~ u l t y .The ~~~,~~~ present authors presume that the preparation of 74 would be more likely to succeed should the glycos-4-ulose having the Darabino configuration (that is, an axially oriented H-3) be used as the starting compound; here, the elimination should proceed more quickly than the undesired side-reactions. The acetonation of dimers having cis, vicinal hydroxyl groups under the catalysis of perchloric acid yields the corresponding isopropylidene a ~ e t a l s ~in~ addition, ~ , ~ ~ ~ the ; dimers of 1,6-anhydro-P-D-xyb hexopyranos-3-ulose and 1,6-anhydro-~-~arabino-hexopyranos-3d o s e yield very interesting, acid-stable s p i r o - a c e t a l ~(76 ~ ~and ~ 77),

76

77

wherein the annelation of three five-membered rings causes the central, pyranoid ring to assume the B,,,(D) form, which manifests itself, in the case of 77, by the values J1,2 0 Hz and J4,5 6.9 Hz. The unexpected formation of dimeric forms, as well as of hydrates (especially of glycos-2-uloses) somehow complicates the interpretation of the n.m.r. and c.d. (see Sect. IV,7,c) spectra of the unsubstituted glycosuloses; in aqueous solution, all of these compounds exist in chair conformations5.417.419~455 ( 1,6-anhydro-~-~ribo-hexopyranos-3-ulose contains a considerable proportion of d i m e r ~ ~ The ~ ~ boat , ~ ~conforma~). ~ ~ ~ not to have been unanibigution of certain g l y ~ o s - 4 - u l o s e sseems ously proved. The oximes of these glycosuloses are convenient starting-substances for the preparation of aminodeoxy derivatives of 1,6-anhydrohexopyranoses455;their catalytic hydrogenation proceeds with a selectivity similar to that of the parent glycosuloses.

I ,&ANHYDRO DERIVATIVES OF ALDOHEXOSES

97

b. Oxidation of an “Isolated” Hydroxyl Group.-The chemical agents most frequently used for the oxidation of an “isolated” hydroxyl group of 2,3-or 3,4-O-isopropylidene derivatives are ruthenium tetra~ ~ i d e ~ and ~ ~ dimethyl , ~ ~sulfoxide-acetic ~ , ~ ~ ~anhydride,424,457,497 , ~ ~ ~ ’ ~ ~ ~ the former reagent being slightly superior; oxidation with dimethyl -dicyclohexylcarbodiimide proceeds with lower sulfoxide and N ,N’ yields,457 and lead tetraacetate in pyridine seems to exert no observable oxidative effect.457These agents, as well as dimethyl sulfoxide-phosphorus p e n t a ~ x i d e , ~do ” not attack the 1,6-anhydride bond. When dimethyl sulfoxide reagents are used, the possibility of simultaneous formation of (methy1thio)methyl ethers,497 and, conceivably, of 0-acetyl should be borne in mind. The oxidation of isopropylidene acetals of 1,6-anhydro-P-~-mannopyranose and -D-galactopyranose yields 1,6-anhydro-2,3-0-isopropylidene-~-1~Zyxo-hex(78) and 1,6-anhydro-3,4-0-isopropylidene~-D-~yxo-hexopyranos-2-u~ose419~424~497 (65). The remaining two possible glycosuloses (having the D-rib0 configuration) were obtained436 on oxidation of the appropriate isopropylidene acetals of 1,6-anhydroP-D-allopyranose and -D-altropyranose. Glycos-2-uloses, especially, tend to produce hydrated forms; the hydrate of 65 is formed simply on allowing the crystalline ketone to stand in the open air.497The formation of the hydrate is facilitated by the electron-withdrawing effect of the vicinal oxygen atoms, and by the stabilization of the hydrated form by intramolecular hydrogen-bonds. Dehydration of the hydrates is best achieved by sublimation in DUCUO. The carbonyl group of these glycosuloses is available for a variety of nucleophilic additions, and the rigidity, as well the steric arrangement, of the tricyclic system endows them with a great selectivity.719 The reduction of ~ Z y x oglycosuloses (65, 78) with complex hydrides leads, in both cases, stereospecifically to isopropylidene acetals of 1 , 6 - a n h y d r o - ~ - ~ - t a l o p y r a n o Reduction s e . ~ ~ ~ ~ can ~ ~ ~be ~ ~ also ~ ~ ~ used ~~~ for the synthesis of selectively deuterated derivatives of 1,6-anhydroP - D - t a l o p y r a n o ~ e . ~On ~ ~ the , ~ ~other ~ , ~ ~hand, ~ catalytic hydrogenation always affords an almost equimolecular mixture of both alcohols pos~ i b l e .A~markedly ~ ~ , ~ easier ~ ~ approach of the reagent from the nonhindered, ‘ ‘ ~ x oside ” of 65 and 78 was used in the synthesis of various branched-chain saccharides; treatment with methylmagnesium iodide, vinylmagnesium chloride, or ethynylmagnesium bromide,461or with (718) K. Onodera, S. Hirano, and N. Kashimura, Carbohydr. Res., 6, 276-285 (1968). (719) It may be expected that the course of reaction of D-ribo glycosuloses (compared to D - ~ ~ X glycosuloses) O will be less selective; however, there has so far been no experimental evidence for this statement.

98

MILOSLAV 6EKNY A N D JAN STANEK, JK.

2-lithi0-1,3-dithiane,4~~~~'~ gave high yields of 2- or 4-C-substituted de(for example, 79, 80, or 81) rivatives of 1,6-anhydro-P-~-talopyranose as valuable intermediates. Analogous sugar phosphonates (for example, 82) were prepared from 65 and 78 by using the Abramov reaction,464,465 and the compounds obtained have been found to be convenient models for studies ~ f ~ ~ P - n . m spectra, .r. especially with respect to the vicinal hydrogen-phosphorus coupling in the P-C-O-H grouping.464Treatment of 78 with diazornethane led to methylene insertion into the carbonyl group, with the formation of the s p i r o - e p o ~ i d e ~ ~ ~ a ~ ~ (83), which can be reduced461with sodium in liquid ammonia to 79. Compounds 65 and 78 can be converted without difficulty into the 2- and 4-deoxy or into the corresponding whose stereospecific hydrogenation on platinum leads to less-accessible aminodeoxy derivatives of 1,6-anhydrohe~opyranoses.~~~~~~~ Laser-Raman spectroscopy was used to examine the C=N absorp78 has also been tion of 1,6-anhydroglycosulose ~ x i m e s . ~ Compound '~ transformed into a stable diazo saccharide, 1,6-anhydro-4-deoxy-4-diazo-2,3-O-isopropylidene-~-~Zyxo-hexopyranose~~~ (84) by application of the Bamford-Stevens reaction. Both ~ Z y x oglycosuloses undergo the Bayer-Villiger reaction in the presence of m-chloroperoxybenzoic acid; only C-1 and C-5 migrate in the intermediary acylals, so that the oxygen atom is inserted into the C-1-C-2, or C-4-C-5 linkage, and into C-2-C-3 or C-3-C-4 (78 -+ 85). It has been ~ h o ~thatnH-3 ~ of~the ~ketone , ~78 is ~ readily ~ exchanged by solvent protons in aqueous base, whereas H-5, which is at the bridgehead of the r3.2.11 bicyclic system, is not exchanged. The same . ~both ~~ is true as regards H-3 or H-1 of the isomeric g l y ~ o s - 2 - u l o s eIn cases, the original stereochemistry about C-3 is regenerated on reprotonation (a truns-dioxolane is less likely), and many selectively deuterated derivatives of D-talose have been prepared in such a way. The possibility of the existence of a 3,4-enediol intermediate has been proved by the preparation of the stable 4-0-acetyl-1,6-anhydro-2,3O-isopropylidene-P-~threo-hex-3-enopyranose~~~ (86)from ketone 78. Similarly, the ~ Z y x ketone o 65 might be converted into the corresponding 2-O-acetyl derivative456(87);however, an attempt to acetylate 1,6anhydro-3,4-O-isopropylidene-~-~ribo-hexopyranos-2-ulose failed.436 A possible explanation, that this failure resides in the different rates of elimination of the axial and the equatorial hydrogen atom on enoli(720) H. Paulsen, V. Sinnwell, and P. Stadler, Angew. Chem., 84, 112 (1972). (721) D. Horton, E. K. Just, and B. Gross, Carbohydr. Res., 16,239-242 (1971). (722) P. Ko11, R. Durrfeld, U. Wolfmeier, and K. Heyns, Tetrahedron. Lett., 5081-5084 (1972).

LlILOSLAV CERNY A N D JAN STANBK, JR.

100

ati ion,^^^ necessitates that all of these glycosuloses exist in a boat conformation; however, to the present authors, the n.m.r. evidence seems to be not unambiguous, and it is likely that the reason could rather be traced to a more unfavorable torsion-angle of 0 - 3 and 0-4 in the enol acetate having the D-erythro configuration, as compared with the Dthreo isomer (87). In the former compound, the shape of the 1,3-dioxolane ring would have to be far from planarity.

AcO 86

87

80

The course of the acetylation of 78 to 86 by the action of acetic anhydride and triethylamine was to be rather complicated. The dimer 88 is first formed; this branched-chain sugar derivative, resulting from the attack of C-3 of the 3,4-enediolate anion on the carbonyl group of the second molecule of ketone 78 (aldolization), is thereafter equilibrated with the final enol acetate (86). Careful hydrolysis of 86 regenerates the starting glycosulose 78; its reduction with sodium borohydride, which does not involve 78 as a reaction intermediate, the D - ~ U Z O derivative (68). The aldolization mentioned was subsequently used461for an interesting synthesis of branched-chain sugars. Thus, on reaction with formaldehyde, 78 gives, stereospecifically, 1,6-anhydro-3-C-(hydroxymethyl)-2,3-0-isopropylidene-~-~Zyxo-hexopyranos-4-ulose, which subsequently undergoes reduction at C-4 by a crossed Cannizzaro reaction leading to 1,6-anhydro-3-C-(hydroxymethyl)-2,3-0-isopropylidene-P-D-talopyranose. On the other hand, an attempt to condense 78 with ethyl formate did not result in the expected 3-C-formyl derivative; only the dimer 88 was obtained.461 Oxidation of dianhydrohexopyranoses with ruthenium tetraoxide yields all four possible k e t o - e p o ~ i d e s these ~ ~ ~ ; can be readily transformed into the 3-deoxy ketones459(see Sect. VII,3,b). The same agent (89). The oxidizes 1,6-anhydro-2,3-di-O-benzoyl-~-~-glucopyranose~~ selectivity of the lithium aluminum deuteride reduction of the glycos-

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

101

4-ulose (90) obtained is far lower than that for the isopropylidene acetals; the ratio of ex0 to endo attack is52only 4.1 : 1, and this can be explained by the influence of the axial 2-benzoyloxy group. (An analogous decrease in selectivity was observed for reactions of glycosuloses with dimethyl phosphite in the presence of t r i r n e t h ~ l a m i n e . Com~~~) pound 90 readily eliminates benzoic acid to give 91; this elimination proceeds even more quickly than hydrogenation of the carbonyl group with hydrogen on platinum, so that the product of such a reduction is a mixture of 1,6-anhydro-2-deoxy-/3-~-hexopyranoses (92). Hydrogenation of the hydrated form of the ketone 90 seems to proceed without eliminati~n.~~

89

90

OBz

HO 92

91

2,4-Di-O-substituted derivatives of levoglucosan and 176-anhydrob-D-galactopyranose were oxidized by chromium trioxide in acetic acid or by dimethyl sulfoxide-acetic anhydride to the corresponding glyco~-3-uloses.~~"*~3~ In the presence of pyridine, the axially oriented p-tolylsulfonyloxy, benzoyloxy, or benzyloxy groups of these ketones move to equatorial positions. For example, the isomerization of 1,6anhydro-2,4-di-O-p-tolylsulfonyl-/3-~-ribo-hexopyranos-3-u~ose (93) follows Scheme 9. The 1,3-diaxial interaction between the p-tolylsulfonyloxy groups in 93 makes the first stage of isomerization far more rapid, so that, according to the reaction conditions, a mixture of 94 and 95, or possibly the D-ZYXO isomer (96),can be ~ b t a i n e d .The ~ ~ pres~,~~~ ence of at least one axial substituent in the vicinity of the carbonyl group makes the approach of sodium borohydride, methylmagnesium iodide, or phenylmagnesium iodide from the exo side almost impos-

102

MILOSLAV ~ E K N Y AND JAN STANEK, JR.

OTs

95 Scheme 9

sible. Consequently, only derivatives having the D - d o , D-altro, and D-guh configurations may be 0 b t a i n e d ~ ~ Oby 3 ~reduction ~~ of 93, 94, and 95; the selectivity of the reactions with Grignard reagents is only slightly less.lo6Only in the D-ZYXO isomer (for example, 96) does the steric hindrance of the 1,6-anhydro ring become dominant, and the reactions yield mainly derivatives having the D - ~ u Z ~c o n f i g ~ r a t i o n . ' ~ ~ , ~ ~ ~ The same is true of the sodium borohydride reduction of 4-deoxy-2-0p-to~y~su~fonylglycos-3-uloses (220 and its D-threo isomer) prepared383 from 1,6-anhydro-4-deoxy-2-O-p-tolylsu~fony~-~-~-~y~o-hexopyranose (212), or of the lithium aluminum hydride reduction of 1,6-anhydro4-O-benzy~-2-deoxy-~-~-erythro-hexopyranos-3-ulose, obtained by the oxidation of the axial hydroxyl group with dimethyl sulfoxideacetic anhydride155;always, more cis- than trans-diol derivative was obtained. Compounds 93-96 tend to form hemiacetals in alcoholic solution.450 It was found that an axial p-tolylsulfonyloxy group promotes hemiacetal formation, whereas an equatorial one results in inhibition. This is presumably due to the stereopolar interaction between the acetal oxygen atoms and the p-tolylsulfonyloxy group, which, for the hemiacetal of 96, is significantly greater (analogy of the Reeves A2 effect) than for the hemiacetals of the three other isomers, especially of 93. Consequently, only 25% of the keto form 93, and 95% of the keto form

1.6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

103

96, exist in the equilibrium mixture in an alcoholic solution of these glyc~suloses.~~~ The p-tolylsulfonyloxy group in glycos-3-uloses is activated by the vicinal keto group in such a way that it can be reductively removed with Raney nickel, or by the action ofzinc in acetic acid, with formation of a methylene Thus, 1,6-anhydro-2,4-dideoxy-fl-D-gZz~cerohexopyranos-3-ulose (97) was from 93, or from 1,6-anhydro-4-deoxy-2-0 - p -tolylsulfonyl-fl-D-erythro -hexopyranos-3-ulO S (220). ~ The ~ ~ketone ~ 96 can be selectively desulfonylated with zinc in acetic acid, to give 1,6-anhydro-4-deoxy-2-O-p-tolylsulfonylp-~-threo-hexopyranos-3-ulose.~~~ Reduction of 220 by zinc in acetic anhydride yields 3-O-acetyl-1,6-anhydro-2,4-dideoxy-fl-~-gZycerohex-%enopyranose, from which the 2,4-dideoxy ketone 97 can also be obtained, but with difficulty.377

mooBo eo 0

97

96

99

Besides 97, the two other possible 1,6-anhydrodideoxy-P-D-hexopyranosuloses (98 and 99) are also known; they have been prepared from the corresponding dideoxyalcohols by ruthenium tetraoxide oxid a t i ~ n . ~Only ? ? 99 yields hydrates or hemiacetals, as a result of the -I effect of the neighboring oxygen atoms as well as through stabilization of the hydrate by hydrogen bonds to 0 - 5 and 0-6. Its ene derivative213,254-257,724,725 (20) is formed by the pyrolysis of cellulose213~254~255~ (compare Refs. 258-260), especially when acid additives are used; both 20 and its isomer 1,6-anhydro-2,3-dideoxy-~-~-glycero-hex2-enopyranos-4-ulose were synthesized by an unambiguous route725 (see also, Ref. 725a). As the simplest possible models, ketones 97-99 were used for evaluating the influence of the 1,6-anhydro ring on the i.r. and U.V.spectral properties of the carbonyl group, and in a study of the optical rotations of 1,6-anhydrohexopyranose derivatives.377 7243725

(723) J. Stangk, Jr., and M. Cern?, unpublished results. (724) F. Shafizadeh and P. P. S. Chin, Carbohydr. Res., 46, 149-154 (1976). (725) P. Koll, T. Schultek, and R.-W. Kennrcke, Clzenr. Ber., 109, 337-344 (1976). (725a) 0. Achmatowicz, Jr., P. Bukowski, B. Szechner, 2. Zwierzchowska, and A. Zamojski, Tetrahedron, 27, 1973-1996 (1971).

MILOSLAV

104

CERN';'

ASD JAN STANEL,JR.

c. Spectral Properties of 1,6-Anhydrohexopyranosuloses.-The stretching frequency of the carbonyl group depends on the distance and number of the vicinal oxygen atoms377,424; in the sequence 97,98, 99, the value vco, as well as A,, increases.377The influence of the orientation of neighboring, electronegative substituents, such as a p-tolylsulfonyloxy group, is also significant, the differences in vco and A,, for 93 and 96 being4'0 14 cm-' and 33 nm. On the other hand, the coincidence of the Cotton effects with the octant rule is questionable, even for such simple compounds as 97, 98, and 99. Some qualitative coincidence can be observed in the case of glycos-3- and - 4 - u 1 0 s e s ~ " ~ ~ ~ ~ ~ 424,436,450,455 (see also, Ref. 5), whereas glycos-2-uloses377~419~4z4~436 and ketones having neighboring ester r e s i d ~ e sare, ~ ~as ~ yet, , ~ ~quite ~ beyond correlation. Therefore, Cotton effects of these compounds can be used for identification, but only with great caution for structural determinations. The position ofthe carbonyl group is readily assigned from the n.m.r. spectra (see Sect. 111); however, distinguishing between the 'c4(D) and B 0 , 3 ( ~conformations ) is complicated, because of the small differences in] values.

8. Products of Cleavage of GlycoI Groupings

Periodate oxidation of all 1,6-anhydro-p-~-hexopyranoses and their amino derivatives yields the same dialdehyde,118~122~124~'s*~161~164-'66,2 341,343,3i8,i00,726,~2i namely, (2R,4R)-dioxolanedicarbaldehyde(100) (see Sects. 111 and VI,2). During the reaction, one equivalent of formic acid is formed, with simultaneous consumption of two equivalents of the oxidizing agent. Even levoglucosan (6), having all-trans, axially attached hydroxyl groups, undergoes cleavage at a rate341'344 sufficiently high for practical lead tetraacetate may also be used for such oxidations.345The free aldehyde form 100, which is obviously in equilibrium with a of hemialdals (101), has been characterized as the crystalline dimedone derivative.IM,"j6The dicarboxylic acid obtained after bromine o ~ i d a t i o n , " ~ , as ' ~ well ~~'~ as~the ~ ~diol ~~

I ? r ?

6

HC II 0

0 100

HO

OH 101

(726) F. W. Lichtenthaler, T. Nakagawa, and A. El-Scherbiney, Angew. Chern., 79, 530-531 (1967). (727) F. W. Lichtenthaler and T. Nakagawa, Cheni. R u . , 101, 1846-1849 (1968).

105

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

prepared by borohydride reduction,730can be used as starting compounds well suited for the preparation of various 1,3-dioxolane derivatives of known absolute and relative configurations; for example, for the preparation of muscarine-related compounds .730 The diol was also that is, to converted into (1R,5R)-6,8-dioxa-3-thiabicyclo[3.2.lloctane, the thia analog of “trideoxylevoglucosan”731(see Sect. VIII). Cyclization of 100 with nitromethane gives a mixture of 1,6-anhydro3-deoxy-3-nitro-p-~-hexopyranoses, from which the isomers having the D-gulo (102),D-dtro (103),and ~ - i d (104) o configurations have been i s ~ l a t e d ~ their ~*,~ precursors ~~; are the aci-nitro forms having the D-XYZU, Durubino, and ~ Z y x oconfigurations .732 As the relatively rigid arrange100

i

e0+ mo+ B0 (1) MeNO,, MeONa (2)

HO

NO2

NO2

OH

102

H+

OH

HO

NO2

OH

HO

103

104

ment of 100 should exert a pronounced steric control on the cyclization, it is no wonder that attempts were made to rationalize the results obtained. Application of the Cram rule led to the conclusion37*that the main product should be the 3-aci-nitro derivative of 1,6-anhydro3-deoxy-/3-~-ribo-hexopyranose,but there is no evidence of its presence in the reaction mixture (although, because there is only a 40% yield ofthe other isomers, its existence cannot be excluded). However, the extent to which the application of Cram’s rule is precise in such a case is questionable. Under the conditions of condensation, the dialdehyde 100 must be presumed to exist mainly as a mixture of henii(728) Periodate cleavage was used in the isolation of 1,6-anhydro-p-D-glucofuranose from the mixture obtained by pyrolysis of D - g ~ u c o ~ e . ~ ~ ~ (729) Z. Fidkiewiczowa, Wind. Chem., 22,421-441 (1968). (730) D. J. Triggle and B. Belleau, Cun. J. Chem., 40, 1201-1215 (1962). (731) K. W. Buck, F. A. Fahim, A. B. Foster,A. R. Perry, M. H. Qadir, and J. M. Webber, Carbohydr. Res., 2, 14-23 (1966). (732) The acidification of the aci-nitro form by means of a cation-exchange resin always yields the more stable form of both of the nitro sugars possible; that is, in this case, the 1,6-anhydrohexose derivative having an equatorial nitro

MILOSLAV C E R N ~ AND ~ JAN STANEK, JR.

106

aldal forms, of which those having at least one axial hydroxyl group (favored through operation of the anomeric effect) could give rise to other configurations. Nevertheless, the aci-nitro form having the D-ribo configuration should preponderate after equilibrium of the aci-nitro forms has been established, that is, in the presence of more than one equivalent of a base. This conclusion follows from the theoretically estimated values of conformational free-energy (Goconf)for the individual isomers,733-735 given in Table 111,as it has the lowest G&,f value of all four isomers. In contrast, in the equilibrium established in the presence of a catalytic amount of a base, and also after the nitromethane cyclization in benzylamine, the composition of the mixture should correspond to the stabilities of the nitro sugars, that is, the id^ isomer should preponderate (see Table 111). The isolation of a 53% yield of 1,6-anhydro-2,4-di(benzylamino)-2,3,4-trideoxy-3-nitro-~-~-idopyranose (155) in the latter case726,727 is, therefore, not surprising. TABLE I11 Estimated Values of the Conformational Free-Energies (GgOonr) of 1,6-Anhydro-3-deoxy3aci-nitro-P-~-hexopyranosesand of the Corresponding 1,6-Anhydro-3-deoxy3-nitro-P-D-he~opyranoses'~~ &-Nitro form Configuration

Nitro form

Gionf(kJ.mo1-')" 20.1 11.7 12.1 6.3

Configuration

nido naltro ngulo nallo

The energy of the fundamental skeleton is not included. gauche NOJOH interactions is not included.

G:,,nf (kJ.mol-')"~* 9.0 9.0 9.4 11.9 The energy of two

The periodate cleavage of 2- or 4-0-substituted derivatives of 1,6anhydro-P-D-hexopyranosesprovides the possibility134J94,383~464 of preparing partially substituted derivatives of D- or L-glyceraldehyde, 2-0-substituted derivatives of D-erythrose or D-threose, and other useful compounds. Attempts to condense the dialdehydes resulting from 2-deoxy, 4-deoxy, and 2-acetamido-2-deoxy derivatives of 1,Banhydro-

(733) Conformational free-energies were c a l c ~ l a t e d , ' by ~ ~ using Angyal's original valueslo0for nonbonding interactions, by the method given in Ref. 735. (734) J. Stanik, Jr., and J. Jar$, unpublished results. (735) J. KovLi, K. Capek, and H. H. Baer, Can. J . Chem., 49,3960-3970 (1971).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

107

hexopyranoses with nitromethane failed to give appreciable amounts of anhydroheptoses having the 7,9-dioxabicyclo[4.2. llnonane skeleton. 736

v. 1,6: 2,3- AND

1,6 : 3,4-DIANHYDROHEXOPYRANOSES 1. Preparation

a. Reaction of Sulfonic Esters and Ha1ogenohydrins.-The most frequently used method for the preparation of dianhydro derivatives consists in the intramolecular, nucleophilic displacement of a p-tolylsulfonyloxy or methylsulfonyloxy group by a suitably trans-oriented, vicinal hydroxyl group. (Usually, sulfonic esters are obtained either directly from the 1,6-anhydrohexoses, or from their partially substituted derivatives, such as isopropylidene acetals; see Sect. IV,3,b.) This reaction is performed at room temperature, most frequently employing a methanolic solution of sodium methoxide in chloroform, but it may be performed even in very dilute, aqueous solutions of alkali A convenient modification of this procedure, replacement of the base by a strongly basic anion-exchange resin, proved especially useful when isomerization of the dianhydro derivatives initially formed was to be impeded.737 A typical example is the synthesis289,509~512~737 (compare Ref. 703) of 1,6 :2,3-dianhydro-p-~-taIopyranose (107) from 1,6-anhydro-3,4-0isopropylidene-/3-D-galactopyranose (62) by the sequence 62+ 105 (or 54)+48 (or 106)+ 107. 1,6 :3,4-Dianhydro-P-~-talopyranose (128) was prepared ~ i r n i l a r l y(compare ~ ~ ~ , ~ ~Ref. ~ 699).

OR 54 R = M s

62R=H 105 R = Ts

OR 4 0 R = Ts 106 R = Ms

107

A 3: 1 mixture of dianhydro derivatives 32 and 110 (having the Dd o configuration) was ~ b t a i n e d (compare ~ ~ ~ j ~ Ref. ~ ~ 679) from the 2,4-bis(benzyl carbonate) 108 by way of 109. (736) 2. Toclik, T. Elbert, J. Stane'k, Jr., and J. Jary', unpublished results (737) J. Stane'k, Jr., and M. <;ern+, Synthesis, 698-699 (1972).

MILOSLAV CERN? A N D JAN STANCK, JR.

108

H0

H O @ O +

PhCH,o,CO

HO

OCO,CH,Ph

-

-

25% 110

108 R = H 109 R = Ms

OH 7 5% 32

1,6: 2,3-Dianhydro-P-~-mannopyranose (117) was prepared by acid hydrolysis of epoxide 111 and subsequent cyclization of the resulting 2-0-p-tolylsulfonyl-levoglucosan(112) in the presence of a strong a n i o n - e ~ c h a n g e r(compare ~~~ Ref. 679), and also from the 4-trityl ether504(113) or, more conveniently, from the 4-benzyl ether155a479 (114) by way of epoxide 115 or 116. Under conditions like those used

111

112

H0B0=h RO‘

__t

RO

OTs 113 R = Tr 114 R = CH,Ph

o o

RO

o o

HO 115 R = T r 116 R = CH,Ph

117

for compound 112, 4-0-p-tolylsulfonyl-levoglucosanyields 1,6 : 3,4dianhydro-&~-galactopyranose~~’ (119).An alternative method for the preparation of dianhydride 119 consists in the reductive cleavage of the p-tolylsulfonyloxy group of epoxide 111 by use of sodium amalgam 15fi,442,496 (compare Ref. 448), or by U.V. i r r a d i a t i ~ n . ~ ~ ~ , ~ ~ ~ , ~ ~ ~ The ready isomerization of dianhydride 117 in alkaline media leads to 1,6:3,4-dianhydro-/3-~-altropyranose~~~,~~~*~~~ (118) (compare Ref.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

109

738). Dianhydride 119 reacts under the same conditions to give 1,6:2,3-dianhydro-P-~-gulopyranose~~~,~~~,~~~ (120);compare Sect. V,2.

mow&o 0

OH

0

HO

K 5%)

(>95%)

117

118

(80%) 120

(20%) 119

A mixture of epoxides 118,119, and 120, accompanied by some additional products, results from the complex reaction of epoxide 111 with sodium hydroxide in aqueous In all of the examples so far described (except the isomerization), the oxirane ring is formed by way of internal, bimolecular replacement of the sulfonyloxy group by an alkoxide ion resulting from the neighboring hydroxyl group under alkaline conditions (see Scheme 10). An energetically advantageous situation for the transition state

d [epoxide] dt

= k [p-toluenesulfonic ester] [RO-1

Scheme 10

(738) It is p r o l d d e that the 2,7 : '~,~-dianhydro-p-~-,nclnno-2-heptulopyra~~ose described by E. Zissis in). Org. Chetn., 32, 660-664 (1967) is actually 2,7:4,5-dianhydrop-D-a~tro-2-heptdopyranose. (739) M. Cem9, I. Buben, and J. Packk, Collect. Czech. Chem. Commun., 28, 15691578 (1963).

MILOSLAV CERNY A N D JAN STANEK, JR.

110

occurs only with diaxial orientation of the hydroxyl and vicinal sulfonyloxy groups. The reaction of the diequatorially oriented groups could eventually proceed in such a way that the 'C,(D) conformation of the pyranose is transformed into the B,,,(D) conformation, with simultaneous reorientation of the equatorial groups to the diaxial position. However, this conformational change is an energetically disfavored process, as deduced from the low reactivity of 1,6-anhydro3-O-p-to~y~sulfonyl-P-D-altropyranose (121), or from the lack of reactivity of the 2-p-toluenesulfonate (122) or similar equatorial esters.681

R' =

/

n, RZ = TS

'17

HO@ O

121

-

OR2

110

I

HO R' = Ts, R2 = H 122

Consequently, the ease of the formation of the oxirane ring on the 1,6-anhydrohexose skeleton can be considered as at least preliminary proof of a diaxial arrangement of the reacting groups. Nevertheless, kinetic studies of oxirane-ring formation have shown that even the reactivity of the axial p-tolylsulfonyloxy group can differ by several orders, depending primarily on its position on the pyranose ring. This was demonstrated for various p-toluenesulfonic esters of levoglucosan (6), where, for example, the 2-, 3-, and 4-0-p-tolylsulfonyl derivatives react to give epoxides in 1: 180:23.3 ratio of relative rates .679 The higher reactivity of the p-tolylsulfonyloxy group on C-4 causes the reaction of 1,6-anhydro-2,4-di-0-p-tolylsulfonyl-~-~-glucopyranose (43)with sodium methoxide to yield exclusively 1,6:3,4dianhydro-2-0-p- tolylsulfonyl-~-~-galactopyranose~~~~~'~~~~~ (lll),and not the isomer 123 having the D - W L U ~ ~ configuration. O The actual

I,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

123

43

111

111

reason for this unambigous course of reaction probably lies in an unfavorable interaction between the negatively charged oxygen atom on C-3 and the oxygen atom of the 1,6-anhydride bond (see 124), which decreases during formation of the 3,d-epoxide (111). In addition,

124

when the different nucleophilicity of alkoxide ions in single positions on the pyranose ring is considered (for example, that of the oxide ion at C-2 is diminished by the -I effect of the acetal grouping), it is not surprising that 1,6 : 3,4-dianhydro-/3-~-allopyranose (32) is formed679 in -70% yield from 1,6-anhydro-3-O-p-tolylsulfonyl-/3-~-glucopyranose (compare Refs. 438 and 498). Many derivatives of the dianhydro compounds have been prepared analogously. Thus , such substituted 1,6 :2,3-dianhydro-P-~mannopyranose (117) derivatives as the 4_0-alky1,52,155,442,479,499,504--506,632.635 4-azid0-4-deoxy,~~~,~~~,'~~ 4 - d e o x y - 4 - f l u o r 0 , ~4-S-benzyl-4-thi0,~~~ ~~~~~~ and 4 - d e 0 x y (compare ~~~ Ref. 329) were prepared from the corresponding 2-sulfonates, and similar derivatives of 1,6:3,4-dianhydro-P-~-

galactopyranose38n~3s4~507~52n~537~62g~678,741 (compare Ref. 329) (119) and

1,6 : 3,4-dianhydro-P-~-allopyranose'~~~~~~ (32) were also prepared. Vicinal, trans-disulfonic esters also afford oxirane derivatives. It may be assumed that this reaction is preceded by a selective, partial (740) M. C:em$, I. Cern?, and J. Pacak, Collect. Czech. Chem. Commun., 41,2942-2951 (1976). (741) H . Paulsen and H. Koebemick, Chem. Ber., 109, 104-111 (1976). (742) M. Cem$ and J. Pacik, Collect. Czech. Chem. Cornmun., 27, 94-105 (1962).

MILOSLAV

112

CEKN-A ~ ND

JAN

STASBK,

JR

desulfonylation by base, so that the main product usually formed is one of the two possible epoxides, as is illustrated by the reactions of 125 and 126 (Refs. 376 and 742) the disulfonic e~ters~55,379,~~8,63~ leading to 127 and 30, respectively. It is worth noting that 176-anhydro-2,3,4-tri-O-p-tolylsulfonyl-~-~-glucopyranose gives mainly the e p ~ x i d e 11 ? ~1.~

I

OTs 125 R' = Ts or Ms, RZ = OCH,Ph

30 R = H 121 R = OCH,Ph

126 R' = Ts or M s , RZ = H

Dianhydro derivatives can also result from vicinal halogenohyd r i n ~ , 3but ~ ~their * ~ ~use ~ is of little preparative value, as these halogenohydrins are themselves usually prepared from the oxirane derivatives. b. Epoxidation of Double Bonds.-This approach was applied in the total synthesis of 1,6-anhydrohexoses from acrolein. The attack of a peroxy acid proceeds with high stereoselectivity from the exo side with respect to the 176-anhydroring, which is sterically the more accessible325~327~328~330~331~333 (see Scheme 11).

c . Deamination.-Dianhydro deamination

of aminodeoxy

derivatives can be formed, through derivatives

of

1,6-anhydrohexopy-

ranoses having a trans-diaxial arrangement of hydroxyl and amino groups, by the action of nitrous acid in buffered solution (see Sect. VI, 1,e).

2. General Properties Dianhydro derivatives are crystalline compounds, readily soluble in water and only slightly soluble in ether (see Table VIII). They constitute a complete series having a very rigid, tricyclic skeleton: 1,6:2,3-dianhydro-p-~-hexopyranoses exist in the 5ff0(D) conformain the 'H,(D) contion, and 1,6: 3,4-dianhydro-p-~-hexopyranoses formation with the conformation of the dioxolane ring approximat(743) R. M. Hann and N. K. Richtniyer, personal ~omiiiunication;see Ref: 513.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

R

=

113

H or OH

@

0

II

RCOOH

Q

R

+

0

R

R=HorOH Scheme 11

ing Eaz (E,J, as shown by n.ni.r. spectroscopy744and by X-ray analy ~ i s respectively. , ~ ~ ~ Of the eight isomers, only 1,6:2,3-dianhydro-p-

107 R' = OH, Rz = H 1,6:2,3-Dianhydro-p-~talopyranose

s~o(~) 110 R' = H, R2 = OH 1,6:2,3 - Dianhydro-p -Dallopyranose

117 R' = n, RZ = OH 1,6:2,3-Dianhydro-p-omannopyranose

120 R' = O H , R2 = H 1,6:2,3-Dianhydro-p-Dgulopyranose

'H~(D)

r

P 'H,(D)

119 R' = H,

Rz = OH

1,6:3,4-Dianhydro-p-ogalactopyranose 128 R' = OH, RZ = n 1,6:3,4-Dianhydro-p-otalopyranose

'H~(D)

3 2 R' = H, R' = OH 1,6:3,4-Dianhydro-p-oallopyranose 118 R1 = OH, R2 H 1,6:3,4-Dianhydro-p-~altropyranose %

(744) M. BiitlGinsk$, M. C:ern$, and T. Tmka, to be published. (745) B. Berking and N. C. Seeman, Actn Cn/stallogr. Sect. B , 27, 1752-1760 (1971).

114

MILOSLAV

ERN+

AND JAN STANEK, JR.

D-gulopyranose (120) does not form an intramolecular hydrogen-bond in carbon t e t r a ~ h l o r i d eFor . ~ ~ measurements ~ by differential thermal analysis, see Ref. 367. The relative stability of the oxirane ring to bases permits selective hydrolysis of the carboxylic or sulfonic ester bond, leaving the oxirane bond i n t a ~ t . ' The ~ ~ , oxirane ~ ~ ~ ring reacts with neither hydrogen on palladium under hydrogenolytic conditions'55~43fi~479~49s~504 nor sodium ama1gam,'5fi~442*49fi but is reductively cleaved by hydrogen on Raney n i ~ k e 1 ~ ~ and~ by , ~complex, ~ ~ , ~ aluminum ~ ~ , ~ ~hydrides.155,376,382,384,fi32 ~ Aqueous mineral acids cleave the oxirane ring to afford trans-diols; however, the 1,6-anhydro ring is simultaneously hydrolyzed,479provided that it is not stabilized by an electronegative s u b ~ t i t u e n on t~~ C-2. The free hydroxyl group of dianhydro derivatives may be acylated,436,437,739 p-toluenesulfony~ated,498,504,fi37,70fi,739 or alkylated45a,434,442, by the conventional methods, and it can also be oxidized (see Sect. IV,7,b). Dianhydro derivatives having a hydroxyl group trans-oriented to the oxirane ring are rapidly equilibrated under alkaline conditions, even at room temperature. (Acid-catalyzed, epoxide equilibration has not yet been observed.) This reaction, sometimes called "epoxide migration," is an intramolecular s N 2 substitution involving rearside attack on the oxirane ring b y an adjacent alkoxide ion formed in the alkaline medium504*fi81*739 (see Scheme 12). The composition of the resulting 511,532c3542,739

Scheme 12

equilibrium mixture can be interpreted in two ways ( u ) Dianhydro derivatives 118 and 120, containing a free, quasi-equatorial, hydroxyl group, are more stable than those in which this group is y u ~ s i - a x i a (117 l ~ ~ ~and 119). ( b ) The isomers 118 and 120 having an exo-oriented oxirane ring are more stable than those having an endooxirane ring, because the latter are destabilized through unfavorable polar interactions between the oxirane ring and the 1,6-anhydride .5043681,739*747

(746) T. Trnka and M. Cern9, Collect. Czech. Chem. Cornnuin., 37,3632-3639 (1972). (747) J. G. Buchanan, R. Fletcher, K. Parry, and W. A. Thomas,]. Chem. S O C . , B , 377385 (1969).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

115

It is also necessary to consider the different nucleophilicity of alkoxide ions; that at C-2 is less5” than that at C-4.

3. Reactions Involving Cleavage of the Oxirane Ring Cleavage of the oxirane ring by nucleophilic, electrophilic, and reducing agents generally proceeds with a high regioselectivity (for a review, see Ref. 748); this permits the preparation of various 1,6anhydrohexoses and hexoses, as well as their amino, deoxy, halogeno, and thio derivatives, in high yield, without the necessity for chromatographic separation of the reaction products. It seems likely that “hard” bases, such as OH-, OR-, and NHR, (where R = H or alkyl), open the oxirane ring (not only of unsubstituted but also of 0-alkylated dianhydrohexopyranoses) predominantly, if not exclusively, diaxially with formation of derivatives having the D-ghco, D - V Z U or ~ ~D-galacto O, configuration. Consequently, substituted hexose derivatives having one of these configurations, not readily obtainable by reactions of the common anhydroglycosides, may conveniently be prepared from the dianhydro derivatives. For example, when exposed to the action of nucleophilic agents, methyl 2,3-anhydro-4,6-0-benzylidene-a-~-allopyranoside (129) affords mainly 2-C-substituted D-&rose derivatives,748whereas 1,6: 2,3-dianhydro-/3-~-allopyranose (110) or its derivative 127 give only the 3-C-substituted D-glucose derivatives’55~379,438~632 (compare Ref. 33 1).

129

110 R = H

127 R = CH,Ph

On the other hand, “anomalous” diequatorial cleavage of an oxirane ring was observed when a-toluenethioxide ion, which is a rather “soft” base, was used as the nucleophilic agent435,443,749 (see Sect. VII,2). An adjacent trans-attached acyloxy group can participate in the cleavage of the oxirane ring by electrophilic agents. This fact was used in the preparation of 1,6-anhydro-/3-~-gulopyranose (46) from 2-0(748) N. R. Williams, Ads. Carbohydr. Chem. Biochern., 25, 109-179 (1970). (749) L. Vegh and E. Hardegger, Helu. Chim. Acta, 56, 1961-1962 (1973).

MILOSLAV k R N Y AND JAN STANEK, JR.

116

acetyl- or 2-O-benzoyl-1,6 :3,4-dianhydro-P-~-galactopyranose (130) by the action of boron trifluoride etherate437;similarly, 1,6-anhydroP-D-altropyranose was obtained from the 4-benzoate of 1,6 : 2,3-dianhydro-P-~-mannopyranose~~~ (117).

I

P

1

5

-@ HO

I

0 '

OH

I

I

R

R

130 R = Me o r Ph

46

In contrast to the dianhydrohexopyranoses, their deoxy derivatives 30, 131, 132, and 133 have an oxirane ring that is quite unsymmetrically s ~ b s t i t u t e dwith ~ ~ ~regard , ~ ~ ~to polar effects. Consequently, in reactions with nucleophiles, polar effects may operate more effectively than steric effects, and this may result in oxirane-ring cleavage at the most electron-deficient position (as indicated by the arrows). Depending on the structure of the dianhydro derivative, the steric

qo

@ O

0 30

131

&(/pJ f

0 132

+ s t e r i c control --•

133

polar control

and polar effects may act in the same or in opposite directions. In the former, the reaction generally proceeds with high regioselectivity, to give a single product, whereas in the latter, mixtures are usually

1,6-ANHYDRO DERIVATlVES OF ALUOHEXOSES

117

formed. Consequently, the D-rib0 derivatives 30 and 133 react with various nucleophiles to give only 3-substituted 1,6-anhydro-4-deoxyP-D-xYZO-or 1,6-anhydro-2-deoxy-~-~-aruhino-hexopyranoses~~~~~ (compare Refs. 325 and 327), whereas, with the D-ZYXO derivatives 131 and 132, a mixture of 2- and 3-, or 3- and 4-substituted 1,6-anhydrodeoxyhexopyranosesis f ~ r r n e d (compare ~ ~ , ~ ~Ref. ~ 329). The ratio of products is sometimes influenced by the nature of the nucleophile; it seems likely that the action of more-polarizable nucleophiles (“soft” bases) is more clearly controlled by polar effects than with less-polarizable nucleophiles (“hard” bases). Therefore, the abnormal, “diequatorial” cleavage is favored when the reacting base is softer, in the sequence I- > NHK, > OH-. 7503751

a. Unsubstituted Dianhydrohexopyran0ses.-By the action of hot, alkali hydroxides, dianhydrides 117- 120 are hydrolyzed to mixtures of 1,6-anhydrohexopyranoseswhose composition is very close to the equilibrium ratio resulting from epoxide migration. It may, therefore, be concluded that the hydrolysis is preceded by rapid, epoxide equilibration, and that the corresponding epoxides undergo ring opening at approximately479the same rate. For example, both 119 and 120 are hydrolyzed when treated with 5%potassium hydroxide, to give a mixture containing 17% of levoglucosan (6) and 83% of 1,6-anhydro-p-~-

W+JY OH

HO

0

wN HO

I

HO

I

OH (17%) 6

OH (83%) 12

(750) T. Ogawa, M. Akatsu, and M . Matsui, Cnrhohydr. Res., 44, c22-c24 (1975). (751) T. Ogawa, M . Akatsu, and M. Matsui, to be published.

118

MILOSLAV CERNY A N D JAN STANEK, JK.

galactopyranose (12); the equilibrium mixture (after the epoxide migration) contains73g119 and 120 in the ratio of 1:4. In a similar way, the D - ~ U T W L O2,3-epoxide 117 and the D - U ~ O3,4-epoxide 118 yield only 1,6-anhydro-P-~-mannopyranose (44), because the equilibrium is almost completely shifted479in favor of 118. The dianhydrides having the D-UZZO (32, 110) and D-~UZO (107, 128) configuration, in which the hydroxyl group and oxirane ring have the cis relationship, decompose479in hot, alkali hydroxide solution (for example, 5% potassium hydroxide), probably by a mechanism involving hydride-ion rearrangement752(see Scheme 13,a). However, an alternative reaction-path (b) through an intermediary enol form cannot be excluded.47g The potential intermediacy of the enol form was demon-

strated by the reaction of the benzyl ether (127) with potassium tertbutoxide, where 134 was isolated479as the major component.

tert-BuO-

PhCH,O

OH 127

134

When the solvolysis of the dianhydrides 32, 107, 110, and 128 is conducted in barium hydroxide or sodium methoxide solution, the aforementioned decomposition does not occur, and 1,6-anhydrohexopyranoses (or their methyl ethers) having the gluco, gulacto, or manno configuration are formed in high yieldlJJ,."",""'."O~ (compare Refs. 438 and 753). (752) J. G . Buchanan, MTP I n t . Rec. Sci.: Org. Ckem. Ser, One-Cor/,ohl/drrrtcs, 7, 31-70 (1973). (753) S. P. James, F. Smith, M. Stacey, arid L. F. Wiggins, Nature, 156,308-309 (1945).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

119

Mineral acids hydrolyze all eight dianhydrides to reducing hexoses. It may be assumed that the oxirane ring is cleaved diaxially, and faster than the 1,6-anhydride bond, as the major products are those having the D-gluco, D-manno, or D-galacto configuration. Only 1,6:3,4dianhydro-P-D-allopyranose (32) yields, surprisingly, a mixture of Dglucose and D-gulose in the ratio47sof 1: 1. Here, a plausible explanation suggests that transition states 135 and 136 have similar stabilities with respect to steric, and polar, intramolecular interactions.752However, it is worth noting that the hydrolysis of the 2,3-isomer 110 proceeds uniquely to give D-glucose, although the transition states 137 and 138 have structures apparently analogous to 135 and 136.

I

n

OH 135

il 136

il n 137

138

Dianhydrides react with other nucleophilic or electrophilic reagents in a steric course similar to that operating with water under basic or acid catalysis, to give amino, halogeno, and thio derivatives (see Sects. VI and VII). Catalytic reduction in the presence of Raney or with lithium aluminum hydride,'55,331affords the mono-155,331,746and di-746deoxy derivatives of 1,6-anhydrohexoses (see Sect. VII,3,a,ii). Like dianhydrohexopyranoses, 1,6 : 2,3-dianhydro-4-deoxy- and 1,6 : 3,4-dianhydro-2-deoxy-~-~-hexopyranoses (30, 131-133) may be utilized for synthesis of derivatives of 2- or 4-deoxy derivatives of 1,6-anhydrohexopyranoses(see Sect. V11,3,b).

120

MILOSLAV C E R N ~A ' N D JAN

STANBE;,JR.

b. Substituted Dianhydrohexopyran0ses.-The O-alkyl and O-sulfonyl derivatives of the dianhydrides are synthetically more useful than the unsubstituted compounds. The p-tolylsulfonyl epoxide 111, readily available (see Sect. V,1) from levoglucosan (6), reacts with a series of reagents, such as alcohols, ammonia, azides, halides, hydrogen, and thiols, to give the 4substituted derivatives of 1,6-anhydro-2-O-p-tolylsulfonyl-~-~-g~ucopyranose (139), where X is H,i42,i54OH,5o4Me0,4g9,505 MezCH0,196

Qow@o

X

OTs 111

OTs 139

H2C=CH-CHz0,434 PhCH20,636Ph0,755PhCH2S,443NH2756(compare Sect. VI,l,b), N3,53i374"3741 F,629and I.630,632,757 Under acid catalysis, the cleavage of the 1,6-anhydride bond stabilized by the p-tolylsulfonyl group is negligible. The other possible reaction, namely, cleavage of the oxirane ring by the acid catalyst, also proceeds to only a small degree; see for example, the formation of the 2,4-di-pt ~ l u e n e s u l f o n a t e(43) ~ ~ ~when p-toluenesulfonic acid is used. However, when alkaline conditions are applied, the primary product that is formed reacts further, by the sequence 139 + 140, to give (usually) symmetrically 2,4-disubstituted derivatives of the D-gluco configuration (140), where X is F~80,507 N 3,740 NH 2, 513,756 PhCHzS,443and Ph0.755 Another valuable, synthetic intermediate for the preparation of 2substituted derivatives 141 and 142 is 1,6 :2,3-dianhydro-4-0-benzylP-D-mannopyranose (116), where, for 141 and 142, X is H,1553376*632 D,155 Me0,155 OH 52 PhCH20,442,629 NH 2, 633,678 NH-alkyl i 5 i N 3, 537 F,380,506 or I.384 Similar cleavages were described for 1,6:3,4-dianhydro-2-O-benzyl-P-~-galactopyrano~e,l56,442,532c,534,542.629,740,758,759 and for the corresponding 2-0-metl1y1,2~~2-O-allyl,434e-O-(tetrahydro11yran-2-y1),~~~ and 2-azido-2-deoxy deriva2

(754) M. Cerny, J. Pacak, and J. Stanlk, Chern. Ind. (London),945-946 (1961). (755) J. Pacak and D. Plocova, Unpublished results. (756) M. Cerny, I. Cemf, and J. Pacik, to be published. (757) T. Tmka and M. Cem9, unpublished results. (758) L. Kalvoda, M. Prystar, and F. sonil, Tetruhedron Lett., 4671-4674 (1973) (759) M. PrystaS and F. Sunn, Tetruhedron Lett., 4097-4100 (1970).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

139

121

-

mo(jq0 J

-

X

X

X 140

@- @ @ 0

PhCH,O

___)

PhCH,O 116

X 141

HO

X 142

t i ~ e ~also, ~ for ~ ~1,6,:2,3-dianhydro-4-0-p-toly~s~i~fonyl-@-~-manno~ ~ ~ ; p y r a n o ~ e , and ~ ~ ~the , ~ ~corresponding ~ 4-0-a~ety14 , ~- 0~ -~r n e t h ~ 1 , ~ ~ ~ 4 - 0 - t e r t - b ~ t y 1 ,4-0-a11y1,434 ~~~ 4-deoxy-4-fluor0,3~~,~~~ and 4-azido-4deoxy derivative^,^^^^^^' and for 1,6 :2,3-dianhydro-4-0-benzyl-P-~a l l o p y r a n ~ s eand ~ ~ ~1,6 ~ :~2,3-dianhydro-4-0-methyl-@-~-talopyran~~ O S ~ . According ~ ~ ~ J to ~ expectation, ~ products of diaxial cleavage having the Dgluco or Dgalacto configuration are mainly formed in all of the foregoing reactions.

VI. NITROGEN DERIVATIVES OF

1,6-ANHYDROHEXOPYMNOSES

1. Amino and Azido Derivatives a. Cyclization of Hexoses and Their Derivatives.-In aqueous solutions of strong acids, amino derivatives of aldohexoses are cy(760) R. W. Jeanloz, J . Am. Chem. Soc., 76, 5684-5686 (1954).

122

MILOSLAV

C E R N ~AND '

JAN STANEK, JK.

clized to 1,6-anhydrides or, more exactly, to an equilibrium mixture containing both of the components m e n t i ~ n e d . ' ~ The ~ ~ ~compo~~~~~'~~~ sition of this mixture depends on the configuration of the amino sugar, and is probably controlled by factors similar to those for hexoses (see Sect. 11,4). For example, 3-amino-l,6-anhydro-3-deoxy-P-D-altropyranose h y d r ~ c h l o r i d e ~ ~(see ~ ~ 'also, ~ ~ * Ref. ~ ~ ~ 761) was prepared b y reaction of methyl 2,3-anhydro-4,6-O-benzylidene-a-~-mannopyranoside with ammonia, followed b y heating of the resulting 3-amino derivative with hydrochloric acid161,1G3 (compare Refs. 761 and 763), or, in a similar way, from the corresponding 2,3-anhydro derivative of a r n y l o ~ eAn . ~ analogous ~~ method was employed for the preparation of 2-amino-1,6-anhydro-2-deoxy-P-~-a~tropyranose'~~,~~~ from methyl 2,3anhydro-4,6-O-benzylidene-a-~-allopyranoside, and also for the preparation of the 2- or 3-amino derivatives of 1,6-anhydro-P-~-idopyranose,130,159,160,166 3-amino- 1,6-anhydro-3-deoxy-2-thio-fi-~-alIopyranose,16' and the 2- or 3-amino derivatives of 1,6-anhydro-P-~g u l o p y r a n ~ s e(2-amino-1,6-anhydro-2-deoxy-/3-~-gulopyranose ~~~~'~~~~~~ was also obtained by acid hydrolysis of streptothricin and ~ t r e p t o l i n ' ~Acid-catalyzed ~). cyclization in boiling benzene was used to prepare the 2- and 3-azido derivatives having the D - d t r o c~nfiguration.~'~ Another method, based on cyclization of glycosyl f l ~ o r i d e s , ~ ~ ~ , ~ ~ such as 143 (for a methyl glycoside as a side-product, see Ref. 766), or of 6-0-p-tolylsulfonyl derivatives of h e x o s e ~ (145), ~ ~ in ~ ~alkaline ~ media, was used for the preparation of 2-amino-l,6-anhydro-2-deoxy/3-D-glucopyranose and its N-substituted derivatives (144). A quite different approach was demonstrated in the preparation (147)from of 2,4-diamino- 1,6-anhydro-2,4-dideoxy-/3-~-talopyranose 146 by the action of phenylhydrazine and iodine, followed by catalytic reduction.433

b. Cleavage of 1,6 :2,3-and 1,6:3,4-Dianhydrohexopyranoseswith Ammonia, Amines, and Azide Ions.-1,6 : 2,3-Dianhydro-fi-~-talopyranose (107)and its 4-methyl ether react with ethanolic ammonia to give the 2-amino-1,6-anhydro-2-deoxy-~-~-galactopyranose (148)and its 4-methyl ether50sa511;under the same conditions, 1,6 :3,4-dian(761) P. A. Levene and G. M . Meyer,]. Biol. Chem., 55,221-227 (1923). (762) M. L. Wolfrorn, H. Kato, M. I. Taha, A. Sato, G. U. Yuen, T. Kinoshita, and E. J. Soltes,J. Org. Chem., 32,3086-3089 (1967). (763) W. H. Myers and G. J. Robertson,]. Am. Chem. SOC.,65, 8-11 (1943). (764) F. Micheel and H. Wulff, Chem. Ber., 89, 1521-1530 (1956). (765) F. Micheel and E. Michaelis, Chem. Ber., 91, 188-194 (1958). (766) F. Micheel and E. Michaelis, Chem. Ber., 96, 1959-1964 (1963).

HomF-w 1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

HO

143

123

NHR 144

OAc

145

147

hydro-P-D-talopyranose (128) yields 4-amino-1,6-anhydro-4-deoxy-pD-mannopyranose (177) as the principal p r o d u ~ t . ~ " s , ~ j 3 In both instances, 3-amino derivative 149 is formed as a minor product. From 1,6 :2,3-(110) and 1,6:3,4-dianhydro-P-~-allopyranose (32), a single product, 3-amino-1,6-anhydro-3-deoxy-~-~-glucopyranose379*438 (150) (or its N-alkyl derivatives when using a m i n e ~ ' ~ 'is ) formed .

\lILOSLAV CEHNY A N D JAN STA\fih, TR

124

HO

HO

HO

e0 R0 OH

I

NHZ

107

-

Q 0

HO

149

140

0 110

a

HO

OH 150

0

OH 32

The cleavage of the 4-methy1505and 4-benzyl ethers of 1,6:2,3-dianhydro-P-D-mannopyranose (117) with a m m ~ n i a , ~or~ of ~ .its ~ 4-0-tert~' butyl derivative with b e n ~ y l a m i n e also , ~ ~ ~occurs with a high regioselectivity, leading to the formation of the corresponding ethers of 2-amino-1,6-anhydro-2-deoxy-~-~-glucopyranose (see Sect. V,3). The 4-benzyl ether of 117 was also employed for the synthesis of 1,6-anhydromuramic acid.63x Ammonolysis of 1,6 :3,4-dianhydro-2-0-benzyl-P-~-galactopyranose (188) affords the 4-amino-4-deoxy derivative.740It was also used for the preparation of the 2-amino-4-fluoro- and 4-amino-2-fluoroThe 2,4-dideoxy derivatives of 1,6-anhydro-P-~-glucopyranose.~"' oxirane ring of most dianhydrides is readily split not only by ammonia but also by its derivatives, such as methylamine, d i i i i e t h y l a ~ n i n e , " ~ ~ ~ ~ ~ ~ and ben~ylamine."~ The course of ammonolysis of 111 is rather complicated, and the reaction results in a mixture containing 2,4-diamino-1,6-anhydro-2,4d i d e o x y - P - ~ - g l u c o p y r a n o s e(154) ~ ~ ~ (compare Ref. 513) and 1,6-anhydro-3,4-dideoxy-3,4-epimino-~-~-altropyranose~~~ (153) as the major products. This reaction course may be most satisfactorily explained b y the sequence 111+151+152, where 4-amino-1,6 :2,3-dianhydro4-deoxy-P-D-mannopyranose (152) partly isomerizes (see Sect. VI,2) to the epimine 153, and partly reacts with ammonia to give740the diamino derivative 154.

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

125

An alternative method for synthesis of the 1,6-anhydrides of aminodeoxyhexoses consists in cleavage of the oxirane ring by azide ions in aqueous ethanol or 2-ethoxyethanol in the presence of ammonium chloride as a buffer379,537-53y~740,741~75",751 (see also, Ref. 45a). The azidohydrins thus formed are reduced by nascent hydrogen (from, for example, zinc and hydrochloric acid), or catalytically in the presence of platinum, palladium, or Raney nickel, to give the corresponding amino derivatives. C. Sulfonic Ester Replacement.-The ammonolysis of sulfonic esters has thus far not proved to be a versatile method for the preparation of amino derivatives of 1,6-anhydrohexoses. It was applied to 1,6-anhydro-2,4-di-O-p-tolylsulfony~-~-~-g~ucopyranose (43),and 2,4diamino- 1,6-anhydro-2,4-dideoxy-P-~-glucopyranose~'~~~~~ (154) was isolated as the principal product; epoxide 111 has been found to be an intermediate.756

8' go Ho -

-

NH,

Ts 0

OTs 43

152

2 NH

NH,

OTs 111

153

HZN

OTs 151

154

Compared to ammonolysis, the replacement of a sulfonyloxy group trans-oriented to an acetamido or benzamido group (in either the diaxial or the diequatorial arrangement), which is effected by acetate ion in boiling, aqueous 2-methoxyethanol, is of much greater synthetic applicability. Under these conditions, the reaction proceeds with neighboring, acylamino-group participation, and results in inver(compare Sect. IV,4). It is worth noting sion of configuration37s~379*51z~700 that even the equatorial methylsiilfoiiyloxy group in Lxetamido1,6-anhydro-2-deoxy-3-O-~e1izoyl-4-O-(me~y~s~ilfonyl)-~-~-gal~i~topyranose (52) is replaced b y azide b y the action of sodium azide ( S N ~

MILOSLAV ~ X R N Y AND JAN STANEK, JR.

126

mechanism) in boiling N,N-dimethylformamide, yielding the 4-azido derivative 53, which was catalytically reduced to the corresponding amino d e r i ~ a t i v e . ~ ' ~ d. Other Methods.-The dialdehyde 100 condenses with nitromethane to give a mixture of 3-deoxy-3-nitro derivatives of 1,6-anhydrohexoses which, when reduced, yield derivatives of the 3-amino1,6-anhydro-3-deoxy-P-~-gulo-, -altro-, and - i d o - p y r a n o ~ e(compare ~~~ Sect. IV,8). By an alternative condensation of 100 with nitromethane in the presence of benzylamine, 1,6-anhydro-2,4-di(benzylamino)2,3,4-trideoxy-3-nitro-P-D-idopyranose (155) was obtained as the principal product; it served as the starting compound for the preparation of the triamino-l,6-anhydro-~-idose derivative 156 by catalytic reduction and d e b e n z y l a t i ~ n . ~ ~ ~ * ~ ~ ~ 0

100

PhCKHN 155

156

3-Amino-1,6-anhydro-3-deoxy-~-~-galactopyranose~~~ and 4-amino1,6-anhydro-4-deoxy-~-~-talopyranose~~~~~~~ have been prepared by the reduction of oximes. e. Properties and Reactions.-Amino derivatives of 1,6-anhydrohexopyranoses and, especially, their hydrochlorides (see Table IX) are ninhydrin-positive, mostly crystalline compounds, usually melting with decomposition, but displaying characteristic optical rotations (compare, Sect. 111); their peracetyl derivatives can be readily crystallized, and are therefore suitable compounds for identification. The

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

127

fact that these peracetates are generally more soluble in water than the peracetates of 1,6-anhydrohexoses should be borne in mind during their isolation. The 'H-n.m.r. spectra of these amino derivatives are very similar to those of 1,6-anhydrohexoses, except for the proton of the methine group linked to the amino group, which is shifted ~ p f i e l d . It ~ ,follows ~ from the J values that these amino derivatives and their hydrochlorides normally adopt the expected 'c4(D) conformation in water and dimethyl sulfoxide. However, 3-amino-l,6-anhydro-3-deoxy-/3-~-glucopyranose (150) is assumed to exist in a dynamic equilibrium of the 'c4(D) and B,,,(D) conformations, which is strongly shifted in acid media in favor of the BO,,(D) conformation438(157). In the crystalline

150

157

state, compound 150 exists in a distorted 'c4(D) conformation (as shown b y neutron diffraction356).The B,,,(D) conformation has also been observed for the dihydrochloride of 2,4-diamino-l,6-anhydro2,4-dideoxy-/3-~-glucopyranose(158)in aqueous solution, and for the corresponding 2,4-diazido derivative in chloroform solution.741Although a simple explanation, based on repulsion between the two ammonium groups, accounts for the stability of the 2,4-diammonium fomi (158), this interpretation fails for the boat form (157). For conversion

158

of the protonated 150 into 157, mutual attraction of the inversely oriented dipoles of both hydroxyl groups and of the ammonium group should be considered, as well as the steric interaction caused by the marked enlargement of the effective volume of the ammonium group by solvation (which is greater than for an unprotonated amino group),

hIILOSLAV i;EHN';' AND JAN STANEK, JR.

128

resulting in repulsion between the 1,6-anhvdro bridge and the ammonium group.438,767 Amino derivatives of 1,6-anhydrohexoses are hydrolyzed far more slowly than 1,6-anhydrohexoses, because of the stabilizing effect of the ammonium group (-I effect) on the acetal grouping (compare Sect. IV,l,a). Among them, the 2-amino derivatives in particular are extraordinarily stable, and are not usually h y d r ~ l y z e d , ~ ~ ~ except with 6 M hydrochloric acid (compare Refs. 438 and 513); the hydrolysis of 4-amino derivatives proceeds with decomposition, and does not lead to reducing aminohexoses439~513 (compare Ref. 768). Occasionally, ammonium chloride may appear in the reaction mixture.lfi6 It is, therefore, advantageous to split the 1,6-anhydride bond by acetolysis.'"~"7x~~12,~1:~ The high stability of 2-aniino-l,6-anhydro-2-deoxyhexopyranoses in acid media permits selective, acid hydrolysis of such hydroxyl-protecting groups as tert-butyla5 and b e n ~ y land , ~ ~of~ the N-acetyl g r o ~ p . ~The ' ~ ,amino ~ ~ ~ anhydrohexoses are oxidized by periodic a c i d l " ~ , " ' , ' ~ ~ -in I ~the ~ , ~same ~ ~ way as their oxygen analogs; an acetamido group hinders the r e a c t i ~ n . ~ ~ ~ ~ ~ ~ During syntheses with amino 1,6-anhydrohexoses, it is often necessary to protect the amino group with a b e n ~ y l acety1,97,161,167,378,s10, ,~~~ 512,633 p-tolylsulfonyl,7G6~769 or benzyloxycarbonyl group.678,G98 The amino group may readily be selectively acylated in the presence of free hydroxyl groups; for example, with acetic anhydride in methano1,'67~s10~s12~G33 or with benzyl chloroformate in alkaline aqueous solution.G78,698 The benzyl and, particularly, the benzyloxycarbonyl group can be removed by hydrogenolysis in the presence of palladium-oncharcoal, the acetyl group by basic or acid hydrolysis, and the p tolylsulfonyl group by sodium in liquid ammonia. A rather complex reaction of the amino 1,6-anhydrohexopyranoses is their deamination with nitrous acid, which was studied for the 2-, 3-, and 4-amino derivatives of 1,6-anhydro-/3-~-glucopyranose~~~ and for 4-amino-l,6-anhydro-4-deoxy-/3-~-mannopyranose.~~~ The formation of epoxides, besides other products, was observed in all instances (compare Ref. 698). On the other hand, according to previous findings,698the deamination of the %amino 3,4-diacetate 159, having no free hydroxyl group, involves rearrangement of the C-1-0-6 (767) A similar eflect has been observedi57 for the mono-,.cli-, and tri-methylanimonio groups.

(768) H. Paulsen, K. Steinert, and K. Heyns, Chem. Ber., 103, 1599-1620 (1970). (769) F. Micheel and W. Opitz, Chem. Ber., 96, 1965-1975 (1963).

(770) J. Defaye, T. Elbert, and M. CemL, to be published. (771) V. G. Bashford and L. F. Wiggins, Nature (London),165, 566 (1950).

1,B-ANHYDRO DERIVATIVES OF ALUOHEXOSES

129

bond, and results, after acetylation, in the formation of 1,3,4-tri-0acetyl-2,6-anhydro-~-mannopyranose~~~ (161). Similarly, even free 2-amino-1,6-anhydro-2-deoxy-~-~-glucopyranose (160) gives, on deamination and acetylation, the anhydride 161, in addition to a dimer of 161 (of not definitively proved structure), whereas formation of epoxide was not o b ~ e r v e d . " ~

161

159 R = Ac 160 R = H

2. Epimines and Amino Epoxides Of the eight epimino derivatives possible, only three are thus far known. 1,6-Anhydro-2,3-dideoxy-2,3-epimino-~-~-mannopyranose (166) was prepared379from the amino derivative 162 on acylation, followed by treatment of 163 or 164 with sodium isopropoxide, and catalytic debenzylation of 165. When a benzoyl group, which is more-

e0-mo >mo 0 Hz7pd*@o

PhCH,O

NH

HO

PhCH,O

OTs

162 R = H 163 R = p-NO,C,H,CO 164 R = Bz

166

/

PhCH,O

NH,

N//c\o

NHz

HO

167

168

169

hlIL0SLAV CEKNY A N D JAN STANEK, J R

130

strongly participating than a p-nitrobenzoyl group, was used, as in 164, an oxazoline derivative (169) was formed as a by-product. Epimines having the D-gulo (173) and ~ - a l t r o(153) configuration are obtainable by i ~ o m e r i z a t i o nof~the ~ ~ amino ~ ~ ~ ~epoxides 172 and 152 having a trans relationship of the oxirane ring and amino group. During this isomerization, performed in hot, alkali hydroxide solution, partial hydrolysis of the oxirane ring occurs, to give the 2- and 4-amino derivatives of levoglucosan (160 and 176, respectively).

eo eo+ H0

Ho -

-

QoH2,Pd

Ts 0 NHR

NHR

170 R = P h C H 2 0 C 0

172

HO-

NH2

172

171 R = P h C H 2 0 C 0

HO

Homo NH

HO

173

=

OTs

N3

176

HZ P

d

Nff2

160

0m

o

H2N

N3

153

177

(772) M. Cernq, 0.JulikovL, J. Pacak, and M. Budc%'iiskS;, Collect. Czech. Claeni. Comrnun.,40, 2116-2119 (1975).

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

131

The starting amino epoxides are usually prepared by methods similar to those used for dianhydro d e r i v a t i v e P (see, for example, 170+-171+172) or by the reduction of azido e p o x i d e ~(see, ~ ~ for ~ example, 174+175+152). The aziridine ring is more stable than the oxirane ring in alkaline solution, as demonstrated by the low reactivity in attempts to accomplish isomerization of the hydroxyepimines to amino epoxides in alkaline media at room temperature, which contrasts with the rapid epoxide migration (see Sect. V,2). Isomerization of hydroxyepimines occurs only at high temperatures, and leads finally to the formation of amino derivatives of 1 , 6 - a n h y d r o h e x o ~ e sFor . ~ ~example, ~ ~ ~ ~ ~ when 166 is heated in 5% potassium hydroxide, 2-amino-1,6-anhydro-2-deoxyP-D-mannopyranose (168) is formed as the main product; this can be explained by transient formation of 2-amino- 1,6:3,4-dianhydro-2deoxy-P-D-altropyranose (167), and its subsequent, diaxial hydrol167 is probably in "equilibrium" with epimine y ~ i s Compound . ~ ~ ~ 166. Acid hydrolysis of the aziridine ring in 153 also follows a diaxial mechanism, without scission of the 1,6-anhydride bond, to give 4amino-1,6-anhydro-4-deoxy-~-~-mannopyranose~~~ (177). Epimines 153, 166, and 173 are crystalline compounds which show a slightly positive reaction in the ninhydrin test, and give characteriistic 'H-n.m.r. spectra closely resembling those of the corresponding dianhydro derivatives (see Sect. 111). Their N-benzoyl derivatives display379a carbonyl stretching absorption at 1690 cm-', shifted to frequencies higher than those of the common benzamides.

-

AND DEOXYDERIVATIVES OF 1,6-ANHYDROHEXOPYFIANOsES

VII. HALOGENO,THIO,

1. Halogeno Derivatives Of the halogenated 1,6-anhydrohexopyranoses,the main interest has been directed to the iodo as intermediates for the synthesis of deoxy sugars, and to the fluoro derivatives (for a review, see Ref. 773), interesting from both the chemical and the biochemical point of view. The chloro and bromo derivatives have been examined only rarely.s4J68,319,437 The syntheses of the title compounds start mostly from 1,6-anhydro derivatives, using either the often regioselective course of the oxirane-ring opening by nucleophilic agents~80,384,437,447,448,~06.~07,~44.629,630,632, 637 (see Sect. V), or the sN2 replacement.632Cyclization of deoxyhalo(773) J. PodeSva and J. Pac&k,Chem. Listy, 67,785-807 (1973).

132

blILOSLAV CERNi' A N D JAN STANEK, JR.

geno derivatives of free hexoses was utilized in the preparation of some isomers of D-~llo'~' (see also, Ref. %), D - ~ ~ t r o , ' and ~ * ~D-ido'iO '~~ configuration only. 1,6-Anhydro-4-O-benzyl-3-bromo-2,3-dideoxy-~D-ribo-hexopyranose (179) was prepared3lSby the action of hydrogen bromide in acetic acid on the enoside 178.

176

L

Br

J

J

B:. 179

The reaction of 26 with bromine in carbon tetrachloride yields325-327 a mixture of exo and endo bromo derivatives (27) in the ratio of 3 : 2 (see also, Section 11,7). The supposed intermediate of this acetal bromination into the 2-position is3263,4-dihydro-W-pyran-2-methanol (25);however, direct conversion of 25 into 27 was not demonstrated. a. Iodo Derivatives.-The cleavage of 1,6 :3,4-dianhydro-%O-ptolylsulfonyl-P-D-galactopyranose (111) by magnesium iodide630or hydrogen iodide,632like the ring opening384,630 in 1,6 :2,3-dianhydro-4-0benzyl-P-D-mannopyranose (116), proceeds diaxially, that is, with formation ofthe ~ g l u c oderivative. The replacement of the polar and bulky benzyloxy group on C-4 in 116 by a hydrogen atom results in a totally different course of reaction; 1,6 : 2,3-dianhydro-4-deoxy-P-~ lyno-hexopyranose (131) yields only the 3-iodo derivative having the Dcircibino configuration as the product of the diequatorial cleavage.384 This behavior is exceptional, as the three other dianhydromonodeoxy derivatives (30, 132, and 133) react with magnesium iodide with the formation of products containing, almost exclusively, axially oriented iodine.384 Compound 180 was converted by way of a redox sequence, into

1,6-anhydro-4-deoxy-4-iodo-2-O-p-tolylsulf~1iy~-~-~-a~~opyranose~~ (182). Iodine in ketone 181 can be very readily eliminated by reduc-

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

133

t i ~ n Similarly, . ~ ~ ~ various deoxy 1,6-anhydrohexopyranosuloseswere prepared from the corresponding i o d o k e t o n e ~(see ~~~ Sect. VII,3,b). 0

180

@.51@ I

OTs 181

OTs 182

b. Fluoro Derivatives.-The benzyl epoxide 116 has also proved useful for the synthesis of fluoro derivatives. Again, the oxirane ring is mainly opened diaxially, with formation of 183, when potassium hydrogenfluoride in ethylene glycol is used; as a by-product, 1,6-anhydro-4-O-benzyl-3-deoxy-3-fluoro-~-~-altropyranose is ~ b t a i n e d . ~ ~ ~ , ~ ~ Compound 183 may be readily converted into the 3,4-anhydro derivative 184 which, on further reaction with potassium hydrogenfluoride, 185. yields380,507 1,6-Anhydro-2,4-dideoxy-2,4-difluoro-p-~-glucopyranose ( 185) can also be ~ r e p a r e d , 4 ~ ~ ~of~the ~ 2,3-epoxide (186), starting from by~ way 1,6-anhydro-4-deoxy-4-fluoro-~-~-glucopyranose~~~~~~~~~~~~ (187) obtained from the D-galacto e p o ~ i d e ~ (119) ~ ~or*its~2-benzyl ~ ~ , ~ether629 ~ ~ (188). The presence of the protecting group on 0 - 2 permits629ready conversion of the intermediary 189 into 186, by way of the 3-O-acetyl derivative, making the partial p-toluenesulfonylation of 187 unnecessary. 1,6:3,4-Dianhydr0-/3-~-altropyranose (118) undergoes cleavage with potassium hydrogenfluoride in ethylene glycol according to the Fiirst-Plattner rule, to give the 3-fluoro derivative of 1,6-anhydroP - D - m a n n ~ p y r a n o s e .As ~~~ these conditions are sufficient for the ~ ' . sulfonyl ~~~ conversion of p-tolylsulfonylhydrins into ~ x i r a n e s , ~the epoxides 111 (Refs. 380 and 507) and 123 (Ref. 629), in a multistage process, finally afford (albeit in low yield) the difluoro derivative 185;

MILOSLAV CERNY AND JAN STANEK, JK.

134

PhCH,OQ0

Q 0

Q 0

OH 116

OCH,Ph

119

Q0

PhCH,O

188

FQo-FQo OH

F

OCH,Ph

'i Q-FQ-FQ 183

187

1

\

F

F

184

185

186

190

191

131

see Sect. V,3,b. If hydrogen fluoride in 1,4-dioxane is used, formation of epoxide does not occur, and the product of the cleavage of 111 is a very small proportion of 1,6-anhydro-4-deoxy-4-fluoro-2-O-p-tolylsulfonyl-~-D-glucopyranose.629 The fluoro derivatives of 1,6-anhydrohexopyranoses undergo all of the common reactions of 1,6-anhydrohexoses. By using a redox sequence, derivatives of 1,6-anhydro-/3-~-allopyranosewere prepared545from 183 and 185. Ammonolysis of the fluoro epoxide 184 leads to the amino derivative3*I190, and hydrogenolysis of 184 gives

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

135

1,6-anhydro-2,4-dideoxy-2-fluoro-~-~-~yZo-hexopyranose~~~ (191), also obtained by reaction of the deoxy epoxide 131 with potassium hydrogenfluoride in ethylene In contrast, compound 192 yields,382 after hydrogenation, both possible fluoro derivatives, namely, 193 and 194. The dianhydro derivative 186 was used for the preparation of Z-amino-l,6-anhydro-2,4-dideoxy-4-fluoro-~-~-glucopyranose."l

192

193

194

The exchange of a hydroxyl group for a fluorine atom causes no noticeable steric or polarizability changes. As a result, the values of the specific rotations of the fluoro derivatives do not differ from the values for the parent anhydrides, and this permits easy structural correlations (see Sect. 111). The values of 62% for 1,6-anhydro-2-deoxy2-fluoro-@-D-altr0pyranose~~~ (for the analogous chloro and bromo derivatives, see Ref. 168), 15% for 1,6-anhydro-2-deoxy-2-fluoro-PD-allopyran~se,'~~ 93% for 1,6-anhydro-3-deoxy-3-fluoro-p-~-idopyranose, 170 as well as the nonexistence508of 1,6-anhydro-2-deoxy-2fluoro-@-D-glucopyranose in the equilibrium mixtures with hexoses, approximate the values summarized in Table I, and indicate that the presence of fluorine in the molecule does not greatly influence the composition of this equilibrium mixture. The presence of the electronegative fluorine atom at C-2 significantly lowers the reactivity of the acetal grouping in the vicinity and, as a result, the hydrolysis or acetolysis of 1,6-anhydro-Z-deoxy2 - f l u o r o - ~ - D - g ~ ~ i c o p y r a n o s1,6-anhydro-Z,4-dideoxy-2,4e,~~~~~~~~~~~~~~~ d i f l u o r o - P - D - g ~ u c o p y r a n ~ s(185), e ~ ~ ~ ~and ~ ~ ~certain other 2-fluoro d e r i ~ a t i v e s ~proceeds ~ l , ~ ~ ~with significantly more difficulty than that of the 3-fluoro or 4-fluoro isomers.170*447,448*544 The stabilization of the C-1-0-6 bond is obviously so profound that, during attempted cleavage of the 1,6-anhydride bond in 195 by the action of hydrogen bromide in acetic acid and acetic anhydride, the C-6-0-6 linkage was cleaved first, to give the 6-bromo-6-deoxy compound, which then reacted to give the glycosyl bromide543(196).It is to be expected that

MILOSLAV &RNY

136

A N D JAN STANEK, JR.

other atoms or groupings having similar electron-withdrawing properties will exhibit an effect analogous to that of the fluorine atom.

boAc]-

AcOQO-1

AcO

195

AcO QBr

196

2. Thio Derivatives Thio derivatives of 1,6-anhydrohexopyranoseshave been prepared by opening of the oxirane ring of dianhydrohexoses by the action of thioxides (see also, Sect. V,3); 3-amino-1,6-anhydro-3-deoxy-2-thio-@D-allopyranose hydrochloride is the only thio compound that has thus far been prepared (from methyl 3-amino-3-deoxy-2-thio-c-u-D-allopyranoside) by acid The reagent used most is sodium a-toluenethioxide, as the benzylthio group can be readily converted into the free thiol group by the action either of sodium in liquid Such an opening of 1,6 :3,4or of sodium dianhydro-P-D-talopyranose(128) resembles the reaction of 128 with other nucleophiles; as a result of the diaxial opening, 1,6-anhydro4-S-benzyl-4-thio-P-D-mannopyranose was obtained in excellent yield, and converted, by isopropylidenation and debenzylation, into

1,6-anhydro-2,3-0-isopropylidene-4-thio-@-~-mannopyranose.~~~ The epoxide ring of 1,6:3,4-dianhydro-P-~-galactopyranose (119) is also opened d i a ~ i a l l y ~ the ~ ~isolation ; of almost 90% of 1,6-anhydro4-S-benzyl-4-thio-P-~-ghcopyranosesuggests that epoxide migration is not concurrent with this oxirane-ring opening. Should the opposite be true,the D-gulo epoxide (120) should preponderate as the starting substance (for this equilibrium, see Sect. V,l,a), yielding7491,6-anhydro-2-S-benzyl-2-thio-@-~-idopyranose(197). Compound 197 is, in fact, the protluct of diequatorial cleavage; diaxial opening leading to 198 has only minor importance.749The predominance of the diequatorial opening was also for 117, where the “no~-mal” diaxial product, namely, 199, constitutes only 22% of the whole mixture. Its desulfurization yielded 201, and acid methanolysis gave a mixture of the anomers of methyl 2-S-benzyl-2-thio-D-glucopyranoside. The main product of mercaptolysis (52%) was identified as the 1,6-anhydro-3-thio-D-altrose derivative 200 by means of ‘H-n.1n.r. spectroscopy of the corresponding 2,4-di-O-acetyl-3-S-acetyl deriva-

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

137

w

I ? HO

HO 197

120 (-

SCH,Ph

199

f

(-,

PhCH,SNa

117 PhCH,SNa

HO

OH 198

7

N

200

I

0

-

199

HO

P

__t

HO 201

117

/

M-N-(L!!y HO

118

AcO

202

203

tive ( J 2 , 3 6.5 H z , J ~1.5 , ~ Hz); also, desulfurization yielded, after acetylation, the known 2,4-di-O-acetyl-1,6-anhydro-3-deoxy-~-~-urabinoh e x ~ p y r a n o s e(203). ~ ~ ~ However, this result of desulfurization does not exclude the possibility of the formation of the 1,6-anhydro-3-thio-~mannose derivative (202),which could be the product of the cleavage of 1,6:3,4-dianhydro-P-~-altropyranose(118) (equilibrium 117%118, see Sect. V,l,a). The n.m.r. data and the values of optical rotation

MILOSLAV ~ E R N Y AND JAN STANEK, JR.

138

(compare Sect. 111)agree better with the second possibility, for which the rate of epoxide migration has to be at least comparable with the rate of the oxirane-ring opening. The reaction of the p-tolylsulfonyl epoxide 111with sodium a-toluenethioxide yields443first the 4-S-benzyl-4-thio derivative (204) (204 can be better prepared by acid-catalyzed, oxirane-ring Then, p-toluenesulfonic acid is eliminated from 204, to give 205, which, on further reaction, yields a 2.2 : 1mixture of the dithio derivatives 206 and 207. Surprisingly, the unsaturated derivatives 208 and

111

PhCQSNa

-

Rom0 PhCQSNa-

PhCH,S

TS

PhCQS 205

204

/

PhCQSNa

+ / SCQPh PhCH,S

SCQPh 206

PhCH$ 207

209 appeared as by-products; they obviously result from 205. However, the mechanism described for their formation (see Scheme 14), involving hydride transfer, seems to the present authors somewhat improbable. The alternative cannot be excluded that the oxirane ring of 205 could be opened under the simultaneous participation of the neighboring thio group. The 1,6-anhydro-di-S-benzyldithio-~-mannose derivative 210 thus formed should eliminate the dibenzyl disulfide found in the reaction mixture, to yield the ene derivative 209. Should this be the true explanation, then even the diol formed by the surprisingly easy hydrolysis of 205-and this is also in agreement with the participation supposed-could have, not the describedM3D - u Z ~ ~ O , but, more probably, the D - ~ U W I O configuration (211). The 'H-n.m.r. 1 H z , J q , g 5 Hz) for 2,3-di-O-acetyl-l,6-anhydro-4-S-benzyl-4data (jl,z thio-&~-altropyranose,4~~ obtained by acetylation of the reaction prod-

139

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

I

P

208

0'

205

f

(PhCH&

209

Scheme 14

uct, correspond better with those expected for the derivative having the D-manno c o n f i g ~ r a t i o n . ~ ~ ~

205

PhCH, S__t

PhCH,S 210

/ \

1 209

208

+

(PhCH,S),

PhCQS 211

The free, S-unsubstituted 1,6-anhydrothiohexopyranoses are very Under the readily oxidized to the corresponding conditions of an acid hydrolysis, the 4-thio derivatives decompose702 (compare Ref. 435); however, their 1,ganhydride bond can generally be readily opened by a c e t o l y s i ~ . ~ ~ ~ * ~ ~ ~

140

MILOSLAV

CERNY

AND JAN STANEK,JR.

3. Deoxy Derivatives All nineteen of the possible deoxy derivatives of 1,6-anhydrohexopyranoses have been described (see Table X). Many of them are suitable precursors of otherwise almost inaccessible deoxy sugars.

a. Formation and Preparation.-i. Cyclization of Hexoses and Their Derivatives. Like their parent hexoses, deoxy sugars (or their acidlabile derivatives) are converted by aqueous acid into the equilibrium mixture aldosesanhydride. For 1,6-anhydro-3-deoxyhexopyranoses, the position of the equilibrium has been systematically studied, and foundg9to agree well with that estimated from conformational interaction-energies (see also, Sect. 11,4). By using the same method, the proportions of anhydrides in equilibrium have been calculated723for the remaining isomers; together with the known experimental data, they are given in Table XI. Preparative utility has been found for the acid hydrolysis of 1,2 :5,6-di-O-isopropylidene-3-deoxy-a-~-xylohexofuranose to 1,6-anhydro-3-deoxy-~-~-xylo-hexopyranose'~~; other anhydrides, such as 1,6-anhydro-4-deoxy-j3-~-urabino-hexopyranose, 132p154 1,6-anhydro-3-deoxy-/3-~-urubino-hexopyranose,'~~ 1,ganhydro2-deoxy-P-D-xyZo-hexopyranose'5'(compare Ref. 774), were prepared from the appropriate methyl glycosides, or their benzylidene acetals [see also, the formation of 1,6-anhydr0-3-C-(cyanomethyl)-2,3-dideoxy-~-~ribo-hexopyranose'~~]. The action of 2.6 M sodium hydroxide on phenyl 3-deoxy-P-~riho-hexopyranoside yields 1,6-anhydro-3-deoxy-P-~-ribo-hexopyranose.'05 For the preparation of 2-deoxy isomers, the same treatment may not be suitable (see Sect. 11,l); the strongly pH-dependent failed reaction of p-nitrophenyl 2-deoxy-cr-~-aruhino-hexopyranoside to give (see Table X) the anhydride expected.77s All 1,6-anhydrohexopyranoses of the DL-series thus far described originate from 1,6-anhydro-2,3,4-trideoxy-~-~~-gZycero-hexopyranose (26), prepared from 3,4-dihydro-2H-pyran-2-methanol (25) in acid media323-326 (see Sect. 11,7). A similar addition is hidden in the reaction of the enoside 178 with hydrogen bromide in acetic acid, which leads319to the derivative 179 having the Dribo configuration (and not Darubino, as originally believed776). (774) Z. Kowalevski, 0. Schindler, and T. Reichstein, Helc. Chim. Acta, 43,1214-1217 ( 1960). (775) R. J. Ferrier, W. C. Overend, and A. E. Ryan,]. Cheni. Soc., 3484-3486 (1965). (776) N . F. Taylor, personal communication; see reference 93a, p. 236, in R. J. Ferrier, Adv. CarbohtJdr.Chem. Biochem., 24, 199-266 (1969).

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

141

ii. Reductive Cleavage of the Oxirane Ring. For this purpose, either Raney nicke1383,384,540,742,'146,7~~ or lithium aluminum hydridelSS,331.376,384,632 was used for dianhydro sugars. A systematic study of hydrogenation of the eight dianhydrohexopyranoses in the presence of Raney nickel under atmospheric pressure at 40"revealed746(see also, Ref. 540) that the cleavage proceeds with high regioselectivity, to give that deoxy sugar which has the newly formed hydroxyl group in the axial position. Only the 2,3-anhydro compounds 107 and 117 form both of the possible monodeoxy 1,6-anhydrohexopyranoses in comparable proportions. Surprisingly, in all cases, the products of a deoxygenation of the epoxide were obtained (that is, 213, 214, 215, or 216) in yields746of 6 to 20%. Similarly, 26 is the by-product in the conversion of dianhydrodeoxy sugars into 1,6-anhydrodideo~yhexopyranoses.~~~ Preparatively the most significant is the regioselective reduction of 111 to 1,6-anhydro-4-deoxy-2-O-p-tolylsulfonyl-~-~-x~Z~~-hexopyranose742,7S4 (212), used as the starting compound for the synthesis of all six of the 1,6-anhydrodideo~yhexopyranoses~~~~~~~ (213-218) and 1,6-anhydr0-4-deoxyhexopyranoses .3833742,754 (107) with Ring opening of 1,6 :2,3-dianhydro-P-~-talopyranose lithium aluminum hydride in boiling tetrahydrofuran also proceeds diaxially, only.1s5The same regioselectivity of the cleavage of 116 yields mainly the 1,6-anhydr0-2-deoxyhexose'~~~~~~ (see also, Ref. 632), and 1,6 : 2,3-dianhydro-4-O-benzyl-~-~-al1opyranose~~~ or DL-epoxide331110 gives mostly the 3-deoxy derivative.

iii. Dehalogenation and Desulfurization of Hexosan Derivatives. Catalytic d e h a l o g e n a t i ~ n ~and ~ ~ *d ~e ~ u ~ l- ~ f u~ r~i z a t i o n ~ ~ ~ ~ ~ ~ of the appropriate derivatives of 1,6-anhydrohexopyranoses,usually conducted in the presence of Raney nicke1376*384,43s,632,713a or palladium,630,631 to some extent complement the aforementioned oxiranering hydrogenolysis, because the selectivity of the epoxide cleavage with such nucleophiles as hydrogen iodide, magnesium iodide, and sodium a-toluenethioxide frequently differs from that of direct hydrogenolysis, thus making the isomeric 1,6-anhydrodeoxyhexopyranoses available. Dehalogenation of iodo derivatives in the presence of palladium-on-carbon also permitted the synthesis of 2-deoxyJI-[~-~H]-,3-deoxy-~-[3-~H]-, and 4 - d e o x y - ~ - [ 4 - ~ H ] - g l u c o sIts e.~~~~~~~ stereospecificity was checked by the 'H-n.m.r. spectra of the products obtained when deuterium, instead of hydrogen, was used. Thus, 2-O-acetyl-l,6-anhydro-4-O-benzyl-3-deoxy-3-iodo-~-~-glucopyranose gives the monodeuterated 3-deoxy-P-D-xylo derivative with 100% retention'j3I of the configuration at C-3. 1,6-Anhydro-4-O-benzyl-2-deoxy-2-iodo-/3-~-glucopyranose is dehalogenated with 70% inver-

MILOSLAV CERNY AND JAN STANEK, JH

142

1 ,6-Anhydro-4-deoxy8-D-xylo-hexase 1,6-Anhydro-4-deoxyp-n- nrabino-hexose

131

216

t

several steps e

O

-

218 R = H 219 R = Ts

217

dTS

30

222

PhCH,O-

215

1,6-Anhydro-4-deoxyp-o-Zyxo-hexose

213

1

NaBH,

98

OTs

@ OTs O -

1,6-Anhydro-4-deoxyp~-ribo-hexose

223

I

H, ,Raney Ni

214

~ i o n ,whereas ~~l for 1,6-anhydro-4-deoxy-4-iodo-2-0-p-tolylsulfonyl-~D-glucopyranose and its Dgulucto isomer, the hydrogenolysis (see also, Ref. 632) is n o n - ~ t e r e o s p e c i f i c 1-Ethylpiperidine .~~~ was used as the base, and N,N-dimethylacetamide as the solvent, in order to prevent simultaneous cleavage of the benzyl ether.631

iv. Miscellaneous Methods. PhotoIysis of 1,6-anhydro-4-0(dimethylthiocarbamoyl) -2,3 -0-isopropylidene -P-D-mannopyranose yields 1,6-anhydro-4-deoxy-2,3-0-isopropylidene-~-~-Zyro-hexopyranose.449However, deoxygenation of secondary alcohols by way of S-methyldithiocarbonates, which are reduced, without isolation, by

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

143

tributyltin hydride in boiling toluene, seems to be more promising; an excellent yield of 224 from 62, or of 1,6-anhydro-2-deoxy-3,4-0isopropylidene-P-D-ribo-hexopyranosefrom the corresponding anhydro-D-altrose derivative, is noteworthy.713Direct replacement of

OH 62

224

the p-tolylsulfonyloxy group by hydrogen has been in the reduction of 212 with lithium aluminum hydride. An intramolecular, s N 2 mechanism leading to 218 is here facilitated by the antiperiplanar arrangement of the -0-A1H3Li and p-tolylsulfonyloxy groupings. The 0 - C bond fission of sulfonic esters is more facile still iodo ketones when activated by a neighboring carbonyl group383,450; are even dehalogenated by iodide anion.459Further possibilities involving interconversions of 1,6-anhydrodeoxyhexopyranoses, as well as those starting from unsaturated 1,6-anhydrohexopyranoses,are discussed in the next subsections.

b. Properties and Reactions.-In many aspects, the deoxy derivatives resemble their parent 1,6-anhydrohexopyranoses in their physical properties and chemical reactions; such are usually discussed only in Sections I11 and IV. The optical rotations of these com~ used ~ ~ ~in ~structural ~ - ~ ~assign~ , ~ ~ ~ ~ ~ pounds may be c a l c ~ l a t e d , ~and ments. Their intraniolecular hydrogen-bonding has been thoroughly s t ~ d i e d . ' In ~ ~g.l.c., ,~~~ they can be analyzed as their acetates99*408~74G or trimethylsilyl ether^,^^*^^^,^^^ or even without d e r i v a t i ~ a t i o n 3 8 ~ , ~ ~ ~ (see also, Ref. 376). Periodate oxidation can be used not only for the discrimination of 3-deoxy from 2-and 4-deoxy derivatives, but also, when measured kinetically, for configurational assignment^.'^^,^^^

AIILOSLAV

144

CERN~’A N D

JAN S T A N ~ K ,J R

The substantially faster hydrolysis of the 1,6-anhydride bond of 2-deoxy derivative^'^^ (see also, Ref. 503) parallels that of other 2deoxyglycosides. Polymerization of 26 yields a completely stereoregular (see Sect. IV,2), ( 1+6)-linked polymer626-62s; polymerization data483and d.t.a.367of 1,6-anhydro-2-deoxy-/3-~-urabino-hexopyranose have also been reported. The kinetics of acetylation of compounds 213-218 have been as well as partial p-toluenesulfonylation of some 1,6-anhydromonodeoxyhexopyranoses (see Sect. IV,3,b).156,329 Oxidation of an “isolated’ hydroxyl group produces the corresponding glycosuloses (such as383220, see Sect. IV,7,b), whose reduction to alcohols proceeds with high ~tereoselectivity.’~~,~~~,~~~ Anhydroglycosuloses having a free hydroxyl group have thus far been prepared only indirectly, by the reaction of keto epoxides (such as 225) with sodium iodide. The iodide anion always attacks the position a to the carbonyl group, and the 3-iodo ketone obtained (for example, 226) is immediately dehalogenated by the excess of iodide to the 3deoxyglycosulose derivative (for example, 227)459; for some properties of 227, compare Ref. 459 with Refs. 255-257.

225

226

227

Sulfonic ester 212 (Refs. 679, 742, and 754; see also, Ref. 329) and 3-O-acetyl-1,6-anhydro-2-deoxy-4-O-p-tolylsulfonyl-~-~-u~ubi~0h e x ~ . p y r a n o s e(see ~~~ also, Ref. 329), were used for the preparation of dianhydrodeoxyhexoses having the D-ZZJXO configuration (131 and 132). 1,6-Anhydro-4- deoxy-2,3-di-O - p -tolylsulfo~~yl -p-D-XYZO - hexopyranose, or its analog 221, when treated with sodium methoxide ~ ~four ”~~ dianhydrides ,~~~ gives the ~ - r i b oepoxide 30 e x c l u ~ i v e l y . ~All (30, 131-133) can also be obtained by the epoxidation of enes 28 and 29, even though, in these instances, the D-rib0 isomers greatly preponderate.325,3z7*328 Alkaline hydrolysis of D - ~ W epoxides (30 and 133) is highly regioselective,325,384,742,754 as both polar and steric effects support the attack at C-3 (see Sect. V,3). This combination of effects is also manifest in even oxirane-ring openings with other nucleophiles327~328~384~750~751; such a bulky reagent as magnesium iodide selectively enters”‘ the

1,G-ANHYDRO DERIVATIVES OF ALDOHEXOSES

145

hindered, axial position at C-3. Epoxides having the D-ZZJXO configuration (131, 132) usually yield mixtures of both isomers329,382,384. , magnesium iodide reacts with 131 to give a diequatorial product only.3M4 c. Unsaturated Derivatives of Hexosans.-Unsaturated compounds 28 and 29 have been ~ r e p a r e d ~ ~by' j the 9~~ elimination ~ of p toluenesulfonic acid from the axial sulfonic esters of 1,6-anhydrodideoxyhexopyranoses. The enopyranoses obtained readily isomerize in an alkaline medium, so that not even the 2- or 4-ester yields37fia completely pure product; when equilibrium is reached, the mixture contains3''j 15.5%of 28, and 84.5% of 29. The 3-p-toluenesulfonate 219, whose sulfonyloxy group is the most readily yields, by the action of potassium tert-butoxide, a 2 : 1 mixture of 28 and 29; with regard to the equilibrium composition, H-2 must be more reactive than H-4. In the DL the isomerization of 28 to 29

28

29

made the readily available mixture of 2-bromo derivatives (27) the starting material for syntheses of all of the 1,6-anhydro-P-~~-hexopyranoses (see Sect. 11,7).The unsaturated 1,6-anhydrohexopyranose 28 gives an excellent yield of 3,4-dihydro-W-pyran-2-methanol (25) on reaction with lithium aluminum hydride in 1,2-dimethoxyethane, whereas 29 gives a mixture of various h e ~ e n o l sBoth . ~ ~ osmium ~ tetraoxide and m-chloroperoxybenzoic acid attack 28 and 29 almost exclusively from the exo side, to give diols or epoxides having the Dribo c o n f i g ~ r a t i o n . Allylic ~ ~ ~ ~ bromination ~ ~ ' ~ ~ ~ ~ of 28 or 29 with N bromosuccinimide in carbon tetrachloride gives only one of the four bromo derivatives possible, that is, 230. In this highly selective process, the %radical (229), evidently more stable than 228, must be attacked from the exo side only.467Solvolysis of 230 yielded4'j7a mixture of 31 and 231 which can also be prepared (together with the two other isomers) in the reaction of epoxides 30, 131, 132, or 133 with b ~ t y l l i t h i u r n , ~or~by ~ -the ~ ~ ~decomposition ~~~~ of thionocarbonates of 1,6-anhydrohe~opyranoses.~~~ On oxidation of these unsaturated alcohols, both possible enones were obtained725(see also, Sect. IV,7,b); the stereoselective epoxidation or hydroxylation of the unsaturated alcohols with osmium tetraoxide permitted the synthesis of 1,6-anhydro-P-DL-hexopyranoses (see Sect. 11,7),with the ratio of endo to exo

146

MILOSLAV CERNY AND JAN STANEK, JR.

!-0 Br

220

229

230

/ OH 31

231

attack strongly dependent on the reaction conditions and on the possible substitution of the free hydroxyl group.330-332 The benzyl ether 223 was synthesized either from 1,6-anhydro-2-

deoxy-4-O-benzyl-3-O-p-tolylfulfonyl-~-~-arubino-hexopyranose by elimination of p-toluenesulfonic or from 222 by displacement with sodium benzyl oxide with simultaneous allylic rearrangement.377 Catalytic hydrogenation of 223 yields 215 or its benzyl ether (accord222 is ing to the reaction ~ o n d i t i o n s ) .The ~ ~ ~p-toluenesulfonate ,~~~ extraordinarily reactive, and could serve for the synthesis of many derivatives substituted in the exo position at C-4. Hydrogenation of 28 or 29 gives 1,6-anhydro-2,3,4-trideoxy-~-~-glycero-hexopyranose (26), also obtained from 1,6-anhydr0-2,4-dideoxy-P-~-gl ycero-hexopyranos-3-ulose (97) by way of a t h i ~ a c e t a l . ~ ~ ~

VIII. 1,6-ANHYDROHEXOPYRANOSE AND 1,6-ANHYDROHEXOFURANOSE ANALOGS Among the 1,6-anhydrohexopyranose analogs, those compounds are

the most important in which 0-6 in the 1,6-anhydride ring or 0-5 in the pyranoid ring, or both, is replaced by sulfur or by nitrogen. Thio analogs so far prepared include 1,6-anhydro-l(6)-thio-P-~-glucopyranose (234)83*371,777 and its 2-(acylamino)-2-deoxy derivativegs (238), 1,6-anhydro-1(6)-thio-P-~-galactopyranose,83 1,6-anhydro-2-deoxy-1(6)-thio-~-~arabino-hexopyranose~~~ (239), and the D-rib0 3,4(777) M. Akagi, S. Tejima, and M. Haga, Chem. Pharm. B u l l . , 11, 58-61 (1963) (778) T. Maki and S. Tejima, Chem. Pharm. B u l l . , 15, 1367-1372 (1967).

1.6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

147

anhydride of 239. Their synthesis was carried out in two principal ways: (a) cyclization of 6-S-acetyl-6-thio derivatives of phenyl glycosides (for example, 232) or glycosyl halides (for example, 233) in the presence of bases,83 and ( b )cyclization of 6-0-p-tolylsulfonyl derivatives of S-glycosyl dithiocarbonates (for example, 235,236,and 237)in the presence of b a ~ e ~ . All ~ ~ of the , ~ aforementioned ~ , ~ ~ ~ , thio ~ ~analogs ~ -I

A

c

O

RO-

m R'

k

OH

232 R1 = Ph or P-O,NC,H,, Ra = H 233 R' = H, Rz = Br

I

N OH

HO

234

235 R = OAc 236 R = NHAc or NHBz 237 R = H

234 R = OH 238 R = NHAc or NHBz 239 R = H

of hexosans are stable in alkaline media, but they are hydrolyzed by acids to the corresponding 6-thioaldoses. The methylsulfonium salt of 1,6-anhydro-1(6)-thio-P-D-glucopyranose (240) is apparently an intermediate in the solvolysis of methyl l-thio-6-O-p-tolylsulfonyl-~-~-glucopyranoside, which involves methyl migration, and results in 6-S-methyl-6-thio-~-glucose.~~~ (779) E. V. E. Roberts, J. C. P. Schwarz, and C. A. McNab, Carbohydr. Res., 7,311-319 (1968).

148

MILOSLAV

CERNY AND

JAN STANEK, JR.

24 0

A distant, sulfur analog of 1,6-anhydro-2,3,4-trideoxy-P-~-glycerohexopyranose (26) is (lR,5R)-6,8-dioxa-3-thiabicyclo[3.2. lloctane (241),which was prepared by periodic acid oxidation of levoglucosan (6), followed by reduction of the resulting dialdehyde 100 to diol 242, and by p-toluenesulfonylation to 243, and replacement of the two sulfonic ester groups of 243 with sodium h y d r ~ g e n s u l f i d e . ~ ~ ~

100

242 R = H 243 R = Ts

241

The and h y d r o g e n o l y ~ i sof~ racemic ~~~ 3,6,8-trioxabicyclo[3.2. lloctane and its methyl derivatives have also been described. (77%) E. C. Hallonquist and H. Hibbert, Can. J. Res., 8, 129-136 (19-33). (77911) J . Gelas, Bull. Soc. Chim. Fr., 4046-4051 (1970).

(77%) P. Calinaud and J. Gelas, Bull. SOC.Chim. Fr., 1155-11.57 (1974). (779d) J. Gelas and S. VeyssiBrea-Rambaud, Carhohydr. Rer.., 37, 293-301 (1974).

