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PREFACE This issue of Advances features an extensive article by García Fernández and Ortiz Mellet (Seville, Spain) on N-thiocarbonyl derivatives of carbohydrates. The classic role of these highly reactive derivatives in the synthesis of heterocyclic structures attached to sugar residues has in recent years expanded greatly and now touches on many areas of glycobiology. These derivatives provide simple and efficient methods for tailored construction of complex structural targets, as already well exemplified in established procedures for preparation of neoglycoproteins; newer and developing aspects include potential applications in such areas as solid-phase synthesis and combinatorial chemistry. A chapter contributed by Varela and Orgueira (Buenos Aires, Argentina) deals with synthetic polyamides formed from sugar derivatives containing amino and carboxyl functionalities. Such chiral analogues of nylon present interesting structural aspects stemming from stereochemical differences in the monomers, and at the practical level they provide a mode for conferring hydrophilicity, biocompatibility, and biodegradability on the polymers. The classic work of Emil Fischer more than a century ago introduced the chemistry of sugars reacting with phenylhydrazine as a key tool in elucidating stereochemical relationships, and subsequent years revealed a rich variety of products arising from the reactions of different hydrazines with sugars. The structural identity of many of these compounds remained controversial for many years, however, until the advent of modern spectroscopic and X-ray techniques. In a comprehensive article that reflects a career-long preoccupation with this subject, El Khadem, in collaboration with Fatiadi (Washington, DC), surveys the entire modern literature on the multifarious compounds resulting from reactions of sugars and their carbocyclic analogues with hydrazine derivatives, emphasizing important applications in synthesis and pointing out areas ripe for further exploration. One of the oldest areas of enzymology is the action of glycosylases on carbohydrate substrates, but precise mechanistic and stereochemical interpretation of the behavior of these enzymes is still lacking. With the aid in particular of extensive recent X-ray structural work on glycoside hydrolases and studies with substrate analogues, Hehre (New York) here presents detailed insight into the stereochemical factors at work in the action of the “inverting” and “retaining” enzymes. Volume 52 of this series featured the comprehensive IUPAC-IUBMB document “Nomenclature of Carbohydrates” that meets a long-standing need for up-to-date standardized nomenclature for sugar derivatives and complex saccharides. Ongoing work of the international committee has ix
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now brought about the updated set of recommendations “Nomenclature of Glycolipids,” which is published in this volume. The life and work of two Nobel Prize winners who made major contributions to the carbohydrate field are recorded here by Buchanan (Bath, UK) writing on Alexander Lord Todd and by Moses (London) with an article on Melvin Calvin. Godshall (New Orleans) provides an appreciation of Margaret Clarke, whose global influence in the field of sugar technology was but one aspect of her remarkable personal talents in bringing together carbohydrate scientists around the world in constructive synergy. Washington, DC September 1999
DEREK HORTON
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LORD TODD
1907–1997 Alexander Robertus Todd was born in Cathcart, a southern suburban area of Glasgow, Scotland, on October 2, 1907, second in a family of three. His father, Alexander Todd, then a clerk in the head office of the Glasgow Subway Railway Company, became its secretary and was later managing director of the Drapery and Furnishing Cooperative Society Limited, a substantial department store at Glasgow Cross. His paternal grandfather was a jobbing tailor living close to the Gorbals area of Glasgow. His maternal grandmother (née Ramsay) was the daughter of a farm worker on the Duke of Hamilton’s estate at Cadzow in Lanarkshire who married Robert Lowrie, a foreman in an engineering works in Polmadie. His mother, Jane Lowrie, was born near to his father’s birthplace. Both parents had only an elementary education and Alexander was essentially self-taught, with the help of night classes. His parents believed passionately in the value of education for their children. In 1912, Alex Todd went to Holmlea Public School in Cathcart, near to his home. When, in 1914, the family moved a few miles to Clarkston, the expectation that the tramway would be extended was not fulfilled and the young Alex had a long walk to and from school each day. In 1918 he entered Allan Glen’s School in the center of Glasgow, accessible by train from Clarkston, and passed the Scottish Education Department’s Qualifying Examination to enter the senior school in 1919. His parents were encouraged in this course of action and in his future education by his uncle, Walter Todd, who was a Glasgow University graduate. Allan Glen’s was also known as the Glasgow High School of Science, and there was a strong emphasis on the teaching of mathematics, physics, and chemistry. Alex’s interest in chemistry, awakened by a home chemistry set and encouraged by the proximity of Baird and Tatlock, the laboratory suppliers to the school laboratory, was fostered by the good teaching of Robert Gillespie. The same could not be said for his physics instruction and Todd, in his autobiography,* blames this in part for his later attitude toward physical chemistry. * “A time to remember: the autobiography of a chemist,” Cambridge University Press (1983). 0065-2318/00 $30.00