1,G-ANHYDRO DERIVATIVES OF ALDOHEXOSES

149

The nitrogen analogs of 1,6-anhydrohexopyranoses constitute an interesting, self-contained group780-782 (for a review, see Ref. 783). It includes derivatives having the P-L-ido configuration, such as the 5-amino-1,6-anhydro-5-deoxy (248), 6-amino-l,6-anhydro-6-deoxy (247), and 5,6-diamino-5,6-dideoxy (249) derivatives; in the D-gluco series, 5,6-diamino-1,6-anhydro-5,6-dideoxy-~-~-glucopyranose (251) is known. These compounds are formed by spontaneous cyclization Y-CH,

I

244 245 246

x = 0, Y = NH, x = m,Y = OH X = NH, Y = NH,

250

247 X = 0, Y = NH 248 = Nn, Y = 249 X = NH, Y = NH

o

x

251

of reducing 5-amino-5-deoxy-, 6-amino-6-deoxy-, or 5,6-diamino5,6-dideoxy-hexoses (244-246 and 250) under alkaline conditions. In the equilibrium mixtures established, the 1,6-anhydro derivative largely preponderates. Even with the D-gluco configuration, -2040% of 251 (having all its hydroxyl groups in axial position) is present in the equilibrium mixture 250G251. As 6-amino-6-deoxy-~-glucose does not form any 1,6-anhydro derivative,780the cyclization must be facilitated783by the geminal, amino alcohol arrangement at C-1, such as that in compounds 245,246, and 250. In acid solutions, such anhydrides, like the corresponding amino hexoses, are dehydrated to give derivatives of pyridine. The imino (780) (781) (782) (783)

H. Paulsen H. Paulsen H. Paulsen H. Paulsen

and K. Todt, Chem. Ber., 99,3450-3460 (1966). and U. Grage, Chem. Ber., 102,3854-3862 (1969). and K. Todt, Angew. Chem., 77, 589 (1965). and K. Todt,Adu. Carbohydr. Chem., 23, 115-232 (1968).

MILOSLAV C E R N AND ~ JAN S T A N ~ KJR. ,

150

group of 248 and 249 was a ~ e t y l a t e dor, ~transformed ~~ to the N-nitroso or N-chloro On catalytic hydrogenation of 248 and 247, the C-1-0 bond is hydrogenolyzed, with formation of 1-amino-1,sanhydro- 1-deoxy-L-iditol (252) and 1-amino-1,6-anhydro-l-deoxy-~iditol(253), respectively.784With diamino derivative 249, the C-1-N-6

y2

HN

HOCH,

I

I

OH

OH

HO

HO

HO

HO

252

253

bond is cleaved selectively.783 Even 6,l-lactones of hexuronic a ~ i d s ,for ~ ~example, ~ , ~ ~ 2,3,4-tri~ O-acety~-~-~-g~ucopyranurono-6,1-~actone~*~ (254) and the corresponding 2,3,4-tri-0-(2,2,2-trichloroethoxycarbonyl) ester,787may be considered to be 1,6-anhydrohexose analogs; however, they behave as ordinary lactones. 0

I

254

Some analogs of 1,6-anhydrohexofuranoses have also been described. Derivatives 257 and 258 of 1,6-anhydro-1(6)-thio-~-~-glucofuranose were respectively prepared from 255 and 256 by the action of acids.788J89Similarly, 1,6-anhydro-2,3-di-O-rnethyl-1(6),4-dithiop-D-glucofuranose (259) was obtained from the corresponding methyl glycopyran~side.~~~ (784) H. Paulsen and K. Todt, Chem. Ber., 100,512-520 (1967). (78.5) E. M. Fry, J . Am. Chem. SOC.,77,3915-3916 (1955). (786) R. R. Whetstone, U. S. Pat., 2,511,890 (1950);Chem. Abstr., 44,8961 (1950). (787) R. Bugianesi and T. Y. Shen, Carhohydr. Res., 19, 179-187 (1971). (788) R. L. Whistler and B. Urbas,J. Org. Chem., 30, 2721-2723 (196.5). (789) J. M. Cox and L. N. Owen,J. Chem. SOC.,C , 1121-1130 (1967).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

151

HzCSRS

I

R z - C F T

RZ-CH I

I

0-CMe,

OH

n, RZ = H, RS = AC 256 R1 = Me, RZ = OMe, RS = H

257 R' =

255 R' =

H,RZ =

n

258 R' = Me, RZ = OMe

OMe 259

As far as the nitrogen analogs are concerned, 1,6-anhydro-(6-acetam i d o - 2 , 3 - d i - O - a c e t y l - 5 , 6 - d i d e o x y - ~ - ~ - x y l r a n o s e (260) ) was isolated after acetylation of the equilibrium mixture prepared from the corresponding 6-amino-5,6-dideoxyhexofuranose; the original mixture also contained the parent sugar and traces of two additional azepine compounds.784

bAC 260

Ix. 1,6-ANHYDROHEXOFURANOSES 1. Formation and Preparation

Individual 1,6-anhydrohexofuranoses(for a review, see Ref. 3) are formed, together with 1,6-anhydrohexopyranoses,as minor products in proportions of -1-5%, by ( a ) pyrolysis of hexoses, for example,

MILOSLAV ~ E R N Y AND JAN STANEK, J R

152

~ - g l ~ c,196,272296,299 os~ D-mannOSe,113"96and of some ~ - g ~ u c o p y r a n o s i d eosl, ~ i g~o~s a c c h a r i d e ~ ,s ~t ~a~r~~~ h ~ ~, ' ~ ~ ~ ' ~ ~ ~ cellulose,196~208~214,232~250,258 and dextran,lgOand ( b )treatment of hexoses with acids .99,'09,'13,114-116,119,121,790 An alternative route consists in isomerization of triacetates of 1,6-anhydroliexo-pyranoses or -furanoses, or both, in the presence of trifluoromethanesulfonic acid in nitromethane .421,422,453,791

D-Salactose,l16,196,294,295,792

The longest known compound in this series is 1,6-anhydro-c-u-~galactofuranose (261). It is relatively easily obtainable, and is usually prepared by pyrolysis of it can also be obtained by pyrolysis of lactose, melibiose, and r a f f i n o ~ e . ' ~An ~,~~~ alternative route consists in the reaction of 0.2 M hydrochloric acid, ~ ~ ~anhydride ~~'~ 261 was or 0.1 M sulfuric acid, with D - g a l a c t o ~ e .The originally mistaken for 1,3-anhydro-/3-~-galactopyranose, because of

261

its resistance to periodate o x i d a t i ~ n The . ~ ~ correct ~ ~ ~ ~ structure was later demonstrated by methylation, followed by hydrolysis to give 2,3,5-tri-0-methyl-D-gala~tose.~~~ Similar structural proofs have been used for other isomers. 1,6-Anhydro-/3-~-glucofuranose (19) can be isolated from the tar s ~ ~ ~ Ref. formed by pyrolysis of D - g ~ u ~ o s~e -, g~ ~~ u~c o s i d e(compare 322), and cellulose250; 1,6-anhydro-/3-~-mannofuranose (262) was similarly prepared from D-mannose. The remaining 1,6-

OH 19

OH

HO 262

263

(790) P. KO11 and H.-P. Nissen, unpublished results; see Ref'. 119. (791) P. L. Durette, P. Kiill, H. Meyborg, and H. Paulsen, Chern. Ber., 106,2333-2338 ( 1973). (792) J. W.-P. Liii :tiid C . Schuerch, ,2fclcrottloleculL.s, 5, 656-657 (1972).

1,6-ANNYDRO DERIVATIVES OF ALDOHEXOSES

153

anhydrohexofuranoses, having the ~ - D U Z Z O ~ ' ~ (263), c r - ~ t a l o ~ ~ ~ ~ (273), P-L-altra lZ1 (268), and C Z - L - ~ U ~configurations O ~ ~ ~ were prepared either by one of the aforementioned methods, or from 1,6-anhydrohexofuranosuloses by reduction (see Sect. IX,3). 2. General Properties Most of the 1,6-anhydrohexofuranosesare crystalline compounds, readily soluble in water or hot ethanol, but poorly soluble in ether (see Table XII). They do not reduce Fehling solution. Although they might be regarded as glycosides of hexofuranoses and might, therefore, be expected to exhibit the characteristic features of hexofuranosides, they actually closely resemble 1,6-anhydrohexopyranoses in their properties (see also, Sect. 111). The fundamental skeletons of both types of compound are, in fact, shaped so alike that they differ only in the location of the oxygen atoms in the dioxabicyclo[3.2.l]octane system (see l a and 2a; Sect. I). In this way, the fact that 1,6-anhydrohexofuranoses, which are stable in alkaline solution,33 are hydrolyzed by acids at approximately the same rate as the corresponding 1,6-anhydrohexopyranoses (to give reducing hexoses) can be at least partially explained. Nevertheless, this hydrolysis proceeds significantly more slowly than with normal alkyl hexofuranosides.251~z94 For example, 1,6-anhydro-~-~-glucofuranose (19) does not react251 in 0.2 M hydrochloric acid during 24 hours at 25", that is, under conditions where methyl D-ghcofuranosides are -50% hydrolyzed. Like the 1,6-anhydrohexopyranoses(see Sect. 11,4), 1,6-anhydrohexofuranoses are present in equilibrium with the free hexoses in aqueous, acid solutions, but to a far lesser degree: 0.17% of D-gluc0,'09 0.95% of ~ - g a l u c t o , '1.1% ~ ~ of (compare Ref. 99), 1.6% of La,!tro,1210.04% of ~ - r n a n n o , '0.6% ~ ~ of L - ~ U ~and O ,2.5% ~ ~ ~of D t d o isomer.99The reason for this phenomenon can be traced to the decreased stability of 1,6-anhydrofuranoses caused by steric repulsions among the substituents on the oxolane (tetrahydrofuran) and 1,3dioxane rings. Consequently, the most stable of the 1,6-anhydro(273), having the hydroxyl furanoses is 1,6-anhydro-a-~-ta~ofuranose groups at C-2 and C-3 in the exo orientation; it is present in the equilibrium mixture in the largest p r o p o r t i ~ n . ~ ~ It follows from the 'H-n.m.r. spectra of the 1,6-anhydrohexofuranose peracetates (see Table IV) that their 1J-dioxane ring exists in the "'C,, confonnationgSJ13~11SJz1J93 and their oxolane ring favors the E , conformation,119although, for the D-galacto triacetate (271), the El conformation of the oxolane ring was a s ~ u m e dFor . ~ 1,6-anhydro-p~ ~ ~ ~ ~ (793) R. U. Lemieux and R. Nagamjan, C a n . ] . Chem., 42,1270-1278 (1964); there is a printer's error in the formula of 1,6-anhydro-a-~-galactofuranose.

MILOSLAV ~ E R N YAND JAN STANEK,JR

154

D-mannofuranose (262),the E arrangement has been verified by X-ray crystallographic analysis .791 TABLEIV Coupling Constants (Hz) of l,f%AnhydrohexofuranoseT r i a ~ e t a t e s " ~ ~ ' ~ ~

H/H (configuration) cis

trans ~~

JI3

J2,3

Js.4

54,s

3.5-4.5

6.3-10"

5.5-7

3.5-4.5

0

1.5-2.5

0

1.3-2

J5,~endo

J5,6ex0

2.5-3.5

6-7

10.5-11.5

1.0-1.5

J6endo,6exo

10-14

~

Such a wide range of J values indicates that the oxolane ring may possibly be distorted.

The anhydro derivatives having the D-ghco (19) and D-gulacto (261) configurations are not oxidized either by periodate solution251~294~295-the same may be predicted for the altro and ido isomers-or by lead tetraacetate in acetic a ~ i d(for ~ overoxidation, ~ ~ , ~ ~ ~ see Ref. 795). This resistance can be accounted for by the rigidity of the diol system of the oxolane ring, having a torsion angle of 120",and is in keeping with the extremely rapid oxidation of the mann no isomer113(262) containing a cis-diol system having a torsion angle of -0"; the ~ t a l isomer o (273) behaves similarly.99Naturally, 1,6-anhydr0-/3-D-glucofuranose~~~ (19) does not form complexes with cupram(261) in monium ions, nor does 1,6-anhydro-/3-~-galactofuranose borate or germanate solution. Other anhydrides containing a vicinal cis-diol, instead of a truns-diol, system should form such complexes (compare Ref. 796). A simple relationship exists between the structure and the optical as shown in Scheme 15. rotation of 1,6-anhydrohexofuranoses,11sJz1~7g1 [MI, values can be calculated for the 1,6-anhydrohe~ofuranoses~~~ and, presumably, also for their amino, fluoro, and deoxy derivatives by using the partial molar rotational contribution of the hydroxyl groups and of the fundamental skeleton. 0.r.d. measurements in the 200-nm region seem also to be potentially valid for structural estimation .797 (7%) J. Lechat and G . A. Jeffrey, Actu Crystallogr., Sect. B , 28, 3410-3415 (1972). (795) A. S. Perlin, cited in L. C. Stewart, E. Zissis, and N. K. Richtmyer,]. Org. Chem., 28, 1842-1844 (1963). (796) R. E. Reeves,]. Am. Chem. Soc., 71,212-214 (1949). (797) I. Listowsky, S. Englard, and G. Avigad, Curhohydr. Re.y., 2, 261-271 (1966).

1,BANHYDRO DERIVATIVES OF ALDOHEXOSES

Rotational contributions: fundamental skeleton s = -10.3" hydroxyl groups a = 35.1:,

+b

-a

-b

c =

15.5

b = 14.5",

30.9

+h

p-D o r a-L configuration [MI, value for 1,6-anhydro-p-o-altrofuranose = S - a -b

+C

= -10.3" -35.1' = -29.0"

-14.5' f 3 0 . 9 '

Scheme 15.- Calculations of [MI, Values for 1,6-Anhydrohexofuranoses.

Mass spectroscopy is another potentially useful tool for the identification of 1,6-anhydrohexofuranoses,47'but the gas-liquid chromatographic technique is the method of choice for their determination; for example, in pyrolytic tar from polysaccharides, or in mixtures with other 1,6-anhydrohexoses.190~196

3. Reactions 2,3,5-Tri-O-substituted derivatives of 1,6-anhydrohexofuranoses have been prepared by standard alkylating and acylating proced ~ r e ~ 1 partial ~ ~ substitution ~ ~ ~ ~has, not ~ yet ~ been ~ described. , ~ ~ ~ ~ Nevertheless, a different reactivity may be assumed for each particular hydroxyl group: first, increased reactivity of the exo-oriented hydroxyl groups on C-2 and C-3 of the oxolane ring compared to the endo hydroxyl groups; second, a reactivity of the axial (exo) 5-hydroxyl group greater than that of the corresponding, equatorially attached group (for comparison, see Sect. IV,3,b). Condensation of 1,6-anhydro-P-~-mannofuranose (262) and of 1,6-anhydro-/3-~-allofuranose (263) with acetone under acid catalysis leads to the formation of 2,3-O-isopropylidene derivatives (264) (Ref. 113) and (265) (Refs. 119 and 422). The D-UZZO derivative 265 is more stable to acid hydroly~is"~ than the D - ~ Z U ~ T Z(264) O and L-guZo (266) isomers, which are hydrolyzed with extreme ease, owing to steric compression caused by the endo-dioxolane ring113; the 1,6anhydride bond is unaffected. The anhydride 261, having an exo, axially oriented H-5, is selectively oxidized121on platinum to give 1,6-anhydro-~-~-arabino-hexofuranos-5-ulose hydrate (267). On the other hand, D - ~ Z U C O isomer 19, having this hydrogen atom in the difficultly accessible m d o , equatorial position, does not react.lZ1In both cases, hydroxyl groups of the trans-diol system on the furanoid ring are resistant to oxidation. It should be noted that the exo-oriented 5-hydroxyl group of 264, which

~

156

hlILOSLAV k:EKN$ A N D JAN STANEK, JR.

I

.

0 ,

/o

CMe,

265

264

261

266

268

might be inert to catalytic oxidation (compare Ref. 121), is oxidized with ruthenium t e t r a o ~ i d e ' to ~ ~give 1,6-anhydro-2,3-0-isopropylidene-p-~Zyxo-hexofuranos-5-ulose (269). Complex hydrides reduce the anhydroglycos-5-ulose hydratelZ1 (267) or -5-ul0se"~ (269) mainly to derivatives having the eiado hydroxyl group (that is, 261, or 266, respectively). As expected, the reducing agent approaches from the less-hindered side, resulting in the highly stereoselective course of this reaction. Reduction of 267 with hydrogen in the presence of platinum proceeds in a similar way,lZ1 whereas reduction in the presence of palladium-on-carbon givesl'l an isomer having the exo-hydroxyl group, namely, 1,6-anhydro-P-~altrofuranose (268).

L

269

H 270

Acetylation of 267 with acetic anhydride in pyridine does not afford a keto-2,3-diacetate, but gives 2,3,5-tri-O-acetyl-1,6-anhydro-p-~-urubino-hex-5-enof~ranose~~~ (270).Treatment of 1,6-anhydro-a-~-galac-

1,6-AKHYDRO DERIVATIVES OF ALDOHEXOSES

157

tofuranose triacetate (271) with trifluoromethanesulfonic acid yields, by way of the cyclic, acetoxonium ion 272, 1,6-anhydro-a-~-taloComfuranose (273), in addition to 1,5-anhydro-a-~-talofuranose.~~~ pound 273 is also formed from the triacetate of 1,6-anhydro-p-~galactopyranose (12) under similar conditions. The contraction of the

2 71

272

273

pyranoid ring does not follow a common mechanism involving oxygen participation and concomitant Walden inversion, but proceeds by way of the oxepanium ion 274, with retention of configuration.4’l The same mechanism probably operates in the i s o m e r i ~ a t i o n ~of~ ’1,6-anhydrofl-D-allopyranose triacetate to 1,6-anhydro-p-~-allofuranose (263) (see Scheme 8, p. 88).

1,6-Anhydro-2,3,5-tri-O-benzyl-a-~-galactofuranose polymerizes with high stereoregularity by the action of phosphorus pentafluoride in d i c h l o r ~ m e t h a n e although ,~~~ not as readily as the corresponding pyranose derivatives, because no considerable gain in energy can be obtained in converting the monomer into the polymer. A rearside attack at C-1 (compare Sect. IV,2), followed by cleavage of the 1,6anhydride bond, gives mainly the (1+6)-fl-D-furanose polymer.7921,6Anhydro-a-D-galactofuranose (261) is cleaved by boron trichloride with formation of D-galactose and some o l i ~ o ~ ~ ~ c c l i ~ ~ i ~ e s . ~ ~ ~

x.

1,6-ANHYDRO

DERIVATIVES OF

OLIGOSACCHAFUDES

In the title oligosaccharides, one of the “sugar” residues is actually a 1,6-anhydrohexose residue. Thus far, only derivatives having a ter-

MILOSLAV CERNY AND JAN STANEK, JR.

158

minal 1,6-anhydrohexose residue, as in maltosan (275), have been described. Derivatives of the other type (for example, 276) might serve as readily available starting-compounds for the synthesis of branched oligosaccharides. The growing interest in these compounds

(-Jou sou frJ r--?

$!H,OH

HO

I

OH

HO

CH,OH

OH

OH

P

275

HO

OH 276

is a consequence of the fact that the 1,6-anhydride bond can be cleaved selectively without any impairment of the glycosidic bonds in the molecule. As one of the primary hydroxyl groups is protected by the 1,Sanhydro ring, important structural modifications at C-6’ can be achieved, modifications that would be practically unrealizable starting from the parent oligosaccharide. Furthermore, cleavage of the 1,6anhydride bond of suitably protected 1,6-anhydrides of oligosaccharides makes available the oligosaccharides having the primary hydroxyl group on C-6 free, and this permits a facile synthesis of oligosaccharides modified at the reducing residue. 1. Preparation

Principally, two synthetic approaches are possible. The older one applies to oligosaccharides the procedures of anhydro-bridge formation previously well tried on simple monosaccharides (see Section 11). It is restricted practically to several readily available oligosaccharides, and has now been displaced by Koenigs-Knorr glycosylation employing various partially protected 1,6-anhydrohexoses as the aglycons .” ‘ I

a. Cyclization of Oligosaccharide Derivatives.-Alkaline cleavage of appropriate aryl P-glycosides provides a facile route to malto-

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

159

san ,798,799 ce11obiosan ,32,800,8011actosan and ma1totri osan.803 a Among several aglycons tested, the o-chlorophenyl group proved the most suitable for high-yield synthesis80’,803 (compare Ref. 803a). These anhydro sugars were also prepared from per-O-acetylglycosyl bromides by way of the trimethylammonium salts804-806; cellobiosan may be obtained from p-cellobiosyl flu~ride.’~ The 1,6-anhydride bond may also be formed on cyclization of oligosaccharide derivatives having on C-6 a reactive substituent, such as a p-tolylsulfonyloxy or methylsulfonyloxy group, as described for l a c t o ~ a nor~ ~ ~ ~ ~ ~ maltotriosan.806aVarious anhydro-oligosaccharides are formed by thermal, or acid-catalyzed, polymerization of levoglucosan (6)(see Sect. IV,2); the disaccharide fraction consists582mainly of a- and p( 1 4 2 ) -and -( 1+4)-linkages. Pyrolysis of maltose was found to give807 an unidentified compound, ClzHzoOlo,called “maltosan,” which is probably a mixture of lower decomposition products of maltoseso8(compare Ref. 809). ,32,800,8023803

b. Glycosylation of 1,6-Anhydrohexopyranoses.-This versatile method has thus far been employed mainly in the synthesis of ( 1 4 ) and (1+3)-linked oligosaccharides. Its large scope is best demonstrated by a series of papers by Shapiro and c ~ w ~ r k e r ~ ~ ~ dealing with the synthesis of the carbohydrate chain of brain gangliosides. An excellent “aglycon” for the unambiguous synthesis of oligosaccharides involving glycosylation at 0-4 of D-glucose was found to (798) L. Asp and B. Lindberg, Acta Chem. Scand., 6,941-946 (1952). (799) Y. Hirasaka and J. Matsunaga, Chem. P h a m . Bull., 13, 176-179 (1965). (800) E. M. Montgomery, N. K. Richtmyer, and C. S. Hudson,J. Am. Chem. Soc., 65, 1848-1854 (1943). (801) S. Tejima and Y. Okamori, Chem. Pharm. Bull., 20,2036-2041 (1972). (802) S. Tejima, Carbohydr. Res., 20, 123-132 (1971). (803) S. Tejima and T. Chiba, Chem. Pharm. Bull., 21, 546-551 (1973). (803a) K. Takeo, K. Mine, and T. Kuge, Carbohydr. Res., 48, 197-208 (1976). (804) P. Karrer and H. Friese, Helu. Chim.Acta, 14, 1317-1318 (1931). (805) P. Karrer and L. Kamieliski, Helu. Chim. Acta, 15, 739-745 (1932). (806) P. Karrer and J. C . Harloff, Helu. Chim. Acta, 16,962-968 (1933). (806a) K. Takeo and T. Kuge, Carbohydr. Res., 48, 282-289 (1976). (807) A. Pictet and A. Marfort, Helu. Chim. Acta, 6, 129-133 (1923). (808) I. E. Puddington, Can. J . Res., 26,415431 (1948). (809) The optical rotation and other properties of the compound described agree well with those of r n a l t o ~ a nprepared ~~~ later. (810) D. Shapiro, Y. Rabinsohn, and A. Diver-Haber, Biochem. Biophys. Res. Commun., 37,28-30 (1969). (811) D. Shapiro, Chem. Phys. Lipids, 5, 80-90 (1970). (812) D. Shapiro and A. J. Acher,J. Org. Chem., 35,229-231 (1970).

MILOSLAV CERNY AND JAN STANEK, JR.

160

be 2,3-di-O-acetyl-1,6-anhydro-/3-~-glucopyranose (278). Under the ordinary conditions of the Koenigs-Knorr condensation, with mercuric cyanide as the catalyst, 278 reacts with tetra-0-acetyl-a-D-galactopyranosyl bromide to give lactosan peracetate in 49% Modified cellobiosan (279) was prepared51 similarly from 277 plus 278, as well as a trisaccharide based on 2-amino-2-deoxy-~-ghcose and D-galactose.680Shapiro's and Sinay's groups almost simultaneously

0

bAC

NHCOCHCI, 277

B

278

z

O

W

I

NHCOCHC1, 279

oBr CH,OBz

+

NH

AcO

PhO, I ,P=O PhO 280

NHAc

h i/ I OCC0,Me

3 steps

I

0

.6/" FH,OAc

NHAc

I

AcO

~ H A C

2 81

utilized Z-acetamido-3-0-acetyl-1,6-a1ihydro-2-deoxy-/3-~-glucopyranose for the preparation of peracetylated 2-acetamido-2-deoxycellobiosan.633,635 The same compound was also condensed with tetra-0acetyl-a-D-galactopyranosylbromide,635and the amino derivative 280. The .halide 280 was employed for synthesis of the disaccharide 281, which is a precursor of the unit of the glycan moiety of the bacterial cell-wall p e p t i d o g l ~ c a n .2-Azido3-O-benzy1, ~~~ 3-azido-2-

1,B-ANHYDRO DERIVATIVES OF ALDOHEXOSES

161

0-benzyl, and other azido derivatives of levoglucosan were used as “aglycons” in disaccharide s y n t h e s i ~ . ~ ~ , ~ ~ , ~ ’ ~ ~ 1,6-Anhydro-2,3-0-isopropylidene-~-~-mannopyranose gives disaccharides by reaction with tetra-0-acetyl-a-D-glucopyranosylbromide705and with tetra-0-acetyl-a-D-galactopyranosyl bromide.7072,3Di-O-acety~-1,6-anhydro-~-~-galactopyranose, used in trisaccharide syntheses,*ll was condensed (together with the isomeric 2,4-diacetate) in nitromethane and benzene, in the presence of mercuric cyanide, with tetra-0-acetyl-a-D-galactopyranosyl bromide; both the a- and p-linked disaccharides were isolated in each case.’13 Possibilities of selective, partial glycosylation were also examined. Reaction of 2-O-acetyl-1,6-anhydro-~-~-galactopyranose halide 277,or with its D-gulacto isomer,812gave a mixture of ( 1 4 )and (1+3) disaccharides in the ratio of 3 :2; with tetra-0-acetyl-a-D-galactopyranosyl bromide, only the (1+4) isomer was isolated.704Almost no selectivity was found in Koenigs-Knorr condensation of 2-substituted levoglucosan with various glycosyl halide^.^^^*^*^ D-Glucosylation of unsubstituted levoglucosan (6) gave501a low yield of cellobiosan.

2. Properties and Reactions Generally, there is no difference between the properties of 1,6anhydro derivatives of oligosaccharides and those of simple 1,6-anhydrohexopyranoses. N o reduction of Fehling solution, and fermentation yielding the single sugar components without affecting the 1,6-anhydride bond,8°5,806*814 serve as examples. It is to be expected that the 1,6-anhydrohexopyranose residue of these compounds exists in the ‘C,(D) conformation, as evidenced by the 220-MHz spectrum of maltosan hexaacetateslj; suggestions as to the existence of the B0,3(D) conformation in lactosan hexaacetate, based on the H- 1 resonance,8O2 are insufficiently well founded (compare Sect. 111). Their reactions closely resemble those of 1,6-anhydrohexoses (compare Sect. IV); for the glycosyl group thereof, all reactions common for glycosides can be performed. The difference in the rate of hydrolysis of the 1,6-anhydride and the glycosidic bond permits a partial hydrolysis of 1,6-anhydro derivatives of oligosaccharides, leading to the (812a) H. Paulsen, 0. Lockhoff, B. Schroder, B. Sumfleth, and W. Stenzel, Tetrahedron Lett., 2301-2304 (1976). (813) M. E. Chac6n-Fuertes and M. Martin-Lomas, Carbohydr. Res., 43,51-56 (1975). (814) M. Sato ancl I. Yamashina,]. Biochem. (Tokyo),70, 683-692 (1971). (815) P. L. Durette, L. Hough, and A. C. Richardson,]. Chem. Soc. Perkin Truns. 1 , 97-101 (1974).

162

MILOSLAV C E R N ~AND ’ JAN STANEK,JR.

parent oligosa~charide.491~j~~,81~-~~~ The same principle may be observed in the preparatively more advantageous a ~ e t o l y s i s . ~ ~ , ~ ~ ~ , ~ 633.635,638,680,704.705,707,800,811--813,819-822 Thus, 2,3-di-O-acetyl-1,6-anhydro4-O-( 2,3,4,6-tetra-O-acetyl-P-D-galactopyranosyl)-P-D-mannopyranose gave 1,2,3,6-tetra-O-acetyl~-O-(2,3,4,6-tetra-~-acety~-~-~-ga~actopyranosyl)-cr-D-mannopyran~se.~~~ Also, the reaction with titanium tetrachloride proceeds so selectively that maltosan hexaacetate gives, without difficulty, 2,3-di-0-acetyl-4-O-(tetra-O-acety~-a-D-glucopyranosy1)-a-D-glucopyranosyl chloride; this was used in the synthesis of various 6-substituted derivatives of p-maltose582~798~799~81~~s1s (see also, Ref. 823). The method is also applicable with c e l l o b i o ~ a nand ~~~~~~~ l a c t o ~ a nMaltosan . ~ ~ ~ ~hexaacetate ~~~ was converted into per-O-acetylmaltosyl bromide (in 77% yield) by the action of hydrogen bromide in acetic a n h ~ d r i d e . ~ ~ (275) and cellobiosan,s17~8z0 followed by Tritylation of maltosan818*s19 acetylation and detritylation, made possible the synthesis of a series of 6’-O-substituted derivatives of disaccharides, and of aldotriouronic acids.816On detritylation in acetic acid, an excess of hydrogen bromide caused migration of an acetyl group from 0-4’to 0-6’ in 2,3,2‘,3‘,4‘penta-O-acetyl-1,6-anhydro-6’-O-trityl-~-cellobiosesz6; this migration was used in the preparationsz0of the 4’-O-p-tolylsulfonyl derivative Benzylidene acetals, and, finally, of 4’-acetamido-4’-deoxy-a-lactose. such as 1,6-anhydro-4’,6’-O-benzylidene-~-lactose8z1~s27 or 1,Banhydro4’,6’-O-benzylidene-~-maltoses2z (282), having only four free, secondary, hydroxyl groups are versatile, key intermediates for chemcia1 modifications of lactose and maltose (see Scheme 16). For the first-mentioned compound, in the selective benzoylation with 2.1 molar equivalents of benzoyl chloride in pyridine, the order of reactivities of the secondary hydroxyl groups iss2’3’> 2 > 3 > 2’;for the 2’ > 2 , 3’ > 3 . (816) N. Roy and T. E. Timell, Carbohydr. Res., 6,475-481 (1968). (817) B. Lindberg and L. Selleby, Actu Chem. Scand., 14, 1051-1053 (1960). (818) H. Arita, M. Iseniura, T. Ikenaka, and Y. Matsushima, B u l l . Chem. SOC.J p n . , 43, 818-823 (1970). (819) G. G. S. Dutton and K. N . Slessor, Can. J . Chem., 44, 1069-1074 (1966). (820) Y. Okamori, M. Haga, and S. Tejima, Chem. Pharm. Bull., 21,2538-2544 (1973). (821) T. Chiba, M. Haga, and S. Tejima, Chem. Pharm. Bull., 23, 1283-1289 (1975). (822) M. Mori, M. Haga, and S. Tejima, Chem. Pharm. Bull., 23, 1480-1487 (1975). (823) M. Mori, M. Haga, and S. Tejima, Chem. P h a m . Bull., 22, 1331-1338 (1974). (824) I. Johansson, B. Lindberg, and 0. Theander, Acta Chem. Scand., 17,2019-2024 ( 1963). (825) S. Tejima, Japan. Kokai, 73 39,499 (1973);Chem. Abstr., 79, 53,736 (1973). (826) N. Roy and T. E. Timell, Carbohydr. Res., 7, 82-83 (1968). (827) T. Chiba, M. Haga, and S. Tejima, Curbohydr. Res., 45, 11-18 (1975). (827a) M. Mori, M. Haga, and S. Tejima, Chem. Pharm. Bull., 24, 1173-1178 (1976).

ooQ

I,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

163

~ ~ ~-~ Q ~ Q 2 steps

O\

OH

BzO

OH

OAc

OAc

282

3 steps

4 stepsoJ=! Q /H o

OAc

OAc

0 OH

OH

OH

Scheme 16

1,6-Anhydromaltose hexabenzyl ether,828and its cellobiose ana10g,8~9can be polymerized in the presence of Lewis acids to combshaped polymers having a linear backbone and pendant monosaccharide groups regularly substituted on each sugar residue in the main chain. The rate of propagation is much lower than that for the tribenzyl ethers of 1,6-anhydrohexopyranoses (see Sect. IV,2), and the stereospecificity is very sensitive to the reaction conditions. Copolymerization of derivatives of 6 and 275 has been Several thio analogs of 1,6-anhydro disaccharides have been prepared by Tejima and coworkers as substrates having potential biological activity affecting P-D-glycosidases. Like the synthesis of “ 6 - t h i o l a ~ t o s a n , ” ~the ~ ~ *synthesis ~~ of “6-thiocellobiosan”801 and “6-thiomalto~an”~~~ started with titanium tetrachloride cleavage of peracetylated 1,6-anhydro disaccharides, and then followed the general scheme by way of 6-0-sulfonylated 0-ethyl dithiocarbonate derivatives, as described for 1,6-anhydro-1(6)-thio-~-~-glucopyranose (see Sect. VII1,l). 1,6-Anhydro-1(6)-thio-~-maltotriose has also been prepared.806a Acid cleavage of persubstituted “6-thiolactosan” leads to 6-thio disaccharides .830 The unusual 1,6-anhydro disaccharide 283, having an ether instead of a glycosidic linkage, was synthesized as an intermediate in the preparation of the exotoxin from Bacillus thuringiensis.442,532c,534*542,758,759

(828) B. Veruovii. and C. Schuerch, Carbohydr. Res., 14, 199-206 (1970). (829) V. Masura and C. Schuerch, Carbohydr. Res., 15,65-72 (1970). (830) S. Tejima, Japan. Kokai, 73 39,418 (1973); Chetn. Abstr., 79, 115,851 (1973).

MILOSLAV ~ E R N Y AND JAN STASEK, JR.

164

HocYY + < , HOCH,

+

(1) Me,SO,Na (2) H,,Pd

cv I

0

OCH,Ph 188

OMe

HO

OH

283

XI. TABLESOF PROPERTIES OF 1,6-ANHYDROHEXOSES AND THEIR DERIVATIVES The following Tables do not constitute a comprehensive list of all of the known derivatives of 1,6-anhydrohexoses, but contain compounds the most utilizable for synthesis and identification. Reference numbers printed in italics correspond to literature data that, in the opinion of the present authors, are the most reliable. The letter i after the Reference number signifies that only incomplete data are given. Throughout the Tables, the following abbreviations are used: A, acetone; AcOH, acetic acid; B, benzene; Bu, 1-butanol; C, cyclohexane; Ch, chloroform; D, 1,4-dioxane; Dch, dichloromethane; Dip, diisopropyl ether; E, ethanol; EA, ethyl acetate; Et, ether; Ip, 2-propanol; M, methanol; Me2S0, dimethyl sulfoxide; P, 1-propanol; Pe, petroleum ether; Py, pyridine; Tch, tetrachloromethane; T, toluene; and W, water.

TABLEV 1,6-Anhydrohexopyranosesand Their Acetates ~~

Compound (configuration)

nallo tri-0-acetylD L - ~ O tri-0-acetyl, Daltro

M.p. (degrees) (solvent)

178.5-180 (E) 88-89 (Ch/Et/Pc) 128-129 (Dch/Pe) 136-138 (EA)

(degrees) (solvent)

-75.8 (W) -70.8 (Ch) -213.0 20.6 (W) -410 (w) - 193.4 20.7 (W) - 172 (Ch) -22.0 (W)b -47 (w) -5.7 (Ch)

[a1436

monohydrate“ tri-0-acetylDgalacto

60-65 (95%E) 100-101 (Et/Pe) 222-223 (E)’

tri-0-acetylDL-galacto, tri-0-acetylDglucoc

73-74 (Pe) 114-115 (Dch) 178-180 (E)b

tri-0-acetyl-

DL-&KO,

tri-0-acetyl-

109-110 (E)”

b.p. 130-131/13 Pa

-66.3 (W)” -70.5 (E) -77.5 (EA) -69.91 (EA) -72.25 (A) -127 (w) -62.0 ( C ~ I ) ~ -45.5 (E) -50.4 k0.6 (E) -51.2 (M)

References

118,419,662 118,42%,636,662 332 664 48,124,125,144i,312,314,3154717 48 134,664 134i,143i,144,312,422i,528,636 30,37i,48i,57,72,73,86,114,190i,288,289,290i,349i,483i,598 48,349 4 1,73,86,421 332 6,26-28,30,33,36,72,73,85,93,184,185,192,195,211,217,293,322, 366,444,483,588,591,593,595,600-602,6O4,651,656,684 6,27,28 6,27 28 28 48,389 33,73,107,195,219,309,310,444,495 6,27,36,72,80,93,563,622 66,71,82,92,593(cf. Ref. 561) 192 331 (Continued)

TABLE V (Continued) Compound (configuration)

Dgulo tri-o-acetylDido

M.p. (degrees) (solvent)

ID (degrees)

154-155 (E) 114-115 (Ch/Pe) 126-127 (EIA)

+50.4 (W) +22.1 (Ch) -92.6 ? I (W) - 118.5 ? 1 (A) [a1436 - 175 (W) -75.1 51.S (Ch) -73.6 (Ch) +113 (A) +74 (Ch) +76 (Ch) -127.5 (W) t01iIA6-241 (w) - 123.6 (Ch) - 100.2 (M) - 103.6 (W) -80.5 (W) -80 '2 (W) -73 + 2 (Ch) -64 (Ch)

66-67 (EtlPe)" 86-87 128-129 (A) 67-68 (E)" 85.5-87 (EtiPe) 2 10

tri-0-acetyl-

L-ido tri-o-acetylDmanno Y

0,

m

tri-0-acetyl-

90-91 (E)

206-208 (E) 185-186 (Ip) 117-118 (Et) 117-119(Et)

DtUlO

tri-o-acetyl-

(solvent)

References

122,127,128i,437 122,313,421,437,636 123 123 48,1283 123,422i,429a,4Si,636 130,133,831 131 138,142i 131 29,30,48i,282,483,597 48 29,282283,312,4221 282 282 99i,4 15i,419,497,636 424 99i,424,453i 636

For levoglucosan and its triacetate, incomplete data " The monohydrate can spontaneously dehydrate, and vice Zjersu. " Average value. are not referenced. The less-stable, crystalline modification.

"

(831) L. F Wiggins, Methods Carhohydr. Chem., 1, 140-143 (1962)

TABLEVI Mono- and Di-O-substituted Derivatives of 1,6-Anhydrohexopyranoses ~~

~

Compound (configuration)

p-Dallo 4-0-benzyl4-0-benzyl-2-0-p-tolylsulfonyl2,4-di-O-acetyl3,4-di-O-acetyl2,4-di-O-p-tolylsulfonyl-

M.p. (degrees) (solvent)

113 (B) 136-138 (Et) 167-168.5 (E) syrup 143-144 (Ch/Et)"

[aID(degrees) (solvent)

-79 (Ch) -51 (Ch) -62.8 (Ch) -32 (Ch)

References

636 636 422 4221 636

p-~~-~llo

-J

2-0-methylp-naltro 2-0-benzoyl4-0-benzoyl2-0-benzoyl-3-O-p-tol ylsulfon yl4-0-benzyl-2-O-p-tol ylsulfonyl2,4-di-O-p-tolylsuIfonyl3,4-di-O-p-tolylsulfonyl2-0-methyl2-0-(methylsulfonyl)2-0-p-tolylsulfonyl3-0-p-tolylsulfonylP-Dgulucto 2-0-acetyl2-0-benzoyl2-0-benzyl2,3-di-O-acetyl2,4-di-O-acetyl2,4-di-O-methyl-

99-100 (dec.)

332

203-204 (E) 139.5 (B) 176-177 (E) 145-148 (Ch/Et) 165-167 (Ch/Et) 209 (E) b.p. 165 (5.3 Pa) 138-140 (E) 129-130 ( E N ) 144-145 (NEt)

-220.5 (A) -213.9 (Me,SO) -238 (Ch) -134 (Ch) - 107 (Ch) - 147 (Ch) - 198 (E) - 186.4 (E) -148.5 (E) - 168.5 (M)

68 1 436 681 636 636 681 134 68 1 681 681

164-165 (E) 104-105 (Et/Dch) 113-115 (Ip/Pe)

+47.2 (Ch) -76.2 22.2 (Ch) -0.8 (Ch) -8.5 -46 t 2 (Ch)

704 289 708a 454,687,832 687 760

syrup syrup

(Continued)

TABLEVI (Continued) Compound (configuration)

M.p. (degrees) (solvent)

3,4-di-O-methyl2,4-di-O-p-tolylsulfonyl2-0-methyl4-0-methyl2-O-(methylsulfonyl)2-04 methylsulfonyl)-3-0-(o-nitrobenzoyl)2-0-phenylcarbamoyl2-0-p-toly Isulfonyl-

[mlD (degrees) (solvent)

8 1 (ENPe) 115-117 (E/Pe) 115- 116 syrup 145 (E) 163-165 (M/Pej 162-163 (W) 114-115 (AcOH)

References

-41.1 (W) -49 (Ch) -35 (W) -28 a1 (Ch) -11 (M) +43 (Ch) +24.7 (M) -20.7 (Ch)

641 450 48,30Si,483i,598,703i 760 509 (cf. 466) 43 1 641 708

P-DL-galUCto ~

2-0-acetyl2-0-methyl-

144-145 (subl.) 124-125 (subl.)

332 332

$? p-D-gluco 3-0-acetyl2-O-all yl4-0-allyl4-0-allyl-2-O-p-toly Isulfonyl2-0-benzoyl4-0-benzoyl2-0-benzoyl-4-0-p-to1ylsulfonyl4-O-benzoyl-2-O-p-tolylsulfonyl2-0-benzyl4-0-benzyl2-0-benzyl-4-0-p-tolylsulfonyl4-O-benzyl-2-~-p-tolylsulfonyl4-0-tert-butyl4-0-tert-butyl-2-0-p-tolylsulfonyl2,3-di-O-acetyl2,4-di-O-acetyl-

111-112.5 (A/Et/Pe) syrup syrup 90-91 (Et/Pe) 162-164 (EA) 123-126 (A/Et/Pe) 114-116 (A/Et/Pe) 162-164 (A/Et/Pe) 73-74 53-54 (Et) 104-106 (B) 126-127 (E) 104-105 (Et/Pe) 125-126 (AfEWPe) b.p. 100 (20-27 Pa) 132-133 (Et)

-62.2 (W) -51 (Ch) -33 (Ch) +28 21 (M) -85 ? l (M) +24 2 2 (Ch) -92 cl (Chj -64 (E) -43 (E) -50 (Ch) - 18 (Ch) -57.0 (Ch) -38.5 (Ch) -45 (Ch) -70.2 (Ch)

520 434 434i 434 38 38 38 38 156 50 156,629 155,156,636 635 635 50,51 51

3,4-di-O-acetyl2,3-di-O-benzoyl2,4-di-O-benzoyl2,4-di-O-benzyl2,4-di-0-(benzyloxycarbonyl)2,3-di-O-methyl2,4-di-O-methyl-

w

g

3,4-di-O-methyl3,4-di-O-p-tolylsulfonyl2,4-di-O-p-tolylsulfonyl2,4-di-0-(trimethylsily1)3-0-galloyl4-0-isopropyl-2-0-p-to1ylsulfonyl2-0-methyl3-0-methyl4-O-meth yl2-O-methyl-4-O-p-tolylsulfonyl3-0-methyl-4-0-p-tolylsulfonyl4-0-methyl-2-0-p-tolylsulfonyl2-09-tolylsulfonyl3-O-p-tolylsulfon yl4-0-p-tolylsulfonyl2-0-p-tolylsuIfonyl-4-0-trityl-

96-97 (EA/Pe) 137-138 (Ch/Dip) 136-138 (NEt) 128-129 (M) 106.5-107 (E) 122-123 (ChlEt) 43-45 (Et/Pe) 68-70 (Pe) b.p. 65-74 (27 Pa) 41-43 (Et/Pe) syrup 116-118 (B) b.p. 210 (13.3 Pa) 250 (W) 105-106 (B) 93-94 (A/Pe) 65-66 (NEt/Pe) 67-68 (NPe) 110-113 (A/Et) 111-113 (A/Et/Pe) 89-90 ( E N ) 117-119 (T/Pe) 117-120 121-123 (A/Pe) 160-170 (dec.) (Ch/M)

-79.5 (Ch) +73 (Ch)* -34 21 (Ch) -34 (Ch) -28.5 (Ch) -36.8 (Ch) -87 (Ch) -63.7 (A) -49.7 (A) -43 (Ch) -32 (Ch) -49.5 (M) [aim -38 (Ch) -72.7 (A) -58 (W) -65.4 (A) -54 23 (M) -33 21 (M) -43.6 (Ch) -48 5 1 (Ch) - 18 (Ch) -57 (Ch) -43 (Ch)

51 52 38 662, see also 520 442,546,6291,691(cf. 531) 520 50,52 (cf. 38) 671i 52 (cf. 2243) 52,156i,483 (cf. 38) 155i 38,106,520,636,679 (cf. 156) 520 546 496 52,155,264,483 38,48,51,52,155,483 52,483,499 (cf. 432) 38,156 38 499,505 52i,155i,504,635,679 (cf. 38) 679 38,448,679 504

P-DL-glUCO

3-O-meth ylP-l)gulo 2-0-benzoyl2-O-benzoyl-4-O-(p-nitrobenzoy1)yl2.3-di-0-n. tolvlsulfon .

b.p. 140-143 (13 Pa) 151-152 (Ch/M) syrup 151-152 (M)

331 +96 (Ch) +51.0 (Ch)

437 313i 122 (Continued)

TABLEVI (Continued) Compound (configuration)

M.p. (degrees)

[aIu(degrees) (solvent)

(solvent)

References

P-L-gU lo

2,3-di-O-methylP-Dido 3-0-methylmono-0-p- tolylsulfonyl-

-97 (W)

126

104-106 (NEt) 70-71 (CWPe)

-84 (W) -63.8 *3 (Ch)

157-157.5 (NPe) SYNP 82-83 (Et) 110-111 (NEt)

+42 (Ch) +86 (Ch) +91 (Ch) +lo8 (A)

122-123 (Ch/Pe) 63-65 (Et/Pe)

85-87 (B/Et) 146-147 (NEt) 168 (EM)

-76 (Ch) -90 (Ch) -117 (W) -42 (Ch) -74 (A) -80.3 (E)

48 285 48,284i ,285i 285 285 706

146-147 (Ch/M) 90-92 (Dip)

-38 (Ch) -50 (M)

636 497

48 (cf. 150,509) 123"

P-L-ido

3-0-benzyl2,3-di-O-methyl2,4-di-O-methyl3-0-methyl-

148,150a 149 148 148

P-DmUnnO

4-0-benzyl3,4-di-O-methyl4-0-methyl4-0-methyl-2-0-p- tolylsulfonyl2-0-p-tolylsulfonyl4-0-p-tolylsulfonylP-Dtalo 2,4-di-O-p-tolylsulfonyl2-0-methyla

Change of modification at 88-100".

SYNP

' The sign is probably wrong.

See Ref. 683, Section IV,3,b.

(832) C. Foces-Foces, F . H. Cano, and S. Garcia-Blanco,Acta Crystullogr.,Sect. B, 32, 427-430 (1976).

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

171

TABLEVII 0-Isopropylidene Derivatives of 1,6-Anhydrohexopyranoses Compound (configuration)

M.p. (degrees) (solvent)

1,6-Anhydro-2,3-0-isopropylideneP-D-allopyranose 88.5 (subl.) p-D- gu lopyranose 93 (subl.) p-D-mannopyranose 161-162 (Ip/Bu) p-D-talopyranose 108.5-109 (Ch/Pe) 1,6-Anhydro-3,4-O-isopropylidenep-D-allopyranose 104 (Et/Pe) 84-85 (Et/Pe) p-D-altropyranose p-D-galactopyranose 151-152 (B) p-D-talopyranose

112-113 (Ip) 117-118 (B) 120-122 (Ip/Et)

[aID(degrees) (solvent)

- 19.8 (Ch)

+49.8 (Ch) -58.8 (W) -34 2 2 (Ch)

-88.1 (Ch) -171 (Ch) -73.3 (Ch) -112.5 21 (Ch) -115 (Ch) - 122 (Ch)

References

436 436 111,283,284i,285, 286,415,457 415i,419,424,468,497

436 134 37,86,288-290,2941, 308,497,833 424 4 19 497

(833) R. W. Jeanloz and P. J. Stoffyn, Methods Carbohydr. Chem., I, 221-227 (1962).

MILOSLAV & R N ~ AND JAN STANEK, JR.

172

TABLEVIII Dianhydrohexopyranoses and Their Derivatives Compound (configuration)

M.p. (degrees) (solvent)

(degrees) (solvent)

References

1,6 :2,3-Dianhydro-p-D-hexopyranoses 93-95 (EAIPe) 94-96 (ENPe) 4-0-benzyl74-76 (ENPe) 4-0-p-tolylsulfonyl- 146-147 (E) Dgulo 135-137 (Et) 4-0-p-tolylsulfonyl- syrup ~irianno 68-70 (A/Et/Pe) 4-0-benzyl64 (Et/Pr) D-UllO

+55 (W) +41 (A) +I27 (Ch) +52 (Cli) +30 (W) 1-26 (Ch) -35 (W) -27 (Ch)

4-0-p-tolyI~~Ifol~yl137-139 (Et) Dtalo 132 (NEt)

498 155 155,379,498,632" 155,498 479,739,749 739 479,504,737 442,479,506,632 (cj: Refs. 52,155) 155,504 509,512i,703,737,833

-37 (Ch) -88 (W)

1,6 :3,4-Dianhydro-p-~-hexopyranoses

104-106 (EA/Pe) 102-103 (EA) 2-O-p-tolyIsulfonyl- 116- 117 (E) DL-all0 108-109 (Dch/Pe) paltro 161-162 (A/Et/Pe)

Dallo

2-0-p-tolylsulfonyl- 104-106 (E) Dgalacto 67-69 (EVPe)

-134 (W) - 125 (A) -95 (Ch)

-121 -124 -76 -80

(W) (A)

(Ch) (A)

2-0-benzyl-

47-48 (Et/Pe)

-55 (Ch)

2-0-p-tolylsulfonyl-

148-150 (ChlE)

-40 (Ch)

73-74 (Et/Pe) 2-0-1,-tolylsulfol~yl- 147-148 ( M )

DtUlO

'I

A negative [ale value was given by mistake.

-49.5 (W) - 19.0 (Ch)

498 155 155,498 33 1 504 681,739 504,739 156,432,448,496,637, 737,739 5 3 2 ~(cf. Refs. 156,442, 629,759) 448,505,513,520,637, 739,743 706,737 706

TABLEIX: Aminodeoxy Derivatives of 1,6-Anhydrohexopyranoses

Compound (configuration)

M.p. (degrees) (solvent)

[ah(degrees) (solvent)

References

2-Amino-l,6-anhydro-2-deoxy-~-~-hexopyranoses DaZtro hydrochloride D g a lac t 0 hydrochloride triacetate Dgluco hydrochloride, hydrate

triacetate Dgulo hydrochloride hydrochloride, hydrate triacetate Dido hydrochloride triacetate D-manno hydrochloride, hydrate IHaZo hydrochloride

350 (dec.) (2 M HCl/A) 168-170 (Ip) 215 (dec.) (M/W) 208 (E) 207 (E) 176 (dec.) (E) 120 (dec.) (WIEIHCI) 94-98 (dec. 160-162) (HCUE) 138 (ENPe)

-160 (W) -27.5 (W) - 15.5 (W) -74.2 (W) -36 (Ch) -74 (W) -45 20.3 (W)

255-260 (dec.) (MIA)

+42 21 (W)

235-240 (dec.) 144-145 (NEt)

-19 k 1 (Ch)

203-204 (dec.) (M/A) 127 (W)

-80 20.5 (W) -39 21 (Ch)

200-203 (dec.) (E/AIW)

-98 (W)

-46 (W) -92 (Ch)

158,165 509 509 509 509 766 766 678 97,633,678,766,772 164,512

164 512 166 159,166

379 439

syrup 3-Amino-1,6-anhydro-3-deoxy-~-~-hexopyranoses

Daltro hydrochloride triacetate Dgalacto hydrochloride Dgluco hydrochloride, hydrate triacetate Dgulo hydrochloride

triacetate Dido triacetate Dmanno hydrochloride triacetate

215-216 (dec.) 169-170 (E) 176-177 (E)

-171.9 (W) - 156 (W) -147 (W)

161,163,378,700,761-763 378,834 161331i

180-185 (dec.) (M/A) 134-135 (E)

-9.0 (W) -57 (W)

455 438

66-84 (W/E/Et) 177-178 (E/Et)

-50 (W) -65.5 (Ch)

229-230 (dec.) (M/A) +46 (W) +44 *2 (W) 245-248 (dec.) (M/E) 166-168 (Ea/Et/Pe) +45 (Ch) 193-196 (dec.) (E) -93 (W) 245-246(E) -71.1 (Ch) 177-180 (dec.) (E/Et) -124 (W) 187-190 (dec.) (E/Et) -105 (W) 169 (sub].) (E) - 106 (Ch)

379,438 379,438 378,700 160 378 378 130,378,509,700 757 757 757 (Continued)

MILOSLAV CERNY AND JAN STAKEK, JR.

174

TABLEIX (Continued) Compound (configuration)

M.p. (degrees) (solvent)

[aID(degrees)

(solvent)

References

4-Amino- 1,6-anhydro-4-deoxy-~-~-hexopyranoses Dgluco hydrochloride triacetate

Dmanno hydrochloride triacetate

160-180 (dec.) (E) 135-136 (Et) 175-180 (dec.) (W/E/HCI) 180 (E)

-65 (W) -29 (Ch)

-100.4 (W) -76.0 (Ch)

438,740 740

509,740 (cf. Ref." 513) 509,740 (cf. Ref." 513)

Dtalo hydrochloride triacetate

170-185 (dec.) (EIT) 140-140.5 (Et)

-66 kl (W) -85 ?2 (Ch)

415,439 4151,439

This compound was mistaken for 4-amino-1,6-anhydro-4-deoxy-~-~-glucopyranose.

(834) B. Coxon, personal communication; see Ref'. 378.

FOOTNOTES TO TABLEx For further data, see Refs. 367,483, and 631. f' Ref. 435 states: syrup, [ale -88" (E); evidently, an impure sample. Ref. 775 states: syrup, [aID-33.1" (E), for a product of the alkaline treatment of the p-nitrophenyl glycoside; its structure is probably quite different. Ref. 632 states: crystalline, hydroscopic compound, without, however, any n1.p. value. In the original paper,?46the opposite sign (printer's error) appeared (see also, the a ~ e t a t e ~ ' ~ , ' Obtained ~~). by sublimation of the lower-melting modification at 85-100". g [aID-9 was given hy mistake. f

TABLEX Deoxy, Dideoxy, and Trideoxy Derivatives of 1,6-Anhydrohexopyranoses Compound (configuration)

M.p. (degrees)

[aID(degrees)

(solvent)

(solvent)

References

1,6-Anhydro-2-deoxyhexopyranose

159-160(EA) 98-101(subl.) 181-182(ENPe) 98-99(EA) 28-31 (subl.) 100-102

p-Darabino P-DL-arabino P-DlYXO

P-Dribo P-DL-rib0 P-DXylo 1,6-Anhydro-3-deoxyhexo-

-118 (W) -70 (W) - 167(W) -31 (W)

155,632,746a.b*c 328,329 155,746 155 328 155 (cf. 151)

pyranose

P-Darabino

syrup

P-DlyXo

66-68

p-pribo P-DL-ribo

syrup

117-119 131-137 138-139(EMPe)

P-DSylo

-156 (W) -86.5(W) -79.9(W) -9.5(W)" -8 (W

105,746 746 105,746d 331 746 156

1,6-Anhydro-4-deoxyhexopyranose

p-Darabino p-L-arabino P-DlyXO

P-nribo P-DL-ribO P-DXylO

P-DL-x~~o

105-107(D/Pe) 106-107(EA) 91-110(subl.) 156' 108-110(M/Et) -30 158-160(subl.) 155-156 (Pe)

-164 (W) + 163.4(W) -87 (W) -89 (W) -16 (W)

65-70(EtlTchlPe) 79-81(subl.) 100-103 (Et/C)

-119 (W)

-39 (W)

742,746,754 152,153,154 383 746 383 328 540,742,746,7Sg 325,329

1,6-Anhydro-2,3-dideoxyhexopyranose

P-nerythro P-DL-erythro P-Dthreo

-57.5(W)

376,384(cf. 746) 328 377

1,6-Anhydro-3,4-dideoxyhexopyranose

P-nerythro P-DL-ery lhro P-Dthreo 1,6-Anhydro-2,4-dideoxy-

85-86(Et/Pe) 81-82(subl.) -28 (dest.)

-58 (W) -133 (W)

384,746 328 377,384,746

hexopyranose

P-Derythro p-nthreo

syrup

37-50(dest.)

-91 (W) -81 (W)

377 377

1,6-Anhydr0-2,3,4-trideoxyhexopyranose

P-Dgl ycero P-m-glycero

44-48 (dest.) 50-52(dest.)

-105 (W)

376 323,324-326,627,628

176

MILOSLAV ~ E R N Y AND JAN STANEK, JR

TABLEXI

Proportion of 1,6-Anhydrodeoxyhexopyranosein Equilibrium at 100" ~~

~

Anhydride (mol %) 1,g-Anhydrohexopyranose

Calc."

Found

References

2-Deoxy-P-

0.8 0.9 71 73.3

D-arabino D-lyXo

D-rib0 D-xylo 3-Deoxy-PDarubino

40

D-lyxo Dribo

69 12.5

Dxylo

37

155 155

23'

151

47.5" 29' 76.5d 10.F 10' 44.5" 26'

99 105 99 99 105 99 156

60' 64'

153 151

4-Deoxy-P-

L-arabino

63

n1yxo

0.7 55.7 0.4

aribo D-xylo

a Values for 3-deoxy derivatives are taken from Ref. 99; the rest were by the same method. * T.1.c. analysis. Preparative yield. G.1.c. analysis. By estimation of the reducing sugar.

"

1,6-ANHYDRO DERIVATIVES OF ALDOHEXOSES

177

TABLEXI1 1,6-Anhydrohexofuranosesand Their Derivatives M.p. (degrees) (solvent)

Compound (configuration)

p-nallo

syrup syrup 147 (DipiPe) 143-145 (EA) syrup 183-184 (E)

tri-0-acetyl2,3-O-isopropylidene-

P-L-altro tri-0-acetylLY-Dgalacto

79-80 (E)

tri-0-acetyltri-0-meth yltri-0-(methylsulfony1)tri-0-p- tolylsulfonylp-ngluco tri-0-acetyltri-0-methyltri-0-( p-nitrobenzoy1)tri-0-p- tolylsulfonylff-L-gulo tri-0-acetyl2,3-0-isopropylidene@-Dido

b.p. 72-83/66 Pa 168-169 (A/W) 143-144 (ChiEtlPe) 110.5-111.5 (E) 82.5-83.5 (Ip) 51-52 (Pe) 231-232 ( M E ) 127-128 (E) 225-230 (Ip) 102.5 (E) syrup

p-nmanno

192-193 (Ip)

tri-0-acetyl2,3-O-isopropylidene5Oacetyltri-0-p- tolylsulfonyla-D-tah tri-0-acetyl-

SYNP

~~

~

93-94 (EtlPe) 102-103 (Pe) 112-113 (E) 107 (EA) 120-121 (Et)

(degrees) (solvent)

[alD

-2 (W)" -54 (Ch) + 14.4 (Ch) + 19 (W) +83.7 (Ch) +56 (W) t 144.9 (Ch)

+73.6 (M) +67.8 (Ch) +36.2 (Ch) +43.3 (W) -15.3 (Ch) + 18.9 (A) +25.3 (A) -38.1 (W) -7.9 (Ch) - 18.4 (Ch) -5.26 0 (W) -86.8 (Ch) + 14.5 (Ch) -18.1 (Ch) -22.5 (Ch) +18.1 (W) +92.2 (Ch)

References 119 119 119,422 121 121 33,114,294, 295 33,121,294, 295,421,4531 295 114 114 251,296,796 251,322 251 250,251,296 251 113 113 113 121 113 113 113 113 113 99,791 42 1,453,791

~~

The calculated value is [uJD+25.5"; see Ref. 121. This is a calculated value; see Ref. 121. a

This Page Intentionally Left Blank

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES HIGHLIGHTS OF THE LITERATURE SINCE 1964, AND A SUPPLEMENT TO THE TABLES

BY ANTHONY N.

DE

BELDER

Research Diuision,Pharmacia AB, Uppsala, Sweden I. Introduction ........................................................................................................... 11. The Acetalation Reaction ..... 111. Physical Methods for S 2. Nuclear Magnetic Resonance Spectroscopy IV. Stereochemistry ..................................................................................................... 1. Conformational Equilibria of Cyclic Acetals ................................................. V. General Features ................................................................................................... ...........,.............................................. 1. Hydrolysis by Acids .................................................... 2. Action of Various Re 3. Applications....................................................................................................... VI. Tables of Properties of Cyclic Acetals of the Aldoses and Aldosides .............

179 180 180 182 192 192 195 198 198 202 202 205 207 209

I. INTRODUCTION Since 1965, when an article on cyclic acetals of the aldoses and aldosides last appeared in this Series,’ there has been prolific activity in this field of research. A number of excellent books on carbohydrates has become available during this period, many of which contain chapters on cyclic acetals.2-6 Capon’ included a valuable assessment of some (1) A. N. de Belder, Ado. Carbohydr. Chem., 20,219-302 (1965). (2) J. F. Stoddart, “Stereochemistry of Carbohydrates,” Wiley-Interscience, New York, 1971, pp. 186-232. (3) A. B. Foster, in “The Carbohydrates: Chemistry and Biochemistry,” W. Pigman and D. Horton, eds., Academic Press, New York, 2nd Edition, 1972, Vol. IA, pp. 391-402. 179

180

ANTHONY N.

DE

BELDER

aspects of cyclic acetals in his review on Mechanism in Carbohydrate Chemistry. Further reviews have Acetal groups as protecting groups in synthesis, and acetals as model compounds for studying various chemical reactions, have continued to maintain their popularity. With the advent and general accessibility of new physical-chemical methods of analysis, particularly, nuclear magnetic resonance (n.m.r,) spectroscopy and mass spectrometry (ins.), considerable progress has been made in our knowledge of the stereochemistry of these fused-ring systems and of such aspects as diastereoisomerism. One interesting developme~itthat may be noted is the advantageous use of chromatography, especially gas-liquid chromatography (g.1.c.) and thin-layer chromatography (t.l.c.), for studying the products and monitoring the reactions. These studies have frequently been employed to optimize the yield of the desired product. Many new synthetic procedures leading to products hitherto unobtainable, or present only as minor components, have evolved. These techniques have, in particular, facilitated the preparation and study of diastereoisomers. Cyclic acetal moieties have been found to occur widely in bacterial polysaccharides, although they do not appear to possess any immunological function. This article is intended as a supplement to the earlier one,’ and certain limitations on the scope have been imposed.

11. THE ACETALATION REACTION 1. Principles Governing the Reaction The formation of cyclic acetals by condensation of a diol(1) with an aldehyde (2) or ketone, the carbonyl compound often also serving as the solvent, may be represented3 as shown in Scheme 1.

~

~~~

(4)L. Hough and A. C. Richardson, in “Rodd’s Chemistry of Carbon Compounds,” S. Coffey, ed., Elsevier, Amsterdam, 1967, Vol. lF, pp. 351-362. (5) J. Stanek, M. Cernj., J. Kocourek, and J. Pacik, “The Monosaccharides,” Academic Press, New York, 1963, pp. 324-357. (6) H. G. Fletcher, Jr., Methods Cnrbnhydr. Chem., 2, 307-308 (1963): T. G. Bonner, ihid.,309-317: 0. T. Schmidt, ihid.,318-325. (7) B. Capon, Chem. Rew., 69,443-448 (1969). (7a) R. J. Ferrier and P. M. Collins, “Monosaccharide Chemistry,” Penguin Books Ltd., London, 1972, pp. 213-222. (8) J. Pacik, M. Cern9, and J. StaiGk, Chem. Listy,61, 191-228 (1967).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

3

2

181

4

Scheme 1

The oxoniurn ion 3 reacts rapidly with the nearest hydroxyl group to give the first (or kinetic) product, which may, however, subsequently rearrange to give the therinodynamically most stable product(s).Thus, the reaction may tie divided into a kinetic and a thermodynamic phase, and the product(s) of each of these niay differ considerably from each other. Whether or not the products isolated are true equilibrium products depends on the stage at which the reaction was terminated, and on such factors as the solubility and the temperature. These principles are clearly illustrated by reference to the reaction between glycerol and benzaldehyde in N,N-dimethylformamide in the presence of p-toluenesulfonic acid.gThe reaction may conveniently be monitored by n.m.r. spectroscopy, which reveals that the cis- and truns-1,3-dioxolanes (5 and 7, respectively) are formed first. These are then slowly converted into the 1,3-dioxanes (6 and 81, which preponderate in the equilibrium mixture. The final ratios for the acetals 6,8,5, and 7 are 1.8:1.8:1.2: 1.0. It may be noted that initial ring-closure of the intermediate oxocarbonium ion (9) affords a five-membered more readily than a six-membered ring. The large differences in entropy between the 1,3-dioxanes and the 1,3-dioxolanes imply that the prodnct composition is temperature-dependent. At low temperatures, the formation of IJ-dioxanes is favored.

HO 5

6

7

8

9

(9) N. Baggett, J. M. Duxbun, A. B. Foster, and J. M. Webber, Carbohydr. Res., 2, 216-223 (1966).

182

ANTHONY N. DE BELDER

Newer synthetic procedures now enable the chemist to impose a considerable degree of kinetic control on the products of the reaction. Thus, good yields of acetals have been obtained from trans (eq-eq), vicinal-diol groupings on pyranoid rings; such acetals are rare if conventional procedures are used. Furthermore, the dominance of kinetic control frequently leads to good yields of diastereoisomers. These aspects will be discussed in more detail in succeeding Sections. One of the essential factors governing the products of acetalation is the disposition of available hydroxyl groupings; of the conceivable products obtained at equilibrium, the relative free-energies of the isomers will be decisive. This, in turn, will involve a consideration of ring strain, nonbonded interactions, and repulsions. It is, for example, immediately evident from an inspection of the data that 0-isopropylidene derivatives of cis-l,2-diols are formed more readily than those of trans-l,2-diols. This is attributed to the facts that acetal formation at the cis-diol requires less distortion, and subsequent strain, of either the five- or six-membered rings. In fact, there does not appear to be any recorded case of a 173-dioxolaneacetal trans-fused to a five-membered ring. Assuming that thermodynamic control is operative, the steric repulsions of substituents, particularly those having an endo disposition, will determine the nature of the products. These principles have been elaborated by Mills.1°

2. Methods of Synthesis a. Conventional Procedures.-The condensation of the sugar or sugar derivative with an aldehyde or ketone in the presence of a desiccant and an acid catalyst continues to be the method of choice for the preparation of many standard compounds, although there now exists a considerable choice of alternative methods. The reader is referred to the previous article' for a discussion of the various factors influencing the reaction. One of the most interesting aspects of the work published during the past 10 years is that the reactions and the products have often been investigated in detail; the main products have been separated, and their structures established. This has, of course, been greatly facilitated by such chromatographic aids as t.1.c. and g.l.c., and such physical-chemical techniques as n.m.r. spectroscopy and m.s. Thus, it is of interest that the acid-catalyzed condensation of D-glucose with acetone affords, in addition to the known, 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose, smaller proportions of 1,2 :3,5-di-0(10) J. A. Mills,Ado. Carbohydr. Chem., 10, 1-53 (1955).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

183

isopropylidene-a-D-ghcofuranose and two di-O-isopropy1idene-Dglucoseptanoses (10 and ll).ll

1,2: 3,4-Di- 0-isopropylidenea-o-glucoseptanose

2,3 :4,5- Di- 0-isopropylidene o-glucoseptanose

10

-

11

The presence of 10 and 11 indicates that the diacetals with glucoseptanoid rings must only be 4-8 kJ.mole-’ less stable than the 1,2:5,6diacetal having the glucofuranoid ring.2Examination of the most-stable twist-chair conformers for the glucoseptanoid ring indicates that many of them can form 1,2:3,4-and 2,3 :4,5-diacetals without imposing much strain on the ring. The low tendency for formation of 4 2 : 3,5-di-O-isopropylidene-aD-ghcofuranose may be explained in terms of the unfavorable interactions between the hydroxymethyl substituent on (2-5 and one of the methyl groups of the 3,5-isopropylidene moiety, which would have a syn-axial relationship. One of the two most probable conformations12 is shown in formula 12.

12

The availability of convenient routes to many rare sugars has prompted studies on their acetalation. Often, the products had previously only been prepared indirectly. Thus, acetonation of D-allose was found to give 2,3 :5,6-di-O-isopropylidene-~-allofuranose as the main product.13J4The corresponding 1,2: 5,8diacetal is also formed, but in very low yield. Likewise, the condensation of acetaldehyde (as (11) J. D. Stevens, Chem. Commun., 1140-1141 (1969). (12) B. Coxon, Carbohydr. Res., 8, 125-134 (1968). (13) M. Haga, M. Takano, and S. Tejima, Carbohydr. Res., 14,237-244 (1970). (14) J. M. Ballard and B. E. Stacey, Carbohydr. Res., 12, 3 7 4 1 (1970).

184

ANTHONY N.

DE

BELDER

paraldehyde) with D-allose afforded two diastereoisomeric 2,3 :5,6di-O-ethyhdene-D-alloses in high yield (84-96%). I 5 The diastereoisomerism was located on the 5,6-ring. Acetonation of D-talose in the presence of anhydrous copper(1I) sulfate and sulfuric acid gave, as the major product, the 2,3:5,6-diacetal (28%)with a smaller proportion of the 1,2: 5,6-diacetal( 10%).I6 These results are in accordance with the predictions of Millslothat the 2,3 : 5,6diacetals of mannose, gulose, allose, and talose would be thermodynamically favored, as they have the minimum number of endo substituents. The condensation of acetone with D-ribose, with sulfuric acid as the catalyst, has also been examined in detail.17 The major component is 2,3-O-isopropylidene-~-ribofuranose (59%), together with three minor components: 1,5-anhydro-2,3-O-isopropylidene-~-ribofuranose (9%), 1,2 : 3,4-di-O-isopropylidene-a-~-ribopyranose (3%),and 1,2-0isopropyhdene-a-D-ribofuranose (6%). The authors observed that the only marked difference when other catalysts (such as copper sulfate or zinc chloride) were used was the absence of the anhydro compounds. Assuming that the l-hydroxyl group is equatorial, the preponderance of the 2,3-acetal is consistent with the thermodynamic stability of the isomer having the least number of endo substituents and with the unfavorable interactions between the acetal rings in the 1,2 :3,4-diacetal, which possesses a cis-syn-cis arrangement of rings.IO A comparable study on the acid-catalyzed benzyiidenation of Dribose has appeared.l8The reaction using zinc chloride and acetic acid as catalyst was studied at 5,27, and 80". As the difference in the energy of the syn and anti isomers of a cis-fused 2-phenyl-1,3-dioxolane ring is small, both products are often present in the products of the acidcatalyzed benzylidenation of vicinal 1,2-diols. Grindley and Szarek18 found that the main product at 5" is the thermodynamically most stable 2,3-O-benzylidene-p-~-ribofuranose (both diastereoisomers). At 27", the main products were found to be di-O-benzylidene-riboses (not characterized), together wih a small proportion of the 2,3-acetal. At 80", however, the preponderant product is di-(2,3-0-benzy~idene-fi-~-ribofuranose) 1.5': lr,5-dianhydride.It is evident that the temperature may play a decisive role in determining the number and type of products. In the previous examples, the composition of the mixture ofproducts is dominated by thermodynamic control. Some examples will now be (15) W. E. Dick, Jr., and D. Weisleder, Carbohydr. Res., 39,87-96 (1975). (16) J. S. Brimacombe and P. A. Gent, Carbohydr. Res., 9,231-236 (1969). (17) N. A. Hughes and P. R. H. Speakman, Carbohydr. Res., 1, :71-175 (1965). (18) T. B. Grindley and W. A. Szarek, Carbohydr. Res., 25, 187-195 (1972).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

185

presented in which a measure of kinetic control has been introduced, leading to rather different reaction-products, The major component of the acetonation of D-galactose with an acid catalyst is the 1,2 :3,4-diaceta1,19~20 the thermodynamically favored product. 1,2: 5,6-Di-O-isopropylidene-a-~-galactofuranose (13) is only formed to a minor extent (3%).'l It may be presumed that the furanose

13

derivative is destabilized by the endo-5,6 acetal ring. It has been found that dissolution of D-galactose in hot N,N-dimethylformamide prior to addition of the acetone and copper(I1) sulfate affordsZZTz3 the furanoid acetal 13 in yields of 20%.It is known that furanose forms are favored at higher temperatures, and in N,N-dimethylformamide as the solvent (see Ref. 22 and references cited therein). Furthermore, the absence of an acid catalyst would seem to confer a measure of kinetic character on the reaction. When the proportion o f acetone is restricted, the main products are mono-O-isopropy1idene-D-galactoses. Thus, the furanoid 5,6- and pyranoid 3,4- and 4,6-isopropylidene acetals were obtained in yields of 22. 15, and 13%,respectively. The absence of 1,e-acetals is significant, and is attributed to an effect of N,N-dimethylf~rmamide.~~*~~ A similar, low activity of the anomeric hydroxyl group has been noted reagent.Z5 with the 2,2-dimethoxypropane-N,N-dimethylformamide Using acetone-copper(I1) sulfate only, MorgenlieZ4 found that D-ribose affords -20% each of the 2,3- (furanose) and 3,4- (pyranose) isopropylidene acetals. With acid-catalyzed reactions, only the former is generally obtained. Thermodynamic stability is a feature of two cis-fused, five-meinbered rings. Likewise, good yields of the 3,4-0(19) I(. Freudenberg and R . 11. Hixon, Ber., 56, 2119-2131 (1823). (20) P. A. Levene and G. hl. Meyer, 1.Riol. C / W ~ L64, . , 473-474 (1925). (21) D. Horton, M. Nakadate, and J. M. J. Tronchet, Curhohydr. Res., 7,56-65 (1968). (22) S. Morgenlie, Acta Chem. Scund., 27, 3609-3610 (1973). (23) S. Morgenlie, Actn Cheni. Scund. Ser. B , 29, 367-372 (1975). (24) S. Morgenlie, Curhohydr. Res., 41, 77-83 (1975). (25) A. Hasegawa and H. G . Fletcher, Jr., Curbohydr. Res., 29,209-222 (1973).

186

ANTHONY

N. DE BELDER

isopropylidene derivatives of D-fucose and 6-0-methyl-~-galactose were ~ b t a i n e d . ' ~ Further examples wherein the use of acetone-copper(I1) sulfate would appear to introduce kinetic control are found in the reactions with methyl a - ~and - P-D-galact~pyranoside~' ~ ~ leading, in both cases, to appreciable proportions of the 4,6-O-isopropylidene derivative. Normally, only the 3,4-acetal is found. Ferrier and Hatton2*found that the condensation of D-xylose with benzaldehyde in tert-butyl alcohol with only anhydrous sodium sulfate as desiccant affords good yields of two diastereoisomeric 1,2 :3 3 di-0-benzylidene-xylofiranoses. The diastereoisomerism is confined to the 1,e-acetal ring. Earlier, standard syntheses had produced only the 1,2-ero isomer. The use of methyl sulfoxide as the solvent and boron trifluoride etherate as the catalyst has been expl0red,2~and has given good yields of acetals from aldehydes (but not ketones). The procedure does suffer from certain disadvantages, in particular, the laborious removal of the solvent by vacuum distillation, and the fact that some anomerization may result when glycosides are so treated.

b. Acetal Exchange.-In this category, reactions based on the principles of acetal exchange will be considered. The equilibrium involved may be formulated as shown for 14. I HCOH I HCOH

I

+

RR'C(OMe),

-

I

HCO, ,R HAO/c\R'

L

+

2MeOH

I

14

Although this technique had earlier been applied to n u c l e o ~ i d e s , 3 ~ , ~ ~ it has only found popularity for the preparation of acetals of aldoses and aldosides during the past few years. Evans and coworker^^^,^^

found that good yields of acetals of methyl a-D-glucopyranoside may be obtained by condensing various dimethyl acetals with a sugar in (26) J. S. Brimacornbe and 0. A. Ching, J. Chem. SOC., C , 1642-1646 (1968). (27) J. Schneider, Y. C . Lee, and H. M. Flowers, Carbohydr. Res., 36,159-166 (1974). (28) R. J. Ferrier and L. R. Hatton, Carbohydr. Res., 5, 132-139 (1967). (29) E. Bergonzi, R. Bernetti, C. Boffi, V. Brocca, and E. A. Cleveland, Staerke, 16, 386-390 (1964). (30) A. Hampton,]. Am. Chem. SOC., 83,3640-3645 (1961). (31) S. Chlidek and J. Smrt, Collect. Czech. Chem. Commun., 28, 1301-1308 (1963). (32) M. E. Evans and F. W. Parrish, Tetrahedron Lett., 3805-3807 (1966). (33) M. E. Evans, F. W. Parrish, and L. Long, Jr., Carbohydr. Res., 3,453-462 (1967).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

187

N,N-dimethylformamide in the presence of an acid catalyst. The products are mainly 4,6-acetals, together with smaller proportions of the 2,3 :4,6-diacetals. The formation of the 2,3-acetal is especially noteworthy, as it is an acetal that bridges vicinal, trans (eq-eq) hydroxyl groups on the pyranose ring; such had previously not been found. This procedure has the added advantage that the formation of 1,3-dioxepan rings at C-2 and C-3 of glucopyranose rings, as found when acetaldeor p r ~ p i o n a l d e h y d eare ~ ~used, is obviated. Thus, D. M. Hall and Stamm36obtained excellent yields of methyl 4,6-O-ethylidenea-D-ghcopyranoside by treating methyl a-D-glucopyranoside with 1,l-dimethoxyethane in the presence of sulfuric acid as the catalyst. However, they also achieved comparable results by using a mixture containing paraldehyde and diethyl ether. The latter modification also afforded improved yields of 4,6-O-alkylidene acetals of D-glucose. the reaction of some aldoses, Hasegawa and F l e t ~ h e P studied ,~~ mainly 2-acetamido-2-deoxyaldohexoses, with 2,2-dimethoxypropane-Nfl-dimethylformamide-p-toluenesulfonic acid at 25 and 80". The products obtained at the two temperatures differed markedly, and, again, lack of activity at the anomeric hydroxyl group in the presence of Nfl-dimethylformamide was noted. To account for this phenomenon, it was postulated that the dimethyl acetal of N,N-dimethylformamide, presumably formed in situ, reacts to afford highly labile (dimethy1amino)methylene acetals which may thereby permit insertion of isopropylidene groups in abnormal positions. Further developments of the acetal-exchange reaction, whereby the equilibrium is shifted to the right by removal of methanol, have enabled the preparation of acetals having strained-ring systems.38This is achieved by boiling the N,N-dimethylformamide under diminished pressure (for example, 70"/15torr) in a fine stream of air. By this means, was premethyl 2,3 :4,6-di-O-cyclohexylidene-a-~-glucopyranoside pared in a yield of 93%.Similar principles were applied in order to obtain good yields of methyl 4,6-O-benzylidene-a- and -p-D-glucosides39 by treating the D-glucoside with a,a-dimethoxytoluene in refluxing N,N-dimethylformamide and p-toluenesulfonic acid. Likewise, Horton and Weckerle40 prepared methyl 2,3 :4,6-di-O-benzyl(34) H. Appel and W. N. Haworth, J . Chem. SOC., 793-798 (1938). (35) E. G. Ansell and J. Honeyman, J . Chem. Soc., 2779-2789 (1952). (36) D. M. Hall and 0. A. Stamm, Carbohydr. Res., 12,421428 (1970). (37) A. Hasegawa and H. G. Fletcher, Jr., Carbohydr. Res., 29,223-237 (1973). (38) F. H. Bissett, M. E. Evans, and F. W. Parrish, Cavbohydr. Res., 5,184-193 (1967). (39) M. E. Evans, Carbohydr. Res., 21,473-475 (1972). (40) D. Horton and W. Weckerle, Carbohydr. Res., 44,227-240 (1975); compare Am. Chem. SOC. S y m p . Ser., 39,22-35 (1977).

188

ANTHONY N. DE BELDER

idene-a-D-mannopyranosidein 95% yield. The n.m.r. spectrum indicated that the 2,3-ring is diastereoisomeric. It is evident from these results that procedures involving acetal exchange may provide a fair measure of kinetic control. c. Acetal Formation from Enol Ethers.-Enol ethers have been used for the preparation of 2’,3’-O-alkylidene derivatives of D-ribonu~leosides.~’ Wolfrom and coworkers4’found that several alkyl vinyl ethers afford the 4,6-O-ethylidene derivative when they react with methyl a-D-glucopyranoside; the cyclization is preceded by an initial attack of the enol ether at C-6. Likewise, isopropylidene acetals were prepared b y treating the sugar with ethyl (or methyl) isopropenyl ether in N,N-dimetliylforillamide containing a trace of p-toluenesulfonic acid as the c a t a l y ~ t .Thus, ~ ~ , ~ under ~ these conditions, D-glucose gave a 95% yield of 4,6-0-isopropylidene-cy,P-D-glucopyrano~e,~~ whereas D-ribose and D-arabinose afforded the respective 3,4-0-isopropylidenepentopyranoses as the major products.43The acetonation of these two sugars by conventional procedures leads mainly to 2,3-O-i~opropylidene-D-ribofuranose~~ or 1,2 : 3,4-di-O-isopropylidene-D-arabinopyranose.’ It is surmised that this reagent reacts under kinetic control, and gives rise to derivatives having strained rings that are not accessible under thermodynamic control. A similar reaction involving the cyclization of monovinyl ethers of 1 , Z - d i o l ~was ~ ~ utilized by Gigg and Warren,46 who isolated 1,2-Opropylidene-a-D-galactose after cyclization of l-propen-l-yl a-D-galactoside with an acid catalyst.

d. gem-Dihalides and Base.-Another route providing good yields of kinetically controlled products employs the reaction of a gem-dihalide with a diol under basic conditions. Thus, dihalomethanes give O-methylene a c e t a l ~ , 4 ~and 3 ~ ~benzylidene gem-dihalides afford 0benzylidene a c e t a l ~ . ~ ~ - ~ ~ (41) Ll. L. Wolfroiii, A. Beattie, and S. Bhattacharjee, ]. Org. Chem., 33, 1067-1070 (1968). (42) M. L. Wolfroni, A. B. Diwadkar, J. Gelas, and D. Horton, Curbohydr. Res., 35, 87-96 (1974). (43) J. Gelas and D. Horton, Carbohydr. Res., 45, 181-195 (1975). (44) P. A. Levene and E. T. Stiller,]. B i d . Chem., 102, 187-201 (1933). (4S) H. S. Hill and L. M. Pidgeon, ]. A m . Chem. Soc., 50, 2718-2723 (1928). (46) R. Cigg and C . D. Warren,]. Cheni. Soc., C , 1903-1911 (1968). (47) S. S. Bhattacharjee arid P. A. J. Gorin, Carbohydr. Res., 12, 57-68 (1970). (48)J. S. Brirnacombe, A. B. Foster, B. D. Jones, and J. J. Willard, /. Clzem. SOL.., C , 2404-2407 (1967). (49) N. Baggett, J . 11.Duxbury, A. B. Foster, and J. M . Webber, Chem. Ind. (London), 1832-1833 (1964).

CYCLJC ACETALS OF THE ALDOSES AND ALDOSIDES

189

Foster and coworkers5" established that benzylidenation under these conditions gives rise to diastereoisomeric 2-phenyl-l,3-dioxane derivatives, indicating that kinetic control is operative. They isolated both diastereoisomers of the 4,6-O-benzylidene derivatives of methyl a-D-gluco- and -galacto-pyranoside (as 2,3-di-O-methyl derivatives). Whereas previous workers had used potassium tert-butoxide in tert-butyl alcohol-toluene, Garegg and Swahnsl found that the reaction proceeds satisfactorily when conducted in boiling pyridine under reflux. However, they noted that only the thermodynamically most stable 1,3-dioxane derivative is obtained in each case. Garegg5Iaremarked, however, that there is, a priori, no reason why the favored transition state should not give the most stable product, provided that the transition state is product-like. However, Gelas51bpointed out that there is evidence that the pyridinium chloride formed may catalyze the transformation of the kinetic into the thermodynamic product. The 1,3-dioxolane rings in, for example, methyl 3,4-O-benzylideneP-D-galactoside are diastereoisomeric. Under these conditions, it is possible to prepare acetals from acetylated and tritylated sugars. Compounds having strained, five-membered rings have been prepared by treating diols with dibromornethane under basic conditions:* and both five- and six-membered rings are possible.47Goodwin and Hodge5' showed that methylene acetals can be prepared by heating glycosides with 1,3,5-trioxane in 1,4-dioxane at 95", with boron trifluoride etherate as the catalyst. The yields were, generally, only fair. However, the method has the advantage that appreciable proportions of oxidodimethylene acetals are not formed. An alternative procedure, based on the intramolecular displacement of a suitable leaving-group by a hemiacetal anion, was explored by Webber and coworkerss3(see Scheme 2). Thus, benzaldehyde was HOCH, I

FH2 f H,CX

PhCHO

+

Br-PhC,

H 0-CH, \I I

FH2

$XH,

n

+

BH -PhC

0-CH,

I CH, I 0-CH,

\ /

\

+

X:-

2X Scheme 2

(50) N . Baggett, J. M. Uuxbury, A. B. Foster, and J. M. Webber, Carbohydr. Res., 1, 22-30 (1965). (51) P. J. Garegg and C.-G. Swahn, Actu Chern. Scund., 26, 3895-3901 (1972). (51a) P. J. Garegg, personal communication. (51b) J. Gelas, personal communication. (52) J. C . Goodwin arid J. E. Hodge, Carbohydr. Res., 28,213-219 (1973). (53) N. Baggett, M. Mosihuzzaman, and J. M. Webber, Carhohydr. Res., 11,263-266 (1969).

190

ANTHONY N.

DE

BELDER

condensed with methyl 2,3-di-O-methy1-6-0-p-to~ylsu~fony~-a-Dglucopyranoside in tert-butyl alcohol with potassium tert-butoxide as the catalyst, to give the 4,6-benzylidene acetal. The yields were generally poor, and did not recommend the procedure for general use. The reaction proceeds under kinetic control, and diastereoisomers are present. e. Acetals from 1,ZAcetoxonium-ion Intermediates.-The basis of this method is the transfer of hydrogen to an intermediate acetoxonium ion, a process that may give rise to both diastereoisomers of the resulting ethylidene acetal. Thus, Buchanan and Edga154 isolated both diastereoisomers of methyl 3,4-0-ethylidene-p-~-arabinopyranoside in a two-stage procedure in which the ethoxyethylidene orthoester (15) was treated with boron trifluoride, and then the intermediate, acetoxonium-ion salt was converted into the ethylidene acetal with lithium aluminum hydride in ether.

15

Similar principles have been applied to the preparation of previously unavailable acetals of D-all~pyranose.~~ In this procedure, penta-0-acetyl-P-D-allopyranose was first converted into the intermediate, 0-acetylated P-D-allopyranosyl chloride, which reacted with sodium borohydride in 1,2-dimethoxyethane, by way of the postulated acetoxonium ion, to give diastereoisomeric 1,2-O-ethylidene-a-~allopyranoses. A wide range of acetals may be prepared by allowing dialkylcadmium derivatives to react with the intermediate 1,2-acetoxonium The bulky, dialkylcadmium presumably approaches from the least-hindered side (exo), leading to the formation of only one isomer. By similar mechanisms, a number of methoxymethylene, (l-methoxyethylidene), and methoxybenzylidene orthoesters underwent stereospecific attack by lithium aluminum hydride-aluminum trichloride to give the corresponding methylene, ethylidene, and ben(54) J. G. Buchanan and A. R. Edgar, Chem. Commun., 29-30 (1967). (55) W. E. Dick, D. Weisleder, and J. E. Hodge, Carbohydr. Res., 42, 65-72 (1975). (56) R. G. Rees, A. R. Tatchell, and R. D. Wells,J. Chem. Soc, C , 1768-1772 (1967).

CYCLIC ACETALS OF T H E ALDOSES AND ALDOSIDES

191

zylidene acetal~.~' N o diastereoisomers could be detected in the products.

f. Miscellaneous Methods.-Hanessian and have developed a potentially useful method for preparing methylene acetals. The alcohol (ROH) is allowed to react with N-bromosuccinimide in dimethyl sulfoxide, giving the acetal RO-CH2-OR.The procedure works well with vicinal cis-diols. A 72% yield of the 2,3-0-methwas ylene derivative of methyl 5-0-benzoyl-p-~-ribofuranoside obtained. 1,2-O-Alkylidene and -arylidene derivatives of D-ghco-, D-allo-, D-manno-, and D-talo-pyranose are difficult to prepare directly. Lemieux and DeterP9 prepared these from the 1,2-0-ethoxyethylidene orthoester, and were able to recover quantitative yields of l72-O-is0propylidene, 1,2-0-cyc10hexy1idene7 172-0-cyclopentylidene, and diastereoisomeric 1,2-O-benzylidene acetals of D-glucopyranose. In their procedure, the orthoester is allowed to react, with scrupulous exclusion of moisture, with a ketone or aldehyde in the presence of an acid catalyst. A host of examples may be found in the literature in which the desired acetals are obtained by chemical manipulation of a preformed, acetal derivative. Many ingenious routes have been devised, but lack of space does not permit more than a passing reference to this approach. By far the most popular method employs the reduction of an intermediate carbonyl derivative of the acetal, whereby the configuration of the original hydroxyl group becomes inverted, as in the formation of 16. This approach demands a considerable degree of stereoselec-

tivity of the reducing agent. Many otherwise difficultly obtainable derivatives have been synthesized by this means.60a-60f It may, in certain instances, be advantageous to proceed by way of reduction of the enol acetate, as in the preparation of D-gulose from D-glucose.61Inversion of the configuration of a carbon atom has been achieved by extra(58) S. Hanessian, P. Lavallee, and A. G. Pemet, Carbohydr. Res., 26,258-260 (1973). (59) R. U. Lemieux and D. H. Detert, Can. J . Chem., 46, 1039-1040 (1968). (60a) J. Defaye and A. Gadelle, Carbohydr. Res., 42,373-378 (1975). (60b) A. H. Haines and P. R. Lundie,]. Chem. Soc., C , 1691-1693 (1970).

192

ANTHONY N.

DE

BELDER

and intra-molecular displacement of a good leaving-group. Likewise, the opening of an epoxide ring has been widely used. The in situ generation of an epoxide from a mono-O-mesyl derivative has provided a convenient route to methyl 4,6-O-isopropylidene-a-~-a~tropyranoside.@ Other procedures frequently adopted involve periodate oxidation of a suitable acetal d e r i ~ a t i v e and , ~ ~ borohydride reduction of acetals of lac tone^.^^ It has also proved feasible to interchange acetals by means of acid ~ a t a l y s i s ~thus, ~ , ~ reaction ~; of a 1,2-O-isopropylidene derivative of D-glucose with benzaldehyde and sulfuric acid afforded the corresponding 1,2-O-benzylidene derivative.

111. PHYSICAL METHODSFOR STRUCTURAL ELUCIDATION 1. Mass Spectrometry Mass spectrometry has proved to be a useful complement to other methods for elucidating the structure of cyclic acetals. The reader is referred to several excellent reviews on the mass spectrometry of carbohydrates that have appeared within the time span covered by this article.65a-65d,66 Mass spectrometry is a valuable aid for distinguishing pyranose from furanose structures, and monoacetals from diacetals. It may also facilitate the assignment of ring location. However, it is generally insensitive to configurational differences. Isopropylidene acetals are by far the most well-studied derivatives. The fragmentation patterns of isopropylidene acetals of pentoses and hexoses have been delineated by DeJongh and Biemc~nn.~' In the pyranose series, the main larger fragments are derived by consecutive loss of parts, or all, of the two isopropylidene groups, for example, M - 15 (A), M - 15 - 58 (B), M - 15 - 60 ( C ) ,M - 15 58 - 60 (D). The M - 15 fragment is often intense, and enables the molecular weight to be calculated. Strong peaks at m/e 100 and 85 in the mass spectra of diacetals may be assigned to 17 and 18.

(60c) J. S. Brimacombe, P. A. Gent, and J. H. Westwood,]. C h e m . SOC.,C , 1632-1635 (1970). (60d) D. C. Baker, D. Horton, and C . G . Tindall, Jr., Carbohydr. Res., 24,192-197 (1972). (60e)K. N. Slessor and A. S. Tracey, Can. ]. Chem., 47,3989-3995 (1969). (60f) Y. Kondo, Carbohydr. Res., 30,386-389 (1973). (61) W. Meyer zu Reckendorf, Angew. Chem., 79, 151 (1967). (62) M. E. Evans, Carbohydr. Res., 30, 215-217 (1973). (63) J. S. Brimacombe, F. Hunedy, and L. C. N. Tucker,]. Chem. SOC., C, 1381-1384 (1968). (64)L. M. Lerner, B. D. Kohn, and P. Kohn, ]. Org. Chem., 33, 1780-1783 (1968).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES r

193

1’

O Y O Me 17

18

The mass spectra of the diisopropylidenealdofuranosesdiffer considerably from those of the corresponding acetals of the pyranoses. The most characteristic process is the scission of the C-4-C-5 bond, resulting in two typical fragments having mle 101 and 159, as shown in 19. The corresponding fragments A, B, C, and D are lessened in inMe,CP-T ‘0-CH

,/

0-CMe,

m / e 159 19

tensity. There are numerous examples in the l i t e r a t ~ r e . ’ ~ ’It~ ~ , ~ ~ , ~ ~ should be stressed that the ion mle 101 may arise from both pyranose and furanose structures, and it is only diagnostic if strong. Chizhov and coworkers6gestablished an important fragmentationpattern (“h-rupture”) that accounts for the ions mle 101, 129, and 159 in the mass spectra of die-isopropylidene-pentoses (20)and -hexoses. By means of 13C-enrichment studies on 1,2 : 5,6-di-O-isopropylidene-a-D-glucofuranose, Schwarcz and Perlin70 have accounted for fragments at mle 131 and 129 (see 21).

(6.54 N. K. Kochetkov and 0. S. Chizhov, Methods Carbohydr. Chem., 6, 540-554 ( 1972). (65b) N. K. Kochetkov and 0. S. Chizhov, Adc. Carbohydr. Chem., 21, 39-94 (1966). (65c) L. Hough and A. C. Richardson, in “Rodd’s Chemistry of Carbon Compounds,” S. Coffey, ed., Elsevier, Amsterdam, 1967, Vol. lF, pp. 133-139. (65d) J. Lonngren and S. Svensson, Ado. Carbohydr. Chem. Biochem., 29, 41-106 (1975). (66) K. Heyns, H. F. Griitzmacher, H. Schammnn, and D. Muller, Fortschr. Chem. Forsch., 5,448-490 (1966). (67) D. C. DeJongh and K. Biemann,]. Am. Chem. Soc., 86, 67-74 (1964). (68) J. S. Brimacombe and P. A. Gent, Carhohydr. Res., 12, 1-8 (1970). (69) 0. S. Chizhov, I,. S. Golovkina, and N. S. Wulfson, Carbohydr. Res., 6, 138-142 ( 1968). (70) J. A. Schwarcz and A. S. Perlin, Carbohydr. Res., 45, 317-319 (1975).

194

ANTHONY N.

DE

BELDER

20

t

m / e 129 "h-rupture"

O-CMe,

m / e 129 21

Similar principles have been used to explain the fragmentation patterns of monoisopropylidenealdo-furanosesand - p y r a n o s e ~ . ~ ~ 0,~~,~' Ethylidene acetals15 display cleavage patterns analogous to those of isopropylidene acetals, except that both [M - H'l and [M - CH;l+ are prevalent. For benzylidene acetals, "h-rupture" constitutes an important cleavage route.69 Thus, for methyl 4,6-O-benzylidenehexopyranosides, the fragments at mle 133 and 149 are characteristic. Further studies on benzylidene derivatives have been reported.71 Horton and coworkers72investigated some isopropylidene acetals by chemical-ionization m.s., and found that the spectra are typified by simpler dehydration and substituent-cleavage patterns. (71) V. KovhCik, P. Kovki., and R. L. Whistler, Carbohydr. Res., 16, 353-361 (1971); 31,377-386 (1973). (71a) J. Mitera, V. Kubelka, A. Zobieovli, and J. Jar$, Collect. Czech. Chem. Commun., 37,3744-3748 (1972). (72) D. Horton, J. D. Wander, and R. L. Foltz, Cnrbohydr. Res., 36, 75-96 (1974). (72a) G. Kotowycz and R. U. Lemieux, Chem. Reu., 73,669-698 (1973).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

195

2. Nuclear Magnetic Resonance Spectroscopy The excellence of n.m.r. spectroscopy for elucidating structural and stereochemical problems is unsurpassed, and is nowhere better illustrated than in the field of cyclic acetals. There are many authoritative reviews on this topic, 72a-72e and, in this article, the discussion will be confined to two main aspects: the application of n.m.r. spectroscopy to the study of ( a ) diastereoisomerism, and (b)conformation. The full implications of n.m.r. spectroscopy for unravelling the stereochemistry of diastereoisomers were first realized by Foster and cow o r k e r ~ . ? They ~ , ~ ~ established that, when the alkylidene methine proton is cis-related to the two methylene protons attached to the ring junction, as in 22, the proton thus deshielded resonates at lower field.

0

H 22

They observed that the chemical shifts of the benzylidene methine and -p-D-gluproton in methyl 2,3-di-O-acety1-4,6-0-benzylidene-acopyranoside (prepared by acid-catalyzed benzylidenation) are identical, and, by analogy with the values for 1,3-dioxanes, they allocated a structure having an equatorial phenyl group.49 When, however, methyl 4,6-0-benzylidene-2,3-di-O-methyl-a-~gluco- and -galacto-pyranoside were prepared (for the first time) under ~,~~ kinetic control, they found, for each, two benzyl s i g n a l ~ , 4indicating the presence of both diastereoisomers. The chemical shifts for the diastereoisomers were as shown. The smaller values in each pair are similar to those for axial protons in that chair form of 2-phenyl-1,3dioxanes having axial protons on the same side of the ring. These isomers are the thermodynamically favored ones. (72b) I.. D. Hall, Adu. Carbohydr. Chem., 19, 51-94 (1964). (72c) B. Coxon, Adu. Carbohydr. Chem. Biochem., 27, 7-83 (1972); Methods Carbohydr. Chem., 6 , 513-539 (1972). (72d) R. J. Ferrier, Prog. Stereochem., 4,43-58 (1969). (72e) J. S. Brimacombe, R. J. Ferrier, R. D. Guthrie, and T. D. Inch, in “Specialist Periodical Reports, Carbohydrate Chemistry,” The Chemical Society, London, 1972, Vol. 5, pp. 159-.169. (73) A. B. Foster, A. H . Haines, J. Homer, J. k h m a n n , and L. F. Thomas,J. Chem. SOC., C, 5005-5011 (1961). (74) K.Baggett, B. Dobinson, A. B. Foster, J. Homer, and L. F. Thomas, Chem. Ind. (London),106-107 (1961).

ANTHONY N. DE BELDER

196

Chemical shifts (CDCld (6)

Methyl 4,6-O-benzylidene-"

a

5.386 5.57 5.61

5.94* 6.28 6.30

a-D-glucopyranoside a-D-galactopyranoside P-D-galactopyranoside 2,3-Di-O-methyl derivatives.

* In CCl,.

It is well known that the condensation of aldehydes with polyalcohols may produce diastereoisomeric 1,3-dioxolane derivatives, as the difference in energy between the endo and exo isomers is small. Foster and colleague^'^,^^ used differences in chemical shift to elucidate the absolute configuration. They found diastereoisomeric forms for the 3,4-O-benzylidene rings of methyl 3,4-O-benzylidene-pL-arabinopyranoside (A), 1,2 : 3,4-di-O-benzylidene-a-~-galactopyranose (B), and methyl 2,3 :4,6-di-O-benzylidene-a-~-rnannopyranoside (C), as shown. By arguments analogous to those used earlier, the Shifts" of benzyl proton in 3,4-ring of diastereoisomers (6) Compound

endo

era

A

5.82 5.98 5.84

5.47 5.38 5.54

B C

* Measured in 1,4-dioxane.

smaller values were assigned to the exo-benzyl proton. It would appear that the benzyl proton of the 4,6-benzylidene ring resonates at higher field than those of 1,2-, 2,3-, or 3,4-dioxolane rings. This may be of some diagnostic value; the evidence is, however, somewhat limited. The stereochemistry of many diastereoisomeric cyclic acetals has been determined. Thus, 1,2 :3,5-di-O-benzylidene-a-~-xylofuranose gave two diastereoisomeric forms (23) having benzyl proton resonances at 6 6.17 and 5.90 (for the l,2-ring).28Grindley and Szarekl' found two diastereoisomers of 2,3-O-benzylidene-/3-~-ribofuranose, (75) N. Baggett, K. W. Buck, A. B. Foster, M. H . Randall, and J. M. Webber,Proc. Chem. S O C . , 118-119 (1964). (76) N. Baggett, K. W. Buck, A. B. Foster, and J. M. Wehber,]. Chern. SOC.,C, 34013407 (1965).

CYCLIC ACETALS OF THE ALDOSES A N D ALDOSIDES

197

H-endo, 6 6.17 23

having 6 5.95 (endo benzyl proton) and 5.75 (exo benzyl proton). By means of X-ray crystallographic studies on methyl 3,4-0-ethylidene-aD-galactopyranoside, Garegg and coworkers76aestablished that the correlations between the chemical shift for the benzylidene methine proton and the stereochemistry at the acetal carbon atom may also be extended to ethylidene acetals. In an investigation of the two diastereoisomers of 2,3:5,6-di-O-ethylidene-a-~-allofuranose, it was found that the isomerism is confined to the 5,6-ring.I5 By reduction of the intermediate acetoxonium ion, Hodge and cow o r k e r ~prepared ~~ (and separated) diastereoisomeric forms of peracetates of 1,2-0-benzylidene-, 1,2-0-ethylidene-, and 1,2 :4,6-di-0ethylidene-a-D-glucopyranose. For the 1,2-0-ethylidene ring, the exo methine proton resonates at 6 4.87-4.83, and the endo at 6 5.47-5.24 (signals as quartets; in benzene-d,). Diastereoisomeric forms of, for example, 1-methylpr~pylidene,~~ onitr~benzylidene,~'and l - b e n ~ y l e t h y l i d e n eacetals ~~ have been reported. N.m.r. spectroscopy has become an indispensable tool in the conformational analysis of acetals. This development is largely attributable to the fact that the spectra can be assigned, and analyzed, on a first-order basis. A well resolved spectrum is a necessary prerequisite for any conformational analysis. In addition to the established aids for analyzing complex spectra, the use of lanthanide shift-reagents now provides an often simpler approach to this problem. By using tris(dipivalomethanato)europium(III), Armitage and L. D. Hall'" revealed that a spectacular simplification of the spectra of diisoP. J. Garegg, K. B. Lindberg, and C.-G. Swahn, Actu Chem. S c u d Ser. B, 28, 381-384 (1974). W. E. Dick, Jr., D. Weisleder, and J. E. Hodge, Carbohydr. Res., 23, 229-242 (1972). P. M. Collins and N. N. Oparaeche, Carhohydr. Res., 3 3 , 3 4 4 6 (1974). D. Joniak, B. KoSikovi, and R. Palovcik, Carbohydr. Res., 36, 181-184 (1974). 1. M. Armitage and L. D. Hall, Chem. Ind. (London), 1537-1538 (1970);see also, L. D. Hal1,Adv. Curbohydr. Chem. Biochern., 29, 1140 (1974), particularly pp. 16-25.

198

ANTHONY N. DE BELDER

propylidene acetals of D-glucose and D-allose may be obtained; their article includes many useful comments about practical aspects of this technique. In a later report,81their studies were considerably amplified, to include, also, the effects of thulium and praseodymium complexes and a wide range of cyclic acetals.“ The structure of the comand the plex between 1,2 :5,6-di-O-isopropylidene-a-~-glucofuranose lanthanide shift-reagent has been i n ~ e s t i g a t e d . ~ ~ Horton and coworkers84 established the potential value of europium(II1)-induced shifts for determining the configuration at tertiary alcohol centers in acetals of branched-chain carbohydrates. In their approach, sets of shift gradients for the unknown and a reference compound are compared. Other studies of isopropylidene acetals have appeared.85Some care must be observed with these shift reagents, as conformational equilibria may be seriously disturbed at higher concentrations of the ~ornplexant.~~ Some explorative studies on 13Cchemical-shifts of cyclic acetals, for example, transfused, bicyclic hexopyranosides,86 1,2-0-isopropylidenehexofuranose~?~ and borate complexes of various acetals,s8have appeared. IV. STEREOCHEMISTRY

1. Conformational Equilibria of Cyclic Acetals The conformational equilibria of cyclic acetals have received much attention during the past decade, a development due essentially to improved instrumental techniques for n.m.r. spectroscopy. Several comprehensive review^^^^^^-*^ of this field have been published; con(81) I. M. Armitage and L. D. Hall, Cnn. /. Chem., 49, 2770-2777 (1971). (82) A. Arduini, I. M. Armitage, L. D. Hall, and A. G. Marshall, Carbohydr. Res., 31, 255-263 (1973). (83) I. M. Armitage, L. D. Hall, A. G. Marshall, and L. G. Werbelow,/. Am. Chem. SOC., 95, 1437-1443 (1973). (84) S. D. Gero, D. Horton, A.-M. Sepulchre, and J . D. Wander,/. Org. Chem., 40, 1061-1066 (1975). (85) D. Horton and J. D. Wander, Carbohydr. Res., 39, 141-146 (1975). (86) E. Conway, R. D. Guthrie, S. D. Gero, G . Lukas,A.-M. Sepulchre, E. W. Hagaman, and E. Wenhert, Tetrahedron Lett., 4879-4882 (1972). (87) J. A. Schwarcz and A. S. Perlin, Can. J . Chem., 50,3667-3676 (1972). (88) P. A. J . Gorin and M. Mazurek, Carbohydr. Res., 27,325-339 (1973). (89a) R. U. Lemieux, in “Molecular Rearrangements,” P. de Mayo, ed., Interscience, N e w York, Pt. 2, 1964, pp. 723-733.

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

199

sequently, only the main features will be summarized here, with some examples from the literature. a. Pyranoid Rings.-There is a convincing body of evidence (mainly from n.1n.r. spectroscopy) that pyranoid rings truns-fused to 4,6-benzylidene acetal rings exist exclusively in the ‘Cc,(D) conformation.50~90-92 Thus, the favored conformation for methyl 4,6-0benzylidene-a-D-altro-, -manno-, -allo-, and -gluco-pyranosides is as shown in formula 24.

I

OMe 24

For cis-fused benzylidene rings, the pattern is somewhat more complicated. Thus, two possible conformations of 4,6-O-benzylideneD-galactopyranoside derivatives are conceivable, namely, the “0” inside and “H” inside structures.” The n.m.r. evidence, in accordance with Mills’s predictions,” favors the “0”inside structure (25) for the more stable diastereoisomer.50On the basis of the evidence adduced from n.m.r. spectroscopy and optical rotation, Paulsen and FriedmannS3concluded that methyl 4,6-O-benzylidene-a-~-idopyranoside adopts conformation 26. This is of interest, as the 4 C 1 ( ~and ) ‘C4(D) conformations would appear to be equally stable. However, the evidence indicated that the conformation of the P-D-idopyranoside approximates to a skew.93 The conformational problems posed by six-membered, saturated rings fused to a 1,3-dioxolane ring (bicyclo[4.3.0] system) have been reviewed by Horton and coworker^,^^^^^^ and will not be elaborated here. Careful assessment of the data would appear to favor a flattened(89b) P. L. Durette and D. Horton, Adu. Carbohydr. Chem. Biochem., 26, 114-122 (1971). L. Hough and A. C. Richardson, in “Rodd’s Chemistry of Carbon Compounds,” S. Coffey, ed., Elsevier, Amsterdam, 1967, Vol. l F , pp. 87-124. B. Coxon, Tetrahedron, 21,3481-3503 (1965). C . B. Barlow, E. 0. Bishop, P. R. Carey, and R. D. Guthrie, Carbohydr. Res., 9, 99-105 (1969). D. H . Buss, L. Hough, L. D. Hall, and J . F. Manville, Tetrahedron, 21, 69-74 ( 1965). H. Paulsen and M. Friedmann, Chem. Ber., 105, 718-730 (1972).

200

ANTHONY N.

DE

BELDER

Ph

@ %

OMe OMe

%

chair conformation for this type of cyclic acetal, rather than the skew forms postulated earlier. Thus, Horton and Wander,s5with the aid of shift reagents, have educed the conformation 27 for 4,6-dideoxy-1,2O-isopropylidene-a-D-xylo-hexopyranoside. The values of J1,2, 52.3, andJ3,4are all intermediate in magnitude between those expected for

21

gauche (2-3 Hz) and antiparallel (8-9 Hz), vicinal protons. Similar conclusions have been reached by Tronchet and coworkers,94who studied 2,3-O-isopropylidene-a-D-mannoand -talo-pyranosides, and by Dick and coworker^,^^ who studied 1,2-O-a~kylidene-a-~-glucopyranose derivatives. The presence of two cis-fused, five-membered acetal rings would, however, appear to constrain the pyranoid compound into a skew c o n f ~ r m a t i o n . ~ ~ ~ ~ ~ The joint effects of both a 4,6-O-benzylidene and a 1,2-O-benzylidene ring were examined by C o ~ o nAs . ~the ~ coupling constants andJ,,4 of the dibenzylidene derivatives are, in all cases, significantly larger than those of the 1,2-O-alkylidene- and -arylidene-a-D-glucopyranoses, there is evidently less conformational distortion of the diacetal than of the monoacetal. The pyranoid part was assigned a flattened-chair form, and the IJ-dioxane ring, a chair form. (94)J. M. J. Tronchet, F. Barbalat-Rey,and J. M . Chalet, Carbohydr. Res., 30,229-238 ( 1973). (95) C. Cone and L. Hough, Carbohydr. Res., 1 , l - 9 (1965). (96)B. Coxon, Carbohydr. Res., 14,9-15 (1970).

CYCLIC ACETALS OF T H E ALDOSES AND ALDOSIDES

201

b. Furanoid Rings.-For two cis-fused, five-membered rings, the and 1,2conformation of the furanoid part in 1,2-0-i~opropylidene-~~ O-benzylidene12-aldofuranoseswas found to correspond to a twist form, namely, T3, (28), characterized by J l , z = 53,4= -3 Hz and J 2 , 3 = 0.5 Hz. 1,2-O-Isopropy~idene-a-~-xy~ofuranose derivatives were found to have similar conformation^.^^ Data for 1,2-0-ethylidene-~-

28

allofuranosesg9also appear to fit those for a twist conformation. The data from X-ray diffraction studies corroborate these conclusions.loO Twist conformations have been assigned to 2,3-O-isopropylideneD-ribofuranose,” but, strangely, the n.m.r. data for 2,3-O-isopropylidene-L-rhamnofuranose derivatives were not evaluated.lO’ The favored conformations of all eight 1,2:5,6-di-O-isopropylideneD-hexofuranoseshave been evaluated by means of a computer-assisted, n.m.r. technique.loZIt was demonstrated that the furanoid conformation is determined by the joint effects of the 1,2-O-isopropylidene part and the 5,6-“tail” unit. The ribo and Zyxo structures were found to approximate to envelope conformations, whereas the arabino- and xylo-furanoses are less distorted, and approximate to twist conformers. The conformations of 3-chloro-3-deoxy-1,2: 5,6-di-O-isopropylidene-p-~-idofuranosel~~ and 3-deoxy-3,4-C-(dichloromethylene)-1,2 :5,6-di-O-isopropylidene-a-~-ga~actofuranose,~~~ as adduced from X-ray diffraction data, are in accordance with the aforementioned studies. Conformational studies of the 1,2:5,6-di-O-isopropylidene derivatives

(97) R. J. Abraham, L. D. Hall, L. Hough, and K. A. McLauchlan, Chem. I d . (London),213-214 (1962);J . Chem. SOC., 3699-3705 (1962). (98) R. C. Young, P. W. Kent, and R. A. Dwek, Tetruhedron, 26, 3983-3991 (1970). (99) W. E. Dick, Jr., D. Weisleder, and J. E. Hodge, Carbohydr. Res., 42,55-63 (1975). (100) G. A. Jeffrey,Abstr. P a p . Am. Chem. SOC.Meet., 167, C ~ m - 2 4(1974). (101) S. J. Angyal, V. A. Pickles, and R. Ahluwalia, Carbohydr. Res., 3,300-307 (1967). (102) L. D. Hall, S.A. Black, K. N. Slessor,andA. S. Tracey,Can.J. Chem.,50,1912-19% (1972). (103) F. W. B. Einstein and K. N. Slessor, Can. /. Chem., 50, 93-98 (1972). (104) J. S. Brimacombe, P. A. Gent, and T. A. Hamor,]. Chem. SOC.,B , 1566-1571 (1968).

202

ANTHONY N.

BELDER

DE

of a-D-gluco-, a-D-galacto-, and a-D-allo-furanose, made with the aid of 300-MHz, n.m.r. spectroscopy, have been p ~ b 1 i s h e d . l ~ ~ " It must be stressed that any discussion of furanose systems in terms of a single, exclusively populated conformation may be unrealistic. However, even approximate conformational evaluations of these systems can yield chemically significant conclusions .102J05

V. GENERALFEATURES 1. Hydrolysis by Acids Whereas a wealth of data on the hydrolysis of individual cyclic acetals may be found in the literature, there are few, systematic, comparative studies on the kinetics of hydrolysis. The literature up to 1969 was reviewed by Capon.7 The generally accepted mechanism for the hydrolysis of cyclic acetals is the A-1 mechanism, involving the rate-determining heterolysis of a protonated intermediate. At present, it is not known which one of the two possible protonated species, 29 or 30, is preponderant. +

8R" " I

R" R"

I

I

R HO-&H HO-C-H

I

'6 / \

H O-c-H R' 29

O-C-H O-C-H

R

1

'c'

' \

H HO-c--H +

I

R' 30

For the 4,6-O-benzylidenealdopyranosides, the trans-fused derivatives ( d o , altro, gluco, and manno) are hydrolyzed 2-3 times as fast as the cis-fused (galacto, gulo, ido, and t a l ~ ) . ' The ~ ~ ~effects ' ~ ~ of the configurations at C-1, C-2, and C-3 were found to be slight. However, substitution at C-2 and C-3 with methoxyl, acetoxyl, or amino groups was found to lower the rate of hydr01ysis.l~~ The effect of the amino group may be understood in terms of the repulsion of the approaching proton by the protonated amino center. A great deal of scattered data exists on the conditions for the partial hydrolysis of various diacetals. Unfortunately, owing to the wide va(104a) A. de Bruyn, D. Danneels, M. Anteunis, and E. Saman,]. Carhohyrlr. Nzicleos. Nucleot., 2, 227-240 (1975). (105) L. D. Hall, P. R. Steiner, and C . Pedersen, Can. J. Chem., 48, 1155-1165 (1970). (106) B. Capon, W. G. Overend, and M. Sobell, Tetrahedron, 16, 106-112 (1961). (107) J. Kovii and J. J a e , Collect. Czech. Chem. Commun., 32,854-867 (1967).

CYCLIC: ACETALS OF THE ALDOSES A N D ALDOSIDES

203

riety of conditions employed, and the fact that the exact course of hydrolysis has often not been monitored, these data are of only limited value. However, some typical data have been abstracted from the literature, in order to provide a basis for discussion. a. 1,2: 5,6-Diacetals.-It is well known that the 5,6-ring in diacetals of this type is the more readily hydrolyzed. 3-Substituted derivatives may require slightly more-forcing conditions. Some representative examples are tabulated. 1,2 :5,6-Di4l-isopropylidene-

Conditions

References

3-0-inethyl-a-D-gulofuranose 3-0-benzyl-a-D-allofuranose a-L-idofuranose 3-0-acetyl-a-D-allofuranose 3-O-benzyl-a-~-gulofuranose a-D-allofuranose

70% HOAc, 6 h, r.t. 75% HOAc, 20 h, r.t. 70% HOAc, 3 h, r.t. 30% HOAc, 16 h, r.t. 30% HOAc, 13 h, 50-60" 25 mM H,SO,, 40 min, 45"

108 109 110 111 112 113

C01lins"~ found that the configuration of C-3 in 1,2: 5,6-di-O-isopropylidenealdofuranoses has only a slight influence on the rate of hydrolysis of the 5,6-ring.

b. 1,2 :3,9Diacetals.-The favored cleavage of the 3,s-dioxane rings in these acetals is well established, and is independent of whether they are formed from aldehydes or ketones. Some examples are given. 1,2 :3,5-Diacetal

Conditions

Di-0-isopropylidene-a-D-xylofuranose 100 mM oxalic acid, 40 min, 25" Di-0-benzylidene-a-D-xylofuranose 0.3%HCI, 2 days, 0" Di-0-cyclohexylidene-a-D-xylofuranose60% HOAc, 24 h, 25"

References 115 28 116

c. 1,2 :3,4-Diacetals (Pyranose).-The difference in the rates of hydrolysis of the two 1,3-dioxane rings is seldom large. Partial hydrolysis of the 3,4-ring is difficult, and yields of the 1,2-monoacetal are low. The examples illustrate this behavior. (108) J. S. Brimacombe, N. Robinson, and J . M . Webber,J. Chem. SOC.,C, 613-618 ( 1971). (109) J. S. Brimacornbe and 0. A. Ching, Carbohydr. Res., €482-88 (1968). (110) R. Schaffer,NntZ. Bur. Stand. U . S. Techn. Note, 427,60-63 (1967). (111) R. L. Whistler, A. K. M. Anisuzzaman, and J. C. Kim, Carbohydr. Res., 31,237-243 (1973).

204

ANTHONY N.

DE

BELDER References

1,2 :S74-Diacetal

Products

Conditions

Di-O-isopropylidene-6-0-ptolylsulfonyl-a-D-galactose Di-O-isopropylideneP-D-altropyranose

6-0-p-tolylsulfonylD-galactose 1,2- and 3,4-monoacetals; low yield complex mixture

Di-O-isopropylideneP-L-arabinose Di-O-isopropylidenea-D-ribopyranose

arabinose

200 mM H,SO,, 4 h, 80" 80% HOAc, 2 h, 50" 1% HNO,, EtOAc 100 mM oxalic acid, 1.5h, 65" 75 mM H,S04, 3 h, 40"

l,2-acetal

117 68 68

115 17

d. Acetals of G1ycosides.-The amount of hydrolytic data that may be abstracted from the literature is massive, but it is of little value for an analysis of the controlling factors, as the conditions vary so widely. Some typical conditions are tabulated. Acetal Methyl 2,3-O-isopropylidenep-D-allofuranoside Methyl 2,3-O-isopropylidenea-D-1y xopyranoside Methyl 4,6-O-isopropylidenea-D-glucopyranoside Methyl 4,6-O-benzylidenea-D-galactopyranoside, 3-O-benzyl-2-O-niethylMethyl 4,6-O-ethyIideneP-D-gaktopyranoside, 2,3-di-O-methylMethyl 4,6-0-( 1-phenylethy1)a-D-glucopyranoside

Conditions

References

100 mM HCl, 35 min, reflux

118

80% HOAc, 5 min, 100"

119

75% HOAc, 90 min, r.t.

33

M HCI, 5 h, reflux

120

20 mM HCI, 8 h, 80"

121

75% HOAc, 4 days, r.t.

33

(112) H. Kuzuhara, H. Terejama, H. Ohrui, and S. Emoto, Curbohydr. Res., 20,165-169 ( 1971). (113) 0. Theander, Actu Chern. Scand., 18, 2209-2216 (1964). (114) P. M. Collins, Tetrahedron, 21, 1809-1815 (1965). (115) R. S. Tipson, B. F. West, and R. F. Brady, Jr., Curhohydr. Res., 10, 181-183 (1969). (116) S. von Schuching and C. H. Frye,]. Org. Chem., 30, 1288-1291 (1965). (117) D. L. Mitchell, C u n . J . Chem., 41, 1837-1841 (1963). (118) J. M. Williams, Carbohydr. Res., 13, 281-287 (1970). (119) N. A. Hughes and P. R. H. Speakman,/. Chem. Soc., C, 1182-1185 (1967). (120) P. P. Singh and G. A. Adams, Curbohydr. Res., 13,229-234 (1970). (121) D. H. Ball,J. Org. Chem., 31,220-223 (1966).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

205

The data for the 4,6-acetals would imply the following order of stability: l-phenylethylidene > benzylidene > ethylidene > isopropylidene. It is, however, patently obvious that there remains considerable scope for kinetic studies of suitably chosen derivatives. A methodlZ2for hydrolyzing benzylidene and isopropylidene acetals by means of 90% trifluoroacetic acid is recommended. The procedure is mild and rapid, and does not affect esters, halogens, sulfonates, or azides. e. Acetal Migration.-Normally, acetal migration in connection with partial hydrolysis with acid is not a serious problem. In organic solvents, some caution must be observed. It has been reported that, when treated with an acid catalyst in N,Ndimethylfornxmide for 7 days, 2,4-O-benzylidene-D-erythrose gave 2,3-0-ben~yliderie-D-erythrose.'~~ The 3-hydroxyl group in the former is well disposed for nucleophilic attack on the benzylic carbon atom, to give the cis-fused, 1,3-dioxolane ring. Similarly, B a l l ~ u found '~~ that 2,4-O-ethylidene-D-erythrose in methanolic hydrogen chloride affords methyl 2,3-O-ethylidene-P-~-erythrofuranoside. Treatment of 1,2 : 5,6-di-O-isopropylidene-a-~-allofuranose with methanolic hydrogen chloride for 20 hours affords the methyl 2,3-0isopropylidene- and 2,3 : 5,6-di-O-isopropylidene-/3-~-allofuranosides;"* again, migration to a favorably disposed hydroxyl group occurs. Evans62 reported the rearrangement of methyl 4,6-0-isopropylidene-a-D-altropyranoside to the 3,4-acetal in acetone-sulfuric acid . One instance of a rearrangement in aqueous solution has been reported; 1,6-anhydro-3,4-0-isopropylidene-/3-~-ta~opyranose gave the 2,3-O-isopropylidene derivative by an intramolecular mechanism.125

2. Action of Various Reagents

The examples provided in this Section are in no way intended to afford a comprehensive and complete treatment of the subject. They serve only to illustrate some of the typical reactions of acetals. a. Hydrogeno1ysis.-The reductive cleavage of cyclic acetals by the lithium aluminum hydride-aluminum chloride reagent has been the (122) J. E. Christensen and L. Goodman, Carbohydr. Res., 7, 510-512 (1968). (123) N. Baggett, K. W. Buck, A. B. Foster, B. H. Ness, and J. M. Webber,]. Chem. Soc., C, 212-215 (1966). (124) C. E. Ballou,]. Am. Chem. Soc., 82,2585 (1960). (125) N. A. Hughes, Carhohydr. Res., 7,474-479 (1968).

206

ANTHONY N. DE BELDER

subject of extensive studies by Bhattacharjee and GorinlZ6and Liptak and coworkers.127Thus, 4,6-benzylidene acetals give 4- or 6-benzyl ethers, and 4,6-methylene acetals give 4- or 6-methyl ethers. 5,6Cyclohexylidene and -isopropylidene acetals were found to give mainly 6-0-cyclohexyl and -isopropyl derivatives, respectively. 1,2Acetals are mostly resistant to cleavage. This technique has been used to synthesize methyl ethers of various amino ~ u g a r s . ~ ~ ~ , ' ~ ~

b. N-Bromosuccinimide.-This reagent has attained considerable popularity, as it readily converts 4,6-benzylidene acetals into 4-0benzoyl-6-bromo-6-deoxy derivatives. 130~131Many applications for preparing deoxy, azido, and amino sugars have a p ~ e a r e d . l ~ ~ - ' ~ ~ c. Methano1ysis.-This procedure may provide a convenient method of preparing glycoside derivatives from the appropriate acetals. Singh and AdamslZ0prepared methyl 6-0-benzyl-a-D-galactopyranoside from 6-0-benzyl-1,2 :3,4-di-O-isopropy]idene-a-~-galactose by treatment with boiling 3% methanolic hydrogen chloride under reflux. The methanolysis of 1,2 : 5,6-di-O-isopropylidene-aD-aIlofuranose has been mentioned earlier (see Section V,l,e).

d. Aceto1ysis.-Acetolysis of cyclic acetals was noted by S ~ w a ' ~ ~ to effect cleavage of 1,2- and 2,3-acetals with inversion at C-2. Thus, ribose acetals may be converted into a mixture of ribose and arabinose,l35.l36 mannose into mannose and glucose,136alIose into allose and a l t r ~ s e , 'and ~ ~ lyxose into lyxose and xy10se.l~~ The starting materials are generally the 1,2- or 2,3-0-isopropylidene-furanose derivatives.

(126) S. S. Bhattacharjee and P. A. J. Gorin, Can. J. Chem., 47,1185-1206, 1207-1215 ( 1969). (127) A. LiptAk, I. Jodal, and P. Nanasi, Carbohydr. Res., 44, 1-11 (1975). (128) P. A. J. Gorin and A. J. Finlayson, Carbohydr. Res., 18,269-279 (1971). (129) P. A. J. Gorin, Carbohydr. Res., 18,281-288 (1971). (130) S. Hanessian, Carbohydr. Res., 2,86-88 (1966). (131) S. Hanessian and N. R. Plessas, J. Org. Chem., 34, 1035-1044, 1045-1053, 1054-1058 (1969). (132) D. Horton and A. E. Luetzow, Carbohydr. Res., 7, 101-105 (1965). (133) G. B. Howarth, W. A. Szarek, and J. K. N. Jones, Carbohydr. Res., 7, 2&1-290 ( 1968). (134) S. Svensson, Acta Chem. Scand., 22,2737-2738 (1968). (135) W. Sowa, Can. J . Chem., 49,3292-3298 (1971). (136) G. J. F. Chittenden, Carbohydr. Res., 22,491-493 (1972). (137) W. Sowa, Can. J . Chem., 50, 1092-1094 (1972).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

207

e. 0zonolysis.-Deslongchamps and coworkers138found that the ozonolysis of 4,6-benzylidene acetals affords mixtures of the 4- and 6-benzoates. f. Trityl F1uoroborate.-This reagent (Ph3C+BF4-) also cleaves 4,60-benzylidene acetals, giving mixed benzoic esters.'39 g. Photo1ysis.-Cleavage of benzylidene acetals to give mixed benzoic esters,140 and loss of 5,6- and 3,5-isopropylidene acetal on photolysis have been reported. The low yield of aldosulose derivative on irradiation of 3-azido-3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose may be due, in part, to loss of the 5,6ring.'42The photolysis of o-nitrobenzylidene acetals has been explored by Collins and O p a r a e ~ h e ' it ~ ~provides ; a useful method for preparing partially protected, aldopyranose derivatives.

h. Oxidation.-Cyclic acetals withstand a wide variety of oxidants currently employed for the introduction of carbonyl groups, for example, ruthenium(1V) t e t r a ~ x i d e , 'chromium ~~ trioxide-dipyridine complex,145dimethyl sulfoxide and an activating e l e ~ t r o p h i l e , 'di~~ methyl sulfoxide-phosphorus p e n t a ~ x i d e ,and ' ~ ~ catalytic oxidation. 14'

3. Applications Limitations of space permit only a brief mention of some of the numerous applications of cyclic acetals that have appeared. Several research groups have used cyclic acetals for studying the selectivity of acylating agents, for example, benzoyl chloride-pyri-

(138) P. Deslongchamps, C. Moreau, D. Frehi.1, and R. C h h e v e r t , Can. j . Chem., 53, 1204-1211 (1975). (139) S. Hanessian and A. P. A. Staub, Tetrahedron Lett., 3551-3554 (1973). (140) K. Matsuura, S. Maeda, Y. Araki, and Y. Ishido, Bull. Chem. Soc. j p n . , 44, 292 (1971). (141) I. V. Balanina, G. M. Zarubinskii, and S. Danilov, Zh. Obschch. Khim., 42, 1876 (1972). (142) D. M. Clode and D. Horton, Carbohydr. Res., 14,405-408 (1970). (143) P. M. Colliris and N. N. Oparaeche,]. Chem. Soc. Perkin Trans. 1 , 1695-1700 (1975). (144) B. T. Lawton, W. A. Szarek, and J. K. N. Jones, Carbohydr. Res., 10, 456458 (1969). (145) R. E. Arrick, D. C. Baker, and D. Horton, Carbohydr. Res., 26,441-447 (1973). (146) D. J. Ward, W. A. Szarek, and J. K. N. Jones, Carbohydr. Res., 21,305-308 (1972). (147) K. Onodera, S. Ilirano, and N . Kashimura, Carbohydr. Res., 6 , 276-285 (1968). (148) B. Lindberg, I.-L. Svensson, 0. Theander, J. S. Brimacombe, and M. C. Cook, Acta Chem. S c a d , 17, 930-932 (1963).

208

ANTHONY N. DE BELDER

dine,149J50 benzoyl chloride-triethylamine,l49 N-benzoylimidazo1e,149J51benzoyl ~yanide,'5~ acetic anhydride-pyridine,152-'54Ptoluenesulfonyl ~ h l o r i d e - p y r i d i n e , ~ and ~ ~ of alkylating agents, for example, 2-(diethylamino)ethyl chloride,15G ally1 and diazomethane.157Lehrfeld158stressed the need for caution in interpreting the relative reactivities from the product distribution, and he analyzed the reactions in terms of the component rate-constants. Cyclic acetals do not necessarily constitute good models for the unsubstituted aldoses. The preparation and properties of trans-cyclic carbonates have been studied by using acetal groups as protecting group^.'^^,'^^ Further examples may be found in studies of epoxy substituents,16' xanthaand halogen s u b s t i t ~ t i o n . ' ~ ~ A number of studies on the polymerization of acetal derivatives of sugars by means of Lewis catalyst^,'^^^'^^ or 6-0-alkene derivatives,lG8 have been published. Innumerable studies testify to the importance of cyclic acetals as

(149) H. Honig and H. Weidmann, Carbohydr. Res., 39,374-378 (1975). (150) G. N . Bollenback and F. W. Pamsh, Carbohydr. Res., 17,431-438 (1971). (151) S. A. Abbas and A. H. Haines, Carbohydr. Res., 39,358-363 (1975). (152) H. B. Boriin, P. J. Garegg, L. Kenne, L. Maron, and S. Svensson, Acta Chem. S c a d . , 26,644-652 (1972). (153) P. J. Garegg, Ark. Kemi., 23,255-268 (1965). (154) D. Horton and J. H. Lauterbach,J. Org. Chem., 34,86-92 (1969). (155) S. E . Creasey and R. D. Guthrie, Carbohydr. Res., 22,487-490 (1972). (156) E. J. Roberts and S. P. Rowland, Carbohydr. Res., 4, 509-511 (1967); 5, 1-12 (1967). (157) G . J. F. Chittenden, Carbohydr. Res., 43, 366-367 (1975). (158) J. Lehrfeld, Carbohydr. Res., 39,364-367 (1975). (159) W. M . Doane, B. S. Shasha, E. 1. Stout, C.R. Russell, and C . E. Rist, Carbohydr. Res., 8,266-274 (1968); 11,321-329 (1969). (160) H. Komura, T. Yoshino, and Y. Ishido, Carbohydr. Res., 40,391-395 (1975). (161) R. E. Wing, W. M. Doane, and C. E. Rist, Carbohydr. Res., 12,285-289 (1970). (162) B. S. Shasha, W. M. Doane, C. R. Russell, and C. E. Rist, Carbohydr. Res., 13, 4 5 7 4 6 0 (1970). (163) B. S. Shasha, W. M. Doane, and C . R. Russell, Carbohydr. Res., 24, 202-206 ( 1972). (164) S. Forsbn, P. J. Garegg, B. Lindberg, and E. Pettersson,Acta Chem. S c a d , 20, 2763-2770 (1966). (165) N. K. Kochetkov and A. I. Usov, Methods Carbohydr. Chem., 6,205-207 (1972). (166) R. L. Whistler and P. A. Seib,]. Polym. Sci. Part A-1, 4, 1261-1275 (1966). (167) R. L. Whistler, G. Ruffini, and R. E . Pyle, J. Polym. Sci. Part A-1, 6, 2501-2510 (1968). (168) W. A. P. Black, J. A. Colquhoun, and E. T. Dewar, Makromol. Chei~z.,122,244260 (1969).

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

209

starting materials for the preparation of branched-chain sugars, nuc l e o ~ i d e s , ' ~and ~ - amino ~ ~ ~ sugar^.'^^,'^^ Benzylidene acetals have been used in studying the action of butyllithium40 to give 2-deoxy-3-ketones, and in examining certain basecatalyzed e1iminati0ns.l~~ It is of interest that a number of studies on cyclic acetals of disaccharides have a ~ p e a r e d . ' ~ ~ . 1 7 ~ ~ Morgenlie described the use of 0-isopropylidene derivatives for the quantitative and qualitative analysis of common aldoses by g.1.c.m.s VI. TABLESOF PROPERTIES OF CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES These Tables are intended as a supplement to those that appeared in Volume 20 of this Series. Similar limitations have been applied. Where they have been established, diastereoisomers are indicated by (D),and a diastereoisomeric mixture by (DM). For the exact stereochemistry of the diastereoisomer, the reader is referred to the literature. Details of n.m.r. and mass spectra are indicated by the letters N and M, respectively, after the reference. Key to rotation solvents: A, acetone; B, benzene, Chf, chloroform; CC1, carbon tetrachloride; CH, cyclohexane; D, N,N-dimethylformamide; DC, dichloromethane; Me2S0,dimethyl sulfoxide; Et,O, ether; EtOH, ethanol; EtOAc, ethyl acetate; Py, pyridine; TCE, 1,1,2,2-tetrachloroethane;and W, water.

(169) J. M . Tronchet and B. Gentile, Carbohydr. Res., 44,23-35 (1975). (170) R. F. Nutt, M. J . Dickinson, F. W. Holly, and E. Walter,]. Org. Chem., 33,17891795 (1968). (171) J. G. Buchanan, A. D . Dunn, and A. R. Edgar, Carbohydr. Res., 36, C5-C7 (1974). (172) J. S. Burton, W. G. Overend, and N. R. Williams,]. Chem. Soc., 3433-3445 ( 1965). (173) A. J. Brink and A. Jordaan, Carbohydr. Res., 34, 1-13 (1974). (174) D. C. Baker, D. K. Brown, D. Horton, and R. G. Nickol, Carbohydr. Res., 32,299319 (1974). (175) S. Hanessian and N. R. Plessas, Chem. Commun., 106 (1968). (176) R. Khan, Carbohydr. Res., 32,375-379 (1974). (177a)R. Khan and K. S. Mufti, Carbohydr. Res., 43,247-253 (1975). (177b)S. Morgenlie, Carbohydr. Res., 41,285-289 (1975).

ANTHONY N.

2 10

DE

BELDER

TABLEI Derivatives of D- and L-Erythrose ~~

Compound

M.p. (degrees)

14”

Rotation solvent

(degrees)

D-Erythrose 2,4-O-benzylidene-20 dimer 145- 146.5 pheny lhydrazone +13.4 + +10.5 99- 100 2,4-O-butylidene2,4-O-ethylidene149-150 -40 dimer I dimer 11 110-1 11 - 14 phen ylh ydrazone 127 +54.7 -+ +37.6 2-methyl-2-phenylhydrazone 152-153 +43.5 -45.8 3-0-benzyl(2,4-dinitrophenyl)hydrazone 167-168 D-Erythrofuranose 2,3-O-benzylidene-P-62 2,3-O-ethylidene-p66-67 -68 1-0-acetyl58 - 135 1-0-benzoyl96-97 -85 L- Erythrofuranose 2,3-0-isopropylidene(67-74°/0.45)a +83.2 1-0-benzoyl+ 104 108-108.5

D Chf

Chf Chf

EtOH W

B B EtOAc Chf

References

178 178 179 180 180 180N 181 181,182 182 178 183N 183 183 l84N 184n

B.p. (Wtorr).

TABLEI1 Derivatives of D- and L-Threose

Compound

D-Threose 2,4-O-ethylidene-, dimer L-Threofuranose 1,2-O-isopropylidene-P-

M.p. (degrees)

ralD (degrees)

Rotation solvent

References

163-165

-5.2

Chf

121

79-8 1

+14.1

Chf

185

(178) N. Baggett, K. W. Buck, A. B. Foster, B. H. Rees, and J. M. Webher,]. Chem. Soc., C, 212-215 (1966). (179) T. G. Bonner, E. J. Bourne, and D. Lewis,]. Chem. Soc., 7453-7458 (1965). (180) I. Ziderman and E. Dimant,]. Org. Chem., 31,223-226 (1966). (181) A. Kampf, A. Felsenstein, and E. Dimant, Carbohydr. Res., 6, 220-228 (1968). (182) J. W. Van Cleve and C. E. Rist, Carbohydr. Res., 4,91-95 (1967). (183) J. W. Van Cleve and C. E. Rist, Carbohydr. Res., 4,82-90 (1967). (184) M. Lerner, Carbohydr. Res., 9, 1-4 (1969). (185) A. D. Ezekiel, W. G. Overend, and N. R. Williams, Carbohydr. Res., 20,252-257 (1971).

TABLEI11 Derivatives of D- and L-Arabinose ~

M.p. (degrees)

Compound

D-Arabinofuranose 1,2-O-benzylidene-p3,5-di-O-methylD- Arabinopyranose 3,4-0-isopropylidene-P1,2-di-O-acetyl-(a) 2-0-methylDArabinopyranoside Benzyl 3,4-0-benzylidene-a- (D)

(D)

(degrees)

Rotation solvent

+7

EtOH

[a]"

-

82-84 118-119 115-117

-156+

-111 (24 h) -49 -

148-149 116-117

+ 10

-

-

83 96

-6 -34.7

+8

w Chf

~~

References

47 43MN 43MN 186

Chf Chf

187N 187N

Chf Chf

188 189 189

L- Arabinofuranose

1,2-O-isopropylidene-P3,5-di-O-benzoyl5-0-benzoyl-3-O-p-tol ylsulfonyl3,5-di-O-p-tolylsulfonylL-Arabinopyranoside Benzyl 3,4-O-isopropylidene-P2-0-benzoylMethyl 3,4-O-(o-nitrobenzylidene)-p2-0-acetyl- (D) Methyl 3,4-O-benzylidene-p2-0-benzoyl- (D)

54-56 110.5-112

+220 +212

2 a

190 190

192-193 116- 118

+66 + 18

Chf Chf

78N 78N

119-120 126-127

+ 174

+224

Chf Chf

76N 76N

4

z

M

!2 w

TABLEIV Derivatives of

Compound

D-Lyxofuranose 2,3-O-isopropylidene-a1,5-di-O-acetyl1,5-di-O-benzoyl5-O-(methylsulfonyl)D-Lyxofuranoside Benzyl 2,3-O-isopropyliclene-a5-O-(inethylsulfonyl)Ethyl 2,3-O-isopropylidene-a4-O-meth yl4-0-p-tolylsulfonylMethyl 2,3-0-isopropylidene-a4-0-methylD-Lyxopyranoside Methyl 2,3-O-isopropyliclene-a4-O-meth yl4-0-p-tolylsulfonylL-Lyxofuranose 1,2-O-isopropylidene-P3-0-henzyl5-O-p-tolylsulfon ylL-Lyxopyranoside Methyl 2,3-0-isopropylitlene-a4-0-~,-tolylsi1lfonyl-

M.p. (degrees)

D-

and L-Lyxose

B.p. ( Wtorr)

8 1.5-82.5 49.5-50.5 93.5-94.5

[ 4 D

(degrees)

+21.4 + i 1 8 . 5 +62.5 + 17 + 14

+ 99

87-87.5 78-79

+68

100(bath)/0.001 95(bath)/0.001 79-80

Rotation solvent

w Chf Chf Chf

191 191 191 63

A

63 63 192 192 192

A A

-

-

+1

References

6510.5

+60

Chf

193

6510.5

+42.7 +60 - 10.2

EtOH Chf EtOH

194 193 194

109-111 61-62 64-65

-20.5 +48.6 -24.4

Me2S0 Chf Chf

112 112 195

51.5-52.5 104.5- 105

-47 + 11.5

EtOH Chf

196 196

40-4 1 96-97

!2 0

5

? ~

M W M

5M P

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

213

(186) L. Hough and A. C. Richardson,]. Chern. Soc., 5561-5563 (1961). (187) P. J. Garegg, L. Maron, and C.-G. Swahn, Actu Chem. Scund., 26, 518-522 (1972). (188) E. M. Acton, K. J. Ryan, and L. Goodwin, ]. A m . Clzem. Soc., 86, 5352-5354 (1964). (189) N. A. Hughes and P. R. H. Speakinan, Carbohydr. Res., 1,341-347 (1966). (190) T. Sivakumaran and J. K. N. Jones, Can. J . Chem., 45,2493-2500 (1967). (191) R. Schaffer,]. Res. N u t / . Bur. Stand., Sect. A, 65, 507-517 (1961). (192) J. Piotrovsky, J. P. Verheijden, and P. J. Stoffyn, Bull. SOC. Chim. Belg., 73, 969975 (1964). N. A: Hughes and P. R. H . Speakman,]. Chem. Soc., C, 1182-1185 (1967). P. W. Kent and P. F. V. Ward,]. Chem. SOC., 416-418 (1953). J. Defaye, D. Horton, and M. Muesser, Carbohydr. Res., 20, 305-318 (1971). E. J . Reist, D. E. Gueffroy, and L. Goodman,J. A m . Chem. Soc., 86, 5658-5663 (1964). K. Onodera, N. Kashimura, and N. ibfiyazaki, Carbohydr. Res., 21, 159-165 (1972). K. Oda and H. Wada, Yakugaku Zasshi, 83,890-891 (1963). J. S. Brimacombe and 0. A. Ching, Carbohydr. Res., 8,374-376 (1968). M. Haga, M. Takano, and S. Tejima, Carbohydr. Res., 21,440-446 (1972). W. Sowa, Can. J. Chem., 46,1586-1589 (1968). J. S. Brimacombe and 0. A. Ching, ]. Claem. SOC.,C , 964-967 (1969). N. J. Leonard and K. L. Carraway, ]. Heterocycl. Chem., 3,485-489 (1966). J. J. Rabelo and T. van Es, Carbohydr. Res., 30,381-385 (1973). S. Hanessian, M. M. Ponpipom, and P. Lavallhe, Carbohydr. Res., 24, 45-56 (1972). P. A. Levene and E. T. Stiller,]. Biol. Chern., 106,421-429 (1934). K. Heyns and 1. Lenz, Chem. Ber., 94,348-352 (1961). 13. Paulsen, K. 'Todt, and K. Heyns, Ann., 679, 168-177 (1964). (209) V. 1. Veksler, Zh. Obshch. Khim., 38, 1649-1653 (1968). (210) H. Kuzuhara and S. Emoto, Agric. B i d . Chem., 28, 900-907 (1964). (211) T. Takamoto, R. Sudoh, and T. Nakagawa, Carbohydr. Res., 27, 135-140 (1973). (211a) P. Kovai. and M. PetrikovL, Carbohydr. Res., 19,249-251 (1971). (212) J . G. Buchanan and E. M. Oakes, Carbohydr. Res., 1,242-253 (1965). (213) €I. S. El Khadern, T. D. Audichya, and M . J. Withee, Carbohydr. Res., 33, 329337 (1974). (214) E. D. M. Eades, D. H. Ball, and L. Long, Jr., ]. Org. Chern., 31, 1159-1162 (1966). (215) K. James, A. R. Tatchell, and P. K. Ray,J. Chem. Soc., C , 2681-2686 (1967). (216) D. Horton and C. G. Tindall, Jr., Carbohydr. Res., 15,215-232 (1970). (217) 0 . Theander, Acta Chem. Scund., 17, 1751-1760 (1963). (218) M. Ishidate, Z. Tamura, and T. Kinoshita, Chem. Pharm. Bull., 10, 1258-1259 (1962). (219) T. Naka, T. Hashizume, and M . Nishimura, Tetrahedron Lett., 95-98 (1971). (220) J. S. Brimacombe, A. M. Mofti, and L. C. N. TuckerJ. Chem. Soc., C, 2911-2915 (1971). (221) J. M. Heap and L. N. Owen,J. Chem. SOC.,C, 707-712 (1970). (222) J. S. Brimacombe and A. M. Mofti, Carbohydr. Res., 18, 157-164 (1971). (223) C. Puente and A. Orlando, Bol. SOC. Quirn.Peru, 36, 13-22 (1970);Chem. Abstr., 73, 110,017 (1970). (224) H. Paulsen and D. Stoye, Chem. Ber., 102,820-833 (1969).

TABLEV Derivatives of D- and L-Ribose

Compound

M.p.

B.p.

(degrees)

(.C/torr)

(degrees)

Rotation solvent

+36.4 -26.6 - 14 -27.8 -68.8 +40

Chf MeOH MeOH MeOH Chf MeOH

References

~

cu-D-Ri bofuranose

1,2-O-benzylidene2,3-0-benzylidene-(P) (DM)

(D) (D) 1,5-di-O-acetyl2,3-0-cyclohexylidene1,2-0-isopropylidene5-0-benzoyl3-0-p-tolylsulfonyl5-0-benzyl3-0-methyl5-0-benzoyl50-p-tolylsulfonyl5-0g-tolylsulfon ylFj-0-trityl3.5-di-0-acetvl3.5-di-0-v-tolvlsulfonvl1,5:2,3-di-O-isopropylidene-( p)

. ,

92-93 120-121 107-108 125-126 78-79 172-174 85 78-79 119 80-8 1 74-76 74-76 108-109 104-107 117

-

123-124 73-74

-

+20.5 96 +42 + 100 +75.2 +60 +26.3 +25.8 + 120.5 -42.5

+

Chf Chf Chf Chf Chf Chf Chf Chf Chf

18N 18N 18N 18N 18N 197 198 198 189 199 200N 200N 200N 147,195 201N 136 199 43MN

P-D-Ribofuranoside Benzyl 2,3-O-isopropylidene5-0-benzylMethyl 2,3-O-isopropylidene5-chloro-5-cleoxy5-O-p-tol ylsulfonylMethyl 2,3-O-methylene5-0-benzoylDRibopyranose 1,2-O-isopropyliderie-a3,4-O-isopropylidene-/31,2 :3,4-di-O-isopropylidene-aP-L-Ribofuranoside Methyl 2,3-0-isopropylidene5-O-p-tolylsulfo11yl-

-75

-82.2 -93 -35.5

Chf Chf Chf EtOH

83.5-84.5

-55.6

Chf

58N

112-114 119- 120 68-69

-26 -85jequil.) -51

W W Chf

17 24 17

-

156-1 62(hath)/0.01 7510.3

75-80/0.05 83-84

i- 74

+38

Chf EtOH

199,202N 203N,204N 205N 204206

z mn 4

63N 63N

U

TABLEVI Derivatives of

Compound a-D-Xylofuranose 1,2:3,s-di-0-benzylidene- (D)

(D) 1,2-O-cyclohexylidene5-04methylsulfony1)5-0-p-tolylsulfonyl1,2-O-isopropylidene3-0-acetyl-5-O-(methylsulfonyl)3-0-benzyl 5-0-benzyl3-0-methyl5-0-trityl3,5-di-O-benzoyl3,s-di-0-benzylp-D-X ylofuranoside Methyl 3,5-O-isopropylidene2-0-methyla-D-Xylofuranoside Methyl 3,5-O-isopropylidene2-0-(methylsulfony1)a-D-Xylopyranoside Methyl 2,3-O-cyclohexylidene4-O-p-tol ylsulfonylMethyl 3,4-O-cyclohexylidene2-O-p-tol ylsulfonyla-L-X ylofuranose 1,2-O-cyclohexylidene5-O-p-tolylsulfonyl1,2 :3,s-di-0-cyclohexylidene-

D-

and L-Xylose

M.p.

B.p.

r 4 D

(degrees)

(OC/torr)

(degrees)

Rotation solvent

E m References

155-156 132-133 91-92 159-162.5 123.5-125

+27 +25 - 12.4 - 13 - 10

w

MeOH Chf

28N 28N 207 208N 209

105-106 63-65

-9.5 -29 - 18.6 -45.4 + 13.3 -50 -51

MeOH Chf MeOH EtOH Chf Chf Chf

98N 98N 210 211a 201N 189 211N

- 65

Chf

139-140/0.01 121 18310.03

69-7010.07

86-87

117.5-118

83-84 124 103-104

+ 103.8

+84 + 79 +0.41 -2.88

Chf Chf

MeOH

204

213N,214

A

38N

B

38N

A

116 116 116

A

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

217

(225) A. B. Foster, R. Hems, and J. M. Webber, Carbohydr. Res., 5,292-301 (1967). (226) B. D. Kohn, P. Kohn, and A. Dubin, Carbohydr. Res., 18,349-355 (1971). (227) B. R. Baker and D. H. Buss,]. Org. Chem., 30,2304-2308 (1965). (228) P. M. Collins and B. R. Whitton, Carbohydr. Res., 33, 25-33 (1974). (229) Y. Kondo, Carbohydr. Res., 30,386-389 (1973). (230) H. Paulsen and D. Stoye, Chem. Ber., 102,834-847 (1969). (231)A. 0. Ching Puente, Bol. Soc. Quim. Peru, 36,45-59 (1970); Chem. Abstr., 74, 64,368 (1971). (232) J. S. Brimacombe, F. Hunedy, and A. Husain,]. Chem. Soc., C, 1273-1277 (1970). (233) F. H. Newth and L. F. Wiggins,]. Chem. Soc., 1734-1737 (1950). (234) N. L. Holder and B. Fraser-Reid, Synthesis, 83 (1972). (235) A. M. Spichtig and A. Vasella, Helv. Chim. Acta, 54, 1191-1194 (1971). (236) A. Zobi6ovj. and J. JarL, Collect. Czech. Chem. Commun., 31, 1848-1853 (1966). (237) D. H. Buss, L. D. Hall, and L. Hough,]. Chem. Soc., 1616-1619 (1965). (238) M. E. Evans and F. W. Parrish, Carbohydr. Res., 28,359-364 (1973). (239) R. C. Chalk, D. H. Ball, and L. Long, Jr., Carbohydr. Res., 20, 151-164 (1971). (240) R. C. Chalk, D. H. Ball, M. A. Lintner, and L. Long, Jr., Chem. Commun., 245-246 (1970). (241) J. Kovii, Can. J. Chem., 48, 2383-2385 (1970). (242) M. Miljkovii:, A. Jokii:, and E. A. Davidson, Carbohydr. Res., 17,155-164 (1971). (243) R. L. Whistler and R. E. Gramera,]. Org. Chem., 29, 2609-2610 (1964). (244) L. Vargha, Chem. Ber., 87, 1351-1356 (1954). (245) M. A. Miljkovii: and E . A. Davidson, Carbohydr. Res., 13,444-446 (1970). (246) J. S. Brimacombe, P. A. Gent, and J. H. Westwood, Carbohydr. Res., 12,475476 (1970). (246a) N. Baggett, P. J. Stoffyn, and R. W. Jeanloz, ]. Org. Chem., 28, 1041-1044 ( 1963). (247) A. ZobiEovi, V. Heimankovi, and J. J a 6 , Collect. Czech. Chem. Commun., 36, 1860-1866 (1968). (248) P. A. Levene and J. Compton,]. Biol. Chem., 116, 189-202 (1936). (249) C. L. Brewer, S. David, and A. Veyrikres, Carbohydr. Res., 36, 188-190 (1974). (250) J. S. Brimacombe, I. Da’aboul, and L. C. N. Tucker,]. Chem. Soc., C, 3762-3765 (1971). (251) J. S. Brimacombe and A. J. Rollins, Carbohydr. Res., 36, 205-206 (1974). (252) H. Paulsen and H. Behre, Carbohydr. Res., 2,80-81 (1966). (253) J. S. Brimacombe, P. A. Gent, and M. Stacey,]. Chem. Soc., C, 567-569 (1968). (253a) R. U. Lemieux and R. V. Stick,Aust. ]. Chem., 28, 1799-1801 (1975). (254) L. V. Volkova, M. G. Luchinskaya, N. A. Sarnoilova, and N. A. Preobrazhenski, Zh. Obshch. Khim., 41,446449 (1971); Chem. Abstr., 75,49,459 (1971). (255) C. E. Ballou and H. 0. L. Fischer,J. A m . Chem. Soc., 76, 3188-3193 (1954); C. E. Ballou, Biochem. Prep., 5, 66 (1957). (256) W. A. P. Black, J. A. Colquhoun, and E. T. Dewar, Carbohydr. Res., 5, 362-365 ( 1 967). (257) R. Gigg and C. D. Warren,J. Chem. Soc., 2205-2210 (1965). (258) K. A. Petrov, E. E . Nifant’ev, A. A. Shchegolev, and V. G. Terekhov,]. Gen. Chem. USSR, 34, 1459-1462 (1964); Chem. Abstr., 61,5,738 (1964). (259) R. L. Whistler, H. P. Panzer, and J. L. Goatley, J. Org. Chem., 27, 2961-2962 ( 1962). (260) S. Nadkami and N. R. Williams,]. Chern. Soc., C, 3496-3498 (1965). (261) J . Gigg and R. Gigg,J. Chem. Soc., C, 82-86 (1966).

TABLEVII Derivatives of D- and L-Allose

Compound

a-D-Allofuranose 1,2-O-cyclohexylidene5,6-di-O-acetyl-3-0-benzyl1,2 : 5,6-di-O-cyclohexylidene3-0-benzyl1,2-0-ethylidene5,6-di-0-acetyl-3-0-benzyl- (DM) 1,2: 5,6-di-O-ethylidene3-0-benzyl- (D) (D) 2,3: 5,6-di-O-ethyIidene- (D) (D) 1,2-0-isopropylidene3-0-acetyl3-0-benzoyl5,6-di-O-(methylsulfonyl)3-0-benzyl5,6-di-0-(methylsu1fonyl)3-0-methyl6-0-benzoyl-5-0-p-tolylsulfonyl3-Op-tolylsulfon yl5,6-di-O-acrtyl5,6-di-O-acetyl3,6-di-O-p-tolylsulfonyI3,5,6-tri-O-acetyl3,5,6-tri-O-henzoyl3-0-methyl-5,6-di-0-(methylsulfony1)3,5,6-tri-0-(methylsulfonyl)-

M.p. (degrees)

111-1 12 123-125.5 -

82.5-83.5 68-7 1 27-29 132-132.5 133-134 107-109 102-104

-

107- 108 119-120 121-122 150-151 91 66.5-67 120-121 79-8 1 116-1 18 102-103

[(YILl

(degrees)

+46.1

+ 115.5"

+ 12.4 + 108"

E m Rotation solvent

EtOH EtOH Chf Chf

+117"

Chf

+ 132.6" + 147.3"

Chf Chf Chf Chf W Chf Chf Chf W Chf Chf Chf D Chf Chf EtOH Chf Chf Chf C

-38.8" -26.7" +44 +294 +117 + 102 + 104 +78 + 103 +66 +95 +89 +98 +67 +111.1 + 107.9 +72 +69.5

References

178,197N 99N 197N,215N 215N 99N 99N 99N 15MN 15MN 216N,217,218

Ill 219 219 109216N 109,223 220N 220N 221N222N 221N 216N 221N222N 200N 200N 220N 224N

i2

2 .1

2 0

g r

g

1,2 :5,6-di-O-isopropylidene3-0-acetyl3-0-benzoyl3-O-benz yl3-0-methyl3-0-p-tolylsulfonyl2,3 : 5,6-di-O-isopropylideneI-O-acetylI-0-benzoylP-D-Allofuranoside Methyl 2,3-O-isopropylidene5,6-di-O-p-tolylsuIfonyl5,6-O-isopropylidenea-D-Allopyranose 1,2-O-ethylidene4,6-di-O-acetyl-3-O-benzyl- (D) 3,4,6-tri-O-acetyl-(D) P-D-Allopyranose 4,6-O-ethylidene3-0-benzyl1,21,2-di-O-acetyl-3-0-benzyl:4,6-di-O-ethylidene3-0-benzyl- (DM) a-D-Allopyranoside Methyl 4,6-O-benzylidenedih ydrate

2-O-benzo yl2,3-di-O-(methylsulfonyl)2,3-di-O-methyl-

74-75 76 75-76 66.0-66.5 (105/0.3)" 120-121 66-67 65-67 51-51.5 109-1 10

+37.8 +64.2 +116 + 106 +86 +87 -27.4 -1 -46.2 -38.5

Chf Chf A

Chf C Chf

w Chf Chf

13MN,60d 13,102N 111 13219 216,224N 200N220N 225 13MN226 14 13 13

-43

W

118

104-120 67-68

-54

Chf

118 118

Chf Chf

55N 55N

-11.6"

111-1 12

+34.7

E:

"

b

> r

m

-

-

2

2 h 9

2 h

cn

158-160

-31.6" (equil.)

103-104

- 116.3"

MeOH Chf

99 99

5

u

9

108-110

+119.4

Chf

55N

175-177 148-149 60 110-115 -

+ 177 + 126

D D D Chf Chf

227,228 229 229 149N 230 231

' 0

-

+110 + 74 +53

-

(Continued)

(D

El El 0

TABLEVII (Continued) Compound

2-O-(methylsulfonyl)2-O-~-tolylsulfony1Methyl 2,3: 4,6-di-O-ethylidcii(.-(DM) P-D-Allopyranoside Methyl 4,6-O-benzylideneMethyl 2,3-O-(o-nitrobenzylidene)p-L-Allofuranoside Methyl 2,3-U-isopropylidene6-O-meth yl5-0-p-tol ylsulfonyla

"

B.p. ("Citorr).

[ffb

M.p. (degrees)

(degrees)

Rotation solvent

143-145 166-167 74-76.5

+58 +35.6 + 121"

D D Chf

227 227 55N

176

-40 -

Chf

228 78N

98-99 (80-851 1)" 74.5-75.5

+77 +67

Chf Chf MeOH

232 232 232

-

+26

References

3> 0

5 ?

wm M

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

221

TABLEVIII Derivatives of D-Altrose

Compound

p-D-Altrofuranose 1,2 : 5,6-di-O-isopropylidene3-0-acetyl3-0-p-tolylsulfonylP-D-Altropyranose 1,2 :3,4-di-O-isopropylidene-

M.p. (degrees)

[a], (degrees)

Rotation solvent

+27 + 14.4

A Chf Chf

68MN,233 102N 68MN

- 13.1

Chf

68MN 233

-5.2 +55.7 +7 +2.1 +43.8 + 103 + 125 +62 + 124 +74

Chf Chf Chf Chf Chf W W Chf W Chf

151 N,234N 90N 90N 235N 230N 62 62,236 62 52N 52N

89-90 92-93 101-102

+29

f3-65

+68

References

a-D- Altropyranoside

Methyl 4,6-O-benzylidene2-0-benzoyl2,3-di-O-acetyl2,3-di-O-benzoyl2,3-di-O-benzyl2,3-di-0-(meth ylsulfonyl) Methyl 3,4-O-isopropylideneMethyl 4,6-O-isopropylidene2,3-di-O-acetylMethyl 4,6-O-methylene2,3-di-O-acetyl-

137-138.5 104-105 88 174-176 61-62 167-169 134-135 114-115 137-138

(262) D. H. Hollenberg, K. A. Watanabe, and J. J. Fox, Carbohydr. Res., 28, 135-139 (1973). (263) G. J. F. Chittenden and J. G. Buchanan, Carbohydr. Res., 11, 379-385 (1969). (264) G. J. F. Chittenden, Carbohydr. Res., 31, 127-130 (1973). (265) A. Stoffyn and P. Stoffyn,J. Org. Chem., 32,4001-4006 (1967). (266) A. Levy, H. M. Flowers, and N. Sharon, Carbohydr. Res., 4, 305-311 (1967). (267) E. G. Gros and I. 0. Mastronardi, Carbohydr. Res., 10, 325-327 (1969). (268) I. Dyong and F. Werner, Carbohydr. Res., 27, 273-277 (1973). (269) D. E. Hoiness, C. P. Wade, and S. P. Rowland, Can./. Chem., 46,667-672 (1968). (270) E. M. Bessell, A. B. Foster, J. H. Westwood, L. D. Hall, and R. N. Johnson, Carbohydr. Res., 19, 39-48 (1971). (271) V. Prey and K.-H. Gump,Ann., 682, 228-241 (1965). (272) S. R. Landor, B. J. Miller, and A. R. Tatchell,]. Chem. Soc., C , 1822-1825 (1966). (273) B. I. Mikhant’ev, V. L. Lapenko, and E. Yu. Ponomarenko, l z u . Vyssh. Uchebn. Zaued. Khirn. Khim. Tekhnol., 12, 1698-1700 (1969); Chem. Abstr., 73, 4,112 (1970). (274) R. E. Gramera, R. M. Bruce, S. Hirase, and R. L. Whistler, J. Org. Chem., 28, 1401-1403 (1963). (275) R. E. Gramera, T. R. Ingle, and R. L. Whistler, J. Org. Chem., 29, 878-880 (1964). (276) I(.Freudenberg and K. V. Oertzen, Ann., 574, 37-53 (1951).

TABLEIX Derivatives of

Compound

p-L-Idofiiranose 1,2-0-isopropylideiie6-0-acetyl6-0-henzoyl3-0-(methylsulfonyl)3-0-p-tolylsulfonyl6-0-acetyls-0-benzoyl6-0-benzoyl6-0-trityl3,6-di-O-benzyl3,5,6-tri-O-acetyl3,6-di-O-acetyl-S-0-benzoyl3,5-di-0-acet yl-6-O-benzo yl3-0-acetyl-S,fidi-0-benzoyl5-0-acetyl-6-O-benzoyl-3-O-(metliylsulfonyl)5-0-acetyl-6-O-benzoyl-3-O-p-tolyIsulfonyl6-0-acetyl-S-O-benzoyl-3-0-p-tolylsulfonyl5,6-di-0-benzoyl-3-0-p-tolyIsuIfonyl3,6-di-0-l~cnzyl-S-0-p-tolylsulfonyl-

M.p. (degrees)

D-

and L-Idose

blo (degrees)

Rotation solvent

112-113 109.5-110.5 129-129.5 99-100

-30

w

-25

Chf Chf

114-116 133.5-134.5 84-86 89-90 82-84 119-121 86-88 120-121

-25

-

107-109

-

126-127 125.5-126.5 145- 147 75-76

-6.4 -27

+2.5 -44

-32.5 -44 -2 -22.9 - 14.9 -22.5 -21.5 -33 -7 -9.5 -8.3 -8.5 - 15.3

Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf

References

237 238N,239N 240N 241 240N,241 242 240N,242N 239N 239N240N 242N 243 237 239N,244 239N 241 237 24 1 240,242N 24 1 239N,240$45 239N242N 243

;p

5 Z

@

' 2

P-L-Idofuranose (contd.) 3,5-0-benzylidene-l,2-O-isopropylidene6-deoxy-6-iodo6-0-p-tolylsulfonyl5,6-O-benzylidene-l,2-O-isopropylidene1,2 :5,6-di-O-isopropyIidene3-0-benzoyla-L-Idopyranoside Methyl 4,W-benzylidene2,3-di-O-methylP-L-Idopyranoside Methyl 4,6-O-benzylidene2,3-di-O-methylP-D-Idofuranose 1,2:5,6-di-O-isoprnpylidene3-0-acetyla-D-Idop yranoside Methyl 4,6-0-benzylidene2,3-di-O-acetyl2,3-di-O-p-tolylsulfonylP-D-Idopyranoside Methyl 4,6-O-benzylidene2-0-acetyl-3-0-methyl-

120-121 159-161 120-121 156-157

+7 -4.1 -5 -61

Chf Chf Chf Chf

239N 239N 239N 239N

108-109.5

-22

Chf

246

148-149 151-153

-47 -69

Chf Chf

246a 246a

159- 161 129-130

+ti7 +51

Chf Chf

246a 246a

75.5-76.5

+ 16

205 153-155

102N

+82.6 +35.7

Chf Chf

93N 247

-28

Chf

93N

9

158

z

TABLEX Derivatives of D-Galactose

Compound a-D-Galactofuranose 1,2-O-isopropylidene3-0-benzoyl6-0-benzoyl3-O-meth yl6-0-p-tolylsulfonyl5-0-(tetrah ydropyran-2-y1)3,6-di-O-benzoyl6-0-benzoyl-3-0-methyl3,6-di-O-methyl5,6-O-isopropylidene1,2 :5,6-di-O-isopropylidene3-0-acetyl3-0-benzoyl3-O-p-tol ylsulfon ylDGalactopyranose 4,6-O-benzylidene2,3-di-O-benzyl3-O-acetyl-l,2-O-propylidene1,2 : 3,4-di-0-cyclohexylidene-a6-0-p-tolylsulfonyl4,6-O-ethylidene1,2-O-isopropylidene-a3-O-eth yl3-O-(methylsulfonyl)-

M.p. (degrees)

B.p. (OC/tolT)

102-103 105-107 93-95 110-1 12(bath) /0.1-0.2 127-129 105(bath)/O.1 83-84 97-98 86-87 95

(degrees)

Rotation solvent

-27 +41 - 13.8 -31 -20 0 + 10.2 -20 -39 -23 -34

Chf Chf Chf Chf Chf Chf Chf Chf MeOH MeOH

b 1 D

-7.5 -2 - 14

153-155 -

+78.4

45-60 72-74 97-99

-43.2

-54

References

Chf Chf Chf

248 249N 249N 250N 250N 249N 249N 250N 251N 23 60e,248,252, 253N,253a 102N 249N2.53N 22 1

Chf Chf

46 46

W

+58

EtOH

+20.5 + 109

EtOH

254 121 121 2 14 121

3,4-0-isopropylidene6-0-methyl4,6-0-isopropylidene1,2:3,4-di-O-isopropylidene-a6-0-allyl6-bromo-6-deoxy6-chloro-6-deoxy6-deoxy-6-iodo6-0-ethyl6-0-(p-nitrobenzoy1)6-O-p-tolylsulfony l1,2:3,4-di-O-methylene-o6-0-( methylsulfony1)6-0-p-tolylsulfonyl1,2-0-propylidene-a3,4,6-tri-O-acetyIa-D-Galactopyranoside Allyl 4,6-0-benzylidene2,3-di-O-benzylAllyl 3,4-0-isopropylidene6-0-benzyl2-0-allylBenzyl4,6-O-benzylidene2,3-di-O-benzylMethyl 3,4-O-benzylidene6-0-benzoyl2-0-acetylMethyl 4,6-0-benzylidene2-0-acetyl3-0-acetyl2-O-meth yl3-0-benzyl2,3-di-O-methyl-(D) (D)

100-102 99- 100 141-143 -

+86 +79 + 153 8610.03

-71.8

Chf

10010.1

-64

Chf

-60.9 -57 -66 -60.8

Chf Chf Chf Chf

-74.9 +93.2 +96.8

Chf MeOH Chf

56 69-69.5 116.5-117.5 99-100 80-81 99.5-100 91-91.5 115-116 -

-

-

-

+ 121

115-117 123-125

+82.4 170/0.1 16010.2

108-109 140

MeOH W MeOH

+82 +94 +117 +111

154-155.5 128-129

+ 128

168-174 152 131.5 117-119 158-160

+ 156" +232" + 165.2

+110

+164.1 + 167 + 109

23 24 23 255 256,257 205N,258 205N 258 259 21N 21N 260 260 260 46 46

Chf Chf

46 46

Chf Chf Chf Chf

26 1 26 1 127N 127N

PY A

262 262

Chf Chf MeOH Chf Chf Chf

152N 152N 120 120 49,50N 49,50N (Continued)

P

z

U

TABLEX (Continued) Compound

Methyl 4,6-O-ethylidene2,3-di-O-rnethylMethyl 3,4-0-isopropylidene6-0-henzyl2-O-meth yl6-0-trityl2-0-benzyl2,6-di-O-benzylMethyl 4,6-0-isopropylidene2,3-di-O-benzylMethyl 4,6-O-methylene2,3-di-O-acetyl2,3-di-O-p-tolylsulfonylMethyl 4,6-O-(o-nitrobeiizylidene). 2,3-di-O-acetylPhenyl 4,6-O-benzylidene2,3-di-O-benzylP-D-Galactopyranoside Benzyl 4,6-O-benzylidene2-0-benzoyl3-0-benzoyl2-0-methyl3-O-meth yl2,3-di-O-benzoyl2-0-benzoyl-3-O-meth yl3-0-benzo).l-2-0-metliylBenzyl 3,4-O-isopropylideiie6-0-benzoyl2-0-benzyl3-0-methvl-

M.p. (degrees)

B.p.

bl”

(“C/tOrr)

(degrees)

+ 177

117-118 115-116

+23.5

-

150/0.2 112-113.5 222-223 109-110 167-168

135-136 192- 194 132 188-189 179-180 106-110 182-183 177-178 168- 170 123-124 118-119 118-118.,5

143.5-144 1.59- 160

+ 101 +84

+29 +56.8

+49.1

+ 182 + 192 + 99 + 16 +95 + 108 i-24

+64.6 -41.2 -44.2 +I18 +42 +61.5 - 1.47 -6 - 18.5 - 10.4 -3.3

Rotati on solvent

References

EtOH Chf

121 121

MeOH Chf Chf Chf

120 120 27N 27N 27N

Chf W Chf Chf

27N 52N 52N 52N

PY Chf

78N 127N 127N

Chf Chf DC DC Chf Chf DC Chf Chf Chf Chf Chf

263 151,263 264 264 263 264 264 265 266N 266N 265 265

6-0-trityl2-0-benzoyl2,G-di-0-acetylBenzyl 4,6-O-isopropylideneMethyl 3,4-O-benzylidene- (D) (D) 2,6-di-O-acetyl- (D) (D) 2,6-di-O-benzyl- (DM) 2-0-acetyl-6-0-trityl- (DM) Methyl 4,6-O-henzylidene2-O-acety l3-0-acetyl2-0-benzyl2,3-di-O-methyl- (D) 2-O-(tetrahydropyran-2-yl)Methyl 3,4-O-ethylidene- (D) (D) 2,6-di-O-benzyl- (DM) Methyl 4,6-O-ethylidene2,3-di-O-methylMethyl 3,4-0-isopropylidene6-0-p-tolylsulfonyl2-0-benz yl6-0-trityl2-O-benz ylMethyl 4,6-O-isopropylidene2,3-di-O-methylMethyl 4,6-O-(o-nitrohenzylidene)2,3-di-O-acetylPhenyl 4,6-O-benzylidene2,3-di-O-benzyl-

87-88 124-125.5 139-141 165-168 130-132 114-115

-

-27 -29.1 -4.4 -66 + 18 - 11 + 19 +31 +11

68-77

-5

Chf Chf Chf Chf EtOH EtOH Chf Chf Chf Chf

266N 265 266N 266 51N 51N 51N 51N 76a 51N

n

8

c,

b M

4

+158-160 75-78 118-119 156.5-157.5 164-165 193-196 169-171 -

+82" +87 +22.4 -27 +29.4

+a

+ 13 +11

Chf' Chf Chf Chf Chf W W Chf

152N 152N 265 50N 267 76aN 76,iN 76aN

$ +-

6

0 v)

80-81 134-135 154-155 93-95 162-164 170-171 155- 157 189-190 199-201 195-196

+9 +8

0 + 19 -20.4 +4.28

Chf A Chf Chf Chf Chi W Chf Chf

121 26N,265 26N 26N 265 265 26N 26N 78N 78N

Chf

268

$ U

+-

a6 v,

8 4

[011546.

TABLEXI Derivatives of D- and L-Glucose

Compound a-D-Glucofuranose 3,5-0-benzylidene-l,2-0-isopropylidene6-0-all yl6-bromo-6-deoxy6-chloro-6-deoxy6-0-(trimethylsily1)1,2-O-cyclohexylidene3-0-benzyl3-O-eth yl3-0-methyl1,2:5,6-di-O-cyclohexylidene3-0-allyl3-0-benzyl 3-0-methyl3-0-vinyl5,6-O-isobutylidene-1,2-O-isopropylidene1,2-O-isopropylidene3-0-benzyl5-0-benzyl6-0-benzyl6-O-(methylsulfonyl)5-O-p-tolylsulfonyl3-0-acetyl-6-0-p-tolylsulfonyl6-0-henzyl-5-0-p-tolylsulfonyl3-0-benzyl-6-0-trityl3-O-(methylsulfonyl)-5-O-p-tolylsulfonyl-

M.p. (degrees)

B.p. (Wtorr)

Rotation solvent

-

References

+9.5

Chf Chf Chf

269 270 270 271

200/0.005

-34.8 - 15.2 -27.2

Chf Chf W

272 272 272

200/0.003 155-159/0.002 137-140/0.1

- 17.4

Chf Chf

273 272 272 273 217

67-67.8 114-115 114-115 92

+ 16 + 18

106

-

145-148

113-114 160-165 88-89 79 92 122 120-121 130-131 116 130-132

[&

(degrees)

-20.5 -30.1 -26.2 -6.8 -3.5 +5.2 -10.1 -36 -35.5

W

EtOH Chf Chf Chf Chf Chf Chf

109,274 261 275 270,276 212,275 277 275 274 278

3-0-methyl-6-0-p-tolylsulfonyl5,6-di-0-acetyl-3-0-allyl3,6-di-O-acetyl-5-O-benzyl5,6-di-0-acetyl-3-0-methyl5-O-acetyl-3-O-allyl-6-0-trityl3-0-acetyl-5,6-di-O-benzyl3,5,6-tri-O-allyl-

85-86 73-74 75-77 202-204 57-59

3-0-allyl-5,6-di-0-benzyl152-153 3-0-acetyl-6-0-benzoyl-5-O-p-tolylsulfonyl132 6-0-acetyl-3-0-benzyI-5-0-p-tolylsulfonyl5,6-di-O-benzyl-3-O-methyl3,6-di-0-be1lzyl-5-O-p-tolylsulfonyl124-125 3-0-benzyl-5,6-di-O-(methyIsulfonyl)97-98 3-O-benzyl-5,6-di-O-p-tolylsulfonyl3-O-benzyl-5-O-p-tolylsulfonyl-6-O-trityl133-134 3-0-benzyl-6-O-methyl-5-0-p-tolylsulfonyl153.5-154.5 6-0-henzoyl-3-O-(metylsulfonyl)-5-0-p-tolylsulfonyl166-167 3-O-(methylsuIfonyl)-5,6-di-O-p-tolylsulfonyl3,5,6-tri-0-(trimethylsi1yl)124-125 5,6-O-isopropylidene1,2:3,5-di-O-isopropylidene6-bromo-6-deoxy6-chloro-6-deoxy92 6-0-(trimethyl5ilyl)1,2:5,6-di-O-isopropylidene3-0-allyl160-165 3-0-benzyl3-chloro-3-deoxy3-O-eth yl44-45 3-0-(trimethylsilyl)-

165-180/0.4 195(bath)/0.01 140/0.003

112/0.15

- 24 - 16 -38.2 - 16 -35 -47.5

EtOH Chf Chf Chf Chf Chf

-3.75 -4.8 -32.4 -14.1 -18.1 - 16 - 13.8 - 14.5 -12.3 -31 -21.6 +9

Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf

-

W

279 261 261 26 1 261 261 269,280 261 237,239 243 28 1 282 224N 109,283 274 282 278 284 27 1 285M

106/0.1 107/0.03

+ 19.2 +48 +9.47

Chf MeOH Chf

205 286,287 271

113(bath)/0.005

- 12.7 -26.2 - 16.5

Chf EtOH Chf

- 15.5

CH

287 274 288,289 290 271

7610.004

(Continued)

lo

TABLEXI (Continued) Compound

D-Glucofuranoside Methyl 5,6-0-isopropylidene-a3 - 0 - mthyl2-O-p-tol ylsulfonylMethyl 5,6-0-isopropylidene-/33-0-methyl24-p-tolylsulfonylD-GhcOpyranOSe 4,6-0-benzylidene-1,2-0-isopropylidene-a3-0-acetyl4,6-0-benzyIidene- 1,2-0-ethylidene-a3-0-acetyl- (D) 4,6-0-butylidene1,2,3-tri-O-acetyI-p1,2-0-cyclopentylidene-a1,2,3-tri-O-acetyl1,2-0-cyclohexylidene-a1,2,3-tri-O-acetyl1,2-0-ethylidene-a3,4,6-tri-O-acetyl- (D) (D) 4,6-0-ethylidene1,2,3-tri-O-acetyl-p1,2 :4,6-di-O-ethylidene-w 3-0-acetyl- (D) (D) 1,2-0-isopropyIidene-a3,4,6-tri-O-acetyl-

M.p. (degrees)

144-145 159-160 147-149 165-168 162-164 113.5-115 68-69

144-148 166-177 124-125 105-106.5 114-1 15.5

87-88

w

0

B.p.

[aylD

(W t o r r )

(degrees)

Rotation solvent

References

90-92/0.00~

+67,2 +75.8

Chf Chf

28 1 28 1

114-1 16/0.005 -

-3.1 -28.5

Chf Chf

28 1 28 1

+85 +77.5

Chf Chf

77N 77N

+43.6 Chf +41 + +0.8(3h) -36.6 Chf

77N 179 36

+34.5

Chf

59

+33

Chf

59

+27 +74

Chf Chf

w

-40.1

Chf

77N 77N 36 36 36

+45

Chf Chf

77N 77N

-

+ 100

S5,77N

4,6-O-isopropylidene-a,p1,2,3-tri-O-acetyl-Pa-D-Glucopyranosidc Benzyl 4,6-O-benzylidene2-0-p-tolylsulfonyl2,3-di-O-acetylMethyl 4,6-O-benzylidene2-0-allyl3-0-allyl2-0-benzoyl-

3-bromo-3-deoxy3-deoxy-3-iodo2-0-ethyl3-O-eth yl2-O-(methylsulfonyl)3-0-(methylsulfonyl)3-0-(tetrahydropyran-2-y1)2,3-di-O-alIyl2,3-di-O-butyl2,3-di-O-(chloroacetyl)3-O-ethyl-2-O-p-tolylsulfonyl2,3-di-O-(methylsulfony1)2,3-di-O-methyl- (D) (D) 2,3-di-O-vinylMethyl 4,6-0-benzylidene-2,3-O-ethylideneMethyl 4,6-O-benzylidene-2,3-O-methyleneMethyl 2,3 :4,6-di-O-benzylideneMethyl 4,6-O-cyclohexylidene2,3-di-O-methylMethyl 2,3: 4,6-di-O-cyclohexylidene-

169.5-170.5 171-172

-7.3(48 h) -30

W Chf

42MN 42MN

152 138-140 103-105

+51 +35 +52.6

Chf Chf Chf

291N 291N 291N

+75.8

Chf Chf

46 46 292,293

115-116 154-155 167-169 169-170 193-194 129-130 168- 169 132-133 142-143 135-142 62-63 89-90 147-148 108-109 188-189 125.5-127 122-123 92-93 139-140 118-119 157-161 120-121 82.5-83 145.5-146.5

+ 104

-

0

Chf

+111.1 +72 +90 +54 +50 +65.4 +45 +49 + 184 + 97 +87.3 + 12 +55 + 122 +113 +77

Chf Chf Chf

-

Chf Chf Chf Chf Chf A A Chf Chf Chf A A A

151 294N 294N

295N 290N 296 296 297N 298 2% 299 290N 296 49N 49N 300N 300N 48N 51N 38N 38N 38N

TABLEXI (Continued) Compound

Methyl 4,60(diphenylmethylidene)Methyl 4,6-O-isopropylideneMethyl 2,3 :4,6-di-O-isopropylideneMethyl 4,6-O-dodecanylideneMethyl 4,6-O-methylene2,3-di-O-acetylMethyl 4,6-O-(o-nitrobenzylidene)Methyl 4,6-0-propylidene2,3-di-O-acetylMethyl 4,6-0-(1-pheny1ethylidene)Methyl 4,6-0-( 1-tert-butylethylidene)Phenyl 4,6-O-benzylidene2-0-p-tolylsulfonyl2,3-di-O-benzylP-DGlucopyranoside Benzyl4,6-O-benzylidene2-0-acetyl3-0-acetyl3-0-benzyl2-O-meth ylMethyl 4,6-O-benzylidene2-0-acetyl3-0-benzyl3-0-acetyl2-0-benzyl-

M.p. (degrees)

113-114 84-86 85 75-76 127-128 118-119 162-163

[a]” (degrees)

+ 101 + 105 + 99

Rotation solvent

References

30 1 33N,42 33N 29 52N 52N 78N 29,36 36 33

+84

Chf W B EtOH W Chf Chf Chf Chf Chf A Chf Chf Chf

167- 168 145-146 127-128 125

-98.4 -80.6 -53 -68

Chf Chf Chf Chf

302 302 303 303

174-177 131-132 162-163 141-143

-74.4 -24 -55.2 -26

Chf Chf Chf Chf

304N 152N 304N 152N

98-100

-

162 174-175 2 13-2 15 184-189 139-139.5

+77.6

+ 120.5 + 132

+ 137 +118.2 +118.5 + 150

+ 100 + 189’ + 129

33 127NJ34 134 127N

5 ?

; m

m

2-bromo-2-deoxy20-(methylsulfonyl)3-O-(methylsulfonyl)2-O-p-tolylsulfonyl3-O-p-tolylsulfon yl2-0-benzoy l-3-0-methyl3-0-methyl-2-0-(methylsulfonyl)2,3-di-O-(methylsulfonyl)2,3-di-O-p-tolylsulfonylMethyl 4,6-O-ethylidene2,3-di-O-benzylMethyl 4,6-O-isopropylidene3-0-benzyl2-0-acetyl2,3-di-O-methylMethyl 4,6-O-propylideneMethyl 4,6-O-(o-nitrobenzylidene)Methyl 4,6-O-methylene2,3-di-O-acetylDClucoseptanose 1,2:3,4-di-0-isopropylidene-a5-0-acetyl2,3 :4,5-di-O-isopropylidene1-O-acetyl-a1-0-acetyl-p1,2-O-isopropylidene-a-

208-209 164-164.5 187-189 122-123 155- 156 146 126.5 148-149 160-161 188-190 92-92.5 128-128.5 -

153-155 176-178 171-172 169- 170 146 151 115 100 169

-20 -69.6 -57 -54.1 -81.4 -9 -56 -60.7 -78.9 0 - 72 -22.5 +5.4 -43 + 109.6

Chf W Chf W Chf Chf Chf Chf

-77 -65

W Chf

-61 -83.7

Chf

-

+ 121 -77.7

-

Chf Chf Chf Chf Chf Chf Chf

Chf

Chf Chf

305 306N 306N 306N 306N 307N 307N 306N 306N 36 308 309 303 303 309 36 78N 52N 52N 11N 1IN

11N 11N 11N

TABLEXII: Derivatives of D- and L-Gulose

Compound a-D-Gulofuranose 1,2-O-isopropylidene3-0-benzyl3-0-methyl.6-O-benzoyl5-0-(methylsulfonyl)5-0-(methylsulfonyl)6-0-(methylsulfonyl)5,6-di-O-(rnethylsulfonyl)1,2 :5,6-di-O-isopropylidene3-0-acetyl3-0-benzoyl3-O-meth yl3-O-p-tol ylsulfon yl2,3 :5,6-di-O-isopropylidenep-D-Gulofuranoside Methyl 2,3-0-isopropylidene5,6-di-O-benzoyl5,6-di-0-( methylsulfony1)Methyl 2,3 : 5,6-di-O-isopropylidenea-D-Gulopyranose 4,6-O-ethylidene-l,2-0-isopropylidene3-O-benzo yl3-0-p-tolylsulfonyla-D-Gulopyranoside Methyl 4,6-O-henzylidene2,3-di-O-acetylp-L-Gulofuranoside Methyl 2,3-0-isopropylidene5,6-di-O-acetylMethyl 2,3 :5,6-di-O-isopropylidene-

M.p. (degrees)

B.p. (wtorr)

[a],

(degrees)

Rotation solvent

References

112,224N 108N 108N,310 108N,310 108N310 108N3 1 1 108N 61N 60e 312N 311 253N 64,313

152-153 124-125 83-84 81-82 114 105-106 73-74 153.5- 154.5 72-73.5 122-123 114-115

+39.1 +37 +25 -*5 -37.5 +31 - 17 +7.5 + 66 + 55 +32.5 +32 -6.3

Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf W

77.4-79.5

-83.6

MeOH

78.5-79

-44.9

Chf

314 314 315N 314

133-134 117-118 138-139

- 19 +61 +34.6

Chf DC D

316 316 316

139-140 149-150

+63 +53

Chf Chf

60aN 60aN

+82.3 +58 +41.Y

MeOH Chf Chf

238N 238N 238N

132-133 60-65(bath)/0. 1-0.2

-

76.5-77 54-55 76-77

-

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

235

(277) M. Nakajima and S. Takahashi,Agric. Biol. Chem., 31, 1079-1081 (1967). (278) J. KovZ and J. J a e , Collect. Czech. Chem. Commun., 33,549-555 (1968). (279) Yu. A. Zhdanov and V. A. Polenov, Carbohydr. Res., 16,466468 (1971). (280) Brit. Pat. 909,278; Chem. Abstr., 59, 11,642 (1963). (281) W. Roth and W. Pigman,]. Org. Chem., 26,2455-2458 (1961). (282) R. E. Gramera, T. R. Ingle, and R. L. Whistler,]. Org. Chem., 29,1083-1086 (1964). (283) J. Defaye and V. Ratovelomanana, Carbohodr. Res., 17, 57-65 (1971). (284) J. JarL, V. HeYmLnkova, and J. Kovhi, Collect. Czech. Chem. Commun., 31,20482058 (1966). (285) S. Morgenlie, Actu Chem. S c a d . , Ser. B , 29, 278-280 (1975). (286) E. Hardegger, G. Zanetti, and K. Steiner, Helv. Chim. Acta, 26,282-287 (1963). (287) W. M. Corbett and J. E. McKay,]. ChenL. Soc., 2926-2930,2930-2935 (1961). (288) C. R. Haylock, L. D. Melton, K. N. Slessor, and A. S. Tracey, Carbohydr. Res., 16, 375-382 (1971). (289) D. M. Brown and G. H. Jones, Chem. Commun., 561-562 (1965). (290) J. T. Marvel, S. K. Sen, J . W. Berry, and A. J. Deutschman, Jr., Carbohydr. Res., 8, 148- 156 ( 1968). (291) T. D. Inch and G. J. Lewis, Carbohydr. Res., 22,91-lOl(l972). (292) R. W. Jeanloz and D. A. Jeanloz, ]. Am. Chem. Soc., 79, 2579-2583 (1957). (293) F. A. Carey and K. 0. Hodgson, Carbohydr. Res., 12,463465 (1970). (294) T. D. Inch and G. J. Lewis, Carbohydr. Res., 15, 1-10 (1970). (295) J. T. Marvel, J. W. Berry, R. 0.Kuehl, and A. J. Deutschmann, Jr., Carbohydr. Res., 9,295-303 (1969). (296) J. Honeyman and J. W. W. Morgan,]. Chem. Soc., 3660-3674 (1955). (297) A. N. de Belder and E. Wirkn Carbohydr. Res., 24, 166-168 (1972). (298) J. S. Brimacomhe, B. D. Jones, M. Stacey, and J. J. Willard, Carbohydr. Res., 2, 167-169 (1966). (299) M. Bertolini and C. P. J. Glaudemans, Carbohydr. Res., 15,263-270 (1970). (300) J. T. Marvel, S. K. Sen, F. T. Unaka, J. W. Berry, and A. J. Deutschmann, Jr., Carbohydr. Res., 6, 18-24 (1968). (301) M. E. Evans, F. W. Parrish, and L. Long, Jr., Carbohydr. Res., 3,453-462 (1967). (302) C. P. J. Glaudemans and H. G. Fletcher, Jr., Carbohydr. Res., 7,480-482 (1968). (303) P. A. Finar and C. D. Warren,]. Chem. SOC., 5229-5235 (1963). (304) A. P. Tulloch and A. Hill, Can. 1. Chem., 46,2485-2493 (1968). (305) H. Nakamura, S. Tejima, and M. Akagi, Chem. Pharm. Bull., 12,1302-1307 (1964). (306) R. D. Guthrie, A. M. Prior, and S. E. Cr&sey,J. Chem. Soc., C, 1961-1966 (1970). (307) M. Miljkovik, M. Gligorijevik, and D. GliSin, J. Org. Chem., 39, 3223-3225 i1974).

(308) D. M. Hall and T. E. Lawler, Carbohydr. R&., 16, 1-7 (1971). (309) F. W. Parrish, R. C. Chalk, and L. Long, Jr., 1. Org. Chem., 33, 3165-3169 (1968). (310) J. S. Brimacombe, N. Robinson, and J. M. Webber, Carbohydr. Res., 14,420421 (1970). (311) J. S. Brimacombe, N. Robinson, and J. M. Webber, Chem. Ind. (London),655-656 (1970). (312) J. S. Brimacombe, A. B. Foster, R. Hems, J. H. Westwood, and L. D. Hall, Can.J. Chem., 48,3946-3952 (1970). (313) R. K. Hulyalkar, Can. J. Chem., 44, 1594-1596 (1966). (314) I,. M. Lemer, ]. Org. Chem., 40,2400-2402 (1975). (315) I,. M. Lemer, Carbohydr. Res., 44, 116-120 (1975).

TABLEXI11 Derivatives of D- and L-Mannose

Compound p-D-Mannofuranose 2,3-O-isopropylidene5,6-di-O-(methylsulfony1)1,2 :5,6-di-O-isopropylidene2,3 :5,6-di-O-isopropylideneI-0-benzoyl2,3 :5,6-di-O-methylenea-D-Mannofuranoside Benzyl 2,3-O-isopropylidene6-O-(methylsulfonyl)5,6-di-U-(methylsulfonyl)Benzyl 2,3 :5,6-di-O-isopropylideneMethyl 2,3-O-isopropylidene5-0-methyl6-O-p-tol ylsulfon yl5,6-di-O-acetylMethyl 2,3 :5,6-di-O-isopropylideneMethyl 2,3-O-methylene5-0-methyl6-U-meth ylMethyl 2,3 :5,6-di-O-methylenej3-DMannofuranoside Methyl 2,3 : 5,6-di-O-isopropylidenej3-DMannopyranose 1,2-O-ethylidene3,4,6-tri-O-methyl-

M.p. (degrees)

142-142.5 51-53.5 122 133 60-61 92-93 107-108 54-55 143.5-145

tffl, (degrees)

- 10 +3 +16.6 (IOmin) +35

+ 90 +69

Rotation solvent

Chf A EtOH Chf

References

232N 60e 63,317,318 319 47 63N 320N 232,320N 63N 238 321N 322 321N,322 321N

94-95 52-53 23

+48 +76.5 +32.6 +76 +4.5 +56 +58.2

A Chf Chf A Chf Chf Chf Chf TCE

70-72

+ 98

EtOH

+78

Chf

47N 47N 47N

-49.3

TCE

32 1

+4

Chf

47N

54

a-D-Mannopyranoside Methyl 4,6-O-benzylidene2-0-acetyl3-O-p-tol ylsulfonyl3-0-acetyl2-09- tolylsulfonyl2-0-benzoyl3-0-methyl3-0-p-tolylsulfonyl3-0-benzoyl2-0-p-tolylsulfonyl2-0-benzyl3-0-p-tolylsulfonyl2-0-p-tolylsulfonyl3-O-p-tolylsulfon yl2,3-di-O-acetyl2,3-di-O-benzoyl2,3-di-O-(methylsulfony1)3-0-methyl-2-0-(methylsulfony1)Methyl 2,3 :4,6-di-O-benzylidene- (D)

143-144 185.5-187.5

-

108- 111 187-189 132- 133 213-215 42-44 93-94

-

155-156 59-63

-

202-204 185-186 180- 181 96-98

Methyl 2,3 :4,6-di-O-cinnamylideneMethyl 2,3 :4,6-di-O-crotonylideneMethyl 2,3 :4,6-di-O-methacrylideneMethyl 2,3-O-isopropylidene6-0-methylMethyl 4,6-O-methylene2,3-di-O-acetylMethyl 2,3 :4,6-di-O-methyleneMethyl 2,3-O-(o-nitrobenzylidene)-

+70.2 +70.2 +6 +46 - 16 -45.1 -48 -34 -26.1 -51 +2 + 18 - 25 i-24.5 +21.4 - 141 - 1.76 +22 0

Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf Chf

-61

Chf

165-166 106-108 102-103

-72.5 0 + 13

Chf Chf Chf

76-77 122-123 168-169 144-145

+ 19.5

Chf

+58

w

+43.8 + 19.4

Chf Chf

323,324 153 153

153 153 151N 307N 151N 151,325N,326N 151N,325N 327N 331 325N 328,329 38,330N 90N 230 307N 76N,332N 40N, 187N 76N,332N 40N,187N 332N 332N 332N 333N 52N 52 47,52 78N

2 n E

n

9

i-

w w

41

(Continued)

tQ

TABLEXI11 (Continued)

Compound Methyl 2,3 :4,6-di-0-(0nitrobenzy1idene)- (D) (D) p-D-Mannopyranoside Methyl 4,6-0-henzylidene2-0-benzoyl-3-0-methyl2-0-benzyl3-0-acetyl3-0-benzyl2-0-acetyl3-0-methyl-2-0-(methylsulfony1)-

M.p. (degrees)

[UID

(degrees)

0 a2

Rotation solvent

References

194- 195 -

+ 10

Chf Chf

78N 78N

180.5-18 1.5 153.5-154 119.5-121 182-182.5

- 98 -112 - 131 - 146 -32 - 76 -79

Chf Chf Chf Chf Chf Chf Chf

153 307N 153 153 153 153 307N

z m

E?

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

239

TABLEXIV Derivatives of D- and L-Talose ~

M.p. (degrees)

Compound P-D-Talofuranose 1,2:.5,6-di-O-isopropylidene3-0-acetylD-Talopyranoside Benzyl4,6-0-benzylidene-P2,3-di-O-acetylMethyl 2,3-O-isopropylidene-a4-0-acetyl-6-O-meth yl/3-L-Talofuranose 1,2-O-isopropylidene3-O-meth yl6-O-benzo yl5,6-di-0-(methylsulfony1)3,5,6-tri-O-benzoyl1,2: 5,6-di-O-isopropylidene3-O-benzo yl50-(methylsnlfony1)6-0-trityl-

~~~

(degrees)

- 7.4

171 137 43.8-45 100-101 54-56 98-99 149-151 156-158 86-87 96-98

Rotation solvent

References

Chf

102N

- 70

+ 19

DC DC

316 316

+38.3

Chf

333MN

MeOH Chf Chf Chf Chf A Chf

219 220N 220N 220N 219 219,246 219

+52 + 103 +63

+32.5 +90 +30 + 107

+ 50

Chf

219

TABLEXV Derivatives of D- and L-Fucose

Compound

M.p. (degrees)

a-L-Fucopyranose 1,2:3,4-di-O-isopropylidenea-L-Fucopyranoside Methyl 2,3-O-isopropylidene146-147/0.8" 4-0-benzylMethyl 3,4-O-isopropylidene2-O-meth ylP-L-Fucopyranoside Benzyl 3,4-O-isopropylideneD-Fucopyranose 3,4-O-isopropylidene110-111 2-0-methyl150-153 P-D-Fucopyranoside Methyl 3,4-O-benzylidene97-99 a

B.p. ("C/torr).

[ffID

(degrees)

Rotation solvent

-62.6

334

A

+3

+71 (24 h) +79 (equil.) +2

References

335 336

Chf W W

Chf

334N 24M 24 337

TABLEXVI Derivatives of L-Rhamnose Compound L-Rhamnofuranose 2,3-O-isopropylidene5-O-meth yl5-0-p-tolylsulfonyl1,S-di-0-acetyl1,S-di-0-benzo yla-L-Rhamnopyranoside Benzyl 2,3-O-isopropylidene4-0-benzylMethyl 2,3-O-(o-nitrobenzylidene)4-0-acetyl- (D) (D) P-L-Rhamnopyranoside Benzyl 2,3-O-isopropylidene4-0-benzyl-

M.p. (degrees)

b I D

(degrees)

Rotation solvent

References

87-89 80 54-55

+ 17.8" (equil.) - 12.3 -43

MeOH Chf

95-97

-67.6

A

339

126-127 101-102

-80 -47

Chf Chf

78N 78N

102-104

W

101,338,339 338 340 101 34 1

339

CYCLIC ACETALS OF THE ALDOSES AND ALDOSIDES

24 1

(316) G. J. F. Chittenden, Carbohydr. Res., 15, 101-109 (1970). (317) L. M. Lemer and P. Kohn,]. Org. Chem., 31,339-341 (1966). (318) J. G. Buchanan, A. U. Dunn, and A. R. Edgar, Carbohydr. Res., 36, c5-c7 (1974). (319) L. M. Lerner and Y. Y. Cheng, Carbohydr. Res., 14,297-303 (1970). (320) J. S. Brimacornbe, F. Hunedy, and M. Stacey, Carbohydr. Res., 13,447-450 (1970). (321) M. H. Randall, Carbohydr. Res., 11,173-178 (1969). (322) A. Dmytraczenko, W. A. Szarek, and J. K. N. Jones, Carbohydr. Res., 26,297-303 ( 1973). (323) C. W. Baker and R. L. Whistler, Carbohydr. Res., 33,372-376 (1974). (324) G. M. Bebault and G. G. S. Dutton, Carbohydr. Res., 37,309-319 (1974). (325) F. R. Seymour, Carbohydr. Res., 34,65-70 (1974). (326) S. Omoto, T. Takita, K. Maeda, and S. Umezawa, Carbohydr. Res., 30, 239-247 (1973). (327) H. B. Borbn, P. J. Garegg, and N. H. Wallin, Actu Chem. Scand., 26, 1082-1086 ( 1972). (328) Y. M. Choy and A. M. Unrau, Carbohydr. Res., 17,439443 (1971). (329) J. G. Buchanan and J. C. P. Schwarz,]. Chem. SOC., 4770-4777 (1962). (330) D. Horton and A. E. Luetzow, Carbohydr. Res., 7, 101-105 (1968). (331) J. G. Buchanan and R. M. Saunders,]. Chem. Soc., 1791-1795 (1964). (332) Z. Jedlinski, J. MaSliliska-Solich, and A. Dworak, Carbohydr. Res., 42,227-231 (1975). (333) J. M. Tronchet and J. M. Chalet, Carbohydr. Res., 24,263-281; 283-296 (1972). (334) H. M. Flowers, A. Levy, and N. Sharon, Carbohydr. Res., 4, 189-195 (1967). (335) A. H. Haines, Carbohydr. Res., 21,99-109 (1972). (336) R. L. Nelson and E. Percival,]. Chem. Soc., 2191 (1957). (337) K. Eklund, P. J. Garegg, and B. Gotthammar,Actu Chem. Scand. Ser. B , 29,633634 (1975). (338) K. Freudenberg and A. Wolf, Ber., 59, 836-844 (1926). (339) A. H. Haines, Carbohydr. Res., 1,214-228 (1965). (340) P. A. Levene and I. E. Muskat,]. B i d . Chem., 106,761-771 (1934). (341) B. R. Baker and K. Hewson,]. Org. Chem.,, 22, 966-971 (1957).

This Page Intentionally Left Blank

THE KOENIGS-KNORR REACTION*

Shionogi Research Laborutory, Shionogi iL Co., Ltd., Fukushima-ku, Osaka 553, Jupun

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 11. Synthesis of Glycopyranosides . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 2. Synthesis of 1;2-trans-Glycopyranosid~s . . . . . . . . . . . . . . . . . . . . 246 256 3. Synthesis of 1,Z-cis-Glycopyranosides. . . . . . . . . . . . . . . . . . . . . 4. Mechanism of Glycosidation Reactions . . . . . . . . . . . . . . . . . . . . . 272 111. Synthesis of Glycosides Other than Pyranosides . . . . . . . . . . . . . . . . . 277 1. General ..................................... 277 2. Synthesis of Glycofuranosides . . . . . . . . . . . . . . . . . . . . . . . . . . 279 3. Synthesis of Glycoseptanosides . . . . . . . . . . . . . . . . . . . . . . . . . 283

I. INTRODUCTION The chemical synthesis of glycosides is still receiving much attention; in particular, the discovery of numerous physiologically active glycosides, such as aminocyclitol antibiotics, glycolipids, glycoproteins, and immunoactive oligo- and poly-saccharides of bacterial cell-walls, has greatly increased interest in glycoside synthesis. Several methods for the preparation of glycosides have been reported.’ The Fischer method,’-3 which consists in treatment of a free Throughout this Chapter, the terms glycow, glvcospl, glpcoside, glpcofiiranositle,

glycopyranoside, and glycoseptanoside refer to aldoses and the corresponding derivatives thereof. (1) For reviews, see: (a) R. U. Lemieux, Ado. Carbohydr. Chern., 9, 1-57 (1954); (b) R. U . Lemieux, Chem. Can., 14-18 (1964);(c) W. G. Overend, in “The Carhohydrates: Chemistry and Biochemistry,” W. Pigman and D. Horton, eds., Academic Press, New York, 2nd Edition, 1972, Vol. IA, pp. 279-353; (d) L. Hough and A. C. Richardson, in “Rodd‘s Chemistry of Carbon Compounds,” S. Coffey, ed., Elsevier, Amsterdam, 2nd Edition, 1967,Vol. IF, pp. 320-345; (e) R. J. Ferrier, Fortschr. Chem. Forsch., 14,389-429 (1970); (r) 6. Wulff and G. Rohle, Angew. Chem. Int. Ed. Engl., 13, 157-170 (1974). (2) E. Fischer, Ber., 26,2400-2412 (1893);28, 1145-1167 (1895).

243

244

KIKUO IGARASHI

sugar with an alcohol in the presence of an acid, is particularly suitable for the preparation of lower alkyl glycosides. A mixture of the anomers of the pyranoside and furanoside forms is obtained, the proportions depending upon the reaction conditions and the stability of the four isomers. a-D-Hexopyranosides are usually obtained in good yield by this method. Alcoholysis of acyclic sugar dithioacetal~',~,~ in the presence of mercury(I1) oxide and mercury(I1) chloride leads to the formation of glycosides. The reaction of phenyl 1-thioglycosides with alcohols in the presence of mercury(I1) salts gives the glycosides with inversion of the configuration at the anomeric carbon atom.5a 1 , 2 - 0 r t h o e ~ t e r sof ' ~acylated ~~~ sugars react with alcohols in the presence of catalytic amounts of mercury(I1) bromide and p-toluenesulfonic acid to give good yields of the 1,Ztruns-glycosides. Dimeric, acylated 2-deoxy-2-nitroso-a-~-glycosyl ~hlorides,',~-'~ which are obtained from glycals by the action of nitrosyl chloride, react with alcohols to give the 1,2-cis-glycosides in good yield. They are readily converted into the 2-amino-2-deoxyglycosidesor into glycosides having a 2-hydroxyl group. Although these methods often give excellent results, and some of them are applicable to the synthesis of complex glycosides, this article deals mainly with the Koenigs-Knorr reaction.

(3) J. E. Cadotte, F. Smith, and D. Spriestersbach, J . Am. Chem. Soc., 75, 15011504 (1952); G. N. Bollenback, Methods Carbohydr. Chem., 2,326-328 (1963). (4) E. Pacsu, Methods Carbohydr. Chem., 2, 354-367 (1963). (5) J. Stanck, M. cernj., J. Kocourek, and J, PacBk, "The Monosaccharides," Academic Press, New York, 1963, pp. 255-290. (5a) R. J. Ferrier, R. W. Hay, and N . Vethaviyasar, Curbohydr. Res., 27,5561 (1973). (6) N . K. Kochetkov, A. Ya. Khorlin, and A. F. Bochkov, Tetrahedron, 23, 693-707 (1967). (7) N. K. Kochetkov and A. F. Bochkov, Methods Carbohydr. Chem., 6, 480-486 (1972). (8) R. U. Lemieux and T. L. Nagabhushan, Methods Carbohydr. Chem., 6,487496 ( 1972). (9) R. U. Lemieux, T. L. Nagabhushan, and K. James, Can. J. Chem., 51, 1-6 (1973). (10) R. U. Lemieux, R. A. Earl, K. James, and T. L. Nagabhushan, Can. J. Chem., 51, 19-26 (1973). (11) R. U. Lemieux, K. James, and T. L. Nagabhushan, Can.J.Chem., 51,42-47 (1973). (12) R. U. Lemieux, K. James, and T. L. Nagabhushan, C a n . ] . Chem., 51,48-52 (1973). (13) K. Miyai and R. W. Jeanloz, Carbohydr. Res., 21,45-55, 57-63 (1972).

THE KOENIGS-KNORR REACTION

245

11. SYNTHESIS OF GLYCOPYRANOSIDES 1. General In 1879, Michael14reported that phenyl P-D-glucopyranoside (3) is obtained by the reaction of tetra-0-acetyl-a-D-glucopyranosy~chloride (1)with potassium phenoxide in aqueous solution. Under the reaction

ox CH,OAc

AcO

+

K

0 CH,OH

O- 0

-

HO

OAc

OH

x=c1

1 2 X=Br

3

conditions, the acetyl groups were also removed. This was the first successful synthesis of a glycoside. In 1901, Koenigs and Kn0rr15prepared 4 from the corresponding bromide (2), with silver carbonate, silver nitrate, or pyridine as the acid acceptor; alkyl tetra-0-acetyl-PD-glucopyranosides (4) were obtained. The reaction proceeds with CKOAc

0 F5OAc

+

ROH

Ag A COs gzo or

+

AgBr

+

H,O

+

C02

AcO OAc 2

OAc 4

net inversion of configuration at the anomeric carbon atom. Whereas the Michael method is suitable only for preparing aryl glycosides, the Koenigs-Knorr reaction is applicable to the preparation both of aryl and alkyl glycosides, and is widely used for the synthesis of glycosides having complex groups attached to the anomeric carbon atom, particularly oligosaccharides. In general, the procedure involves the treatment of a per-0-acylated glycosyl halide with an alcohol in the presence of a heavy-metal salt or an organic base as the acid acceptor; the latter enhances the rate of reaction and also prevents side reactions (for example, deacylation).

(14) A. Michae1,Am. Chem./., 1,305-312 (1879); Compt. Rend., 89,355-358 (1879). (15)W. Koenigs and E. Knorr, Ber., 34,957-981 (1901).