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Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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Alex Todd passed the Scottish Higher Leaving Certificate in the spring of 1924 and entered Glasgow University a few days before his 17th birthday. In his first year he won the Joseph Black medal and Roger Muirhead prize, which provided him with a scholarship for the remainder of his course. He did not enjoy the strong emphasis on quantitative inorganic analysis in the practical classes, but in his final year he worked with T. S. Patterson, Professor of Organic Chemistry, on the reaction of phosphorus pentachloride with diethyl tartrate. The B.Sc. course also involved the study of subsidiary subjects which included physics, mathematics, geology, bacteriology, and metallurgy. He showed a marked aptitude for mathematics and became very interested in geology, including paleontology, which gave him an introduction to biology. Todd graduated in June, 1928 with first class honors, top of his year, and was awarded a Carnegie Research Scholarship to work with Professor Patterson on the optical rotatory dispersion of mannitol derivatives. He soon realized that the organic chemistry of naturally occurring compounds was the subject which most appealed to him. With Patterson’s encouragement he applied to and was accepted by Professor Walther Borsche in the University of Frankfurt-am-Main, to work on bile acids, beginning in October, 1929. The move to Germany widened his horizons in many ways. The combination of natural product and synthetic organic chemistry in Frankfurt was much to his liking and the level of equipment and availability of experimental techniques, particularly catalytic hydrogenation and microanalysis, was much better than he had known before. He found that he had a flair for languages, and much later in his career took great pride in introducing speakers in their native language, including Russian and, in one case at least, Mandarin Chinese. In addition, he formed lifelong frienships with other British chemists who had made the pilgrimage to Germany, particularly B. K. Blount and A. L. Morrison. Two of his Glasgow contemporaries, T. F. Macrae and A. Lawson, went to Munich at the same time. Todd submitted his Dr. phil.nat. thesis in the early summer of 1931 and, on Patterson’s advice, applied for an 1851 Exhibition Senior Studentship. When this was successful he joined Oriel College, Oxford in September, 1931 to work with Robert Robinson, who had recently moved from Manchester. Following earlier synthetic studies by Alexander Robertson, he synthesised the diglucoside anthocyanins hirsutin, malvin, pelargonin, peonin, and cyanin as their chloride salts.1 In his autobiography Todd recalls the first crystallization of the intermediate crucial to the project, 2-O(2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)phloroglucinaldehyde, which had proved intractable up to this point. His laboratory was adjacent to that of Robinson, and during a tea break devoted to solving the Times crossword with Robinson and Blount, a methanolic solution was dropped accidentally
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into a hot water bath. The following morning crystals had appeared in the dirty flask, which awaited washing up. The almost daily contact with Robinson also led to a collaboraiton with Professor Harold Raistrick on some anthraquinone pigments isolated from plant pathogens of the Helminthosporium group. In 1934 Todd, as a Research Assistant and then a Beit Memorial Research Fellow, joined George Barger, Professor of Medicinal Chemistry at the University of Edinburgh, to study the chemistry of the antiberiberi vitamin B1 (thiamine). The laboratory was a cosmopolitan one and he formed his first research group, which included Franz Bergel, recently arrived from Freiburg. Through Barger, Todd established contacts with Hoffmann-La Roche of Basle, where concentrates of the vitamin were prepared. This was his first experience of an industrial collaboration and one which was to last for the remainder of his career. In competition with well-financed groups in Germany and the United States (Merck), Todd and Bergel produced a synthesis of the vitamin2 which was not only the most elegant of the first syntheses but, in its essentials, is used industrially to this day. In 1936, when J. M. Gulland left the Lister Institute of Preventive Medicine to take up the Chair of Chemistry in Nottingham, Todd was appointed in his place and was made Reader a few months later. The head of biochemistry at that time was Robert Robison, well known for his pioneering work on sugar phosphates, and the Institute itself had a strong reputation in the field of vitamins. At the Lister, Todd completed the work on thiamine and its analogs and began studies on vitamin E. Making use of the animal facilities in the Institute he isolated 웁-tocopherol from rice-germ oil, helped to establish the main features of its structure, and began its syntheses and that of 움-tocopherol. He also studied the active principle of Cannabis indica (C. sativa) and the hyaluronidase in testicular extracts. In 1937 Todd was approached by R. A. Millikan, President of the California Institute of Technology, with a view to a new Professorship of Bioorganic Chemistry in Pasadena. In March the following year he and his wife made the trip to California, by ship and train, spending several weeks there and making plans for future equipment, courses, and research. He established a lasting friendship with Linus Pauling, who would have been his colleague. He returned to Britain with a firm offer in his hand, having promised to give Millikan a definite reply within 10 days of his arrival home. Unexpectedly, there was a telegram awaiting him from the ViceChancellor of Manchester University. A few days later he found himself being interviewed to replace Professor I. M. Heilbron, who was moving to Imperial College, London. At the age of 30, he was appointed to the Sir Samuel Hall Chair of Chemistry in Manchester University. The decision to go to Manchester was a turning point in his career.