246

KIKUO IGARASHI

For glycopyranosyl halides, an anomer having the halogen substituent in the axial orientation is, because of the anomeric effect,16 thermodynamically more stable than the corresponding anomer having the halogen substituent equatorially attached. Under the usual reaction-conditions, the more-stable anomer is obtained, and the lessstable anomer can be prepared only by a kinetically controlled reaction. Per-0-acylated glycosyl bromides react faster than the corresponding chlorides, and are preferred for most reactions. The chlorides react too slowly under the usual conditions, but, in some cases, they react satisfactorily (see later). Glycosyl fluorides do not react under the conditions of the Koenigs-Knorr reaction, but are readily converted into glycosides by the action of metal a1ko~ides.I~ Treatment of tetra-0-acetyl-a-D-glucopyranosyl fluoride with methanol (2 molar equivalents) in the presence of boron trifluoride etherate gives a mixGlycosyl ture of methyl tetra-0-acetyl-a- and -P-~-ghcopyranosides.'~ iodides are rarely used, because of their instability. Although silver carbonate or silver oxide is usually used as the acid acceptor in the Koenigs-Knorr reaction, numerous variations and improvements have been reported. Zemp1i.n and c o w o r k e r ~ ~used ~-~~ mercury(I1) acetate instead of a silver salt. Helferich and coworker^^^-^^ used mercury(I1) cyanide and mercury(I1) bromide. Wulff and Rohlel(f) used the silver salts of a number of organic acids. 2. Synthesis of 1,2-trans-Glycopyranosides 1,2-trans-Glycopyranosides are usually obtained by the reaction of the corresponding l,e-cis(or trans)-glycopyranosyl bromide with an alcohol in the presence of silver carbonate or silver oxide. The water formed during the reaction also reacts with the halide, to give a byproduct. To remove the water, Drierite25(anhydrous calcium sulfate) is often used, and the addition of iodine may improve the yield.26-28 Reynolds and Evans26obtained P-gentiobiose octaacetate (6) in 82% (16) R. U. Lemieux, Pure A p p l . Chem., 25, 527-548 (1971). (17) F. Micheel and A. Klemer, Adti. Carhohydr. Chern., 16,88-95 (1961). (18) K. Igarashi, unpublished data. (19) G. Zemplen and A. Gerecs, Ber., 63,2720-2729 (1930). (20) G. ZemplCn and 2. Csiiros, Ber., 64, 993-1000 (1931). (21) G. Zempkn, Ber., 74A, 75-92 (1941). (22) B. Helferich and K. F. Wedemeyer, Ann., 563, 139-145 (1949). (23) B. Helferich and K. Weis, Chem. Ber., 89, 314-321 (1956). (24) B. Helferich and J. Zirner, Chem. Ber., 95,2604-2611 (1962). (25) L. C. Kreider and W. L. Evans,]. A m . Chem. SOC.,58, 797-800 (1936). (26) D. D. Reynolds and W. L. Evans,J. Am. Chern. SOC.,60,2559-2561 (1938). (27) B. Helferich, E. Bohn, and S. Winkler, Ber., 63, 989-998 (1930). (28) P. A. J. Gorin and A. S. Perlin, Can. J. Chem., 39,2474-2485 (1961).

THE KOENIGS-KNORR REACTION

247

yield by the reaction of tetra-0-acetyl-a-D-glucopyranosyl bromide (2) with 1,2,3,4-tetra-O-acety1-p-D-glucopyranose ( 5 ) in the presence

OAc

5

6

of silver oxide, iodine, and Drierite. Similarly, Takiura and coworkers2s obtained p-gentiotriose undecaacetate (8) in 43% yield from 2 plus hepta-0-acetyl-p-gentiobiose (7). Hanessian and prepared p-D-glucopyranosides in good yields by using silver trifluoromethanesulfonate as the catalyst and 1,1,3,3-tetramethylurea as the acid acceptor.

I

OAc 7

OAc 8

The procedure developed by Meystre and Miescher,3Oin which the water formed is removed as its azeotrope with benzene, has been used extensively (see, for examples, Refs. 31 and32). The yields ofthe aforementioned gl ycosidation reactions are moderate to good with primary alcohols, but are often rather poor with secondary alcohols, particu(29) K. Takiura, S. Honda, T. Endo, and K. Kakehi, Chern. P h a m . Bull., 20,438-442 (1972). (29a) F. Arcamone, S. Penco, S. Redaelli, and S. Hanessian,]. Med. Chem., 19, 14241425 (1976); S. Hanessian and J. Banoub, Am. Chem. SOC.Symp. Ser., 39, 3663 (1976); Carbohydr. Res., 53, c13-cl6 (1977). (30) C. Meystre and K. Miescher, Helu. Chirn. Acta, 27, 231-236 (1944). (31) W. W. Zorbach, S. L. DeBemardo, and K. V. Bhat, Carbohydr. Res., 11,567-570 (1969). (32) J. J. Schneider, Curbohydr. Res., 17, 199-207 (1971).

KIKUO IGARASHI

248

larly cyclic alcohols, because of side reactions, one of which is orthoester formation. Orthoesters (11) can readily be obtained, by way of 9 and 10 (see Scheme l),by the reaction of tetra-0-acetyl-a-D-gluco$?&OAc

CH,OAc

0,

o\cp I

/o

C' I

CH,

CHS

2

9

CH,OAc

ChOAc

I

QT AcO E Q7

AcO

0-c:

0-C\

Hf

CH,

OR

11

10

Scheme 1

pyranosyl bromide (2) with an alcohol in the presence of 2,6-lutidine, s - ~ o l l i d i n elead , ~ ~carbonate ~~~ in ethyl acetate,6 s-collidine containing a tetraalkylammonium silver salicylate in tetrah~drofuran,3~ or silver nitrate.36Wulff and c o w ~ r k e r s l ( ~extensively ) , ~ ~ , ~ ~ studied this competitive reaction,fortetra-0-acetyl-a-Dglucopyranosyl bromide (2) and cholesterol or tigogenin (12) in the presence of a number of silver salts; silver 4-hydroxypentanoate in diethyl ether favors the foiiiiation of D-glucopyranosides. Compound 12 gives the P-D-glucopyranoside (13)plus the l,&-orthoacetate (14). The results are shown in Table I. Kochetkov and C O W O ~ ~ ~found ~ S a ~ route ~ ~ to * glycosides ~ ~ * ~ ~ from orthoB. Helferich, A. Doppstadt, and A. Gottschlich, Naturwissenschaften, 40, 441442 (1953). R. U. Lemieux and A. R. Morgan, Can. J . Chem., 43,2199-2204 (1965). G. Wulff and W. Kriiger, Carbohydr. Res., 19, 139-142 (1971). S. E. Zurabyan, M. M. Tikhomirov, V. A. Nesmeyanov, and A. Ya. Khorlin, Carbohydr. Res., 26, 117-123 (1973). (a) G. Wulff, G. Rohle, and W. Kriiger, Angew. Chem. Int. Ed. Engl., 9,455-456 (1970); (b) Chem. Ber., 105,1097-1110 (1971). N. K. Kochetkov, A. Ya. Khorlin, A. F. Bochkov, and I. G. Yazlovetsky, Carbohydr. Res., 2, 84-85 (1966).

THE KOENIGS-KNORR REACTION

249

TABLEI

reaction^^''^' of Tigogenin (12) with Tetra-O-acetyla-D-glucopyranosyl Bromide (2) in Ether in the Presence of Silver Salts at 20" Yield (%) of

13

Salt

CzH,COdg Cl,CCO,Ag HOCH,--(CH,),-CO,Ag CH,-CHOH-(CHZ),-COzAg CH,-CHOH-( CHz),-COzAg CH3-CHOH-CHz-COzAg Silver salicylate

14

24 25 26 25 55 65" 40

1 2 20 30 40

60 50"

a

-

41 55" 40 35 45 50 40

CzH,-COH(CH,)-CO,Ag Disilver maleate Disilver malonate Disilver oxalate Silver carbonate Silver oxide Silver nitrate

5 20 5 1 5

Reactions were conducted at -10".

2

+

HO

H 12

0-c-0 /

H,c OAc 13

14

H

KIKUO IGARASHI

250

esters by the action of catalytic amounts of mercury( 11) bromide and p-toluenesulfonic acid. They extended the method to the synthesis of polysac~harides.4~,~~ Franks and Montgomery4' also studied the stereoselective ring-opening of P-D-mannopyranose 1,2-(alkyl orthoacetates). Bredereck and c o w o r k e r ~ prepared ~ ~ , ~ ~ p-D-glucosides by using O-tritylated sugars. Thus, the reaction of 1,2,3,4-tetra-O-acetyl-6-0trityl-P-D-glucopyranose ( 15) with tetra-0-acetyl-a-D-glucopyranosyl

2

+

OAc OAc 15

6

bromide (2) in nitromethane in the presence of silver perchlorate gave P-gentiobiose octaacetate (6) in 58% yield. They proposed that D-glucopyranosyl perchlorate is an intermediate. Khorlin and used the 2,3-diphenyl-Zcyclopropen- l-yl (Ph'cp) group for activation of secondary, as well as primary, hydroxyl groups of sugars in the Koenigs-Knorr reaction. The Phzcp ethers are readily obtained from suitably protected sugars by reaction with 2,3-diphenyl-2-cyclopropen-l-yliumperchlorate in the presence of s-collibromide (16) dine. Reaction of tetra-O-acetyl-a-D-galactopyranosyl with benzyl 2-acetamido-3,6-di-O-acetyl-2-deoxy-4-0-(2,3-diphenyl2-cyc~opropen-l-y~)-c-u-D-g~ucopyranoside (17) in benzene in the presence of silver perchlorate gave the P-D-ghcopyranoside (18) in 35% yield. ~~

~

(39) N. K. Kochetkov, A. F. Bochkov, and I. G. Yazlovetsky, Carbohydr. Res., 9,49-60, 61-69 (1969). (40) N. K. Kochetkov, A. F. Bochkov, T. A. Sokolovskaya, and V. J. Snyatkova, Curhohydr. Res., 16, 17-27 (1971). (41) N. K. Kochetkov, Pure A p p l . Chem., 33, 53-72 (1973). (42) N. E. Franks and R. Montgomery, Carbohydr. Res., 3,511-512 (1966);6,286-298 (1968). (43) H. Bredereck, A. Wagner, G . Faber, H . Ott, and J. Rauther, Chem. Ber., 92,11351I39 (1959). (44) H. Bredereck, A. Wagner, H . Knhn, and H. Ott, Chem. Ber., 93,1201-1206 (1960). (45) A. Ya. Khorlin, V. A. Nesmeyanov, and S. E. Zurabyan, Carbohydr. Res., 43, 69-77 (1975).

THE KOENIGS-KNORR REACTION

CH,OAc

CH,OAc

AcoQBr

25 1

+

Ph,cpOQocHzph=

OAc

NHAC

16

17

OAc

Pbcp

=

Ph

18

Knochel and c o ~ o r k e r sreported ~ ~ * ~ ~the use of a cyclic polyether, namely 1,4,7,10,13,16,19-hexaoxadibenzo[b,klcyclooctadecane (dibenzo-[ 181-crown-6) (19), and nitrogen-containing cyclic polyethers (20 and 21) in the Koenigs-Knorr reaction. Silver nitrate is soluble in

a mixture of certain alcohols and a small proportion of the polyethers,

and the reaction is complete within 5 min. aceA number of mercury(I1) salts, such as mercury(I1) can satisfactorily be used in place k~te,'~-''cyanide and of silver salts in the Koenigs-Knorr reaction. Among them, mercury(I1) cyanide alone and a mixture of mercury(I1) cyanide and mercury(I1) bromide are most frequently used. However, it is difficult to predict (46) A. Kniichel, G . Rudolph, and J. Thiem, Tetrulzedron Lett., 551-552 (1974). (47) A. Knochel and G. Rudolph, Tetrahedron Lett., 3739-3740 (1974). (48) L. R. Schroeder and J. W. Green,J. Chem. Soc., C , 530-531 (1966).

KIKUO IGARASHI

252

the steric course of the reaction starting from a per-0-acylated glycopyranosyl halide, as one reaction gave mainly the 1,2-truns-glycopyranoside, whereas another gave 1,2-cis-glycopyranoside under similar condition^.^^ Reaction of benzyl2-acetamido-4,6-0-benzylidene-2-deoxy-a-D-glucopyranoside (22) with an equimolar amount of tetra-0acetyl-a-D-galactopyranosyl bromide (16)in 1: 1 (v/v) nitromethanebenzene in the presence o f mercury(I1) cyanide gave benzyl 2-acetamido-4,6-0 -benzylidene-2-deoxy-3-0 -( tetra-0-acetyl-P-D-galactopyranosy1)-a-D-glucopyranoside (23) in 53% yield.50In contrast, reaction

NHAc

OAC

22

NHAC 23

of benzyl 6-0-benzoyl-3,4-O-isopropylidene-~-~-ga~actopyranoside (25)with tri-0-acetyl-a-L-fucopyranosyl bromide (24) (0.8molar equivalent) in 1 : 1 (v/v) nitromethane-benzene in the presence o f mer-

cury(I1) cyanide gave, after removal of the isopropylidene benzyl 6-0-benzoy~-2-O-(tri-O-acety~-cw-~-fucopyranosy~)-~-~-ga~act pyranoside (26)in 41% yield.

CH,OBz

I

I

AcO

OH 24

25

AcO 26

Other workers have also studied the Koenigs-Knorr reaction, using mercury(I1) salts as catalyst, to give 1,2-tr~ns-glycopyranosides~~~~~~ 483-59 or 1,2-cis-glycopyranosides.z4~60-62 No reasonable reaction mech(49) H. M. Flowers, Methods Carbohydr. Chem., 6, 474-480 (1972). (50) H. M. Flowers and R. W. Jeanloz,J. Org. Chem., 28, 1377-1379 (1963). (51) A. Levy, H. M. Flowers, and N. Sharon, Carbohydr. Res., 4, 305-311 (1967).

THE KOENIGS-KNORR REACTION

253

anism has, however, yet been proposed to correlate the apparently contradictory results obtained. Conrow and B e r n ~ t e i nrecommended ~~ the use of cadmium carbonate instead of silver salts to prepare glucosiduronic acids of phenolic steroids. The yields are usually better than those obtained by use of silver salts. Rohle and B r e ~ e also r ~ ~used cadmium carbonate in the synthesis of a glucosiduronic acid of estra-1,3,5(10)-trien-2,3,17P-triol 17-monoacetate, which is oxidizable with silver salts. Thus, methyl tri-0-acetyl-a-D-glucopyranosyluronate bromide (27), on reaction with estrone (28) afforded 3-O-(methyl2,3,4-tri-O-acetyl-P-D-ghcopyranosy1uronate)estrone (29). C02Me

27

28

I

J I

OAc 29

(52)

8. Bar-Guilloux, J. Defaye, H. Driguez, and D. Robic, Carbohydr. Res., 45,217-

2:36 (1975). (53) D. Shapiro and 13. M. Flowers,,/. Am. Chetii. Soc., 83, 3327-3332 (1961). (54) E. S. Hachaman and R. W. Jeanlox, Carbohydr. Res., 10, 429-434 (1969). (55) M. A. E. Shaban and R. W. Jeanloz, Carbohydr. Res., 17, 411-417 (1971); 19, 311-318 (1971); 23,243-249 (1972). (56) V. A. Derevitskaya and 0. S. Novikova, Bull. Acad. Sci. U S S R , Diu. Chem. Sci., 24, 1330-1332 (1975). (57) H. M. Flowers, Carbohydr. Res., 46, 133-137 (1976). (58) G. Excoffier, D. Y. Gagnaire, and M. R. Vignon, Carbohydr. Res., 46, 201-213 ( 1976). (59) C. Aug&and A. Veyrikres, Carbohydr. Res., 46, 293-298 (1976). (60) J. Lehmann and D. Beck, Ann., 630, 56-58 (1960). (61) H. M. Flowers, A. Levy, and N. Sharon, Carbohydr. Res., 4, 189-195 (1967).

254

KIKUO IGARASHI

The glycosides of 2-amin0-2-deoxyaldoses~~ cannot be prepared directly by use of an alcohol in the presence of an acid, owing to the electrostatic shielding of the -NH3 group, but may be prepared indirectly by using N-substituted derivatives. Alkyl 2-acylamido-2-deoxy-D-glucopyranosides are prepared by treatment of 2-acylamido-2deoxy-D-glucose with alcohols in the presence of acid66or cation-exchange resin (H+).67Higher temperatures appear to favor formation of the a-D-ghcopyranoside, and the proportion of the P-D-glUcOpyranOside increases at lower temperatures .66,67 The 1,2-trans-D-glycopyranosides are also obtained by the KoenigsKnorr reaction. Treatment of 3,4,6-tri-O-acetyl-2-amino-2-deoxy-a-Dgalactopyranosyl bromide hydrobromide (30) with methanol in the presence of silver carbonate and Drierite gives the corresponding methyl P-D-galactopyranoside6* (31). Similarly, methyl 3,4,6-tri-OCH,OAc

CH,OAc

NH,Br

30

NH2 31

acetyl-2-amino-2-deoxy-~-~-glucopyranoside hydrobromide was obtained by treatment of the corresponding a-D-glucopyranosyl bromide with methanol in the presence of p ~ r i d i n e . ~ ~ . ~ ~ 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-a-~-glucopyranosyl bromide can also be used,71but the more stable chloride is preferred for genera1 use, as the bromide is unstable and changes to 1,3,4,6-tetraO-acetyl-2-amino-2-deoxy-D-glucopyranose hydrobromide during isoa 3,4,6-tri-O-acetyI-2-(acylamido)-2-deoxy-aI a t i ~ n . Furthermore, ~~-~~ (62) S. Kamiya, S. Esaki, and F. Konishi, Agric. Biol. Chem., 40, 273-276 (1976). (63) R. B. Conrow and S. Bernstein,j. Org. Chem., 36, 863-870 (1971). (64) G. Rohle and H. Breuer, Z. Physiol. Chem., 355, 490-494 (1974). (65) A. B. Foster and D. Horton, Adc. Carbohydr. Chem., 14, 240-246 (1959). (66) A. B. Foster, D. Horton, and M . Stacey,J. Chem. SOC.,81-86 (1957). (67) F. Zilliken, C. S. Rose, G. A. Braun, and P. Gyiirgy, Arch. Biochem. Biophys., 54, 392-397 (1955). (68) M. L. Wolfrom, W. A. Cramp, and D. HortonJ. Org. Chem., 28,3231-3232 (1963). (69) J. C. Irvine, D. McNicoll, and A. Hynd,]. Chem. Soc., 99, 250-261 (1911). (70) M. L. Wolfrom and T. M. Shen Han,J. Org. Chem., 26, 2145-2146 (1961). (71) R. Kuhn and W. Kirschenlohr, Chem. Ber., 86, 1331-1333 (1953). (72) F. Micheel, F.-P. van de Kamp, and H. Wulff, Chem. Ber., 88,2011-2019 (1955).

255

T H E KOENIGS-KNORR REACTION

D-glucopyranosyl halide (for example, 32) often gives an o ~ a z o l i n e ~ ~ , ~ ~ (33) or o x a ~ o l i d i n e(34) ~ ~type of derivative, which is transformed into a P-~-glucopyranoside~~ (35)(see Scheme 2). YH,OAc

FH,OAc

Qy lRoH

AcO AcOQC1

L

NHBZ

32

N=C, P h

33

“

?H,OAc

Q!

AcO

+N=C H “Ph Br-

34

?H,OAc

NHBZ 35

Scheme 2

The N-acetyl and -benzoyl groups, however, cannot be removed without damaging the glycoside linkage. The benzyloxycarbonyl group, which may be removed by catalytic hydrogenolysis or by reduction with sodium in liquid ammonia,fifi is commonly used to obtain glycosides of 2-amino-2-deoxy sugars. TrifluoroacetylEoand dichloroacetyls’’82 groups are also used as readily removable N-protecting groups. 3-Amino-6-0-(2-amino-2-deoxy-~-~-glucopyranosyl)-3-deoxyD-glucose was obtained by the reaction of 3,4,6-tri-O-acetyl-2-deoxy(73) Y. Inouye, K. Onodera, S. Kitaoka, and H. Ochiai,]. Am. Chem. S O C . , 79,42184222 (1957). (74) D. H. Leaback and P. G. Walker, Chem. Znd. (London),1017-1018 (1956). (75) D. H. Leaback and P. G. Walker,]. Chem. Soc., 4754-4760 (1957). (76) F. Micheel and A. Kochling, Chem. Ber., 91, 673-676 (1958). (77) W. Meyer zu Reckendorf and W. A. Bonner, Chem. Ber., 95, 996-999 (1962). (78) F. Micheel and H . Petersen, Chem. Ber., 92,298-304 (1959). (79) F. Micheel and A. Kochling, Chem. Ber., 93,2372-2377 (1960). (80) W. Meyer zu Reckendorf and N. Wassiliadou-Micheli, Chem. Ber., 103, 17921796 (1970). (81) D. Shapiro, Chem. Phys. Lipids, 5, 80-90 (1970). (82) D. Shapiro, A. J. Acher, and Y. Rabinsohn, Chem. Phys. Lipids, 10,28-36 (1973).

256

KIKUO IGAFiASHI

Z-(trifluoroacetamido)-a-D-glucopyranosyl bromide with 3-azido-3-deoxy-1,2-O-isopropylidene-a-D-glucofuranose in nitromethane in the presence of mercury(I1) cyanide and mercury(I1) bromide, with subsequent removal of the acetyl groups with sodium methoxide, the trifluoroacetyl group with methanolic ammonia, and the isopropylidene group with trifluoroacetic acid, and catalytic hydrogenation of the azide group.80 3. Synthesis of 1,2cis-Glycopyranosides As already mentioned, l,2-cis-glycopyranosides are obtained in some cases from per-O-acylated 1,2-cis-glycopyranosyl halides in the presence of mercury(I1) salts. 1,2-cis-Glycopyranosidesare, however, usually obtained from glycopyranosyl halides having a nonparticipating group at C-2. A useful method involves the use of the 1,2-transglycopyranosyl halides. Brigl and Kepplers3 prepared methyl a-D-glucopyranoside (38) by glucopyranosyl treating 3,4,6-tri-O-acetyl-2-0 - (trichloroacetyl)-P-Dchloride (Brigl’s chloride) (36) with boiling methanol in the presence of silver carbonate, followed by deacetylation with ammonia. Hickinbottoms4prepared 38 by using a mixture of silver nitrate and pyridine, chloride (37). and also from 3,4,6-tri-O-acetyl-~-D-glucopyranosyl

OR 36 R = OCCC1, 37 R = H

OH 38

Wolfrom and coworker^^^-^^ prepared p-isomaltose (40) and p-gentiobiose octaacetates (6) in 55 and 6% yields, respectively, by the reacchloride (39) tion of 3,4,6-tri-O-acetyl-2-O-nitro-p-~-glucopyranosyl (83) P. Brigl and H. Keppler, Ber., 59, 1588-1591 (1926). (84) W. J. Hickinbottom,J. Chem. Soc., 1676-1687 (1929). (85) M. L. Wolfrom and I. C. Gillam, Science, 130, 1424 (1959). (86) M. L. Wolfrorn, A. 0. Pittet, and I. C. Gillam, Proc. Natl. Acad. Sci. U.S.A., 47, 700-705 (1961). (87) M. L. Wolfrom and D. R. Lineback, Methods Carbohydr. Chem., 2 , 341-345 (1963). (88) M. L. Wolfrom, A. Thompson, and D. R. Lineback, J . Org. Chem., 28, 860861 (1963).

THE KOENIGS-KNORR REACTION

FH,OAc

0

YH,OH

Q

AcO

A c O V O f

f

OAc

ON4

OAc

39

257

6

AcO

5

OAc 40

with 1,2,3,4-tetra-O-acetyl-P-D-ghcopyranose ( 5 ) in anhydrous ether in the presence of silver carbonate, silver perchlorate, and Drierite, followed by denitration by catalytic reduction and acetylation. Glycosy1 chlorides were rarely used in the Koenigs-Knorr reaction until this report appeared, as they react so slowly under the usual condit i o n ~ . However, *~ the use of silver perchlorate, which is soluble in such organic solvents as benzene, ether, and nitromethane, and which can be readily purified?O speeds up the reaction, and so, glycosyl chlorides can be used for the Koenigs-Knorr reactions. Wolfrom and Koizumisl also prepared panose and its isomeric trisaccharide in 17 and 7% yields, respectively, by the reaction of 0-(2,3,4-tri-O-acety1-60 - trityl-a-D-glucopyranosyl)-(1+4)-tetra-O-acety~-~-D-glucopyranose with 3,4,6-tri-O-acety~-2-0-nitro-P-~-ghcopyranosy~ chloride in nitromethane in the presence of silver perchlorate. The glucopyranosyl chlorides (37 and 39) can be prepared readily from Brigl’s chloride (36). For the preparation of P-D-g~ycopyranosy~ chlorides (43) in high yield, Igarashi and coworkersszfound a general method in which the corresponding a-Danomers (41) were treated with silver perchlorate (to give 42) and tetraethylammonium chloride, successively, at low temperature. Originally, Lemieux and Hayamig3 CH,OAc

AcO

OR

OR

OR 41

42

43

(89) L. J. Haynes and F. H. Newth, Ado. Carbohydr. Chem., 10,207-256 (1955). (90) Y. Pocker and D. N. Kevil1,J. Am. Chem. Soc., 87,4760-4770 (1965). (91) M. L. Wolfrom and K. Koizumi,J. Org. Chem., 32, 656-660 (1967). (92) K. Igarashi, T. Honma, S. Mori, and J. Irisawa, Carbohydr. Res., 38, 312-315 (1972). (93) R. U. Lemieux and J. Hayami, Can. J. Chem., 43,2162-2173 (1965).

KIKUO IGARASHI

258

prepared 2,3,4,6-tetra-0-acetyl-p-D-glucopyranosyl chloride from the a - anomer ~ by the action of tetraethylammonium chloride, but isolated it in low yield. Ishikawa and FletcherY4prepared 2-O-benzyl-3,4,6-tri-O-(p-nitrobenzoy1)-,2,3-di-O-benzyl-4,6-di-O-(p-nitrobenzoy1)-, and 2,3,4-tri-0benzyl-6-O-(p-nitrobenzoyl)-~-~-glucopyranosy~ bromides from the corresponding 1-0-( p-nitrobenzoyl) derivatives by the action of hydrogen bromide in dichloromethane. These compounds are now often used. Jennings and prepared chlorosulfates of p-D-glycosyl chlorides by the reaction of free sugars with sulfuryl chloride in chloroform and pyridine. 6-0-a-D-Xylopyranosyl-D-mannose (46) was prepared by the reaction of P-D-xylopyranosyl chloride 2,3,4-tris(chlorosulfate) (44) with 1,2,3,4-tetra-O-acetyl-p-D-mannopyranose (45) in the presence of silver carbonate, silver perchlorate, and Drierite, followed by removal of the protecting groups.

d/l 0CH,OH

OsO2Cl

OAc

~

AcO

CS0,O

mo2c1 44

45 46

Austin and coworkersg7prepared a-D-gluco- (48) and -galactopyranosides, mainly, by the reaction of 2,3,4,6-tetra-O-benzyl-~-gluco(47) and -galactopyranosyl chlorides (a mixture of the anomers) with 1,3-di0-benzylglycerol in the presence of silver carbonate, silver perchlorate, and Drierite. ChittendenY8prepared aptrehalose in 18%yield by the reaction of tetra-0-benzyl-a-D-glucopyranosyl chloride with 2,3,4,6-tetra-O-benzyl-D-glucopyranose in benzene in the presence of silver carbonate, silver perchlorate, and Drierite, followed by catalytic hydrogenolysis of the benzyl groups. (94) T. Ishikawa and H. G. Fletcher, Jr.,J. Org. Chem., 34,563-571 (1969). (95) H. J. Jennings and J. K. N. Jones, Can. J. Chem., 40, 1408-1414 (1962). (96) H. J . Jennings, Can. J. Chem., 46, 2799-2805 (1968). (97) P. W. Austin, F. E. Hardy, J. G. Buchanan, and J. Baddiley,J. Chem. SOC., 21282137 (1964); 1419-1424 (1965). (98) G. J. F. Chittenden, Carbohydr. Res., 9,323-326 (1969).

THE KOENIGS-KNORR REACTION

CI

+

259

C&OC&Ph HO~H I CH,OCH,Ph

OCqPh 47

t CH,OCH,Ph I

OCH,Ph 48

+

6-0 anorner

I CH,OCH,Ph

(major)

Ness and Fletcherg9prepared a sucrose derivative by the reaction of 1,3,4,6-tetra-O-benzyl-~-fructofuranose with 2,3,4,6-tetra-O-benzyl-aD-glucopyranosyl bromide in benzene in the presence of silver perchlorate, silver carbonate, and molecular sieves, and isolated octa-0benzylsucrose as the carbon tetrachloride solvate in a yield of 4.5%. Jeanloz and coworkersloOprepared a 2-acetarnido-2-deoxy-6-0-/3-~mannopyranosyl-D-glucose derivative in 32% yield by the reaction of 4,6-di-O-acetyl-a-D-mannopyranosylbromide 2,3-carbonate with benzyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-a-~-glucopyranoside in the presence of silver carbonate. Igarashi and coworkers1o1J02 studied the Koenigs-Knorr reactions of 3,4,6-tri~-acetyl-2-chloro-2-deoxy-a-(49a) and -/?-D-glucopyranosyl chloride (49b)and 3,4,6-tri-O-acetyl-2-O-benzyl-a(50a)and -D-D-glucopyranosyl chloride (50b) with methanol, methyl trityl ether, and 2propanol in the presence of a mixture of silver carbonate, silver perchlorate, and Drierite, or silver perchlorate with, or without, s-collidine, comparing these reactions with the reactions of the corresponding glucosyl perchlorates (49c and 50c). The results obtained with the 2-O-benzyl derivatives are given in Table 11. They found the follow-

(99) H. K. Ness and H . G. Fletcher, Jr., Carbohydr. Res., 17,465-470 (1971). (100) M. A. E. Shaban, I. E. Ary, D. A. Jeanloz, and R. W. Jeanloz, Carbohydr. Res., 45, 105-114 (1975). (101) K. Igarashi, T. Honma, and J. Irisawa, Carbohydr. Res., 15,329-337 (1970). (102) K. Igarashi, J. Irisawa, and T. Honma, Carbohydr. Res., 39, 213-225 (1975).

KIKUO LGARASHI

260

TABLEI1 The Koenigs-Knorr101,102 Reactions" of 3,4,6-Tri-O-acetyl-2-O-benzyl-a(50a) and -P-D-Glucopyranosyl Chlorides (50b) and the Perchlorate (50c) with Isopropyl Alcohol and Methyl Trityl Ether at 0" Compound

Solvent

50a

Ether

AgZCO, AgCIO, (mole/mole)

1

50b 50c 50a

1

Toluene

1

0.2 1 0.2 1

1

50c 50a

Nitromethane

50b

50a 50b 50c 50a 50b 50c 50a 50b

1 1

0.2 1 0.2 1 0.2 1

Ether

1 1

Toluene

1

1 Ni tromethane

1 1 1

0.2 1

50b

S-Collidine

1 1

1

1 1

1 1

Ratiob of 54a 86.4 89.9 96.5 96.6 97.1 73.7 79.5 85.7 86.0 90.7 54.9 57.6 51.1 57.6 52a 96.5 97.9 98.1 69.8 70.9 71.4 46.5 47.5

54b 13.6 10.1 3.5 3.4 2.9 26.3 20.5 14.3 14.0 9.3 45.1 42.4 48.9 42.4 52b 3.5 2.1 1.9 30.2 29.2 28.6 53.6 52.6

Total yield (%)

Yield(%)" of 56

71.3 91.5 66.7 90.9 85.4 87.5 87.9 81.7 86.5 71.2 65.2 75.3 67.6 79.2

23d 9 2gd 10 7

90.3 84.5 81.9 84.0 82.9 67.3 74.5 82.5

2" 4' 6"

5d

4 6d 6 3 2od 8 17d 9

1' 2" 2e 4e 5"

Reactions were performed with 1 molar equivalent of isopropyl alcohol or methyl trityl ether. Analyzed by gas chromatography (g.1.c.). ' Analyzed by g.1.c. after acetylation. Reactions were conducted in the presence of Drierite. Methyl bityl ether was used.

ing facts. (1)A mixture of silver perchlorate and s-collidine (1 : 1 molar ratio) is superior to a mixture of silver carbonate, silver perchlorate, and Drierite. With the former, the proportion of the a-D-glucopyranosides (51a-%a) and the yields of the D-glucopyranosides are higher than those with the latter, in which relatively large proportions of the hydrolysis products (55 and 56) are obtained, as the D-glucosyl perchlorates react at a significant rate with the water formed during the reactions, as compared with the rate of absorption by Drierite. ( 2 )The reactions mainly proceed via the D-glucosyl perchlorate, which reacts

THE KOENIGS-KNORR REACTION

26 1

with alcohols and methyl trityl ether principally via the solvent-separated ions or the free ions, leading to a mixture of the a- and p-D-glucopyranosides. (3) Formation of the a-D-glucopyranosides is favored in nonpolar solvents, particularly diethyl ether, in which participation of the ether may play a role to some extent. In (polar) nitromethane, an -1 : 1 mixture of the a- and -P-D-ghcopyranosides is obtained. The octaacetates of p-isomaltose, p-maltose, P-nigerose, and a-kojibiose were obtained in 80, 55.8, 67, and 64% yields, respectively, by reaction of 50b with the appropriately protected D-glucopyranose derivatives in the presence of silver perchlorate and s-collidine, followed by hydrogenolysis and acetylation. P-Isomaltose octaacetate was also obtained in 79.4% yield by the reaction of 50b with 1,2,3,4-

(J-

AcO

498

R' = C1 x = a-C1

49b

R' = C1 x = p-c1

49c

R'= C1 x = a-OC10,

50a

R' = OCH,Ph x = a-C1

50b

R' = OCHzPh x = p-c1

50C R' = OCH,Ph

x = a-OC10,

iR*OH CH,OAc

Q

AcO

ORz

CH,OAc

+.

R' (51-54)a 51 R' = C1,

R7 = Me

52 R' = OCH,Ph, R = Me

53 R' = Cl, RZ = CHMe, 54 R' = OCH,PH, Rz = CHMe,

Q

AcO

R' (51-54)b

CKOAc

.+

AcOQ - O R R' 55 R ' = C1 56 R' = OCH,Ph

262

KIKUO IGARASHI

tetra-O-acetyl-6-O-trityl-P-D-g~ucopyranose in ether in the presence of silver perchlorate, followed by hydrogenolysis and a~ety1ation.l'~ Kronzer and Schuerchlo4 studied the glycosidation reactions of 2,3,4,6-tetra-O-benzyl-a-~-glucoand -galactopyranosyl iodides, which are obtained from the corresponding glycosyl bromides or chlorides by the action of sodium iodide, with alcohols in the presence of 2,6-lutidine, and obtained mainly the alkyl a-D-glycopyranoalso studied the alcoholysis of sides. Schuerch and 6-0-substituted 2,3,4-tri-O-benzyl-~-gluco- and -galactopyranosyl p-toluenesulfonate, p-bromobenzenesulfonate, and trifluoromethanesulfonate (which are obtained by treatment of the corresponding glycosy1 bromide with the silver salts of p-toluenesulfonic acid, p-bromobenzenesulfonic acid, and trifluoromethanesulfonic acid, respectively), and observed the effects, on the glycosidation, of the 6-0substituents and the solvents used. In applying their method, methyl a-isomalto-oligosaccharides were prepared in high yields. Machinami and Suami'O8 similarly prepared 2-0-benzyl- 1-O(methylsulfonyl)- 3,4,6- tri-0 - ( p -nitrobenzoyl)-a-D-glucopyranose, which gave mainly the methyl a-D-glucopyranoside by methanolysis. Nakajima and coworkers also prepared 1,2-cis-glycosides, including kanosamine, kanamycin A,109and paromamine derivatives,'l' by the reaction of appropriately protected a-D-glycopyranosyl halides of aminodeoxy-D-glucoses with deoxystreptamine derivatives in the presence of silver perchlorate, silver carbonate, and Drierite in benzene or chloroform containing 10-20% of 1,4-dioxane. In the Koenigs-Knorr reactions of glycosyl halides having a nonparticipating group at C-2, mercury(I1) salts are also used as the acid acceptor. The reactions give a mixture of glycoside anomers, in which the a - anomer ~ is usually preponderant. Umezawa and coprepared kanainyciiis A, B, and C , and many other (103) K. Igarashi, J. Irisawa, and T. Honma, Curbohydr. Res., 39, 341-343 (1975). (104) F. J. Kronzer and C. Schuerch, Carbohydr. Res., 34, 71-78 (1974). (105) R. Eby and C . Schuerch, Carbohydr. Res., 34, 79-90 (1974). (106) R. Eby and C . Schuerch, Macromolecules, 7, 397-398 (1974). (107) T. J. Lucas and C . Schuerch, Carbohydr. Res., 39,39-45 (1975). (108) T. Machinami and T. Suami. Chem. Lett., 1177-1180 (1974). (109) A. Hasegawa, K. Kurihara, D. Nishimura, and M. Nakajima, Agric. Biol. Chem., 32, 1123-1129, 1130-1134 (1968). (110) A. Hasegawa, D. Nishimura, T. Kurokawa, and M . Nakajima,Agric. B i d . Chem., 36, 1773-1776 (1972). (111) S. Umezawa, Adu. Carbohydr. Chem. Biochem., 30, 111-182 (1974), and references cited therein. (112) S. Umezawa, S. Koto, K. Tatsuta, and T. Tsnmura, Bull. Chem. Soc.Jpn., 42,529533 (1969).

T H E KOENIGS-KNORR REACTION

263

aminocyclitol antibiotics, b y using mercury(I1) cyanide as the catalyst. Treatment of 6-0-[2-0-benzyl-3-(benzyloxycarbonylamino)-3-deoxy4,6-0 -isopropylidene-a-D-glucopyranos yll-N,N’-di(benzy1oxycarbonyl)-2-deoxystreptamine (57) with 2,3,4-tri-O-benzyl-6-(N-benzylacetamido)-6-deoxy-a-~-glucopyranosyl chloride (58) in a mixture of 1,4dioxane and benzene in the presence of mercury(I1) cyanide and Drierite gave mainly a kanamycin A derivative, which was converted into crystalline hepta-O-acetyl-tetra-N-(2,4-dinitrophenyl)kanamycin A (overall yield, 10%). Ac I

Mezc& ’ o&~

\0

QclOCH,Ph

+

-

bnamycin derivativeA

PhCQO

OCH,Ph

OCGPh 57

58

0 II

(Z = PhCH,OC)

Flowers and Dejter-Juszyn~ki~~,~~~,~’~ also prepared such a-linked disaccharides as ( a ) 6-O-cy-D-glucopyranosyl-D-galactose,which was obtained by partial, acid hydrolysis of polysaccharides contained in Salmonella spp.,117,118 ( b )3-O-a-D-glucopyranosy~-D-ga~actose, which was obtained from lipopolysaccharide of many Gram-negative bacteria,l1’,ll8 and ( c ) 2-acetamido-2-deoxy-6-O-a-~-fucopyranosy~-~-g~ucose. Reaction of 2-0-benzyl-3,4,6-tri-O-( p-nitrobenzoy1)-P-D-glucopyranosyl bromide (59) with 4,6-0-ethylidene-1,2-0-isopropylidenea-D-galactopyranose (60) in 1: 1 nitromethane-benzene in the presence of mercury(I1) cyanide for 2 days at 40” gave 3-0-(2-O-benzyla-D-glucopyranosyl)-4,6-0 -ethylidene- 1 , 2 - 0- isopropylidene-a-Dgalactopyranose (61)in 47% yield. (113) S. Umezawa, K. Tatsuta, and S. Koto, Bull. Chem. Sac. Jpn.,42,533-537 (1969). (114) S. Umezawa, S. Koto, K. Tatsuta, H. Hineno, Y. Nishimura, and T. Tsumura, Bull. Chern. Soc. Jpn., 42,537-541 (1969). (115) H. M. Flowers, Carbohydr. Res., 18,211-218 (1971). (116) M. Dejter-Juszynski and H . M. Flowers, Carbohydr. Res., 18, 219-226 (1971); 2 3 , 4 1 4 5 (1972). (117) B. A. D. Stocker, A. M. Staub, R. Tinell, and B. Kopacka,Ann. Znst. Pasteur Paris, 98, 505-523 (1960). (118) 0. Liideritz, K. Jann, and R. Wheat, in “Comprehensive Biochemistry,” M. Florkin and E. H. Stotz, eds., Elsevier, Amsterdam, 1968, Vol. 26A, pp. 105-228.

KIKUO IGAHASHI

264

PNBO

OPNB 0

0-CMe,

OC&Ph 59

OCH,Ph

60

PNB

=oc0

61

N

0

I 0-CMe,

2

Similarly, Suami and coworkers119~120 prepared raffinose (64) (and planteose) derivatives, respectively, by the reaction of tetra-o-benzyla-D-galactopyranosyl chloride (62) with 2,3,4,1‘,3’,4‘,6’-hepta-Oacetylsucrose (63) (and 2,3,4,6,1’,3‘,4’-hepta-O-acetylsucrose) in benzene in the presence of mercury(I1)cyanide and Drierite.

qH,OC&Ph

CH,OH

OCH,Ph

OAc

62

AcO 63

PhC&O

I

\i

OCH2Ph &-yH*

OAc

AcO

64

(119) T. Suami, T. Otake, T. Nishimura, and T. Ikeda, Carbohydr. Res., 26, 234-239 (1973). (120) T. Suami, T. Otake, T. Nishimura, and T. Ikeda, Bull. Chem. Soc. Jpn., 46,10141016 (1973).

THE KOENIGS-KNORR REACTION

265

Defaye and coworkers52prepared a-D-ghcopyranosyl a-D-XylOpyranoside (67) and a-D-ghcopyranosyl a-D-mannopyranoside in 49 and 44% yields, respectively, by the reaction of the appropriately protected glycopyranosyl bromide (65) with 2,3,4,6-tetra-O-acetyl-D-glucopyranose (66) in a mixture of benzene and acetonitrile in the presence of mercury( 11) bromide and mercury(11) cyanide.

H

66

W

Po\I

OAe

OChPh 65

O

H

O

V OH

67

Helferich and Mul1er1'lJz2 prepared a-D-glucopyranosides, including some disaccharides, by the reaction of 3,4,6-tri-@acetyl-@-D-glucopyranosyl chloride with alcohols in the presence of mercury(I1) succinate. Other g r o ~ p s ~have ~ ~ also , ' ~ prepared ~ a-D-linked oligosaccharides by using mercury(I1) cyanide as the catalyst. In the original report of Koenigs and Knorr,15 phenyl tetra-O-acetyl-@-D-glucopyranosidewas obtained by treatment of tetra-o-acetyla-D-ghcopyranosyl bromide with phenol in the presence of pyridine. However, it was found that pyridine is not a suitable acid acceptor, as it reacts with 2 to give N-(tetra-O-acetyl-a- and -p-D-ghcopyranosy1)pyridinium bromides (68 and 69).lZ5A detailed study was made by Lemieux and Morgan.lZ6Quinoline, s-collidine, and 2,6lutidine are, however, suitable as acid acceptors, and give a mixture of

(121) B. Helferich and W. M. Miiller, Naturwissenschaften, 57,496 (1970). (122) B. Helferich and W. M. Miiller, Chem. Ber., 104,671-673 (1971); 106, 715-716, 941-943, 2508-2512 (1973). (123) H. H. Baer, J. M. J. Frkchet, and U. Williams, Can. /. Chem., 52, 3337-3342 (1974). (124) K. Takiura, K. Kakehi, and S. Honda, Chem. Pharm. Bull., 21, 523-527 (1973). (125) E. Fischer and K. Raske, Ber., 43, 1750-1753 (1910). (126) R. U. Lemieux and A. R. Morgan,J. Am. Chem. S O C . , 85, 1889-1890 (1963).

KIKUO IGARASHI

266

YH,OAc I n

CH,OAc

OAC 2

1

OAc

Br-

AcO

1 Br-

68

69

a- and p-glycosides. Fischer and von Meche1lZ7obtained a mixture of the anomers of phenyl tetra-0-acetyl-D-glucopyranoside ( a:p = 2 :3) by the reaction of 2 with phenol in the presence of quinoline. Helferich and coworkers33prepared methyl a-D-glucopyranoside in 70% yield from 3,4,6-tri-O-acetyl-/3-D-glucopyranosy~ chloride (37) and methanol in the presence of 2,6-lutidine or s-collidine. West and SchuerchlZ8reported that the reactions of tetra-o-benzyla-D-glucopyranosyl bromide with triethylamine, dimethyl sulfide, or triphenylphosphine give the corresponding onium salts. The nuclear magnetic resonance (n.m.r.) spectra showed that they are 1 : 1 complexes of the glucosyl bromide and the nucleophiles, and the anomeric configurations are p. Treatment of the onium salts with anhydrous methanol in ether or dichloromethane gave methyl tetra-0benzyl-a-D-glucopyranosidesin good yields. In applying this procedure, Schuerch and coworkers obtained a mixture of isomaltose and gentiobiose derivatives in 50% yield.129,130 Zen and coworkers131prepared isomaltose, isomaltotetraose, and isomalto-octaose by the reaction sequence shown in Scheme 3 . Another very valuable principle for glycosidation reactions, introduced by Lemieux,8 is the so-called “halide ion-catalyzed glycosidation reaction.” In an equilibrium reaction with tetraethylammonium halide, an a-D-glycosyl halide that is more stable can be converted into the thermodynamically less stable p-D anomer, which may be present in much lower concentrations. The latter, however, reacts (127) E. Fischer and L. von Mechel, Ber., 49,2813-2820 (1916). (128) A. C. West and C. Schuerch,]. Am. Chem. SOC., 95, 1333-1335 (1973). (129) F. J. Kronzer and C. Schuerch, Carbohydr. Res., 33,273-280 (1974). (130) R. Eby and C. Schuerch, Carbohydr. Res., 39, 33-38 (1975). (131) S. Koto, T. Uchida, and S. Zen, Bull. Chem . S O C . ] p n . , 46, 2520-2523 (1973).

T H E KOENIGS-KNORR REACTION

267

OCH,Ph 70

71

OCH,Ph 72

CH,OH

OCH,Ph PhCKO O O - C H ,

I

,,,)-

2,e-lutidine

/

12

isomaltotetraose d e r i r

isomalto-octaose derivative

OCqPh 74

Scheme 3

much faster than the (Y-Danomer to give the l,2-cis-glycoside. Lemprepared many a-D-linked oligosaccharides ieux and in good yield by the reaction of per-0-benzylated 1,2-cis-glycopyranosyl bromides of D-glucose, D-galactose, and L-fucose with suitably protected sugar derivatives in dichloromethane alone (or with addi(132) R. U. Lemieux, K. B. Hendriks, R. V. Stick, and K. James,]. Am. Chem. SOC., 97,4056-4062 (1975). (133) R. U. Lemieux and H. Driguez, J. Am. Chem. SOC., 97, 4063-4069, 4069-4075 (1975).

268

KIKUO IGARASHI

tion of N,N-dimethylformamide) in the presence of tetraethylammonium bromide and ethyldiisopropylamine. For example,133the reaction of 2,2,2-trichloroethyl 2-acetamido-6-0-acetyl-2-deoxy-3-0(tetra-O-acetyl-B-D-galactopyranosyl)-P-D-glucopyranoside (75) with tri-0-benzyl-L-fucopyranosyl bromide (76) in a mixture of dichloromethane and N,N-dimethylformamide in the presence of tetraethylammonium bromide and ethyldiisopropylamine for 4 days at room temperature gave the 1,2-cis-glycoside 77 in 83% yield. De-

ws

+

CQOAc

H

3

W

OCH,CCl,

AcO

B

r

OCH,Ph

AcHN

OCH,Ph PhCH,O 76

75

AcO

OCH,CCl,

AcO 77

acetylation, followed by reduction with zinc to remove the 2,2,2-trichloroethyl group, and catalytic hydrogenolysis of the benzyl groups, gave 2-acetamido-2-deoxy-4-O-ar-~-fucopyranosyl-3-0-~-~-galactopyranosyl-D-glucose, which is known as the Lewis a , blood-group antigenic determinant. Gent and Gigg134a1s o prepared benzy 1 3,4,6-tri-O-benzyI-2-0-( 2,3,4, 6-tetra-O-benzy~-cr-~-g~ucopyranosy~)-a-~-ga~actopyranoside in 23% yield by this method. The preparation of 1,2-cis-glycosides of 2-amino-2-deoxy sugars has also been studied. Lloyd and S t a ~ e yand ' ~ ~Lloyd and c o ~ o r k e r s ~ ~ ~ J ~ ' (134) P. A. Gent and R. Gigg,J. Chem. S O C . Perkin Trans. I , 1446-1455 (1974). (135) P. F. Lloyd and M. Stacey, Tetrahedron, 9, 116-124 (1960). (136) P. F. Lloyd and G . P. Roberts, J. Chem. SOC., 2962-2971 (1963); 6910-6913 (1965). (137) P. F. Lloyd, B. Evans, and R. J. Fielder, Carbohydr. Res., 9, 471-481 (1969); 22, 111-121 (1972).

THE KOENIGS-KNORR REACTION

269

used the 2,4-dinitrophenyl group (DNP) to protect the amino group at C-2. The reaction of 3,4,6-tri-O-acetyl-2-deoxy-2-(2,4-dinitroanilino)a-D-glUCOpyranOSyl bromide (78) with an excess (10 molar equiva(79) in lents) of 1,2: 3,4-di-O-isopropy~idene-a-~-ga~actopyranose pyridine gave a-and p-linked disaccharides (80 and 81) in 30 and 15%

+ 8-Danomer (81) 78

79

6-CMez 80

DNP

c

-NO,

yields, respectively, together with N-[3,4,6-tri-O-acety1-2-deoxy-2(2,4-dinitroanilino)-~-~glucopyranosyl]pyridinium bromide. Meyer zu Reckendorf and Wassiliadou-MichelisOprepared a mix-acetylture of 3-azido-3-deoxy-1,2-0-isopropylidene-6-0-[3,4,6-tri-O 2-deoxy-2-(2,4-dinitroanilino)-aand -~-D-g~ucopyranosy~]-a!-D-g~ucofuranoses (a:p = 3 : 1) by the reaction of 3,4,6-tri-O-acety1-2-deoxy2-(2,4-dinitroanilino)-a-~-glucopyranosyl bromide with 3-azido-3deoxy-1,2-0-isopropylidene-a-~-glucofuranose in benzene in the presence of mercury(I1) cyanide and mercury(I1) bromide. Diphenoxyph~sphinyl~~~J~~ and p-methoxyben~ylidene~~~ groups are also used as protecting groups. The glycosidations gave a mixture of a-and 0-D-glucopyranosides. The synthesis of oligosaccharides on polymer supports by using the Koenigs-Knorr reaction has been studied by several g r o ~ p s . ' ~ - ' ~ ~ Frkchet and S c h ~ e r c h ' ~ ~used ~ ' ~ ' poly[p-(3-hydroxy-l-propenyl)styrenel(82) (@-CH=CH-CH,OH) as apolymer support, andallowed (138) F. E. Hardy,J. Chem. Sod., 375-377 (1965). (139) K. Heyns, K. Propp, R. Hamson, and H. Paulsen, Chem. Ber., 100, 2655-2663 (1967). (140) J. M. Frbchet and C. Schuerch,J. Am. Chem. Soc., 93,492496 (1971); 94,604609 (1972). (141) J. M. Frbchet and C. Schuerch, Carbohydr. Res., 22, 399-412 (1972). (142) J. M. Frechet and G. Pelle,]. Chem. Soc. Chem. Commun., 225-226 (1975). (143) U. Zehavi and A. Patchornik,J. Am. Chem. SOC., 95,5673-5677 (1973). (144) R. D. Guthrie, A. D. Jenkins, and J. StehEek,]. Chem. Soc., C , 2690-2696 (1971). (145) R. D. Guthrie, A. D. Jenkins, and G. A. F. Roberts,]. Chem. Soc. Perkin Trans. 1 , 2414-2417 (1973).

KIKUO IGARASHI

270

it to react with 2,3,4-tri0-benzyl-6-O-(~-methoxybenzoy~)-c~-~-g~ucopyranosyl bromide (83) in benzene in the presence of 2,6-lutidine, to give the resin-bound monosaccharide (84). The hydrolysis product (85) of 84 was again allowed to react with 83, to give the resin-bound disaccharide (86) (see Scheme 4). Removal of the resin was accomplished by ozonolysis, and the disaccharide derivative obtained was ~COCOC,~OMe-P

+

@CH=CH-C~OH

PhCKO OCSPh

82

83 2,B-lutidine CKOH

n,qOCOC,H+OMe-

OCKPh

OCbPh L

85

84

1.3

H&OCOC kOMe-P

6

0

bCH,Ph 86

I

C%OAc

P

!

OAc 87

Scheme 4

T H E KOENIGS-KNORR REACTION

271

reduced with sodium borohydride; then, successive hydrolysis of the p-methoxybenzoyl group, removal of the benzyl groups with sodium in liquid ammonia, and acetylation, gave isomaltose derivative 87, which showed + 122.6" (c 1.3, chloroform). Similarly, Zehavi and P a t ~ h o r n i kprepared '~~ an isomaltose derivative by using a light-sensitive polymer (88) prepared by attaching 6nitrovanillin to a chloromethylated styrene-divinylbenzene copolymer, followed by reduction of the aldehyde group to the alcohol with sodium borohydride. The polymer then reacted with 2,3,4-triO-benzyl-6-O-(p-nitrobenzoyl)-/3-~-glucopyranosy~ bromide (89) in benzene in the presence of pyridine to give the resin-bound monosaccharide 90, which was hydrolyzed, and retreated with 89 to give the resin-bound disaccharide 91. Release of the disaccharide was achieved by photolysis, to give the isomaltose derivative 92 (see Scheme 5).

0Z.N

OCHph 88

OCH,Ph

89

90

(1) OH(2) 89

OCqPh 91

(1) OH'

(2)hv

OCH,Ph 92

Scheme 5

0J-J

O J

272

KIKUO IGARASHI

Guthrie and coworker^'^^,^^^ used copolymers of styrene as soluble supports and 1,2,3,4-tetraC)-acetyl-6-O-(p-vinylbenzoyl)-~-D-glucopyranose or the corresponding 6-0-(p-vinylphenylsulfonyl) derivative. The polymer was treated with hydrogen bromide in acetic acid to give the resin-bound D-ghcopyranosyl bromide. This was converted into a 1,2-orthoester of methyl 2,3,4-tri-0-benzoyl-a-~-glucopyranoside in the presence of s-collidine and tetrabutylammonium bromide.34Rearrangement of the 1,2-0rthoester to the isomeric disaccharide derivative was achieved by refluxing in 1,2-dichIoroethane in the presence of 2,6-lutidinium perchlorate, p-toluenesulfonic acid, and a catalytic amount of methyl 2,3,4-tri-O-benzoyl-a-~-glucopyr a n 0 ~ i d e . The l ~ ~ resin-bound disaccharide derivative was hydrolyzed to remove the resin and the acyl groups, and the disaccharide obtained was purified by benzoylation and separation of the benzoates by preparative, thin-layer chromatography, to give methyl hepta-0benzoyl-a-gentiobioside in 7.1% yield (based on the starting polymer).

4. Mechanism of Glycosidation Reactions The general course of glycosidation from glycosyl halides having a participating group at C-2 may be depicted as shown in Scheme 6. Favored formation of a 1,2-trans-glycopyranoside(93) from the corresponding 1,2-cis-glycopyranosyl halide (95) by use of a large excess of an alcohol in the presence of a catalyst having a strong affinity for the halogen (a silver or mercury salt) can be explained by an sN2 type of mechanism. However, under the usual conditions of the KoenigsKnorr reaction, in which a limited amount of alcohol is used, the reactions may proceed via an intimate ion-pair (96), leading to the 1,2trans-glycopyranoside (93), and a solvent-separated ion or a free ion (97). The ion (97) reacts with alcohol to give the 1,2-trans- (93) and -cis-glycopyranosides (101),and is also transformed into an acyloxonium ion (98), leading to 93 or a 1,e-orthoester (94), or both, the formation of which depends upon the reaction conditions and the nature of the catalyst and alcohol used. As a result, the formation of 93 or 94 becomes the main route, as 101 can only be formed from 97 in competition with the formation of 93 and 98. Sometimes, it has been postulated that solvent participation can occur, to give an ion (100) from which 98 is formed. Furthermore, the 1,2-cis-glycopyranoside

(146) A. F. Bochkov, V. I. Snyatkova, and N. K. Kochetkov, Izu. Akad. Nauk S.S.S.R. Ser. Khim., 2684-2691 (1967).

THE KOENIGS-KNORR REACTION

273

(101)is mainly obtained from 95 in some cases when a mercury(I1) salt is used as the but the mechanism is still unclear.

95

96

97

1I

0

95

98

99

_r,./'

/

/

/

, /

/

;-.-x-

/'

-2

o \ cI p

OCOR

R 100

101

Scheme 6

When a l,2-truns-glycopyranosyl halide (99) is used as the starting material, the truns-glycopyranoside (93) with retention of configuration at the anomeric carbon atom or the o r t h o e ~ t e r (94) ' ~ ~(or ~ ~both) ~~ is mainly obtained. The use of mercury(I1) salts, or a combination of a silver salt and iodine,26-28often favors the formation of the 1,2-trunsglycopyranosides (93). As mentioned earlier, 1,2-cis-glycopyranosidesare usually obtained from glycopyranosyl halides having a nonparticipating group at C-2. In model experiments, the solvolysis of glycopyranosyl halides has been studied in detai1.94J40*'41,149-154 In general, it is found that, in the (147) R. U. Lemieux and C. Brice, Can.J. Chem., 33, 109-119 (1955). (148) R. U. Lemieux and J. D. T. Cipera, Can. /. Chem., 34,906-910 (1956). (149) A. J. Rhind-Tutt and C. A. Vernon, J . Chem. Soc., 4637-4644 (1960). (150) B. Capon, Chem. Reo., 69,407-498 (1969).

KIKUO IGARASHI

274

solvolysis of the glycopyranosyl halides, an s N 1 mechanism is normally involved, but, with strong nucleophiles and in solvents of low polarity, an s N 2 mechanism obtains. Rhind-Tutt and Vernon'49 found that the methanolysis of 2,3,4,6tetra-0-methyl-a-D-ghcopyranosyl chloride proceeds by an s N 1 mechanism, and mainly gives methyl tetra-0-methyl-fl-D-glucopyranoside (with inversion of configuration at the anomeric carbon atom). Ishikawa and Fletcherg4 studied the methanolysis of D-ghcopyranosyl bromides (102-105) having a nonparticipating group at C-2, 102 103 104 105

R1= R2 = R3 = CH,Ph R' = R2= CH2Ph, RS = COC,H,NO,-p R' = CH2Ph, Rz = Rs = COC,KN02-p R'

=

R2 = R3 = COC,H,NO,-P

and found that, in the presence of tetrabutylammonium bromide, the corresponding methyl a-D-glucopyranosides are mainly obtained, regardless of the anomeric configuration of the bromide used. They also observed the effects of the substituents at C - 3 , 4 , and -6 upon the rate of reaction and the proportion of the a-D-ghcopyranoside (see Table 111), and explained the results by the principle of the halide ion-cataTABLEI11 MethanolysisW of 3,4,6-Tri-O-substituted 2~-Benzyl-D-glucopyranosyl Bromides (102-105) in the Presence of Tetrabutylammonium Bromide (4 Molar Equivalents)

Compound 102 103 104 105

Configuration of bromide a

a

P a orp

Ratio of methyl D-glucopyranosides, tl/, ( m i d

ff:p

17 43 178 840

18:7 9:1 23:2 19:1

(151)C.P.J. Glaudemans and H. G. Fletcher, Jr., J. Am. Chem. SOC.,87, 2456-2461, 4636-4641 (1965). (152)L. R. Schroeder, J. W. Green, and D. C. Johnson,/. Chem. Soc., B , 447-453 ( 1966). (153)F.J. Kronzer and C . Schuerch, Carbohydr. Res., 27, 379-390 (1973). (154) J. M. J. Frichet and H. H. Baer, Can. I . %hem., 53,670-679 (1975).

THE KOENIGS-KNORR REACTION

275

lyzed reaction. The ratio of methyl a- and P-D-ghcopyranosides obtained depends upon the relative differences between the rates kl,k2,k3, and k4, as shown in Scheme 7. The rates of the equilibrium R

2 CHzORs 0 m

B

r

k,

R

zc

~ Oo ~ 3W

__t

R’O

R’O PhCH,O

R

2CH,ORS0

PhCH,O

q

k,

R

’

O

OMe

S

__f

OMe PhCH,O

PhCH,O

Br Scheme 7

reactions (k,and k2),in which k, is much greater than k, (as it is well known that an a-D-glucopyranosy1 bromide is thermodynamically more stable than the p-Danomer, with bromide ion formed or added), must be greater than those of the solvolysis (k,and kJ, in which k, is much greater than k4, as is also well known. As a result, formation of a-D-glucopyranosides is favored. Furthermore, the equilibrium reactions may proceed by an s N 2 mechanisms3 and the solvolysis may proceed by an s N 1 mechanism by way of intimate ion-pairs, which give the D-glucopyranosides with inversion of configuration at the anomeric carbon atom. Schuerch and c o w o r k e r ~ ’ ~also ~J~ studied ~ the methanolysis of 6-0acy~-2,3,4-tri-O-benzy~-a-~-g~ucopyranosy~ halides, and observed the effects of the 6-0-acyl substituent upon the reaction rate and the ratio of methyl a- to P-D-glucopyranoside. In applying this principle, Lemieux and coworker^^^^,^^^ prepared oligosaccharides in good yield as mentioned earlier. The preponderant formation of the 1,2-cis-glycopyranoside from a 1,2-ci.s-glycopyranosyl bromide, catalyzed by mercury(I1) bromide or mercury(II) cyanide, or both, or by tertiary amines, can similarly be explained.8 Another approach to the preparation of glycosides involves the use of silver salts, especially soluble silver perchlorate. It is well known that the nucleophilicity and the leaving-group ability155of the per(155)E. R. Thornton, “Solvolysis Mechanisms,” Ronald Press Co., New York, 1964, pp. 161-166.

KIKUO IGARASHI

276

chlorate ion are respectively much smaller and much better than those of halide ions. From these facts, and the experimental results obtained, it is likely that the Koenigs-Knorr reactions of the glycopyranosyl halides having a nonparticipating group at C-2, when silver perchlorate is used, proceed by way of oxocarbonium ions. Igarashi and coworkers101,102 studied such glycosidation reactions in detail, using both the a (49a and 50a) and the p anomers (49b and 50b) of 3,4,6-tri-O-acetyl-2-chloro-2-deoxyand -2-O-benzyl-~-ghcopyranosyl chloride (see Scheme 8), and confirmed that the reactions proceed FH,OAc

I

I R'

R'

49c R' = C1 SOC R' = 0CH;Ph

4911 R 1 = C1 50a R' = O C K P h I

/

I

I

/

I

/

/

/

t

I R'

J'

CH,OAc

!I

I I

t

CH,OAc

CH,OAc

Q - Q-

AcO

AcO

bc103

R' (51-54) b

R'

49b R'= C1 50b R' = OCH,Ph I I

AcOQoR* R'

(51-54)a

106

A' 107

Scheme 8

via common intermediates, such a: the glucopyranosyl perchlorates

(49c and ~ O C ) ,which mainly react with alcohols or methyl trityl ether by way of D-glucosyl perchlorate ions (107) (probably the solvated or free ions) (see Section 11,3). The observations that, in a nonpolar solvent, a-D-glucopyranosides (51a-54a) are mainly obtained, and that

THE KOENIGS-KNORR REACTION

277

the proportion of P-D-glucopyranoside (51b-54b) increases in a polar solvent, are reasonable, as the group moments of the C-5-0-C-1 and C-1-0 bonds in the formation of a-D-glucopyranosides are approximately opposed; consequently, the net moment would be expected to be smaller than that in the formation of P-D-glucopyranosides, where the group moments are approximately aligned (see Scheme 9). Moreover, the charge separation is unfavorable in nonpolar solvents, and favorable in polar s01vents.l~~ 4

I

R Scheme 9

Schuerch and studied the effects of solvents and 60-substituents in the glycosidation reactions of 1-0-p-tolylsulfonyl, 9-bromophenylsulfonyl, and -trifluoromethylsulfonyl derivatives of and -galactopyranose with 6-0-subs tituted 2,3,4-tri-O-benzyl-~-glucoalcohols. In the D-glucose series, the 6-O-(N-phenylcarbamoyl) derivative in diethyl ether as the solvent gives a higher yield of a-D-ghcopyranoside, whereas, in the D-galactose series, the 6-0-substituents play a minor role, and acetonitrile gives a higher yield of a-D-galaCtOpyranoside than is obtained in diethyl ether. They explained the results by a principle similar to the halide ion-catalyzed glycosidation, but further study may be needed in order to explain the complicated results clearly.

111. SYNTHESISOF GLYCOSIDES OTHER THAN PYRANOSIDES 1. General

Examples of the preparation of glycosides other than pyranosides by use of the Koenigs-Knorr reaction are rare compared with those of glycopyranosides. The glycofuranosides have been reviewed in this Series by Green.157Several methods other than the Koenigs-Knorr method have been reported for the preparations of glycofuranosides. Glycosidation (156) K. Igarashi, T. Honma, and T. Imagawa,]. Org. Chem., 35, 610-616 (1970). (157) J. W. Green,Adu. Carbohydr. Chem., 21,95-142 (1966).

278

KIKUO IGARASHI

of a free sugar (Fischer's method) with an alcohol in the presence of a low concentration of acid under kinetically controlled reaction-conLevene and coworkersl'O ditions gives alkyl glycofuranoside~.'~~*~~~ studied the rate of glycoside formation of free sugars, and clarified the initial formation of glycofuranosides, and their subsequent conversion into glycopyranosides. Pacsu and Green161J62 prepared alkyl glycofuranosides by treatment of the corresponding sugar dialkyl dithioacetals with alcohols in the presence of mercury(I1) chloride and mercury(I1) oxide at low temperature. In some cases, aqueous sodium hydroxide was used, instead of mercury(I1) oxide, to neutralize the hydrogen chloride formed. Wolfrom and coworkers163prepared ethyl p-D-galactofuranoside in 8590% yield from D-galactose diethyl monothioacetal. Ethyl p-D-g1ucofuranosidelMwas obtained by the reaction of 1,2O-isopropylidene-a-D-glucopyranose 5,6-carbonate with ethanol in the presence of hydrogen chloride, followed by hydrolysis with sodium hydroxide. Aryl glycofuranosides have generally been prepared by fusion of the corresponding furanose acetates with the appropriate phenol in the presence of p-toluenesulfonic acid or zinc c h l ~ r i d e . l ~ ~ - ' ~ ~ Fletcher and coworker^^^^-^^^ found that phenyl and methyl p-Dribofuranoside (1,2-truns) are obtained by treatment of 2,3,5-tri-Obenzoyl-D-ribofuranosyl bromide with sodium phenoxide and methoxide, respectively, whereas favored formation of P-D-arabinofurano(158) E. Fischer, Ber., 47, 1980-1989 (1914). (159) C. B. Purves and C. S. Hudson,]. Am. Chem. Soc., 56, 708-711 (1934). (160) P. A. Levene, A. L. Raymond, and R. T. Dillon,]. Biol. Chem., 95,699-713 (1932). (161) E. Pacsu and J. W. Green,]. Am. Chem. Soc., 58, 1823-1824 (1936). (162) E. Pacsu, Methods Carbuhydr. Chem., 2,354-367 (1963). (163) M. L. Wolfrom, D. I. Weisblat, and A. R. Hanze,]. Am. Chem. Soc., 66,2065-2068 ( 1944). (164) W. N. Haworth and C. R. Porter,]. Chem. SOC.,2796-2806 (1929). (165) K.-C. Tsou and A. M. Seligman,]. Am. Chem. SOC.,74, 5605-5608 (1952); 75, 1042-1044 (1953). (166) M. Ishidate and M. Matsui, Yakugaku Zasshi,82,662-669 (1962); Chem. Abstr., 58,4639 (1963). (167) T. Shimadate, N i p p o n Kagaku Zasshi, 83, 214-217 (1962); Chem. Abstr., 59, 6498 (1963). (168) H. Borjeson, P. Jerkeman, and B. Lindberg, Acta Chem. Scand., 17, 1705-1708 ( 1963). (169) P. Jerkeman and B. Lindberg,Acta Chem. Scand., 17, 1709-1711 (1963). (170) E. Vis and H. G. Fletcher, Jr.,J. Am. Chem. SOC., 79, 1182-1185 (1957). (171) C. Pedersen and H. G. Fletcher, Jr.,]. Am. Chem. SOC.,82,941-945 (1960). (172) C. P. J. Glaudemans and H. G. Fletcher, Jr.,/. Org. Chem., 28,3004-3006 (1963).

THE KOENIGS-KNORR REACTION

279

side (1,2-cis) is observed in the reaction of 2,3,5-tri-O-benzyl-~-arabinofuranosyl chloride with sodium methoxide. was obtained Ethyl 2,3,5,6-tetra-O-acety1-P-~-galactofuranoside by treatment of 2,3,5,6-tetra-O-acetyl-D-galactofuranose with ethyl iodide in the presence of silver o ~ i d e . " ~ Hanessian and B a n o ~ b prepared l ~ ~ ~ P-D-ribofuranosides by the reaction of 1-0-acety~-2,3,5-tri-O-benzoy~-~-~-ribofuranose with N,N-dimethylformamide dialkyl acetals in the presence of stannic chloride. Methyl 2,3,4,5-tetra-O-methyl-P-D-ghcoseptanoside was obtained in 70% yield by the reaction of 2,3,4,5-tetra-0-methyl-D-glucose with methanol in the presence of a cation-exchange resin (H+).174 Methyl 2,3 :4,5-di-O-isopropy1idene-aand -P-D-glucoseptanoside were obtained in 53.6 and 29.2% yield, respectively, by methylation of 2,3 :4,5-di-O-isopropylidene-~-g~ucoseptanose with methyl iodide in the presence of silver 0 ~ i d e . l ~ ~ 2. Synthesis of Glycofuranosides

As with the pyranosides, glycofuranose 1,2-orthoesters or 1,Ztrunsglycofuranosides are obtained by treatment of 1,2-truns-glycofuranosyl halides having a participating group at C-2 with certain alcohols, and 1,2-cis-glycofuranosides are obtained from glycofuranosyl halides having a nonparticipating group at C-2. G ~ r i n ' ?studied ~ the Koenigs-Knorr reaction of 2-O-substituted 3,sdi-O-benzoyl-a-L-arabinofuranosyl (108) and -D-ribofuranosyl (111) bromide with methanol and 1,2,3,4-tetra-O-acety1-P-D-glucopyranose (see Table IV). Compound 108 gave the 1,Zorthoester 109 plus the glycoside 110, and bromide 111 gave the 1,2-orthoester 112 plus the glycoside 113. Per1ini7' reported that a syrup tentatively assigned the structure of methyl 5,6-di-O-acetyl-p-~-mannofuranoside 2,3-carbonate was obtained by treatment of the corresponding furanosyl bromide with methanol in the presence of silver oxide, whereas methyl a-D-mannofuranoside was obtained in high yield by the action of sodium hydroxide in methanol.

(173) H. H. Schlubach and K. Meisenheimer, Ber., 67,429-430 (1934). (173a) S. Hanessian and J. Banoub, Tetruhedron Lett., 657-660, 661-664 (1976). (174) E. F. L. J. Anet, Curbohydr. Res., 8, 164-174 (1968). (175) J. D. Stevens, Aust. J. Chem., 28,525-557 (1975). (176) P. A. J. Gorin, Can. J . Chem., 40, 275-282 (1962). (177) A. S. Perlin, Can. J . Chem., 42, 1365-1372 (1964).

TABLEIV reaction^"^ of 2-U-Substituted 3,5-Di-O-benzoyl-~-arabino(108) and -D-ribofuranosyl Bromides (111)with Methanol or 1,2,3,4-Tetra-@acetyl-P-D-glucopyranose

2-Substituted bromide derivatives ~~

~

Specific rotation (degrees)

Product from methanol"

Product from 1,2,3,4tetraa-acetyl-P-Dglucopyranoseb

~

108 2-O-Acetyl-, a2-O-Benzoyl-, a2-O-(p-Nitrobenzoyl)-, a-

-112

-63

mainly orthoacetate, plus a- and p-glycosides orthobenzoate, plus a- and p-glycosides ( p > a) ortho-( p-nitrobenzoate), plus a- and P-glycosides

(P > 4 e-O-Nitro-, a2-Hydroxyl-, a-

111 2-O-Acetyl-, p2-O-Benzoyl-, 02-0-(p-Nitrobenzoyl)-, pe-O-Nitro-, p2-Hydroxyl-, a-

-65 - 103 -52 -11

+8

-39

+ 109

p-glycoside P-glycoside orthoacetate, plus a- and P-glycosides orthobenzoate, plus p-glycoside ortho-( p-nitrobenzoate), plus a-and p-glycosides a-glycoside, plus trace of p a- and P-glycosides

a-disaccharide, trace of p a-disaccharide, trace of p a-disaccharide, trace of p p-disaccharide, trace of a a-and p-disaccharides ( a : p = 39:61) orthoester orthoe ster p-disaccharide, plus orthoester a- and p-disaccharides ( a : p = 8 : 17) a- and p-disaccharides (a:P = 23:27)

~

" Reactions were conducted by using a large excess of methanol in the presence of silver oxide. * Reactions were performed by using about five molar equivalents of 1,2,3,4-tetra-O-acetyI-p-D-glucopyranose in the presence of silver oxide, iodine, and Drierite.

2 1$

s

THE KOENIGS-KNORR REACTION

BzOH,C Qr OR

+

-

7Q

BzOH,C

R'oH

OR

110

109

Br + R!OH

OR

BzOH,CQ-OR.

0-C-OR' I R"

108

RzO

+

28 1

+ B

- B z o H 2 c ~ T

BzO

0-C-OR'

I

z

o

H

BzO

2

c

~

~

OR

R" 111

112

113

G. R. Barker and obtained methyl a-D-ribofuranoside by the reaction of 5-O-(methoxycarbonyl)-~-ribofuranosy~ chloride 2,3-carbonate with methanol in the presence of silver carbonate, followed b y deacylation. R. Barker and F1etche1-l~~ reported that methyl a-D-ribofuranoside was mainly obtained by treatment of 2,3,5-tri-O-benzyl-~-ribofuranosyl bromide with methanol in the presence of silver carbonate. Zorbach and coworkers180obtained methyl 2-deoxy-a- and p-~-ribohexosides (a:p = 3 : 17) by treatment of 2-deoxy-3,5,6-tri-O-(p-nitrobenzoy1)-a-DI-ibo-hexosyl bromide with methanol in the presence of silver carbonate. Frgchet and B a e P 4 found that, in the methanolysis of 2,3-di-Obenzyl-5,6-di-O-(p-nitrobenzoy~)-~-~-ga~actofuranosyl bromide and chloride in the presence of tetrabutylammonium bromide, mercury(I1) cyanide, or silver tetrafluoroborate, the corresponding methyl a-D-galactofuranoside is mainly obtained, regardless of the catalyst used. Pedersen and coworkers181reported that, in the methanolysis of 3 , s di-O-acyl-2-bromo-2-deoxy-a-~-arabino-and -P-D-xylo-furanosyl bromide in the presence of silver carbonate, a preponderance of the corresponding methyl 1,2-cis-furanoside was obtained. In the total synthesis of dihydrostreptomycin, S. Umezawa and co-

(178) G . R. Barker, I. C . Gillam, and J. w. Spoors, Chem. Ind. (London), 1312 (1956). (179) R. Barker and H. G. Fletcher, Jr.,]. Org. Chem., 26,4605-4609 (1961). (180) C. C. Bhat, K. V. Bhat, and W. W. Zorbach, Carbohydr. Res., 10,197-212 (1969). (181) K. Bock, C. Pedersen, and P. Rasmussen,Acta Chem. Scand., Ser. B,29,185-190 (1975).

~

f

KIKUO IGARASHI

282

workers18' reported that the reaction of the a-l-dihydrostreptobiosamine derivative 114 with the racemic streptidine derivative 115 in benzene in the presence of silver carbonate, silver perchlorate, and molecular sieve gives four products, one of which proved to be identical with a derivative (116) of natural dihydrostreptomycin.

dI

AcN-C=N-CO,C&Ph

I Ac @-;;N-C02CsPh

8

(182) S. Umezawa, T. Tsuchiya, T. Yamasaki, H. Sano, and Y. Takahashi,J. Am. Chem. SOC.,96,920-921 (1974).

THE KOENIGS-KNORR REACTION

283

3. Synthesis of Glycoseptanosides There is no evidence that aldohexoses in aqueous solution exist to any extent as septanoses. However, in an n.m.r. study, C o x ~ nfound '~~ that 2,3,4,5-tetra-O-methyl-D-glucose in chloroform contains 60% of the P-septanose and 40% of the acyclic form. Micheel and S u ~ k f U l lfirst ' ~ ~ prepared methyl 2,3,4,5-tetra-O-acetyla-D-galactoseptanoside by treatment of the corresponding septanosyl chloride with methanol in the presence of silver carbonate. Whistler and Campbellla5 and Cox and Owen186similarly prepared methyl 6-thio-a- and -P-D-galactoseptanoside derivatives.

(183) B. Coxon, Carbohydr. Res., 12, 313-334 (1970). (184) F. Micheel and F. Suckfull, Ann., 507, 138-143 (1933). (185) R. L. Whistler and C. S. Campbel1,J. Org. Chem., 31, 816-818 (1966) (186) J. M. Cox and L. N. Owen,/. Chem. Soc., C, 1121-1130 (1967).

This Page Intentionally Left Blank

METABOLISM OF D-FRUCTOSE

B Y MINSHEN C H E N AND ROY L. WHISTLER Department of Biochemistry, Purdue Unioersity, Lafayette, Indiana 47907 I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 11. Assimilation from Intestine . ........... 287 1. Hydrolysis of Sucrose . . . . 2. Mechanism of Absorption 111. Metabolism of D-Fructose in 1. Uptake of D-Fructose b y Liver . . . . . . . . 2. Degradation of D-Fructose to Triose .......................... 3. Regeneration of D-Glucose from D-Fructose, Involving Triose 294 Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Production of D-Glucose from D-Fructose, Involving D-Glucose &Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 5. Control of Metabolism of D-Fructose in L i v e r . . ....................... 296 IV. Metabolism of D-Fructose in Adipose Tissue ............................ 297 V. Metabolism of D-Fructose in Blood and Muscle Cells VI. Metabolism of D-Fructose in Testes and Spermatozoa 1. Biosynthetic Pathway for Production of D-Fructose in the Accessory Reproductive Organs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 2. Fructolysis by Spermatozoa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3. Regulation of D-Fructose Metabolism in Spermatozoa . . . . . . . . . . . . . . 303 4. Significance of D-Fructose in Male Fertility VII. Inborn Errors of D-Fructose Metabolis 1. Hereditary, D-Fructose Intolerance 2. Deficiency of Hepatic D-Fructose 1 VIII. Metabolism of D-Fructose in Micro-organisms ........................... 310 1. PEP-dependent Phosphotransferase System ........................... 310 2. Respiration-coupled Transport System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 314 3. Carrier-mediated Transport System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. Synthesis and Degradation of D-Fructans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 317 x . Effect of D-Fructose on Metabolism of Ethanol .......................... XI. Effect of D-Fructose on the Nucleotide Pool in Liver . . . . . . . . . . . 322 XII. Effect of D-Fructose on the Energy Metabolism of Intestinal, Epit .......................................................... 324 uctose on Lipid Metabolism ............................... 325 XIV. Key Enzymes in Metabolism of D-Fructose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 1. D-Fructokinase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 2. D-Fructose (D-Mannose) Kinase. ................. 33 1 285

286

MINSHEN CHEN AND ROY L. WHISTLER

3. D-Fructose 1-Phosphate Kiiiase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 4. D-Fructose Diphosphate Aldolase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 5. Triose Kinase ....................... . . . . . . . . . . . . . . 335 6. D-Fructose l,6-Diphosphatase ........................ 335 7. D-Glucitol Dehydrogenase (Sorbitol Dehydrogenase) . . . . . . . . . . . . . . . . . . 340 8. L-Glutamine :D-Fructose &Phosphate Aminotransferase . . . . . . . . . . . . . . . 341 XV. Use of D-Fructose ................................ . . . . . . . . . . . . . . . . . 343

I. INTRODUCTION D-Fructose has been a human dietary item from the time when prehistoric, ancestral humans first tasted honey and found pleasure in a sweet substance. Since then, sugars in one form or another have become an increasing component of the human diet. Industrial sucrose has existed since its first production in northeastern India, and it underwent a rapid development following its introduction into the growing conditions of the Western hemisphere b y colonists with Columbus on his second voyage in 1493. Beet sugar developed industrially in Europe some 300 years later, in the latter part of the eighteenth century and especially in the early years of the nineteenth century, because of the continental blockade during the Napoleonic wars. However, sugar cane still represents the largest single source of sucrose, half of which can give rise to D-fructose. Within the past five years, another development of great magnitude has taken place in sugar sweeteners; this is the result of the coming of age of enzyme engineering. Specifically, the development is the industrial, enzymic conversion of starch into D-glucose by glucoamylase (EC 3.2.1.3) and the subsequent conversion of the D-glucose into an equilibrium mixture with D-fructose b y using the enzyme isomerase ( E C 5.3.1.5).Five billion pounds of plant capacity for this conversion is now being added to American industry, and further construction of conversion plants is occurring outside North America. Economics will dictate the extent ofthis sweetener revolution, but it will proceed much further in the years ahead. In fact, the use of some agricultural land now devoted to beet and cane may be altered to cereal crops for starch, protein, and oil production, with the starch further transformed into Dglucose-D-fructose mixtures. In recent years, crystalline D-fructose has been produced and offered not only as an unusually sweet sugar but as a beneficial sweetening agent for people with certain ailments or, because of its claimed ease of metabolism, for athletes in whom it is said to provide quick energy. A review of the voluminous literature on the metabolism of D-fructose presents relatively clear information, and an attempt is made in this article to set forth a useful summary.

METABOLISM OF D-FRUCTOSE

11. ASSIMILATIONFROM

287

INTESTINE

1. Hydrolysis of Sucrose D-Fructose in the human diet derives mainly from sucrose, fruits, and honey. Sucrose is P-D-fructofuranosyl a-D-glucopyranoside, and, after hydrolysis by invertase (EC 3.2.1.26),to D-glucose and D-fructose, can be absorbed from the sniall intestine. In the human intestine, invertase, as well as a-D-glucosidases, is developed very early in fetal life, and even appears much earlier than lactase (EC 3.2.1.23).There is no significant, intestinal transport of unhydrolyzed sucrose, and, in animal experiments, sucrose administered b y injection is quantitatively excreted in the urine.' Intestinal invertase is produced by mucosal cells localized in the brush-border membrane of the mucosal epithelia. Invertase is not secreted,'-4 and little or no invertase (sucrase) has been found in the intestinal lumen.' The specific localization of sucrase at the mucosal, luminal interface is thought to be of functional importance in coupling sucrose digestion to transport.' Hydrolysis of sucrose occurs rapidly within the outer portion of the brush-border, plasma membrane, whereupon most of the monosaccharides released are transported across a permeability barrier located in the inner portion of the same membrane. Some hydrolytic products diffuse backward from the mucosal site of formation, and accumulate ~ - ~mucosal site of hydrolysis is identified by the use in the l ~ m e n . The of fluorescent antibodies against sucrase8 and by differential centrifugation of intestinal preparations.2 D-Glucose is absorbed from the intestine much more rapidly than D-fructose, and the rate of hydrolysis of sucrose only slightly exceeds that of D-glucose abs0rption.j After hydrolysis of sucrose in the intestine, only 10%of the theoretical amount of the D-glucose released appears in the lumen, whereas almost 50% of the D-fructose released accumulates intral~minally.~ The rise in serum D-fructose levels is significantly higher when D-fructose is given orally as a component of (1) A. Dahlquist,Acta Aled. Scand. S u p p l . , 542, 13-18 (1972). (2) D. Miller and R. K. Crane, Biochirn. Biophys. Acta, 52, 293-298 (1961). (3) A, Dahlquist,j. Clin. Incest., 41, 463-470 (1962). (4) S . Anricchio, A Rubino, R. Tosi, G. Semenza, M. Limdolt, H. Kistler, and A. Prader, En~yrnoZ.B i d . Clin., 3, 193-208 (1963). (5) G. M. Gray and F. J. Ingelfinger,j. Clin. Incest., 45,388-398 (1966). (6) G. M . Gray and F. J. Ingelfinger,j. Clin. Incest., 44,390-398 (1965). (7) J. F. Detheridge, J. Matthews, and D. H . Smyth,]. Physiol. (London),183,369-377 ( 1966). (8) R. G. Doell, G. Rosen, and N. Kretchower, Proc. Natl. Acad. Sci. U.S.A.,54, 1268-1273 (1965).

288

MINSHEN CHEN AND ROY L. WHISTLER

sucrose than when it is given in an equivalent amount as invert sugarg (see Fig. 1).Thus, D-fructose released by sucrose hydrolysis is ab-

-

E 10 0

0 L

e0

a o?

-f

8/

30

4

p-

--0

,P's,crose

60

90

120

Time (min)

FIG.1.-Mean Increase9 in Serum D-Fructose Level in Man After Oral Administration of Sucrose (2 g per g of body weight) or an Equivalent Amount of a Mixture of D-Glucose (1.052 g) and D-Fructose (1.052 g ) .

sorbed faster than D-fructose entering the intestine as a monosaccharide m i ~ t u r e .This ~ , ~ more-rapid absorption does not result from a difference in the rate of delivery from the stomach to the duodenum,1° or from the actual rate of absorption of D-fructose by the i n t e ~ t i n eas ,~ these parameters are almost the same on administration of either sucrose or the component monosaccharides. Nor is the hydrolytic step rate-limiting for the overall absorption of sucrose. Instead, it is probable that a high, local concentration of D-fructose is achieved from splitting of sucrose at the brush-border membrane near the transport site, thereby increasing the transport of D-fructose from the sucrose over that achieved through diffusion of D-fructose from a luminal, monosaccharide m i ~ t u r e . ~ , ~ The more rapid absorption of D-fructose derived from sucrose over that of administered free D-fructose can be observed clinically. Thus, 100 g of D-fructose administered by mouth usually results in an osmotic diarrhea, whereas 200 g or more of sucrose similarly administered rarely produces diarrhea.s (9) I. MacDonald and L. J. Turner, Lancet, 841-843 (1968). (10) E. Elias, G . J. Gibson, L. F. Greenwood, J. N. Hunt, and J. H. Trupp,]. Physiol. (London), 194,317-326 (1968).

METABOLISM OF D-FRUCTOSE

289

2. Mechanism of Absorption of D-Fructose Existence of an active-transport system for D-glucose in mammalian intestine has been recognized for some time, but the mechanism of D-fructose transport is still controversial. Part of the controversy can be attributed to species differences in transport systems. Although the rate of uptake of D-fructose is lower than that observed for actively transported sugars, such as D-glucose and D-galactose (see Table I), TABLEI Absorptive Rate" of Monosaccharides by the Human Jejunum, Compared to the Rate of Absorption of D-Glucose Sugar perfused (g/min/30 cm of jejunum) 1 .o

0.5 0.2

D-Glucose

D-Galactose

1.00 1.00 1.00

1.07 1.07 1.04

D-FIWCtose 0.89

0.65 0.64

D-xylose

L-sor-

bose

D-Mannose

0.43

0

0

absorption is relatively efficient, and D-fructose is absorbed faster than such sugars as L-sorbose or D-mannose, which are thought to enter intestinal cells by passive diffusion." Partial conversion of D-fructose into D-glucose within the intestinal mucosa has been demonstrated in the dog,12 guinea pig,13 and hamster.14 It has been suggested that this conversion into an actively transported sugar may account for the enhanced rate of disappearance of D-fructose over that observed for L-sorbose or D-mann0~e.l~ Conversion of D-fructose into lactate has also been considered a possible explanation for the higher rate of D-fructose uptake.15 Kiyasu and ChaikofP5found a 70% conversion of labeled D-fructose into D-glucose in guinea-pig intestine, and Shoemaker and coworkers12 reported 58% conversion in dog intestine. In the rat, however, only about 10%of the absorbed D-fructose is recovered as D-glucose15

(11) C. D. Holdsworth and A. M. Dawson, Proc. S O C . E r p . Biol. Med., 118, 142-145 ( 1965). (12) W. C. Shoemaker, H. M. Yanof, L. N. Turk, and T. H . Wilson, Gnstroenterology, 44,654-663 (1963). (13) E. Riklis and J. H. Quastel, Can.]. Biochem. Physiol., 36, 347-362 (1958). (14) T. H. Wilson and T. N. Vincent,J. Biol. Chem., 216, 851-866 (1955). ( 1 5 ) J. Y. Kiyasu and I. L. Chaikoff,]. Biol. Chem., 224, 935-939 (1957).

290

MINSHEN CHEN A N D ROY L. WHISTLER

As D-fructose is not rapidly metabolized in rat (or human) intestinal cells, rat intestine can be effectively used for transport measurements. D-Fructose is actively transported in rat small-intestine by a process demonstrating Michaelis-Menten kinetics. The cellular accumulation of D-fructose is an energy-dependent process, and is inhibited by 2,4dinitrophenol, fluoride, anoxia, and h y p ~ t h e r m i a . ' ~ Phlorizin ,'~ at a concentration of 0.1 mM does not adversely affect a c c ~ m u l a t i o n , ' ~ ~ ~ ~ but is said to inhibit cellular accumulation at 0.5 mM to 5 mM concentrations;I6 however, Guy and Deven18 failed to observe inhibition by phlorizin. It is not known if the active transport involves Na+. In the brush border of rat or hamster ~ ~ n a l l - i n t e s t i n eor, 'in ~ ~sheets ~ ~ of rabbit ileum, D-fructose transport is not affectedz1by Na+. In contrast, Gracey and coworkers, working with segments of rat small-intestine found that replacement of Na+ by K+, Li+, or Tris+ markedly lowers the uptake of D-fructose, and inhibits its active, cellular accumulation.16 When these tissues are transferred to a normal medium containing 145 mM or higher of sodium ions, almost normal restoration ofD-fructose uptake occurs. MacRae and N e ~ d o e r f f e ralso ' ~ reported a sodium dependence for absorption of D-fructose. However, replacement of sodium chloride with choline hydrochloride causes a significant increase in absorption of D-fructose. Because different substitutes for NaCproduce differences in the amount of D-frUctoSe absorption, it is possible that there may not be strict dependence on Na+ for uptake of D-fructose. It is conceivable, also, that D-fructose uptake may be influenced by secondary events resulting from a deficiency of sodium ions. The D-fructose transport-system seems to be highly sugar-specific, although a decrease in uptake occurs in the presence of D-sorbose, Dglucose, D-galactose, 3-O-methyl-D-glucose, and sucrose. Little effect on uptake is shown by the presence of D-arabinose, D-fucose, D-mannose, L-sorbose, D-tagatose, and D-xylo~e.'~ Cellular accumulation of D-fructose is inhibited by the presence of glycine, L-hydroxyproline, L-lysine, and L-phenylalanine. There is a well known relationship between transport systems for hexose and amino acid in intestine and k i d n e ~ . D-Fructose ~ ~ - ~ ~ inhibits transport of L-alanine and glycine in rat intestine, but has no effect on transport (16) M. Gracey, V. Burke, and A. Oshin, Biochim. Biophys. Acta, 226,397-406 (1972). (17) A. R. MacHae and T. S. Neudoerffer, Biochim. Biophys. Acta, 288,137-144 (1972). (18) M. J. Guy and J. J. Deven, Am.]. Physiol., 221, 1051-1056 (1971). (19) A. M. Goldner, S. G. Schultz, and P. F. Curran,]. Gen. Physiol., 53,362-383 (1969). (20) K. Sigrist-Nelson and U. Hopfer, Biochim. Biophys. Acta, 367, 247-254 (1974). (21) S. G. Schultz and C. Strecker, Biochim. Biophys. Acta, 211, 586-588 (1970). (22) S. Segal, S. Their, M. Fox, and L. Rosenberg, Biochim. Biophys.Acta, 65,567-568 (1962).

METABOLISM OF D-FRUCTOSE

29 1

of L-inethionine or proli line.'^,'^ Because of structural dissimilarity between D-fmCtOSe and the L-amino acids, the inhibition between them may result from simple, competitive utilization of energy for active transport. It may be concluded that, at present, the major source of D-fructose in the human diet is sucrose. Sucrose is hydrolyzed in the brushborder membrane, and the D-fructose is actively transported by a highly specific and energy-dependent process that may be Na+-iondependent, but is inhibited by amino acids.

111. METABOLISMOF D-FRUCTOSE IN LIVER,INTESTINE, AND KIDNEY

1. Uptake of D-Fructose by Liver Liver is the principal site of D-fructose metabolism. D-Fructose is transported to the liver from the small intestine by way of the portal blood-vessel. Experiments with perfused pig and rat livers revealed that the rate of elimination of D-fructose from blood is a function of the sugar ~oncentration,'~,'~ and follows Michaelis-Menten kinetic^.'^,'^ Carrier-mediated, liver-membrane transport of D-fructose has a high29 K , and V,,, , in comparison to the intracellular phosphorylation constants of D-fructose in both pigeon and rat liver^.^^,^^ For example, the calculated rat-liver transport for D-fi-uctose has a K , of 67 mM and a V,,, of 30 pmole.min-'.g-', in contrast to the lower, calculated frucof 10.3 pmole.min.-'.g-' with D-fructokinase K , of 1.0 mM and V,, tose and K , of 0.54 mM with adenosine 5'-triphosphate (ATP).In perfused pig-liver,28the transport K, for D-fructose is only ten times that of intracellular phosphorylation by fructokinase. Hence, D-fruCtoSetransport values suggested that, at physiological D-fructose concentrations, membrane transport limits the rate of uptake, thereby protecting the liver from severe depletion of adenine n u ~ l e o t i d e . * * ~ ~ ~

(23) S. Their, M. Fox, L. Rosenberg, and S. Segal, Biochim. Biophys. Acta, 93,105-115 (1964). (24) J. K. Bingham, H. Newey, and D. H. Smyth, Biochim.Biophys. A c t a , 120,314-316 ( 1966). (25) S . J. Saunders and K. J. Isselbacker, Biochim. Biophys. A c t a , 102,397-409 (1965). (26) L. Sestoft, S. Damgaard, N. Tygstrup, and F. Lundquist,Acta Med. Scand. S u p p l . , 542, 119-129 (1972). (27) L. Sestoft, Biochim. Biophys. Acta, 343, 1-16 (1974). (28) L. Sestoft, K. T ~ n n e s e n F. , V. Hansen, and S. E. Damgaard, Eur. J. Biochem., 30, 542-552 (1972). (29) L. Sestoft and P. Flerou, Biochim. Biophys. Acta, 345,27-38 (1974).

MINSHEN CHEN AND ROY L. WHISTLER

292

2. Degradation of D-Fructose to Triose The same pathway is followed for D-fructose metabolism in liver, intestine, and kidney (see Scheme 1).30-33Phosphorylation of D-fruc-

fructokinase

-

t

glucokinase hexokinase

D-glucitol dehydrogenases D-glucose 6-phosphate

D-fructose 6-phosphate D-

Fructose 1-phosphate

a l d o l a s e h

-

glycerone phosphate

t -

It--

L-glycerol 3-phosphate glycerolkinase

r

D-fructose 1,6diphosphatas e

aldolase

I

glycerol

alcohol dehydrogenases

II

dehydrogenase D-Glycerate

: 2-0-phosphono-D-glycerate

t

2

I

glycerate kinase pyruvate, lactate Metabolism of D-Fructose in Liver Scheme 1

(30) R. C. Adelman, F. J. Ballard, and S. Weinhouse, I . B i d . C h e m . , 242, 3360-3365 (1967). (31) F. Heinz and F. Weiner, Comp. Biochem. Physiol., 31,283-296 (1969). ( 3 2 ) F. Heinz, F. Schilegel, and P. H. Krause, E n z y m e , 19, 85-92 (1975). (33) F. Heinz, F. Schilegel, and P. H. Krause, E n z y m e , 19, 93-101 (1975).

METABOLISM O F D-FRUCTOSE

293

tose to D-fructose 1-phosphate is catalyzed by fmctokinase (EC 2.7.1.4).34D-Fructose 1-phosphate is cleaved to 1,3-dihydroxy-2-propanone (glycerone) phosphate and D-glyceraldehyde by aldolase B (EC 4.1.2.13).32Glycerone phosphate enters the triose phosphate pool, and is metabolized either to pymvate or to D-glucose or glycogen, depending upon whether glycolysis or gluconeogenesis is dominant. D-Glyceraldehyde appears to be used by three different routes: (a) direct conversion into D-glyceraldehyde 3-phosphate by triose kinase ( b ) reduction to glycerol by NADH- or NADPH(EC 2.7.1.28),"5,36 specific37alcohol dehydrogenase (EC 1.1.1.1 or EC 1.1.1.2), followed by phosphorylation to afford 3-O-phosphono-~-glycerate,~~~~~ and (c) oxidation to D-glycerate by aldehyde dehydrogenase (EC 1.2.l.2):0941 followed by phosphorylation to 2-0-phosphono-D-glycerate by glycerate kinase (EC 2.7.1.31).42Burch and coworkers believed that the as D-fructose is utilized faster than glycerol. If first route is glycerol is the first product, the level of glycerol phosphate should be very high, whereas the concentration is only a little higher than that of glycerone. Then, too, if glycerate is the first product, it would be expected that a higher level of glycerate 3-phosphate than of glycerone would be found, which is not observed. The demonstration of a low K , (0.01 mM) for triose kinase, in contrast to the higher K , for aldehyde dehydrogenase (0.3mM), alcohol dehydrogenase with NAD (11 mM), and alcohol dehydrogenase with NADP (0.6 mM), points to a preferential transformation of glyceraldehyde into glyceraldehyde 3phosphate in the liver metabolism of D-fructose. Fructokinase and triose kinase have a parallel distribution and development in rat liver.44 (34) G. T. Cori, S. Ochoa, M. W. Slein, and C. F. Cori, Biochim. Biophys. Acta, 7, 304-317 (1951). (35) H. G. Hers and T. Kusaka, Biochim. Biophys. Acta, 11,427-437 (1953). (36) F. Heinz and W. Lamprecht, H o p p e - S e y l e r ' s 2. P h y s i o l . Chem., 324, 88-100 (1961). (37) H. P. Wolf and F. Leuthardt, Helu. Chim. Acta, 36, 1463-1467 (1953). (38) C. Buhlitz and E. P. Kennedy,J. B i d . Chenz., 211, 951-961 (1954). (39) 0. Wieland and M. Suyter, Biochem. Z., 329,320-331 (1957). (40) E. Racker,J. Biol. Chem., 177,883-892 (1949). (41) A. Holldorf, C. Holldorf, G. Schneider, and H. Holzer, Z. Naturforsch. Teil B, 14, 229-234 (1959). (42) W. Lamprecht, T. Diamantstein, F. Heinz, and P. Balde, Hoppe-Seyler's Z. Physiol. Chem., 316, 97-112 (1959). (43) H. B. Burch, 0. H. Lowry, L. Meinhardt, P. Max, Jr., and K. Chyu,]. Biol. Chem., 245,2092-2102 (1970). (44) A. Sillero, M. A. G. Sillero, and A. Sols, Enzymol. Biol. Clin., 11, 563-566 (1970).

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In kidney, the reduction of D-glyceraldehyde to glycerol by alcohol dehydrogenase might be favorable in D-fructose metabolism, as, after giving D-fructose to rats, the ratio of glycerol phosphate to glycerone phosphate increases 13-fold, with but minor change in the lactate :pyruvate ratio. Thus, a large fraction of the glyceraldehyde produced from D-fructose l-phosphate is metabolized through glycerol, and causes the same disproportionate increase in glycerol phosphate as is seen when glycerol is given alone.43In addition, a high level of NADPlinked alcohol dehydrogenase is observed,45which might be responsible for reduction of glyceraldehyde. The alcohol dehydrogenase activity of kidney is increased in the presence of D - f r u c t o ~ e . ~ ~

3. Regeneration of D-Glucose from D-Fructose, Involving Triose Condensation Production of D-glucose from D-fructose can proceed through the condensation of glycerone phosphate with D-glyceraldehyde phosphate to form D-fructose 1,6-bisphosphate, which is converted into D-fructose 6-phosphate by removal of phosphate with D-fructose 1,6diphosphatase (EC 3.1.3.11). D-Glucose is formed by isomerization of D-fructose 6-phosphate to D-glucose 6-phosphate, with subsequent hydroly~is.~' This path requires D-glucose 6-phosphatase for conversion of D-glucose 6-phosphate into free D-glucose. The absence of D-glucose 6-phosphatase (EC 3.1.3.9) from rat intestine accounts for the small conversion of D-fructose into D-glucose in this It is now generally accepted that D-glucose 6-phosphatase is present in human i n t e ~ t i n e , 4 ~although -~* earlier reports to the contrary can be found.48There is a lack of agreement, however, as to the degree of conversion of D-fructose into D-glucose in human intestine. Ockerman and L ~ n d b o r g reported ~~ that up to 70% of the D-fructose absorbed is recovered in the mesenteric veins as newly isomerized D-glucose. Holdsworth and Dawsonll found a small conversion of D-fructose into lactate, but none into D-glucose, and White and Landau53and (45) F. Heinz, Hoppe-Seyler's Z. Physiol. Chem., 349, 399404 (1968). (46) B. W. Moore,/. A m . Chem. Soc., 81,5837-5838 (1959). (47) H. R. Williams and B. R. Landau, Arch. Biochem. Biophys., 150, 708-713 (1972). (48) V. Ginsburg and H. G . Hers, Biochim. Biophys. Acta, 38, 427-434 (1960). (49) H. E. Williams, P. L. Johnson, L. F. Fenster, L. Laster, and J . B. Field, MetahoZism, 12,235-241 (1963). (50) P. A. Ockerman, CZin. Chim. Acta, 9, 151-156 (1964). (51) P. A. Ockerman, Biochim. Biophys. Acta, 105, 22-33 (1965). (52) P. A. Ockerman and H. Lundborg, Biochim. Biophys. Acta, 105, 34-42 (1965). (53) L. W. White and B. R. Landau,/. Clin. Znuest., 44, 1200-1213 (1965). (54) 6. C. Cook, Clin. Sci., 37,675-687 (1969).

METABOLISM OF D-FRUCTOSE

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respectively found 16 and 15% conversion of D-fructose into D-ghcose. White and Landau53also found a 2-10% incorporation of the radioactive label from D-fructose into tissue glycogen. The differences in these findings is not clear, but the fact that Ockerman and Lundof D-fructose of 19-75 g/100 ml in their b ~ r used g ~ concentrations ~ perfusions, whereas the other investigators used 5-10 g/100 ml of solution, may be of some significance. Conversion of D-fructose into lactic acid is apparently of little significance in human intestine,54but may be important in rat i n t e ~ t i n e . ' ~ 4. Production of D-Glucose from D-Fructose, Involving D-Glucose 6-Phosphate

Another route of D-fructose transformation into D-glucose involves its 6-O-phosphorylation, with subsequent isomerization to D-glucose 6-phosphate, and hydrolysis thereof to free D-glucose. However, in liver, the high K , (2-6 mM) of hexokinase (EC 2.7.1.1) with D-fruc, ~ ~ it tose,55,56 compared with the K , of 0.1 mM for D - g l u ~ o s e makes unlikely that hexokinase would normally produce appreciable quantities of D-fructose 6 - p h o ~ p h a t e .Although, ~~ in contrast, intestinal hexokinase rapidly converts D-fructose into the 6-phosphate, the reaction is strongly inhibited in the presence of D-glucose, owing to the much lower K , of the enzyme for D-glucose than for D-fru~tose.~' Under physiological conditions, this difference in K , values probably precludes the conversion of D-fructose into D-glucose by this pathway.53 In both of the aforementioned transformations of D-fructose into D-glucose, D-glucose 6-phosphate is an intermediate. Muntz and VankoG0 found that, after intraportal injection of rats with D-[ 1-14C]fructose, the subsequent specific activity of liver D-glucose is higher than that of D-glucose 6-phosphate. The distribution of carbon-14 in C-1 and C-6 of D-glucose is different from that in D-glucose 6-phosphate after injection of D-[ 1-14C]- o r ~-[6-'~C]-fructose. This indication that D-glucose may be formed from D-fructose by a pathway not requiring Dglucose 6-phosphate as a precursor has been confirmed by others.61 In contrast, however, Williams and Landau4' found that D-[ 1-14C]or D-[6-14C]-fructoseincubated with liver slices, or injected intraportally into rats, gave the same distribution of carbon-14 in the D-g~UcOSe (55) D. L. Dipietro,J. Biol. Chem., 239, 4051-4055 (1964). (56) H. G. Hers, Biochim. Biophys. Acta, 8, 4 1 6 4 2 3 (1952). (57) D. G. Walker, Biochem. J., 87,576-581 (1963). (58) R. C. Adelman, Acta Med. Scand. S u p p l . , 542, 47-56 (1972). (59) A. Sols, Biochim. Biophys. Acta, 19, 144-152 (1956).

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residues of glycogen as in D-glucose 6-phosphate, indicating that Dglucose 6-phosphate is, in fact, an obligatory intermediate in the conversion of D-fructose into glycogen. In liver tissue cultured with added D-[6-14C]fructose,the distribution of radioactivity in D-glucose 6-phosphate is the same as in the D-glucosyl residues of the glycogen formed. Yet, when D-[ l-14C]fmctoseis present, there is a difference in the distribution of radioactivity in the D-glucose 6-phosphate formed and the D-glucosyl residues of the evolved glycogen. Whether this difference can be interpreted to explain the existence of a new pathway for conversion of D-fructose into D-glucose remains open.47

5. Control of Metabolism of D-Fructose in Liver Liver metabolizes up to 85% of orally administered D-fructose. Fructokinase, aldolase, and triose kinase are important control enzymes for hepatic D-fructose metabolisrn.'j2 The activities of these enzymes are subject to dietary composition and hormonal control. Total fructokinase, aldolase, and triose kinase decrease to about half or less of their normal activity on fasting for 48 to 72 hours, and are restored to normal in 24 hours upon D-fructose administration. Longterm feeding of D-fructose results in the maintenance of a considerably higher level of all three enzymes, an effect also seen with rats maintained on a high-fat or high-protein diet.62 Levels of all three enzymes are unchanged in the alloxan diabetic rat. Consequently, as expected, the utilization of D-fructose and its conversion into D-glucose, carbon dioxide, and glycogen is unimpaired in liver slices from diabetic Fructokinase activity of adrenalectomized or hypophysectomized, but fed, rats is at the fasting level of normal rats, and does not respond to fasting or further feeding In adrenalectomized or hypophysectomized rats, aldolase and triose kinase activities are normal, but decrease sharply on fasting, without recovery on subsequent feeding of D-glucose or D-fructose. Lack of responsiveness to D-fructose feeding, as well as the low levels of activ-

(60) J. A. Muntz and M. Vanko,]. Biol. Chem., 237, 3582-3587 (1962). (61) C. J. Threlfall and D. F. Heath, Biochern. I., 110, 303-312 (1968). (62) R. C. Adelman, P. D. Spolter, and S. Weinhouse,]. B i d . Chem., 241, 5467-5472 (1966). (63) M. Miller, W. R. Drucker, J. E. Owens, J. W. Craig, and H. Woodward, Jr.,]. Clin. Inuest., 31, 115-125 (1952). (64) S. S. Chernick and I. L. Chaikoff,]. Biol. Chem., 188, 389-396 (1951). (65) A. E. Renold, A. B. Hastings, and F. B. Nesbett,J. B i d . Chem., 209, 687-696 (1954).

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ity of these enzymes in hypophysectomized rats, may be attributed also to lack of glucocorticoid secretion, as aldolase and triose kinase levels are normalized by hydrocortisone administration.'j2 It was reported that D-fructose perfusate concentrations of'j610 mM 30 mM do not induce glucagon to stimulate gluconeogenesis in liver. However, for D-fructose at 2 mM concentration, which is near to the physiological concentration in liver, Veneziale found that glucagon stimulates conversion of D-fructose into D-gluCose.'j8The site(s) and mechanism for glucagon stimulation of D-fructose conversion are still uncertain.6s Thus, the major metabolic pathway for D-fructose passes through Dfructose 1-phosphate to D-glyceraldehyde and glycerone phosphate. D-Glyceraldehyde is phosphorylated to D-glyceraldehyde 3-phosphate, or is reduced to glycerol and then phosphorylated at a primary position, or, as a third, alternative pathway, may be oxidized to D-glycerate followed by phosphorylation to 2-0-phosphono-~-glycerate. Products from any one of the three routes enter the triose phosphate pool, where they are further metabolized in the glycolytic pathway. A fourth route for the products may lead to the production of D-glucose; this occurs by recombination of the two triose monophosphates to D-fructose 1,8bisphosphate, isomerization, and dephosphorylation.

I N ADIPOSE TISSUE Iv. METABOLISM OF D-FRUCTOSE

In adipose tissue, as in other tissues, D-fructose is transported by a mechanism different from that of D - g l u c ~ s eand , ~ ~by a system that is not in~ulin-dependent.~~ Metabolism of D-fructose is rapid, and is accomplished with the participation of fructokinase'j2 and a nonspecific h e x o k i n a ~ e . D-Fructose ~~,~~ utilization effectively occurs in adipose tissue of diabetic animals and of animals with inherited intolerance to D-fructo~e.~~

(66) B. D. Ross, R. Hems, and H. A. Krebs, Biochem.J., 102,942-951 (1967). (67) J. H. Exton, L. E. Mallette, L. S. Jefferson, E. H. A. Wong, N. Friedmann, T. B. Miller, Jr., and C. R. Park, Recent Prog. Horm. Res., 26, 411-461 (1970). (68) C. M. Veneziale, Biochemistry, 10, 3443-3447 (1971). (69) E. R. Froesch, Acta Med. Scand. S u p p l . , 542, 37-46 (1972). (70) E. R. Froesch and J. L. Ginsberg,J. Biol. Chem., 237,3317-3324 (1962). (71) K. G. Gromova, Biokhimiya, 30, 563-566 (1965). (72) E. R. Froesch, H. P. Wolf, H. Baitsch, A. Prader, and A. Labhart, Am. J . Med., 34, 151-167 (1963).

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v . METABOLISM OF D-FRUCTOSE I N BLOODAND MUSCLECELLS Erythrocytes and leucocytes metabolize D-fructose and D-glucose to approximately the same extent when either of the sugars is present in the medium. D-Glucose oxidation is not affected by addition of D-fructose to the medium, because the K , of hexokinase is much lower for D-glucose than for D-fructose. By measuring formation of 14C02from D-[14C]fructose,an inhibition is observed on addition of D-glucOSe to the incubation medium. Therefore, under normal, physiological conditions, erythrocytes and leucocytes, as well as brain cells, probably do not utilize D-fructose for this reason, and also because they are devoid of fi-u~tokinase.~~ Use of D-fructose by muscle cells is still a matter of debate. The results of in vitro experiments indicate rapid, muscular uptake of Dfructose, with both incorporation into glycogen and oxidation to carbon dioxide. However, when D-glucose is added in increasing amounts to muscle-tissue slices, D-fructose utilization decreases. It follows that metabolism of D-fructose in muscle under normal circumstances is limited, owing to competitive inhibition by D - g l u ~ o s e . ~ ~ VI. METABOLISMOF D-FRUCTOSE IN TESTESAND SPERMATOZOA D-Fructose has long been recognized as the principal, free reducing sugar in the seminal plasma of many mammalian specie^,^^-^^ including man and certain other primates It provides essential energy for the survival and motility of s p e r m a t o z ~ a Seminal .~~~~~ Dfructose originates from blood D - g l ~ c o s e ,and ~ ~ the production site appears to be within the seminal vesicle.76 .75,77378

1. Biosynthetic Pathway for Production of D-Fructose in the Accessory Reproductive Organs

Considerable effort has been devoted to elucidating the biosynthetic pathway for the production of D-fructose from D-glucose. Two pathways for biosynthesis in seminal vesicles have been proposed. The (73) E. R. Froesch, J. Zapt, U. Keller, and 0. Oelz, Eur. J. Clin. Inwest., 2,8-14 (1971). (74) T. Mann and C. Lutwak-Mann, Biochem. J., 43,266-270 (1948). (75) T. Mann, Biochem. J., 40, 481-491 (1946). (76) T. Mann, “The Biochemistry of Semen and of the Male Reproductive Tract,” Methuen, London, 1964. (77) A. B. Kar, S. R. Chowdury, A. R. Chowdury, V. P. Kamboj, and H. Chandra, Steroids, 5, 519-537 (1965). (78) R. C. Reznichek, J. D. Roussel, N. L. Mangelson, R. T. Kado, and A. T. K. Crockett, Fertil. Steril., 19, 376-381 (1968). (79) T. Mann and M. Parsons, Biochem. J., 46,440-450 (1950).

METABOLISM OF D-FRUCTOSE

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first, or “phosphorylative,” pathway involves ( a ) phosphorylation of D-glucose to D-glucose 6-phosphate b y hexokinase, followed by ( b ) conversion of D-glUCoSe 6-phosphate into D-fructose 6-phosphate catalyzed by D-glUCoSe 6-phosphate isomerase (EC 5.3.1.9) and, finally, ( c ) dephosphorylation of D-fructose 6-phosphate to free sugar and inorganic p h o ~ p h a t e . ~ The ~ , ~ second, ~ - ~ ~ “nonphosphorylative,” p a t h ~ a y involves ~ ~ - ~ ~(d ) an initial reduction of D-glucose to D-glucitol by NADPH-requiring reductase (EC 1.1.1.21),and ( e ) oxidation

( a ) D-Glucose + ATP -+ ~-glucose-6-P+ ADP ( b )D-Glucose-6-P D-fructose-6-P ( c ) D-Fructose-6-P + H,O -+ D-fructose + Pi D-Glucose + ATP + H,O -+ D-fructose + ADP + Pi of the D-glucitol to D-fructose by an NAD-dependent enzyme, D-ghcitol dehydrogenase (ketone reductase) (EC 1.1.1.14).The nonphosphorylative pathway is supported by the finding of D-glucitol in

( d ) D-Glucose + NADPH + H+ D-glucitol + NADP+ ( e ) D-Glucitol + NAD+ & D-fructose + NADH + H+ D-Glucose + NADPH + NAD+ -+ D-fructose + NADP+ + NADH seminal p l a s i ~ i a and , ~ ~ observing its metabolization by ram and bull spermatozoa under aerobic conditions. An NAD-dependent D-glucitol dehydrogenase is also present in seminal vesicless4 and spermatoZ O ~ ~ this ~ , ~implies ~ ; an interrelationship of the concentrations of D-fructose and D-glucitol. In the absence of D-glucitol, incubated, washed, ram spermatozoa . ~ ~the convert about 20% of the D-fructose present into D - g l ~ c i t o lIn presence of low concentrations of D-glucitol, the conversion of D-fructose into D-glucitol is depressed, and, when the D-fructose to D-glucitol ratio is 3 : 1, D-fructose is converted quantitatively into lactate, with no D-glucitol produced. D-Fructose is used in preference to D(80) T. Mann and C. Lutwak-Mann, Biochern. J . , 48, xvi-xvii (1951). (81) G. M. Kellerman, Aust. J. Exp. Biol. Med. Sci., 33, 579-592 (1955). (82) R. E. Kuhlman, Proc. Soc. Exp. Biol. Med., 85,458-460 (1954). (83) H. G. Williams-Ashman and J. Banks, Arch. Biochem., 50, 513-515 (1954). (84) H. G. Hers, Biochirn. Biophys. Actu, 22, 202-203 (1956). (85) H. G. Williams-Ashman, J. Banks, and S. K. Wolfson, Jr.,Arch. Biochem. Biophys., 72,485-494 (1957). (86) H. G. Hers, Biochirn. Biophys. Actu, 37, 120-126 (1960). (87) H. G. Hers, Biochirn. Biophys. Actu, 37, 127-137 (1960). (88) L. T. Samuels, B. W. Harding, and T. Mann, Biochem. I., 84, 3 4 4 5 (1962). (89) T. E. King and T. Mann, Proc. R . Soc. London Ser. B, 151,226-243 (1959). (90) T. E. King and T. Mann, Nature, 182, 868-869 (1958). (91) T. O’Shea and R. G. Wales,/. Reprod. Fertil., 10, 353-368 (1965).

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glucitol and, even in the presence of concentrations of D-glucitol, 80% of the oxygen taken up by the system is used for the oxidation of Dfructose. When D-glucitol is the only substrate in the incubation medium, no utilization occurs under anaerobic conditions, but, under aerobic conditions, a large part of the D-glucitol is o ~ i d i z e d .It ~ 'seems most likely, in light of these results, that the primary function of Dglucitol dehydrogenase is the production of D-fructose from D-glucitol, and not the reverse reaction. Engel and coworkersg2reported that aldose reductase and D-glUCitOl dehydrogenase present in the seminal-vesicle tissue of the rhesus monkey oxidize D-glucitol to Dfructose more slowly than D-glucose is reduced to D-gluCitOl. Thus, the oxidation of D-glUCitOl is the rate-determining step. However, accumulation of D-glucitol does not occur, because the K , of D-glucose for aldose reductase is 14 mM, a value considerably higher than the normal 4 to 8 mM concentration of D-glucose in blood. The overall conversion of D-glucose into D-fructose in vivo may be limited not so much by the activity of aldose reductase and D-glucitol dehydrogenase as by the availability of D - g l u c o ~ e . ~ ~ ~ ~ ~ Further evidence of the role of the nonphosphorylative pathway in the synthesis of D-fructose is based on considerations of the kinetic characteristics of the enzyme involved. The aldose reductase catalyzing the first reaction is really a polyol dehydrogenase, with a favorable K , for the reduction of D-glucose, and a correspondingly unfavorable K , for the oxidation of D-glucitol. The NAD-D-glucitol dehydrogenase has the opposite characteristics, with the K , for conversion of Dglucitol being relatively low, even though the free-energy change for the reaction is nearly the same as that of the reduction. Although the enzyme is catalyzing thermodynamically similar reactions, the kinetics favor red~ction.'~ The ratio [NADH]/[NAD] controls the formation of D-fructose. The ratio is low in cytosol, leading to a concentration of seminal Dfructose derived from blood D-glucose without energy expenditure beyond that required to maintain a favorable ratio of the nicotinamide nucleotide~.~~ 2. Fructolysis by Spermatozoa

Spermatozoa in ejaculated, mammalian semen are unusual in their considerable reliance on the metabolism of D-fructose, the principal (92) R. M. E. Engel, D. D. Hoskins, and H. G . Williams-Ashman, Inuest. Urol., 7, 333-352 (1970). (93) F. K. Hilton and E. R. Graviss, Proc. Soc. E r p . Biol. Med., 124, 956-959 (1967).

METABOLISM OF D-FRUCTOSE

30 1

carbohydrate present, to supply energy for motility. Also, there is positive correlation between the rate of fructolysis and the concentration of motile ~permatozoa.g~-~~ D-Fructose is metabolized by spermatozoa to lactate, presumably by way of the normal, Embden-Meyerhof, glycolytic pathway. Intermediate products of fmctolysis have now been identified, in an analysis made difficult by the low, steady-state concentrations of hexose phosphate intermediates. There are still many questions regarding intermediary metabolites of spermatozoa, and the factors affecting the inechanisnis that regulate the formation and degradation of nietabolites. Mann7' was unable to isolate hexose phosphates when D-fructose was added to incubated spermatozoa, and Szepesi and Hopewoods7 also found almost negligible amounts of hexose phosphates, but showed the presence of small amounts of D-fructose 1,6-bisphosphate. Flipse and Andersong8identified radioactive D-fructose 6-phosphate, D-glucose 6-phosphate, and enolpyruvate phosphate as sperm metabolic products from D-[14C]fructose.They also identified aspartate, glutamate, citrate, funiarate, malate, and succinate from D-[''c]fructose metabolism, thus confirming the presence of a small oxidative metabolism of D-fructose by the citric acid cycle, as suggested previ0usly.~9-~0~ The general, enzyme profile in sperm is typical of cells exhibiting a pronounced Pasteur effect (oxygen inhibition of glycolysis).lo2Thus, the ratio of glyceraldehyde 3-phosphate dehydrogenase (EC 1.2.1.12) to phosphofructokinase (EC 2.7.1.11) is 3.2: 1, and the ratio of phosphoglycerate kinase (EC 2.7.2.3) to phosphofructokinase is 24 : 1. However, the difference between the anaerobic and aerobic rate of D-glucose utilization and lactate formation in ejaculated, human spermatozoa is slight, indicating a small Pasteur effect.lo2Consistent with this conclusion is the observation that 2,4-dinitrophenol, an agent known to release the inhibitory effects of oxidative metabolism

(94) J. Anderson,]. Agric. Sci., 36, 260-262 (1946). (95) M. Bishop, R. C. Campbell, J. L. Hancock, and A. Walton,J. Ag?:' ,Cci., 44, 227-248 (1954). (96) P. S. Vaishwanar, Am. /. Obstet. Gynecol., 75, 139-143 (1958). (97) B. Szepesi and M. L. Hopwood,]. Doiril Sci., 49, 1235-1239 (1966). (98) R. J. Flipse and W. R. Anderson,]. Dairy Sci., 52, 1070-1073 (1969). (99) R. N. Murdoch and I. G . White,/. Reprod. FertiZ., 16, 351-361 (1968). (100) C . N . Graves, J. R. Lodge and G. W. Salisbury, Nature, 211, 308-309 (1966). (101) R. G . Wales and E. J. Humphries, Aust. J. B i d . Sci., 22, 1005-1014 (1969). (102) R. N. Peterson and M. Freund, FertiZ. Steril., 21, 151-158 (1970).

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on glycolysis, causes only a slight stimulation of the aerobic rate of sperm g l y c o l y ~ i s . ' ~ ~ The small Pasteur effect observed in spermatozoa may result from fructolysis in ejaculated cells proceeding normally at close to the maximum rate, essentially in an uninhibited state.'"

3. Regulation of D-Fructose Metabolism in Spermatozoa Various factors, including inorganic ions,99J05-'07hormones,'08-110 female reproductive-tract fluid^,'^^-'^^ and glycolytic enzyme^,'^^,'^^* 116-119 have been shown to influence spermatozoa1 metabolism. The potential for enzymic regulation of fructolysis in ejaculated, monkey spermatozoa exists at the level of either hexokinase or pyruvate kinase (EC 2.7.1.40).'02In addition, neither glyceraldehyde 3-phosphate dehydrogenase nor phosphoglycerate kinase can be excluded as regulatory enzymes. Furthermore, the important role of phosphofructokinase in regulating glycolysis in other tissues102J16-118 might implicate this enzyme at a control point in spermatozoa metabolism. The observation that extracts of bull-epididymal sperm and rhesusmonkey sperm catalyze the conversion of D-fructose 1,6-bisphosphate into lactate at a rate greater than from D-fructose 6-phosphate indeed indicates a control point at the level of phosphofr~ctokinase.~~~J'~ The mechanism for regulation of phosphofructokinase in other tissues has proved to be one of controlling the rate of enzyme activity by varying the binding to its substrate, D-fructose 6-phosphate. The solubilized enzyme from rhesus-monkey spermatozoa is found to pos-

(103) R. N. Peterson and M. Freund, B i d . Reprod., 1, 238-246 (1969). (104) D. D. Hoskins, D. T. Stephens, and E. R. Cassillas, Biochim. Biophys. Actu, 237, 227-238 (1971). (105) R. N. Murdoch and I. G. White,Aust. J . B i d . Sci., 19, 857-870 (1966). (106) J. C. Wallace and R. G. Wales,J. Reprod. Fertil., 8, 187-203 (1964). (107) R. G. Wales, J . Reprod. Fertil., 10, 369-377 (1965). (108) J. F. Masken, R. P. Martin, and M. L. Hopwood, J . Dairy Sci., 47, 1257-1260 ( 1964). (109) M. S. Mounib, Acta Endocrinol., 45, 631-640 (1964). (110) H. A. Lardy and P. H. Philips,J. Biol. Chem., 149, 177-182 (1943). (111) R. N. Murdoch and I. G. White,]. Reprod. Fertil., 14, 213-223 (1967). (112) R. N. Murdoch and I. G. White, Aust. J. Biol. Sci., 21, 961-972 (1968). (113) M. S . Mounib and M. C. Chang, Nature, 201, 943-944 (1964). (114) B. J. Restall and R. G. Wales, Aust. J . Biol. Sci., 21,491-498 (1968). (115) R. G. Wales and B. J. Restal1,Aust. J. Biol. Sci., 19, 199-209 (1966). (116) J. V. Passonneau and 0. H. Lowry, Adv. Enzyme Regul., 2,265-274 (1964). (117) E. A. Newsholme and W. Gevers, Vitam. Horm. (N. Y . ) ,25, 1-87 (1967). (118) D. E. Atkinson, Science, 150,851-857 (1965). (119) B. 2. Morton and H. A. Lardy, Biochemistry, 6, SO-56 (1969).

METABOLISM OF D-FRUCTOSE

303

S ~ S Sproperties similar in most respects to those of phosphofructokinase from mammalian, diploid cells. Sperm phosphofructokinase has a p H optimum of 7-9, and an absolute requirement for Mg2+.ATP is a substrate, and, at high concentrations, is a potent inhibitor of the sperm enzyme (as it is in other tissues), but the inhibition is abolished by inorganic phosphate. Inorganic phosphate enhances phosphofructokinase activity at optimum, ATP-substrate levels. ADP, 3',5'cyclic AMP, 3'-AMP, and 5'-AMP also effectively lessen ATP inhibition, but with greatest diminution by ADP and 3',5'-cyclic AMP. 3',5'-Cyclic AMP and inorganic phosphate both alter the K , of sperm phosphofructokinase for D-fructose tj-phosphate, without affecting the V,,, of the reaction. As observed in other tissues, citrate is a regulator of sperm-enzyme activity, but inhibition by citrate can be partially overcome by higher concentrations of D-fructose 6-pho~phate.''~ Hoskins and Stephens concluded that the activity of this phosphofructokinase is consistent with the enzyme's assuming a role in the regulation of sperm-cell glycolysis.lZoHowever, fructolytic rates in intact cells are only marginally affected by compounds affecting either phosphofructokinase or the soluble fructolytic system. Grabers and coworkers121observed that adenine nucleotide may be a factor in the control of fructolysis in intact sperm, as the ratio of (ADP plus AMP) to ATP is quite high in sperm, in comparison to that for other tissues. The calculated energy-charge ratio (ATP to mono- and di-nucleotide) is -0.5, indicative of a rapid reaction for spermatozoa1 f r u c t o l y ~ i s . ' ~ ~ Considerable work has been done on cyclic AMP as a second messenger in the metabolic control of semen s p e r m a t o z ~ a ,as ~ ~nucleo~~'~~ tide concentration is closely correlated with motility of spermatozoa from boar, bull, cock, ram, and stallion.

4. Significance of D-Fructose in Male Fertility Seminal D-fructose concentration is an indicator of the size and secretory capacity of the seminal vesicles.'24 As seminal vesicles are testosterone-dependent tissues, seminal D-fructose values have been taken as an easily measured indicator of human androgenic activity.1253126 However, examination of the relationship between plasma (120) D. D. Hoskins and D. T. Stephens, Biochirn. Biophys. Acta, 191,292-302 (1969). (121) D. L. Grabers, W. D. Lust, N. L. First, and H . A. Lardy, Biochemistry, 10, 1825-1831 (1971). (122) D. D. Hoskins,]. Biol. Chem., 248, 1135-1140 (1973). (123) J. S. Tash and T. Mann, Proc. R. SOC. London Ser. B , 184, 109-114 (1973). (124) T. Mann and C. Lutwak-Mann, Physiol. Reu., 31,27-55 (1951). (125) R. L. Landau and R. Longhead,]. Clin. Endocrinol. Metab., 11,1411-1424 (1951). (126) J. Kimming, 0. Steeno, and C. Schinen, Internist, 8,25-34 (1967).

MINSHEN CHEN AND ROY L. WHISTLER

304

testosterone and human seminal D-fructose values indicates no quantitative correlation between these two, but suggests that a low threshold of testosterone can produce normal D-fructose concentrations in seminal vesicles (all-or-none law).127-130 Large doses of testosterone sharply lower seminal D-fructose concentrations in an as-yet-indefinite way. Thus, it would seem inexact to use D-fructose concentrations as an indicator of hormonal activity.131 The content of D-fructose in semen varies inversely with sperm population. This relationship is apparent in Table 11, where D-frucTABLEI1 C o r r e l a t i ~ n between '~~ Sperm Counts and Concentration of D-Fructose

Groups" Normospermic (with sperm count over 40 million. ~ m - ~ ) Normospermic, with proved fertility Moderate oligospermia (with sperm count between 10 and 40 million. ~ r n - ~ ) Severe oligospermia (with sperm count below 10 million. ~ r n - ~ ) Nonobshuctive azoospermia Obstructive azoospermia a

Concentration of D-fructose (mg/100 ml) 23 1 253 293 309 326 254

Each of 51 cases.

tose concentration is low in the normospermic group, and is higher, and increases, from oligospermia to the nonobstructive, azoospermia group.132Low, seminal D-fructose levels in normospermic men could result from utilization of D-fructose by spermatozoa. The progressively higher values for seminal D-fructose in cases of oligospermia and azoospermia are explained as resulting from the lower use of Dfructose by the progressively declining number of spermatozoa. Of

(127) K. H. Moon, R. H. Osborn, and M. E. Yannone, Inuesk. Urol., 7,478-486 (1970). (128) K. H. Moon and R. G. Bunge, Inljest. Urol., 8,373-376 (1971). (129) F. Dondero, F. Sciarra, and A. Isidori, Fertil. Steril., 23, 168-171 (1972). (130) J. Maws, G. Borsch, and L. Totok, Fertil. Steril., 25, 411-415 (1974). (131) M. Freund and J. MacLeod,]. A p p l . Physiol., 13, 506-509 (1958). (132) A. M. Phadke, N. R. Samaut, and D. D. Shubhada, F e d . Steril., 24, 894-903 (1973).

305

METABOLISM OF D-FRUCTOSE

course, one reason for low concentrations of D-fructose in semen133 containing high concentrations of spermatozoa is that the &lls occupy an appreciable volume of the ejaculate. From this reasoning, it might be supposed that the seminal D-fructose concentration in cases of obstructive azoospermia would be high, as there are no spermatozoa to utilize D-fructose or to occupy partial volume. However, the mean D-fructose concentration is identical with the mean Dfructose concentration in fertile individuals. By contrast, there is a high D-fructose concentration in cases of nonobstructive azoospermia. Phadke and coworker~ concluded ~~~ that D-fructose production varies inversely with sperm count, and that seminal D-fructose content depends on the state of the germinal epithelium rather than on the number of spermatozoa. Semen D-fructose content is highest (357.3 mg/100 ml) in cases of germinal-cell aplasia, in which the germinal epithelium is absent, and seminiferous tubules are lined by Sertoli cells only. The lowest values for seminal D-fructose occur in cases of obstructive azoospermia, where spermatogenesis is normal (see Table 111). TABLEI11 Mean, Seminal D-Fructose Values'32 in Different Lesions in Testicular Biopsies

Testicular lesion

No. of cases

Seminal D-fructose (mg/100 ml)

Normal spermatogenesis (obstructive azoospermia) Normal spermatogenesis (with severe oligospermia) Spermatogenic arrest at various levels Severe, tubular atrophy or hyalinization of tubules, or both Germinal, cell aplasia

51

255.1

56

283.0

67 46

312.0 342.6

85

357.3

Rationalization for the presence of D-fructose, rather than D-glucose, in semen is that it provides, for spermatozoa, an energy reservoir that is not readily utilized by seminal-vesicle cells, but does not prevent vesicle cells from utilizing D-glucose. I n summary, it may be concluded that the biosynthesis of D-fructose from D-glucose in seminal vesicles follows a nonphosphorylative path by using D-glucitol as an intermediate. The principal function of Dfructose is to provide energy for sperm motility. Spermatozoa use D-fructose by glycolysis. (133) Z. T. Typer, Fertil. Steril., 6,247-256 (1955)

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MINSHEN CHEN A N D ROY L. WHISTLER

VII. INBORN ERRORSO F D-FRUCTOSE METABOLISM 1. Hereditary, D-Fructose Intolerance

Hereditary, D-fructose intolerance (HFI) is a rare, inborn error of metabolism, described by Chambers and Pratt134and later characterized by Froesch and coworker^.'^^ The primary defect is a deficiency in D-fructose 1-phosphate aldolase (aldolase B), which splits D-fructose 1-phosphate into D-glyceraldehyde and glycerone p h 0 ~ p h a t e . l ~ ~ Patients with this ailment lack D-fructose 1-phosphate aldolase activity, and have only 10-20% of normal, D-fructose 1,6-bisphosphate aldolase a ~ t i v i t y . ' ~As ~ , 'a~ result, ~ the liver-enzyme activity'38 of Dfructose 1,6-bisphosphate compared to D-fructose 1-phosphate (FDP/F-1-P) is in the ratio of 6: 1, rather than the normal 1:1. This high ratio is a characteristic of HFI, and is not encountered in other diseases, such as hepatoma.139-'41The difference in enzyme activities may be due to different substrate sites on the same p r ~ t e i n . ' ~ ~ J ~ * Three types of aldolase enzyme are k n o ~ n : ' aldolase ~ ~ ~ ' ~A~(muscle type), aldolase B (liver type), and aldolase C (brain type). Aldolase B occurs in the liver, renal cortex, and intestinal mucosa, but, in HFI, its activity is absent, or negligible, in all three t i ~ ~ u e ~ . ~ ~ ~ , ~ ~ I n liver, intestinal mucosa, and kidney cortex, aldolase B provides practically all of the splitting activity for D-fructose I-phosphate, and most of the splitting of D-fructose 1,6-bisphosphate. The latter is also split by This conclusion was reached from aldolase A or muscle ald01ase.l~~ the observation that residual, D-fructose 1,6-bisphosphate-splitting activity in HFI is inhibited by ATP, which inhibits muscle aldolase, but not liver ald01ase.l~~ Further support was provided by the observation that aldolase activity in HFI liver extract is inhibited by antibody to aldolase A, but very poorly by antibody to aldolase B.I3*Using antibody to aldolase B, Nordmann and found that extracts from h e r s of persons intolerant to D-fructose contain only 25-30% of the normal content of aldolase protein. Because the activity of this enzyme is only 3% of the normal value (when tested against D-fmctose 1-phosphate) it was concluded that the defect in HFI is due to (134) R. A. Chambers and R. T. C. Pratt, Lancet, 340 (1956). (135) E. R. Froesch, A. Prader, A. Labhart, H . W. Stuber, and H. P. Wolf, Schweiz. Med. Wochenschr., 87, 1187-1171 (1957). (136) H. G. Hers and G. Joassin, Enzymol. B i d . Clin., 1, 4-14 (1961). (137) E. A. Nikkila, D. Somersalo, E. Pitkanen, and J. Perheentupa, Metabolism, 11, 727-730 (1962). (138) Y. Nordmann, F. Schapira, and J. C. Dreyfus, Biochern. Biophys. Res. Comrnun., 31,884-889 (1968).

METABOLISM OF D-FRUCTOSE

307

a mutation of the structural gene for liver-type aldolase, and not to a lack of enzyme s y n t h e ~ i s . ' ~Indeed, ~ ~ ' ~ ~the K , value of the enzyme towards Dfmctose 1-phosphate is 6 to 20 times the normal ~ a 1 u e .It l~~ is interesting that, if the D-fmctose-intolerant liver is extracted with buffer containing EDTA and 2-mercaptoethanol, or if 2-mercaptoethanol is added to the assay medium, the affinity of the enzyme for D-fructose 1-phosphate becomes n ~ r m a l . ' ~ ~ The , ' ~ primary ~ defect of this genetic disease, therefore, probably involves the thiol groups of aldolase B.150 In most of the family relationships examined, the occurrence of HFI conforms to an autosomal, recessive inheritance best illustrated in a study with eight patients reported by Foresch and coworkers.72However, a few families are known with an apparent, autosomal, dominant i n h e r i t a n ~ e . l ~ l These - ' ~ ~ may be instances of pseudodominance, but real genetic and biochemical heterogeneity of the syndrome is also possible. A test to indicate the heterozygous state for HFI would be of value. HFI is characterized by attacks of nausea, vomiting, sweating, trembling, somnolence, and coma, which occur only after intake of D-fructose-containing foods. D-Fructose loads given orally or intravenously are accompanied by a profound hypoglycemia and abnormally high and persisting fructosuria. During acute D-fructose-induced hypoglyY. Nordmann and F. Schapira, Eur. 1. Cancer, 3,247-250 (1967). F. Schapira, J. C. Dreyfus, and G. Schapira, Nature, 200, 995-997 (1963). T. Mizuno, Kansai Zka Daigaku Zasshi, 22,63-80 (1970). H. G. Hers, Le Metabolisme du Fructose, Arscia, Bruxelles, 1957. E. Penhoet, T. Rajkumar, and W. J. Rutter, Proc. Natl. Acad. Sci. U.S.A., 56, 1275-1282 (1966). J. Perheentupa and H. Hallman, in "Genetic and Endocrine Diseases in Childhood," L. I. Gardner, ed., Saunders, Philadelphia, 1967. R. C. Morris, Jr., I. Ueki, D. Loh, R. Z. Eanes, and P. McLin, Nature, 214, 920-921 (1967). J. F. Kranhold, D. Loh, and R. C. M o m s , Jr., Science, 165,402-403 (1969). K. Raivio, J. Perheentupa, and E. A. Nikkila, Clin. Chim. Acta, 17, 275-279 (1967). P. D. Spolter, R. C. Adelman, and S. Weinhouse,]. Biol. Chem., 240, 1327-1337 (1965). F. Schapira, Y. Nordmann, and C. Gregori, Acta Med. Scand. Suppl., 542,77-83 (1972). F. Lemonnier, C. Gregori, and F. Schapira, Biochem. Biophys. Res. Commun., 61, 306-312 (1974). M. Comblath, I. M. Rosenthal, S. H. Reisner, S. H. Wybregt, and R. K. Crane, New Engl. J. Med., 269, 1271-1278 (1963). P. Kohlin and K. Melin, Acta Paediatr. Scand., 57, 24-32 (1968). L. Linden and J. Nissell, Suen. Laekartidn., 61,3185-3195 (1964).

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MINSHEN CHEN AND ROY L. WHISTLER

ceinia, serum p h o s p h o r ~ s ~ ' Jand ~ ~potassium J~~ decrea~e,~ and ' serum magnesium and transaminase increase.'54 D-Fructose administration leads to decreased plasma i n ~ u l i n ~ or ~ insulin-like ~ ~ ' ~ ~ a~tivity,~' h y p e r ~ r i c e m i a , and ' ~ ~ renal, tubular acidosis.'57 Repeated hypoglycemic episodes and disturbances in renal function caused b y HFI may result in albuminuria, aminoaciduria, hepatomegaly, jaundice, cirrhosis, and physical and mental r e t a r d a t i ~ n . ~ ' ~ ' ~ ~ ~ ' ~ ~ Because many of the acute symptoms of HFI result from the marked hypoglycemia caused by D-fructose intake, the mechanism by which D-fructose produces this precipitous fall in blood D-glucose is of interest. As the aldolase defect does not in itself impede spot maintenance of normal, blood D-glucose, D-fructose 1-phosphate (which accumulates on loading with D-fructose) must cause a secondary block at some stage of gluconeogenesis or D-glucose mobilization, or both. ,~~~~~ only ~~ Insulin release does not cause the h y p o g l y ~ e m i a because low or normal levels of plasma insulin are found during D-fructoseinduced h y p ~ g I y c e m i a . ~ Furthermore, ~ ~ ' ~ ~ J ~ ~ HFI patients do not respond to g l u c a g ~ n ' ~ during ~ ~ ~D-fructose-induced ~ ~ ~ ' ~ ~ hypoglycemia, which might indicate an inhibition in the production of D-glucose from liver glycogen. It is possible that hypoglycemia results from an inhibition of enzymes by the accumulating D-fructose 1-phosphate, as D-fructose 1-phosphate has been reported to inhibit phosphoglucomutase ( E C 2.7.5.1) and D-glucose 6-phosphate isomerase.I6OFroesch and coworkers72 and Comblath and coworker^'^' suggested that lowered inorganic phosphate levels and accumulation of D-fructose 1-phosphate could lead to a diminution of liver-glycogen phosphorylase (EC 2.4.1.1) activity. This hypothesis has since been confi~med.'~l--l~~ In uitro, inhibition of mouse and dog-liver phosphorylase A by D-fructose 1-phosphate is competitive to phosphate, with a K i of 1.19 and 4.0 mM, respectively. The o f K i l K , f o r the two phosphorylases is 1:1. The activity of phosphorylase A and its inhi(154) B. Levin, V. G. Oberholzer, G. Snodgrass, L. Stimmler, and M. J. Wilmers, Arch. Dis. Child., 38, 220-230 (1963). (155) E . Samols and T. L. Dormandy, Lancet, 478-479 (1963). (156) J. Perheentupa and K. Raivio, Lancet, 528-531 (1967). (157) R. E. Mass, W. R. Smith, and J. R. Walsh, A m . ] . Med. Sci., 251, 516-523 (1966). (158) T. L. Dormandy and R. J. Porter, Lancet, 1189-1194 (1961). (159) B. R. Landau, J. S. Marshall, J. W. Craig, K. Y. Hostetler, and S. M. Genuth,J. Lab. Clin. Med., 78, 608-618 (1971). (160) J. Zalitis and I. T. Oliver, Biochem. J., 102, 753-759 (1967). (161) U. Kaufmann and E. R. Froesch, Eur. J . Clin. Invest., 3,407-413 (1973). (162) G. V. D. Berghe, L. Hue, and H. G. Hers, Biochern. J., 134, 637-645 (1973). (163) J. H. Thurston, E. M. Jones, and R. Z. Hanhart, Diabetes, 23, 597-604 (1974).

METABOLISM OF D-FRUCTOSE

309

bition by D-fructose 1-phosphate depend very much on the concentration of phosphate."jl In uiuo, phosphorylase activity is lowered by 40-80% in D-fructose-injected litter-mates. Thus, it appears that liverglycogen phosphorylase activity in D-fructose-injected animals should be seriously lessened by two mechanisms: first, by lower levels of active phosphorylase, and second, by diminished activity of remaining active enzyme, by lower levels of inorganic phosphate, and by elevated D-fructose 1-ph0sphate.l~~ In addition, Hers and coworkers"j2postulated that a decrease in free, cyclic-AMP levels might also be involved in the inactivation of liver-glycogen phosphorylase. Besides hypoglycemia, D-fmctose-induced renal acidification in the HFI defect involves a lowered hydrogen-ion secretory capacity of the proximal nephron, as evidenced by a 20 to 30%diminution in renaltubular (T) reabsorption of bicarbonate (THCO;) and simultaneous occurrence, and persistence throughout D-fructose administration, of impaired tubular reabsorption of phosphate, a-amino nitrogen, and uric acid. This abnormality of renal metabolism affects the renal cortex, which contains aldolase B, but does not affect the renal medulla. Thus, the abnormality may result from accumulation of D-fructose 1-phosphate in the renal cortex. The intimate, biochemical mechanism for renal, tubular acidosis is still ~ n k n 0 w n . l ~ ~ Subcellular pathology in HFI patients is observed with the electron microscope two hours after injection of 50 g of D-fructose. In the jejunum, the brush-border region of the absorptive cells remains normal, but concentric arrays of smooth membranes are noted in supranuclear regions. In the liver, the changes are most elaborate and widespread. Concentric, and irregularly disposed, membranous arrays occur in the glycogen area of most hepatocytes, and are associated with marked rarefaction of the hyaloplasm. Many of the membranous formations resemble c y t o l y ~ o m e s .The ~ ~ ~formation of the lesions is probably related to the intracellular accumulation of D-fructose 1 - p h o ~ p h a t e . I ~ ~

Symptoms of HFI in infants typically start after ~ e a n i n g , 7 ~and, .'~~ in some cases, weaning may be difficult to accomplish because of aversion to sweetened food. Many infants with HFI die of the disease, because they are unable to select their food."j6In older patients, the dietary history of aversion to sugar, sugar-containing foods, fruits, and berries is almost diagnostic. Confirmation of diagnosis is obtained by (164) R. C. Morris, J. Clin. Invest., 47, 1389-1397 (1968). (165) M. J. Phillips, J. A. Little, and T. W. Ptak, Am. J. &fed.,44, 910-920 (1968). (166) R. H. Herman and D. Zakim,Am. J . C2in. Nutr., 21, 693-698 (1968).

310

MINSHEN CHEN AND ROY L. WHISTLER

a test involving intravenous injection of 0.25 g of D-fructose per kg as a 10%solution during 2 minutes, and determination of blood D-glUcOSe and inorganic phosphate for 80 minutes. A distinct lowering of both blood D-glucose and inorganic phosphate is indicative of HFI. Although many HFI patients seem to select a D-fructose-free diet spontaneously, strict instructions for D-fructose abstinence are given them.144In the acute stage of D-fructose poisoning in HFI, treatment consists of intravenous administration of D - g ~ u ~ o s e . ~ ~ ~ ' ~ ~ ~ ' ~ ~ The molecular basis of HFI involves the deficiency of normal Dfructose l-phosphate aldolase activity, and low activity of D-fruCtOSe 1,8bisphosphate aldolase in liver, intestine, and renal cortex. Accumulated D-fructose l-phosphate leads to a diminution of liver-glycogen phosphorylase activity, causing severe hypoglycemia. An accumulation of D-fructose l-phosphate produces renal acidification and subcellular pathology of the jejunum and liver.

2. Deficiency of Hepatic D-Fructose 1,6-Diphosphatase Activity Another inborn error of metabolism involves D-fructose 1,Bbisphosphatase defi~iency."j'~'~* Hepatic glycogen synthesis and degradation are normal, as are oral D-glucose- and D-galactose-tolerance tests. However, oral D-fructose and glycerol provoke hypoglycemia and acidosis. The hypoglycemia may possibly result161from an acute disturbance of glycogenolysis at the level of phosphorylase A.

VIII. METABOLISM OF D-FRUCTOSE IN MICRO-ORGANISMS 1. PEP-dependent Phosphotransferase System D-Fructose transport in micro-organisms, and the rapid utilization of D-fructose by bacteria is generally assumed to require the activity of a PEP (enol pyruvate phosphate)-dependent, phosphotransferase system (PTS).169In this system, enzyme I catalyzes the transfer of phosphate from PEP to a nitrogen atom of a histidine residue in a small, high-energy protein, HPr, according to reaction 1 . In a subsequent step, enzyme 11, in the presence of factor 111, catalyzes the transfer of

(167) L. Baker and A. I. Winegrad, Ltrncet, 13-16 (1970). (168) K. Baerlocher, R. Gitzelmann, R. Nussli, and G. Dumermuth, Helo. Puediutr. Actu, 26, 498-506 (1971). (169) R. L. Anderson and W. A. Wood,Annu. Reu. Microbiol., 539-578 (1969).

METABOLISM OF D-FRUCTOSE

311

phosphate from phosphorylated HPr to sugar, with generation of HPr. It is known that, in Escherichia coli, as in Aerobacter aerogenes, BaEnolpyruvate phosphate

+ HPr

I

' phosphono-HPr + pyruvate (1)

Phosphono-HPr

+ sugar

I'

sugar phosphate

+ HPr

cillus subtilis, Arthrobacter p yridinolis, Vibrio cholerae, and Clostridium thermocellum, the phosphorylation product of reaction 2 is virtually only D-fructose 1-phosphate when a low concentration (G2 mM) of D-fructose is present. D-Fructose 6-phosphate is also formed in the presence of a high concentration of D-fructose. The consumption of the 6-phosphate appears insufficient to account for the rate of utilization of D-fructose by cells growing on h e ~ 0 s e .Nevertheless, l~~ most of the data on D-fructose metabolism in E. coli and A. aerogenes favor the major pathway proceeding through D-fructose 1-phosphate. Hanson and Anderson170resolved the phosphorylation system of Acetobacter aerogenes into four components: enzyme I, HPr, and two components required for the activity of enzyme 11. The components of enzyme II are a protein of high molecular weight and a smaller, inducible protein that increases the affinity of the system for D-fructose. The D-fructose-PEP-transferase system is similar to those involved with D-fructose phosphorylation in Arthrobacter pyridinolis, and with hexose phosphorylation in Staphylococcus aureus. 171 Non-sulfur, purple, photosynthetic bacteria, Rhodospirillum rubrum and Rhodopseudomonas s p h e r o i d e ~ , ' also ~ ~ possess a PEP-dependent D-f?uCtoSe phosphotransferase. Two protein fractions are required for D-fructose phosphorylation. In contrast to PEP-dependent, phosphotransferase systems isolated from other bacteria, the aforementioned two organisms have one active protein fraction tightly associated with the membrane fraction, while another in the crude extract is solubilized by extraction with water, and has a molecular weight of about 200,000. There is no evidence for the presence of a The phosphate-carrier protein of low molecular weight like HPr.171,173 (170) T. E. Hanson and R. L. Andersvn, Proc. Natl. A c a d . Sci. U.S.A.,61, 269-276 (1968). (171) S. Roseman,]. Gen. Physiol., 34, 138s-180s (1969). (172) M. H. Saier, Jr., B. U. Feucht, and S. Roseman,J. B i d . Chern., 246, 7819-7821 ( 1971). (173) W. Kundig and S. Rosenian,J. Biol. Chem., 246, 1393-1406 (1971).

MINSHEN CHEN AND ROY L. WHISTLER

312

different character of these proteins suggests that they may catalyze reactions by a mechanism different from the PTS operative in other micro-organisms. The demonstration of 1-phosphofructokinase (EC 2.7.1.56) in phototrophic bacteria'74 suggests that D-fructose is degraded by the Embden-Meyerhof pathway, in contrast to D-glucose, which is degraded by the Entner-Doudoroff pathway.'75 On entry into the microbial cell, sucrose is hydrolyzed by an induced sucrase, and the D-fructose obtained is phosphorylated by a specific, sucrose-induced fructokinase (ATP:D-fructose 6-phospho(see Scheme 2). Mutants deficient in transferase, EC 2.7.1.4)176,177 (extracellular)

phosphogluconate pathway

(intracellular)

D-glucose

glucokinase

tI

c ~-glucose-6-P

ATP

1oc sucrase

D-

Fructose

o-fructose-1-P

o-fructose

ATP fructokinas e

ATP

-

L

11

~-fructose-6-P

*Tpit~~~

D-fructose-l,g-diP

fructose 1 -phosphate kinase

i

Embden-Meyerhof pathway Metabolic Routes of 0-Fructose and Sucrose in Aerobacter aerogenes Scheme 2

fructokinase cannot readily phosphorylate D-fructose derived from sucrose hydrolysis. In other than wild-type organisms, free D-frUctOSe induces formation of the enzymes in the D-fructose 1-phosphate pathway (see Scheme 2).176

2. Respiration-coupled Transport System

Arthrobacter pyridinolis and a variety of other bacteria have a respiration-coupled, transport system (RCS) for D-fructose. A characteristic of the respiration-coupled, transport system is a malate-dependent uptake of D-fructose, but not of D-glucose or LR. Conrad and H. G. Schlegel, Biochim. Biophys. Acta, 358,221-225 (1974). L. Eidels and J . Preiss, Arch. Biochern. Biophys., 140, 75-89 (1970). N. E. Kelker, T. E. Hanson, and R. L. Anderson,J. Bid. Chem., 245,2060-2065 (1970). M. Y. Kamel, D. P. Allison, and R. L. Anderson,./. B i d . Chem., 241, 690-694 (1966).

METABOLISM OF D-FRUCTOSE

313

rhamnose. L-Malic dehydrogenase linked with flavine adenine dinucleotide is detectable in membrane vesicles, as well as in whole cells.178Both PTS and respiration-coupled systems of D-fructose transport are constitutive. Nevertheless, in whole cells growing on Dfructose as the sole carbon source, the inducible phosphotransferase system is used for t r a n ~ p 0 r t . lMutants ~~ deficient in the D-fructosespecific component of the respiration-coupled system cannot grow on D-fructo~e.'~~ Thus, in the absence of a functional, respirationcoupled, transport system, D-fructose-specific enzyme I1 and factor 111 of the phosphotransferase system fail to be induced by exogenous D-fructose. Sufficient free D-fructose, or D-fructose 6-phosphate derived from it, must be present inside the cell for induction of the phosphotransferase system. The two pathways of D-fructose uptake in Arthrobacter pyridino2isls0 are given in Fig. 2. In addition to the two nolpyruvote phosphate (PEP)

D- fructose !-phosphate

FIG.2.-Route~'*~of D-Fructose Uptake and Metabolism in Arthrobacter pyridinolis. (Open circles represent inducible proteins, and hatched circles represent phosphate constitutive proteins involved in transport; PEP = enolpyruvate phosphate.)

systems mentioned, extracts of Aerohacter aerogenes contain an acyl phosphate : hexose p h o ~ p h o t r a n s f e r a s e .This ~ ~ ~ system can transport D-glucose, D-fructose, and D-mannose. However, it possibly does not initiate the metabolism of D-fructose, owing to its low specific activity and its low affinity for conversion of D-fructose into D-fructose 1phosphate."jg (178) E. B. Wolfson, M. E. Sobel, R. Blanco, and T. A. Krulwich, Arch. Biochem. Biophys., 160, 440-444 (1974). (179) E. B. Wolfson and T. A. Krulwich, Proc. Natl. Acad. Sci. U.S.A., 71, 1739-1742 ( 1974). (180) T. A. Krulwich, M. E. Sobel, and E. B. Wolfson, Biochem. Biophys. Res. Commun., 53, 258-263 (1973).

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MINSHEN CHEN AND ROY L. WHISTLER

3. Carrier-mediated Transport System

The PEP-fructophosphotransferase system does not exist in Spirillum itersoii, Pseudomonas aeruginosa,1s1~1s2 or several other genera of aerobic, oxidative bacteria.IE3The transport system for D-ghOSe, D-fructose, and D-mannitol is energy- and temperature-dependent, obeys saturation kinetics, and is inducible.'81*182 This indicates the presence of a carrier-mediated tran~port-system.'~~ D-Fructose is transported as the free sugar, and trapped intracellularly by phosphorylation. An inducible fructokinase (EC 2.7.1.4)converts transported Dfructose into D-fructose 6-phosphate.lsl I n such fungi as Aspergillus n i d ~ l a n s and l ~ ~Streptomyces violaceoruber,186the transport of D-fructose appears to be mediated by a highly specific carrier, as transport is unaffected by addition of large amounts of analogs. D-Fructose transport in yeast has not been reported, whereas D-glucose transport is known to be mediated by a stereospecific membrane carrier.187Js8 OF D-FRUCTANS IX. SYNTHESISAND DEGRADATION

D-Fructans are polymers of D-fructose having the general formula Glc-Fru-(Fru),. They are food reserves in plants, occurring primarily in the Compositae and Gramineae f a r n i l i e ~ . ' ~ ~In-ulin, ' ~ ~ common in the Compositae, has (2 + 1)-linked p-D-fructofuranosyl residues, and a variety of D-fructans having (2 + 6)-linked p-D-fructofuranosyl residues are present in grasses and vary in degree of p o l y m e r i z a t i ~ n ~ ~ ~ - ~ ~ ~ from about 26 to 260. D-Fructans are also reported to occur in Aspara-

(181) P. V. Phibbs, Jr., and R. G . Eagon,Arch. Biochem. B i o p h y s . , 138,470-482 (1970). (182) R. G. Eagon and P. V. Phibbs, Jr., C u f 1 . j . Biochem., 49, 1031-1041 (1971). (183) A. H. Romano, S. J. Eberhard, S. L. Dingle, and T. D. McDowell, J. Bacteriol., 104, 808-813 (1970). (184) P. B. Hylemon, N. R. Kreig, and P. V. Phibbs,.\. Bacteriol., 117, 144-150 (1974). (185) C. G. Mark and A. H. Romano, Biochim. Biophys. Acta, 249, 216-226 (1971). (186) B. Sabater and C. Asensio, Eur. J. Biochem., 39, 201-205 (1973). (187) V. P. Cirillo,J. Bacteriol., 95, 603-611 (1968). (188) V. P. Cirillo, J . Bacteriol., 84, 485-491 (1962). (189) J. S. D. Bacon and J. Edelman, Biochem.J., 51,208-213 (1951). (190) J. S. D. Bacon, Bull. Soc. Chirn. Biol., 42, 1441-1449 (1960). (191) T. Akazawa, in "Plant Biochemistry," J. Bonner and J. E. Varner, eds., Academic Press, New York, 1965, pp. 258-297. (192) R. D. Grotelueschen and D. Smith, C r o p Sci., 8, 210-212 (1968). (193) D. Smith, Crop Sci., 7, 62-67 (1967). (194) D. Smith,J. Brit. Grassl. Soc., 23, 306-309 (1968).

METABOLISM OF D-FRUCTOSE

315

gus racemows as a s p a r a g o ~ i n . ' ~Micro-organisms ~*'~~ produce D-fruc-

tans called levans, and have commonly been isolated from Bacillus subtilis and Aerobacter levanicum. lg7-lS9 Information on the nietabolism of D-fructans is derived mainly from examination of inulin. Sucrose-sucrose 1-fructosyltransferase (SST) and transfructosylase (FFT) are responsible for the synthesis of Dfructans, whereas hydrolases A and B are involved in their breakdown. SST is found to catalyze the formation of a trisaccharide from sucrose, as shown by equation 3.200,201 The enzyme has a high specificity for sucrose, with little or no activity for trisaccharide as a donor, Glc-Fru -t Glc-Fru + Glc-Fru-Fru

+ Glc

(3)

or for D-glucose as an acceptor. SST catalyzes an essential, irreversible reaction, and further addition of D-fructofuranosyl groups to the trisaccharide is made by transfructosylase, which transfers single, terminal, D-fructofuranosyl groups to create new, p-D-(2 4 1)-linked residues.202The trisaccharide is the donor, as sucrose does not donate its D-fructofuranosyl group to the chain, but acts only as an acceptor. D-Fructans are hydrolyzed by two D-fructofuranosidases designated Enzymic hydrolysis breaks only the p-Dhydrolase A and B.203-205 (2 -+ 1)-linkage between a terminal D-fructofuranosyl group and its adjacent, D-fructOfUranoSyl chain unit as shown in equation 4 . Glc-Fru, -!.%Glc-Fru,-,

+ Fru

(4)

Sucrose is the sole source for synthesis of D-fructan in artichoke tubers.206Thus, the level of this disaccharide can play an important role in the regulation of enzyme a c t i v i t i e ~ . ~ ~Sucrose ~ J ~ ~ , strongly *~~ inhibits the enzymic hydrolysis of inulin by D-fructan hydrolases, as (195) G. Tanret, Bull. Soc. Chim.Fr., 5, 889-895 (1909). (196) V. K. E. Madan, Z . Pflanzenphysiol., 68,272-280 (1972). (197) S. Hestrin, S. Areneri-Shapiro, and M. Aschner, Biochem.J., 37,450-456 (1943). (198) S. Hestrin and S. Areneri-Shapiro, Biochem.]., 38, 2-10 (1944). (199) S. Areneri-Shapiro and S. Hestrin, Biochem. J., 39, 167-172 (1945). (200) R. W. Scott, T. G. Jefford, and J. Edelman, Biochem. J., 100, 23 (1966). (201) K. R. Chandorkar and F. R. Collins, Can. J . Bot., 52, 1369-1377 (1974). (202) J. Edelman and A. G . Dickerson, Biochem. J., 98, 787-794 (1966). (203) J. Edelman and T. G . Jefford, Biochem. J., 93, 148-161 (1964). (204) P. P. Rutherford and A. C . Deacon, Biochem. J., 126, 569-573 (1972). (205) P. P. Rutherford and A. C. Deacon, Biochem. J., 129, 511-512 (1972). (206) A. G. Dickerson and J. Edelman,]. E x p . Bot., 17, 612-619 (1966). (207) H. G . Pontis, Physiol. Plant., 23, 1089-1100 (1970).

MINSHEN CHEN AND ROY L. WHISTLER

3 16

well as affecting the transfer of D-frUCtOfUranOSyl groups from the trisaccharide. Scott found a definite correlation between the occurrence of SST and the net synthesis of D-fructans in Jerusalem artichoke tubers and onion bulbs.z08 During D-fructan depolymerization and mobilization, the activity of SST disappears.z0sChandorkar and F. R. Collinszo1observed the appearance of SST in response to the uptake and accumulation of sucrose in lettuce-leaf discs. All observations were consistent with the hypothesis that sucrose has a regulatory role for the induction of SST activity. D-Fructosylsucrose also influences D-fructan metabolism; its net synthesis controls the synthesis of high

polymer^.^^^-^^^ UDP-D-fructose is found in dahlia and Jerusalem artichoke tubers. However, it is not known whether UDP-D-fructose is involved in the formation of D-fructan in a manner similar to UDP-D-glucose involvement in the biosynthesis of a-D-glUcans.210-212 I n Bacillus subtilis and Aerobacter leuanicum, levans synthesized ~~-’~~ with levansucrase (EC 2.4.1.10)are highly b r a n ~ h e d . ~ Levansucrase catalyzes the synthesis from sucrose, as shown in equation 5 .

n Sucrose

* levan [(~-fructose),l+ n D-glucose

(5) The enzyme from Bacillus subtilis has a niolecular weight of 40,000, does not contain cysteine, and forms tetramers in the presence of ferric ions (which stabilize the enzyme against thermal denaturation) The donor must have a nonsubstituted D-fructofuranosyl group (2 -+ 1)-linked to an aldosyl group. Donor activity is not abolished if the D-glucosyl group in sucrose is replaced by a D-xylosyl, Larabinosyl, D-galactosyl, lactosyl, melibiosyl, or D-glucosyluronic acidZl5group. The enzyme transfers D-fructofuranosyl groups to such acceptors as methanol, glycerol, a,a-trehalose, or ketoses.lZ4Transfer is by a ping-pong mechanism, making possible the isolation of a Dfructofuranosyl-enzyme .2133214

(208) R. W. Scott, “Transfructosylation in Higher Plants Containing Fructose Polymers,” Ph.D. Thesis, Univ. of London (1968). (209) J. Edelman and T. G. Jefford, New Phytol., 67, 517-531 (1968). (210) N. S. Gonzalez and H. G . Pontis, Biochim. Biophys. Actu, 69, 179-181 (1963). (211) J. Baddiley, Biochem. J., 75,428-434 (1960). (212) Y. Umenura, M. Nakamura, and S. Funachashi, Arch. Biochem. Biophys., 119, 240-252 (1967). (213) R. Dedonder, E. Jozon, G. Rapoport, Y. Joyeux, and A. Fritsch, Bull. Soc. Chim. Biol., 45, 477-492 (1963). (214) R. Dedonder, Methods Enzymol., 8, 500-505 (1966). (215) S. Hestrin and G. Avigad, Biochem. I., 69, 388-398 (1958). (216) H. Dedonder, in “Biochemistry of the Glycosidic Linkage,” R. Pivas and H. G. Pontis, eds., Academic Press, New York and London, 1972, pp. 21-78.

METABOLISM OF D-FRUCTOSE

x. EFFECT O F

317

D-FRUCTOSE O N METABOLISM O F ETHANOL

In contrast to most foodstuffs, ethanol need not be digested, and is readily absorbed from the gastrointestinal tract. Ethanol is normally metabolized at a constant rate by the liver of man and animals.217Ingested alcohol is 90% enzymically oxidized to carbon dioxide and water. Only a few percent of the unmetabolized ethanol is excreted in the urine, in the expired air, in perspiration, and in milk during lactation.’18 Ethanol could be oxidized by catalase (EC 1.11.1.6), alcohol dehydrogenase (ADH), in the cytosol portion of hepatocytes, or by the microsomal, ethanol-oxidizing system involving NADPH and cytochrome p-450.219-221 However, catalase is generally believed to play a minor role under in vivo conditions.”’ Also, there is no substantial evidence for the oxidation of ethanol by the microsomal, ethanol-oxidizing system.”’ In the first phase of hepatic oxidation, ethanol is oxidized, mainly by alcohol dehydrogenase, to acetaldehyde. The further oxidation of acetaldehyde to acetate or its activated form, acetyl coenzyme A, is catalyzed, for the most part, by aldehyde dehydrogenase. Both enzymes transfer hydrogen from the substrate to the coenzyme, nicotinamide adenine dinucleotide (NAD). The ratelimiting step in the cytosol oxidation of ethanol to acetaldehyde by alcohol dehydrogenase is the dissociation of the NAD-NADH comp l e ~ . NADH ’ ~ ~ competes with NAD for binding sites on the enzyme (alcohol dehydrogenase) and, in sufficient concentration, may inhibit the rate of ethanol d e h y d r o g e n a t i ~ nReoxidation .~~~ of NADH is also rate-limiting for the overall metabolism of Because cytoplasmic reactions appear insufficient to reoxidize the NADH generated by ethanol metabolism, it is necessary that some of it be oxidized by material that can enter the mitochondria for oxidation b y the electron-transport chain. As mitochondria are impermeable to NADH,2z6several substrates have been proposed for the (217) C. S. Lieber, Annu. Rer;. Med., 18, 35-54 (1967). (218) H. Kalant, in “The BiolobT of Alcoholism,” B. Kissin and H. Begleiter, eds., Plenum Press, New York and London, 1971, Vol. 1, pp. 1-62. (219) W. H. Orme-Johnson and D. M. Ziegler, Biochem. Biophys. Res. Commun., 25, 420-430 (1965). (220) C. S. Lieber and L. h4. DeCarli, Science, 162, 917-918 (1968). (221) C. S. Lieber and L. M. DeCarli,J. B i d . Chem., 245, 2505-2512 (1970). (222) J. P. Von Wartburg, in “The Biology of Alcoholism,” B. Kissin and H. Begleiter, eds., Plenum Press, New York and London, 1971, Vol. 1, p. 85. (223) H. Theorell and B. Chance, Acta Chem. Scand., 5, 1127-1144 (1951). (224) H. R. Mahler, R. H. Baker, and V. J. Shiner, Biochemistry, 1,47-52 (1962). (225) J. J. Vitale, D. M. Hegsted, H. McGrath, E. Grafle, and M. Zanicheck, /. B i d . Chem., 210, 753-759 (1954). (226) H. R. Mahler and E. H. Cordes, “Biological Chemistry,” Harper and Row, New York, 2nd Edition, 1971, p. 685.

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MINSHEN CHEN AND ROY L. WHISTLER

transport of reducing equivalents into mitochondria. These are the a-glycerophosphate (D-glycerol 1-phosphate, L-glycerol 3-phosphate),227,228 the m a l a t e - a ~ p a r t a t e , and ~ ~ ~the ~ ~ ~fatty ~ acid shuttle However, the most important route for reoxidation of NADH probably involves the transfer of reducing equivalents to the mitochondria by coupling reoxidation to oxidative phosphorylation which transports hydrogen equivalents from NADH across the mitochondrial membrane by a-glycerophosphate, 3-hydroxybutyrate, malate, and L-glutamate. The lactate: pyruvate ratio is assumed to be a particularly reliable index of the concentration ratio of free NADH : NAD in the cytoplasm, and the redox state of the mitochondria is characterized by the 3-hydroxybutyrate :acetoacetate ratio. A number of metabolically active substances, such as D-glucose, D-fructose, pyruvate, amino acids, 2,4-dinitrophenol, insulin, and thyroid hormone, have been investigated as possible affectors of the rate of metabolism of ethanol, but, to date, only D-fructose is thought to affect the process appreciably. Sucrose is presumably active because of its D-fructosyl moiety.232,233 D-Fructose increases the rate of elimination of ethanol by 80% in dogs receiving 1 to 2 g of D-fructose per hour, and by -70% in human subjects having D-fructose intravenously infused in comparable quantities .234,235 Oral intake of D-fructose in man is said to give similar results.236Although a number of investig a t o r ~ have ~ ~ ~been - ~ ~ unable ~ to show enhancement of metabolism of ethanol by D-fructose, failure has been attributed to the low concentrations of sugar used. In an attempt to understand the effect of D-fructose, the mechanism has been studied. In the liver, D-fructose is converted into D-fructose 1-phosphate, which is then split into glyc(227) M. Klingenberg and T. Bucher, Biochem. Z., 334, 1-17 (1961). (228) P. Borst, in “Funktionelle and Morphologische Organization der Zelle,” P. Karlson, ed., Springer Verlag, New York, 1963, pp. 137-162. (229) T. Bucher and M. Klingenberg, Angew. Chem., 70,552-570 (1958). (230) A. Whereat, M. W. Orishimo, and J. Nelson, J. Biol. Chem., 244, 6498-6506 ( 1969). (231) N. Grunnet, Biochem. Biophys. Res. Commun., 41,909-917 (1970). (232) G. L. S . Pawan, Nature, 220,374-376 (1968). ~ (233) G. L. S. Pawan, Biochem. J., 106, 1 9 (1968). (234) A. Pletscher, A. Bernstein, and H. Staub, Experientia, 8, 307-308 (1952). (235) A. Pletscher, A. Bernstein, and H. Staub, Helo. Physiol. Pharmacol. Acta, 10, 74-83 (1952). (236) F. Lundquist and H. Wolthers, Actu Phurmacol. Toxicol., 14,290-294 (1958). (237) K. Johannsmeier, H. Redetzki, and G . Pfleiderer, Klin. Wochenschr., 32,560-563 (1954). (238) F. Lundquist, I. Svedsen, and P. H. Petersen, Biochem. J., 86, 119-124 (1963). (239) I. Hassinen, Ann. Med. Erp. Biol. Fenn., 42, 76-79 (1964).

METABOLISM OF D-FRUCTOSE

319

erone phosphate and D-glyceraldehyde. Glycerone phosphate is mainly converted into D-glucose and glycogen, whereas D-glyceraldehyde may be metabolized by several different pathways: ( 1 ) phosphorylation to D-glyceraldehyde 3-phosphate by triose k i n a ~ e ,(2) ~~,~~ reduction to glycerol by aldehyde dehydrogenase, followed by phosphorylation to 3-0-phosphono-~-glycerate,~~*~~ and (3) oxidation to glycerate by aldehyde d e h y d r o g e n a ~ e . ~ ~ , ~ ~ reported that, in man, when D-fructose Tygstrup and alone is infused, D-glyceraldehyde is metabolized primarily by way of pathway 3 , but, when ethanol is given in addition to D-fructose, the situation is changed. Under these conditions, oxidation of ethanol to acetate is approximately twice that found in control experiments without D-fructose, but the quantity of D-fructose phosphorylated is unchanged, as is the quantity of D-glyceraldehyde produced. Uptake of D-fructose is increased, and a corresponding amount of alditols (D-glucitol and glycerol) is formed. Output of lactate and pyruvate is drastically decreased, and a corresponding increase in the output of D-glucose is observed.240In an early attempt to explain the “fructose effect,” it was suggested that, in the presence of D-fructose, the acetaldehyde formed by oxidation of ethanol competes efficiently for the aldehyde dehydrogenase responsible for the oxidation of glyceraldehyde to glycerate, thus inhibiting pathway 3 . Following the explanation originally proposed by Holzer and S ~ h n e i d e r ,Tygstrup ~~’ and cow o r k e r ~suggested ~~~ that the D-glyceraldehyde could be reduced by the ADH-NADH complex (pathway 2) to glycerol, with reoxidation of NADH, thus partially explaining the “fructose effect.” Because the reduction of D-glyceraldehyde to glycerol is accomplished by the ADH-NADH complex without prior dissociation, the slow step in ethanol oxidation is, therefore, circumvented. The glycerol formed could then be converted into glycerol phosphate, which is oxidized by way of the mitochondria. This conversion of D-glyceraldehyde into glycerol can account for reoxidation of 60% of the NADH produced by the increased ethanol oxidation,238indicating that mechanisms other than formation of glycerol would have to be involved. The authors propsed that the reduction of D-fructose to D-glucitol probably contributes significantly to the reoxidation of the remaining NADH. In a subsequent, in vitro investigation, using rat-liver slices, Thieden and L u n d q u i ~showed t ~ ~ ~ that, consistent with their explanation of the fructose effect,” D-glyceraldehyde causes an increase in the rate of “

(240) N. Tygstrup, K. Winkler, and F. Lundquist, J. Clin. I n m s t . , 44,817-830 (1965). (241) H. Holzer and S. Schneider, Klin. Wochenschr., 33, 1006-1009 (1955). (242) H. I. D. Thieden and F. Lundquist, Biochern. J,, 102, 177-180 (1967).

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MINSHEN CHEN AND ROY L. WHISTLER

oxidation of ethanol, and addition of glycerol to a medium containing D-fructose and ethanol lowers the rate of ethanol oxidation. VanHarken and M a n n e ~ - i n greported ~~~ that, in the isolated, perfused, rat liver, the rate of disappearance of ethanol from the perfusate decreases with time, presumably because of a rate limitation imposed by the relatively slow oxidation of acetate in the perfused liver in the absence of extrahepatic tissues. Diminished rates of ethanol oxidation can be restored when pyruvate or D-fructose is added to the perfusion fluid, and this restoration is attributed to the ability of these compounds to promote the conversion of NADH into NAD. Similar results and conclusions have been reported for D-frUCtose, D-glyceraldehyde, and pymvate by Berry.244,245 However, this concept of D-fructose metabolism is incompatible with the observed effects of D-fructose on the intracellular, redox state, and is one of the most cogent arguments against the explanation of the “fructose effect” proposed by Tygstrup and coworkers.240It has been demonstrated by several investigator^'^^-^^^ that D-fructose causes an increase in both the lactate :pyruvate ratio and the a-glycerophosphate : glycerone phosphate ratio, indicating an increase in the NADH :NAD ratio. The simultaneous addition of ethanol has been reported to lead to an even greater increase in the 1actate:pyruvate ratio,249making it difficult to support the concept that D-fructose promotes the oxidation of NADH to NAD. These results, together with fundamental, kinetic parameters determined for the enzymes involved in D-fructose and ethanol metabolism led to the statementZ5lthat the theories previously proposed to explain the effects of D-fructose, D-glyceraldehyde, and pyruvate on ethanol metabolism are irreconcilable with the experimental results. According to calculations made,251the steady-state concentration of D-glycer(243) D. R. VanHarken and G. J. Mannering, Biochenr. Pharmucol., 18, 2759-2766 (1969). (244) M . N. Berry, Biochem. J., 1 2 3 , 4 0 ~(1971). ~ (245) M. N. Berry, Biochem. I., 123, 4 1 (1971). (246) J. Papenberg, J. P. Von Wartburg, and H. Aebi, Enzymol. Biol. Clin., 11,237-250 (1970). (247) I. Hassinen, R. H. Ylikahri, and M. T. Kahonen,Ann. Med. E r p . Biol. Fenn., 48, 176-183 (1970). (248) K. 0. Lindros and M. E. Hillborn,Ann. Med. E x p . Biol.Fenn., 49,162-169 (1971). (249) R. H. Ylikahri, I. Hassinen, and M. T. Kihonen, Metabolism, 20,555-567 (1971). (250) R. H. Ylikahri, M. T. Kahonen, and I. Hassinen, Acta Med. Scund. Suppl., 542, 141-150 (1972). (251) H. I. D. Thieden, N. Grunnet, S. E. Danigaard, and L. Sestoft, Eur. J. Biochem., 30, 250-261 (1972).

METABOLISM OF D-FRUCTOSE

32 1

aldehyde would have to be 2 mM to provide a sufficient reduction of D-glyceraldehyde by the ADH-NADH complex to account for the increase in the rate of ethanol oxidation observed after infusion of Dfructose in man. The concentration of D-glyceraldehyde in human liver has not yet been determined, but, in rat liver, the concentration is below 0.1 mM, and, in the isolated, perfused, pig liver, it is251below 0.5 mM. It may be expected that the concentration of D-glyceraldehyde is even lower in human liver.251A simple reduction of pyruvate to lactate cannot be the cause of the D-fructose effect, as no net formation of NAD occurs during the metabolism of D-fructose to lactate. It was proposed, therefore, that malate dehydrogenase (EC 1.1.1.37), malic enzyme (EC 1.1.1.40), pyruvate carboxylase (EC 4.1.1.1), and transfer of oxalacetate from the mitochondria1 to the extramitochondrial compartment account for the transfer of hydrogen from NADH to NADP, thus increasing the rate of removal of NADH from the cytoplasm. This malic enzyme, shuttle theory has also been discussed by Damgaard and coworker^.^^^,^^^ In this mechanism (see Scheme 3),252 Mitochondria

Cytoplasm

malic vate

Ethanol

pymvate carboxylase D-glyceraldehyde

Acetaldehyde

oxalacetate - - - -

- - - - - - - - ---

- -0xalacetate

citrate L-aspartate L-glutamate The Malic Enzyme Shuttle Scheme 3

the reaction responsible for the increase in the rate of ethanol metabolism b y oxidation of the cytoplasmic NADH is reduction of oxalacetate to malate, catalyzed by malate dehydrogenase. Activity of this enzyme is very high and sufficient to account for the increase in oxidation of (252) S. E, Damgaard, L. Sestoft, F. Lundquist, and N. Tygstrup, Acta Med. Scand. S u p p l . , 542, 131-140 (1972). (253) S. E. Damgaard, F. Lundquist, K. Tonnesen, F. V. Hansen, and L. Sestoft, E u r . ] . Biochem., 33, 87-97 (1973).

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MINSHEN CHEN AND ROY L. WHISTLER

ethanol during D-fructose metabolism,254provided that the production of oxalacetate is increased in this condition. Oxalacetate has been shown to increase the rate of ethanol metabolism in rat-liver It was suggested that, as malate accumulates in the liver cell during D-fructose metabolism, the flow of malate through the reaction catalyzed by the malic enzyme limits the increase in rate of ethanol oxidation. This mechanism requires that the NADPH produced in the conversion of malate into pyruvate by malic enzyme be oxidized efficiently. Sestoft and coworkers251proposed that this may occur by reduction of D-glyceraldehyde by the NADP-depepdent, alcohol dehydrogenase, by fatty acid synthesis, by NADPH oxidase, or by the microsomal, hydrolase complex. Finally, as the rate-limiting step in the alcohol dehydrogenase-catalyzed reaction is the dissociation of the enzyme-NADH c o m p l e ~ ,D-fructose ~ ~ ~ , ~ ~(or~ pyruvate) metabolism might indirectly activate the dissociation by increasing the rate of NADH oxidation, mediated by way of the malic enzyme shuttle .257,258 XI. EFFECT OF D-FRUCTOSE ON THE NUCLEOTIDE POOL I N LIVER

Because of the rapid and efficient utilization of D-fructose in the liver, this sugar has been used for intravenous feeding.156However, ample evidence indicates that rapid infusion of D-fructose causes breakdown of adenine nucleotide, and induces h y p e r u r i ~ e r n i a . ~ ” ~ ~ ~ ~ The mechanism of D-fructose-induced hyperuricemia is probably by way of the rapid phosphorylation of D-fructose to D-fructose l-phosphate (by ketofructokinase) which causes liver depletion of ATP and inorganic p h o ~ p h a t e .When ~ ~ ~ a, ~fasted ~ ~ animal receives an intraperi(254) E. Shargo, H. A. Lardy, R. C . Nordlie, and D. 0 . Foster, J . Biol. Chem., 238, 3188-3192 (1963). (255) L. F. Leloir and J. M. Mufioz, Biochern. J., 32, 299-307 (1938). (256) H. Theorell and R. Bonnichsen,Acta Chem. Scand., 5, 1105-1126 (1951). (257) N. Grunnet, B. Quistorff, and H. I. D. Thieden, Eur. J . Biochern., 40, 275-282 (1973). (258) F. Lundquist, S. E. Damgaard, and L. Sestoft, in “Alcohol and Aldehyde Metabolizing Systems,” R. G. Thurman, T. Y. Onetani, J. R. Williamson, and B. Chance, eds., Academic Press, New York and London, 1974, pp. 405-416. (259) P. H. Maenpaa, K. 0 . Raivio, and M. P. Kekomaki, Science, 161, 1253-12.54 (1968). (260) K. 0. Raivio, M. P. Kekomaki, and P. H. Maenpad, Biochern. Pharmacol., 18, 2615-2624 (1969). (261) G. Nikiforuk and S. P. Colowick,J. Biol. Chem., 219, 119-129 (1956).

METABOLISM OF D-FRUCTOSE

323

toneal injection of 40 mmoles (7.2 g) of D-fructose per kg, the contents of liver ATP, UTP, and UDPG drop profoundly. As the nucleotide pool decreases, D-fructose 1-phosphate increases to 18 mmoledkg. The lower level of liver inorganic phosphate resulting from D-fructose administration strongly diminishes phosphate inhibition of adenylate deaminase (EC 3.5.4.2)261 and 5’-nucleotidase (EC 3.1.3.5).262 The latter enzyme is also inhibited by ATP, which is also lowered in concentration by D-fructose a d m i n i ~ t r a t i o n When . ~ ~ ~ the inhibition of AMP deaminase is low, the hepatic IMP concentration rises, and AMP and IMP are dephosphorylated with the eventual formation of uric acid and a l l a n t ~ i n .I.~ H. ~ ~Fox , ~ and ~ ~ Kelley266summarized the probable mechanism of D-fructose-induced hyperuricemia as shown in Scheme 4.266 D-Fructose administration causes an early and profound o-Fructose

k

AMP IATP

ADP

D-Fructose- 1-P

tPi

i

nucleotidase (inhibited by ATP) deaminase (inhibited by ATP and Pi)

inosine

i

hypoxanthine

1

xanthine

i

uric acid

adtoin Possible Mechanism of D-Fructose-induced Hyperuricemia in Man Scheme 4

elevation of hepatic IMP, and a later rise of inorganic phosphate. As both I M P and inorganic phosphate are inhibitor^'^^*^^* of 5-0phosphono-D-ribosylamidotransferase,their increase influences a decrease in the rate of de novo synthesis of uric acid.267D-Fructose (262) H . L. Segal and B. M. Brenner,]. Biol. Chem., 235,471474 (1960). (263) H . P. Baer, 6.I. Drummond, and E. L. Duncan, Mol. Phurmacol., 2,67-76 (1966). (264) H. F. Woods, Actu Med. Scund. S u p p l . , 542, 87-103 (1972). (265) I. H. Fox and W. N. Kelley, Metabolism, 21, 713-721 (1972). (266) I. H. Fox and W. N. Kelley, Adw. Erp. A4ed. Biol., 41B, 463-470 (1974). (267) J. B. Wyngaarden and D . M. Ashton,J. Biol. Chem., 234, 1492-1496 (1959). (268) E. W. Holmes, J. A. McDonald, J. M. McCord, J. B. Wyngaarden, and W. N. Kelley,J. B i d . Chem., 248, 144-150 (1973).

324

MINSHEN CHEN AND ROY L. WHISTLER

causes hyperuricemia by stimulating the conversion of purine nucleotides into uric acid, and does not increase de novo synthesis of uric acid.269D-Fructose-induced hyperuricemia and hyperuricosuria are transient, however, as injection of larger quantities of D-fructose over a 24-hr period causes no detectable effect on uric acid production.269 D-Fructose can cause structural alterations of liver in 10 to 90 minutes after intraperitoneal injection. Dense plaques appear in 20% of the liver nucleoli, and the plaques become more prominent in 3 hours. However, a similar change is also seen in the same number of nucleoli when D-glucose is given.270Administration of D-fructose by intravenous perfusion induces ultrastructural alterations in smooth membrane, proliferations, cytolysome formation, and hyaloplasmic rarefaction. However, ATP content must decrease b y 50% or more before gross, structural changes are observed.270

XII. EFFECTOF D-FRUCTOSE ON THE ENERGYMETABOLISM OF INTESTINAL, EPITHELIALCELLS The low activity of D-glucose 6 - p h o ~ p h a t a s eand ~ ~ D-fructose l-phosphate a l d o l a ~ ein ~~ epithelial . ~ ~ ~ cells does not allow extensive transformation of absorbed D-fructose. After a large, intraluminal dose of D-fructose, D-fructose l-phosphate accumulates in luminal, epithelial cells as a result of the high affinity of D-fructose for intestinal fructokinase ( K , = 0.1 mM)45 and the lower affinity (1 tenth) of D-fructose l-phosphate for aldolase ( K , = 1.1 mM).271 The accumulated D-fructose l-phosphate causes a 30% decrease of phosphate, and a 45% decrease of creatine phosphate, although the levels of ATP, ADP, and AMP remain unaffected. Rapid phosphorylation of Dfructose to D-fructose l-phosphate leads to a lower concentration of phosphate. The level of creatine phosphate also declines, possibly due to its use to compensate for ATP breakdown. The partial depletion of creatine phosphate by D-fructose is a specific action for D-fructose, as equivalent amounts of D-glucose or 3-O-methyl-D-glucose do not produce the effect.272 Intraluminal administration of D-fructose has a negligible effect on the ATP content of liver, although, as described earlier, an intrave(269) R. Narins, J. S. Weisberg, and A. R. Myers, Metabolism, 23, 455-465 (1974). (270) P. J. Goldblatt, H . Witschi, M. A. Friedman, R. J . Sullivan, and K. H. Shull, Lab. Znwest., 23, 378-385 (1970). (271) K. Kjerulf-Jensen, Acta Physiol. Scand., 4, 225-248 (1952). (272) J. M. J. Lamers, and W. C.Hulsmann, Biochim. Biophys. Acta, 313, 1-8 (1973).

METABOLISM O F D-FRUCTOSE

325

nous dose of D-fructose in adult rats, or administration of D-fructose by liver perfusion, causes a significant depletion of ATP in liver.43*259,273

XIII. EFFECTOF D-FRUCTOSEON LIPID METABOLISM Feeding of D-fructose or sucrose produces hyperlipemia (increase in serum triglyceride levels) in man15y,274-283 and laboratory anim a l ~ . Induced ~ ~ ~ -hyperlipemia ~ ~ ~ may cause a t h e r o ~ c l e r o s i sThus, .~~~ it is important to understand the mechanism by which D-fructose induces increased levels of serum triglyceride. The rate of initial phosphorylation of D-fructose exceeds that for Dglucose in r a t ~ because , ~ ~ ~ liver fructokinase activity is greater than that of hexokinase and of glucokinase (EC 2.7.1.2).294Human liver has a greater capacity for phosphorylating D-fructose than for phosphorylating D-glucose (see Table IV). Thus, phosphorylation of D-fructose will occur in preference to D-glucose phosphorylation. The subse-

(273) H. F. Woods, C. V. Eggleston, and H. A. Krebs, Biochem.J., 119,501-510 (1970). (274) N. A. Kaufmann, R. Poznanski, S. H. Blondheim, and Y. Stein, Zsr. J. Med. Sci.,2, 715-726 (1966). (275) N. A. Kaufmann, J. Kapitulnik, and S. H. Blondheim, Isr. J. Med. Sci., 6, 80-85 (1970). (276) J. W. Farquhar, A. Frank, R. C. Gross, and G. M. Reaven,J. Clin.Inuest., 45, 1648-1656 (1966). (277) R. H. Herman, D. Zakim, F. B. Stifel, Fed. Proc. Fed. A m . SOC.E x p . Biol., 29, 1302-1307 (1970). (278) I. MacDonald, Clin. Sci., 29, 139-193 (1965). (279) N. A. Kaufmann, R. Poznanski, S. H. Blondheim, and Y. Stein, Am. J. Clin. Nutr., 18,261-269 (1966). (280) I. MacDonald, Proc. Nutr. Soc., 25, ii-iii (1966). (281) A. M. Cohen, N. A. Kaufmann, R. Poznanski, S. H. Blondheim, and Y. Stein, Br. Med. J., 339-340 (1966). (282) P. T. Kuo and D. R. Bassett, Ann. Intern. Med., 62, 1199-1212 (1965). (283) I. MacDonald and D. M. Braithwaite, Clin.Sci., 27, 23-30 (1964). (284) P. Hill, Lipids, 5, 621-627 (1970). (285) E. A. Nikkila and K. Ojala, Life Sci., 4, 937-943 (1965). (286) N. Baker, A. S. Garfinkel, and M. C. Schotz,J. Lipid Res., 9, 1-7 (1968). (287) E. A. Nikkila, Scand. J. Clin.Lab. Znuest. S u p p l . , 92, 76-77 (1966). (288) H. Bar-on and Y. Stein,J. Nutr., 94, 95-105 (1968). (289) E. A. Nikkila and K. Ojala, Life Sci., 5, 89-94 (1966). (290) M. M. Gale and M. A. Crawford, Metabolism, 18, 1021-1025 (1969). (291) J. N. Pereira and N. 0. Jangaard, Metabolism, 20, 392-400 (1971). (292) M. Waddell and H. J. Fallon,]. Clin. Znuest., 52, 2725-2731 (1973). (293) I. MacDonald,]. Clin. Pathol. S u p p l . , 5, 22-25 (1973). (294) D. Zakim, R. S. Pardini, R. H. Herman, and H. E. Sauberlich, Biochim. Biophys. Acta, 144, 242-251 (1967).

TABLEIV

R

Comparison277of Enzyme Activities for Those Primarily Effective in Liver Metabolism

n

Enzyme

Enzymic activity"

Fructokinase

20.4 k3.6 (6)

D-Fructose 1-phosphate aldolase

50.4 58.8 (4)

Enzyme Glucokinase Hexokinase Phosphofructokinase D-Fructose 1,6-diphosphate aldolase Pyruvate kinase

z Enzymic activity"

2.83 20.47 (9) 1.55 20.28 (9) 30.5 25.5 (6) 54.7 27.0 (4) 221.0 239.4 (3)

" Units of activity equal nmoles of' substrate metabolized per min per ing of' protein. Each value given is the means 2SE. Number of livers measured is given in parentheses.

Ez

*Z

G

METABOLISM OF D-FRUCTOSE

327

quent portions of the metabolic pathway appear also to have a greater capacity for handling D-fructose and its metabolites than for handling D-glucose and its metabolite^.^^^^^^ Also, the incorporation of D-[6-I4c]fructose into labeled-carbon fatty acid in human-liver slices is greater than carbon incorporation from D-glucose. Sucrose, D-fructose, and Dglucose contribute differently to the amount of serum triglyceride, formed because of the greater capacity of the glycolytic pathways for handling D-fructose than D - g l ~ c o s e . ~ ~ ~ A diet high in D-fructose produces increased concentrations of pyruvate, malate, and acetyl coenzyme A ( A ~ S C O A ) D-Fructose .~~~,~~~ enhances formation of AcSCoA from pyruvate b y stimulating pyruvate oxidation.296As D-fructose causes a fall in the hepatic ATP concentration, pyruvate dehydrogenase (EC 1.2.4.1) is activated, and it produces an increase in AcSCoA formation from p y r u ~ a t e Thus, .~~~ dietary sucrose and D-fructose produce higher hepatic fatty acid synthesis than does dietary D-glucose, because of their stimulation of AcSCoA formation. A number of investigations have indicated that D-fructose increases the a-glycerophosphate concentration in liver. Bar-on and Steinzs8 suggested that the sequence of events occurring in rats after D-fructose feeding, leading to subsequent formation of triglyceride, could be explained on the basis of the low activity of D-glucose 6-phosphatase in rat intestine, which allows significant amounts of D-fructose to be absorbed directly into the portal circulation, and its conversion in the liver into a-glycerophosphate. At the same time, no repression of the outflow of free fatty acid from adipose tissue occurs, leading to increased formation of triglyceride in the liver, and its secretion into the serum. As feeding of D-fructose does not induce lipoprotein lipase (EC 3.1.1.3)activity in adipose tissue, the egress of triglyceride from the serum (and, thus, the homeostatic regulation of triglyceride levels) should be impaired, leading to triglyceride accumulation in the blood stream. As yet, the concept has not been confirmed by experimental observation. Intravenous injection of D-fructose (200 to 400 mg) into an anesthetized rat produces a prompt increase in hepatic a-glycerophosphate concentration. This increase is transient, as the a-glycerophosphate concentration returns to the normal level within 20 minutes after D-fructose i n j e c t i ~ n . ”Oral ~ ingestion of large amounts of (295) G. Griffaton, R. Rozen, R. Ardouin, and R. Lowry, Enzyme, 17, 319-332 (1974). (296) H. D. Soling, B. Wills, and G . Janson, FEBS Lett., 11, 324-327 (1970). (297) T. G. Linnet, F. M. Pettit, and L. J. Reed, Proc. Natl. Acad. Sci. U.S.A., 62, 235-241 (1969). (298) D. Zakim and R. H. Herman, Biochim. Biophys. Acta, 165, 374-379 (1968).

328

MINSHEN CHEN AND ROY L. WHISTLER

D-fructose or sucrose does not increase hepatic a-glycerophosphate concentration over that produced by ~ - g l u c o s e .Although ~~~,~~ Exton ~ and Park300reported that 20 mM D-fructose increases the a-glycerophosphate Concentration in the perfused liver to 430-38 10 nmoledg (dry weight) in 1 h, Wieland and Matschinsky found only 75-150 nmoles/g (wet weight) increase after 2 hours of D-fructose perfusion.301Thus, the effect of D-fructose on hepatic fatty acid metabolism is not related to the increase in hepatic a-glycerophosphate concentration. It is well known that the rate of triglyceride formation is not the only determinant of serum triglyceride level. The rate of triglyceride formation and its release from liver and, most important, the net rate of serum triglyceride removal, may influence serum concentration.302*303A diet high in D-fructose increases the rate of [1,3-14C]glycerol incorporation into hepatic triglycerides. D-Fructose at 75% of the diet produces a consistent and substantial increase in serum t r i g l y c e r i d e ~In . ~ animals ~~ fed high levels of D-glucose, the increased production of triglycerides is balanced by an accelerated, net triglyceride The mechanism for removal of triglyceride from the circulation depends on hydrolysis of the triglyceride in the capillary beds of the extrahepatic tissues b y the enzyme clearing-factor, lipase or lipoprotein l i p a ~ e . ~Both O ~ D-fructose and sucrose fail to raise either the adipose-tissue, clearing-factor, lipase activity or the plasma, immunoreactive, insulin concentration above the value found in control animals given only water (see Table V). D-Glucose administration, on the other hand, causes the concentration of plasma insulin to rise to equivalent values for animals fed orally, and causes the adiposetissue, clearing-factor, lipase activity to increase t ~ o - f o l d Feeding .~~~ of sucrose or D-fructose fails to enhance the rate of removal of triglyceride from plasma. This observation, together with the effect that D-fructose or sucrose has in increasing the rate of entry of triglyceride into the plasma from the liver, could be responsible for the hypertriglyceridemia.

(299) D. Zakim, R. S. Pardini, R. H. Herman, and H. E. Sauberlich, Biochim. Biophys. Acta, 137, 179-180 (1967). (300) J. H. Exton and C. R. Park,]. Biol. Chem., 240, PC 955-956 (1965). (301) 0 . Wieland and F. Matschinsky, Life Sci., 2,49-54 (1962). (302) S. H. Quarfordt, A. Frank, D. M. Shank, M. Berman, and D. Steinberg,J. Clin. Inuest., 49, 2281-2297 (1970). (303) R. J. Havel, J. P. Kane, E. 0 . Balasse, N. Segel, and L. V. Basso,]. Clin. Invest., 49,2017-2035 (1970). (304) V. J. Cunningham and D. S. Robinson, Biochem. ]., 112,203-209 (1969).

TABLEV

z

EffectJu5of Oral Sugars on Plasma Constituents and on Adipose-tissue, Clearing-factor, Lipase Activity in 24-Hour-Starved Rats

m

*

4

m Plasma concentration of

Substance administered

D-Glucose (mg/100 ml)

D-Fructose (mg/100 ml)

Triglyceride (pmo1/100 ml)

D-Fructose D-Glucose Sucrose Water Animals fed ad libitum

99 t 2 1 89 210 95 +14 52 k 8 127 211

27 t 1 0 15 2 4 -

120 223 55 +32 121 +35 58 k 2 8 103 226

Free fatty acid (pmo11100 ml)

Immunoreactive insulin (punits/ml)

Adipose-tissue, clearing-factor, lipase activity (units/g of fresh wt. of tissue)

82 ?

47 22 36 75 28

28 26 +6 210 t6

29 +9 67 r 1 8 36 tll 26 +14 69 r 1 4

44 +14 119 230 51 +14 40 220 218 255

z

0 4

a

m

330

MINSHEN CHEN A N D ROY L. WHISTLER

Dietary D-fructose significantly decreases the lipogenesis in adipose tissue, but increases hepatic lipogenesis. Ample evidence has indicated that such hepatic, lipogenic enzymes as D-glucose 6-phosphate dehydrogenase ( E C 1.1.1.49),306-308malic enzyme,306,307*309 fructokinase,306fatty acid syncitrate-cleavage enzyme (EC 4. 1.3.8),306 thetase ( E C 2.3.1.38),310 and 6-O-phosphono-~-gluconatedehydroare all elevated in rats fed D-fructose. In congenase (EC 1.1.1.43)306 trast, the activity of these enzymes and of hexokinase is decreased in adipose tissues of rats fed D-fructose.30633083310 Incubation of adipose and liver tissue from rats fed radioactive Dfructose, D-glucose, or sucrose shows that the major, lipogenic site shifts from adipose tissue in rats fed D-fructose to liver tissue. Findings from in vivo experiments also support such a shift. In response to feeding of D-fructose, there is a greater percentage increase in the in vivo incorporation of D-[U-14C]glucoseinto liver lipids and fatty acid than into adipose tissue.311Thus, substituting D-fructose for D-glucose in the diet of rats leads to changes in lipid metabolism. Based on in vitro and in oivo data, as well as on lipogenic enzyme-activity data, it appears that, indeed, the relative importance of the liver to total, de novo, fatty acid synthesis increases, while that of the adipose tissue decreases when rats are fed D-fructose as a source of carbohydrate. The data seem to suggest that D-fructose-induced hyperlipemia may result from the greater capacity of the glycolytic pathway for handling D-fructose than for handling D-glucose, coupled with the failure of Dfructose to increase the rate of removal of triglyceride from plasma, and the shift in major lipogenic sites from adipose tissue to liver.

XIV. KEY ENZYMESIN METABOLISMOF D-FRUCTOSE 1. D-Fructokinase Fructokinase ( E C 2.7.1.3) catalyzes the reaction D-Fructose

+ ATPMg + ADPMg + D-fructose

l-phosphate

(305) A. Cryer, S. E. Riley, E. R. Williams, and D. S. Robinson, Biochem. J., 140, 561-563 (1974). (306) M . M. Chevalier, J. H. Wiley, and G. A. Leveille,]. Nutr., 102, 337-342 (1972). (307) A. M. Cohen, S. Briller, and E. Shafir, Biochim. Biophys. Acta, 279, 129-138 (1972). (308) D. J. Naismith, Proc. Nutr. SOC., 30, 259-265 (1971). (309) W. M. Firch and I. L. Chaikoff,J. Biol. Chem., 235, 554-557 (1960). (310) K. R. Kruckdorfer, I. H. Khan, and J . Yudkin, Biochem. J , , 129,439455 (1972). (311) D. R. Romsos and G. A. Leveille, Biochim. Biophys. Acta, 360, 1-11 (1974).

METABOLISM OF D-FRUCTOSE

33 1

Fructokinase is found in 1iver,56,312-315 kidney,32 intestinal mucosa,33,316adipose t i s s ~ i e , and ~ ~ ,lenses,317 ~~ but not in heart muscle, skeletal muscle, brain, and seminal vesicles.57 Fructokinase isolated from rat liver has a K , of 0.46 and 0.8 mM for D-fructose, and a K , of 1.56 and 1.33 mM for ATPMg at a concentration of K+ of 0.4 and 0.1 M , respectively. The enzyme is also active toward L-sorbose, ~ - t a g a t o s e , ~and l ~ D-threo-pentulose (D-xyluRanshel and Cleland318 examined the structural-substrate requirement for fructokinase, and found that the P-D-fructofuranose tautomer is essential. The position of the terminal hydroxymethyl group on C-5 is relatively unimportant, as both D-fructose and Lsorbose are substrates. The anomeric hydroxyl group is not needed for activity, but this group is involved in binding to the enzyme. For activity, the 3-hydroxyl group must be trans to the 2-hydroxymethyl group. The chirality of C-4 is unimportant, if C-3 and C-5 have the same chirality as those in D - f r u c t o ~ e . ~ ' ~ Requirement of K+ by fructokinase has been d e m o n ~ t r a t e d . ~ ~ ~ * ~ ~ The K+ ion acts as an allosteric activator, and it cooperatively increases the reaction velocity.320The Mg2+ion is also important, as the activity of fructokinase depends on the ratios of ATP4- :MgATP2- and of KATP3- : MgATP2-. The optimal ratios vary, depending upon the enzyme saturation and the K+ c o n c e n t r a t i ~ n . ~ ~ ~

2. D-Fructose (D-Mannose) Kinase This fructokinase catalyzes phosphorylation to afford D-fructose 6-phosphate; this enzyme activity was detected in the cytoplasm of Streptococcus f a e c a l i ~ Echinococcus ,~~~ g r ~ n u l o s u s and , ~ ~in ~ pea.323 (312) R. E. Parks, E. Ben-Gerhorn, and H. A. Lardy, ]. B i d . Chem., 227, 231-242 (1957). (313) R. C. Adelman, F. J. Ballard, and S. Weinhouse,]. B i d . Chem., 242, 3360-3365 (1967). (314) J. J . Sanchez, N. S. Gonzalez, and H. G. Pontis, Biochim. Biophys. Acta, 227, 67-78 (1971). (315) F. Heinz, W. Lamprecht, and J. Kirsch,]. Clin. Inuest., 47, 1826-1832 (1968). (316) E. Cadenas and A. Sols, Biochim. Biophys. Acta, 42,490-498 (1960). (317) C. Ohrloff and H. Hockwin, Ophthalmic Res., 5, 121-128 (1973). (318) F. M. Ranshel and W. W. Cleland,]. Biol. Chem., 248,8174-8177 (1973). (319) H. G. Hers, Biochim. Biophys. Acta, 8,424-430 (1952). (320) J. J. Sanchez, N. S. Gonzalez, and H. G. Pontis, Biochim. Biophys. Acta, 227, 79-85 (1971). (321) L. D. Moore and D. J. O'Kane,]. Bacteriol., 86, 766-772 (1963). (322) M. Agosin and L. Aravena, Biochim. Biophys. Acta, 34, 90-102 (1959). (323) A. Medina and A. Sols, Biochim. Biophys. Acta, 19, 378-379 (1956).

332

MINSHEN CHEN AND ROY L. WHISTLER

Accumulated reaction-products do not inhibit the enzyme.223For the , ~ ~K~, value for D-fructose is 620 pM, enzyme from E . g r a n u l o s u ~the but is less than 1mM for the enzyme from pea.3z3The enzyme purified from Leuconostoc r n e s e n t e r o i d e ~ can ~ ~ ~phosphorylate ,~~~ either Dfructose or D-mannose at the same rate ( K , 0.4 mM). However, the pH-activity curves are different for the two hexoses, with the ratio of activity of D-fructokinase to that of D-inannokinase being about 1 : 1 at pH 6.9, 0 . 5 :1 at pH 8.5, and 0.3: 1 at pH 8.9.

3. D-Fructose I-Phosphate Kinase D-Fructose 1-phosphate kinase catalyzes the phosphorylation of D-fructose 1-phosphate to D-fructose 1,6-bisphosphate. The enzyme has been purified from Aerobacter ~ e r o g e n e sand ~ ~ ~Bacteroides

sy r n b i o ~ i s . ~ ~ ~ The molecular weight is32875,000, and the K,, for D-fructose l-phosphate is3260.3 mM at an p H of 8. No phosphorylation is ohserved with L-fructose 1-phosphate, D-mannose 6-phosphate, D-fructose 6-phosphate, D-glucose 6-phosphate, or D-glucose 1-phosphate.”* The enzyme requires Mn2+ or Mg2+ for catalytic activity,3”+but K+, Rb+, and NH4+ increase the enzymic activity.329ATP inhibits the kinase, as the ratio of concentration of Mg2+ to ATP decreases below 2 : 1. The ATP inhibition can be released by Mg2+. Citrate ( K i 0.85 mM), D-fructose 1,6-bisphosphate ( K i 4.4 mM), and D-fructose 6-phosphate (Ki1.0 mM) inhibit D-fructose 1-phosphate kinase competitively with D-fructose l - p h o ~ p h a t e . ~ ~ ~

4. D-Fructose Diphosphate Aldolase D-Fructose diphosphate aldolase (EC 4.1.2.13) catalyzes a reversible aldol reaction, yielding two different triose phosphateh, ;IS follows. D-Fructose 1,6-bisphosphate glycerone phosphate

+ D-glyceraldehyde 3-phosphate

Two distinct types of aldolase are known. Class I aldolases occur in animals, plants, protozoans, and algae, and Class 11, in bacteria, fungi, (324) V. Sapico and R. L. Anderson, J . B i d . Chem., 242, 5086-5902 (1967). (325) R. L. Anderson and V. L. Sapico, in “The Enzymes,” W. A. Wood, ed., Academic Press, New York, San Francisco, London, 1975, Vol. 42, pp. 39-43. (326) T. E. Hanson and R. L Anderson,]. Biol. Chem., 241, 1644-1645 (1966). (327) R. E. Reeves, L. G . Warren, and D. S. Hsu,J. Biol. Chem., 241,1257-1261 (1966). (328) V. Sapico and R. L. Anderson,J. Biol. Chem., 244,6280-6288 (1969). (329) V. Sapico and R. L. Anderson,J. B i d . Chem., 245,3252-3256 (1970).

METABOLISM OF D-FRUCTOSE

333

and blue-green algae.330-332Aldolase is absent from certain heterofermentative bacteria, such as Leuconostoc mesenteroides,”’ and from certain aerobic organisms, such as Acetobacter ~ u b o x y d a n s . ~ ~ “ Class I aldolases do not require metal-ion cofactors, and react with substrate to form an intermediate, Schiff b a ~ e .The ~ ~enzymes ~ , ~ ~are~ inactivated by reduction with borohydride in the presence of the substrate.337*338 Class 11 aldolases are not inactivated by reduction with borohydride .330 Class I aldolases of mammals and other vertebrates can be subdivided into three distinct i ~ o e n z y m e s . ’ ~Identification ~,~~~ of the parental aldolases A, B, and C has been made from their substrate specificities (ratio of activity towards D-fructose 1,6-bisphosphate and towards D-fructose 1-phosphate), electrophoretic mobilities, tissue distribution, and specific immunological properties. Aldolase A is the major form, present in muscle; aldolase B, the predominant form in liver and kidney; and aldolase C, present in brain with aldolase A. In tissues where more than one aldolase isoenzyme occurs, a hybrid form is often observed.=l The cell distribution of aldolase B corresponds with its proposed role in gluconeogenesis and D-fructose metabolism.339 Muscle aldolase B acts primarily on D-fructose 1,6-bisphosphate, whereas the aldolase from liver facilitates the cleavage of D-fructose 1,6-bisphosphate and D-fructose 1-phosphate at about equal rates. As a consethe metabolism of D-fructose by way of D-fructose 1-phosphate can readily occur in liver, where it is the primary, metabolic route. Rabbit-muscle, Class I aldolase has been the most fully character(330) W. J. Rutter, Fed. Proc. Fed. A m . Soc. E x p . Biol., 23, 1248-1257 (1964). (331) H. G. Lebherz and W. J. Rutter, Biochemistry 8, 109-121 (1969). (332) B. L. Horecker, 0.Tsolas, and C. Y. Lai, in “The Enzymes,” P. D. Boyer, ed., Academic Press, New York, 1972, Vol. 7, pp. 213-258. (333) R. D. Demoss, R. C. Bard, and I. C. Gunsalus,J. Bacteriol., 62, 499-511 (1951). (334) T. E. King and V. H. Cheldelin,/. Bacteriol., 66, 581-584 (1953). (335) I. A. Rose and S. V. Rieder, J. A m . Chem. Soc., 77,5764-5765 (1955). (336) B. L. Horecker, S. Pontremoli, C. Ricci, and T. Cheng, Proc. Natl. Acad. Sci. U.S.A., 47, 1949-1955 (1961). (337) E. Crazi, T. Cheng, and B. L. Horecker, Biochem. Biophys. Res. Commun., 7,253 (1963). (338) B. L. Horecker, P. T. Rowley, E. Grazi, T. Cheng, and 0. Tchola, Biochem. Z . , 338, 36-51 (1963). (339) W. J. Rutter, R. E. Blostein, B. M. Woodfin, and C . S. Weber, Adv. Emzyme Regul., 1, 39-56 (1963). (340) P. Christen, U. Rensing, A. Schmid, and F. Leuthardt, Helu. Chim. Acta, 49, 1827-1875 (1966).

334

MINSHEN CHEN AND ROY L. WHISTLER

i ~ e dThe . ~ enzymes ~ ~ of molecular weight 160,000 are tetramers. Two functional, lysine residues are located at the active site. The first lysine residue reacts with the carbonyl group of D-fructose 1-phosphate to afford a Schiff base,33s,336,341,342 and the second lysine residue interacts with the phosphate Other amino acid residues at the active site are C-terminal t y r ~ s i n eand ’ ~ ~h i ~ t i d i n e , 3 and ~ ~ -a~thiol ~ ~ is present. 346 Plant aldolases are similar to mammalian aldolases, but have smaller molecular The aldolases from Lactobacillus casei and Micrococcus a e r ~ g e n e are s ~ ~similar ~ to the mammalian enzymes with respect to Schiff-base formation349and to involvement of specific amino acid residues.350However, the amino acid composition of the enzyme from M . aerogenes is different from those of rabbit aldolases.351 Class I1 aldolases are normally dimeric, having a molecular weight for the subunit lying352between 30,000 and 40,000. The K , (for Dfructose 1,6-bisphosphate) of these aldolases may be as high as 300 p M , in contrast to 5 pM for Class I a l d o l a s e ~ . The ~ ~ ~enzyme - ~ ~ ~ shows no activity toward D-fructose 1-phosphate. Class I1 enzymes are inhibited by EDTA and require Zn2+ or other metals for catalytic activity. The metal ion may involve polarization of the carbonyl group

F. J. Castellino and R. Barker, Biochem. Biophys. Res. Commun., 23, 182-187 (1966). A. Ginsburg and A. H. Mehler, Biochemistry, 5,2623-2634 (1966). L. C. Davis, L. W. Brox, R. W. Gray, and B. L. Horecker,Arch. Biochem. Biophys., 140,215-222 (1970). F. C. Hartman, S. Byungse, M. H. Welch, and R. Barker,]. B i d . Chem., 248, 8233-8239 (1973). P. A. M. Eagles, L. N. Johnson, M. A. Joynson, C . H. McMurray, and H. Gutfreund,/. Mol. B i d , 45, 533-544 (1969). C. Y. Lai, C . Chen, J. D. Smith, and B. L. Horecker, Biochem. Biophys. Res. Commun., 45, 1497-1505 (1971). G. Rapoport, L. Davis, and B. L. Horecker, Arch. Biochem. Biophys., 132, 286-293 (1969). H. G. Lebherz and W. J. Rutter,J. Biol. Chem., 248, 1650-1659 (1973). G. S. Kaklij and G. B. Nadkami, Arch. Biochem. Biophys., 140,334-340 (1970). G. S. Kaklij and G . B. Nadkami, Arch. Biochem. B i o p h y s . , 160, 47-51 (1974). H. G. Lebherz, R. A. Bradshaw, and W. J. Rutter,J. Biol. Chem., 248, 1660-1665 (1973). W. J. Rutter, in “Evolving Genes and Proteins,” V. Bryson and H. J. Vogel, ecls., Academic Press, New York and London, 1965, pp. 279-291. W. J. Rutter, J. R. Hunsley, W. E. Groves, J. Cader, T. V. Rajkumar, and B. M. Woodfin, Methods Enzymol., 9, 479-498 (1966). D. E. Morse and B. L. Horecker, Adu. Enzymol., 31, 125-187 (1968).

METABOLISM O F D-FRUCTOSE

335

involving C-2 of D-fructose 1,6-bisphosphate, and it may also influence the o r i e n t a t i ~ n of ~ ~the ’ phosphate group on C-1. F i ~ t t e r ~proposed ~O that the classes of aldolase might have evolved independently from separate, genetic origins, although, within each class, the enzymes from different species are homologous. However, in E . coli (Crookes strain), the appearance of a Class I or Class I1 aldolase seems to depend on the growth condition. Appearance of aldolase of Class I is favored by conditions of g l u c o n e ~ g e n e s i s . ~ ~ ~

5. Triose Kinase Triose kinase (EC 2.7.1.28) uses ATP to phosphorylate the primary hydroxyl groups of D-glyceraldehyde or glycerone. Triose kinase activity is found in liver,35,142,315,356 intestine, kidney of mammalian system,32,33*3L5,357 and human erythrocytes,358and it has been partially purified from beef liver, guinea-pig liver,359and human erythrocytes.358The Michaelis-Menten constant of the liver enzyme for D-glyceraldehyde is 125 p M , and for glycerone, 0.02 mM; and the pH is 7.0. The enzyme from erythrocytes358has a K , of 0.5 p M for glycerone, and a K , of 11 p M for D-glyceraldehyde. With Dglyceraldehyde as the substrate, the K , for the MgATP2- complex is 1.45 mM, and no cooperative interaction is observed. With glycerone as the substrate, there is cooperative interaction with the MgATP2complex358at the optimal pH of 6.6. No other triphosphate can replace ATP as the phosphate donor.358L-Glyceraldehyde, D-glycerate, D-glucose, and D-fructose do not serve as substrates.358

6. D-Fructose l$-Diphosphatase D-Fructose 1,6-diphosphatase (FDPase) (EC 3.1.3.11)catalyzes the irreversible reaction: D-Fructose 1,Bbisphosphate + D-fructose 6-P

+ Pi.

Fructose 1,G-diphosphatase can be isolated from many mammalian systems, including rabbit liver,360m u s ~ l e ,rabbit ~ ~ , kidney,363 ~ ~ ~ swine (355) D. Strihling and R. N. Perham, Biochem J., 131,833-841 (1973). (356) E. Hemreich, S. Goldschmit, W. Lemprecht, and F. E. Ritzl, Hoppe-Seyler’s Z . Physiol. Chem., 292, 184-206 (1953). (357) 0. Lindherg, Biochim. Biophys. Acta, 7, 349-353 (1957). (358) E. Beutler and E. Guinto, Blood, 41, 559-568 (1973). (359) H. G. Hers, Methods Enzymol., 5, 362-364 (1962). (360) S. Pontremoli, S. Traniello, B. Luppis, and W. A. Wood, J . B i d . C h ~ m .240, , 3459-3463 (1965).

336

MINSHEN CHEN AND ROY L. WHISTLER

kidney,364,365 chicken liver and breast muscle,366and rat liver, kidney, and leg m u ~ c l e . ~The ~ ~ enzyme , ~ ~ * has been isolated from such microorganisms as Dictyostelium d i ~ c o i d e u m Candida ,~~~ ~ t i l i s Poly,~~~ sphondylium p a l l i d ~ m , ~Pseudomonas ~' s a c c h a r ~ p h i l i a E, ~. ~~ ~o l i , " ~ Acinetobacter sp,374and Hydrogenomonas e ~ t r o p h a The . ~ ~ ~plant enzyme has been isolated from castor-bean endosperm, castor leaf,376 navy bean,377wheat embryo,378and spinach chloroplast.379 D-Fructose 1,6-diphosphatase utilizes both D-fructose 1,6-bisphosphate and sedoheptulose 1,7-bisphosphate as substrate, but the affinity for D-fructose 1,6-bisphosphate is the greater. However, D-fructose 1,6-diphosphatase isolated from Candida ~ t i 2 i or s ~spinach ~~ chlorois specific for D-hctose 1,6-bisphosphate, and does not attack sedoheptulose 1,7-bispho~phate.~~~,~*~ The enzyme from C. utilis has an alkaline pH optimum (9.0-9.5), and a requirement for Mg2+ or Mn2+.At pH 7.5-8.0, the enzyme is inactive, unless EDTA is added.380 (361) J. Fernando, M. Enser, S. Pontremoli, and B. L. Horecker, Arch. Biochem. Biophys., 126, 599-606 (1968). (362) J. Fernando, S. Pontremoli, and B. L. Horecker, Arch. Biochem. Biophys., 129, 370-376 (1969). (363) M. Enser, S. Shapiro, and B. L. Horecker,Arch. Biochem. Biophys., 129,377-383 ( 1969). (364) F. Marcus, Arch. Biochem. Biophys., 122, 393-399 (1967). (365) J. Mendicino, C. Beaudreau, L. C. Hsu, and R. Medicus, J . Biol. Chem., 243, 2703-2709 (1968). (366) J. P. Olson and R. R. Marquardt, Biochim. Biophys. Acta, 268,453-467 (1972). (367) K. Sato and S. Tsuiki, Arch. Biochem. Biophys., 129, 173-180 (1969). (368) S. Traniello, Biochim. Biophys. Acta, 341, 129-137 (1974). (369) P. Baumann and B. E. Wright, Biochemistry, 8, 1655-1659 (1969). (370) M. Chakravorty, L. A. Veiga, M. Bacila, and B. L. Horecker,J. Biol. Chem., 237, 1014-1020 (1962). (371) 0. M. Rosen, Arch. Biochem. Biophys., 114, 31-37 (1966). (372) D. D. Fossitt and I. A. Bernstein,]. Bacteriol., 86, 598-599 (1963). (373) D. G. Frankel, S. Pontremoli, and B. L. Horecker,Arch. Biochem. Biophys., 114, 4-12 (1966). (374) A. J. Mukkada and E. J. Bell, Biochem. Biophys. Res. Commun., 37, 340-346 (1969). (375) A. T. Abdelal and H. G. Schlegel,J. Bacteriol., 120, 304-310 (1974). (376) J. Scala, C . Patrick, and G. Macbeth, Arch. Biochem. Biophys., 127, 576-584 (1968). (377) J. Scala, C. Patrick, and G. Macbeth, Arch. Biochem. Biophys., 131, 111-115 (1969). (378) R. Bianchetti and M. L. Sartirana, Biochem. Biophys. Res. Commun., 27,378-383 (1967). (379) A. M. El-Badry, Biochim. Biophys. Acta, 333,366-377 (1974). (380) 0. M. Rosen, S. M. Rosen, and 8. L. Horecker, Arch. Biochem. Biophys., 112, 411-420 (1965).

METABOLISM OF D-FRUCTOSE

337

In contrast, native liver and kidney enzymes exhibit maximal activitySR1,382 at neutral pH. Muscle and kidney enzymes at neutral p H require the metal ion-EDTA complex in the presence of free Mn2+or Mg2+ions for optimal a c t i v i t ~ . ~ ~ ~ , ~ ~ ~ D-Fructose 1,6-diphosphatases from rabbit liver and muscle are similar in their cation-requirement profile, molecular weight, substrate affinity, and substrate inhibition, but have different amino acid compositions, and the muscle enzyme does not cross-react with antibody to the purified l i ~ e r - e n z y m e .The ~ ~ ~muscle , ~ ~ ~ enzyme is more sensitive to AMP than the enzyme from liver or kidney.3s5 The native form of enzyme in mammalian liver and kidney is a tetramer of four identical subunits having molecular eight^^^^,^^^ -35,000. The existence, per enzyme molecule, of four substrate-binding sites and four allosteric sites for the inhibitor AMP has been demo r ~ s t r a t e d . ~On ~ ~the - ~ ~other ~ hand, the enzyme of Candida utilis has a molecular weight of 100,000,and contains only two subunits.380 Both by proteolytic enzymes and sulfhydryl reagents, D-fructose 1,6-diphosphatase can be modified to act as an alkaline enzyme with optimal a c t i ~ i t y ~ ~at~p~H " '9 or as a neutral enzyme with pH optimum at or near n e ~ t r a l i t y . ~Upon g ~ conversion of native (neutral) enzyme into the altered (alkaline) enzyme, at least three general, enzymic properties are significantly changed, including ( 1 ) a shift in the p H

-

(381) S. Traniello, S. Pontremoli, Y. Tashima, and B. L. Horecker, Arch. Biochem. Biophys., 146, 161-166 (1971). (382) S . Traniello, E. Melloni, S. Pontremoli, C. L. Sia, and B. L. Horecker,Arch. Biochem. Biophys., 149,222-231 (1972). (383) A. Van Tol, W. J. Black, and B. L. Horecker, Arch. Biochem. Biophys., 151, 591-596 (1972). (384) J. S. Rosenberg, Y. Tashima, B. L. Horecker, and S. Pontremoli, Arch. Biochem. Biophys., 154,283-291 (1973). (385) A. Von Tol, Arch. Biochem. Biophys., 162,238-247 (1974). (386) J . Mendicino, N. Kratowich, and R. M. Oliver, J. Biol. Chem., 247, 6643-6650 (1972). (387) Y. Tashima, G. Tholey, G. Drummond, H. Bertrand, J. S. Rosenberg, and B. L. Horecker, Arch. Biochem. Biophys., 149, 118-126 (1972). (388) S. Pontremoli, E. Grazi, and A. Accorsi, Biochemistry, 7, 1655-1661 (1968). (389) S. Pontremoli, E. Grazi, and A. Accorsi, Biochemistry, 7, 3628-3633 (1968). (390) M. G. Sarngadharan, A. Watanabe, and B. M. Pogell, Biochemistry, 8,1411-1419 ( 1969). (391) G. J . S. Rao, S. M. Rosen, and 0. M. Rosen, Biochemistry, 8,4904-4909 (1969). (392) K. Nakashima, B. L. Horecker, S. Traniello, and S. Pontremoli, Arch. Biochem. Biophys., 139, 190-199 (1970). (393) A. M. Geller, G. T. Rajagopolan, E. H. Ellis, and W. L. Byrne, Arch. Biochem. Biophys., 146, 134-143 (1971).

338

MINSHEN CHEN AND ROY L. WHISTLER

optimum from neutral to alkaline pH values; (2) loss of activation by K+; and ( 3 )diminished sensitivity to inhibition by AMP.394In conversion of the native enzyme into an alkaline enzyme, a tryptophan unit is lost from the amino-terminal region. This loss of tryptophan changes the pH optimum to a more alkaline value.395Thus, the tryptophancontaining peptide appears to determine the functional properties of the native enzyme. D-Fructose 1,6-diphosphatase is a regulatory enzyme playing a key role in the control of gluconeogenesis. A number of mechanisms have been proposed for the regulation of D-fructose 1,6-diphosphatase activity, including allosteric control by inhibition by D-fructose 1,6-bisphosphate, ADP, or ATP, and modification of the sulfhydryl groups of the The specific inhibition of D-fructose 1,6-diphosphatase b y AMP decreases if the pH of the solution moves399to above 9. Inhibition by AMP and catalytic activity can be lost by acetylation of the tyrosine residues with l-acetylimidazole. The presence of substrate or allosteric effectors protects the tyrosine from a ~ e t y l a t i o n . ~Pyridoxal '~ phosphate can also desensitize the enzyme by forming a Schiff base with L-lysinyl residues401; this indicates some participation of L-lysinyl residues in allosteric r e g u l a t i ~ n . ~ ~ ' , ~ ~ ~ The increase in enzyme inhibition with increasing substrate concentration may be interesting from a physiological point of view. When glycolysis operates at a low level, and energy production is low, AMP will accumulate and tend to inhibit D-fructose 1,Bdiphosphatase. Concurrently, accumulation of D-fructose 1,6-bisphosphate niay inhibit the D-fructose 1,8diphosphatase reaction, favoring glycolysis and increased production of ATP. However, D-fructose 1,6-diphos~ ~ ~from the phatase isolated from Gram-negative A c i n e t o b u ~ t e rand slime mold Polysphondylium p ~ l l i d u r nis~not ~ ~inhibited b y AMP at (394) G. Colombo and F. Marcus,]. Biol. Chem., 248, 2743-2745 (1973). (395) S. Pontremoli, E. Melloni, A. DeFlora, and B. L. Horecker, Proc. Natl. Acad. Sci. U.S.A., 70, 661-664 (1973). (396) K. Taketa and B. M. Pogell,]. B i d . Chem., 240, 651-662 (1965). (397) S. Pontremoli, S. Traniello, M. Enser, S. Shapiro, and B. L. Horecker, Proc. Natl. Acad. Sci. U.S.A., 58, 286-293 (1967). (398) K. Taketa, M. G. Samgadharan, A. Watanabe, H. Aoe, and B. M. Pogell,]. B i d . Chem., 246, 5676-5683 (1971). (399) S. Pontremoli, E. Grazi, and A. Accorsi, Biochem. Biophys. Res. Comnaun., 33, 335-339 (1968). (400) J. F. Riordan, E. C. Warner, W. E. C. Wacker, and B. L. Vallee, Biochemistry, 4, 1758-1765 (1965). (401) T. A. Krulwich, M. Enser, and B. L. Horecker, Arch. Biochem. Biophys., 132, 331-337 (1969). (402) G. Colombo, E. Hubert, and F. Marcus, Biochemistry, 11, 1798-1803 (1972).

METABOLISM OF D-FRUCTOSE

339

any pH, and, in this regard, it is quite different from the D-fructose 1,6-diphosphatase from mammalian systems. Enzyme from ungerminated, castor-bean endosperm is inhibited by AMP. However, a second D-fructose 1,6-diphosphatase synthesized in the endosperm during a 3-day germination, or the enzyme found in the leaves and cotyledons of castor bean were not inhibited376by AMP. Thus, it is unlikely that AMP regulation of D-fructose 1,6-diphosphatase is an important factor in regulating gluconeogenesis in the castor bean.37s reported that ATP and ADP inhibit rabbitTaketa and liver D-fructose 1,6-diphosphatase, and that the inhibition results from a conversion of the enzyme into a conformer having low activity. Skeletal-muscle enzyme is inhibited by ADP. The binding of AMP, D-fructose l,Bbisphosphate, and ATP to the kidney 1,6-diphosphatase markedly influences the binding of each of the others. ATP and AMP both increase the affinity of the enzyme for D-fructose 1,6-bisphosphate. In contrast, a decrease in the affinity of the enzyme for ATP is observed when AMP or D-fructose 1,Bbisphosphate is present. ATP decreases the affinity of the enzyme for AMP, and D-fructose 176-bisphosphate increases the affinity of the enzyme for AMP. These cooperative interactions between the AMP, ATP, and D-fructose 1,6-bisphosphate binding-sites suggest that the structural alterations that occur in the enzyme upon binding of any one compound leads to changes in the affinity of the enzyme for other compounds.403,404 Regulation of liver D-fructose 1,6-diphosphatase could involve modification of the sulfhydryl group of the enzyme.397Cystamine (2,2’-dithiobisethylamine) or homocysteine undergoes a disulfide exchange-reaction with two reactive cysteine residues. This exchange leads to a four-fold increase in catalytic activity.405Other sulfhydryl reagents, such as l-fluoro-2,4-dinitrobenzene (FDNB), p-mercuribenzoate (PMB), and 2-iodoacetamide, also activate liver D-fructose 1,6-phosphatase a ~ t i v i t y .Horecker ~~~,~~ and ~ coworkers405found that rabbit-liver D-fructose 1,Bdiphosphatase can be activated in the presence of CoA or an acyl-carrier protein. At pH 8.5, activation also results from a disulfide interchange-reaction between the protein and the oxidized coenzymes.407Thus, the activation of D-fructose 1,6-diphosphatase by formation of mixed disulfides might play a role in in (403) N . Kratowich and J. Mendicino,]. BioZ. Chem., 249, 5485-5494 (1974). (404) J. Y. Fu and R. G. Kemp,J. B i d . Chem., 248, 1124-1125 (1973). (405) K. Nakashima, B. L. Horecker, and S . Pontremoli, Arch. Biochem. Biophys., 141, 579-587 (1970). (406) C. Little, T. Sanner, and A. Pihl, Eur. J. Biochem., 8,229-236 (1969). (407) K. Nakashima, S. Pontremoli, and B. L. Horecker, Proc. NatZ. Acad. Sci. U.S.A., 64, 947-951 (1969).

340

MINSHEN C H E N A N D ROY L. WHISTLER

uiuo enzyme regulation. CoA cannot serve as a physiological regulator, as fatty acid catabolism during gluconeogenesis would leave very little CoA in the free sulfhydryl form.4o8A more attractive possibility is the activation of D-fructose 1,8diphosphatase by homocysteine, because the gluconeogenic process is accompanied b y increased catabolism of protein^.^"

7. D-Glucitol Dehydrogenase (Sorbitol Dehydrogenase) D-Glucitol dehydrogenase (EC 1.1.1.14) catalyzes the interconversion of D-glucitol and D-fructose, with the coaction of NAD+. D-G~ucitol dehydrogenase has been purified from rat,409 rabbit,410guinea sheep liver,412human r e d - ~ e l land , ~ ~from ~ Bacillus s ~ b t i l i s , ~ ~ ~ Acetobacter s ~ b o x y d a n s , ~and ’ ~ Aspergillus High enzymic activity is found in testis of ram,417bull, boar, stallion, rhesus monkey,418and guinea pig,419and is present in the testes of birds, reptiles, and amphibian^,^"^^^^ as well as in human, umbilical-cord tissue.4z22~423 u-Glucitol dehydrogenase has broad substrate-specificity. The enzyme oxidizes D-glucitol, L-iditol, ribitol, and xylitol in the presence of NAD+ ofa actor.*^^*^^^ NAD+ can be replaced by 3-acetylpyridine adenine dinucleotide (AcPyAD), 3-thionicotinamide adenine dinucleotide (TNAD), or nicotinamide hypoxanthine dinucleotide (NHD).414 S. Pontremoli and B. L. Horecker, in “The Enzymes,” P. D. Boyer, ed., Academic Press, New York and London, 1971, Vol. 4, pp. 611-646. R. L. Blackly, Biochem. J., 49,257-271 (1951). T . Moriyama, T. Nakano, T. Wada, T. Kakihana, K. Kida, Y. Kida, and K. Shimamoto, Nara Igaku Zasshi, 24, 356-362 (1973). J. Hickman and G. Ashwel1,J. Biol. Chem., 234,758-761 (1959). M. G. Smith, Biochem. J., 83, 135-144 (1962). 0. C. Barretto, J . Lab. Clin. Med., 85, 645-649 (1975). S. B. Horwitz and N. 0. Kaplan,]. B i d . Chern., 239,830-838 (1964). J. T. Cummins, V. H. Cheldelin, and T. E. King,]. Biol. Chem., 226, 301-306 (1957). B. M. Pesai, V. V. Modi, and V. K. Shah, Arch. Mikrobiol., 67, 16-20 (1969). A. W. Blackshaw and J. I. Samisoni, Res. Vet. Sci., 8, 187-194 (1967). M. E. Rainer, D. D. Hoskins, and H. G. Williams-Ashman, Inuest. Urol., 7, 333-352 (1970). D. W. Bishop, W. W. Schrank, A. D. Musselman, and E. C. Muecke, Fed. Proc. Fed. Am. SOC. E m . Biol.. 26. 646 (1967). (420) D. W. Bishop, J. Gen. Physiol., 50, 2504 (1967). (421) D. W. Bishop,/. Reprod. Fertil., 17, 410-411 (1968). (422) E . A. Brachet, Biol. Neonut., 23, 314-323 (1973). (423) N. E. Kelker,]. Bacteriol., lOS, 160-164 (1971). (421) T . E. King and T. R l a n n , Jfcthods E i ~ z y i i i o l . 9, , 1.59-163 (1966).

METABOLISM OF D-FRUCTOSE

34 1

I n contrast to the mammalian and bacterial enzymes, the enzyme from A . niger416 has an absolute substrate-specificity for D-glucitol, D-fructose, NAD+, and NADH. The K , for D-glucitol varies with the enzyme source. The K , of D-glucitol from ram spermatozoa424is 9.8 mM, in contrast to 98 pM for the enzyme from A . n i g e ~ - .The ~ ' ~ optimal pH -8. Christensen and coworkers suggested that D-glucitol dehydrogenase follows a rapid-equilibrium, random mechanism.426 Rat-liver D-glucitol dehydrogenase exhibits multiple molecular forms when subjected to electrophoresis in sodium borate.427Hof and coworkers428suggested that the swine enzyme is a tetramer. The rabbit-liver enzyme has a molecular weight of 110,000. It occurs as a tetramer of four similar, polypeptide chains, each having410a molecular weight of 27,000 to 28,000. As the enzyme is susceptible to inhibitors that react with sulfhydryl groups, such as p-chloromercuribenzoate (PCMB),416and fluorescein mercuric acetate (FMA),4'9 a thiol group must be required for enzyme activity.

8. L-Glutamine :D-Fructose 6-Phosphate Aminotransferase L-Glutamine : D-fructose &phosphate aminotransferase (EC 2.6.1.16) is widely distributed in mammalian t i s s ~ e , ~and ~ ~ ,i n~ ~ ' E . coli,q30Neurospora c r a ~ s a , ~and ~ OB. s t ~ b t i l i s . ~The ~ ' , enzyme ~~~ catalyzes the formation of 2-amino-2-deoxy-D-glucose &phosphate: D-Fructose 6-P

+ L-glutarnine + 2-amino-2-deoxy-D-glucose 6-P

+ L-glutamic acid

The molecular weight of the mammalian enzyme is in the range of 340,000-400,000, in comparison to 1,000,000 for the bacterial en~ y m eIt. is~possible ~ ~ that the mammalian enzyme is a subunit of the latter.435 (425) J. B. Wolff, Methods Enzymol., 1, 348-350 (1955). (426) U. Christensen, E. Tuchsen, and B. Anderson, Biochemistry, 29, 81-87 (1975). (427) R. N. Murray, I. Gadacz, M. Bach, S. Hardin, and H . P. Morris, C a n . J . Biochem., 47, 587-593 (1969). (428) 0. Hof, J. U. Wolf, and W. Krone, Humangenetik, 8, 178-182 (1969). (429) J. R. Heitz, 1.Biol. Chem., 248, 5790-5793 (1973). (430) S. G . Ghosh, H. J. Blumenthal, E. Davidson, and S. Roseman,]. B i d . Chem., 235, 1265-1273 (1960). (431) B. M.Pogell and R. M. Gryder,/. Biol. Chem., 228, 701-712 (1959). (432) J. S. Clarke and C . A. Pasternak, Biochem. J., 81, l p - 2 ~(1961). (433) R. E. Strange and F. A. Dark, Nature, 188, 741-742 (1960). (434) R. Kornfeld,]. B i d . Chem., 242, 3135-3141 (1967). (435) D. B. Ellis and K. M. Sommar, Biochini. Biophys. Acta, 276, 105-112 (1972).

342

MINSHEN CHEN AND ROY L. WHISTLER

The liver enzyme is subject to feedback inhibition by UDP-2-acetamido-2-deoxy-~-glucose( U D P - G ~ C N A K ~ )~. r~n~f~e l dand ~ ~ Winter~ burn and Phelps437,438 further showed the presence of feedback inhibition of the amidotransferase in other mammalian tissues, as well as the absence of inhibition in Salmonella paratyphi, B. subtilis, andE. coli. UDP-GlcNAc binds to an enzyme site distinct from the active site .434,439 The pattern of UDP-GlcNAc inhibition is different for different sources. The feedback inhibition of UDP-GlcNAc of the enzyme from HeLa cell, mouse liver, rat liver, and bovine trachea is a competitive type of inhibition with respect to D-fructose 6-phosphate.434,436,440 The aminotransferase from bovine retina differs markedly from the ratliver enzyme in its feedback-inhibition pattern.441The kinetics of inhibition of the retinal enzyme b y UDP-GlcNAc are noncompetitive with respect to D-fructose 6-phosphate. In addition, retinal enzyme becomes susceptible to inhibition by high concentrations of L-glutamine in the presence of UDP-GlcNAc, whereas the liver enzyme shows a simple, noncompetitive inhibition of UDP-GlcNAc with respect to L-glutamine. In the case of aminotransferase from bovine trachea, the enzyme has the same inhibition pattern as liver enzyme for D-fructose 6-phosphate, but L-glutamine causes substrate inhibition which is independent of the feedback control.440 The negative feedback control of aminotransferase by UDPGlcNAc in mammalian tissues allows the synthesis of UDP-GlcNAc relatively independent of the concentration of hexose 6-phosphate, which fluctuates widely in response to feed442or other changes in the rate of g l y c o l y ~ i sIn . ~ addition, ~~ when the rates of synthesis of glycoprotein and glycolipid are altered, the tissues are able to adjust rapidly to the rate of synthesis of UDPGlcNAc and to the requirement for this intermediate. The level of the enzyme in the pathway concerned in the synthesis of UDP-GlcNAc may thus be maintained high enough to meet with increased demand, without imposing on the (436) S. Kornfeld, R. Kornfeld, E. F. Neufeld, and P. J. O’Brien, Proc. Natl. Acacl. Sci. U.S.A., 52, 371-379 (1964). (437) P. J. Winterburn and C . F. Phelps, Biochem. ]., 121, 701-709 (1971). (438) P. J. Winterburn and C . F. Phelps, Biochern. J., 121, 711-720 (1971). (439) A. Endo, K. Kakiki, and T. Misato,]. Bacterial., 103, 588-594 (1970). ~ . 230, 531-534 (1971). (440) D. B. Ellis and K. M. Sonimar, Biochitn. B i o p h { ~Acta, (441) R. G. Mazlen, C. G. Mullenberg, and P. J. O’Brien,Exp. Eye Res., 9, 1-11 (1970). (442) D. J. Steiner and R. H. Williams,J. B i d . Chem., 234, 1342-1346 (1959). (443) 0. H. Lowry, J . V. Passonneau, F. X. Hasselberger, and D. W. Schultz,]. B i d . Chem., 239, 18-30 (1964).

METABOLISM O F D-FRUCTOSE

343

cells the burden of continuous overproduction of the amino sugar nucleotide~.~~~

xv. USE

OF

D-FRUCTOSE

D-Fructose is the sweetest natural sugar. Its use as a natural sweetener is, therefore, increasing rapidly. It is absorbed slowly from the intestine, and thus does not cause abrupt changes in the serum levels of carbohydrates. It has little, if any, effect on insulin secretion. Thus, it exerts beneficial effects as a component of diets for mild and well-balanced diabetes, but should be taken within caloric restrict i 0 n , 4 ~as~ obesity impairs D-glucose tolerance and increases the insulin resistance of peripheral tissue.446Use of D-fructose in the direct treatment of diabetic ketoacidosis does not offer advantages over routine, fluid therapy, and may even be dangerous on the basis that rapid infusion of large amounts of D-fructose may cause lactate acidosis. Although D-fructose stimulates ethanol metabolism in tissues and perfused liver, the use of D-fmctose in the treatment of ethanol intoxication in intact animals still remains controversial .234--239 D-Fructose shows beneficial effects as a dietary sweetener. Palm4-” indicated that exchange of 100 grams of D-fructose per day for most of the insulin-inducing carbohydrates in a control diet maintained a sufficiency of blood sugar to prevent the stress of hypoglycemia. Palm stated that a D-fructose-diet program could eliminate the hunger, fatigue, and anxiety that accompany most weight-reduction diets. He indicated that replacement of other dietary carbohydrates by D-fmctose might be advantageous to many who have no recognized pathology. He also considered that D-fructose could provide an advantage to the athlete, as it is rapidly metabolized and does not induce insulin release. D-Fructose lessens dental plaque and, in double-blind tests, produces fewer caries than sucrose.448

(444) J. L. Trujillo and J. C . Gan, Int. J . Biochem., 5, 515-523 (1974). (445) J. K. Huttunen, Postgrad. Med. J., 47, 654-659 (1971). (446) M. Perley and V. M. Kipnis, Diabetes, 15, 867-874 (1966). (447) J. D. Palm, in “Physiological Effect of Food Carbohydrates,” A. Jeanes and J. Hodge, eds., ACS Symposium Series, Washington, D.C., 1975, pp. 54-72. (448)G . Frostell, P. H. Keyes, and R. H. Larson, J . Nutr., 93, 65-76 (1967).

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BIBLIOGRAPHY OF CRYSTAL STRUCTURES OF CARBOHYDRATES, NUCLEOSIDES, AND NUCLEOTIDES* 1975

BY GEORGEA.

JEFFREY** AND

MUTTAIYA SUNDARALINGAM

Department of Chemistry, Brookhaven National Laboratory, Upton, Long Island, New York 11973; Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706

I. Introduction . . . . . . . . . . . . . . ............................. 11. Data for CarbQhydrates . . . . . . . . . . . . . . . . . . .................. 111. Data for Nucleosides and Nucleotides . . . . . . . . . . . . . ............. IV. Preliminary Communication 1. Carbohydrates . . . . . . . . . . 2. Nucleosides and Nucleot ...........................

345 346 362

372

I. INTRODUCTION

The form of this bibliography is similar to that of previous As for that for 1974, projection diagrams of the carbohydrate, nucleoside, or nucleotide molecules or ions have been provided, where possible. The diagrams were produced directly from the unit-cell and atomic positional parameters given in the papers. In a few cases, corrections were necessary. * Work supported by NIH Grants GM-21794 and GM-17378, and the College of Agricultural and Life Sciences, University of Wisconsin, Madison. The authors express their gratitude to Larry Lewis and John McAlister for the preparation of the Figures. ** Present address: Department of Crystallography, University of Pittsburgh, Pittsburgh, Pennsylvania 15260. (1) G. A. Jeffrey and M. Sundarahgam, Adv. Carbohydr. Chem. Biochem., 30, 445-466 (1974). (2) G. A. Jeffrey and M. Sundaralingam, Ado. Carbohydr. Chem. Biochem., 31,347-371 (1975). (3) G. A. Jeffrey and M. Sundaralingam, Ado. Carbohydr. Chem. Biochem., 32, 353-384 (1976). 345

346

GEORGE A. JEFFREY AND MUTTAIYA SUNDAMLINGAM

For the carbohydrate structures, the CRY SNET facility was used.4 The carbon and hydrogen atoms are shown as small, solid circles, and other atoms by the appropriate symbol. Where positions of hydrogen atoms were not reported, or could not be deduced, the atom is indicated by H. For the nucleosides and nucleotides, the perspective drawings of structures are given for the correct enantiomorph, when coordinates are available. The drawings were made by using the ORTEP program on an on-line, Versatec plotter linked to a PDP 11/35computer housed in the Madison laboratory. The hydrogen and carbon atoms are represented by solid circles, and double bonds are indicated conventionally. As a general rule, the nucleosides and nucleotides are viewed approximately normal to the three-atom plane constituted by C-4’-C-lf-C-6 in pyrimidines and C-4’-C-l’-C-8 in purines, to give the “best” view of the molecule for the common C-2’ endo and C-3’ endo sugarpuckerings. In the Section on preliminary communications, the calculated density is not given whenever the authors did not define the unit-cell constants or the stoichiometry of the compound.

11. DATAFOR CARBOHYDRATES C6H8031,4 :2,5 :3,6-Trianhydro-~-mannitol~

\ P4$,2; Z = 4; D, = 1.497; R = 0.05 for 544 intensities at -100”. The molecule has three fused tetrahydrofuran rings, with a two-fold axis of symmetry through the oxygen atom and the mid-point of the C-3- C4 bond of the central ring. All three rings have the 3T, conformation. (4) “CRYSNET Manual,” BNL Informal Report, BNL 21714, H. M . Bernian, F. C. Bernstein, H. J. Bernstein, T. F. Koetzle, and G . J. B. Williams, eds., Brookhaven National Laboratory, Upton, N. Y., 1976. (5) F. W. B. Einstein and K. N. Slessor, Acta Crystallogr. Sect. B , 31, 552-554 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

347

There is considerable strain in the molecule, with bond angles between 91 and 119". The C-C bond lengths are 149.3 and 150.6 pm (1.493 and 1.506 A). C,H,BrCaO, . 3H,O

Calcium bromide a-D-glucopyranuronate trihydrate6

P2,; Z = 2; D, = 1.988; R = 0.025 for 1,082 intensities. The absolute configuration was confirmed. The Caz+ions are eight-coordinated to two hydroxyl groups and a ring-oxygen atom, in addition to the carbonyl oxygen atoms and water molecules. The pyranose ring is considerably distorted, with ring torsion-angles varying between 45 and 70". The orientation of the carboxyl group is such that the ringoxygen atom and carboxyl group lie almost in one plane. This conformation is different from that observed in potassium p-Dglucuronate d i h ~ d r a t e . ~ ( C6H9O7),CaNa. 6Hz0 Calcium sodium a-D-galactopyranuronate hexah ydrates 0

0-

(6) L. DeLucas, C. E. Bugg, A. Terzis, and R. Rivest, Carbohydr. Res., 41,19-29 (1975). (7) G . E. Gun, A c f a C q s t a l l o g r . , 16, 690-698 (1963). (8) S. E. B. Gould, R. 0.Gould, D. A. Rees, and W. E. ScottJ. Chem. SOC.Perkin Trans. 2,237-240 (1975).

348

GEORGE A. JEFFREY AND MUTTAIYA SUNDARALINGAM

P6,; Z = 2; D, = 1.64; R = 0.12 for 837 intensities (film measurements). The sodium ions have distorted, octahedral coordination involving 0 - 2 and 0 - 3 of three sugar anions. The calcium ions are nine-coordinated by three water-oxygen atoms, three carbohydrateoxygen atoms, and, more distantly, by three ring-oxygen atoms. There is, also, inter-residue hydrogen-bonding. The pyranose ring has the 4C, conformation and is relatively undistorted, with torsion angles between 52 and 64".Most of the hydrogen atoms were located, but the accuracy of the analysis was low. The same structure has been independently determined (R = 0.09 for 1,077 diffractometer intensities), and reported, without atomic parameters, in a preliminary communication.Y (C6H907),NaSr. 6H20 Sodium strontium a-D-galactopyranuronate hexahydrate8

P6,; Z = 2 ; D, = 1.71; R = 0.08 for 946 intensities (film measurements). The structure is isomorphous with that of the CaNa compound, with differences that correspond to the increase of 14 pm (0.14 A) for the Sr2+ionic radius.

/O

P2,2,2,; Z = 4; D, = 1.608; R = 0.031 for 896 intensities. This confirms the structure previously reported." A comparison of the two sets of parameters indicates that the errors are random, and that the standard deviations of positional coordinates had been correctly estimated. (9) J . Hjortas, B. Larsen, and S. Thanomku1,ActaChem. S c a d Ser. B , 28,689 (1974). (10) K.B. Lindberg,Acta Chem. Scand. Ser. A, 28,1181-1182 (1974).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

349

C,H,,O, . H 2 0 a-L-xylo-Hexulopyranosonic acid non no hydrate'^

P2,2,2,; Z = 4; D, = 1.600; R = 0.044 for 1,393 intensities. The molecule is the a anomer, and has the 2C, conformation. The a-hydroxyl group of the carboxylic acid group is almost coplanar with the carbonyl group, and is normal to the plane of the pyranose ring. The anomeric, C-0 bond is short, 138.1 pm (1.381 A), and the two ring C-0 bond-lengths are different, 144.9 and 142.7 pm (1.449 and 1.427 A). The crystal structure closely resembles that of a-L-sorb0pyrano~e.l~ The atomic coordinates given in the paper are for the D enantiomer.

P2,; Z = 2; D, = 1.65; R = 0.029 for 743 reflections. The sugar has a 4C1conformation in which the pyranose ring is significantly distorted,

with ring torsion-angles ranging from 49 to 67". The primary alcohol group is -sc. The anomeric bond-length is 140.0 pm (1.400 A),and the (11) Y. J. Park, H. S. Kim, and C . A. Jeffrey, Actu Crystullogr. Sect. B . 27, 220-227 (1971);see A d v . Carbohydr. ChenL. Biochem., 30, 448 (1974). (12) J. Hvoslef and B. Bergen, Actu CrystaZlogr. Sect. B , 31, 697-702 (1975). (13) S.-H. Kim and R. D. Rosenstein, Actu Cq/stallogr., 22, 648-6513 (1967). (14) W. Choong, I>. C. Craig, N. C. Stephenson, and J. D. Stevens, Cryst. Struct. Coinmun., 4, 111-115 (1975).

350

G E O R G E A. J E F F R E Y A N D MUTTAIYA SUNDARALINGAM

two ring C-0 bonds are of almost equal length, 142.9 and 143.0 pm (1.429 and 1.430 A). There is an "infinite" chain of intermolecular hydrogen-bonds which includes all of the hydroxyl groups, but not the fluorine or ring-oxygen atoms.

P2,; z = 2; Ix = 1. 8; R = 0.031 for 758 intensities. The oxacycloheptane ring has an almost ideal, twist-chair (435TC6,0) conformation, which is one of the two T C conformations shown by IH-n.1n.r. spectroscopy to exist in pseudorotational equilibrium in aqueous solution. There is extensive, intermolecular hydrogen-bonding which includes all of the hydroxyl groups and the ring-oxygen atom.

/

0 I

/" (15) P. Luger, R. Reinhardt, a n d H. Paulsen, Chem. Ber., 108, 3201-3209 (197.5). (16) F. Longchambon, J. O'Hannession, D. Avenel, and A. Neuman, Actu Crystallogr. Sect. B , 31, 2623-2627 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

351

P2,2,2,; Z = 4, D, = 1.485; R = 0.08 for 662 intensities. The pyranose has the ' C , (undistorted) conformation, with torsion angles between 56 and 62". The anomeric C-0 bond-length is short, 139.5 pm (1.395A),and the ring C-0 bond-lengths are different, 141.1 and 148.0 pm (1.411 and 1.480 The molecules are linked by finite chains of hydrogen bonds which include all of the hydroxyl groups and the ring-oxygen atoms, but some are questionable, with O-H . . * 0 angles of 95 and 123".The accuracy of the analysis is low, owing to the poor quality of the crystals examined.

A).

CGH120, * CaBr, . 3H20 a-L-Fucopyranose . calcium bromide, trihydrate17 OH

Hd P2,2,2,; Z

= 4; D, = 1.865; R = 0.05 for 1,442 intensities. The conformation of the pyranose is 'C4. The hydrogen atoms were not located. The calcium ions are seven-coordinated to two a-L-fucopyranose molecules and three water molecules, with no direct, calcium-to-bromide, ionic contact.

C6H1206 P-D-Galactopyranosel'

(17) W. J . Cook and C. E. Bugg, Biochim. Biophys. Acta, 389,428435 (1975).

352

G E O R G E A. J E F F R E Y A N D MUTTAIYA SUNDARALINGAM

P2,2,2,; Z = 4; D, = 1.485; R = 0.03 for 756 intensities. The pyranose has the 4c, conformation, with torsion angles between 52 and 65". The primary alcohol group is +sc (t-54"). The anomeric C-0 bond-length is short, 138.1 pin (1.381 A), and the ring C-0 bondlengths are unequal, 141.3 and 143.8 pm (1.413, 1.438 &. The molecules are linked by "infinite" chains of hydrogen bonds, which include all of the hydroxyl groups but not the ring-oxygen atom. C,H,,FO, Methyl 4-deoxy-4-fluoro-a-~-glucopyranoside~~

I

P2,2,2,; Z = 4; D, = 1.52; R = 0.028 for 965 intensities. The molecular dimensions are similar to those of methyl a-D-glucopyranoside,lXawith ring torsion-angles between 54 and 62", except for the orientation of the primary alcohol group, which is -sc (-64"). All of the hydroxyl groups are involved in hydrogen bonding, but not the fluorine or ring-oxygen atoms. C7H1406Methyl cr-D-ahropyran~side~~ P2,2,2,; Z = 4; D, = 1.417; R = 0.089 for 1,835 neutron diffraction intensities. The molecular dimensions are the same as for the X-ray study,20except for the more accurate location of the hydrogen atoms. (18) W. Choong, N. C . Stephenson, and J. D . Stevens, Cryst. S t m c t . Coin~nun.,4, 491-494 (1975). (18a) H. M. Berman and S.-H. Kim, Acta Crtjstullogr. Sect. B , 24, 897-904 (1968). (19) B. J. Poppleton, G. A. Jeffrey, and G. J. B. Williams, Acta Crystallogr. Sect. B , 31, 2400-2404 (1975). (20) B. M . Gatehouse and B. J. Poppleton, Acta Crystallogr. Sect. B, 27, 871-876 (1971); see Adv. Carbohydr. Chern. Biochem., 30, 451 (1974).

BIHLIOGRAPHY OF CRYSTAL STRUCTURES

353

The bifurcated hydrogen-bonding, which includes a vicinal, intramolecular interaction, is confirmed, with H . * 0 distances of 209 to 319 pm (2.09 to 2.19 hi). C,H,,NO,

Ethyl 3-cyano-3,4-dideoxy-a-~~-threo-pentopyranoside~~

w

i'---i.

0

N

P2,/n; Z = 4; D, = 1.30;R = 0.168 for 780 intensities (film measurements). The D-pyranoside has the 'C, conformation (with all substituents equatorially attached). The hydrogen atoms were not located, and the accuracy of the molecular dimensions is low. The coordinates and formula given are those of the D enantiomer. C,Hl3NzO,S 4-/3-~-Erythrofuranosyl-l-methyl-4-imidazoline2-thioneZ2

P2,; Z = 2; D, = 1.41;R = 0.055for 1,040intensities. The furanosyl group has the 'T3 conformation, and the glycosylic torsion-angle is 44". The imadazoline ring is planar. The hydrogen positions were not reported. (21) B. P. Biryukov, B. V. Unkovskii, B. V. Mochalin, and A. N . Kornilov, Zh. Strukt. Khirn., 14, 580-581 (1973). (22) A. Conde, E. Moreno, and R. MBrquez, Acta Crystollogr. Sect. B , 31, 648-652 (1975).

354

GEORGE A. JEFFREY A N D MUTTAIYA SUNDARALINGAM

+4

H3

HO

C,H,,N06 2-Acetamid0-2-deoxy-a-D-glucopyranose~~

P2,; Z = 2;D, = 1.505;R = 0.02for 1,230intensities. The pyranose is in the 4C,conformation, with torsion angles from 53 to 63".The orientation of the primary alcohol group is -sc (-61"). The anomeric C-0 bond is short, 139.0pm (1.390A), and the two C-0 ring-bonds are unequal, 143.4 and 144.8 pm (1.434and 1.448A). The N-acetyl group is nonplanar, with a C-N-C-0 torsion-angle of 9.9". The presence in the crystal of 20-25% of the p anomer, reported in a previous was not found.

P2,;Z = 2; D, = 1.376;R

=

0.04 for 1,204 intensities. This is the

same structure as previously (23) F. Mo and L. H. Jensen, Acta Crystallogr. Sect. B , 31, 2867-2873 (1975). (24) L. N . Johnson, Acta Crystallogr., 21, 885-891 (1966). (25) A. Neuman, H. Gillier-Pandraud, F. Longchambon, and D. Rabinovich, Acta Crystullogr. Sect. B , 31,474-477 (1975). (25a) H. D. Gilardi and J. L. Flippen, Acta Crystallogr. Sect. B , 30,2931-2933 (1974); see A d o . Carbohydr. Chem. Biochem., 32, 361 (1976).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

355

C8HI5NO6 . H 2 0 2-Acetamido-2-deoxy-p-~-mannopyranosemonohydratez6

P2,2,2,; Z = 4; D, = 1.484; R = 0.07 for 1,608 intensities. The pyranose has the 4c, conformation, with ring torsion-angles between Fjl and 68". The primary alcohol group is -sc (-71"). The anomeric bond is short, 138.8 pm (1.388 A), and the ring C-0 bond-lengths are unequal, 142.7 and 144.2 pm (1.427 and 1.442 A). The N-acetyl torsion angle, C-1-C-2-N-C-7, is -48". C,H,,NO,

0-P-D-Xylopyranosyl-L-serine, L-serine p-D-xylopyranoside2,

1

P2,; Z = 2; D, = 1.453; R = 0.58 for 907 intensities. The molecules are zwitterions. The p-D anomeric configuration was confirmed. The pyranosyl group has an almost ideal 4C1conformation, with torsion angles of 54 to 62" and dimensions similar to those in CX-D-XY~Opyranose.28 The glycosyl-peptide bond torsion-angles, 0-5-C-1-0(26) A. Neuman, H. Gillier-Pandraud, and F. Longchambon, Acta Crystallogr. Sect. B, 31, 2628-2631 (1975). (27) L. T. J. Delbaere, B. Kamenar, and K. Prout,Acta Crystallogr. Sect. B , 31,862-865 (1975). (28) A.Hordvik, Acta Chenz. Scand., 25,2175-2182 (1971);see Adu. Carbohydr. Chem. Biochem., 30,447 (1974).

356

GEORGE A. JEFFREY AND MUTTAIYA SUNDAMLINGAM

1-C, C-1-0-1-C-C, and 0-1-C-C-C are -88, -89, and +171". The intermolecular hydrogen-bonding involves all of the nitrogen and oxygen atoms, except the glycosidic oxygen atom. The atomic coordinates given refer to the L-xylosyl-D-serine enantiomer.

(CsH14N0,),Cu Cu(1I) complex of O-~-D-xy~opyranosy~-L-serineZ7 P4,2,2; Z = 4;D, = 1.736; R = 0.093 for 733 reflections. The conformation of the ligand differs from that of the uncomplexed molecule. The 0-5-C-l-O-l-C, C-1-0-1-C-C, and 0-1-C-C-C torsion-angles are -85, -153, and -63". The amino group is significantly less planar, and there are small differences in the conformation of the pyranosyl group. The Cu2+is complexed to two, cis, planar, amino acid chelates, with the Cu-N bond 199 pm (1.99 A) and the Cu-0 bond 192 pm (1.92 A), and two ring-oxygen atoms at 275 pm (2.75 A). The atomic coordinates refer to the enantiomer named. The hydrogen positions were not given.

OH

P1; Z = 1; D, = 1.475; R = 0.045 for 827 intensities. The acyclic molecule has a planar, zigzag conformation; carbon atoms 2 to 6 are coplanar within 1pm (0.01A). The hydrogen atoms attached to oxygen and nitrogen atoms were not located, and a detailed description of the hydrogen bonding could not be given.

P2,2,2; Z = 4; D, = 1.48; R = 0.034 for 1,549 reflections. The chloromethyl and methyl sulfonyloxy substituents are trans-disposed.

(29) L. 0.G . Satzke and M. F. Mackay,Acta Crystallogr. Sect. B , 31,1128-1132 (1975). (30) W. Clegg, Acta Crystallogr. Sect. B , 31, 2722-2724 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

357

Both rings have an envelope conformation, with the out-of-plane carbon atom endo in the thiofuranose ring and exo in the isopropylidene ring. The valence angle of the ring-sulfur a t o r is 94".

C,H,,O,S,

5-Deoxy-3-C-formyl-~-~-lyxofuranose 3l-(trimethylene dithi~acetal)~~

P2,; Z = 2; D, = 1.458;R = 0.04for 514 intensities. This is a more complete crystallographic description of a structure previously reported.32 C,,H,,O, a-D-Xylopyranose 1,2,4-0rthobenzoate~~ HO I

3

(31) V. W. Depineier and 0. H. Jarchow,Acta Crystallogr. Sect. P 31,945-949 (1975). (32) V. W. Depmeier, 0. H. Jarchow, P. Stadler, V. Sinnwell, anu H. Paulsen, Curbohydr. Res., 34,219-226 (1974); see Ada. Carbohydr. Chem. Biochem., 32, (a) 362; (b) 366 (1976). (33) L. G. Vorontsova, V. I. Andrianov, and B. L. Tarnopol'skii, Zh. Strukt. Khim., 16, 242-246 (1975).

358

GEORGE A. JEFFREY AND MUTTAIYA SUNDARALINGAM

P2,; Z = 2; R = 0.107 for 685 intensities. The pyranose, dioxane, and dioxolane rings have distorted boat, distorted chair, and twist conformations, respectively. The hydrogen atoms were not located. Cl2H2,O4S2 5-Deoxy-3-C-formyl-1,2-0-isopropylidene-~-~-lyxofuranose 3l-(trimethylene d i t h i ~ a c e t a l ) ~ ~ P2,; Z = 2; D, = 1.363; R = 0.035 for 1,373 intensities. A more complete, crystallographic description of a structure previously reported.32 C12H,lNOll * H,O

2-Amino-2-deoxy-3-0-(~-D-glucopyranosy~uronic acid)-a-D-galactopyranose monohydrate; chondrosine r n ~ n o h y d r a t e ~ ~

HO

HO

bH

OH

P2,2,2,; Z = 4; D, = 1.57; R = 0.094 for 1,201 intensities (film measurements). The molecule is a zwitterion, and the reducing residue is the a anomer. The P-D-(~ -+ 3)-linkage torsion-angles are 0-5-C1-0-1-C-3, -84.1", and C-l-O-l-C-3'-C-4', +55.4". The torsion angle of C-4-C-5-C-6-0-7 of the D-glucosyluronic acid group is -45.6'. There is an intramolecular hydrogen-bond between OH-4 of the 2-amino-2-deoxy-D-galactose residue and the ring-oxygen atom of the D-glucopyranosyluronic group. The water molecule is hydrogen-bonded to 0 - 2 and N-2' on the other side of the molecule. The hydrogen atoms were located, but their coordinates were not reported. CI3HlYNOj Methyl 4-(cyanoniethylene)-4-deoxy-2,3-O-isopropylidene-6-O-methyl-a-~-Zyxo-hexopyranoside~~ (34) V. W. Depmeier and 0. H. Jarchow, Actu Crystallogr. Sect. B, 31, 939-944 (1975). (35) M. Senma, T. Taga, and K. Osaki, Che7n. Lett., 1415-1418 (1974). (36) G. Bernardinelli and R. Gendil, Helo. Chim. Acta, 57, 1459-1466 (1974).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

359

1

P2,2,2,; Z = 4; D, = 1.20; R = 0.058 for 1,268 reflections. The pyranoside has the 3 S , conformation, with ring torsion-angles ranging from 9 to 67". The isopropylidene ring has a twist conformation ( $ T ) . The MeOC and M e 0 groups are f s c (+63", +66").

C,JI,$v,O,

*

H,O

p-Nitrophenyl 2-acetamido-2-deoxy-~-D-glucopyranoside m ~ n o h y d r a t e ~ ~

P2,2,2,; Z = 4; D, = 1.407; R = 0.061 for 1,368 intensities. The plane of the amido group is approximately normal to the mean plane of the pyranoside ring, with a C-1-C-2-N-2-0-7 torsion-angle of 110". The torsion angles of the glycosidic linkage to the benzene ring, 0-5-C1-0-1-C-9 and C-1-0-1-C-9-C-10, are -81" and -166". The bond lengths in the sequence C-5-0-5-C-1-0-9 are 144.2, 140.9, 139.9, and 137.7 pm (1.442, 1.409, 1.399, and 1.377 A). All of the hydroxyl groups are involved in hydrogen bonding, but not the glycosidic or the ring-oxygen atom. There is also N-H . . * O=C hydrogenbonding. (37) L. Brehm and J. Moult, Proc. R. SOC. London Ser. B , 188, 425-435 (1975).

360

GEORGE A. JEFFREY AND MUTTAIYA SUNDARALINGAhl

C,,Hz0O,, Methyl 1,2,3,4-tetra-O-acetyl-P-D-galactopyran~ronate,~~ m.p. 145°C

P2,; Z = 2; D, = 1.30;R = 0.031for 2,093intensities. The pyranose with ring torsion-angles between 55 and 64". The conformation is TI, planes of the acetyl groups are approximately normal to the mean plane of the sugar ring.

(38) K. Nimgirawath, V. J. James, and J. D. Stevens, C r y s t . Struct. Commun. 4,617-622 (1975). (39) J. O h , V. J. James, and J. D. Stevens, Cryst. Struct. Commun., 4,215-220 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

36 1

P2,2,2,; Z = 4; D, = 1.35; R = 0.043 for 2,122 reflections. The compound has the 4c, conformation, with axially attached acetoxyl groups on C-1, C-2, and C-4. The ring is flattened at C-2, with ring torsion-angles of 46 and 48".The 0-1* . * 0 - 3 non-bonded distance is 280 pm (2.80 A), that is, 25 pm (0.25 hi) less than in methyl p-Daltropyranoside,20 due to the small, repulsive interactions of the acetoxyl oxygen atoms. The ring C-0 distances are different, namely, 139.6 and 144.0 pm (1.396 and 1.440 A). Cl7H2,N,O5Sz

7-Azido-S-deoxy-1,2 :3,4-di-O-isopropylidene-6,7-dithio-6,7-S -trimethylene-Derythro-a-Dgalactooctopyrano~e~~

P2,2,2,; Z = 4; D, = 1.362; R = 0.046 for 1,929 intensities. The configuration at C-7 was determined to be s. The pyranose has a distorted 2 B , conformation. The isopropylidene rings have distorted envelope and twist conformations. The dithiepane ring has a twist-chair conformation. C26H32BrN013m-Bromobenzyl 5-acetamido-4,7,8,9-tetra-O-acetyl3,5-dideoxy-~gl ycero-a-Dgalacto-2-nonulopyranosidonic acid, m-bromobenzyl5-N-acetyl-4,7,8,9-tetra-Oacetyl-a-D-neuraminic acid4,

(40) C. Riche and C. Pascard-Billy, Acta Crystallogr. Sect. B , 31,2565-2570 (1975). (41) H. Wawra, Z. Nuturforsch., Teil. C , 29, 317-332 (1974).

362

GEORGE A. JEFFREY AND MUTTAIYA SUNDARALINGAM

P2,2,2,; Z = 4; D, = 1.41; R = 0.095 for 2,000 intensities. The conformation of the pyranoside is T 5with , torsion angles between 51 and 64". The carboxylic group is oriented almost parallel to the ring C-2-0 bond, with 0-C-C-0 = 7.8". The benzoyl torsion-angle, C-0-C-C is -153". The hydrogen atoms were not located, and the accuracy was low, with C-C bond-lengths between 150 and 163 pm (1.50 and 1.63

A). C36H60030 .

. 3H,O a-Cyclohexaamylose-p-iodoaniline trihydrate4,

P2,2,2,; Z = 4; D, = 1.610; R = 0.072 for 5,007 intensities. This inclusion complex is of the cage type, with the iodobenzene residue within the cavity, and the amino group projecting outside. The six aD-glucosyl residues form a truncated cone, as in the hexahydrate4 and the l-propanol complex.44The D-glucopyranosy~residues have the 4C, conformation, with ring torsion-angles between 45 and 65". The linkage bonds, as defined by 0-5-C-1-0-4'-C-4', C-l- 0-4'-C4'-C3' are in the range 102 to 114", and 123 to 136", respectively. All six primary alcohol groups are -sc relative to the ring-oxygen atoms, but one is disordered. The water molecules are outside the cavity, and lie between the cyclohexaamylose molecules. The amino group forms hydrogen bonds to the cyclohexaamylose molecules in an adjacent layer.

111. DATAFOR NUCLEOSIDESAND NUCLEOTIDES C,H,J,O,S

4-p-~-Erythrofuranosyll-methyl-4-imidazoline-2thioneZ2

For data on this C-nucleoside, see Section 11. ( C ~ ~ l ~ , o ~ ) ( C , , H.l2H,O ~ N ~1 6:)1 Cytidine-N-benzyloxycarbonylL-glutamic acid d i h ~ d r a t e ~ ~ (42) K. Harata, Bull. Chern. SOC.J p n . , 48, 2409-2413 (1975). (43) P. C. Manor and W. Saenger,J. Am. Chem. SOC., 96,3630-3639 (1974); see Adv. Carbohydr. Chern. Biochem., 32,371 (1976). (44) W. Saenger, R. K. McCullan, J. Fayos, and D. Mootz,Acta Crystallogr. Sect. B, 20, 2019-2028 (1974); see Ado. Carbohydr. Chern. Biochem., 32, 371 (1976). (45) T. Hata, M. Yoshikawa, S. Sato, and C. Tamura, Acta Crystallogr. Sect. B , 31, 312-314 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

363

HO

P2,; Z = 2; D, = 1.40; R = 0.10 for 1,380 reflections. The glycosyl disposition is anti (-4.8'), and the conformation of the D-ribosyl group is 3T2(185.6'). The exocyclic C-4'-C-5' bond torsion-angle is -55.2'. The N-3 atom of the base is protonated by the a-carboxylic acid group of the L-glutamic acid component. The nucleoside and the L-glutamic acid derivative are hydrogen-bonded to each other through the imidine group in cytidine and the a-carboxylic acid group in N benzyloxycarbonyl-L-glutamic acid. The structure is suspected to be disordered, but this has not been accounted for in the refinement.

(46) E. A. Green, R. D. Rosenstein, R. Shiono, and D. J. Abraham; B. L. Trus and R. E. Marsh, Actu Crystallogr. Sect. B , 31, 102-107 (1975). Errata, ibid.,p. 1221.

364

GEORGE A. JEFFREY A N D MUTTAIYA S U N D A M L I N G A M

P2,; Z = 4; D, = 1.597; R = 0.033 for 2,232 reflections. There are two crystallographically independent molecules which exhibit very similar conformations. The gIycosyl dispositions are anti (18.3', 24.3'), and the conformation of the D-ribosyl group is 3Tz (3.7", 14").The exocyclic C-4'-C-5' bond torsion-angles are -72.9 and -77.7". All available hydrogen atoms are engaged in hydrogen bonding. N-3-H of the base is involved in a bifurcated, hydrogen bond to the carbonylo4 and to 0-3' of the D-ribosyl group in adjacent molecules. The former is the only interbase hydrogen-bonding. C,H,,N,O, . H,O Bredinin monohydrate (4-carbamoyl-l-~-~-ribofuranosylimidazolium-501ate)47

P2,2,2,; Z = 4; D, = 1.548; R = 0.034 for 915 reflections. The molecule has a zwitterion structure. The proton originally bonded to the exocyclic oxygen atom may be regarded as being transferred to a ring nitrogen atom. The conformation of the D-ribosyl group is 3T, (12.5"), and the glycosyl disposition is anti (24.5").The exocyclic C-4'-C-5' bond torsion-angle is -62.5'. There is an intramolecular hydrogenbond involving the carbamoyl nitrogen atom and the exocyclic oxygen atom.

P1; Z = 2; D, = 1.560;R = 0.054 for 1,274 reflections. There are two independent molecules which display opposite conformations for the (47) H. Yoshioka and K. Natatsu; M. Hayashi and K. Mizuno, Tetruhedron Lett., 4031-4034 (1975). (48) D. W. Young and H. R. Wilson, Acta C r y s t d o g r . Sect. B , 31, 961-965 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

365

2-deoxy-~-erythro-pentofuranosyl groups; one is 3T2 (13.4'), and the other is 2T3(168.7"). In both molecules, the glycosyl disposition is anti (17.8", 44.1"), and the exocyclic C-4'-C-5' bond torsion-angles are -61.1 and -59.3'. The two molecules form a trans base-pair such that they are related by a pseudo-diad normal to the base planes. The interbase hydrogen-bonding occurs between the N-6 amino groups and the ring N-3 atoms. The sugar ring-oxygen atom of the second molecule is involved in a weak hydrogen-bond to 0-H-5' of the first molecule.

/

CI

(49) H. Stemglanz and C. E. Bugg, Acta Crystallogr. Sect. B , 31, 2888-2891 (1975).

366

GEORGE A. JEFFREY AND MUTTAIYA SUNDAMLINGAM

C2; Z = 4; D, = 1.605; R = 0.040 for 1,162 reflections. The conformation of the D-ribosyl group is 3T4(20'), and the glycosyl disposition is s y n (-83.5'). The exocyclic C-4'-C-5' bond torsion-angle is -62.5'. There is stacking of the base rings. C,,H,,CoN,O,P

. 7H,O Cobalt inosine 5'-phosphate, heptahydratejO

P2,2,2,; Z = 4; D, = 1.821; R = 0.051 for 1,420 reflections. The conformation of the D-ribosyl group is 3Tz (11.4") and the glycosyl disposition is anti (25.4"). The exocyclic C-4'-C-5' bond torsion-angle is -71.6'. The N-7 atom of the hypoxanthine base and five water molecules form an octahedral coordination around the cobalt atom. The Co-N distance is 2.162 A (216.2 pm), and the Co-0 distances average 2.094 A (209.4 pm). The metal lies in the plane of the base ring. There is no direct cobalt-phosphate bonding. Three of the coordinated water molecules are engaged in intracomplex hydrogen-bonds to 0 - 6 of the base and to two of the phosphate oxygen atoms. C,oH,,N4Ni08P . 7 H 2 0 Inosine nickel 5'-phosphate, heptahydrateso (50) K . Aoki, Bull. Chem. Soc. Jpn., 48,1260-1271 (1975); see Adv. Carbohydr. Chem. Biochem., 32, 381,ref. 76 (1976).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

367

P2,2,2,; Z = 4; D, = 1.840; R = 0.075 for 1,500 intensities. This structure is isomorphous to the cobalt complex.50The disposition of the base is anti (24.0"), and the conformation of the D-ribosyl group is 3T, (98"). The exocyclic C-4'-C-5' bond torsion-angle is -73.7". The octahedral coordination around the nickel atom is similar to that for the cobalt atom. The Ni-N distance is 2.105 A (210.5 pm) and the average Ni-0 (water) distance is 2.063 A (206.3 pm).

(51) A. Ducruix and C . Pascard-Billy, Actcr C~-!/stclllogr. Sect. B , 31, 1987-1992 (197.5).

368

GEORGE A. JEFFREY A N D MUTTAIYA S U N D A M L I N G A M

P2,; Z = 2; D, = 1.537; R = 0.063 for 1,059 intensities. The conformation of the 2-deoxy-D-erythro-pentofuranosyl group is 3T4(29"), and the exocyclic C-4'-C-5' bond torsion-angle is -60". The glycosyl '-C-l'-C-8-N-7) is 81.4". There is interbase hydrotorsion-angle (0-1 gen-bonding, N-1-H . . * N-3. CloH13N5Na06P . 6 H 2 0 2'-Deoxyadenosine 5'-phosphate, sodium salt, h e ~ a h y d r a t e ~ ~

P2,2,2,; Z = 4; D, = 1.489; R = 0.060 for 1,806 intensities. The disposition of the base is anti (63.4'). The conformation of the 2deoxy-z>-erythro-pentofuranosyl group is 2T1 (149.7"), and the exocyclic C-4'-C-5' bond torsion-angle is -72.1". The oxygen atom of the sugar ring is engaged in a weak hydrogen-bond to the amino group. The sodium ion is octahedrally coordinated to six water molecules at distances of 2.374 to 2.454 A (237.4 to 245.4 pm). The bases are partially stacked. The atomic coordinates reported were for the L enantiomorph.

P2,2,2,; Z = 4; D, = 1.47; R = 0.057 for 1,380 reflections. The glycosyl disposition is anti (47.2"), and the conformation of the Dribosyl group is 2T3 (167.3"). The exocyclic C-4'-C-5' bond torsionangle is -64.5". The atomic coordinates reported were for the L enantiomorph. (52) B. S. Reddy and M. A. Viswarnitra, Acta Crystallogr. Sect. B , 31, 19-26 (1975). (53) T. Takeda, Y. Ohashi, and Y. Sasada; M. Kakudo, Acta Crystallogr. Sect. B , 31, 1202-1204 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

369

P C,,H,,N60 6-Amino- lO-(P-~-ribofuranosy~amino)pyrimido[5,4-d]py~imidine~~

P1; Z = 1; D, = 1.61; R = 0.049 for 1,123 reflections. The conformation of the D-ribofuranosyl group is OE (91’), and the exocyclic C-4’-C5’ bond torsion-angle is - 174.7’. The glycosyl torsion-angle (0-1’-Clr-N-10-C-10) is - 102.4’. There is an intramolecular hydrogen-bond, 0-3’-H * . * 0-2’ between the vicinal hydroxyl groups of the sugar residue. The pyrimidopyrimidine bases are stacked. Cl,H16N20,. H 2 0 Uridine-5-oxyacetic acid, methyl ester, monohydratej5 P2,; Z = 2; D, = 1.45; R = 0.04 for 1,332 reflections. The glycosyl disposition is anti (34.3”). The conformation of the D-ribosyl group is 3Tz (14.1’), and the exocyclic C-4’-C-5’ bond torsion-angle is -58.7”. (54) P. Narayanan and H. M. Berman, Carbohydr. Res., 44, 169-180 (1975). (55) K. Morikawa, K. Torii, Y . Iitaka, and M. Tsuboi, Acta Crystallogr. Sect. B , 31, 1004-1007 (1975); FEBS Lett., 48,279-282 (1974).

370

GEORGE A. JEFFREY A N D MUTTAIYA SUNDARALINGAM

C,,H,,N50,P . H,O Adenosine 3’,5’-monophosphate, P,O-ethyl ester, mon~hydrate~~

0

P2,; Z = 2; D, = 1.54; R = 0.102 for 708 reflections. The glycosyl disposition is anti (75”).The conformation of the D-ribosyl group is J 3 (44”). The disposition around the C-4’-C-5’ bond is fixed in the trans orientation by the formation of the six-membered, cyclic phosphate ring. The P-0 bond carrying the ethyl group is axial, and the ethyl group is endo to the base. (56) F. A. Cotton, R. G. Gillen, R. N. Gohil, E. E. Hazen, Jr., C. R. Kirchner, J. Nagyvary, J. P. Rouse, A. G. Stanislowski, J. D. Stevens, and P. W. Tucker, Proc. N d . ACUU!. Sci. U.S.A., 72, 1335-1139 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

371

C13HllClzN30,* 2-(4-0-Acetyl-2,3-dideoxy-~-~-gZycero-pent-2-enopyranosyl)-5,6-dichlorobenzotriazo1e5’

P2,2,2,; Z = 4; D, = 1.49; R = 0.050 for 1,143 reflections. The glycosy1 disposition is anti, and the torsion-angle (O-1‘-C-lr-N-1-N-2) is -99.9”. The glycero-pent-2-enopyranosyl group is in a sofa conformation, with C-5’ exhibiting the greatest puckering. The acetate group is in the extended shape. The figures given in the original paper were for the a-D enantiomorph, but the atomic coordinates reported correspond to the title compound.

IV. PRELIMINARY COMMUNICATIONS 1. Carbohydrates

C&,,O, GHgO, (C6H907)&a.3HzO

Erythritol (neutron D-Glucaro- 1,4-1actone5’ Calcium D-arabino-hexulosonate

trihy-

drate60

CciHizO,

* Omitted from the

a-D-Galactopyranose61 1973 Bibliography.

(57) L. de Lerma, S. Martinez-Carrera, and S. Garcia-Blanco, Acta Crystallogr. Sect. €3, 29, 537-541 (1973). (58) A. Shimada, T. Higuchi, M. Fukuyo, and F. Hirotsu, Acta Crystallogr. Sect. A , 31, Abstr. 10.3-13 (1975). (59) M. E. Gress and G. A. Jeffrey, A m . Crystallogr. Assoc. Abstr., A2 (1975). (60) M. A. Mazid, R. A. Palmer, and A. A. Balchin, Acta Crystallogr. Sect. A, 31, Abstr. 03.7-6 (1975). (61) B. Sheldrick, Acta Crystallogr. Sect. A . , 31, Abstr. 06.1-28 (1975).

372

GEORGE A. JEFFREY AND MUTTAIYA SUNDARALINGAM

p-D-Galactopyranose61 D-Fructose (sodium 1,6-bisphosphate) heptahydrate62 Methyl (methyl a-~-galactosid)uronate~~ 2,5-Di-O-acetyl-l,4 :3,6-dianhydro-1(4),3(6)-dithio-~-iditold i s ~ l f o x i d e ~ ~ (Z)-l-O-Acetyl-2,3:4,5-di-O-isopropylidene-D-erythro-pent-l - e n i t 0 1 ~ ~ 4-a-~-Erythrofuranosyll-p-tolylimidazoIine-2-thi0ne~~ Methyl 2,3,4,6-tetra-O-acetyl-cu-D-mannopyran~side~~ Di-N-acetyl-a-chitobiose monohydrate68 Di-N-acetyl-P-chitobiose trihydrate6* Decyl a-D-glucopyran~side~~ D-Ribose diphenyl dithioacetaP5 Stachyose hydrate70 D-Glucosylphytosphingosinehydrochloride71 Bis(cyclohexaamy1ose)lithium triiodide complex, o ~ t a h y d r a t e ~ ~ 2. Nucleosides and Nucleotides

P2,; Z = 2; D, = 1.556; R = 0.052 for 741 reflections. The conformation of the D-ribosyl group is C-3' endo, and the glycosyl disposition is anti. The exocyclic C-4'-C-5' bond torsion-angle is g+. (62) G. A. Clegg and L. C. G. Goaman, Acta Crystallogr. Sect. A, 31, Abstr. 06.1-25 (1975). (63) J. Hjortas, B. Larsen, F. Mo, and S. Thanomku1,Acta Chem. Scand. Ser. B , 28, 133 (1974). (64)K. B. Lindberg and A. Wagner,Acta Crystallogr. Sect A, 31, Abstr. 06.1-21 (1975). (65) A. Ducruix, C. Pascard-Billy, S. J . Eitelman, and D. Horton, J. Org. Chem., 41, 2652-2653 (1976); A. Ducruix, D. Horton, C. Pascard-Billy, and J. D. Wander, Abstr. Regional Meet. Am. Chem. Soc., Memphis, TN, Oct. 31, 1975, Abstr. 466; A. Ducruix and C. Pascard-Billy,Acta Crystallogr. Sect. A, 31, Abstr. 06.1-23(1975). (66) I. Barragan, A. Lopez-Castro, and R. Marquez, Acta Crystallogr. Sect. A, 31, Abstr. 06.1-24 (1975). (67) J. Hjortas, Acta Crystallogr. Sect. A, 31, Abstr. 06.1-27 (1975). (68) F. Mo and L. H. Jensen, Acta Crystallogr. Sect. A, 31, Abstr. 06.1-30 (1975). (69) P. C. Moews and J. R. Knox, Am. Crystallogr. Assoc. Abstr., B5 (1975). (70) R. D. Gilardi and J. L. FIippen,J. Am. Chern. Soc., 87, 6264 (1975). (71) B. Dahlen, Acta Crystallogr. Sect. A, 31, Abstr. 03.2-8 (1975). (72) W. Saenger and M. Noltemeyer,Acta Crystallogr. Sect. A, 31, Abstr. 06.3-1 (1975). (73) M. S. Poonian, E. F. Nowoswiat, J. F. Blount, T. H. Williams, R. G. Pitcher, and M . J. Kramer,]. Med. Chem., 19, 286-290 (1976).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

373

CgHl,FNzO,S S-FIuor0-4’-thiouridine~~

P2,; Z = 2; D, = 1.492; R = 0.045. The glycosyl disposition is anti (59”),and the conformation of the 4-thio-~-ribosylgroup is 3T2.The exocyclic C-4’-C-5’ bond torsion-angle is trans ( 1 8 0 O ) . The replacement of 0 by S in the sugar ring gives C-S bond-lengths greater than the C-0 bond-lengths, and decreases the C-S-C valence angle compared to the corresponding value for the D-ribosyl ring. CgH,,CdN30,P . 2 H z 0 Cadmium cytidine 5’-monophosphate, dihydrate75a76 P2,2,2,; Z = 4; D, = 2.108; R = 0.07 for 1,104 reflection^;^^ R = 0.035 for 1,551 reflection^.^^ The distorted, square-pyramidal coordination around the cadmium atom includes N-3 of the cytosine residue, three oxygen atoms of different phosphate groups, and a water molecule. The nucleotide exhibits the anti conformation for the base, the C-3’ endo pucker for the D-ribosyl group, and the g- orientation around the C-4’-C-S’ bond.

CgHlzCoN30$ * H 2 0 Cobalt cytidine 5’-monophosphate, monohydrate75

P2,; Z = 2; D, = 1.892; R = 0.092 for 871 reflections (refinement incomplete). The Co(I1) ion is tetrahedrally coordinated-to N-3 of the cytosine base, to two oxygen atoms of different phosphate groups, and to a water molecule. The nucleotide displays the anti conformation for the base, the C-2’ e,ndo pucker for the D-ribosyl group, and the g - orientation around the C-4’-C-S’ bond. C9HlzN2Na20,P 5 H z 0 2’-Deoxyuridine 5’-phosphate, disodium salt, p e r ~ t a h y d r a t e ~ ~

P2,; Z = 4; I>, = 1.643; R = 0.089. The two crystallographically independent molecules have very similar conformations. The glycosyl dispositions are anti (57.1 and S9.9”),and the exocyclic C-4’-C-S’ bond torsion-angles are trans (171.1 and 172.2’). The conformations of

(74) M. Bobek, A. Bloch, R. Parthasarathy, and R. L. Whistler, J . Med. Chem., 18, 784-787 (1975). (75) G. R. Clark and J. D. Orbel1,J. Chem. SOC.Chem. Commun., 697-698 (1975). (76) D. M. L. Goodgame, I. Jeeves, C. D. Reynolds, and A. C. Skapski, Biochem.j., 151, 467-468 (1975). (77) M. A. Viswamitra, T. P. Seshadri, and M. L. Post, Nature, 258, 542-544 (1975).

374

G E O R G E A. J E F F R E Y A N D MUTTAIYA SUNDARALINGAM

the 2-deoxy-D-erythro-pentofuranosylgroups are fT (143.4’) and 1T2 (132.1’). CIoHl2N5NiO7P . 6 H 2 0 Adenosine nickel 5’-monophosphate, hexahydrate78 C2; Z = 4;D, = 1.764; R = 0.095 for 158 projection hkO reflections. The disposition of the base is anti, and the conformation of the Dribosyl group is C-3’ endo. The exocyclic C-4’-C-5’ bond torsioiiangle is g-. The nickel atom is coordinated to N-7 of the adenine residue and to five water molecules. Two of these water molecules are engaged in intramolecular hydrogen-bonds to two separate phosphate oxygen atoms. The bases exhibit pronounced stacking. (C,H13N305)(C,H5N203)Cu * 2H,O

Cytidine, glycylglycinatocopper(II), dihydrate7,

P2,; Z = 4; D, = 1.676; R = 0.14 for 2,165 reflections. There are two crystallographically independent complexes that have almost identical conformations. The conformation of the D-ribosyl group is C-3’ endo, and the glycosyl disposition is anti (average, 16.7”).The exocyclic C-4’-C-5’ bond torsion-angle is g-. The coordination around the copper atom is approximately square planar, and involves the tridentate glycylglycine diamine ligands and N-3 of the cytosine base. The carbonylo-2 of the base is involved in a weak coordination (Cu0-2 = 2.74,2.88 A;274, 288 pm) in the axial position, thus extending the coordination geometry of the copper to square pyramidal. C,H,,N30,,P, . H,O Cytidine 5’-diphosphate, monohydrateso C2; Z = 4; D, = 1.749; R = 0.063 for 1,398 reflections. The nucleotide exists as a zwitterion, with N-3 of the base protonated by a phosphate proton. The glycosyl disposition is anti (22.9.), and the conformation of the D-ribosyl group is C-3‘ endo. The exocyclic C-4’C-5’ bond torsion-angle is g- (-60.2’). The pyrophosphate group ex-

(78) A. D. Collins, D. De Meester, U. X I . L. Goodganre, and A. C. Skapski, Biochim. Biophys. Acta, 402, 1-6 (1975). (79) D. J. Szalda, L. G. Marzilli, and T. J. Kistenmacher, Biochenz. Biophys. Res. COWL~U 63,601-605 ~., (1975). (80) M. A. Viswamitra, T . P. Seshadri, hl. L. Post, and 0. Kennard, Nature, 258, 497-501 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

375

hibits the staggered conformation about the P-0 virtual bond. The torsion angle about the Pa-0-5’ bond is g+.

[CloHlzN,0,P)2Pt(NH3)z]Na4-z,. 16Hz0,where x = -0.56. Inosine cis-platinumdiammonio 5‘-monophosphate, sodium salt, 16 hydrates1 C222,; Z = 4; R = 0.078 for 2,404 reflections. The platinum atom lies on a crystallographic, two-fold axis and is bonded to N-7 of two 5’-IMP

molecules. The two NH3 groups and the N-7 atoms form a squareplanar arrangement around the Pt atom. The metal is markedly displaced (0.59 A, 59 pm) from the base plane. The nucleotide assumes the anti disposition for the base, the C-2’ endo pucker for the Dribosyl group, and the g- orientation around the exocyclic C-4’-C-5’ bond.

(CloH13N50s)zPt(CzH6Nz)zCll.sIo.5 . 2 H z 0 Guanosine, platinum ethylenediamine, mixed chloride iodide salt, dihydrates2 1,122; Z = 8; D, = 1.859; R = 0.059 for 1,146 reflections. The platinum atom is on a crystallographic, two-fold axis. It is coordinated to the N-7 sites of two diad-related, guanosine moieties and the nitrogen atoms of an ethylenediamine molecule. The Pt-N-7 distance is 1.967 A (196.7 pm). The nucleoside exhibits the anti conformation for the base, the C-3’ endo pucker for the D-ribosyl group, and the g- orientation around the exocyclic C-4’-C-5’ bond.

(CloHl,N,0~)-(C,oH,zN,0sP),2-Cdz . 12Hz0 Cadmium inosine 5’monophosphate dodecahydratea3 C2; Z = 4; D, = 1.845; R = 0.041 for 4,198 reflections. The two, independent, cadmium atoms are octahedrally coordinated. Cd-1 is bonded to the N-7 sites of 5’-IMP-1 and S’-IMP-2, to a phosphate oxygen atom of S’-IMP-3, and to three water molecules. Cd-2 is bonded to one atom (N-7) of 5’-IMP-3, to the two D-ribosyl oxygen atoms ( 0 - 2 and 0-3) of 5’-IMP-2, and to three water molecules. The (81) D. M. L. Goodgame, I. Jeeves, F. L. Phillips, and A. C. Skapski, Biochim. Biophys. Acta, 378, 153-157 (1975). (82) R. W. Gellert and R. Bau, J . Am. Chem. Soc., 97, 7379-7380 (1975). (831 D. M. L. Goodgame, I. Jeeves, C. D. Reynolds, and A. C. Skapski, Nucleic Acids Res., 2, 1375-1379 (1975).

376

GEORGE A. JEFFREY AND MUTTAIYA SUNDAKALINGAhl

nucleotide exhibits the anti disposition for the base, the C-3‘ endo pucker for the D-ribosyl group, and the g- orientation around the exocyclic C-4’-C-S’ bond. Cl4Hl8N2O,

S-Acety~-1-(3,5~-isopropy~idene-~-~-xy~ofuranosy~) uracils4

P2,2,2,; Z = 4; R = 0.048 for 1,684 reflections. The disposition of the group base is anti (16.9”), and the conformation of the D-xy~ofuranosy~ is 3T4 (31.2’). The six-membered, isopropylidene ring is in a chair conformation, constraining the orientation around the C-4’-C-S‘ bond to g-. C14H,,N4Na0,,P2. 5H,O Cytidine (choline 5’-diphosphate), sodium salt, pentahydrateso P2,2,2,; Z = 4; D, = 1.553; R = 0.091 for 1,439 reflections. The glycosy1 disposition is anti (60.4’), and the conformation of the D-ribosyl group is C-2’ endo. The exocyclic C-4‘-C-S’ bond torsion-angle is g-. The pyrophosphate group exhibits the staggered conformation about the P-P virtual bond. The torsion-angle about the Pa-0-5’ bond is g-. The disposition of the choline moiety around the C-C bond is g+. The molecule is folded so that the choline group lies over the cytosine base. The N-3 and 0 - 2 atoms of the base are coordinated to the Na+ ion, and the amino group of the base is hydrogen-bonded to a neighboring phosphate oxygen atom and to the carbonyl oxygen atom of another neighboring base. Cl~H,,N4011P2 . H,O Cytidine (choline 5’-diphosphate), monohydratee5 P2,2,2,; Z = 4; D, = 1.57; R = 0.13 for 1,860 reflections. The molecule is in the folded conformation, as found in the sodium salt,*O but with a C-3’ endo sugar-pucker. The disposition of the base is anti, and the orientation around the exocyclic C-4‘-C-S’ bond is g-. The pyrophosphate group exhibits a staggered conformation around the P-P virtual bond. The orientation of the choline moiety around the C-C bond is g+. (84) D. W. Jones, P. W. Rugg, G. Shaw, and J. M. Sowden,J. Carbohydr. Nucleos. N u cleot., 2, 165-169 (1975). (85) H. Nakamachi, K. Kamiya, Y. Wada, S. Fujii, Y. Matsukura, H. Nakamura, and M. Nishikawa,J. Takeda Res. Lab., 34, 358-368 (1975).

BIBLIOGRAPHY OF CRYSTAL STRUCTURES

377

C2; Z = 8; R = 0.20 for 2,017 reflections. There are two independent, ioUpA molecules held together by the conventional, Watson-Crick, U-A base pairing. One of the ethidium groups is involved in intercalcative binding, and is lodged between the ioU-A base pairs of the miniature helix. The other ethidium group is stacked between the base pairs of the neighboring, ioU-A, miniature helices in adjacent unit-cells. The ethidium-ioU-A complex possesses an approximate, two-fold-symmetry axis which coincides with the pseudo-two-fold symmetry of the ethidium ring system and the two-fold symmetry that relates the two sugar phosphate, backbone chains within and neighboring ioU-A molecules. The phenyl group of the ethidium group involved in the intercalative binding lies in the narrow groove of the miniature, ioU-A, double helix. Both amino groups of ethidium are, perhaps, involved in weak hydrogen-bonds to the respective phosphodiester 0-5‘ atoms of the adenosine moiety. The ethidium group that is stacked between neighboring, miniature, double helices faces the opposite direction, such that the phenyl and ethyl groups are in the “broad groove” side and next to the iodine atoms of 5-iodouracil. The amino group of this ethidium group are hydrogen bonded to water of crystallization. The intercalative binding induces perturbations in the sugar-phosphate backbone conformation. The disposition of the bases is anti, the conformation of the D-ribosyl group of the 5iodouridine moiety is C-3’ endo, and that of the adenosine moiety is C-2’ endo. The orientations around the exocyclic, C-4’-C-5’ bonds are in the g- range. The internucleotide P-0 bond orientations are in the g- range. The complex is heavily solvated in the crystal lattice.

(C,,H,,Ni01,r~)-(C,,HiiN2)+ . 15H& Adenylyl-(3’ + 5’)-uridine (ApU), 9-aminoacridine complex, 15 hydrates7

P2,; Z

= 2; Dx = 1.413; R = 0.07 for 2,874 reflections. The adenine and uracil bases participate in the Hoogsteen base-pairing scheme, with the uracil and adenine bases of two, different, ApU molecules. The N-6-H of adenine is hydrogen-bonded to 0 - 4 of uracil, and the (86) C . Tsai, S. C. Jain, and H. M.Sobell, Proc. Natl. Acad. Sci. U.S.A., 72, 628-732

(1975). (87) N. C. Seeman, R. 0. Day, and A. Rich, Nature, 253, 324-326 (1975).

378

G E O R G E A. JEFFREY A N D MUTTAIYA S U N D A M L I N G A M

N-3-H of uracil is hydrogen-bonded to N-7 of adenine. The Hoogsteen A-U pairs and the 9-methylacridine molecules form an infinite column of alternate, stacked rings. The adenine and uracil bases are in the anti disposition, and the conformation of the D-ribosyl group is C-2’ endo in the adenosine moiety and C-3’ endo in the uridine moiety. The orientation around both phosphoric diester P-0 bonds is g+, resulting in a nonhelical conformation. (C19H2JV7012P),Ca . 18H20 Guanylyl-(3’ +-5’)-cytidine monophosphate (GpC), calcium salt, 18 hydrates8 P2,; Z = 8; D, = 1.482; R = 0.126 for 2,918 reflections. There are four, crystallographically independent, GpC molecules in the asymmetric unit, and they occur as two Watson-Crick, hydrogen-bonded dimers (miniature helices). The molecules in the unit cell are related by a pseudo-C face-centering. The dimers themselves possess a pseudo-two-fold axis broken by the Ca2+ions and associated water of hydration. The four molecules are conformationally similar, and are also similar to the RNA helix. The disposition of all eight bases is anti, and the conformation of the D-ribosyl group is C-3’ endo. The orientation around the exocyclic C-4’-C-5’ bond is g-. The internucleotide, P-0 bond orientations are in the g- range. The Ca2+ ions are octahedrally coordinated to oxygen atoms of phosphate groups of the different dimers and to four water molecules. The average dihedral angle between the base planes of the G-C, Watson-Crick pairs is 6.9”. The average P-P and C-l’-C-I’ separations of the sugar phosphate chains in the miniature helices are 17.66“ and 10.55 A (1.055 nm), respectively.

(88) B. Hingerty, E. Subramanian, S. U. Stellman, S . B. Broyde, T. Sato, and R. Langridge, Biopolymers, 14, 227-236 (1975).

AUTHOR INDEX Numbers in parentheses are reference numbers and indicate that a n author's work is referred to, although his name is not cited i n the text.

A Abbas, S. A., 208, 221(151),226(151), 231(151),237(151) Abdelal, A. T., 336 Abe, H., 70 Abelin, J., 50 Abraham, D. J., 363 Abraham, R. J., 201 Accorsi, A., 337, 338 Acher, A. J., 60, 75, 80, 82(680),84(454), 111(635),121(635),125(635), 128(635),159, 160(635,680), 161(454, 680), 162(454,635, 680, 812), 167(454),168(635),169(635), 255 Achmatowicz, O., Jr., 103 Acton, E. M., 211(188),213 Adams, G. A., 204, 206, 225(120), 226(120) Adamson, J., 64, 135(508) Adelman, R. C., 292, 295, 296, 297(62), 306(148),307, 327(62),331 Aebi, H., 320 Agosin, M., 331, 332(:322) Ahluwalia, R., 37, 201, 239(101) Akagi, M., 33, 122(97),128(97),146, 147(777),165(93),173(97),233(305), 233 Akatsu, M., 67(750, 751), 117, 125(750, 751), 144(750. 751) Akazawa, T., 314 Alexander, B. H., 45, 46(295), 90(295), 152(295),154(295),155(295), 177(295) Alger, R., 43 Allerton, R., 33, 65, 74(533),77(533), 165(92) Allinger, N. L., 35 Allison, D. P., 312 Alsups, I., 63 Anderson, B., 341 Anderson, J., 301 Anderson, L., 32 Anderson, R. L., 310, 311, 312, 313(169). 332

Anderson, W. R., 301 Andrianov, V. I., 357 Andrievskaya, E. A., 39(206,216, 217), 40, 41, 44(216, 217), 45, 74(632), 75, 76, 77(217), 85, 86(632), 105(296), 111(632),112(632), 114(632), 115(632),120(632), 121(632), 131(632),141(632), 152(296), 165(217),172(632),174(632), 175(632),177(296) Anet, E. F. L. J., 279 Angus, J. F., 55 Angyal, I., 85, 169(691) Angyal, S. J., 34, 35, 36(99),37, 50(99), 55, 56, 57(99),58(99),59(99),61(403, 404a, 405, 406), 62(99),63(99),65, 66(531),77(99, 531), 85(531), 140(99), 143(99), 152(99), 1S3(99), 154(99),166(99),169(531),176(99), 177(99),201, 239(101) Anisuzzaman, A. K. M., 203, 218(111), 219(111) Anno, K., 36, 51(107), 165(107) Anricchio, S., 287 Ansell, E. G., 187 Anteunis, M., 202 A m , H., 338, 339(398) Aoki, K., 366, 367(50) Apostolides, C., 74 Appel, H., 187 Apsite, B., 70, 72, 74, 76, 93, 165(604) Araki, Y., 207 Aravena, L., 331, 332(322) Arcamone, F., 247 Archer, A. J., 28, 60(51),62(51),66(51), 75(51),83(51), 166(51),169(51) Ardouin, R., 327 Arduini, A., 198 Areneri-Shapiro, S., 315,316(197, 198, 199) Arita, H., 162 Armitage, 1. M., 197, 198 Anick, R. E., 207 Arseneau, D. F., 39, 41, 52(193),69(193) Arthur, J. C., Jr., 44 Arvinen, A., 63

379

AUTHOR INDEX

380

Ary, I. E., 259 Aschner, M., 315, 316(197) Asensio, C., 314 Ashton, D. M., 323 Ashwell, G., 340 Asp, L., 159, 1624798) Aspinall, G. O., 45, 64(285), 75(%5), 81(285), 90(285), 170(285),171(285) Atkinson, D. E., 302 Atlani, P., 69 Audichya, T. D., 213, 216(213) Augk, C., 252(59), 253 Augustin, H., 38(175),39, 40, 41(212), 44(212), 45(212), 52(175, 212), 69(212) Austin, P. W., 258 Avenel, D., 350, 351(16) Avigad, G., 154, 316

B Babaeva, A. V., 55 Bach, M., 341 Bacila, M., 336 Bacon, J. S. D., 314 Baddiley, J . , 258, 316 Badding, V. G., 48, 69(324), 140(324), 175(324) Baer, H. H., 65, 106, 172(532),265, 273(154), 274, 281 Baer, H. P., 323 Baerlocher, K., 310 Baggelt, N., 37, 77(149), 170(148, 149), 181, 188, 189, 195, 196, 199(50),205, 210, 211(76), 217, 218(178), 223(246a), 225(49, 50), 227(50), 231(49), 237(76) Bains, M. S., 43, 44(265), 52(265), 69(265) Baitsch, H., 297, 307(72), 308(72), 309(72), 310(72), 331(72) Bakassian, G., 48 Baker, B. R., 217, 219(227),220(227), 240(341), 241 Baker, C . W., 237(323), 241 Baker, D. C . , 191(60d), 192, 207, 209, 219(60d) Baker, L., 310 Baker, R. H., 317 Bak6, P., 56, 67(412,414)

Balanina, I. V., 29, 77(67), 207 Balasse, E. O., 328 Balchin, A. A., 371 Balde, P., 293 Ball, D. H., 204, 210(121), 213, 216(214), 217, 222(239, 240), 223(239), 224(121, 214), 229(239) Ballard, F. J., 292, 331 Ballard, J. M., 183, 193(14),219(14) Ballou, C. E., 28, 29(46), 205,217, 225(255) Banks, J., 299 Banoub, J., 247, 279 Barbalat-Rey, F., 200 Bard, R. C., 333 Bardolph, M. P., 28, 29(49), 77(49) Bardysheva, K., 40, 84(224), 169(224) Barford, A. D., 60, 64(448), 66(448), 75, 80(448), 108(448, 637), 109(448), 111(448), 114(637), 121(448), 131(447,448,637), 133(447,448, 637), 134(447, 448), 169(448), 172(448, 637) Bar-Guilloux, E., 252(52), 253, 265(52) Barker, G. R., 35, 36(104), 50(104), 55, 28 1 Barker, R., 281, 334 Barker, R. H., 26, 39(22), 42(22), 56(22), 69(22) Barlow, C. B., 199 Barnett, J. E. C . , 31 Bar-on, H., 325, 327(288) Barragan, I., 372 Barretto, 0. C., 340 Barton, D. H. R., 93, 143(713) Barysheva, G. S., 26, 38(11), 69 Basch, A., 41, 63(229, 231) Bashford, V. G.. 128 Baskevitch, Z., 37, 165(144) Bassett, D. R., 325 Basso, L. V., 328 Bau, R., 375 Bauer, H., 54 Bauer, 27, 165(41) Baum, G., 27, 31, 32(36,72, 73), 159(72), 165(36, 72, 73), 166(72,73) Baumann, P., 336 Beattie, A., 188 Beaudreau, C., 336 Bebault, G. M., 237(324), 241 Beck, D., 252(60), 253, 273(60)

s.,

AUTHOR INDEX Beck, L. R., Jr., 63 Bedford, G. R., 42, 46(253) Behre, H., 217, 224(252) Beiser, A., 65 Bell, E. J., 336, 338(374) Bell, R. H., 60, 92(449), 142(449) Bellas, T. E., 26 Belleau, B., 105 BeneS, J., 74(630), 75, 120(630), 131(630), 132(630), 141(630), 142(630) Ben-Gerhorn, E., 331 Bentz, F., 77 Beran, P., 63, 64(498). 74(498), 80(498), 107(498), 111(498), 112(498), 114(498), 172(498) Beresneva, Z. Ya., 76 Bergen, B., 349 Berghe, G. V. D., 308,309( 162) Bergmann, M., 66 Bergonzi, E., 186, 232(29) Berking, B., 113 Berkowitz-Mattuck, J. B., 41, 43(241), 44(241) Berman, H. M., 352,369 Berman, M., 328 Bernardinelli, G., 358 Bernetti, R., 186, 232(29) Bernstein, A., 318, 343(234, 235) Bernstein, H. J., 60 Bernstein, I. A., 336 Bernstein, S., 253, 254 Berry, J. W., 229(290), 231(290, 295, 300), 235 Berry, M. N., 320 Bertolini, M., 231(299), 235 Bertrand, H., 337 Bessell, E. M., 58, 62(434), 65(434), 114(434), 120(434), 121(434), 168(434), 221, 228(270) Beutler, E., 335 Bhat, C. C., 281 Bhat, K. V., 247, 281 Bhattacharjee, S. S., 79, 93(677), 188, 189(47), 191(47), 206, 236(47), 237(47) Bhattacharya, A., 71, 165(598), 168(598) Bianchetti, R., 336 Biemann, K., 192, 193, 194(67) Bingham, J. K., 290(24), 291 Birch, G. G., 50, 58, 63, 77(481) Birkofer, L., 77

381

Biryukov, B. P., 353 Bishop, D. W., 340 Bishop, E. O., 199 Bishop, M., 301 Bissett, F. H., 187, 216(38), 231(38), 237(38) Bister, W., 37(166), 38, 104(166), 122(166), 128(166), 173(166) Black, S. A., 201, 202( 102), 219(102), 221( 102), 223( 102), 224( 102), 239( 102) Black, W. A. P., 208, 217, 225(256) Black, W. J., 337 Blackly, R. L., 340 Blackshaw, A. W., 340 Blanco, R., 313 Bloch, A,, 373 Blomqvist, G., 63, 64(491), 162(491) Blondheim, S. H., 325 Blostein, R. E., 333 Blount, J. F., 372 Blumenthal, H. J., 341 Bobek, M., 373 Bochkov, A. F., 64, 111(499), 120(499), 121(499), 169(499), 244, 248, 250, 272 Bock, K., 281 Borjeson, H., 278 Borsch, G., 304 Boffi, C., 186, 232(29) Bognlr, R., 32, 68, 165(80) Bohn, E., 246, 273(27) Bollenback, G. N., 208, 243(3), 244 Bolz, F., 64 Bonner, T. G., 68,157(567), 179(6), 180, 210, 230(179) Bonner, W. A., 255 Bonnichsen, R., 322 Borbn, H. B., 208, 225(152), 227(152), 232(152), 237(327), 241 Bomnann, D., 31, 32(77) Borst, P., 3 18 Bourne, E. J., 54, 55(393), 68, 157(567), 210, 230( 179) Brachet, E. A., 340 Bradshaw, R. A., 334 Brady, R. F., Jr., 203(115), 204 Bragg, P., 51, 54(352) Braithwaite, D. M., 325 Braun, G., 63, 64(490), 77(490) Braun, G. A., 254

382

AUTHOR INDEX

Braunovi, M., 66, 134(545) Bredereck, H., 46(309), 47,74(309), 165(309),250 Brehm, L., 359 Brenner, B. M., 323 Breuer, H., 253, 254 Brewer, C. L., 217, 224(249) Brice, C., 29, 46(66), 165(66),273 Brigl, P., 256 Briller, S., 330 Brimacombe, J. S., 37(167, 170), 38, 58(170), 60(170), 77, 80(662), 82(662), 86(662), 90,122(167), 132(170), 135(170), 165(662), 168(662), 184, 186, 188, 189(48), 191(60c), 192, 193, 195, 201, 203, 204(68),207, 212(63), 213, 214(99), 215(63, 199, 202), 217, 218(109, 220, 222), 2 19(220),220(232),22 1(68), 223(246),224(250, 251, 253), 227(26), 228(109),229(109), 231(48, 298), 234(108, 253, 310, 311, 312), 235, 236(63, 232, 320), 239(22), 241 Brink, A. J., 209 Brocca, V., 186, 232(29) Brodde, 0.-E., 47, 77(316) Broido, A,, 39(213), 40, 41(213), 42, 43, 44(213, 261), 61(254), 62(254), 63, 69(213, 254), 77(213), 102(254,261), 102(213), 143(286) Brown, D. K., 209 Brown, D. M., 229(289), 235 Brown, R. K., 48, 49, 57(325, 332), 58(332),SS(325, 328, 332), 60(325, 327, 328, 329), 62, 69, 80(329), 111(329),112(325,327, 328, 330, 331, 333), 115(331), 117(325,327, 329), 118(330, 331),119(331), 124(329), 132(325,326, 327), 140(325,326), 144(325,327, 328), 145(325,326, 327, 328, 329, 330, 467, 577), 146(330), 165(331,332), 167(332), 168(332), 169(330), 172(331), 175(325,326, 328, 331) Browne, L. E., 26 Brownlee, R. G., 26 Brox, L. W., 334 Broyde, S. B., 378 Bruce, R. M., 221, 228(274),229(274) Bryce, D. J., 39, 41(191), 45(191)

Buben, I., 109, 114(739), 118(739), 172(739) Buchanan, J. G., 37, 114, 118, 119(752), 166(142), 190, 209, 213, 221, 226(263), 228(212), 236(318), 237(329), 241, 258 Buck, K. W., 105, 148(731),196, 205, 210, 211(76), 218(178), 237(76) BudGinsky, M., 36, 37(106), 53(106, 381), 54, 55(106), 59(106, 381, 438), 60(106, 381), 61(106), 62(106), 79(106), 90(106), 91(106), 92(106), 102(106), 107(438), 111(438),113, 114(744), 115(438), 118(438), 120(381), 123(438), 125(381), 127(438), 128(438), 130, 134(381), 135(381), 169(106), 173(438,772), 174(438) Bucher, T., 318 Bugg, C. E., 347,351,365 Bugianesi, R., 150 Buhlitz, C., 293, 319(38) Bukowski, P., 103 Buncel, E., 37, 39(125), 45(125), 75(125), 77(1254, 86(123, 90(125), 165(125) Bunge, R. G., ,304 Bunton, C. A., 33, 62(96) Burch, H. B., 293, 294(43), 325(43) Burke, V., 290 Burton, J. S., 209 Buss, D. H., 199, 217, 219(227), 220(227), 222(237), 229(237) Byrne, G. A., 39(214),40, 41(214), 43(214), 63(2 14), 77(2 14),152(214) Byme, W. L., 337 Byungse, S., 334

C Cader, J., 334 Cadotte, J. E., 243(3),244 Cagnoli-Bellavita, N., 37, 165(143) Calinaud, P., 148 Campbell, C . S., 283 Campbell, R. C., 301 Cano, F. H., 167(832), 170 Cantor, S. M., 67, 165(561) tapek, K., 106 Capon, B., 29, 179, 180,202, 273 Carey, F. A,, 231(293), 235

AUTHOR INDEX Carey, P. R., 199 Carlberg, L. G., 76, 77(643) Carlson, L. J., 38(178), 39,42(178),64, 79(505), 110(505), 111(50s), 120(505), 124(505), I28(505), 13I(S05), 169(505), 172(505) Carraway, IS.L., 213, 215(203) Carroll, B., 44, 45(271) Carter, H. E., 37, 38, 63(174), 77(147), 104(164),122(164), 128(164), 173(164) Case, G. S., SO Cassillas, E. R., 302, :303(104) Castelho, F. J., 334 Casu, B., 37 Ceccherelli, P., 37, 165(143) CernL, I., 111, 120, 124(740,756), 125(740, 756), 130(740), 131(740, 756), 174(740) CernL, M., 24, 36, 37(106),52(372), 53, 54, 55(106, 391), 56, 58, 59, 60, 61(106, 377, 450), 62, 64,65, 66, 69(372),74, 75, 76(383), 77(479, 520), 79(106, 520, 636), 80, 82(520), 83(408),84(408), 85(383, 504,520), 86(377),87(379), 90(106, 636), 91(106), 92(106), 93(383, 520), lOl(450, 636), 102(106, 383, 636), 103, 104(377,450), 106(383),107, 108(479, 504, 544, 679, 737), 109, llO(520, 679), 111, 112(376,379, 384, 498, 742), 113, 114, 115(379, 438,504), 116(384,742), 117(384, 479, 742), 118(438,479, 739), 119 (479, 746), 120, 121(379,381), 122(379), 123(438, 756), 124(678, 740, 756, 757), 125(379,381, 740, 756), 127(438), 128, 129(379),130, 131(379,380, 384, 506, 507, 544, 629, 630, 631, 678, 740, 756), 132(384, 630), 133(380, 506, 507, 544, 629), 134(381, 545, 629), 135(380,381, 382, 506, 507, 543, 544, as), 139(723), 140(723), 141(376, 377, 383, 384, 630, 631, 742, 746, 754), 142(630,631), 143(376,377, 383, 408, 450, 746), 144(376,377, 383, 384, 408, 679, 742, 754), 145(376, 377, 382, 384), 146(376,377), 165(636), 166(636),

383

167(636), 168(450, 520, 629), 169(106, 504, 520, 629, 636, 679), 170(636), 172(379,479, 498, 504, 506, 520, 629, 737, 739), 173(379, 438, 757, 772), 174(438,479, 631, 740, 746), 175(376, 383, 384, 742, 746, 754), 176(723), 179(5), 180, 244 Chac6n-Fuertes, M. E., 84, 161, 162(813), 167(687) Chaikoff, I. L., 289, 295(15), 296, 330 Chaimovich, H., 33, 62(96) Chakravorty, M., 336 Chalet, J. M., 200, 237(333), 239(333), 24 1 Chalk, R. C., 217, 222(239, 240), 223(239), 229(239), 233(309), 235 Chambers, R. A,, 306 Chance, B., 317 Chandorkar, K. R., 315, 316 Chandra, H., 298 Chang, M. C., 302 Chatterjee, A. K., 58, 59(439),64(439), 86, 90(439), 98(439), 126(439), 128(439),173(439), 174(439) Chatterjee, P. K., 43 Cheldelin, V. H., 333, 340 Chen, C., 334 Chiinevert, R., 207 Cheng, T., 333, 334(336) Cheng, Y. Y., 236(319), 241 Chepigo, S. V., 26, 38(11), 69 Chemeva, E. P., 76 Chemick, S. S., 296 Chevalier, M. M., 330 Chiba, T., 159, 162 Chin, P. P. S., 39,52(194),63(194),77(194), 81(194), 93(I%), 103, 106(194) Ching, 0. A., 186, 203, 213, 214(199), 215(199, 202), 218(109), 227(26), 228(log), 229(109) Ching Puente, A. O., 217, 219(231) Chittenden, G. J. F., 37, 166(127),206, 208, 214(136), 221, 226(263, 264), 234(316),239(316), 241, 258 Chiu, S.-H. L., 32 Chizat, F., 48 Chizhov, 0. S., 62, 192(65a,65b), 193, 194(69) Chladek, S., 186, 188(31) Choong, W., 349, 352

384

AUTHOR INDEX

Chowdury, A. R., 288 Chowdury, S. R., 298 Choy, Y. M., 237(328), 241 Christen, P., 333 Christensen, J. E., 37(162), 38, 122(162), 136(l62), 205 Christensen, U., 341 ChvalovskL, V., 59 Chyu, K., 293, 294(43), 325(43) Cifonelli, J. A,, 37, 62(140) Cipera, J. D. T., 273 Cirillo, V. P., 314 Clark, G. R., 373 Clarke, J. S., 341 Clasper, P., 69 Clegg, G. A., 372 Clegg, W., 356 Cleveland, E. A,, 186, 232(29) Clingman, A. L., 28, 62(54) Clode, D. M., 207 Cohen, A. M., 325, 330 Coleman, G. H., 27, 28(32), 29(32, 49), 31(32), 159(32) Collins, A. D., 374 Collins, F. R., 315, 316 Collins, P. M., 58, 59(431), 62, 75(431), 93(466), 168(431,466), 180, 197, 203, 204, 207, 211(78), 217,219(228), 220(78, 228), 226(78), 227(78), 233(78), 237(78), 238(78), 239(78) Colombo, G . , 338 Colowick, S. P., 322, 323(261) Colquhoun, J. A., 208, 217, 225(256) Compton, J., 217, 224(248) Conde, A., 353, 362(22) Cone, C., 200 Conrad, C. M., 43 Conrad, R., 312 Conrow, R. B., 253, 254 Conway, E., 198 Cook, A. F., 37(154), 38, 140(154), 175(154), 176(154) Cook, G . C., 294, 295(54) Cook, M. C., 207 Cook, W. J., 351 Corbett, W. M., 229(287), 235 Cordes, E. H., 317 Cori, C . F., 293 Cori, G. T., 293 Comhlath, M., 307, 308, 310(151)

Cotton, F. A., 370 Cottrell, A. G., 37, 39(l25), 45(125), 75(l25), 77(125), 86(125), W( 125), 165(125) Cox, E. G., 46(308), 47, 50(308),51(308), 64(308), 77(308), 90(308),168(308), 17l(308) Cox, J. M., 150, 283 Coxon, B., 37(161), 38, 59, 65(161), 104(16l), 122(161), 128(161), 173(161), 174, 183, 195, 199, 200, 221(W), 237(90), 283 Craig, D. C., 349 Craig, J. W., 296, 308, 325(159) Cramer, M., 39, 50(186),66(186),94(186) Cramp, W. A., 254 Crane, R. K., 287, 307, 308(151), 310(151) Crawford, M. A., 325 Creasey, S. E., 208, 233(306),235 Crews, L. T., 94 Crockett, A. T. K., 298 Cryer, A., 328(305), 329(305),330 Csiiros, Z., 39, 56, 65, 66, 67, 68, 77( 195, 531, 563), 85(531), 165(195, 563), 169(531),246, 251(20) Cummins, J. T., 340 Cunningham, V. J., 328 Curran, P. F., 290 Cyr, N., 61

D

Da’aboul, I., 217, 224(250) Dahlen, B., 372 Dahlquist, A., 287 Daignault, R. A,, 48, 69(324), 140(324), 175(324) Damgaard, S. E., 291,320,321,322 Daniels, E. E., 37(164), 38, IW(164), 122(164), 128(164), l73( 164) Danilov, S. N., 29, 77(67), 207 Danneels, D., 202 Dark, F. A., 341 da Silva Carvalho, J., 70 David, S., 217, 224(249) Davidson, E. A,, 65,217,222(242,245),341 Davis, H. A., 42, 152(251), 153(251), 154(251), 155(251), 177(251)

AUTHOR INDEX

Davis, L. C., 334 Davydova, G. V., 37, 45, 75, 77( 128, 286, 290,634), 78, 90(286, 290), 165(290), 166(128),173(674) Dawes, K., 34, 35(99),36(99), 37(99), 50(99), 57(99), 58(99), 59(99), 62(99), 63(99), 77(99), 140(99), 143(99), 152(99), 153(99), 154(99), 166(99), 176(99), 177(99) Dawson, A. M., 289,294 Day, R. O., 377 Deacon, A. C., 315 Deik, G., 39, 56, 66, 67, 68,77(195, 563), 165(195, 563) de Belder, A. N., 179, 188(1),231(297), 235 DeBemardo, S. L., 247 DeBlauwe, F., 64, 144(503) de Bruyn, A., 202 DeCarli, L. M., 317 Dedonder, R., 316 Defaye, J., 128, 191, 212(195),213, 214(195),229(283), 234(60a),235, 252(52), 253, 265 DeFlora, A., 338 Dejmek, L., 52(373), 53 DeJongh, D. C., 192, 193, 194(67) Dejter-Juszynaki, M., 263 Delbaere, L. T. J., 355, 356(27) de Lerma, L., 371 DeLucas, L., 347 De Meester, D., 374 Demoss, R. D., 333 Depmeier, V. W., 357,358 Derbisher, G. V., 55 Derevitskaya, V. A,, 252(56),253 Descotes, G., 48 Deslongchamps, P., 69, 207 Detert, D. H., 191, 230(59) Detheridge, J. F., 287 Deutschmann, A. J., Jr., 229(290), 231(290, 295, 300), 235 Deven, J . J., 290 Dewar, E. T., 208, 217. 225(256) Diamantstein, T., 293 Dick, W. E., Jr., 184, 190, 192(55), 194(15), 197, 201, 218(15, 99), 219(55, 99), 220(55), 230(55, 77) Dickerson, A. G . , 315 Dickinson, M. T., 209

385

Diehl, H. W., 33, 165(92) Dimes, M. T., 50, 104(345) Dillon, R. T., 278 Dimant, E., 210 Dimitrijevich, S., 47, 60(319), 74(319), 75(319), 131(319), 132(319), 140(319) Dimler, R. J., 24, 39, 40(190),41(190), 42,45, 46(295), 63(190), 77(190), 151(3), 152(190, 251, 295), 153(251), 154(251,295), 155(190,251, 295), 165(190), 177(251, 295) Dingle, S. L., 314 Dipietro, D. L., 295 Diver-Haber, A., 28, 60(51),62(51), 66(51), 75(51), 80, 82(680),83(51), 159(680), 160(680), 161(680), 162(680), 166(51), 169(51) Diwadkar, A. B., 188, 211(42),231(42), 232(42) Dmytraczenko, A,, 236(322),241 Doane, W. M., 208 Dobinson, B., 195 Dobrzhinskaya, M. S., 75, 77(634), 78(634) Doell, R. G., 287 Doihara, T., 43, 69(269) Doleial, J., 54, 55(391) DoleialovL, J., 53(382), 54,56(382), 82, 114(382), 135(382), 145(382) Domburgs, G., 46 Dondero, F., 304 Doppstadt, A., 248, 266(33) Dorfman, A., 37, 62(140) Dormandy, T. L., 308 Drake, G. L., Jr., 26, 39(22), 42(22), 56(22), 69(22) DraSar, P., 53(381), 54,59(381), 60(381), 74, 111(629), 120(381, 629), 121(381), 125(381), 134(38 1, 629), 135(38 1), 168(629), 169(629), 172(629) Dreyfus, J. C., 306(140), 307(138) Driguez, H., 252(52), 253, 265(52), 267, 268(133), 275(133) Drucker, W. R., 296 Drummond, G., 337 Drummond, G. I., 323 Dryselius, E., 28, 50(57) Dubin, A., 217, 219(226) Ducruix, A., 367, 372 Durr, W., 64

AUTHOR INDEX

386

Diirrfeld, K., 98 Duff, R. B., 90, 107(703), 168(703), 172(703) Dumermuth, G., 310 Duncan, E. L., 323 Dunn, A. D., 209, 236(318), 241 Durette, P. L., 57, 58(421, 422, 429a), 59(421), 60, 62(453), 87(422), 88(421, 422, 429a, 453), 89(453), 152, 153(791),154(791), 155(422,791), 157(421), 161, 165(421,422), 166(422,429a, 453), 167(422), 177(421,422,453,791),198(89b),199, 201(89b) Durynina, L. I., 39(209),40,41, 42(209), 52(364), 53 Dutton, G. G. S., 162, 237(324), 241 Duxbury, J. M., 181, 188, 189, 195(49, 50), 199(50),225(49, 50), 227(50), 231(49) Dwek, R. A., 201, 216(98) Dworak, A,, 237(332), 241 Dyer, J. R., 37(la), 38, 1O4(164), 122(la), 128(164), 173(164) Dyfverman, A., 27, 28(35), 29(35) Dyong, I., 221, 227(268) Dzvinko, B., 72, 74, 120(620),165(601)

E Eades, E. D. M., 213, 216(214), 224(214) Eagles, P. A. M., 334 Eagon, R. G., 314 Eanes, R. Z . , 306(145), 307 Earl, R. A,, 244 Eberhard, S. J., 314 Eberstein, K., 61, 100(459), 133(459), 143(459), 144(459) Ebert, R., 54 Eby, R., 65, 75(536), 77(536), 262, 266, 277(105, 106) Edelman, J., 314, 315, 316 Edgar, A. R., 190, 209, 236(318), 241 Edo, H., 45, 46, 55(301), 62(297, 301) Edwards, T. E., 36, 62(112), 152(109), 153(109) Eggleston, C. V., 325 Eidels, L., 312 Einstein, F. W. B., 201, 346 Eitelman, S. J., 372 Eklund, K., 239(337), 241

El-Badry, A. M., 336 Elbert, T., 53(379), 54,58(379),59(379), 62(379),87(379), 107, 112(379), 115(379), 121(379), 122(379), 125(379),128, 129(379), 131(379), 172(379),173(379) Elids, E., 288 Eliel, E. L., 35, 48, 69(324), 140(324), 175(324) El Khadem, H . S., 213, 216(213) Ellis, D. B., 341, 342 Ellis, E. H., 337 El-Scherbiney, A., 104, 106(726) Emoto, S., 47, 58(317), 59(317), 122(317), 203(112),204, 212(112), 213, 216(210),234(112) Endo, A., 342 Endo, T., 247 Engel, R. M. E., 300 Engelhardt, G., 59 England, S., 154 Enser, M., 335(361, 363), 336, 337(361), 338, 339(397) Epshtein, Ya. V., 38(174, 176), 39,40, 41, 42(209), 52(364), 53, 76 Erdiis, G., 65 Ermolenko, I. N., 43 Esaki, S., 252(62), 254 Esterer, A. K., 38(179, 180, 181), 39, 42(179, 181) Evans, B., 268 Evans, M. E., 186, 187, 192, 204(33), 205, 216(38), 217, 221(62), 222(238), 231(38), 232(33, 301), 234(238),235, 236(238),237(38) Evans, T. H., 63, 64(492), 77(492) Evans, W. L., 246, 273(26) Everett, M. R., 94 Evett, M., 39(213), 40, 41(213), 42(213), 43(213), 44(213), 69(213), 77(213), 103(213) Ewald, L., 63, 64(491), 162(491) Excoffier, G., 252(58), 253 Exton, J . H., 297, 328 Ezekiel, A. D., 210

F Faber, G., 250 Fahim, F. A,, 105, 148(731)

AUTHOR INDEX Fallon, H. J., 325, 328(292) Farkas, I., 68 Farmer, D. W. A,, 86 Farquhar, J. W., 325 Fayos, J., 362 Fedorishchev, T., 39(203), 40, 41(203) Fellig, J., 84 Fenichel, L., 56, 67(412, 414, 563), 68, 77(563), 165(563) Fenster, L. F., 294 Fentiman, A. F., Jr., 26 Fernando, J., 335(361,362), 336, 337(361) Femez, A., 27, 90(37), 165(37),171(37) Ferrier, R. J., 140, 174(775), 180, 186, 195, 196(28),205(28), 216(28), 226(28),243, 244(1) Feucht, B. U., 31 I Fialkiewiczowa, Z., 104(729), 105 Field, J. B., 294 Fielder, R. J . , 268 Filatova, N. P., 55 Finar, P. A,, 232(303), 233(303),235 Finlayson, A. J., 206 Fioroni, W., 52(361, 362), 53 Firch, W. M., 330 First, N. L., 303 Fischer, E., 243, 265, 266,278 Fischer, H. 0. L., 53(378), 54, 87, 104(378,700), 105(378), 125(378, 700), 126(378), 128(378),173(378, 700), 174(378),217, 225(255) Fischer, M. H., 48, 62(322),63(322), 152(322),165(322), 177(322) Fisher, G . A., 59, 77(444), 165(444) Flerou, P., 291 Flesch, H., 67 Fletcher, H. G., Jr., 28, 32, 33, 65, 74(533),77(91, 533), 165(92),179(6), 180, 185, 187, 232(302),233(302), 235, 258, 259, 273(151),274, 278, 281

Fletcher, R., 114 Flippen, J. L., 354, 372 Flipse, R. J., 301 Flitsch, R., 31, 32(74) Flowers, H. M., 186, 221, 226(266), 227(266),239(334), 241, 252, 253, 263, 273(51, 61) Foces-Foces, C., 167(832),170

387

Fodor, G., 92 Folk, R. L., 26, 62, 74(476), 194 ForsCn, S., 208 Fossitt, D. D., 336 Foster, A. B., 37(158, 165, 170), 38, 58(170), 60, 64, 66(448), 75, 80(448), 104(158, 165), 105, 108(448, 637), 109(448), 111(448), 114(637), 121(448), 122(158, 165), 128(158, 165), 131(447, 448, 637), 132(170), 133(447,448, 637), 134(447,448), 135(170, 508), 148(731),169(448), 172(448,637), 173(158), 179, 181, 188, 189, 195, 196, 199(50),205, 210, 211(76), 217, 218(178),219(225), 221, 225(49, 50), 227(50), 228(270), 231(48, 49), 234(312), 235, 237(76), 254, 255(66) Foster, D. O., 322 Fox, I. H., 323 Fox, J. J., 221, 225(262) Fox, M., 290, 291 Frahn, J. L., 55 Frank, A., 325, 328 Frankel, D. G., 336 Franks, N. E., 250 Fraser-Reid, B., 217, 221(234) Frechet, J. (M. J.), 65, 73, 77(615), 172(532),265,269,273(140,141,154), 274, 275(140), 281 FrehC1, D., 69, 207 Frenzel, H., 28, 31(65) Freudenberg, K., 63, 64(491),65, 66, 161(501), 162(491, 501, 5-52), 185, 221, 228(276), 240(338), 241 Freund, M., 301, 302, 304 Friedman, M. A,, 324 Friedmann, M., 199, 223(93) Friedmann, N., 297 Friese, H., 159 Fritsch, A., 316 Froesch, E. R., 297, 298,306, 307, 308, 309(72, 161),310(72, 161), 331(72) Frostell, G., 343 Fry, E. M., 150 Frye, C. H., 203(116), 204, 216(116) Fu, J. Y., 339 Fu, Y. L., 41, 43(235), 44(235), 70(235), 77(235) Fujii, S., 376

388

AUTHOR INDEX

Gilardi, R. D., 354,372 Gillam, I. C., 256, 281 Gillen, R. G., 370 Gillier-Pandraud, H . , 354, 355 Ginsberg, J. L., 297 G Ginsburg, A,, 334 Ginsburg, V., 294, 324(48) Gadacz, I., 341 Gitzelmann, R., 310 Gadelle, A,, 191, 234(60a) Gladding, E. K., 32, 67(90), 77(90) Gager, F. L., Jr., 46 Glassner, S., 43, 69(267) Gagnaire, D. Y., 252(58), 253 Gale, M. M., 325 Glaudemans, C. P. J., 28, 231(299), 232(302),233(302), 235, 273(151), Gal-Or, B., 26, 38(12, 13),39(12, 13), 274,278 42(13) Can, J. C . , 343 Gligorijevic, M., 233(307), 235, 237(307), Garcia-Blanco, S., 167(832),170, 371 238(307) Gardiner, D., 39, 40, 41(214), 42, 43(196, GliSin, D., 233(307), 235, 237(307), 238(307) 214), 44(196),45(196), 46(196, 253), Goaman, L. C. G., 372 63(196, 214), 77(214), 135(196), Goatley, J. L., 217, 225(259) 152(196, 214), 15S(196) Gohil, R. N., 370 Garegg, P. J., 188(51), 189, 197, 208, Golab, T., 37(151), 38, 140(151), 211(187), 213, 225(152), 227(51, 76a, 152),231(51),232(152),237(IS3,327), 175(151), 176(151) Goldblatt, P. J., 324 239(337), 241 Goldner, A. M., 290 Gasman, R. C., 27, 28(43) Gatehouse, B. M., 352, 361(20) Goldschmit, S.,335 Goldstein, I. J., 69, 71, 165(597) Gatovskaya, T. V., 39(210),40, 41(210) Golova, 0. P., 26, 38(174, 176),39, 40, Gelas, J., 148, 188, 189, 211(42, 43), 41, 42,43(16, 205), 44,45, 55, 70, 214(43),231(42), 232(42) 74(593, 632), 75, 76, 77, 84(671),85, Geller, A. M., 337 86(632), 105(296), 111(632), Gellert, R. W., 375 112(632), 114(632),115(632), Gendil, R., 358 120(632), 12l(632) 131(632), Gent, P. A,, 27, 66(45a), 90, 114(45a), 141(632), 152(208,250, 296), 125(45a),l84,191(60c), 192,193,201, 204(68), 217, 221(68), 223(246), 16q217, 593), l69(67I), 172(632), 224(253), 234(253), 268 174(632), 175(632), 177(250,296) Gentile, B., 209 Golovkina, L. S., 193, 194(69) Genuth, S. M., 308, 325(159) GonzQIez,N. S., 316, 331 Goodgame, D. M. L., 373, 374, 375 Georg, A,, 70 Goodman, L., 37(162), 38, 122(162), Gerasimenko, A. A,, 67 Gercev, V. V., 70, 75(591), 165(591) 136(162),205, 212(196), 213 Gerecs, A,, 25, 39(7), 41(7), 45, 50(282), Goodwin, J. C . , 189, 221(52), 226(52), 64(282), 67(7, 282), 77(282), 166(282), 232(52),233(52), 237(52) 246, 251(19) Goodwin, L., 211(188), 213 Gore, W. E., 26 Gero, S. D., 198 Gorin, P. A. J., 55, 61, 69, 79, 93(677), Gevers, W., 302 Ghosh, S. G., 341 188, 189(47), 191(47), 198, 206, Gibbs, C. F., 34 236(47),237(47), 246, 273(28), 279, Gibson, G. J., 288 280(176) Gigg, R., 27, 66(45a), 90(45a), 114(45a). Gotthammar, B., 239(337), 241 125(45a),188, 208(46), 217, 224(46), Gottschlich, A., 248, 266(33) 225(46, 257, 261), 228(261), 229(261), Goudet, H., 26(26), 27, 46(26), 165(26) 231(46), 268 Gould, R. O., 347, 348(8)

Fukuda, T., SO, 104(344) Yukuyo, M., 371 Funachashi, S.,316 Fung, D. P. C., 41,43(236)

AUTHOR INDEX Gould, S. E. B., 347. 348(8) Grabers, D. L., 303 Gracey, M., 290 Grafle, E., 317 Grage, U., 149, lSO(781) Gramera, R. E., 217, 221, 222(243), 228(274),229(243, 274, 275, 282), 235 Graves, C . N., 301 Graviss, E. R., 300 Gray, G. M., 287, 288(5) Gray, R. W., 334 Grazi, E., 333, 337, 338 Green, E. A,, 363 Green, J. W., 251, 252(48), 273(152), 274, 277,278 Greenwood, C. T., 39,41(191), 45(191) Greenwood, L. F., 288 Greeves, D., 55, 56, 61(403, 404a) Gregori, C., 307 Cress, M. E., 371 Greve, W., 61, 90(464, 465), 91(464, 465), 98(464,465), 101(464), 106(464) Griffaton, G., 327 Griffith, C . F., 37 Grindley, T. B., 184, 196, 201(l8), 214(18) Gromova, K. G., 297, 331(71) Gros, E. G., 221, 227(267) Gross, B., 98 Gross, H., 68 Gross, R. C., 325 Grotelueschen, R. D., 314 Groves, W. E., 334 Griitzmacher, H. F., 62, 193 Grunnet, N., 318, 320, 321(251), 322 Gryder, R. hl., 341 Gudkova, I. P., 68, 60(569) Gueffroy, D. E., 212(196),213 Guintn, E., 335 Gump, K.-H., 221, 228(271),229(271) Gunsalus, I. C., 333 Gurr, G. E., 347 Gusev, S. S., 43 Guseva, A. V., 41, 43(246), 44(246) Gustafsson, H., 58, 59(437), 77(437), 89(437), 114(437), 116(437), 131(437),165(437), 169(437) Gut, V., 6.5, 75(520), 77(520),79(520), 80(520),82(520), 85(520), 93(520), 110(52O),I I1(52O), If%(520), 169(520),172(520)

389

Gutfreund, H., 334 Guthrie, R. D., 195, 198, 199, 208, 233(306),235, 269, 272 Guy, M. J., 290 Gyorgy, P., 254 Gyurkovics, I., 56, 67(411), 68(411)

H Habermann, J., 26(25), 27 Haga, M., 33, 122(95, 97), 128(97), 146, 147(95, 777), 162, 164(823),165(93), 173(97), 183, 193(13),213, 214(200), 218(200), 219( 183, 200) Hagaman, E. W., 198 Haines, A. H., 191, 195, 208, 221(151), 226(151), 231(151), 237(151), 239(335),240(339),241 Hakomori, S. I., 27, 75(38), 77(38), 79(38), 80(38), 81(38), 82(38), 166(38), 169(38) Halbych, J., 53(384), 54,111(384), 112(384), 114(384), 116(384), 117(384), 120(384), 131(384), 132(384), 141(384), 144(384), 145(384), 175(384) Hall, D. M., 187, 230(36), 232(36), 233(36, 308), 235 Hall, H. K., Jr., 64, 74, 144(503, 628), 175(628) Hall, L. D., 57, 58(423,425,426,427, 428, 429), 59(423, 425, 426, 427, 428), 60, 64, 66(448), 75(448), 80(448), 108(448), 109(448), 111(448), 121(448), 131(447,448), 133(447,448), 134(447,448), 135(508), 169(448), 172(448),195, 197, 198, 199, 201, 202, 217, 219(102), 221, 222(237), 223(102), 224(102), 228(270), 229(237), 234(312), 235, 239(102) Hallman, H., 306(144), 307, 310(144) Hallonquist, E. G., 148 Halpem, Y., 39(215), 40, 41, 42, 43(232), 44, 61(254), 62(254), 63(232), 69(254), 102(254), 152(232) Hainor, T. A., 201 Hampton, A,, 186 Hancock, J . L., 301 Hanessian, S., 191, 206, 207, 209, 213, ZlS(58, 205), 225(20S),229(205), 247, 279

390

AUTHOR INDEX

Hanhart, R. Z., 308,309(163) Hann, R. M., 45, 46(294), SO(283, 288, 289), 63, 64(283, 493), 77(283, 289), 90, 93(288, 289), 104(283),107(289, 706), 112, 114(706), 152(294), 153(294),154(294), 155(294), 161(707), 162(705, 707), 165(288, 289), 166(283), 167(289,708), 168(708), 170(706), 171(283,288, 289, 294), 172(706), 177(294) Hansen, F. V., 291, 321 Hanson, T . E., 311, 312,332 Hanze, A. R., 278 Haq, S., 32, 62(82), 67(82), 165(82) Haraszthy, M., 39, 67, 68(195, 562), 77(195), 165(195) Haraszthy-Papp, M., 56, 66, 67(411, 564), 68 Harata, K., 362 Hardegger, E., 58, 59, 65(432), 66, 75(432), 108(432), 111(443),115, 119(540, 120(443), 136(432,435, 443, 749), 137(435), 138(443),139(432, 435, 443), 141(435, S O ) , 169(432), 172(432, 749), 174(435),175(540), 229(286), 235 Hardin, S., 341 Harding, B. W., 299 Hardy, F. E., 258,269 Harloff, J. C., 159, 161(806) Harrison, R., 269 Hart, J. P., 94 Hart, V. E., 39(207),40, 41,43(230), 44(207, 230), 56(207, 230), 63(230) Hartman, F. C., 334 Hasegawa, A,, 185, 187, 262 Hashizume, T., 213, 218(219),219(219), 239(219) Haskins, W. T., 63, 64(493), 90, 161(705, 707), 162(705, 707) Hasselberger, F. X., 342 Hassinen, I., 318, 320, 343(239) Hastings, A. B., 296 Hata, T., 362 Hatton, L. R., 186, 196(28),2OS(ZS), 216(28), 226(28) Havel, R. J., 328 Hawkins, W. L., 63, 64(292), 77(492) Haworth, W. N., 187,278 Hay, R. W., 244 Hayami, J., 257, 275(93) Hayashi, M., 364

Haylock, C. R., 229(288), 235 Haynes, L. J., 257 Hazen, E. E., Jr., 370 Heap, J. M., 213, 218(221),224(221) Heath, D. F., 295(61), 296 Hegsted, D. M., 317 Heinz, F., 292, 293, 294, 319(36), 324(45), 331(32, 33), 335(32, 33) Heitz, J. R., 341 Helferich, B., 246, 248, 25l(22, 23, 24), 252(22, 23, 24), 265, 266, 273(24, 27) Hems, R., 37(170), 38, 58(170), 60(170), 132(170), 135(170),217, 219(225), 234(312), 235, 297 Hemriech, E., 335 Hendriks, K. B., 267, 275(132) Hendrix, J. E., 26, 39(22), 42(22), 56(22), 69(22) Heritage, C . C., 38( 180), 39 Herman, R. H., 309, 325, 326(277),327, 328 Heimhkova, V., 217, 223(247),229(284), 235 Hers, H. G., 293, 294, 295, 299, 306, 307, 308, 309(162), 319(34), 324(48), 331(56), 335 Hess, K., 54 Hesse, R. H., 64, 135(508) Hestrin, S., 315, 316 Hewson, K., 240(341), 241 Heyns, K., 24, 36, 37(119),45,46(113), 51(5), S6(50), 57, 58(5),59(5,436), 60(5),61, 62, 63(113, 119, 121), 77(119, 121, 470, 471), 89(436), 90(113, 119, 419, 436), 91(419, 436), 93, 94(5, 419, 436, 455, 460), 95(419, 436, 456, 460), 96(5, 419, 455, 456, 460), 97(419, 436), 98, lOO(436, 469), 104(5, 419, 436, 455, 456), 116(436), 126(455), 128, 141(713a),152(113, 119, 121), 153(113, 119, 121), 154(113, 119, 121), 155(113, 119, 121,471), 156(113, 121), 165(419), 166(419), 168(436), 171(419,436), 173(113,455), 177(119, 121), 193, 213, 216(207, 208), 269 Hibbert, H . , 63, 64(492), 77(492), 148 Hibino, Y., 74, 144(626) Hickinbottom, W. J., 256 Hickman, J., 340 Hickman, R. J., 55(406), 56, 61(406) Higuchi, T., 371

AUTHOR INDEX Hilbert, G. E., 39, 41(192), 42, 66, 152(251),153(251), 154(251), 155(251),165(192), 177(251) Hill, A., 232(304), 235 Hill, H. S., 188 Hill, P., 325 Hillbom, M. E., 320 Hilton, F. K., 300 Himeno, H., 262(114), 263 Hingerty, B., 378 Hinojosa, O., 44 Hirano, S., 50, 97, 104(344),207, 214(147) Hirasaka, Y., 159, 162(799) Hirase, S., 75, 90(641), 168(641),221, 228(274),229(274) Hirotsu, F., 371 Hirst, E. L., 37, 58(126), 59(126), 66(126),68(126), 77(126, 146), 170(126) Hixon, R. M., 185 Hjortas, J., 348, 372 Hockett, R. C., 50, 104(345) Hodge, J. E., 189, 190, 192(55), 197, 201, 218(99),219(55, 99), 220(55), 221(52), 226(52), 230(55, 77), 232(52), 233(52), 237(52) Hodges, C. C . , 39(213), 40,41(213), 42(213),43(213), 44(213), 69(213), 77(213), 103(213) Hodgson, K. O., 231(293), 235 Hohne, H., 57, 58(429a), 88(429a), 166(429a) Hoelscher, H. E., 26, 38, 39(12, 13, 171, 172),41(171, 1721, 43(13, 171, 172) Honig. H., 208, 219(149) Hook, J . E., 63, 64(496), 75(496),76(496), 108(496),114(496), 120(496), 169(496), 172(496) Hoschele, G., 46(309), 47, 74(309), 165(309) Hof, O., 341 Hoiness, D. E., 221, 228(269),229(269) Holder, N. L., 217, 221(234) Holdsworth, C. D., 289, 294 Holick, S. A., 32 Holldorf, A,, 293, 319(41) Holldorf, C . , 293, 319(41) Hollenberg, D. H., 221, 225(262) Holly, F. W., 209 Holly, S., 56, 67(412, 413, 414) Holmes, E. W., 323

39 1

Holmes, F. H., 39(211, 214), 40, 41(211, 214), 43(214), 44(211), 63(211, 214), 77(214), 152(2 14), 165(211) Holzer, H., 293, 319 Homer, J., 195 Honda, S., 247, 265 Honeyman, J., 187, 231(296), 235 Honma, T., 90, 257, 259, 260(101, 102), 262, 276(101, 102), 277 Hopfer, U., 290 Hopwood, M. L., 301,302 Hordvik, A., 355 Horecker, B. L., 333, 334(332),335(332, 361, 362, 363), 336, 337, 338, 339, 340 Horton, D., 53, 54, 57, 58, 59(416, 424, 439), 60, 61, 62,63(424),64(439), 70, 74(476), 77(424), 86, 90, 91(415, 418, 424, 475), 92(415, 416, 418, 710), 94(415), 96(468), 97(415, 416, 418, 424, 457, 461, 468), 98, lOO(461, 468), 104(424), 126(439,457), 128(439), 142(449), 143(374,373, 159(582), 162(582), 166(415,424), 171(415,424, 457,468), 174(415, 439), I85,187,188,191(60d), 192,194, 198(89b),199,200,201(89b),206,207, 208, 209, 211(42,43),212(195),213, 214(43, 195), 218(216),219(60d, 216), 225(21), 231(42), 232(42),237(40), 254, 255(66), 372 Honvitz, S. B., 340 Hoskins, D. D., 300, 302, 303, 340 Hostetler, K. Y., 308, 325(159) Hough, L., 37(161), 38, 57, 58(427), 59(427), 60(427), 65(161), 104(161), 122(161),128(161), 161, 173(161), 179(4), 180, 192(65c), 193, 198(89c), 199, 200, 201, 211(186),213, 217, 222(237), 229(237), 243, 244(1) Houminer, Y., 44, 45, 46(291), 63, 70, 143(486),152(272, 291, 299) Howarth, G. B., 206 Hoz, S., 45 Hsu, D. S., 332 Hsu, L. C., 336 Hubert, E., 338 Hudson, C. S., 27, 28(33), 29(30), 30(29, 30), 32(30), 36, 37, 45, 46(294), 50, 63, 64(283, 493), 65, 77(283, 289), 90, 93(288, 289), 94, 104(124,283, 341), 107(289,706), 114(706), 152(33,294),

AUTHOR INDEX

392

153(33, 294), 154(294), 155(294),159, 161(707), 162(705, 707,800), 165(30, 33, 124,288,289, 528, 717), 166(29, 30, 283), 167(289,708), 168(708), 170(706), 171(283,288, 289, 294), 172(706),177(33, 294), 278 Hue, L., 308, 309(162) Hiirzeler-Jucker, E., 50 Hughes, N. A., 63, 86, 90(497), 91(497), 97(497), 166(497), 170(497), 171(497), 184, 204, 205, 211(189), 212(193),213, 214(189), 215(17), 216(189) Hullar, T. L., 69 Hulsmann, W. C., 324 Hulyalkar, R. K., 234(313), 235 Humphries, E. J., 301 Hunedy, F., 192, 212(63), 215(63), 217, 220(232), 236(63, 232, 320), 241 Hunsley, J. R., 334 Hunt, J. N., 288 Hurd, C. D., 67, 165(561) Hunvitz, O., 52(360), 53 Husain, A., 217, 220(232), 236(232) Hutson, D. H., 54, 55(393) Huttunen, J. K., 343 Hvoslef, J., 349 Hylemon, P. B., 314 Hynd, A., 254

I Igarashi, K., 90, 246, 257, 259, 260(101, l02), 262, 276(101, 102), 277 Iitaka, Y., 369 Ikeda, T., 264 Ikenaka, T., 162 Imagawa, T., 277 Inatome, M., 36, 51(107), 67, 165(107) Inch, T. D., 195, 231(291, 293), 235 Ingelfinger, F. J.. 287, 288(5) Ingle, T. R., 221, 228(275), 229(282),235 Inouye, Y., 254(73), 255 Irisawa, J., 90, 257, 259, 260(101, 102), 262, 276(101, 102) Irvine, J. C., 39, 41(188), 47(188), 50(188, 347), 51, 54( 188), 64(188), 67(347), 70, 77(188), 254 Isemura, M., 162 Ishidate, M., 213, 218(218), 278 Ishido, Y., 207, 208

Ishikawa, T., 258, 274 Isidori, A., 304 Isselbacker, K. J., 290(24), 291 Ito, H., 41 Ivanov, M. A,, 52(366), 53, 56(366), 165(366) Ivanov, V. I., 39(218), 40, 41(218), 44(218)

J Jackson, E. L., 50, 104(341) Jain, S. C., 377 James, K., 213, 218(215), 244, 267, 275(132) James, S. P., 64, 65(509), 90(509), 107(509). 118, 122(509),123(509, 753), 128(509),168(509),170(509), 172(509), 173(509),174(509) James, V. J., 360 Jancke, H., 59 Jangaard, N. O., 325 Jann, K., 263 Janson, G., 327 Janson, J., 28 Jarchow, 0. H., 357, 358 Jar$, J., 56, 83(408), 84(408), 106, 107, 143(408), 144(408), 194, 202, 217, 221(236), 223(247), 228(278), 229(278, 284), 235 Jeanes, A. R., 50, 66, 104(343) JeanIoz, D. A., 37(159, 160), 38, 122(159, 160), 173(159, 160), 231(292),235, 259 Jeanloz, R. W., 27, 37, 38, 64,65, 75(38), 77(38, 131, 149), 79(38),80(38), 81(38), 82(38, 512), SS(Sl0, S13), 87(51I), 90(51l), 107(512), 110(513), 112(513),114(511), 120(513),121, 122(159, 160, 511, 512), 124(513), 125(511,513), 126(513), 128(510, 511,512,513), 166(38, 131),167(760), 168(760), 169(39), 170(148, 149), 171, 172(512, 833), 173(159, 160), 174(513), 217, 223(246a),231(292),235, 244, 252, 253, 259 Jedlinski, Z., 237(332), 241 Jeeves, I., 373, 375 Jefferson, L. S., 297 Jefford, T. G . , 315, 316 Jeffrey, G. A., 24, 51, 127(355),154, 201, 345, 348(11), 349, 352, 371

AUTHOR INDEX Jenkins, A. D., 269, 272(144, 145) Jennings, H. J., 33, 34, 131(94),132(94), 258 Jensen, L. H., 354, 372 Jerkeman, P., 278 Jewell, J. S., 57, 58, 59(416, 424, 439), 60(424),61, 62(418), 63(424), 64(439), 77(424), 86, X(415, 418, 424, 439, 457), Yl(415, 418,424), 92(415, 416, 418), 94(415),97(415, 416,418, 424, 457), 98(415, 416, 418, 439, 457), 104(424), 126(439,457), 128(439), 166(415,424), 171(415, 424), 174(415,439, 457) Joassin, G., 306 Jochims, J. C., 59(446), 60 Jodal, I., 206, 225(127), 226(127), 232(127) Johannsmeier, K., 318, 343(237) Johansson, I., 37(169), 38, 53(169), 77, 135(169),162, 165(664) Johnson, D. C., 27, 28(43), 273(152),274 Johnson, L. N., 334, :354 Johnson, P. L., 294 Johnson, R. N., 60, 64, 66(448), 75(448), 80(448), 108(448), 109(448), 111(448),121(448), 131(448), 133(448), 134(448), 135(508), 169(448), 172(448),221, 228(270) Jokii., A,, 217, 222(242) Jones, B. D., 188, 189(48),231(48, 298), 235 Jones, D. W., 376 Jones, E. M., 308, 309(163) Jones, G. H., 229(289), 235 Jones, J. K. N., 33, 37, 39(125),45(1254, 75(125), 77(125), 86(125), 90(125), 131(94), 132(94), 165(125),206, 207, 211(190),213, 236(322),241, 258 Joniak, D., 197 Jordaan, A., 209 Josephson, K., 50(348), 51, 66, 67(348) Joyeux, Y., 316 Joynson, M. A., 334 Jozon, E., 316 Julkkovk, E., 54,55(391) Julikova, O., 80, 111(678),120(678), 124(678), 128(678), 130, 131(678), 173(772) Jung, J . R., Jr., 51, 54(351) Just, E. K., 57, 59(416), 61, 62, W(418,

393

461, 475), 91(418, 475), 92(416, 418), 94(416, 418), %(468), 97(416,418, 468), 98, lOO(461, 468), 171(468)

K Kado, R. T., 298 KAonen, M. T., 320 Kakehi, K., 247, 265 Kakihana, T., 340, 341(410) Kakiki, K., 342 Kaklij, G. S., 334 Kakudo, M., 368 Kalant, H., 317 Kalnin’sh, A., 38(174, 176), 39, 40, 4 1(174) Kalvoda, L., 65, 66, 75, 79(636), 90(636), 101(636), 102(636), 103(636), 114(532c,542), 120, 164(532c,542, 758), 165(636),166(636),167(636), 169(636), 170(636) Kamboj, V. P., 298 Kamel, M. Y., 312 Kamenar, B., 355, 356(27) Kamieliski, L., 159, 161(805) Kamiya, K., 376 Kamiya, S., 252(62), 254 Kamiyama, S., 90, 161(704), 162(704), 167(704) Kane, J. P., 328 Kapitulnik, J., 325 Kaplan, N. O., 340 Kaputskii, F. N., 43 Kar, A. B., 298 Kargin, V. A., 39(210), 40, 41(210), 76 Karmanova, L. S., 76 Karrer, P., 32, 40, 45, 50, 52(360, 361, 362), 53, 66(346), 67(346), 75, 77, 84, 159, 161(805, 806),165(85,293) Kasai, A,, 41 Kashimura, N., 97, 207, 213, 214(147, 197), 218(197) Kato, H., 122, 173(762) Kat6, K., 42, 43, 44, 54(257),69(269, 276), lOZ(255,256,257), 144(255,256, 257) Katz, J. R., 54 Kaufmann, N. A., 325 Kaufmann, U., 308, 309(161),310(161) Keglevii., D., 65 Kekomaki, M. P., 322, 325(259)

394

AUTHOR INDEX

Kelker, N. E., 312, 340 Keller, U., 298 Kellerman, G. M., 299 Kelley, W. N., 323 Kemp, R. G., 339 Kennard, O., 374, 376(80) Kenne, L., 208, 225(152), 227(152), 232(152) Kennedy, E. P., 293, 319(38) Kent, P. W., 86, 201, 212(194),213, 2 16(98) Keppler, H., 256 Kerb, J., SO Kerb-Etzdorf, E., SO Kevill, D. N., 257 Keyes, P. H., 343 Khan, I. H., 330 Khan, R., 209 Kheiri, M. S., 63, 77(481) Khomenkov, A. K., 85 Khorlin, A. Ya., 46(311), 47, 244, 248, 250 Kida, K., 340, 341(410) Kida, Y., 340, 341(410) Kilzer, F. J., 43, 44(261), 102(26l) Kim, H. S., 24, 51, 348(11), 349 Kim, J. C., 203, 218(111), 219(111) Kim, S.-H., 349,352 Kimming, J., 303 King, T. E., 299, 333, 340, 341(424) Kinoshita, T., 122, 173(762),213, 218(218) Kinzer, G. W., 26 Kipnis, V. M., 343 Kirby, R., 27 Kirchner, C . R., 370 Kirsbaums, I., 46, 63 Kirschenlohr, W., 254 Kisic, A,, 37, 63(147), 77(147) Kislitsyn, A. N., 41, 43(246), 44 Kiss, J., 37(150a), 38, 170(150a) Kistenmacher, T. J., 374 Kistler, H., 287 Kitaoka, S., 254(73), 255 Kiyasu, J. Y., 289, 295(15) Kjerulf-Jensen, K., 324 Klar, J., 69(579), 70 Klemer, A., 31, 32(72, 74), 67, 74, 159(72), 165(71, 72), 166(72),246 Klier, M., 69 Klimov, E. M., 32, 47

Klingenberg, M., 318 Klinger, G., 66, 85(546), 169(546) Klyava, Z. Zh., 63 Knauf, A. E., 45, 50(283), 64(283), 77(283), 90(283), 104(283),166(283), 171(283) Knochel, A., 251 Knorr, E., 245, 265 Knox, J. R., 372 Kochetkov, N. K., 32, 47, 62, 68, 69(569), 192(65a,65b), 193,208,244,248,250, 272 Kocourek, J., 179(5), 180, 244 Koebernick, H., 66, 111, 120(537, 741), 121(537,741), 125(741),127(741), 13S(537) Kochling, A,, 255 Koehler, L. H., 27 Kohlin, P., 307 Koll, P., 36, 37(119), 45(113, 116), 46(113, 116), 58, 59(436),61, 62, 63(113, 116, 119, 121), 77(113, 116, 119, 121), 89(436), 90(113, 116, 119, 4361, 91(436), 93, 94(436, 460), 95(436, 456, 460), 96(456, 460), 97(436),98, 100(436,459, 469), 103, 104(436,456), 111(537), 116(436), 120(537), 121(537), 125(537), 133(459),141(713a),143(459), 144(459),145(725), 152, 153(113, 119, 121, 790, 791), 154(113, 119, 121, 791), 155(113, 119, 121, 791), 156(113, 121), 168(436),171(436), 173(113), 177(119, 121, 791) Koenig, H., 75, 77(639) Koenigs, W., 245, 265 Kohn, B. D., 192, 217, 219(226),234(64) Kohn, P., 192, 217, 219(226),234(64), 236(317), 241 Koizumi, K., 257 KolBi-, 66, 125(539), 161(539) Kollmann, M., 36, 37(106), 53(106), 55(106), 59(106), 60(106),61(106), 62(106), 79(106), 90(106), 91(106), 92(106), 102(106), 169(106) Kolodny, S., 39, 65 Komazawa, K., 41 Komburgs, I., 63 Komura, H., 208 Kondo, S., 50, 104(344) Kondo, Y., 191(60f), 192, 217, 219(229)

c.,

AUTHOR INDEX Konishi, F., 252(62), 254 Koob, J. L., 37, 63(147), 77( 147) Kopacka, B., 263 Kopanica, M., 54, 55(391) Kops, J., 74, 144(627), 175(627) Kornfeld, R., 341, 342 Komfeld, S., 342 Kornilov, A. N., 353 Korshak, V. V., 70, 72, 74, 77(593), 165(593) KoSik, M., 40,41, 90(:234) KoSikovi, B., 197 Kostelian, L. I., 74(6:32), 75,85, 86(632), 111(632), 112(632), 114(632), 115(632),120(632), 121(632), 131(632), 141(632), 172(632), 174(632),175(632) Kotake, M., 26 Koto, S., 262, 263, 266 Koto, T., 64(516, 517), 65 Kotow-ycz, G., 194, 195(72a) KovaE, P., 194, 213, 216(211a) Kovsik, V., 194 KovG, J., 106, 202, 217, 222(241), 228(278), 229(278, 284), 235 Kowalevski, Z., 140 Gamer, M. J., 372 Kranhold, J. F., 306(146), 307 Kratowich, N., 337, 339 Krebs, H. A., 297,325 Kreider, L. C., 246 Kreig, N. R., 314 Kretchower, N., 287 Krone, W., 341 Kronzer, F. J., 262, 266, 273(1S3), 274, 27S(1S3), 277(104) Kruckdorfer, K. R., 330 Kriiger, W., 248, 249(37b) Krulwich, T. A., 313,338 Krylova, R. G., 39(205, 210, 216), 40, 41, 42(242, 243), 43(205), 44(216), 45(216) Kubelka, V., 194 Kuehl, R. O., 231(295), 235 Kuge, T., 159, 164(806a) Kuhfittig, G., 54 Kuhlman, R. E., 299 Kuhn, H., 250 Kuhn, L. P., 56, 77 Kuhn, R., 37(166), 38, 104(166),122(166), 128(166), 173(166),254

395

Kuhn, W., 64 Kuhne, H., 61, 90(465), 91(465), 98(465) Kullnig, R. K., 60 Kundig, W., 311 Kuo, P. T., 325 Kurihara, K., 262 Kurokawa, T., 262 Kusaka, T., 293, 319(35), 335(35) Kuzuhara, H., 47, 58(317), 59(317), 122(317),203(112), 204, 212(112), 213, 216(210), 234(112) Kyle, J., 28

L Labhart, A., 297, 306, 307(72), 308(72), 309(72), 310(72), 331(72) Lai, C. Y., 333, 334, 335(332) Lai, Y. Z., 27, 43(44), 44(44), 46, 69(44, 303) Lakshmanan, C. M., 26, 38, 39(12, 13, 171, 172), 41(171, 172), 42(13, 171, 172) Lamers, J. M. J., 324 Lamprecht, W., 293, 319(36) Landau, B. R., 294, 295, 296(47), 308, 32S(159) Landau, R. L., 303 Landor, S. R., 221, 228(272) Langridge, R., 378 Lapenko, V. L., 65, 76, 77(521, 644), 93(521), 221, 228(273) Lardy, H. A., 302, 303, 322, 331 Larsen, B., 348, 372 Larson, R. H., 343 Larsson, L. I., 37, 62(139) Laster, L., 294 Lauterbach, J. H., 208 Lavallee, P., 191, 213, 215(58, 205),

225(205), 229(205) Lawler, T. E., 233(308), 235 Lawton, B. T., 207 Lazdina, B., 72, 76, 165(600,601, 602, 651, 656) Leaback, D. H., 254(74, 75), 255 Lebherz, H. G., 333,334 Lechat, J., 154 Lee, C. K., 50, 58 Lee, E. E., 46(310), 47, 62(310), 74(310), 165(310) Lee, Y. C., 186

396

AUTHOR INDEX

Lees, E. M., 54, 55(392) Lehmann, J., 37, 195, 252(60), 253, 273(60) Lehrfeld, J., 208 Leloir, L. F., 322 Lemieux, R. U., 28, 29, 46(66), 60, 153, 165(66), 191, 194, 195(72a),198, 217, 224(253a),230(59), 243,244, 246, 248, 257, 265, 266,267, 268(133), 272(34), 273, 275(8, 92, 132, 133) Lemonnier, F., 307 Lemprecht, W., 335 Lenz, J., 213, 216(207) Lenze, F., 77 Leonard, N. J., 213, 215(203) Lemer, L. M., 192,210,234(64,314,315), 235, 236(317, 319) Lettinger, F., 45, 90(284), 170(284), 171(284) Leung, F., 51(357),52 Leuthardt, F., 293, 319(37),333 Levdik, I. Yu., 52(366), 53, 56(366), 165(366) Leveille, G. A., 330 Levene, P. A., 122, 173(761),185, 188, 213, 215(206), 217, 224(248), 240(340),241, 278 Levi, I., 63, 64(492), 77(492) Levin, B., 308, 309(154), 310(154) Levy, A., 221, 226(266), 227(266), 239(334), 241, 252,253,273(51, 61) Lewin, M., 41, 63(229, 231) Lewis, D., 210, 230(179) Lewis, G. J., 231(291, 293), 235 Libert, H., 27, 73(45), 77(45) Lichtenthaler, F. W., 104, 106(726, 727) Lieber, C. S., 317 Lieser, T., 54,75, 85(642) Limdolt, M., 287 Limontschew, W., 45,90(284), 170(284), 171(284) Lin, J. W.-P., 73, 74, 77(616), 152, 155(791) Lindberg, B., 27, 28, 29(35), 37(169), 38, 50(56, 57), 53(169), 55, 63, 64(494, 496), 71, 75(496), 76(496),77(494), 108(496), 114(496), 120(497), 135(169), 159, 162, 165(57),169(496), 172(496),278 Lindberg, K. B., 51, 197, 207, 208, 227(76a),348, 372 Lindberg, O., 335

Linden, L., 307 Lindenberger, W. H., 74, 77(617), 163(617) Lindros, K. O., 320 Lineback, D. R., 256 Linnet, T. G., 327 Lintner, M. A., 217, 222(240) Lipska, A. E., 43, 102(260) Liptik, A., 206, 225(127), 226(127), 232(127) Liskowitz, J . W., 44, 45(271) Listowsky, I., 154 Little, C., 339 Little, J. A., 309 Littlemore, L., 55(404a), 56, 61(404a) Lloyd, P. F., 268 Lockhoff, O., 161 Lodge, J. R., 301 Lonngren, J., 192(65d), 193 Loh, D., 306(145, 146), 307 Long, L., Jr., 186, 204(33), 213,216(214), 217, 222(239, 240), 223(239), 224(214), 229(239), 232(33, 301), 233(309),235 Longchambon, F., 350,351(16), 354,355 Longhead, R., 303 Lopez-Castro, A., 372 Lowry, 0. H., 293, 294(43), 302, 325(43), 342 Lowry, R., 327 Lozanova, A. V., 78 Lucas, T. J., 262, 277(107) Luchinskaya, M. G., 217,224(254) Ludowieg, J., 37, 62(140) Liideritz, O., 263 Luetzow, A. E., 206 Luger, P., 350 Lukas, G., 198 Lundborg, H., 294,295 Lundie, P. R., 191 Lundquist, F., 291, 318, 319(238), 320(240),321, 322, 343(236, 238) Lundstrom, H., 38(182), 39,40(182), 41(182),42(182), 43(182),46(182) Luppis, B., 335 Lust, W. D., 303 Lutwak-Mann, C., 299, 303, 316(124) Luiikovi, V., 41, 90(234)

M Macbeth, G., 336, 339(376) McCasland, G. E., 43, 102(260)

AUTHOR INDEX

McCloskey, C. M., 27, 28(32), 29(32), 31(32), 159(32) McCombie, S. W., 93, 143(713) McCord, J. M., 323 McCreath, D., 46(308), 47, 50(308), 51(308),64(308), 77(308),90(308), 168(308),171(308) McCullan, R. K., 362 MacDonald, I., 288, 325 McDonald, J. A,, 323 McDowell, T. D., 314 McGinnis, G. D., 39, 52(194,365,367, 369), 53, 59(367),61(367, 369), 63(194,369), 69(369), 77(194), 81(194), 93(194), 106(194), 114(367), 174(367) McGrath, D., 46(310),47, 62(310), 74(310), 165(310) McGrath, H., 317 Machinami, T., 262 McIntyre, C. R., 38(182), 39, 40(182), 41( 182), 42(182), 43(182),46( 182), 52(371), 53, 146(371) McKay, J. E., 229(287), 235 Mackay, M. I?., 356 McLauchlan, K. A,, 201 MacLeod, J., 304 Macleod, J. M., 37(156), 38, 56(156), 57(156), 58(156), 59(156), 75(156), 77(156),79(156), 80(156), 81(156), 84(156), 108(156), 114(156), 120(156), 140(156), 143(156), 144(I S ) , 168(156), 169(156), 172(156),175(156), 176(156) McLin, P., 306(145), 307 McMurray, C. H., 334 McNab, C. A., 147 McNally, S., 68, 157(567) McNicoll, D., 254 MacovB, J., 66, 108(544), 131(544), 133(544) MacRae, A. R., 290 Madan, V. K. E., 315 Madorsky, S. L., 39(207), 40,41,43(230), 44(207, 230), 56(207, 230), 63(230) Maeda, K., 237(326), 241 Maeda, S., 207 Maenpi%,P. H., 322, 325(259) Mahler, H. R., 317 Mai, L. A., 59, 77(444), 165(444) Makarova-Zemlyanskaya,N. N., 77

397

Makarov-Zemlyanskii, Ya. Ya., 70, 75(591), 165(591) Maki, T., 146, 147(778) Maksimenko, N. S., 38(174, 176),39, 41(174), 76 Malaval, A,, 69 Mallette, L. E., 297 Malysheva, N. N., 47 Mangelson, N. L., 298 Mann, T., 298, 299, 300(79), 301, 303, 316(124), 340, 341(424) Mannering, G. J., 320 Manor, P. C., 362 Manville, J. F., 57, 58(425, 426, 428, 429), 59(425, 426, 428), 60(426, 429), 199 Marchessault, R. H., 51(357), 52 Marcus, F., 336, 337(364), 338 Marfort, A., 159 Mariani, R., 37, 165(143) Mark, C. G., 314 Markova, G. G., 65, 77(521), 93(521) Maron, L., 208, 211(187), 213, 225(152), 227(152), 232(152) Marquardt, R. R., 336 Mkquez, R., 353, 362(22), 372 Marsh, R. E., 363 Marshall, A. G., 198 Marshall, J. S., 308, 325(159) Martin, J. A., 37, 63(147), 77(147) Martin, R. P., 302 Martin, W. J., 46 Martinez-Carrera, S., 371 Martin-Lomas, M., 84, 161, 162(813), 167(687) Martinsson, E., 62 Marvel, J. T., 229(290), 231(290, 295, 300), 235 Marzilli, L. G., 374 Masamune, H., 90, 161(704),162(704), 167(704) Masken, J. F., 302 MaSlinska-Solich, J., 237(332),241 Mass, R. E., 308 Mastronardi, I. O., 227(267) Masura, V., 163 Matschinsky, F., 328 Matsui, M., 67(750, 751), 117, 125(750, 751), 144(750, 751),278 Matsui, T., 69 Matsukura, Y., 376 Matsunaga, J., 159, 162(799)

398

AUTHOR INDEX

Matsushima, Y., 162 Matsuura, K., 207 Matthews, J., 287 Matveev, V. K., 76 Mauss, J., 304 Max, P., Jr., 293, 294(43), 325(43) Mazid, M. A., 371 Mazlen, R. G., 342 Mazurek, M., 55, 198 Medicus, R., 336 Medina, A., 331, 332(323) Mehler, A. H., 334 Mehltretter, C. L., 45, 46(295), 90(295), 152(295), 154(295), 155(295), 177(295) Meinhardt, L., 293, 294(43),325(43) Meisenheimer, K., 279 Melin, K., 307 Melloni, E., 337, 338 Melton, L. D., 229(288), 235 Mendicino, J., 336, 337, 339 Menyhht, M., 68 Merlis, N. M., 39, 40, 42, 44(217),45, 55, 70, 74(593, 632), 75, 76, 77, 84(67l), 85, 86(632), 105(296), 111(632), 112(632), 114(632), 115(632), 120(632), 121(632), 131(632), 141(632), 152(208,250, 296), 1654217, 593), 169(67 1),172(632), 174(632), 175(632), 177(250,296) Merser, C., 75, 125(638), 160(638), 162(638) Messmer, E., 54 Meyborg, H., 152, 153(791),154(791), 155(791), 177(791) Meyer, F., 26 Meyer, G. M., 122, 173(761),185 Meyer zu Reckendorf, W., 58,59(433, 446), 60, 122(433), 191(61), 192, 234(61), 255, 256(80), 269 Meystre, C . , 247 Mian, A. J., 74, 77(622), 80(622), 165(622) Michael, A,, 245 Michaelis, E., 122, 128(766),173(766) Micheel, F., 27, 31, 32,44,45(86),47, 64(86), 67, 77(316), 86, 90(86), 94(86), 122, 128, 129(698),159(72), 165(36, 71, 72, 73, 86),166(72,73) 171(86), 173(766),246, 254, 255, 283 Micheel, H., 32

Michlik, I., 41 Miescher, K., 247 Mikhailov, G. M., 43, 52(263) Mikhant’ev, B. I., 76, 77(644),221, 228(273) Miljkovii., M., 217, 222(242, 245), 233(307), 235, 237(307), 238(307) Miller, B. J., 221, 228(272) Miller, D., 287 Miller, M., 296 Miller, T. B., Jr., 297 Mills, J. A., 35, 55, 182, 184(lo), 199(10) Minakova, V. I., 76 Mine, K., 159 Misato, T., 342 Mitchell, D. L., 204 Mitera, J., 194 Mittag, T . W., 47 Miyai, K., 244 Miyazaki, K., SO Miyazaki, N., 213, 214(197),218(197) Mizuno, K., 364 Mizuno, T., 306(141), 307 Mo, F., 354, 372 Mochalin, B. V., 353 Modi, V. V., 340, 341(416) Moews, P. C., 372 Mofti, A. M., 37(167), 38, 122(167),213, 218(220, 222), 219(220), 239(220) Molinari, E., 46 Montalti, A., 39(202), 40, 41(202) Montgomery, E. M., 27, 28(33), 29(30), 30(29, 30), 32(30), 90(30), 152(33), 153(33), 159, 162(800), 165(30,33), 166(29, 30), 177(33) Montgomery, R., 250 Moon, K. H., 304 Moore, B. W., 294 Moore, L. D., 331 Moore, R. H., 70, 159(582), 162(582) Mootz, D., 362 Moreau, C., 69, 207 Moreno, E., 353, 362(22) Morgan, A. R., 248, 265, 272(34) Morgan, J. W. W., 231(296), 235 Morgenlie, S., 185, 186(24), 194(24),209, 215(24),224(23), 225(23, 24), 229(285),235, 239(24) Mori, M., 162 Mori, S., 90, 257 Morikawa, K., 369

AUTHOR INDEX Moriyama, T., 340, 341(410) Morns, H. P., 341 Morris, R. C., Jr., 306(145, 146),307, 309 Morrison, G. A., 35 Morse, D. E., 334 Morton, B. Z., 302 Mosihuzzaman, M., 189 Moult, J., 359 Mounib, M. S., 302 Muecke, E. C., 340 Muller, D., 62, 193 Muller, F., 27, 50(28), 57(28),64(28), 77(28), 94(28), 165(28) Muller, W. M., 26.5 Muesser, M., 212(195), 213, 214(195) Mufti, K. S., 209 Mukkada, A. J., 336, 338(374) Mullenberg, C. G., 342 Mu~ioz,J. M., 322 Muntz, J. A., 295, 296 Murdoch, R. N., 301, 302 Murray, R. N., 341 Murray, T. P., 48, 49, 59(328),60(328, 329), 62(326, 328, 329), 80(329), 111(329),112(328), 117(329), 124(329),132(326), 140(326), 144(328,329), 145(326,328, 329), 175(326,328, 329) Muskat, I. E., 240(340), 241 Musselman, A. D., 340 Mutti, I., 39(202), 40, 41(202) Myers, A. R., 324 Myers, W. H., 122, 173(763)

N Nadkarni, G. B., 334 Nadkami, S., 217, 225(260) Nageli, C., 52(360),5.3

Nagabhushan, T. L., 244, 266(8), 275(8) Nagai, W., 64,161(501), 162(501) Nagarajan, R., 153 Nagel, F., 65 Nagel, W., 75, 85(642) Nagyvary, J., 370 Naismith, D. J., 330 Naka, T., 213, 218(219), 219(219), 239(219) Nakadate, M., 185, 225(21) Nakagawa, T., 104, 106(726,727), 213, 216(211)

399

Nakajima, M., 228(277), 235, 262 Nakamachi, H., 376 Nakamura, H., 233(305), 235, 376 Nakamura, M., 316 Nakano, T., 340, 341(410) Nakashima, K., 337,339 Nanasi, P., 206, 225(127), 226(127), 232(127) Narayanan, P., 369 Narins, R., 324 Natatsu, K., 364 Naya, Y., 26 Nedlock, J. W., 46 Neiberte, B., 63 Neier, W., 86, 128(698), 129(698) Nelson, J., 318 Nelson, R. L., 239(336), 241 Nerudova, J., 74, 111(629), 120(629), 131(629), 133(629), 134(629), 168(629), 169(629), 172(629) Nesbett, F. B., 296 Nesmeyanov, V. A., 46(311), 47,248, 250 Ness, B. H., 205 Ness, R. K., 28, 259 Neudoerffer, T. S., 290 Neufeld, E. F., 342 Neukom, H., 37(152, 153), 38, 140(152, 153), 17S(152, 153), 176(153) Neuman, A., 350, 351(16), 3.54, 355 Newey, H., 290(24), 291 Newsholme, E. A., 302 Newth, F. H., 37, 38, 75(134), 81, 90(134, 681), 106(134), 108(681), 110(681), 114(681),131(168), 132(168), 165(134), 167(134, 681), 171(134), 172(681),217, 221(233), 257 Nickol, R. G., 209 Nifant’ev, E. E., 68, 69(569), 217, 225(258)

Nikiforuk, G., 322, 323(261) Nikitin, V. N., 52(366), 53, 56(366), 165(366) Nikkila, E. A., 306, 307, 325 Nikolaeva, I. I., 39, 41, 44 Nimgirawath, K., 360 Nishikawa, M., 376 Nishimura, D., 262 Nishimura, M., 213, 218(219),219(219), 239(2 19) Nishimura, T., 264 Nishimura, Y., 262(114), 263

AUTHOR INDEX

400

Nissell, J., 307 Nissen, H.-P., 152, 153(790) Noguchi, T., 41, 43(241), 44241) Nolte, M., 67 Noltemeyer, M., 372 Noordik, J. H., 51, 127(356) Nordiek, H., 67 Nordlie, R. C., 322 Nordmann, Y., 306, 307 Nomnan, B., 84 Nosova, N., 40,42, 84(224), 169(224) Novikova, 0. S., 252(56), 253 Nowak, B. E., 48, 69(324), 140(324), 175(324) Nowoswiat, E. F., 372 Nussli, R., 310 Nuhn, P., 28, 31(47) Nunomura, A., 41 Nutt, R. F., 209

0 Oakes, E. M., 37, 166(142),213, 228(212) Oberholzer, V. G., 308,309( 1S4), 310(154) O’Brien, P. J., 342 Ochiai, H., 254(73), 255 Ochoa, S., 293 O’Colla, P. S., 46(310), 47, 62(310), 74(310), 16S(3 10) Oda, K., 213, 214(198) Odintsov, P., 38(174, 176), 39, 41( 174) Ockerman, P. A., 294,295 Oelz, O., 298 Oertzen, K. V., 221, 228(276) Otvos, L., 92 Ogawa, T., 67(750, 751), 117, 125(750, 751), 144(750, 751) O’Hannession, J., 350, 351(16) Ohashi, Y., 368 Ohle, H., 66, 93 Ohnishi, A,, 42, 43, S4(257), 102(255, 256, 257), 144(255,256, 257) Ohrui, H., 47, 58(317), 59(317), 122(317), 203(112), 204,212(112), 234(112) Ojala, K., 325 Okada, M., 74, 144(626) Okamori, Y., 159, 162, 164(801) O’Kane, D. J., 331 Oldham, J. W. H., 39,41(188), 47(188),

SO(188, 347), 51, S4(188),64(188), 67(347, 556), 70, 77(188) Olds, D. W., 39, 41(192), 42(192), 165(192) Oliver, I. T., 308 Oliver, R. M., 337 Ollis, J., 360 Olson, J. P., 336 Omoto, S., 237(326), 241 Onodera, K., 97, 207, 213, 214(147, 197), 218(197), 2S4(73),255 Oparaeche, N. N., 58, 59(431),62, 75(431), 93(466), 168(431,466), 197, 207, 211(78), 220(78), 226(78), 227(78), 233(78), 237(78),238(78), 239(78) Opitz, W., 128 Orbell, J. D., 373 Orishimo, M. W., 318 Orlando, A., 213,218(223) Orme-Johnson, W. H., 317 Osaki, K., 358 Osawa, T., 65 Osbom, R. H., 304 O’Shea, T., 299, 300(91) Oshin, A,, 290 Ostojic, N., 52(369), 53, 61(369),63(369), 69(369) Otake, T., 264 Ott, H., 250 Ough, L. D., 36, 37(108), 62(108) Overend, W. G., 37(154, 168), 38, 131(168), 132(168), 140, 174(775), 175(IS)176( , 154),202, 209, 210, 243, 244(1) Owen, L. N., 59(702), 90, 136(702), 138(702), 150, 213, 218(221), 224(221), 283 Owen, O., 36, 152(log), 1S3(109) Owens, J. E., 296

P Pacak, J., 36, 37(106), 52(372),53, 54, S5(106),56(382), 58, 59(106, 379, 438), 60, 61(106, 450), 62(106, 379), 63, 64,65, 66, 67(543), 69(372), 74, 75, 76(383), 77(520), 79(106, 520, 636), 80, 81(450), 82(520),85(383, 504, 520), 87(379), 90(106, 636), 91(106), 92(106), 93(383, 520),

AUTHOR INDEX 101(450,636), 102(106, 383, 450, 636), 103(383,450, 636), 104(450), 106(383), 107(438,498, 679), 108(504, 544, 679), 109, 110(520, 679), 111, 112(379,498, 742), 114(382,498, 504, 739, 742), 115(379,438, 504), 116(742), 117(742),118(438, 739), 120, 121(379,381), 122(379),123(438), 124(678,740, 756), 125(379,381, 740, 756), 127(438),128(438, 678), 129(379), 130, 131, 133(380,506, 507, 544, 629), 134(381,545, 629), 135(380,381, 382, 506, 507, 543, 544,545), 141(383, 742, 754), 143(383,450), 144(383,679, 742, 754), 165(636), 166(636),167(636), 168(450,520, 629), 169(106, 504, 520, 629, 636, 679), 170(636), 172(379,498, 504, 506, 520, 629, 739), 173(379,438, 772), 174(438, 740), 175(383, 742, 754), 179(5), 180, 244 Pacsu, E., 39(204), 40, 41(204),244, 278 Page, T. F., Jr., 26 Pakhomov, A. M., 39(206, 216, 217, 218), 40, 41, 44, 45(216, 217), 77(217), 165(217) Palm, J. D., 343 Palmer, R. A., 371 PalovEik, R., 197 Panagiotopoulos, N. C., 92 Panasyuk, V. G., 38(174, 176),39, 41( 174) Panzer, H. P., 217, 225(259) Papenberg, J., 320 Pardini, R. S., 325, 327(294),328 Park, C. R., 297, 328 Park, Y. J., 24, 51, 348(11), 349 Parker, W. J., 43 Parks, R. E., 331 Parrish, F. W., 74, 186, 187, 204(32), 208, 216(38),217, 222(238), 231(38), 232(33, 301), 233(309), 234(238),235, 236(238),237(38) Parry, K., 114 Parsons, M., 298, 300(79) Parthasarathy, R., 373 Pascard-Billy, C., 361, 367, 372 Pashinkin, A. S., 52(364), 53 Passonneau, J. V., 302, 342

401

Pastemak, C . A., 341 Patai, S., 39(215), 40, 41, 43(232), 44, 45, 46(291), 63, 70, 77(232), 143(486), 152(232,272, 291, 299) Patchomik, A., 269, 271 Patrick, C., 336, 339(376) Paulsen, H., 36, 45, 46(113), 57, 58(421, 422,429a), 59(421), 60, 61, 62(113, 453,456), 63(113), 66, 68, 77(113), 87(422), 88(421,422, 429a, 453), 89(453), 90(113, 419, 464, 465), 91(419, 464, 465), 94(419, 455), 95(419, 456), 96(419, 455), 97(419), 98, 101(464), 104(419,455,456), 106(464), 111, 120(537,741), 121(537,538, 741), 125(741), 126(455), 127(741), 128, 135(539), 149, 150, 151(784), 152, 153(113, 791), 154(113, 791), 155(113,422, 791), 156(113), 157(421), 161, 165(419,421, 422), 166(419,422, 429a, 453), 167(422), 171(419), 173(113,455), 177(421,426, 453, 791), 199, 213, 216(208), 217, 218(224), 219(224, 230), 221(230), 223(93), 224(252), 229(224), 234(224),237(230), 269, 350, 357, 358(32) Pawan, G. L. S., 318 Pazel’skaya, K. V., 76 Pearce, G. T., 26 Peat, S., 24, 36, 62(112), 152(log), 153(109) Pecka, J., 53(376, 377), 54, 56(377), 59(376), 61(377), 62(376, 377), 86(377), 103(377), 104(377), 112(376), 114(376), 120(376), 141(376,377), 143(376,377), 144(376,377), 145(376,377), 146(376,377), 175(376,377) Pedersen, C., 46(312, 313), 47, 57(313), 58(313), 59(313), 62(314), 89(312, 313, 314, 315), 165(312,314), 166(312,313), 169(313),202,278, 281 PellC, G., 269 Penco, S., 247 Penglis, A. A. E., 27, 66(45a), 90(45a), 114(45a),125(45a) Penhoet, E., 306(143), 307, 333(143) Perchemlides, P., 65

402

AUTHOR INDEX

Percival, E., 37, 77(146), 239(336),241 Pereira, J. N., 325 Perfilova, G. V., 77, 78(673) Perham, R. N., 335 Perheentupa, J., 306,307, 308, 310(144), 322(156) Perley, M., 343 Perlin, A. S., 37, 61, 62(138), 154, 166(138), 193, 198, 246, 273(28), 279 Pernet, A. G., 191, 215(58) Pemikis, R., 70, 72, 74, 76, 83, 93, 120(620), 165(595, 600, 601, 602, 604,651, 656,684) Perrine, T. D., 28 Perry, A. R., 105, 148(731) Pesai, B. M., 340, 341(416) Petersen, H., 255 Petersen, P. H., 318, 319(238) Peterson, R. N., 301, 302 Petrikovh, M., 213, 216(211a) Petropavlovskii, G. A., 43, 52(263) Petrov, K. A., 217, 225(258) Pettersson, E., 208 Pettit, F. M., 327 Pevzner, N. D., 46 Peyer, J., 77 Pfleiderer, G., 318, 343(237) Phadke, A. M., 304,305 Phelps, C. F., 342 Phibbs, P. V., Jr., 314 Philips, K. D., 58, 59(439), 64(439), 90(439), 98(439), 126(439),128(439), 173(439), 174(439) Philips, P. H., 302 Phillips, F. L., 375 Phillips, M. J., 309 Philpot, C . W., 52(365, 367), 53, 59(367), 61(367), 114(367), 174(367) Pickles, V. A,, 55, 56, 61(403, 404a), 201, 239(101) Picon, M., 39, 45( 197) Pictet, A., 26(26), 27, 38(15), 39, 45(185), 50(185, 186), 65, 66(186), 70, 77(184, 185), 93(518), 94(186), 159, 165(184, 185, 588) Pictet, J., 70 Pidgeon, L. M., 188 Pierce, A. R., 111, 43, 69(267) Pierce, J. V., 37(164), 38, 104(164), 122(164), 128(164), l73( 164) Pigman, W., 229(281), 230(281), 235

Pihl, A., 339 Piotrovsky, J., 212(192), 213 Pitcher, R. G., 372 Pitkanen, E., 306 Pitman, G. B., 26 Pittet, A. O., 256 Plessas, N. R., 206, 209 Pletscher, A., 318, 343(234, 235) PlocovB, D., 120 Pocker, Y., 257 PodeSva, J., 53(380), 54, 60(380),64, 74(380), 80(380, 507), lll(380, 507), 120(380,507), 131, 133(380,507), 135(380,507) Pogell, B. M., 337, 338, 339(398),341 Pola, J., 59 Polenov, V. A., 229(279), 235 Polonsky, J., 37, 165(144) Pongor, G., 32, 165(80) Ponomarenko, E. Yu., 65, 76, 77(521, 644), 93(521), 221, 228(273) Ponpipom, M. M., 213, 215(205), 225(205), 229(205) Pontis, H. G., 315, 316, 331 Pontremoli, S., 333, 334(336),335, 336, 337,338, 339, 340 Poonian, M. S., 372 Poppleton, B. J., 352, 361(20) Porter, C. R., 278 Porter, R. J., 308 Post, M. L., 373, 374, 376(80) Poznanski, R., 325 Prader, A., 287, 297, 306, 307(72), 308(72), 309(72), 310(72),331(72) Pratt, J. W., 36, 37(105, 118), 77(118), 80(118),104(118),140(105), 165(118),175(105), 176(105) Pravdii., N., 65 Preiss, J., 312 Preobrazhenski, N. A,, 217, 224(254) Prey, V., 221, 228(271), 229(271) Prihar, H. S., 90,92(710) PrikylovB, V., 66, 67(543), 135(543) Pringsheim, H., 39, 41(187), 65, 70(187) Prins, W., 70 Prior, A. M., 233(306), 235 Propp, K., 269 Prout, K., 355, 356(27) PrystaS, M., 58, 59, 62(442), 64(442), 65, 66, 75(442),77(437), 89(437), 108(442), 111(442), 114(437,442,

AUTHOR INDEX 532c, 5421, 116(437), 120, 131(437), 164(442,532c, 534, 542, 758), 165(437),169(437,442),172(442,759) Ptak, T. W., 309 Puddington, I. E., 159 Puente, C., 213, 218i223) Purves, C. B., 32, 67(90), 77(90), 278 Pyle, R. E., 208

v Qadir, M. H., 105, 148(731) Quarfordt, S. H., 328 Quastel, J. H., 289 Quinn, E. J., 74, 77(622),80(622), 165(622) Quistorff, B., 322

R Rabelo, J. J., 213, 215(204),216(204) Rabinovich, D., 354 Rabinsohn, Y., 28, 60(51), 62(51), 66(51), 75, 80, 82(680), 83(51),111(635), 121(635), 125(635), 128(635), 159(635, 680), 160(635,680), 161(680), 162(635,680), 166(51), 168(635), 169(51, 635), 255 Rachaman, E. S., 60, 84(454), 159(454), 161(454), 162(454), 167(454), 252(S4), 253 Racker, E., 293, 319(40) Rafal’skii, N. G., 43 Ragg, P. L., 59(702), 90, 136(702), 138(702) Rainer, M. E., 340 Raivio, K. O., 306(147),307,308,322(156, 259, 260) Rajagopolan, G. T., 337 Rajkumar, T., 306(143), 307, 333(143) Rajkumar, T. V., 334 Ramsden, H. E., SO, 104(345) Randall, M. H., 37, 196, 236(321),241 Ranganayakulu, K., 49, 60(329),62, 80(329), 111(329),112(333), 117(329), 124(329),144(329), 145(329,467), 175(329) Rao, G. J. S., 337 Rapin, A. M. C., 27, 64,65(513), 75(38), 77(38),79(38),80(38),81(38),82(38), 85(513), 110(513), 112(513),

403

120(513), 124(513), 125(513), 126(513), 128(513), 166(38),169(38), 174(513) Rapoport, G., 316,334 Rake, K., 265 Rasmussen, P., 281 Ratovelomanana, V., 229(283),235 Rauther, J., 250 Ray, P. K., 213, 218(215) Raymond, A. L., 278 Reaven, G. M., 325 Redaelli, S., 247 Reddy, B. S., 368 Redetzki, H., 318, 343(237) Reed, L. J., 327 Rees, B. H., 210, 218(178) Rees, D. A,, 37, 58(126), 59(126), 63, 66(126), 68(126), 77(126,484), 170(126), 347, 348(8) Rees, R. G., 190, 192(56), 197(56) Reese, E. T., 74 Reeves, R. E., 28, 35, 37(48), 51, 54, 90(48),154, 165(48, 349, 389), 168(48), 169(48), 170(48), 177(796), 332 Reichel, F. H., 65, 93(518) Reichel, L., 65 Reichstein, T., 36, 37, 38, 50(123), 65(123, 133), 82(123), 94(123), 140, 166(123), 170(123), 175(151), 176(151) Reilly, J., 44, 45, 77(292) Reinhardt, R., 350 Reinking, K., 47, 77(316) Reiser, V., 40, 41, 90(234) Reisner, S. H., 307, 308(151),310(151) Reist, E. J., 212(196), 213 Rendleman, J. A., Jr., 54, 55, 56 Rennecke, R.-W., 61, 62, 93, 98(713a), lOO(459, 469), 103, 133(459), 141(713a),143(459), 144(459), 14S(725) Renold, A. E., 296 Rensing, U., 333 Restall, B. J., 302 Reyes-Zamora, C . , 28, 31(63) Reynolds, C. D., 373, 37.5 Reynolds, D. D., 246, 273(26) Reznichek, R. C., 298 Rhind-Tutt, A. J., 273, 274 Ribaldi, M., 37, 165(144)

404

AUTHOR INDEX

Ricci, C., 333, 334(336) Rich, A., 377 Richards, C . M., 37(157), 38, 140(157) Richardson, A. C., 53(378), 54, 58, 87, 104(378, 700), lOS(378, 700), 125(378, 700), 126(378), 128(378), 161, 173(378, 700), 174(378),179(4), 180, 192(65c), 193, 198(89c),199, 211(186), 213, 243, 244(1) Riche, C . , 361 Richtmyer, N. K., 27, 28, 29(30, 39), 30(20, 30, 39), 32(30), 36, 37, 50(122),55(114), 62(54), 65, 66(122), 77, 80(118), 81(122), 90(30, l l l ) , 94, 104(118, 124, 122), 112, 140(105), 152(33, 114, 115),153(33, 114), 154, 155(114), 159, 162(800),165(30,33, 114, 118, 528, 664, 717), 166(29,30, 122), 169(122), 171(111),175(105), 176(105),177(33, 114) Riedel, T., 86, 128(698), 129(698) Rieder, S. V., 333, 334(335) Riffer, R., 42, 61(254), 62(254), 69(254), 102(254) Riklis, E., 289 Riley, S. E., 328(305), 329(305),330 Riordan, J. F., 338 Rist, C . E., 75, 77(640), 208, 210 Ristii., P., 31, 32(72), 159(72), 165(72), 166(72) Ritchie, R. G. S., 61 Ritter, A,, 77 Ritzl, F. E., 335 Rivest, R., 347 Roberts, E. J., 208 Roberts, E. V. E., 147 Roberts, G. A. F., 269, 272(145) Roberts, G. P., 268 Robertson, G. J., 37, 122, 173(763) Robic, D., 252(52), 253, 265(52) Robinson, D. S., 328, 329(305),330 Robinson, N., 203, 234(108, 310, 311), 235 Robinson, R., 71, 166(597) Roderig, C., 41 Rodionova, Z. M., 41, 43(246), 44(246) Rbhle, G., 243, 244(l),246(If), 248, 249(37b), 253, 254 Rohwer, R. G., 36, 37(108), 62(108) Rollins, A. J., 217, 224(251) Romano, A. H., 314

Romsos, D. R., 330 Rose, C . S., 254 Rose, I. A,, 333, 334(335) Roseman, S., 311, 341 Rosen, G., 287 Rosen, 0. M., 336, 337, 338(371) Rosen, S. M., 336, 337 Rosenberg, J. S., 337 Rosenberg, L., 290, 291 Rosenstein, R. D., 349, 363 Rosenthal, A., 37(157), 38, 140(157) Rosenthal, I. M., 307, 308(151),310(151) Ross, B. D., 297 Ross, J. H., 70, lSS(S88) Rossinskaya, G. A., 46 Roth, W., 229(281), 230(281),235 Rouse, J. P., 370 Roussel, J. D., 298 Rowland, S. P., 208, 221, 228(269), 229(269) Rowley, P. T., 333 Roy, N., 162 Rozen, R., 327 Rubino, A., 287 Ruckel, E. R., 59, 63(441), 73, 74(441), 77(441) Rudolph, G., 251 Ruffini, G., 208 Rugg, P. W., 376 Russell, C . R., 208 Rutherford, P. P., 315 Rutter, W. J., 306(143), 307, 333, 334 Ryan, A. E., 140, 174(775) Ryan, K. J., 211(188),213 S

Sabater, B., 314 Saenger, W., 362, 372 Saier, M. H., Jr., 311 Sakai, F., 43, 69(269) Saldadze, K. M., 39 Salisbury, G. W., 301 Salomon, H. R., 85 Saman, E., 202 Samaut, N. R., 304, 305 Samisoni, J. I., 340 Samoilova, N. A,, 217, 224(254) Samols, E., 308 Samuel, J. W. B., 63, 77(484) Samuels, L. T., 299

AUTHOR INDEX

Samuelson, O., 37, 62 SBnchez, J. J., 331 Sandermann, W., 38(175), 39, 40, 41(212),44(212), 45(212), 52(175, 212), 69(212) Sanderson, G. R., 37, 62(138), 166(138) Sanner, T., 339 Sano, H., 282 Sapico, V., 332 Sarasin, J., 26, 38(141, 39,45(185), 50(185), 77(184, 185), 165(184, 185) Samgadharan, M. G., 337,338,339(398) Sartirana, M. L., 336 Sasada, Y., 368 Sato, A., 122, 173(762) Sato, K., 336 Sato, M., 161 Sato, S., 362 Sato, T., 378 Satzke, L. 0. G., 356 Sauberlich, H. E., 325,327(294), 328(294) Saunders, R. M., 237(331),241 Saunders, S. J., 290(25), 291 Savin, V. A., 76 Savinych, V. I., 41, 43(246),44(246) Sawardeker, J. S., 39, 40(190), 41(190), 63(190), 77(190), 152(190),155(190), 165(190) Scala, J., 336, 339(376) Schaffer, R., 203,212(191), 213 Schapira, F., 306, 307 Schapira, G., 306(140), 307 Scharmann, H., 62, 77(470,471), 155(471),193 Schiff, H., 26(24), 27,46(24) Schilegel, F., 292, 293(32), 331(32, 33), 335(32, 33) Schindler, O., 140 Schinen, C., 303 Schiweck, H., 65 Schlegel, H. G., 312,336 Schlubnach, H. H., 279 Schmalz, K., 39, 41( 187), 70(187) Schmid, A., 333 Schmid, D. M., 64,85(510), 128(510) Schmidt, H. W. H., 37(152, 153), 38, 14q152, 153), 143(153), 175(152, 153), 176(153) Schmidt, 0. T., 66,85(546), 169(546) Schmitt, F., 75, 83(633), 85(633), 120(633),124(633), 128(633),

405

160(633), 161(633),162(633), 173(633) Schneider, G., 293, 319(41) Schneider, J., 186 Schneider, J. J., 247 Schneider, S., 319 Schneider, W. G., 60 Schraml, J., 59 Schrank, W. W., 340 Schrijder, B., 161 Schroeder, L. R., 37(156), 38,56(156), 57(156), 58(156), 59(156), 75(156), 77(156), 79(156), 80(156), 81(156), 84(156), 108(156), 114(156), 120(15% 140(156), 143(156), 144( 156), 168(IS), 169(156), 172(156), 175(156), 176(156),251, 252(48), 273(152), 274 Schuchardt, W., 50 Schiiep, W., 58, 59(435), 136(435), 137(435), 139(435), 141(435), 174(435) Schuerch, C., 27, 59, 63(441),65, 69(580, 581), 70, 71, 73, 74, 75(536), 77(45, 441, 536, 613, 615, 616, 617, 622), 80(622), 152, 155(791), 163, 165(598, 622), 168(598),262, 266, 269, 273(140, 141, 153),274, 275, 277 Schultek, T., 103, 145(725) Schulk, D. W., 342 Schultz, S. G., 290 Schwarcz, J. A., 193, 198 Schwarz, J. C. P., 147 Schwenker, R. F., Jr., 39(204),40, 41(204), 63 Sciarra, F., 304 Scott, R. W., 315, 316 Scott, W. E., 347, 348(8) Seeman, N. C., 113,377 Segal, H. L., 323 Segal, S., 290, 291 Segel, N., 328 Seib, P. A., 28, 32, 37(155, 156), 38, 43, 44(264), 53(155),56(52, 156), 57(52, 155, 156), 58(50,52, 155, 156, 264), 59(52, 155, 156, 264), sO(50, 52, 155, 264), 62(155), 63,64(50,264,483), 70(483), 71(483), 72(483), 75(156), 77(156, 483), 79(52), 80(155, 156), 81(156), 84(52, 156),94(52), 96(52), 100(52), 101(52), 102(155),108(155,

406

AUTHOR INDEX

156), 111(52, 155), 112(155),114(155, 156), 115(155),118(155),119(155), 120(52, 155, 156, 264), 140(156), 141(155), 143(155, 156), 144(155, 156, 483), 146(83), 147(83),159(52), 160(552), 162(52), 165(483),166(50, 483), 168(52, 155,483), 169(50, 52, 155, 156, 264, 483), 172(52, 155, 156), 174(483), 175(155, 156), 176(155, 156), 208 Seiberlich, J., 54 Seligman, A. M., 278 Selleby, L., 162 Semenza, G., 287 Sen, S. K., 229(290), 231(290, 300), 235 Senma, M., 358 Sepulchre, A.-M., 198 Serdyuk, 0. G., 28 Sergeev, V. A., 70, 74, 76, 77(593), 165(593,600, 601) Sergeeva, V. N., 38(174, 176), 39,40, 41(174), 63 Seshadri, T. P., 373, 374, 376(80) Sestoft, L., 291, 320, 321, 322 Seymour, F. R., 237(325), 241 Shaban, M. A. E., 252(55), 253,259 Shafir, E., 330 Shafizadeh, F., 26(23), 27, 38(182), 39, 40, 41, 42(182), 43(23, 44, 182, 235), 44(23,44, 225, 235), 46, 52(194, 225, 365, 367, 369, 370, 371), 53, 59(367), 61(225, 367, 368, 369), 63(194, 369), 69(23, 44, 225, 303, 369), 70(235), 76, 77(194, 235,643), 81(1%),93(194), 103, 106(194), 114(367),144(367), 146(371), 174(367) Shah, V. K., 340, 341(416) Shallenberger, R. S., 50 Shank, D. M., 328 Shapiro, D., 28, 60, 62(51), 66(51), 75, 80, 82(680), 83(51), 84(454), 111(635), 121(635), 125(635), 128(635), 159, 160(635,680, 810), 161(454, 680, 811), 162(454,635, 680, 811, 812), 166(51), 167(454), 168(635), 169(51, 635), 252(53), 253, 255 Shapiro, S., 335(363), 336, 338, 339(397) Shaposhchnikova, E. B., 67 Shargo, E., 322

Sharon, N., 221, 226(266), 227(266), 239(334), 241, 252, 253, 273(51, 61) Shasha, B. S., 208 Shashtaeva, M. V., 76 Shaw, C . J. G., 39(211), 40, 41(211), 44(211), 63(211), 165(211) Shaw, D. F., 35, 36(104), 50(104),55 Shaw, G., 376 Shchegolev, A. A,, 217, 225(258) Sheldrick, B., 371, 372(61) Shen, T. Y., 150 Shen Han, T. M., 254 Shimada, A., 371 Shimadate, T., 278 Shimamoto, K., 340, 341(410) Shiner, V. J., 317 Shiono, R., 363 Shneer, R. Ya., 70, 74(593), 77(593), 165(593) Shoemaker, W. C., 289 Shorygin, P. P., 77 Shorygina, N. N., 37, 45, 75, 77, 78, 90(286, 290), 165(290),166(128), 171(286),173(674) Shubhada, D. D., 304,305 Shull, K. H., 324 Sia, C . L., 337 Signst-Nelson, K., 290 Silbennan, H. C., 36 Sillero, A,, 293 Sillero, M. A. G., 293 Silverstein, R. M., 26 Sinay, P., 75, 83(633), 85(633), 120(633), 124(633), 128(633, 638), 160(633, 638), 161(633), 162(633, 638), 173(633) Singh, P. P., 204, 206, 225(120),226(120) Singh, U . P., 49, 57(332),58(331, 332), 59(328, 332), 60(328, 329), 62(328, 329, 331, 332), 80(329), 111(329), 112(328,330, 331), 115(331), 117(329),118(330, 331), 119(331), 141(329),144(328), 145(328,329, 330), 146(330,331), 165(331,332), 167(332), 168(332), 169(331), 172(331),175(328,331) Sinke, G. C., 52(363), 53 Sinnott, M. L., 50 Sinnwell, V., 61, 98, 357, 358(32) Sinou, D., 48

AUTHOR INDEX Sivakumaran, T., 211(190), 213 Skapski, A. C., 373, :374, 375 Slein. M. W., 293 Slessor, K. N., 162, 191(60e), 192, 201, 202(102),219(102),221(102),223(102), 224(60e, 102), 229(288), 234(60e), 235, 236(60e), 239(102), 346 Sloneker, J. H., 39, 40(190), 41(190), 63(190), 77(190), 152(190),155(190), 165(190) Smejkal, J., 65, 66(535) Smimoff, A. P., 32, 50, 66(346),67(346), 165(85) Smith, D., 314 Smith. F., 46(308), 47, 50(308),51(308), 64, 65(509), 77(308), 90(308, 509), 107(509),118,122(509),123(509,753), 128(509), 168(308, 509), 170(509), 171(308), 172(509, 173(509), 174(509),243(3), 244 Smith, G. W., 52(368), 53, 61(368) Smith, J. D., 334 Smith, M. G., 340 Smith, W. R., 308 Smrt, J., 186, 188(31) Smyth, D. H., 287,290(24), 291 Snodgrass, G., 308, 309(I S ) , 310(154) Snyatkova, V. I., 250, 272 Sobel, M. E., 313 Sobell, H. M., 377 Sobell, M., 202 Soling, H. D., 327 Soff, K., 63,64(491),65,66, 162 (491,552) Sokolovskaya, T. A., 250 Soldat, W.-D., 36, 63(121), 77(121), I52(121), 153(121), 1S4(121), 155(121),156(121), 177(121) Solov’eva, L. V., 43 Sols, A,, 293, 295, 331, 332(323) Soltes, E. J., 122, 173(762) Somersalo, D., 306 Sommar, K. M., 341, 342 Sorkin, E., 36,37, 38(133), SO(123), 65(123, 133), 82(123), 94(123), 166(123), 170(123) Sorm, F., 58, 59, 62(442), 65, 66, 75(442), 77(437),89(437), 108(442),111(442), 114(437,442, 532c, 542), 116(437), 120, 131(437), 164(442,532c, 542,

407

758), 165(437),169(437,442),172(442, 759) Sorokin, I. S., 26, 38(177), 39, 42(10) Soukupovk, V., 74(630, 631), 75, 120(630),131(630, 631), 132(630), 141(630,631), 142(630,631), 174(631) Sowa, W., 206, 213, 214(201),216(201) Sowden, J. M., 376 Sozmen, M., 27, 45, 77(287) Speakman, P. R. H., 184, 204,211(189), 212(193), 213, 214(189), 215(17), 216(189) Spencker, K., 66, 93 Spichtig, A. M., 217, 221(235) Spolter, P. D., 296,297(62),306(148),307, 327(62) Spoors, J. W., 281 Spriestersbach, D., 243(3), 244 Srivastava, R. M., 48, 60(327), 112(327), 117(327),132(327), 144(327), 145(327) Stacey, B. E., 183, 193(14),219(14) Stacey, M., 37(158, 165, 167), 38,64, 65(509), 104(158, 165), 109(509), 118, 122(158,165,167,509), 123(509,753), 128(165, 509), 168(509),170(509), 172(509), 173(158, 165, 509), 174(509),217, 224(253), 231(298), 234(253),23.5, 236(230), 241, 254, 255(66), 268 Stadler, P., 61, 98, 357, 358(32) Stamm, 0. A., 187, 230(36), 232(36), 233(36) StanBk, J., 24, 52(372), 53, 60, 61(450), 64,69(372), 81(450), 85(504), 101(450),102(4S0), 103(450), 104(450), 108(504), 111(504), 114(504), 115(504), 120, 141(754), 143(450), 144(754), 168(450), 169(504), 172(504), 175(754), 179(56), 180, 244 StanBk, J., Jr., 53(377, 383), 54, 56, 61(377), 62(377), 75(383), 76(383), 80, 83(408), 84(408),85(383), 86(377), 93(383), 102(383),103, 104(377),106, 107, 108(679,737), 110(679),111(679), 139(723), 140(723),141(377, 383), 143(377, 383, 408), 144(383, 408, 679),

408

AUTHOR INDEX

Strange, R. E., 341 145(377), 146(377), 169(679), Straus, S., 39(207), 40, 41, 43(230), 172(737),176(723), 177(377,383) 44(207, 230), 56(207, 230),63(230) Stanislowski, A. G., 370 Stribling, D., 335 Stanwick, J. J. J., 41 StropovP, D., 53(381), 54, 59(381), Staub, A. M., 263 60(381), 66, 120(381), 125(381), Staub, A. P. A., 207 134(381,545), 135(381) Staub, H . , 318, 343(234, 235) Stuber, H. W., 306 Staub, M., 40 Stull, D. R., 52(363), 53 Stecker, C., 290 Stute, R., 45 Steeno, O., 303 Suami, T., 262, 264 StehliEek, J., 269, 272(144) Subramanian, E., 378 Stein, Y., 325, 327(288) Suckfull, F., 283 Steinberg, D., 328 Sudoh, R., 213, 216(211) Steinbrunn, G., 64 Steiner, D. J., 342 Sugisawa, H., 45, 46, 55(301),62(297, 30 1) Steiner, K., 229(286), 235 Sullivan, R. J., 324 Steiner, P. R., 202 Sumfleth, B., 161 Steinert, K., 128 Sumi, K., 41, 43, 63(258), 102(258), Stellman, S. D., 378 Stenzel, W., 66, 111(537), 120(537), 152(258) 121(537, 538), 135(539),161 Sumitomo, H., 74, 144(626) Sundaralingam, M., 345 Stepanenko, B. N., 28 Suma, J., 70, 72, 74, 76, 83, 93, 120(620), Stephens, D. T., 302,303 165(595,600, 601, 602, 604, 651, Stephenson, N. C., 349,352 656, 684) Stemglanz, H., 365 Susott, R. A,, 46, 52(365, 367, 370, 371), Steuck, M. J., 74, 144(628),175(628) 53, 59(367), 61(367), 69(303), Stevens, J. D., 183, 233(11), 279, 349, 352, 360, 370 114(367), 144(367), 146(371), Stewart, L. C., 36, 37(122), 50(122), 174(367) Suyter, M., 293, 319(39) 65(122), 66(122), 77(122),81(122), Svedsen, I., 318, 319(238) 90(111), 104(122), 154, 166(122), Svensson, I.-L., 207 169(122), 171(111) Svensson, S., 192(65d), 193, 206, 208, Stick, R. V., 217, 224(253a),267, 225(152), 227(152), 232(134, 152) 27S(132) Swahn, C.-G., 197, 211(187),213, Stifel, F. B., 325, 326(277),327(277) 227(76a) Stiller, E. T., 188, 213, 215(206) Swan, B., 55 Stimmler, L., 308, 309(154),310(154) Stima, U., 70,72,76,83,165(604,656,684) Sweet, F., 48, 49(325), 57(325),59(325), Stocker, B. A. D., 263 60(325), 62(325), 112(325), 117(325), 132(325),140(325), 144(325), Stoddart, J. F., 179, 183(2), 198(2) 145(325), 175(325) Stoffyn, A., 221, 226(265), 227(265) Szabo, I. F., 68 Stoffyn, P. J., 27, 37, 64,77(131, 149), Szalda, D. J., 374 85(5lo), 90(37), 114(51l),12l(51l), Szarek, W. A,, 184, 196, 201(18),206, 122(511), 128(510, 511),165(37), 207, 214(18), 236(322), 241 166(131), 170(149), 171, 172(833), Szechner, B., 103 212(192), 213, 217,221, 223(246a), Szepesi, B., 301 226(265), 227(265) Stout, E. I., 208 T Stoye, D., 213, 217, 218(224),219(224, Taga, T., 358 230), 221(230), 229(224),234(224), Taha, M. I., 122, 173(762) 237(230)

AUTHOR INDEX Taigel, G., S9(446),60 Takagi, E., 42,43,54(257),102(25S,256,

257),144(255,256,257) Takahashi, N.,44 Takahashi, S.,228(277),235 Takahashi, Y., 282 Takamoto, T., 213,216(211) Takano, M.,183,193(13),213,214(200), 218(200),219(13,200) Takeda, T., 368 Takeo, K., 159,164(806a) Taketa, K., 338,339(398) Takita, T., 237(326),241 Takiura, K., 247,265 Tamura, C., 362 Tamura, Z., 213,218(218) Tanret, G., 25,27,50(6,27), 51(27),64(27), 77(6,27),165(6,27),315 Tarasieiska-Glazer, Z., 37(159),38, 122(150),173(159) Tamopol’skii, B. L., 357 Tash, J. S., 303 Tashima, Y.,337 Tatchell, A. R., 190,192(56),197(56), 213,218(215),221,228(272) Tatsuta, K., 262,263 Taylor, N.F., 47,60(319), 74(319),75(319), 86,131(319), 132(319),140 Tchola, O., 333 Tejima, S., 33,122(95,97),128(97),146, 147(95,777,778),159,161(802),162, 164,165(93),173(97),183,193(13), 213,214(200),218(200),219(13,200), 233(305),235 Tenu, J.-P., 50 Terejama, H., 203(112),204,212(112), 234(112) Terekhov, V. G., 217,225(258) Terzis, A., 347 Thanomkul, S., 348,372 Theander, O., 28,50(57),162,165(57), 203(113),204,207,213,218(217), 228(217) Their, S., 290,291 Theorell, H., 317,322 Thieden, H. I. D., 319,320,321(251), 322 Thiem, J., 251 Tholey, G., 337 Thomas, L. F., 195 Thomas, W., 114

409

Thompson, A., 36,40,51(107),63,

64(495),67,70,159(582),162(582), 16S(107,495), 256 Thornton, E. R.,275 Threlfall, C. J., 295(61),296 Thurston, J. H., 308,309(163) Tikhomirov, M.M., 248 Timell, T. E., 162 Tindall, C. G., Jr., 191(6Od),192,213, 218(216),219(60d,216) Tinell, R., 263 Tipson, R. S.,203(115),204 Tishchenko, D. V., 26,38(10,177),39(203), 40,41(203),42(10),77,84(224), 169(224) ToMk, Z., S3(380),54, 60(380),64, 74(380),80(380),107,111(380), 120(380,506),131(380,506), 133(380,506),135(380,506), 172(506) Todt, K., 149,150,151(784),213, 216(208) Tbnnesen, K., 291,321 Torgov, V. I., 47 Toni, K., 369 Tork, L., 67 Tosi, R., 287 Totok, L., 304 Tracey, A. S.,191(60e),192,201,202(102), 219(102),221(102),223(102), 224(60e, 102),229(288),234(60e), 235,236(60e),239(102) Traniello, S., 335,336,337,338,339(397) Tret’yakova, G. S., 67 Triggle, D. J., 105 Trnka, T., 53(382,384),54, 56(382),58, 59(438),62,63,64(498),74(498), 75(479),77(479),80(498),86, 107(438,498,699),108(479), 109(479), lll(384,438,479,498), 112(384,498),113,114,115(438), 116(384),117(384,479),118(438, 479),119(479,746),120,123(438, 757),124(757),127(438),128(438, 757),131(384),132(384,699), 133(699),135(382),141(384,746), 143(746), 144(384),145(382,384), 172(479,498),173(438,757), 174(438,479,746),175(384,746) Tronchet, J. M. J., 185,200,209,225(21), 237(333),239(333),241

410

AUTHOR INDEX

Truchly, J., 27, 165(41) Trujillo, J. L., 343 Tmpp, J. H., 288 Trus, B. L., 363 Tsai, C., 377 Tsai, C. S., 28, 31(63) Tse, J., 37 Tsolas, O., 333, 334(332), 335(332) TSOU,K.-C., 278 Tsuboi, M., 369 Tsuchiya, T., 282 Tsuchiya, Y., 41, 43, 63(258), 102(258), 152(258) Tsuiki, S., 336 Tsumura, T., 262,263 Tu, C. C., 74 Tuchsen, E., 341 Tucker, L. C. N., 77, 80(662),82(662), 86(662), 165(662), 168(662),192, 212(63), 213, 215(63), 217, 218(220), 219(220),224(250), 236(63),239(220) Tucker, P. W., 370 Tulloch, A. P., 232(304), 235 Turk, L. N., 289 Turner, L. J., 288 Turunen, J., 63 Turunen, K., 63 Tygstrup, N., 291, 319,320, 321 Typer, Z. T., 305

U Uchida, T., 64(516, 517), 65, 266 Ueki, I., 306(145), 307 Umenura, Y., 316 Umezawa, S., 237(326),241, 262, 263, 282 Unaka, F. T., 231(300), 235 Unkovskii, B. V., 353 Unrau, A. M., 237(328), 241 Urbas, B., 150 Uryu, T., 27, 73, 77(45) Usov, A. I., 208 Usteri, E., 75, 77(639) V Vaishwanar, P. S., 301 Valatin, T., 45, 56(282), 64(282), 67(282), 77(282), 166(282) Vallee, B. L., 338 Valueva, S. P., 76

Van Cleve, J. W., 210 van de Kamp, F.-P., 254 van Es, T., 213, 215(204), 216(204) VanHarken, D. R., 320 Vanko, M., 295,296 van Tamelen, E. E., 37(164), 38, 104(164), 122(164), 128(164), 173(164) Van Tol, A,, 337 Vardheim, S. V., 37(158, 165),38, 104(158, 165), 122(158, 165), 128(158, 165), 173(158, 165) Vargha, L., 217, 222(244) Vasella, A., 217, 221(235) Vasil’eva, G. G., 43, 52(263) Vasil’eva, N. L., 76, 77(644) Vasyunina, N. A,, 69 Vegh, L., 58, 59, 65(432), 66, 75(432), 108(432),111(443), 115, 119(540), 120(443), 136(432,443, 749), 138(443), 139(432,443), 141(540), 169(432), 172(432, 749), 175(540) Veiga, L. A., 336 Veksler, V. I., 213, 216(209) Veneziale, C. M., 297 Venn, H. J. P., 39, 41(201) VereS, K., 74(630, 631), 75, 120(630), 131(630,631), 132(630),141(630, 631), 142(630, 631), 174(631) Verheijden, J. P., 212(192),213 Vernon, C. A., 273, 274 VeruoviE, B., 69(580),70, 163 Vethaviyasar, N., 244 VeyriBres, A., 217, 224(249), 252(59), 253 Veyssi&res-Rambaud,S., 148 Vignon, M. R., 252(58), 253 Vincent, T. N., 289 Vis, E., 77, 278 Viscontini, M., SO Viswamitra, M. A,, 368, 373, 374, 376(80) Vitale, J. J., 317 VitB, J. P., 26 Voelter, W., 54 Volf, J., 64 Volkova, L. V., 217, 224(254) Volodina, Z. V., 39(208),40, 42,45, 77, 84(671), 105(296), 152(208,250, 296), 169(671), 177(250,296) Vongerichten, E., 27, 50(28),57(28), 64(28),77(28), 94(28), 165(28) von Hochstetter, H., 64

AUTHOR INDEX von blechel, L., 266 von Schuching, S., 203(116), 204, 2 L6(116) Von Wartburg, J. P., 317, 320 Vorontsova, L. G., 357 Voznyi, Ya. V., 64, 11 1(499), 120(499), 121(499), 169(499) Vyacheslavova, L. V., 43 W Wacek, A. v., 38(173), 39,40,45, 77(222) 90(284), 170(284), 171(284) Wacker, W. E. C., 338 Wada, H., 213, 214(198) Wada, T., 340, 341(410) Wada, Y., 376 Waddell, M., 325, 328(292) Wade, C. P., 221, 228(269), 229(269) Walti, A., 52(360), 53 Wagler, M., 28, 62(55) Wagner, A., 250, 372 Wagner, G., 28, 31(47, 65), 62(55) Wagner, H., 38( 173), 39, 40, 77(222) Wagstaff, A. I., 46(308), 47, 50(308), 51(308), 64(308), 77(308), 90(308), 168(308),171(308) Wales, R. G., 299, 300(91),301, 302 Walker, D. G., 295, 331(57) Walker, P. G., 254(74, 754, 255 Wallace, J. C., 302 Wallin, N. H., 237(327), 241 Walsh, J. R., 308 Walter, E., 209 Walton, A,, 301 Wander, J. D., 54, 57, 59(416), 61(416), 62, 74(476), 90(418, 475), 91(418, 475), 92(416, 418). 94(416,418), 97(416, 418), 98(416,418), 143(374, 375), 194, 198, 199(85),200, 372 Ward, 1). J., 207 Ward, P. F. V., 212(194), 213 Ward, R. B., 25, 39(8),41(8), 63, 64(495), 70, 159(582),162(582), 165(495) Warner, E. C., 338 Warren, C . D., 188, 208(46), 217, 224(46), 225(46, 257), 231(46), 232(303), 233(303), 235 Warren, L. G . , 332 Wassiliadou-Micheli, N., 255, 256(80), 269 Watanabe, A., 337, 338, 339(398)

411

Watanabe, K., 75, 90(641), 168(641) Watanabe, K. A., 221, 225(262) Wawra, H., 361 Webber, J. M., 105, 148(731), 181, 188, 189, 195(49, SO), 196, 199(50), 203, 205, 210, 211(76), 217,218(178), 219(225), 225(49, SO), 227(50), 231(49), 234(108, 310, 311), 235, 237(76) Weber, C. S., 333 Weckerle, W., 187, 209(40), 237(40) Wedemeyer, K. F., 246, 251(22), 252(22) Weidmann, H., 208, 219(149) Weigel, H., 54, 55 Weiner, F., 292 Weinhouse, S., 292, 296, 297(62), 306(148), 307, 327(62), 331 Weis, K., 246, 248(23), 251(23), 252(23) Weisberg, J. S., 324 Weisblat, D. I., 278 Weisleder, D., 184, 190, 192(55), 194(15), 197, 201, 218(15, 99), 219(55, 99), 220(55), 230(55, 77) Welch, M. H., 334 Wells, R. D., 190, 192(56), 197(56) Weltzien, W., 54 Wenhert, E., 198 Wenusch, A., 46 Werbelow, L. G . , 198 Werner, F., 221, 227(268) West, A. C., 266 West, B. F., 203(115), 204 Westermann, H., 67 Westrum, E. F., 52(363), 53 Westwood, J. H., 37( 170), 38, 58, 60, 62(434), 64(448), 65(434), 66(448), 75, 80(448), 108(448, 637), 109(448), 111(448), 114(434, 637), 120(434), 121(434, 448), 131(447, 448, 637), 132(170), 133(447, 448, 637), 134(447,448), 135(170), 168(448), 169(448), 172(448,637), 191(60c), 192, 217,221,223(246),228(270),234(312), 235 Weyer, J., 24, 56(5), 57, 58(5),59(5), GO(S), 61, 90(419), 91(419), 94(5, 419, 4 5 3 , 95(419), 96(5, 419, 455), 97(419), 104(5, 419, 455), 126(455), 165(419), 166(419), 171(419), 173(455) Wheat, R., 263

412

AUTHOR INDEX

Whelan, W. J., 32, 36, 62(82, 112), 67(82), 152(109), 153(109), 165(82) Whereat, A., 318 Whetstone, R. R., 48, 140(323), 150, 175(323) Whistler, R. L., 32, 47, 146(83), 147(83), 150, 194, 203, 208, 217, 218(111), 219(111), 221, 222(243), 225(259), 228(274, 275), 229(243, 274, 282), 235, 237(323), 241, 283, 373 White, I. G., 301, 302 White, L. W., 294,295 Whitton, B. R., 217, 219(228), 220(228) Wickberg, B., 63, 64(494), 77(494) Wieland, O., 293, 319(39), 328 Wiggins, L. F., 37, 38, 64,65(509), 75( 134), 90( 134,509), 106(134), 107(509), 118, 122( 130, 509), 123(509,753), 128,131(168), 132(168), 165(134), 166, 167(134), 168(509), 170(150, 509), 171(134), 172(509), 173(130, 134, 509, 831), 174(509), 217, 221(233) Wiley, J. H., 330 Wilham, C. A., 50, 66, 104(343) Will, W., 77 Willard, J . J., 188, 189(48), 231(48, 298), 235 Williams, C . S., 48, 62(326), 132(326), 140(326), 145(326), 175(326) Williams, D. M., 60, 92(449), 143(449) Williams, E. B., 328(305), 329(305), 330 Williams, G. J. B., 352 Williams, H. E., 294 Williams, H. R., 294, 295, 296(47) Williams, J . M., 37, 204, 205(118), 219( 118) Williams, N. R., 115, 209, 210, 217, 225(260) Williams, R. H., 342 Williams, T. H., 372 Williams, U., 265 Williams-Ashman, H. G., 299,300,340 Wills, B., 327 Wilmers, M. J., 308, 309(154), 310(154) Wilson, H. R., 364 Wilson, T. H., 289 Winegrad, A. I., 310 Wing, R. E., 208 Winkler, K., 319, 320(240) Winkler, S., 246, 273(27)

Winterbum, P. J., 342 Winter-Mihaly, E., 60, 92(449), 142(449)

WirBn, E., 231(235), 235 Withee, M. J., 213, 216(213) Witschi, H., 324 Wodley, F. A., 43, 69(259), 102(259) Wold, J. K., 37, 77( 146) Wolf, A., 240(338), 241 Wolf, H. P., 293, 297, 306, 307(72), 308(72), 309(72), 3 10(72), 3 19(37), 33 1(72) Wolf, J . U., 341 Wolff, I. A,, 39, 41(192), 42(192), 75, 77, 165(192) Wolff, J. B., 341 Wolfmeier, U., 98 Wolfrom, M. L., 36, 40, 51(107), 63, 64(495), 67, 70, 122, 159(582), 162(582), 165(107, 495), 173(762), 188, 211(42), 231(42), 232(42), 254, 256,257,278 Wolfson, E. B., 313 Wolfson, S. K., Jr., 299 Wollwage, P. C., 28, 43, 44(264), 56(52), 57(52), 58(52, 264), 59(52, 264), 60(52, 264), 63, 64(264,483), 70(483), 71(483), 72(483), 77(483), 79(52), &1(52), 94(52), W52), 100(52), 101(52), 111(52), 120(52, 264), 144(483), 159(52), 160(52), 162(52), 165(483), 166(483), 168(52, 483), 169(52, 264, 483), 172(52), 174(483) Wolthers, H., 318, 343(236) Wong, E. H. A., 297 Wood, D. L., 26 Wood, H. B., Jr., 32, 33, 77(91), 165(92) Wood, W. A., 310, 311(169), 313(169), 335 Woodfin, B. M., 333,334 Woods, H. F., 323, 325 Woodward, H., Jr., 296 Wright, B. E., 336 Wulff, G . , 243, 244(1), 246(1f), 248, 249(37b) Wulff, H., 122, 254 Wulfson, N. S., 193, 194(69) Wybregt, S. H., 307, 308(151), 310(151) Wyngaarden, J. B., 323 Wyss, P. C., 37(150a), 38, 170(150a)

AUTHOR INDEX

Y Yamamoto, K., 33,122(95), 146(95),147(95) Yamasaki, T., 282 Yamashina, I., 161 Yannone, M. E., 304 Yanouf, H. M., 289 Yazlovetsky, I. G., 248, 250 Ylikahri, R. H., 320 Yoshikawa, M., 362 Yoshino, T., 208 Yoshioka, H., 364 Young, D. W., 364 Young, R. C., 201, 216(98) Yudkin, I., 330 Yuen, G. U., 122, 173(762) Yung-Lung Fu, 38(182),39,40( 182), 41 (182), 42( 182), 43( 182), 46( 182)

Z Zachoval, J., 69(580), 70, 73, 77(45, 613) Zakim, D., 309, 325, :326(277),327, 328 Zakis, G., 63 Zalitis, J., 308 Zamcheck, M., 317 Zamojski, A., 103 Zanetti, G., 229(286), 235 Zapt, J., 298

4 13

Zara-KacziQn,E., 56, 67(411, 413), 68(411) Zarubinskii, G. M., 29, 77(67), 207 Zega, Z., 77 Zehavi, U., 269, 271 ZemplBn, G., 25, 32, 39(7), 41(7), 45, 50(282), 63, 64(282, 490), 65, 66(531), 67, 68(557), 77(282, 490, 531), 85(531), 165(80), 166(282), 169(531), 246, 251(19, 20, 21) Zen, S., 64(516, 517), 65, 266 Zezin, A. B., 76 Zhbankov, R. G., 56 Zhdanov, Yu. A., 229(279), 235 Zhdanova, K. I., 55, 76, 85 Ziderman, I., 210 Ziegler, D. M., 317 Zilliken, F., 254 Zimer, J., 246, 251(24), 252(24), 273(24) Zissis, E., 27, 29(39),30(39), 36, 90(111), 109, 154, 171(111) ZobaEovQ,A,, 194, 217, 221(236), 223(247) Zolotarev, B. M., 62 Zorbach, W. W., 247, 281 Zurnbiilte, F., 31, 32(72), 159(72), 165(72), 166(72) Zurabyan, S. E., 46(311), 47,248,250 Zweifel, G., 45, 64(285), 75(285), 81(285), 90(285), 170(285), 171(285) Zwierzchowska, Z., 103

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SUBJECT INDEX A Abramov reaction, 98 Acetalation, see ulso Acetonation; Benzylidenation I$-acetoxonium ion in, 190 of 1,6-anhydrohexopyranoses, 89-93 with gem-dihalides and base, 188-190 with enol ethers, 188 miscellaneous methods of, 191 principles governing, 180-182 Acetaldehyde, reaction with D-allose, 183, 184 Acetals cyclic, acetolysis of, 206 of aldoses and aldosides, 179-241 applications of, 207-209 cleavage by trityl fluoroborate, 207 conformational analysis of, 197 confonnational equilibria of, 198-202 diastereoisomerism of, 195-197 formation of, 180-182 hydrogenolysis of, 205 hydrolysis by acids, mechanism of, 202 mass spectrometry and structure of, 192-194 methanolysis of, 206 migration in, 205 nuclear magnetic resonance spectroscopy and structure of, 195-198 oxidation of, 207 ozonolysis of, 207 photolysis of, 207 reactions with N-bromosuccinimide, 206 synthesis and degradation of, 8 synthesis of, 182-192 cyclic di-, hydrolysis of 203, 204 dithio-, glycoside synthesis by alcoholysis of acyclic sugar, 244 exchange of, 186-188, 192 preparation from enol ethers, 188 synthesis of, 182-192 Acetic acid, trifluoroanhydride, 1,6-anhydrohexopyranose cleavage by, 66 for hydrolysis of cyclic acetals, 205

in organic syntheses, 8 Acetolysis of aminodeoxy I,&anhydrohexopyranoses, 128 of 1,6-anhydrohexopyranoses,65, 162 of cyclic acetals, 206 Acetonation, see also Acetalation of D-allose, 183 of D-galactose, 185 of D-glucose, 182, 183 of D-ribose, 184, 185 of D-talose, 184 1,2-Acetoxonium ion, in acetal preparation, 190 Acetylation, of 1,6-anhydrohexopyranoses, 83 Acrolein 1,6-anhydrohexopyranosesfrom, 112 Diels-Alder condensation and reduction of, 48 Acylating agents, selectivity, cyclic acetals in study of, 207 Acyloxonium ions, formation from 1,6-anhydrohexopyranoses,87-89 Adenosine 3‘,5’-monophosphate P,O-ethyl ester monohydrate, crystal structure bibliography, 370 nickel 5’-monophosphate hexahydrate, crystal structure bibliography, 374 -, 2‘-deoxy-, 5‘-phosphate sodium salt hexahydrate, crystal structure bibliography, 368 -, 5iodouridylyl-(3’ 4 5)-, ethidium complex, niethanolate hydrate, crystal structure bibliography, 377 Adhesives, from copolymers of levoglucosan with alcohols and ethers, 73 Adipose tissue, D-fructose metabolism in, 297 Agar, pyrolysis of, 45 Alcohols, copolymerization with levoglucosan, 72 Alditols, synthesis of, trifluoracetic acid in, 8 Aldofuranoses, ethylidene-, fragmentation patterns of, 194

415

416

SUBJECT INDEX

-, monoisopropylidene-, fragmentation patterns of, 194 Aldohexofuranoses, 1,6-anhydro-p-D-, preparation, properties, and conformation of, 24 Aldohexopyranoses,see also Hexopyranoses preparation, properties, and conformation of, 24 -, ethylidene-, fragmentation patterns of, 194 -, monoisopropylidene-, fragmentation patterns of, 194 Aldohexopyranosides, methyl 4,6-0benzylidene-, hydrolysis of, 202 Aldohexoses 1,6-anhydroderivatives, 23-177 cyclization by acids, 34-37 pyrolysis of reducing, anhydride formation by, 45 -, 1,4:3,6-dianhydro-,formation by pyrolysis of monosaccharides, 46 Aldolase, control enzyme in D-fructose metabolism in liver, 296 Aldoses analysis of, cyclic acetals in, 209 cyclic acetals of, 179-241 Aldosides, cyclic acetals of, 179-241 Aldotriouronic acids, synthesis of, 162 Alkylating agents, specificity, cyclic acetals in study of, 208 Alkylation, of 1.6-anhydrohexopyranoses, 84 Allofuranose, 3-0-acetyl- 1,2:5,6-di0-isopropylidene-a-D-, hydrolysis of, 203 -, 1,6-anhydro-p-~acetonation of, 155 preparation of, 153, 157 -, 3-0-benzyl-1,2:5,6-di-O-isopropyli-

dene-a-D, hydrolysis of, 202 -, 2,3:5,6-di-O-ethylidene-a-~-, diastereoisomers, 197 -, 1,2:5,6-di-O-isopropylidene-a-Dacetal migration in, 205 conformation of, 201, 202 formation of, 183 hydrolysis of, 203 methanolysis of, 205, 206 -, 2,3:5,6-di-O-isopropylidene-D-, preparation of, 183

-, 1,2-O-ethylidene-D-,conformation of, 20 1 Allofuranoside, methyl 2,3:5,6-di-Oisopropylidene-p-D-, formation by acetal migration, 205 -, methyl 2,3-o-isopropylidene-p-~formation by acetal migration, 205 hydrolysis of, 204 Allopyranose, 3-amino-1,6-anhydro3-deoxy-2-thio-p-~hydrochloride, preparation of, 136 preparation of, 122 -, 1,6-anhydro-P-Dacetalation of, 90,91 per-0-substituted, 77 preparation of, 86 properties and complexes of, 55 p-toluenesulfonylation of, 82 -, 1,6-anhydro-~~-, preparation of, 49 -, 1,6-anhydro-2-deoxy-2-fluoro-p-D-, specific rotation of, 135 -, 1,6-anhydro-4-deoxy-4-iodo-2-0-p-

tOlylSulfOnyl-~-D-, preparation of, 132 -, 1,6-anhydro-3-C-methyl-p-D-, acetalation of, 91 -, 1,6-anhydro-2,3,4-trii-O-p-tolylsulfonyl-p-D, preparation of, 80 -, 1,6:2,3-dianhydro-p-~-,preparation of, 107, 113 -, 1,6:3,4-dianhydro-P-~-,preparation of, 107, 111, 113 -, 1,6:2,3-dianhydro-4-O-benzyl-p-~, as synthetic intermediate, 121 -, 1,2-O-ethylidene-a-D-,preparation of isomers, 190 -, tri-O-acetyl-l,6-anhydro-p-~-, reaction with trifluoromethanesulfonic acid, 88 Allopyranoside, methyl 4,6-0-benzylidene-a-Dconformation of, 199 hydrolysis of, 202 -, phenyl a - ~1,Banhydride , formation from, 29 -, phenyl p-D-,alkaline cleavage of, 29 Allose D-, acetonation of, 183 derivatives, Table, 218-220 reaction with acetaldehyde, 183, 184 L-, derivatives, Table, 218-220

SUBJECT INDEX -, 1,6-anhydro-o-, preparation of, 36, 37 -, 2,3:5,6-dia-ethylidene-~-,preparation of, 184 Ally1 perchlorate, in anhydridization of hexoses, 46 Altrofuranose, 1,6-anhydro-p-~-,preparation of, 153, 156 -, 1,2:5,6-diO-isopropylidene-~-, conformation of, 201 Altropyranose, 2-amino-1,6-anhydro2-deoxy-p-D-, preparation of, 122 -, 3-amino- 1,6-anhydro-3-deoxy-p-~-, preparation of, 122, 126 -, 1,6-anhydro-~complexes, 54 formation of, 47 -, 1.6-anhydro-p-Dconfornation of, 61 per-0-substituted, 77 3,4-phenylboronate, 93 preparation of, 89, 116

417

-, methyl 4,Ci-0-benzylidene-a-Dconformation of, 199 hydrolysis of, 202 -, methyl 3,4-O-isopropylidene-a-D-, formation by acetal migration, 205

-, methyl 4,6-O-isopropylidene-a-~acetal migration in, 205 preparation of, 192 Altrose, derivatives, Table, 221 -, 1,6-anhydro-~-,preparation of, 36, 37 Amylopectin, synthesis of, 6 Amylose, synthesis of, 6 1,6-Anhydrides, of aldohexoses, 23-177 Antibiotics aminocyclitol, preparation of, 263 effect on enzymic synthesis and degradation of carbohydrates, 8 Antigenic determinant, Lewis a bloodgroup, preparation of, 268 Antimony pentachloride, reaction with levoglucosan triacetate, 89 -, 1.6-anhydro-2-azido-2-deoxy-~-~-, Arabinofuranose, conformation of, 201 -, 5-chloro-5-deoxy-1,2-O-isopropylipreparation of, .L22

-, 1,6-anhydro-3-azido-3-deoxy-p-~-,

dene-3-O-(methylsulfonyl)-4-thiop-L-,crystal structure bibliography, preparation of, 122 -, 1,6-anhydro-2-O-benzoyl-3-O-p356 Arabinofuranoside, methyl p-D-, preparatolylsulfonyl-p-l>-, preparation of, 81 tion of, 278, 279 -, 1,6-anhydro-3-S-benzyl-3-thio-~-, Arabinofuranosyl bromide preparation of, 136 -, 1,6-anhydro-2-deoxy-2-fluoro-p-~-, -, 2-0-acetyl-3,5-dia-benzoyl-a-~-, reaction with methanol or with specific rotation of, 135 1,2,3,4-tetra-O-acetyl-p-~-gluco-, 1.6-anhydro-3-deoxy-3-fluoro-p-~-, pyranose, 280 preparation of, 133 -, 1.6-anhydro-3-deoxy-3-nitro-p-~-, -, 3,5-di-O-acyl-2-bromo-2-deoxy-a-~-, preparation of, 105, 126 methanolysis of, 281 -, 1,6-anhydro-3,4-dideoxy-3,4-epimino- -, 3,5-di-O-benzoyl-a-~-,reaction with F-D-, preparation and properties methanol or with 1,2,3,4-tetra-Oof, 124, 125, 130, 131 acetyl-p-D-glucopyranose, 280 -, 1,6-anhydro-3,4-0-isopropylidene-, 3,5-di-O-benzoy1-2-0-nitro-a-~-, reacP-D-, as synthetic intermediate, 90 tion with methanol or with 1,2,3,4tetra-0-acetyl-p-D-glucopyranose, -, 1,6:3,4-dianhydro-p-~-,preparation 280 of, 108, 113 -, 3,5-di-O-benzoyl-2-0-( p-nitroben-, 1.2:3,4-di-O-isopropylidene-p-D-, hydrolysis of, 204 zoyl)-a-~-,reaction with methanol or -, pentaa-acetyl-a-D-, crystal strucwith 1,2,3,4-tetra-O-acetyl-p-Dture bibliography, 360 glucopyranose, 280 -, tri-O-acety1-1,6-anhydro-p-D-, reaction -, 2,3,5-tri-O-benzoyl-a-~-, reaction with methanol or with 1,2,3,4-tetrawith trifluoromethanesulfonic acid, 0-acetyl-p-D-glucopyranose, 280 87 Arabinopyranose, 1,2:3,4-di-O-isopropylAltropyranoside, methyl a - D - , crystal idene-D-, preparation of, 188 structure bibliography, 352

418

SUBJECT INDEX

-, 3,4-O-isopropylidene-D-, preparation of, 188 Arabinopyranoside, methyl 3,4-0-benzylidene-P-L-, configuration of, 196 -, methyl 3,4-O-ethylidene-p-~-, preparation of, 190 Arabinose, D-, derivatives, Table, 211 -, L-, derivatives, Table, 211 -, 1,2:3,4-di-O-isopropylidene-p-~-, hydrolysis of, 204 Aziridine ring, stability of, 131 Azoospennia, D-fructose level in, 304

B Bacillus thuringiensis, exotoxin from, preparation of, 170 Baeyer-Villiger reaction, 98 Bamford-Stevens reaction, 98 Beet sugar, history, 286 Benzaldehyde, reaction with glycerol, 181 Benzotriazole, 2-(4-O-acetyl-2,3dideoxy-p-~-gl ycero-pent-2-enopyranosyl)-5,6-dichloro-, crystal structure bibliography, 371 Benzoylation, of 1,6-anhydrohexopyranoses, 82 Benzylation, of 1,6-anhydrohexopyranoses, 85 Benzylidenation with gem-dihalides and base, 189 of D-ribose, 184 of D-xylose, 186 Bibliography of crystal structures of carbohydrates, nucleosides, and nucleotides, 345-378 of Edward John Bourne’s published works, 13-22 Bis(cyclohexaamy1ose) lithium triiodide complex, crystal structure bibiliography, 372 Blood, D-fructose metabolism in, 298 Blood-group antigenic determinant, Lewis a , preparation of, 268 Borohydride reduction, of acetals, 192 Boron tribromide, 1,6-anhydrohexopyranose cleavage by, 68 Boron trichloride 1,6-anhydrohexopyranose cleavage

by, 68 in demethylation of methyl ethers of sugars, 8 Boron trifluoride etherate 1,6-anhydrohexopyranose cleavage by, 66 as catalyst in acetalation, 186 Bourne, Edward John, obituary, 1-22 Bredinin monohydrate (4-carbamoyl-l-pD-r~bofura~iosv~~m~dazo~~um-~-o~~~te crystal structure bibliography, 364 Brigl’s anhydride, see Glucopyranose, 3,4,6-tri-O-acetyl-1,2-anhydro-c~-~Brigl’s chloride, see Glucopyranosyl chloride, 3,4,6-tri-O-acety1-2-O(trichloroacety1)-p-DButyllithium, reaction with cyclic acetals, 49,409

C Cadmium carbonate, in Koenigs-Knorr reaction, 253 Calcium bromide a-D-glucopyranUrOnate trihydrate, crystal structure bibliography, 347 Calcium sodium cu-D-galactopyranurOnate hexahydrate, crystal structure bibliography, 347 Caramelization, of D-glucose, 46 Carbohydrates, crystal structure bibliography, 345-378 Carbonates, preparation and properties of trans-cyclic, acetals in, 208 Carbonrd nuclear magnetic resonance spectroscopy, of 1,6-anhydrohexopyranoses, 61 Catalysts, for polymerization of l,6-anhydrohexopyranoses, 70, 74 Cellobiosan, synthesis of, 159-161 -, 2-acetamido-2-deoxy-, preparation of peracetate, 160 -, 6-thio-, synthesis of, 170 Cellobiose, pyrolysis of, 45 Cellotetraose, pyrolysis of, 45 Cellotriose, pyrolysis of, 45 Cellulose levoglucosan from, 38-40 pyrolysis of, 38-43, 152 mechanism of, 43-45

SUBJECT INDEX

-, 2-0-methyl-, thermal degradation of, 44 Cellulosic waste, levoglucosan from, 40 a-Chitobiose, di-N-acetyl-, monohydrate, crystal structure bibliography, 372 P-Chitobiose, di-N-acetyl-, trihydrate, crystal structure bibliography, 372 Chloral, levoglucosan cleavage by, 65 Chloralose, preparation from IevogIumsan, 65 Chlorinolysis, of glycosidic bond, 47 Cholesterol, glucosidation of, 248 Chondrosine, monohydrate, crystal structure bibliography, 358 Chromatography of 1,6-anhydrohexofuranoses,155 of 1,6-anhydrohexopyranoses,62 of cyclic acetals, 180 Chromium trioxide, 1,fi-anhydrohexopyranose oxidation by, 101 Coatings, levoglucosan esters, 76 Combustion, flaming, levoglucosan in, 26 Configuration, of cyclic acetals, nuclear magnetic resonance spectroscopy and, 195-198 Conformation of aminodeoxy 1,fi-anhydrohexopyranoses, 127 of 1,6-anhydrohexofuranoses, 24, 153 of 1,6-anhydrohexopyranoses,24, 51 and proton magnetic resonance spectroscopy, 56-61 of cyclic acetals, nuclear magnetic resonance spectroscopy and, 195-198 equilibria, of cyclic acetals, 198-202 of glycosuloses, 100 of hexopyranosuloses, 96 Cotton effects, and octant rule, 104 Cram rule, 105 Crystal structure analysis, of 1,6-anhydrohexopyranoses, 51 Crystal structures, of carbohydrates, nucleosides, and nucleotides, bibliography, 345-378 Cyclization of aldohexoses by acids, 34-37 of hexopyranosyl derivatives containing reactive substituents, 31-33 of oligosaccharides, 158 of fi-C-substituted hexopyranoses,

4 19

33,34 a-Cyclohexaamylose-p-iodoaniline, trihydrate, crystal structure bibliography, 362 Cyclopenten-1-ylium perchlorate, 2,3-diphenyl-, in Koenigs-Knorr reaction, 250 Cytidine cadmium 5’-monophosphate dihydrate, crystal structure bibliography, 373 (choline 5’-diphosphate) monohydrate, crystal structure bibliography, 376 (choline 5‘-diphosphate) sodium salt pentahydrate, crystal structure bibliography, 376 cobalt 5’-monophosphate monohydrate, crystal structure bibliography, 373 5’-diphosphate monohydrate, crystal structure bibliography, 374 glycylglycinatocopper(I1) dihydrate, crystal structure bibliography, 374 -, 2’-deoxy-, crystal structure bibliography, 364 -, guanylyl-(3’+ 5’)-,monophosphate calcium salt, octadecahydrate, crystal structure bibliography, 378 1:1 Cytidine-N-benzyloxycarbonylL-glutamic acid, dihydrate, crystal structure bibliography, 362, 363

D Deamination of aminodeoxy 1,6-anhydrohexopyranoses, 128

dianhydrohexopyranoses prepared by, 112 Debenzylation, of henzyl ethers of 1,6-anhydrohexopyranoses,74, 75 Degradation, thermal, of polysaccharides, 38-45 Dehalogenation, deoxy sugars prepared by, 141 Desulfurization, deoxy sugars prepared by, 141 Dextrans levoglucosan from, 40

420

SUBJECT INDEX

in metabolism of D-fructoSe, 330-343 pyrolysis of, 152 in syntheses and degradations, 8 Dextrins, starch, levoglucosan from, 40 Epithelial cells, D-fructose effect on Diabetes, levoglucosan role in, 50 energy metabolism of intestinal, 324 Diastereoisomerism, of cyclic acetals, Epoxidation, of double bonds, 1,6-anhynuclear magnetic resonance spectrodrohexopyranoses prepared by, 112 scopy and, 195-198 Diels-Alder condensation, and reducErythritol, crystal structure bibliography, tion of acrolein, 48 371 gem-Dihalides, in acetal preparation, Erythrofuranoside, methyl 2,3-0-ethyl188, 189 idene-P-D-, formation by acetal miDimethyl sulfoxide, in anhydridization, gration, 205 48 Erythrose, D- and L-, cyclic acetals, Dimethyl sulfoxide-acetic anhydride, Table, 210 for oxidation of “isolated” hydroxyl -, 2,3-O-benzylidene-D-, formation groups, 97 by acetal migration, 205 2,8-Dioxabicyclo[3.2.l]octane,stmc-, 2,4-O-benzylidene-D-, migration of ture for 1,6-anhydro-P-~-aldohexoacetal group in, 205 furanoses, 24,25 -, 2,4-O-ethylidene-D-, migration of 6,8-Dioxabicyclo[3.2. lloctane acetal group in, 205 preparation of, from acrolein, 48 Esculin, levoglucosan from, 27 structure for 1,6-anhydro-P-D-aldohexo- Esterification pyranoses, 24, 25 of, 1,6-anhydrohexopyranoses, -, 2-bromo-, preparation of, 48 74-8s -, 1,5-dimethyl-, in aggregation partial, of 1,6-anhydrohexopyranoses, pheromones of western-pine bark78-85 beetle, 26 Estrone, 3-O-(methyl 2,3,4-tri-O-acetyl-, exo-7-ethyl-5-methyl-, in aggregaP-D-g1ucopyranosyluronate)-, tion pheromone of western-pine synthesis of, 253 bark-beetle, 26 Ethanol, metabolism of, effect of D-fruc1,3-Dioxan-S-o1,2-phenyl-, preparation tose on, 317-322 of, 181 Etherification, of 1,6-anhydrohexo(lR,5R)-6,8-Dioxa-3-thiabicyc10[3.2.1]pyranoses, 74-85 octane, preparation of, 105, 148 Ethers, copolymerization with levoglu(2R,4R)-Dioxolanedicarbaldehyde, cosan, 7 2 from 1,6-anhydro-p-~-hexopyranoses,Europium(II1) complex, in confonna104 tional analysis of‘acetals, 197 1,3-Dioxolane-4-methanol, 2-phenyl-, Exotoxin, from Bacillus thuringiensis, cis- and trans-, formation of, 181 preparation of, 170 Di-/3-D-ribofuranose 1,s’:1’,5-dianhyExtraction apparatus, countercurrent, 9 dride, 2,3:2’,3’-dia-benzylidene-, preparation of, 184 F Disaccharides cyclic acetals, 209 Fertility, male, D-fructOSe significance synthesis of, 160, 161 in, 303-305 Fire retardation, levoglucosan formation and, 38 E Fischer method, of glycoside synthesis, Enzyme Q, in starch synthesis, 6 243, 278 Enzymes Foams, levoglucosan esters, 76 for hepatic D-fructose metabolism Fragmentation, of 1,6-anhydrohexocontrol, 296 pyranoses, 62

SUBJECT INDEX Fragmentation patterns, of isopropylidene acetals ofpentoses and hexoses, 192-194 Fructans D-, metabolism of. 315 synthesis and degradation of, 314-31 6 Fructokinase control enzyme in D-fructose metabolism in liver, 293, 296 enzymic activity in liver metabolism, 326 in metabolism of D-fructose, 330, 331 occurrence of, 331 Fructolysis, by spermatozoa, 300-302 Fructose, D-, absorption of, mechanism of, 289-291 assimilation from intestine, 287-291 biosynthesis in seminal vesicles, pathways of, 298-300 carrier-mediated transport system for, 314 degradation to triose, in liver, intestine, and kidney, 292-294 Dglucose regeneration from, by Dglucose 6-phosphate, 295 by triose condensation, 294 effect on energy metabolism of intestinal epithelial cells, 324 on lipid metabolism, 325-330 on metabolism of ethanol, 317-322 on nucleotide pool in liver, 322324 hereditary intolerance of, 306-310 history, 286 in male fertility, significance of, 303-305 metabolism of, 285-343 in adipose tissue, 297 in blood and muscle cells, 298 control in liver, 296, 297 inborn errors of, 306-310 key enzymes in, 330-343 in liver, intestine, and kidney, 291-297 in micro-organisms, 310-314 by spermatozoa, 300-302 in testes and spermatozoa, 288-305 phosphorylation of, by liver, 325-330 pyrolysis of, 45

42 1

respiration-coupled transport system for, 312, 313 sodium 1,6-bisphosphate heptahydrate, crystal structure bibliography, 372 uses of, 286,343 D-Fructose 1,6-diphosphatase, in metabolism of D-fructose, 335-340 D-Fructose 1,6-diphosphatase activity, deficiency of hepatic, 310 DFructose 1,6-diphosphate aldolase, enzymic activity in liver metabolism, 326 in metabolism of D-fructose, 332-335 D-Fructose 1-phosphate aldolase, enzymic activity in liver metabolism, 326 D-Fructose 1-phosphate kinase, enzymic activity in liver metabolism, 326 in metabolism of D-fructose, 332 Fucopyranose, a - ~ calcium bromide salt, trihydrate, crystal structure bibliography, 351 crystal structure bibliography, 350 Fucose, D-, cyclic acetals, Table, 239 -, L-, cyclic acetals, Table, 239 -, 3,4-O-isopropylidene-~-, preparation of, 186 Fungi, D-fructoSe transport in, 314 Furanoid rings, conformations of, 201

G Galactofuranose, 1,6-anhydro-a-~-, preparation and history of, 152 -, 1,6-anliydro-2,3,5-tri-~-l~eiizyl-a-~-, polymerization of, 157 -, 3-deoxy-3,4-C-(dichloromethylene)1,2:5,6-di-O-isopropylidene-a-~-, conformation of, 201 -, 1,2:5,6-di-O-isopropylidene-a-Dconformation of, 201, 202 formation of, 185 -, 5,6-0-isopropylidene-~-, preparation of, 185 Galactofuranoaide, ethyl P-D-, prepnration of, 278 -, ethyl 2,3,5,6-tetra-O-acetyl-p-D-, preparation of, 279

422

SUBJECT INDEX

Galactofuranosyl bromide, 2,3-di-0-, 1,6-anhydro-3,4-0-isopropylidenep-Dbenzyl-5,6-di-O-( p-nitrobenzoy1)formation of, 46 P-D-, methanolysis of, 281 oxidation of, 97 Galactopyranose, a-D-, crystal struc-, 1,6-anhydro-1(6)-thio-p-~-, preparation ture bibliography, 371 -, p a of, 146 crystal structure bibliography, 351, 372 -, 1,6-anhydro-2-O-p-tolylsulfonylp-D, preparation of, 86 1-mesitoic ester, 1,6-anhydride from, -, 1,6-anhydro-2,3,4-tri-O-benzyl-p-~-, 32 -, 2-acetamido-l,6-anhydro-2-deoxypolymerization of, 73 P-D-, benzoylation of, 82 -, 3-0-(2-O-benzy~-a-D-glucopyranosyl)-, 2-acetamido-1,6-anhydro-2-deoxy-34,6-O-ethylidene- 1,2-0-isopropylO-benzoyl-4-0-(methylsulfony1)idene-a-D, preparation of, 263 P-D-,azide replacement of methyl-, 1,6:3,4-dianhydro-p-~-,preparation sulfonyloxy group in, 85, 125 of, and derivatives, 108, 111, 113 -, 2-acetamido-2-deoxy-a-~-,crystal -, 1,6:3,4-dianhydro-Z-O-benzyl-p-~-, structure bibliography, 354 as synthetic intermediate, 120 -, 2-amino-1,6-anhydro-2-deoxy-p-~-, -, 1,6:3,4-dianhydro-2-0-p-tolylsulpreparation of, 122 fon y l-p-D-, 3-amino-1,6-anhydro-3-deoxy-p-~-, de-p-toluenesulfonylationof, 75 preparation of, 126 preparation of, 80, 110 -, 2-amino-1,6-anhydro-2-deoxy-4-0- -, 1,2:3,4-di-O-benzylidene-a-~-, methyl-p-D-, preparation of, 122 configuration of, 196 -, 2-amino-2-deoxy-3-0-(p-~-gluco- -, 1,2:3,4-di-O-isopropylidene-a-~, pyranosyluronic acid)-a-D-, monohylow-pressure distillation of, 46 -, 1,2:3,4-di-0-isopropylidene-6-[3,4,6drate, crystal structure bibliography, 358 tri-O-acetyl-2-deoxy-2-(2,4-dinitro-, 1,6-anhydro-~anilin0)-a-D-glucopyranos y 11-a-D-, acetolysis of, 65 and p-D anomer, preparation of, 269 complexes, 54 -, 3,4-O-isopropylidene-~-, preparation -, 1,6-anhydro-p-~of, 185 -, 4,6-O-isopropylidene-~-, preparaacetylation of, 84 from agar pyrolysis, 45 tion of, 185 Galactopyranoside, benzyl 6-0-benzoylalkylation of, 84 2-O-(tri-O-acetyl-a-~-fucopyranosyl)cleavage b y hypophosphorous acid, 68,69 p-D-,synthesis of, 252 copolymers with tribenzyl ethers of -, benzyl 3,4,6-tri-O-henzyl-2-0-(2,3,4,6te tra-0-benzyl-a-D-glucopyranosyl). levoglucosan, 73 a-D-,preparation of, 268 crystal structure of, 51 -, bis(benzy1oxy)isopropyl 2,3,4,6from lactose pyrolysis, 45 tetraa-benzyl-a-D-, preparation per-0-substituted, 77 3,4-phenylboronate, 93 of, 258 polymerization of, 71 -, methyl 6-0-benzyl-a-D-, preparation by methanolysis, 206 preparation of, 27, 32 -, methyl 3-0-benzyl-4,6-0-benzylproperties of, 50 p-toluenesulfonylation of, 81 idene-2-O-methyl-a-~-,hydrolysis of, 204 --, 1,6-anhydro-p-~~-, preparation of, -, methyl 4,6-0-benzylidene-~49 -, 1,6-anhydro-2,4-di-O-p-tolylsulfonyl- conformation of, 199 p-D-,preparation of, 81, 82 hydrolysis of, 202

SUBJECT INDEX

423

-, methyl 4,6-0-benzyIidene-2,3-di-O- Galactoseptanoside, methyl 2,3,4,5-tetraO-acetyl-a-D-, preparation of, 283 methyl-a+, preparation of, 189, 195 -, methyl 4,6-0-benzylidene-2,3-die- -, methyl 6 - t h i o - a - ~and -P-D-, derivaInethyl-p-D, diastereoisomers, 196 tives, preparation of, 283 -, methyl 3,4-O-ethyhdene-a-~-, a-D-Galactosiduronic acid, methyl, diastereoisomers, 197 methyl ester hydrate, crystal struc-, methyl 4,6-0-ethylidene-2,3-di-Oture bibliography, 372 methyl-p-D-, hydrolysis of, 204 Gangliosides, synthesis of carbohydrate -, methyl 4,6-0-isopropylidene-a-~chain of brain, 159 and -P-D-, preparation of, 186 Gentiobiose -, methyl 3,4,6-tri-O-acety-2-amino-2preparation of, 266 deoxy-P-D-, synthesis of, 254 pyrolysis of, 45 -, phenyl WD-, 1,6-anhydride formap-Gentiobiose tion from, 29, 30 octaacetate, synthesis of, 246, 250, 256 -, phenyl P-D-, alkaline cleavage of, undecaacetate, synthesis of, 247 29 Gentiobioside, methyl hepta-0-benzoylGalactopyranosyl bromide, 2,3,4,6-tetraa-, preparation of, 272 &We@l-a-D-,reaction with triGlucagon, effect on D-fructose convermethylamine and anhydridization, 32 sion into D-glucose, 297 Galactopyranuronic acid, (Y-DGlucaro-1,4-lactone, D-, crystal stmccalcium sodium salt hexahydrate, ture bibliography, 371 D-Glucitol dehydrogenase, in nietal)olism crystal structure bibliography, 347 sodium strontium salt hexahydrate, of D-fructose, 340, 341 crystal structure bibliography, 348 Glucofuranose, 1,6-anhydro-p-~-, 1,2,3,4-tetra-O-ac:etyl-p-D-, methyl formation during pyrolysis of starch and cellulose, 42, 43 ester, crystal structure biblihydrolysis of, 153 ography, 360 preparation of, 152 Galactose, properties of, 153 D-, absorptive rate by human jejunum, -, 1,6-anhydro-2,4-di-O-methyl-1(6),4289 dithio-p-D-, preparation of, 150 acetonation of, 185 -, 1,6-anhydro-1(6)-thio-p-D-,preparaderivatives, cyclic acetals, Table, tion of, 150 224-227 -, 3-azido-3-deoxy-l,2:5,6-di-O-isopyrolysis of, 45, 152 propylidene-a-D-, photolysis of, 207 -, 1,6-anhydro-~-, formation of, 36 -, 6-O-benzyl-l,2:3,4-di-O-isopropyl-

idene-a-D-, methanolysis of, 206

-, 1,2:3,4-di--isopiopylidene-D-, preparation of, .L85 -,

1.2:3,4-di-0-isopropylidene-6-0p-tolylsulfoIiyl-tu-D-, hydrolysis of, 204

-, 3-O-a-D-glucopyranOSyl-D-, prepara-

tion of, 263

-, 3-azido-3-deoxy-1,2-0-isopropyl-

idene-64-[3,4,6-tri-O-acetyl-2deoxy-2-(2,4-dinitroanilino-aand -P-Dg-lucopyranosyl]-a-D-,prepara-

tion of, 269 -, 1,2:3,5-di-O-isopropylidene-a-~-, formation of, 182, 183 -, 1,2:5,6-di-O-isopropylidene-a-~-

conformation of, 201, 202 formation of, 182 tion of, 263 fragmentation pattern for, 193 levoglucosan from pyrolysis of, 46 -, 1.2-0-isopropylidene-a-D-, preparaGlucofuranoside, ethyl p-D-, preparation tion of, 188 -, 3,4-O-isopropylitlene-6-0-1nethyl-D-, of, 278 preparation of, 186 Glycofuranosides, synthesis by Koenigs-, 6-O-a-D-glucopyranosyl-D-, prepara-

SUBJECT INDEX

424

Knorr reaction and other methods, -, 277-283 -, Glucokinase, enzymic activity in liver metabolism, 326 Gluconamide, N-(2-chloroethyl)-D-, crystal structure bibliography, 356 -, Glucopyranose, P-D, I-mesitoic ester, 1,6-anhydride from, 32 -, 2-acetamido-1,6-anhydro-4-azido-3-0- -, benzoyl-2-deoxy-p-D-, preparation of, 85, 125, 126 -, -, 2-acetamido-2-deoxy-a-~-,crystal -, structure bibliography, 354

-, 2-O-acetyl-l,6-anhydro-3,4-di-0benzyl-p-D-, formation of, 47 -, 1,2-0-alkylidene-a-~-,conformation of, 200 -, 2-amino-1,6-anhydro-2-deoxy-p-Ddeamination of, 128, 129 4- ethers, preparation of, 124 preparation of, and N-derivatives, 122 -, 3-amino- 1,6-anhydro-3-deoxy-p-~-, conformation of, 127 deamination of, 128 hydrochloride, conformation of, 59 preparation of, 123

1,6-anhydro4-deoxy-4-fluoro-p-~-, preparation of, 133 1,6-anhydro-4-deoxy-4-fluoro-2-0p-tolylsdfonyl-P-D-, preparation of, 134 1,6-anhydro-4-deoxy-3-O-methyl-2O-p-tOlylsulfOnyl-p-D-,acid cleavage of, 64 1,6-anhydro-2,4-diazido-2,4-dideoxyp-D-,conformation of, 127 1,6-anhydro-2,3-di-O-benzoyl-p-~-, oxidation of, 100 1,6-anhydro-2,4-di-O-benzyl-p-~-, p-toluenesulfonylation of, 80 -, 1,6-anhydro-3,4-di-O-benzyl-2-deoxyP-D-, debenzylation of, 75 -, 1,6-anhydro-2,4-dideoxy-2,4-difluoro-

p-Dhydrolysis or acetolysis of, 135 preparation of, 133

-, 1,6-anhydro-2,3-di-O-methyl-p-~, preparation of, 79 -, 1,6-anhydro-2-0-methyl-p-~-, from 2-0-methylcellulose pyrolysis, 44 -, 1,6-anhydro-1(6)-thio-p-~-, preparation of, 146 -, 4-amino-1,6-anhydro-4-deoxy-p-~-, -, 1,6-anhydro-2,3,4-tri-O-benzyl-~deamination of, 128 preparation of, 47 -, 2-amino-l,6-anhydro-2,4-dideoxyreaction with ethanethiol and zinc 4-Huoro-p-1,-, preparation of, 124, 135 chloride, 64

-, 4-amino-1,6-anhydro-2,4-dideoxy-2- -, 1,6-anhydro-2,3,4-tri-O-benzyl-p-~-, fluoro-p-D-. preparation of, 124

-, 1,4-anhydro-a-~-, from 2-0-methylcellulose pyrolysis, 44

-, 1,6-anhydro-p-~-,see also Levoglucosan acetolysis of, 65 crystal structure bibliography, 348 history, preparation, and uses of, 25 per-0-substituted, 77 preparation and history of, 27 -, 1,6-anhydro-4-0-benzyl-P-D-, p-toluenesulfonylation of, 80

preparation of, 32 -, 1,6-anhydro-2,3,4-tri-O-methyl-P-~-, copolymerization with Lewis acids, and with styrene, 74

-, 1,6-anhydro-2,3,4-tri-O-p-tolylsul-

fOnyl-p-D-, preparation of, 80 -, 1,2-O-benzylidene-D-, preparation of, 191 -, 1,2-O-benzylidene-a-~-,diastereoisomers, 197 -, 2-0-benzyl-l-@(methylsulfonyl)3,4,6-tri-0-( p-nitrobenzoy1)-a-D-, --, 1,6-anhydro-4-S-benzyl-4-thio-p-~-, preparation of, 262 preparation of, 136 -, 1,2-0-cyclohexylidene-~-, prepara-, 1,6-anhydro-4-S-benzyl4-thio-2-O-ption of, 191 tOlylSUlfOnyl-P-D-, preparation -, 1,2-0-cyclopentylidene-D-, preparaof, 138 tion of, 191 -, 1,6-anhydro-2-deoxy-2-fluoro-p-~-, -, 3,4-di-O-acetyl-2-amino-1,6-anhydrohydrolysis or acetolysis of, 135 2-deoxy-p-~-,deamination of, 128 preparation of, 67 -, 2,3-di-O-acetyl-1,6-anhydro-p-~-,

SUBJECT INDEX in synthesis of oligosaccharides, 160

425

of, 258,259

-, 2,4-diamino-1,6-anhydr0-2,4-dideoxy--, decyl a-D-, crystal structure bibp-Dliography, 372 conformation of, 127 -, methyl (Y-D-,preparation of, 256, 266 preparation of, 124, 125 -, methyl 4,6-0-benzylidene-~-, hy-, 5,6-diamino-1,6-anhydro-5,6-dideoxydrolysis of, 202

p-D-, formation of, 149

.

-, methyl 4,6-0-benzylidene-a-~-, conformation of, 199 diastereoisomers, 197 -, methyl 4,6-0-benzylidene-2,3-di-, 1,2-@ethylidene-a-D-, diastereo0-methyl-a-Disomers, 197 preparation of, 189, 190 preparation of diastereoisomers, 195 -, 1,2-O-isopropylidene-~-, preparation of, 191 -, methyl 4-deoxy-4-fluoro-a-D-, crystal -, 4,6-0-isopropylidene-a,p-~-, structure bibliography, 352 preparation of, 188 -, methyl 2,3-di-O-acetyl-4,6-0-benzyl-, 1,2,3,4-tetra-0-acetyl-p-Didene-a-D-, and -p-D-, preparation 1,6-anhydride fonnation from, 46 and stereochemistry of, 195 reactions with 2-0-substituted 3,5-di-, methyl, 2,3:4,6-di-O-cyclohexylidenea-D-,preparation by acetal exchange, O-benzoyl-L-arabino- and -D-ribo187 furanosyl bromides, 280 -, 1.2,3,4-tetra-O-acetyl-6-deoxy-6-, methyl 2,3-di-0-p-tolylsulfonyl-a-D-, distillation and attempted cyclizaiodo-a-D-, 3,6-anhydride from, 33 -, 1.2,3,4-tetra-O-acety1-6-0-p-tolyltion of, 47 SUlfOnyl-p-D-, reaction with sodium -, methyl 4,6-0-ethylidene-a-D-, methoxide, 33 preparation by acetal exchange, -, 1.2,3,4-tetra-O-acetyl-6-0-trityl-p-D-, 187 -, methyl 4,6-0-isopropylidene-a-~-, 1,6-anhydride formation from, 46 hydrolysis of, 204 -, 3,4,6-tri-O-acetyl-l,2-anhydro-a-D-, -, methyl 4,6-0-( l-phenylethyl)-a-D-, levoglucosan synthesis from, 29, 48 -, 2,3,4-tri-0-benzyl-p-D-,azeotropic hydrolysis of, 204 dehydration with p-toluenesulfonic -, methyl tetra-0-benzyl-a-D-, preparaacid, 47 tion of, 266 -, 3,4,6-tri-O-benzyl-1,2-0-( l-ethoxy-, methyl 2,3,4,6-tetra-0-(chlorosulethy1idene)-a-D-, anhydridization fony1)-a-D-, reaction with aluminum with mercuric chloride, 47 chloride 34, 35 -, 2,3,4-tria-methyl-p-D-, azeotropic -, methyl tetraa-methyl-p-D-, preparadehydration of, 47 tion of, 274 Glucopyranoside, alkyl tetra-0-acetyl-P-, methyl 3,4,6-tri-O-acetyl-2-aininoD-, synthesis and history of, 245 e-deoxy-p-D-, hydrobromide, syn-, benzyl 2-acetamido-4,6-0-benzylthesis of, 254 idene-2-deoxy-3-0-( tetra-0-acetyl-, p-nitrophenyl 2-acetamido-2-deoxyp-D-galactopyranosyl)-a-D-, synP-D-, monohydrate, crystal structhesis of, 252 ture bibliography, 359 -, benzyl 2-acetamido-3,6-di-O-acetyl-2- -, phenyl a - ~ -1,6-anhydride , formadeoxy-4-O-(tetra-O-acetyl-a-Dtion from, 29 galactopyranosy1)-, synthesis of, -, phenyl P-D250,251 alkaline cleavage of, 29 -, benzyl 2,3,4-tri-O-benzyl-l-thio-p-~-, synthesis and history of, 245 reaction with methyl iodide, 32 -, phenyl tetraa-acety-a-D- and -, bis(benzy1oxy)isopropyl 2,3,4,6-p-D-, preparation of, 265, 266 tetra-0-benzyl-wD-, preparation -, phenyl I-thiO-p-D-, 1,6-anhydrohexo-

-, 1,2:4,6-diOethylidene-a-~-,

SUBJECT INDEX

426 pyranose from, 28

-, vinyl p-D-, levoglucosan from, 28

-, 3,4,6-tri-O-acetyl-2-chloro-2-deoxy-

a-D-and -P-D-, Koenigs-Knorr reacGlucopyranosides, D-, pyrolysis of, 152 tion with, 259 Glucopyranos-4-ulose, 1,6-anhydro-2,3-, 2,3,4-tri-0-acetyl-6-O-(dichlorodie-benzoyl-p-D-, preparation and methyl)-a-D-, preparation of, 68 reactions of, 100, 101 -, 2,3,4-tri-O-acetyl-6-O-formyl-a-D-, Glucopyranosyl azide, P-D-, 1,6-anhypreparation of, 68 dride from, 32 -, 3,4,6-tri-O-acetyl-2-O-nitro-p-D-, Glucopyranosyl bromide, 6-0-acetylpreparation of, 257 2,.3,4-tri-0-acyl-a-D-, preparation -, 3,4,6-tri-0-acetyl-2-O-(trichlorofrom levoglucosan triesters, 66 acetyl)-p-D-, methyl a-D-gluco--, 2-0-benzyl-3,4,6-tri-O-( p-nitropyranoside from, 256 benzoy1)-a-D- or -P-D-, inethanolysis Glucopyranosyl Huoride, o-m, ant1 P-D-, of, 274 cyclization of, 31 -, 2-0-benzyl-3,4,6-tri-O-( p-nitro-, tetra-0-acetyl-a-D-, preparation of, 67 benzoyl)-p-D-, preparation of, 258 Glucopyranosyl nitrate, LU-D-, 1,6-anhy-, 3,4-di-O-act:tyI-2,6-dibromo-2,6dride from, 32 dideoxy-pa-, preparation of, Glucopyranosyl perchlorate, 3,4,6-tri-0135, 136 acety-2-0-benzyl-a-D- and -P-D-, .-, 2,3-di-O-benzyl-4,6-di-O-(p-nitroKoenigs-Knorr reaction with, 259,260 benzoyl)-p-D-, 3,4,6-tri-O-acetyl-2-ch1oro-2-deoxymethanolysis of, 274 a-D- and -p-D, Koenigs-Knorr preparation of, 258 reaction with, 259 -, 2,3,4,6-tetra-O-acetl-a-D-, reaction Glucopyranuronic acid, a-D-, calcium with trimethylamine and anhybromide salt trihydrate, crystal dridization, 32 structure bibliography, 347 -, 2,3,4,6-tetra-O-benzyl-a-~-, Glucopyranurono-6,l-lactone, 2,3,4-trimethanolysis of, 274 0-acetyl-P-D, and 2,3,4-tris--, 2,3,4-tri-O-acetyl-a-~-, preparation (2,2,2-trichloroethoxycarbonyl)ester, of, 67 150 --, 2,3,4-tri-O-acetyl-6-bromo-6-deoxy- p-Glucosan, see Levoglucosan a-D-, preparation of, 67 Glucose, --, 2,3,4-tri-0-acetyl-6-O-propionyl-a-~-,D-, absorption from intestine, 287, 288 preparation of, 66, 68 caramelization of, 46 -, 2,3,4-tri-O-benzyl-6-O-(p-nitroderivatives, cyclic acetals, Table, 228-233 benzoy1)-a-D-, methanolysis of, 274 --, 2,3,4-tri-O-benzy1-6-0-( p-nitropyrolysis of, 45, 152 benzoyl)-p-D-, preparation of, 258 reaction with acetone, 182, 183 Glucopyranosyl chloride, 2,3,4,6-tetra-0regeneration from D-fructose, by acetyl-p-D-, preparation of, 258 D-glucose 6-phosphate, 295 -, 2,3,4,6-tetra-O-(chlorosulfony1)-6by triose condensation, 294 0-methyl-a-D-, formation of, 34, 35 transport in mammalian intestine, -, 2,3,4,6-tetra-O-methyl-a-~-, 289 Glucose, L-, derivatives of cyclic acetals, methanolysis of, 274 -, 2,3,4-h-i-o-acetyl-a-D-, preparation Table, 228-233 -, 2-acetamido-2-deoxy-6-0-a-~-fucoof, 67 -, 3,4,6-tri-O-acety]-P-D-, preparation pyranosyl-D, preparation of, 263 -, 2-acetamido-2-deoxy-4-O-a-~-fucoof, 257 --, 3,4,6-tri-O-acety1-2-O-benzyl-oc-Dpyranosy~-3~-P-D-galactopyranosy1and -P-D-, Koenigs-Knorr reaction D-, preparation of, 268 with, 259,260 -, 2-acetamido-2-deoxy-6-0-p-~-rnanno-

SUBJECT INDEX pyranosyl-D-, derivative, preparation of, 259 -, 3-amino-6-0-(2-amino-2-deoxy-

427

synthesis of 1,2-cis-, 256-272 of 1,2-truns-, 246-256 Glycopyranosyl fluorides, cyclization P-Dglucopyranosy~)-3-deoxy-~-, of, 31 synthesis of, 255 Glycoseptanosides, synthesis of, 283 -, 2-amino-2-deoxy-6-0-p-tolylsulfonyl- Glycosidation D,anhydride formation from, 33 of 1,6-anhydrohexopyranoses,64 -, 1,6-anhydro-~-,formation of, 36 halide-ion catalyzed, 266 -, 1,2:5,6-di-O-isopropylidene-a-D-, mechanism of, 272-277 from levoglucosan, chloral, and acid, Glycosides 65, 93 acetals, hydrolysis of, 204 -, 6-S-methy1-6-thio-o-, preparation 1,2-cis-, of 2-amino-2-deoxy sugars, of, 147 preparation of, 268 -, trie-acetyl-D-, 1,6-dinitrate, preparacleavage with bases, 26-31 tion of, 67 synthesis of, 243,244 Glucmeptanose, 1,2:3,4-di-O-iso-, phenyl l-seleno-p-D-, alkaline propyhdene-a-D-, formation of, 183 cleavage of, 28 -, 2,3:4,5-di-O-isopropylidene-a-~-, Glycosylation, of 1,6-anhydrohexoformation of, 183 pyranoses, 159-161 Glucoseptanoside, methyl 2,3:4,5-di-0Guanosine, platinum ethylenediamine, mixed chloride iodide salt dihydrate, isopropylidene-a-D- and -P-D-, crystal structure bibliography, 375 preparation of, 279 Gulofuranose, 1,6-anhydro-a-~-, -, methyl 2,3,4,5-tetra-O-methyl-p-~-, preparation of, 153 preparation of, 279 -, 3-O-benzyl-l,2:5,6-di-O-isopropy1Glucose-6-sulfonic acid, D-, sodium idene-a-D-, hydrolysis of, 203 salt, preparation of, 69 -, 1,2:5,6-di-O-isopropylidene-~-, Glucoside, ethyl 2,3,4-tri-O-benzyl-lconformation of, 201 thio-a-D-, preparation of, 64 -, 1,2:5,6-di-O-isopropylidene-3-O-, inethyl 4,6-O-benzylidene-a-D- and methyl-a-D-, hydrolysis of, 203 -P-D, preparation by acetal exchange Gulopyranose, 2-amino-1,6-anhydro-2187 deoxy-P-D-, preparation of, 122 Glucosides, pyrolysis of, 46, 152 -, 3-amino- 1,6-anhydro-3-deoxyDGlucosyl phosphate, conversion into P-0-, preparation of, 122, 126 aniylopectin, 6 -, 1,6-anhydro-, complexes, 54 Glutamic acid, N-benzyloxycarbonyl-, 1,6-anhydro-p-~L-, cytidine-, dihydrate, crystal chiroptical properties of, 52 structure bibliography, 362, 363 conformation of, 61 L-Glutamine: D-fructoSe 6-phosphate per-0-substituted, 77 aminotransferase, in metabolism 2,3-phenylboronate, 93 of D-fructose, 341-343 preparation of, 115 Glyceraldehyde, D-, from D-fructose in and triacetate, 89 liver, 292, 293 reaction with hydrogen bromide and Glycerol, reaction with benzaldehyde, bromine, 66 181 p-toluenesulfonylation of, and 2,3Glycerone phosphate, from D-fructose phenylboronate, 81 in liver, 292, 293 -, 1,6-anhydro-3-deoxy-3-nitro-P-~-, Glycopyranosides preparation of, 105, 126 1,2-cis- and l,2-truns-, mechanism of' -, 1,6-anhydro-2,3-dideoxy-2,3-epiminopreparation by Koenigs-Knorr reacP-D-, preparation and properties tion, 272-277 of, 130, 131 synthesis and history of, 245, 246

428

SUBJECT INDEX

-, 1,6-anhydro-2,3-di-O-p-tolylsul-

formation during pyrolysis of starch and cellulose, 42, 103 synthesis of, 103 Hexitol, 1,5-anhydro-2-deoxy-~-arabino-, preparation by hydrogenolysis of levoglucosan, 69 Hexofuranose, 1,6-anhydro-(6-acetamido-2,3-di-O-acetyl-5,6-dideoxyP-D-x~ZO-, preparation of, 151 Hexofuranoses, 1,5-anhydro-, formation of, 88 -, 1,6-anhydroanalogs, 146-151 H complex formation with, 154 Heat of combustion, for levoglucosan, and derivatives, Table, 177 52 formation and preparation of, 88, 151 Heat of dehydration, for levoglucosan, by pyrolysis of monosaccharides, 46 52 properties of, 153-155 Heat of evaporation, for levoglucosan, reactions of, 155-157 52 -, 1,2:5,6-di-O-isopropylidene-~-, Heat of formation, for levoglucosan, 52 conformation of, 201 2-Heptulopyranose, 2,7:3,4-dianhydro-p- Hexofuranos-5-ulose, 1,6-anhydro-2,3-0D-munno-, structure of, 109 isopropylidene-p-D-lyxo-, prepara-, 2,7:4,5-dianhydro-p-~-aZtro-, struction of, 156 ture of, 109 Hexoglycosuloses, 1,6-anhydro-, 1,4,7,1O,13,16-Hexaoxadibenzo[b,k]conformation of, 100 cyclooctadecane, in Koenigs-Knorr Hexokinase, enzymic activity in liver reaction, 251 metabolism, 326 Hex-1-enitols, 1,5-anhydro-2-deoxy-, Hexopyranose, 1,6-anhydro-2-bromo1,6-anhydrohexoses from, 47,48 2,3,4-trideoxy-P-~~-, preparation Hex-5-enofuranose, 2,3,5-tri-O-acetylof, 48 -, 1,6-anhydro-3-C-(cyanomethyl)-2,31,6-anhydro-p-~-urabino-,preparadideoxy-p-D-ribo-, preparation of, tion of, 156 140 Hex-2-enopyrariose, 3-0-acetyl-1,6anhydr0-2,4-dideoxy-p-~-glycero-, -, 1,6-anhydro-2-deoxy-p-~-xylo-, preparation of, 103 preparation of, 140 -, 1,6-anhydro-3-deoxy-p-~-arabino-, -, 1,6-anhydro-2,3,4-trideoxy-p-DLglycero-, preparation and epoxidation preparation of, 140 of, 48 -, 1,6-anhydro-3-deoxy-p-D-ribo-, Hex-3-enopyranose, 4-0-acetyl-1,6preparation of, 140 anhydro-2,3-0-isopropylidene-, 1,6-anhydro-3-deoxy-P-~xyZo-, p-D-threO-, preparation of, 98 preparation of, 140 Hexenopyranoses, 1,6-anhydro-, prepp-toluenesulfonylation of, 81 -, 1,6-anhydro4-deoxy-p-~-urubino-, aration of, 145 I3ex-2-enopyranos-4-ulose, 1,6-anhydropreparation of, 140 -, 1,6-anhydro-4-deoxy-4-diazo-2,3-02,3-dideoxy-p-~-glycero-, synthesis isopropylidene-p-D-lyxo-, preparaof, 103 tion of, 98 I3ex-3-enopyranos-2-ulose, 3-0-acety1,6-anhydro-4-deoxy-p-~-glycero-, -, 1,6-anhydro-2-deoxy-1(6)-thio-p-Dpreparation of, 96 arabino-, preparation of, 146 --, 1,6-anhydro-3,4-dideoxy-p-~-gZycero-,-, 1,6-anhydro-3-deoxy-2-O-p-tolylsulfonyl-6-D-, preparation of, 81 -, 1,6-anhydro-2,3-0-isopropylideneP-D-. as synthetic intermediate, 90 -, 1,6:2,3-dianhydro-p-~-,preparation of, 109, 113 Gulopyranoside, methyl 4,6-O-benzylidene-, hydrolysis of, 202 Gulose, D- and L-, derivatives of cyclic acetals, Table, 234 -, 1,6-anhydro-~-,preparation of, 36, 37

SUBJECT INDEX fonyl-P-D-xyb, preparation of, 81 -, 1,6-anhydro-4-deoxy-2-O-p-tolylsulfonyl-P-D-xylo-, preparation of, 141 -, 1,6-anhydro-2,4-dideoxy-2-fluorop-D-xylo-, preparation of, 135 -, 1,6-anhydro-2,3,4-trideoxy-, structure of, 26

-, 1,6-anhydro-2,3,4-trideoxy-p-~glycerochiroptical properties of, 52 preparation of, 146

-, 1,6-anhydro-2,3,4-trideoxy-p-~~-

429 129-131

etherification and esterification of,

74-76 formation and preparation of, 26-49 formation by mineral acids, 34-37 fragmentation processes, 62 glycosylation of, 159-161 halogeno derivatives, 131- 136 infrared spectroscopy of, 56 isopropylidene derivatives, Table

VII, 171

mass spectrometry of, 62 glycero-, methanesulfonylation of, 82 acid cleavage of, 64 mono- and die-substituted derivapolymerization of, 74 tives, Table VI, 166-169 preparation from acrolein, 48 nitrogen analogs, 121-131,149 reductive cleavage of, 69 nucleophilic substitutions in, 85-87,92 -, 2,4-di-O-acetyl-l,6-anhydro-3oxidation (partial) of, 93-96 deoxy-p-D-urubino-, preparation of, partially substituted, 78-85 periodate oxidation of, 104-107 137 -, 1,6:2,3-dianhydro-4-deoxy-p-~~I-ibo-, per-0-substituted, 77,78 polymerization of, 69-74 reaction with butyllithium, 49 properties of, 50-63 Hexopyranoses proton magnetic resonance spectroscyclization of 6-C-substituted, 33,34 copy of, and conformation, 56-61 -, 1,6-anhydropyrolysis of, 69 acetalation of, 89-93 reactions of, 63-107 acetates, Table, 164,165 with boron tribromide or trichloride, acetylation of, 83 68 alkylation of, 84 with trifluoromethanesulfonic acid, aminodeoxy, preparation of, 98 87,88 Table, 173,174 reductive cleavage of, 69 amino derivatives, properties and structure of, 50, 51 reactions of, 126-129 analogs, 146-151 synthesis of, 75,145 benzoylation of, 82 from acrolein, 112 thio derivatives, 136-139 chiroptical propelties of, and aminop-toluenesulfonylation of, 80 deoxy, deoxyfluoro, and deoxy unsaturated, preparation of, 145,146 derivatives, 52,53 -, dianhydrochromatography of, 62 and derivatives, Table, 172 cleavage of, by acid 63-69 hydrogenation of, reductive cleavage complexes, 54,55 of, 141 conformation of, 51 oxidation of, 100 dehalogenation and desulfurization of, 141 properties of, 112-115 reactions of substituted, 120,121 deoxy, dideoxy, and trideoxy, Table X, Table XI, 175,176 of unsubstituted, 117-119 deoxy, formation and preparation, -, 1,6:2,3-dianhydro140-143 cleavage of, with ammonia, amine, and properties and reactions of, 143-145 azide ions, 122-125 dideoxy, synthesis of, 141 Preparation of, 107-112 epimines and amino epoxides of, -, 1,6:3,4-dianhydro-

430

SUBJECT INDEX

cleavage of, with ammonia, amine, 0-substituted, 73 and azide ions, 122 Hexoses, pyrolysis of, 151-153 preparation of, 107-1 12 -, 1,6-anhydroHexopyranoside, methyl 4,W-benzylpreparation of, 32 idene-, fragmentation patterns of, from 2,3-unsaturated hexopyrano194 sides, 47 -, methyl 4-(cyanomethylene)-4-deoxysynthesis from acrolein, 49 2,3-O-isopropylidene-6-O-methyl-, 1,4:3,6-dianhydro-,formation during a-D-lyxo-, crystal structure biblipyrolysis of starch and cellulose, 42 ography, 358 Hexoside, niethyl 2-deoxy-a-~-and -, methyl 4,6-dideoxy-l,2-O-isopropyl- p - ~ - r i b ~preparation -, of, 281 idene-a-D-xylo-, conformation of, Hexosyl bromide, 2-deoxy-3,5,6-tri-03200 (p-nitrobenzoy1)-a-D-ribo-, Hexopyranos-2-ulose, 1,6-anhydro-3,4methanolysis of, 281 dideoxy-, preparation of, 103 Hexulopyranosonic acid, a-L-xylo-, -, 1,6-anhydro-3,4-O-isopropylidenemonohydrate, crystal structure bibliP-D-lyxo-, preparation and reducography 349 tion of, and hydrate, 91, 97 Hexulosonic acid, D-UrUbhO-, calcium -, 1,6-anhydro-3,4-O-isopropylidenesalt trihydrate, crystal structure p - ~ r i b o -acetylation , of, 98 bibliography, 371 Hexopyranos-3-ulose, 1,6-anhydro-P-~Hydrogen fluoride, in anhydridization urubino-, dimers and acetals, 96 of hexoses, 46 -, 1,6-anhydro-P-~-lyxo-,preparation Hydrogenolysis of, 95 of 1,6-anhydrohexopyranose ethers -, 1,6-anhydro-p-D-ribo-,dimers, 96 and esters, 74, 75 -, 1,6-anhydro-p-~-xylo-, dimers and of cyclic acetals, 205 acetals, 96 of levoglucosan, 69 -, 1,6-anhydro-4-deoxy-2-O~-tolylsul- Hydrolysis fonyl-p-D-threo-, preparation of, of aminodeoxy 1,6-anhydrohexo103 pyranoses, 128 -, 1,6-anhydro-2,4-dideoxy-p-~-glycero-, mechanism of, of cyclic acetals, preparation of, 103 202-205 -, 1,6-anhydro-2,4-di~-p-tolylsulfonyl- Hyperuricemia, mechanism of D-fructoseP-DI-ibo-, isomerization of, 101 induced, 322-324 -, 2,4-di-O-acetyl-1,6-anhydro-P-~Hypochlorous acid, in chlorinolysis of glycosidic bond, 48 lyxo-, preparation of, 96 Hexopyranos-4-ulose, 1,6-anhydro-2,3Hypophosphorous acid, 1,6-anhydrohexodideoxy- preparation of, 103 pyranose cleavage by, 69 Hypoxanthine, 8-(2-deoxy-a-~-erythro-, 1,6-anhydro-3C-(hydroxymethyl)2,3-O-isopropylidene-~-~-lyxv-, pentofuranosy1)-, crystal structure preparation of, 100 bibliography, 367 -, 1,6-anhydr0-2,3-O-isopropylidene-

p-D-lyxo-, preparation and reduction of, 97-100 Hexopyranosuloses, preparation of, 93-104 -, 1,Banhydropreparation of, 94-96 properties of, 104 spectral properties of, 104 Hexosans, polymerization of 2,3,4-tri-

I Iditol, I-amino-1,s-anhydro-I-deoxy-L-, preparation of, 150 -, l-amino-1,6-anhydro-l-deoxy-~-, preparation of, 150 -, 1,6-anhydro-~-, crystal structure bibliography, 350 -, 2,5-di-O-acetyl-1,4:3,6-dianhydro1(4);3(6)-dithio-~-, disulfoxide,

SUBJECT INDEX

43 1

Inosine crystal structure bibliography, 372 Idofuranose, 3-chloro-3-deoxy-1,2:5,6-di- cadmium 5’-monophosphate dodecahydrate, crystal structure bibli0-isopropylidene-p-D-, conformation of, 201 ography, 375 -, 1,2:5,6-di-O-isopropylidene-o-, cobalt 5’-phosphate heptahydrate, conformation of, 201 crystal structure bibliography, 366 nickel 5’-phosphate heptahydrate, -, 1.,2:5,6-di-O-isopropylidene-a-~-, hydrolysis of, 203 crystal structure bibliography, 366 cis-platinumdiammonio 5’-monophosIdopyranose, 2-amino-1,6-anhydro-2deoxy-Pa-, preparation of, 122 phate sodium salt 16 hydrate, -, 3-amino-1,6-anhydro-3-deoxy-p-~-, crystal structure bibliography, preparation of, 122, 126 375 -, 5-amino-l,6-anhydro-5-deoxy-p-~-, Invertase, in human intestine, 287 Isomalto-octaose, preparation of, 266 formation of, 149 -, 6-amino-1,6-anhydro-6-deoxy-p-~-, Isomaltose formation of, 149 derivative, preparation of, 270, 271 -, 1,6-anhydro-p-D-, per-0-substituted, preparation of, 266 77 p-Isomaltose, octaacetate, preparation -, 1,6-anhydro-2-S-henzyl-2-thio-~-~-, of, 256,261 Isomaltotetraose, preparation of, 266 preparation of, 136 -, 1,6-anhydro-3-deoxy-3-fluoro-p-D-, specific rotation of, 135 -, 1,6-anhydro-3-deoxy-3-nitro-p-r-, K preparation of, 105, 126 Kanamycin A, preparation of, 262 -, 1,6-anhydro-2,4-di(benzylamino)-, hepta-O-acetyl-tetra-N-(2,4-dinitro2,3,4-trideoxy-3-nitro-p-~-, preparapheny1)-, preparation of, 263 tion of, 106, 126 -, 5,6-diamino-1,6-anhydro-5,6-dideoxy- Kanamycin B, preparation of, 262 Kanamycin C, preparation of, 262 p-L-,formation of, 149 -, 2,3,4-tri-O-acetyl-1,6-anhydro-p-D-, Kanosamine, preparation of, 262 Koenigs-Knorr reaction, 243-283 reaction with trifluoromethanesulfonic acid, 88 glycosylation of anhydrohexopyranoses, -, 2,3,4-triamino-1,6-anhydro-2,3,4160, 161 trideoxy-p-D-, preparation of, 126 history, 245 selectivity in, 85 Idopyranoside, methyl 4,6-0-benzyla-Kojibiose, octaacetate, preparation idene-a-Dof, 261 conformation of, 199 hydrolysis of, 202 -, methyl 4,60-benzylidene-p-D-, L conformation of, 199 Lacquers, from copolymers of levogluIdose, D and L-, derivatives of cyclic cosan with alcohols and ethers, 73 acetals, Table, 222, 223 -, 1,6-anhydro-~-,preparation of, 36, 37 Lactosan, synthesis of, 159, 160 -, 6-thio-, synthesis of, 170 4-Imidazoline-2-thione, 4-a-D-erythrofurLactose, pyrolysis of, 45, 152 anosyl-1-p-tolyl-, crystal structure -, 4’-acetamido-4’-deoxy-a-, preparation bibliography, 372 of, 162 -, l-methyl-4-/3-D-erythrofuranosyl-, Lanthanide shift-reagents, in conformacrystal structure bibliography, tional analysis of acetals, 197 353,362 Levoglucosan Infrared spectroscopy, of 1,6-anhydroacetylation of, 83 hexopyranoses, 56, 63

432

SUBJECT INDEX

2-amino-2-deoxy derivatives, preparation of, 31 benzylation and tritylation of, 85 chiroptical properties of, 52 chromatography of, 63 cleavage of, by acid, 64-69 by hypophosphorous acid, 68,69 by periodate oxidation, 104 reductive, 69 by sodium hydrogen sulfite, 69 complexes, 93 complex formation by, 5 4 , 5 5 conformation of, and triacetate, 51 co-polymerization with alcohols and ethers, 72 determination of, 63 in flaming combustion, 26 glycidyl ethers, 76 heat action on, 52 heats of combustion, formation, dehydration, and evaporation, and vapor-tension data for, 52 history, preparation, and uses of, 2 5 2 7 hydrogenolysis of, 69 infrared spectroscopy of, and derivatives, 56, 63 methylation of, 84 oxidation of, 94 partially substituted, 78 per-0-substituted, 77 polymerization of, 70, 159 preparation of, 27, 32, 33 from acrolein, 48, 49 from monosaccharides, 46 production of, 3845 properties of., SO pyrolysis of, 69 structure of, 50 synthesis of, from Brigl’s anhydride, 29,48 synthetic exploitation of, 79 p-toluenesulfonylation of, 80 triacetate, acid cleavage of, 67 cleavage by dichloromethyl methyl ether and zinc chloride, 68 formation of, 46 reaction with antimony pentachloride, 89 reaction with trifluoromethanesulfonic acid, 88

Shorygina reaction in ammonia, 78 tributyrate, tripropionate, tribenzoate, and tristearate, reactions with titanium tetrachloride, 67 Levoglucosan, 2-amino-2-deoxy-, preparation of, 130 -, 4-amino-4-deoxy-, preparation of, 130 Lewis acids copolymerization with 1,6-anhydro2,3,4-tri-O-methyl-p-~-glucopyranose, 74 in degradation of acetals, 8 levoglucosan complexes with, 55, 56 in polymerization reactions, 163 Lichenan, levoglucosan from, 40 Lipid, D-fructose effect on metabolism of, 325-330 Lithium, butyl-, reaction with cyclic acetals, 49, 209 Lithium aluminum hydride, reductive cleavage of 1,6-anhydrohexopyranoses by, 69 Liver D-fructose uptake by, 291 nucleotide pool in, effect of D-fructose on, 322-324 Lyxofuranose, conformation of, 201 -, S-deoxy-3-C-formyl-p-~-,3I-(trimethylene dithioacetal), crystal structure bibliography, 357 -, 5-deoxy-3-C-formyl-1,2-0-isopropylidene-p-L-, 3l-(trimethylene dithioacetal), crystal structure bibliography, 358 Lyxopyranoside, methyl 2,3-O-isopropylidene-cl-D-, hydrolysis of, 204 Lyxose, D- and L-, derivatives of cyclic acetals, Table, 212

M

Maltosan, synthesis of, 158, 159 -, 6-thio-, synthesis of, 170 Maltose, pyrolysis of, 45, 159 -, 1,6-anhydro-hexa-O-lienzyl-, polyni-

erization of, 163 P-Maltose octaacetate, preparation of, 261 synthesis of derivatives of, 162

SUBJECT INDEX

433

Maltotriosan, synthesis of, I59 -, 2-deoxy-2-fluoro-p-D-, crystal strucMaltotriose, pyrolysis of, 45 ture bibliography, 349 -, 1,6-anhydro-I(6)-thio-p-, preparation -, 1,6:2,3-dianhydro-p-~-,preparation of, of, 170 and derivatives, 108, 111, 113 Mannans, pyrolysis of, from ivory-nut -, 1,6:2,3-dianhydro-4-O-benzyl-p-~, kernels, 44 conversion to 1,6-anhydro-2,3-di-OMannitol, 1,4:2,5:3,6-trianhydro-, crystal methyl-P-Dglucopyranose, 79 structure bibliography, 346 as synthetic intermediate, 120 Mannofuranose, 1,6-anhydro-p-~-, 1,6:2,3-dianhydro-4-O-p-tolylsulacetonation of, 155 fonyl-P-D-, as synthetic intermediate, conformation of, 153, 154 121 preparation of, 152 -, 1,2,3,6-tetra-O-acety1-4-0-(2,3,4,6-, 1,2:5,6-di-O-isopropylidene-~-, conte tra-O-acetyl-p-D-galactopyranosy1)formation of, 201 a-D-, preparation of, 162 Mannofuranoside, methyl 5,6-di-O-acetyl- -, tri-O-acetyl-l,6-anhydro-p-D-, reac0-D-,2,3-carbonate, preparation of, tion with trifluoromethanesulfonic and a - anonier, ~ 279 acid, 87 -, 1,3,4-tri-O-acetyl-2,6-anhydro-D-, Mannopyranose, 2-acetamido-2-deoxypreparation of, 129 P-D-, monohydrate, crystal strucMannopyranoside, a-D-glucopyranoSyl ture bibliography, 355 a-D-,preparation of, 265 -, 2-amino-1,6-anhydro-2-deoxy-P-D-, preparation of, 131 -, methyl 4,6-O-benzylidene-a-Dconformation of, 199 -, 4-amino-1,6-anhydro-4-deoxy-/3-Dhydrolysis of, 202 deamination of, 128 -, methyl 2,3:4,6-di-O-benzylidenepreparation of, 123, 131 a-D-, 1,6-anhydro-~configuration of, 196 acetolysis of, 65 preparation by acetal exchange, 187,188 formation of, 47 -, methyl 2,3-O-isopropylidene-a-D-, -, 1,6-anhydro-p-Dconformation of, 200 Conformation of, 61 -, methyl 2,3,4,6-tetra-o-acetyl-a-D-, copolymer with tribenzyl ethers of crystal structure bibliography, 372 levoglucosan, 73 -, phenyl CX-D-and p-D-,1,6-anhydride per-0-substituted, 77 formation from, 29, 30 2,3-phenylboronate, 93 Mannopyranosyl fluoride, a-D-, reacpolymerization of, 71 tion with sodium methoxide, 31 p-toluenesulfonylation of, 81 Mannose, -, 1,6-anhydro-3-S-benzyl-3-thio-D-, D-, absorptive rate by human jejunum, preparation of, 137 289 -, l,B-anhydr0-4-S-benzyl-4-thio-P-D-, preparation of, 136 derivatives, cyclic acetals, Table, 236-238 -, 1,6-anhydro-3-deoxy-3-fluoro-p-D-, pyrolysis of, 46, 152 preparation of, 1.33 -, 1,6-anhydro-2,3-dideoxy-2,3-epimino- L-, derivatives, cyclic acetals, Table, 236-238 p-D-,preparation of, 129, 131 -, 1,6-anhydro-D-, formation of, 36 -, 1,6-anhydro-2,3-0-isopropylidene-, 1,6-anhydro-p-~p-D-,oxidation of, 97 complexes, 54, 55 -, 1,6-anhydro-2,3-0-isopropylidene4-thio-p-D-, preparation of, 136 from mannan pyrolysis, 44 -, 1,6-anhydro-2-O-p-tolylsulfonyl-, 6-O-a-D-xy1opyranosyl-D-, preparation of, 258 0-D-,preparation of, 81

434

SUBJECT INDEX

DMannose kinase, in metabolism of D-fructose, 331 Mass spectrometry of 1,6-anhydrofuranoses, 155 of 1,6-anhydrohexopyranoses,62 and structure of cyclic acetals, 192194 Melibiose, pyrolysis of, 45, 152 Mercuric chloride, in anhydridization of hexoses, 47 Mercury salts, in Koenigs-Knorr reaction, 246, 251, 252 Metabolisni of epithelial cells of intestine, effect of Dfructose on, 324 of ethanol, effect of Dfiuctose on, 317-322 of Dfructans, 315 of Dfructose, 285-343 inborn errors of, 306-310 key enzymes in, 330-343 in micro-organisms, 310-314 of lipids, D-fmctOse effect on, 325-330 Methane, dibromo-, methylene acetals prepared with, 189 Methanesulfonic acid, trifluoro-, reaction with 1,6-anhydrohexopyranoses, 87,88 Methanesulfonylation, of 1,6-anhydrohexopyranoses, 82 Methanolysis of cyclic acetals, 206 of glucopyranosyl chlorides and bromides, 274, 275 of glycofuranosyl bromides and chlorides, 279-281 Methylation analysis, of 1,6-anhydrohexopyranoses, 50 Methyl sulfoxide, as solvent in acetalation, 186 Michaelis-Menten kinetics, of D-fructose transport, 290,291 Micro-organisms, D-fructose metabolism in, 310-314 Monosaccharides, pyrolysis of, 45, 46 Muramic acid, 1,6-anhydro-, synthesis of, 124 Muscarine-related compounds, preparation of, 105

Muscle cells, &fructose metabolism in, 298

N Neuraminic acid, 5-N-acety14,7,8,9-tetra0-acetyl-a-D, rn-bromobenzyl glycoside, crystal structure bihliography, 361 P-Nigerose, octaacetate, preparation of, 261 2-Nonulopyranosidonic acid, m-bromobenzyl S-acetamido-4,7,8,9-tetra-Oacetyl-3,5-dideoxy-~-glycero-a-~ galacto-, crystal structure bibliography, 361 Nuclear magnetic resonance spectroscopy, see also Proton magnetic resonance spectroscopy of 1,6-anhydrohexopyranoses,51 and conformational equilibria of cyclic acetals, 198-202 and structure of cyclic acetals,195-198 Nucleophilic agents, oxirane ring cleavage by, 115 Nucleophilic substitution in 1,6-anhydrohexopyranoses,85-87, 92 dianhydrohexopyranose preparation by, 107 Nucleosides, crystal structure bibliography, 346,363-378 Nucleotide pool, in liver, effect of D-fructose on, 322-324 Nucleotides, crystal structure bi bl iography, 346,362-378

0 Obituary, Edward John Bourne, 1-22 Octopyranose, 7-azido-8-deoxy-1,2:3,4di-O-isopropylidene-6,7-dithio6,7-s -trimethylene-D-ery throa-D-galacto-, crystal structure bibliography, 361 Oligosaccharides 1,6-anhydro, preparation of, 158-161 properties and reactions of, 161-163, 170 methyl a-isomalto-, preparation of, 262

SUBJECT INDEX preparation of, 267, 275 pyrolysis of, 45, 152 synthesis of, 159 on polymer supports, by KoenigsKnorr reaction, 269 Oligospemlia, D-fructose level in, 304 Optical rotation, of 1,6-anhydrohexofuranoses, 154 1,2-Orthoesters, of acylated sugars, glycoside synthesis from, 244, 248 Oxidation, see also Periodate oxidation of cyclic acetals, 207 partial, of 1,6-anhydrohexopyranoses, 93-96 Oxirane ring cleavage of, reactions involving, 115-1 17 reductive cleavage of, 141 stability of, 131 Oxonium ion, in acetalation reaction, 181 Ozonolysis, of cyclic acetals, 207

Y Panose, preparation of, 257 Paromamine, derivatives, preparation of, 262 Pasteur effect, oxygen inhibition of glycolysis, in spermatozoa, 301 Pent- L-enitol, 1-0-acetyl-2,3:4,5-di-Oisopropylidene-D-erythro-, crystal structure bibliography, 372 Pentopyranoside, ethyl 3-cyano-3,4dideoxy-cu-DL-threo-,crystal structure bibliography, 353 Peptidoglycan, synthesis of disaccharide of, 160 Perchloric acid, 1,6-anhydrohexopyranose cleavage by, 66 Periodate oxidation of acetals, 192 of arninodeoxy 1,6-;mhydrohexopyranoses, 128 of 1,6-anhydrohexofuranoses,154 of 1,6-anhydro-~-~-hexopyranoses, 104-107 and 1,6-anhydrohexopyranose structure, 50 Phenols, from 1,6-anhydrohexopyranose

435

trimethyl ethers in liquid ammonia,

77 Pheromones, 1,6-anhydro-2,3,4-trideoxyhexopyranoses in aggregation, of westem-pine bark-beetle, 26 Phlorizin, levoglucosan from, 27 Phosphofructokinase, enzymic activity in liver metabolism, 326 Phosphorus pentduoride, as catalyst in polymerization of 1,6-anhydrohexopyranoses, 74 Phosphorylation, of D-fructose by liver, 325 Phosphotransferase system, PEPdependent, 310-312 Photolysis, of cyclic acetals, 207 Phytosphingosine, D-glucosyl-, hydrochloride, crystal structure bibliography, 372 Planteose, derivative, preparation of, 264 Polymerization of acetals, 208 of 1,6-anhydrohexopyranoses,69-74 Poly saccharides enzymic synthesis and degradation of, 8 pyrolysis of, 3845 synthesis of, 250 Praseodymium complex, in conformational analysis of acetals, 198 Proton magnetic resonance spectroscopy of amino 1,6-anhydrohexopyranoses, 127 of 1,6-anhydrohexofuranoses,153 of 1,6-anhydrohexopyranoses,56-61 Purine, 6-chloro-9-p-~-ribofuranosyl-, crystal structure bibliography, 365 -, 6-methyl-9-p-D-ribofuranosyl-,

crystal structure bibliography, 368 2H-Pyran-2-methanol,3,4-dihydropreparation and cyclization of, 48 preparation of, 145 Pyranoid rings, conformation of, 199, 200 P y ridinium bromide, N-[3,4,6-tri-O acetyl-2-deoxy-2-(2,4-dinitroanilino)p-~glucopyranosyl]-,preparation of, 269 Pyrimido[5,4d]pyrimidine, 6-amino-10(p-D-ribopyranosy1amino)-,crystal structure bibliography, 369

SUBJECT INDEX

436

Pyrolysis of hexoses, 1,6-anhydrohexofuranoses prepared by, 151-153 of levoglucosan, 69 mechanism of, of starch and cellulose, 43-45 of monosaccharides, 45, 46 of oligosaccharides, 45, 152 of polysaccharides, 38-45 Pyruvate kinase, enzymic activity in liver metabolism, 326

R Raffinose derivatives, preparation of, 264 pyrolysis of, 152 Rearrangement, acetal migration, 205 Resins, levoglucosan derivatives, 76 Rhamnofuranose, 2,30isopropylideneL-, nuclear magnetic resonance spectra of, 201 Rhamnose, L-, derivatives, cyclic acetals, Table, 240 Ribofuranose, conformation of, 201 -, 1,5-anhydro-2,3-0-isopropylideneD-, formation of, 184 -, 2,3-O-benzylidene-P-D diastereoisomers, 196 preparation of, 184 -, 1,2-O-isopropylidene-a-~-, formation of, 184 -, 2,3-O-isopropylidene-~conformation of, 201 preparation of, 184, 185, 188 Ribofuranosidr:, methyl (Y-D-,preparation of, 281 -, methyl p-D-,preparation of, 278 -, methyl 5-0-benzoyl-2,3-0-methyleneP-D-, preparation of, 191 -, phenyl p-D-,preparation of, 278 Ribofuranosyl bromide, 2-0-acetyl3,5-di-O-benzoyl-p-~-,reaction with methanol or with 1,2,3,4-tetra-Oacetyl-,&D-glucopyranose, 280 -, 3,5-diU-benzoyl-a-~-,reaction with methanol or with 1,2,3,4-tetra-Oacetyl-P-D-glucopyranose, 280 -, 3,5-di-O-benzoyl-2-O-nitro-@-~-, reaction with methanol or with

1,2,3,4-tetra-0-acetyl-P-D-glucopyranose, 280 -, 3,5-di-O-benzoy1-2-0-( p-nitrobenzoyl)-p-D-, reaction with methanol or with 1,2,3,4-tetra-O-acetyl-P-Dglucopyranose, 280 -, 2,3,5-tri-O-benzoyl-P-~-,reaction with methanol or with 1,2,3,4-tetra0-acety-P-D-glucopyranose, 280 -, 2,3,5-tri-O-benzyl-~-,methanolysis of, 281 Ribofuranosyl chloride, 5-O-(methoxycarbony1)-D-, 2,3-carbonate, methanolysis of, 281 D-Ribonucleosides, acetalation by enol ethers, 188 Ribopyranose, 1,6-anhydro-40-benzyl-3bromo-2,3-dideoxy-p-~-,preparation of, 132 -, 1,2:3,4-di-O-isopropylidene-a-D-, formation of, 184 hydrolysis of, 204 -, 3,4-O-isopropylidene-D-, preparation of, 185, 188 Ribose D-, acetonation of, 184, 185 benzylidenation of, 184 derivatives of cyclic acetals, Table, 214, 215 diphenyl dithioacetal, crystal stmcture bibliography, 372 L - , derivatives of cyclic acetals, Table, 214, 215 -, di-0-benzylidene-D-, preparation of, 184 Ruthenium tetraoxide, for oxidation of “isolated” hydroxyl groups, 97, 100

S Salicin, levoglucosan from, 27 Semen, D-fructose in, 304, 305 Serine, O-@-D-x)/lop)/ranosyl-L-, copper(I1) complex, crystal structure bibliography, 356 crystal structure bibliography, 355 Shorygina reaction, 78 Silver salts, in Koenigs-Knorr reaction, 246,275

SUBJECT INDEX Sodium hydrogen sulfite, 1,6-anhydrohexopyranose cleavage by, 69 Sodium strontium a-D-gahctopyranuronate hexahydrate, crystal structure bibliography, 348 Solvents, effect on glycosidation reactions, 277 Sophorose, pyrolysis of, 45 Sorbose, L-, absorptive rate by human jejunum, 289 Spermatozoa fructolysis by, 300-302 D-fiuctose metabolism in, 298-305 regulation of, 302 Stachyose, hydrate, crystal structure bibliography, 372 Stannic chloride, in anhydridization of hexoses, 46 Starch enzymic conversion into Dglucose and D-glucose-D-fructose mixture, 286 enzymic synthesis and degradation of, 6 pyrolysis of, 38-45, 152 mechanism of, 43-45 Stereochemistry, of cyclic acetals, 198-202 Stevioside, 1,6-anhydride formation from, 33 Streptolin, hydrolysis of, 122 Streptomycin, dihydro-, synthesis of, and derivative, 281, 282 Streptothricin, hydrolysis of, 122 Structure of cyclic acetals, mass spectrometry and, 192-194 nuclear magnetic resonance spectroscopy and, 195-198 Styrene, copolymerization with 1,6-anhydro-2,3,4-tri-O-methyl-P-D-ghcopyranose, 74 Succinimide, N-bromoin acetal preparation, 191 reactions with cyclic acetals, 206 Sucrose effect on metabolism of ethanol, 318 history, 286 hydrolysis in human intestine, 287,288 pyrolysis of, 45

437

-, 2,3,4,lr,3’,4’,6’-hepta-0-acetyl-,

Koenigs-Knorr reaction with, 264 -, 2,3,4,6,1’,3’,4’-hepta-O-acetyl-, Koenigs-Knorr reaction with, 264 -, octa-0-benzyl-, preparation of, 259 Sugars 2-amino-2-deoxy, 1,2-cis-glycosides, preparation of, 268 branched-chain, cyclic acetals in preparation of, 209 synthesis of, 97, 100, 158 synthesis of, trifluoroacetic acid in, 8 Sulfonic esters, nucleophilic displacement of, 85, 107, 125

T Talofuranose, 1,5-anhydro-a-~-,preparation of, 157 -, 1,6-anhydro-a-~ preparation of, 153, 157 stability of, 153 -, 1,2:5,6-di-O-isopropylidene-~-, conformation of, 201 Talopyranose, 4-amino- 1,6-anhydro-4deoxy-P-D-, preparation of, 126 -, 1,6-anhydro-, per-0-substituted, 77 -, 1,6-anhydro-~-,acetolysis of, 65 -, 1,6-anhydro-p-Dacetalation of, 90,91 complexes, 55 conformation of, 61 deuterated and other derivatives, synthesis of, 97-99 p-toluenesulfonylation of, 82 -, 1,6-anhydro-2,4-di-0-p-tolylsulfonylp-D-,preparation of, 82 -, 1,6-anhydro-3-C-(hydroxymethyl)2,3-O-isopropylidene-p-D-, prepara-

tion of, 100 -, 1,6-anhydro-2,3-0-isopropylidene-

p-Dformation by acetal migration, 205 mass spectrometry of, 62 -, 1,6-anhydro-3,4-0-isopropylidenep-D-

acetal migration in, 205 mass spectrometry of, 62 -, 2,4-diamino-l,6-anhydro-2,4-dideoxyp-D-, preparation of, 122

SUBJECT INDEX

438

-, 1,6:2,3-dianhydro-p-~mass spectrometry of, 62 preparation of, 107, 113 -,

1,6:3,4-diarthydro-p-~-, preparation

of, 107, 113 -, 1,6:2,3-dianhydro-40rnethyl-p-~-, as synthetic intermediate, 121 -, tri-O-acetyl-1,6-anhydro-p-~-, reaction with trifluoromethanesulfonic acid, 88 Talopyranoside, methyl 4,6-0-benzylidene-, hydrolysis of, 202 -, methyl 2,3-0-isopropyhdene-a-~-, conformation of, 200 Talose, D-, acetonation of, 184 derivatives, cyclic acetals, Table, 239 L-, derivatives, cyclic acetals, Table, 239 -, 1,6-anhydro-D-, formation of, 36 -, 1,2:5,6-di-C-isopropylidene-~-, formation (of, 184 -, 2,3:5,6-di-O-isopropylidene-~-, preparation of, 184 Testes, D-fructose metabolism in, 298-305 Testosterone, plasma, and seminal D-fructose values, 303-305 Tetrazole, 1-p-D-ribofuranosyl-, crystal structure bibliography, 372 Threose, D- and L-, derivatives, cyclic acetals, Table, 210 Thulium complex, in conformational analysis of acetals, 198 Tigogenin, reaction with tetra-0-acetya-D-glucopyranosyl bromide in presence of silver salts, 249 Titanium tetrabromide, 1,8anhydrohexopyranose cleavage by, 67 Titanium tetrachloride, 1,6-anhydrohexopyranose cleavage by, 67 Tobacco smoking, levoglucosan fonnation in, 46 Toluene, apdihalo-, benzylidene acetals prepared with, 188 p-Toluenesulfonic acid, in anhydridization of hexoses, 46,47 p-Toluenesulfonylation, of 1,6-anhydrohexopyranoses, 80 Trehalose, pyrolysis of, 45

a,a-Trehalose, preparation of, 258 Triose kinase control enzyme in D-fructose metabolism in liver, 296 in metabolism of D-fructose, 293, 335 3,6,8-Trioxabicyclo[3.2.lloctane, preparation and hydrogenolysis of, and methyl derivatives, 148 Tritylation, of levoglucosan, 8.5 Trityl fluoroborate, cleavage of cyclic acetals by, 207

U Uracil, 5-acetyl-1-(3,5-0-isopropylidenep-D-xybfuranoSyl)-, crystal structure bibliography, 376 Uridine, crystal structure bibliography, 363 -, adenylyl-(3’-, 5 ’ ) - ,9-aminoacridine complex, pentadecahydrate, crystal structure bibliography, 377 -, 2‘-deoxy-, 5‘-phosphate disodium salt pentahydrate, crystal structure bibliography, 373 -, 5-fluoro-4’-thio-, crystal structure bibliography, 373 Uridine-5-oxyacetic acid, methyl ester monohydrate, crystal structure bibliography, 369

V Vapor-tension data, for levoglucosan, 52

W Walden inversion, in 1,Banhydrohexopyranoses, 85, 87 Wood, levoglucosan from, 38, 40

X X-ray diffraction, and furanoid ring structure, 201 Xylofuranose, conformation of, 201 -, 1,2:3,S-di-O-benzylidene-a-~-, diastereoisomers, 196 hydrolysis of, 203 preparation of, 186 -, 1,2:3,5-di-C-cyclohexylidene-a-~-, hydrolysis of, 203

SUBJECT INDEX -, 1,2:3,5-di-O-isopropylidene-a-o-,

hydrolysis of, 203 -, 1,2-O-isopropylidene-a-r>-, conformation of, 201 Xylofuranosyl bromide, 3,5-di-@acyl2-bromo-2-deoxy-p-~-,methanolysis of, 281 Xylopyranose, (Y-D-, 1,2,4-0rthobenzoate, crystal structure bibliography, 357 Xylopyranoside, a-D-glucopyranosyl WD-,preparation of, 265 -, swine p-D-, and copper(I1) complex, crystal structure bibliography, 355

A 8 7 C 8 D 9

E O F

1

G

2

H 3 1 4 J 5

439

Xylose, D-, absorptive rate by human jejunum, 289 benzylidenation of, 186 derivatives, cyclic acetals, Table, 216 L, derivatives, cyclic acetals, Table, 216

Z Zinc chloride, in anhydridization of hexoses, 46

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