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Established in Manchester, Todd continued research on vitamin E and the constituents of Cannabis. He had many wartime commitments, including research on chemical defence and antimalarials, and was a member of the British team on penicillin. He was, however, able to begin the work whose ultimate objective was the synthesis of the nucleotide coenzymes, several of which are closely related to the B vitamins, and potentially leading to a study of the nucleic acids. Attention was directed initially to each of the components, the heterocyclic bases, the nucleosides, and the chemistry of phosphoric esters. This broad strategic plan,3 begun in Manchester, was continued and expanded when Todd was appointed to the Chair of Organic Chemistry in Cambridge in 1944.
There already existed a large body of structural work on nucleosides and nucleotides, mainly by P. A. Levene and his collaborators at the Rockefeller Institute in New York. The Lister Institute had an excellent library on its top floor and it is said that while he was there Todd became familiar with the Levene and Bass monograph “Nucleic Acids.” The structures of the pyrimidine nucleosides uridine and cytidine had been established, apart from their anomeric configurations. Gulland and his colleagues had shown, by UV spectroscopy, that in the purine nucleosides adenosine and guanosine the point of attachment of the ribofuranosyl unit to adenine and guanine was N9 rather than N7, but again the anomeric configuration was in doubt. Confirmation of the ribonucleoside structures by chemical synthesis was highly desirable, and an unambiguous synthesis of adenosine was an early objective. The first “nucleoside,”D-glucopyranosyladenine, had been synthesized as long ago as 1914 by Emil Fischer and B. Helferich. The UV spectrum, studied later by Gulland, indicated that, like adenosine, it had N9 substitution and its synthesis from “acetobromoglucose” implied the 웁configuration. A synthesis from a suitable acylated ribofuranosyl halide, not then available, would undoubtedly have led to adenosine but this would not have established rigorously the N9 substitution. In his earlier synthetic
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work with thiamine (vitamin B1) Todd had gained experience of pyrimidine chemistry and of 4,5-diaminopyrimidines in particular. He envisaged a synthesis of adenosine from a 4(6)-amino-6(4)-glycosylaminopyrimidine,4–6 followed by introduction of a 5-amino group. In the well-known Traube purine synthesis, a 4,5-diaminopyrimidine is heated with formic acid to form the imidazole ring, conditions which would certainly cause cleavage of a glycosylamino compound.
During the thiamine work Todd had prepared 4-amino-5-thioformamido6-methylpyrimidine under mild conditions from the diamine and found that it underwent cyclization when heated above its melting point to give 6-methylpurine,7 a reaction which he was now able to exploit for purine nucleoside synthesis. A practical difficulty at the time was the scarcity of D-ribose as a starting material. Under wartime conditions and for some time thereafter, ribose was treated with great respect and most of the early exploratory work was carried out with D-xylose. The first adenine nucleoside to be synthesised by the unambiguous route was 9-D-xylopyranosyladenine,8,9 to be followed by 9-D-ribopyranosyladenine.10 The lactol ring size was determined by periodate oxidation.11 An important synthesis, an early success after the move to Cambridge, was that of 9-D-mannopyranosyladenine.12 When subjected to periodate oxidation it gave the same dialdehyde as from adenosine and Fischer’s glucopyranosyladenine,13 thereby establishing 9-substitution and the 웁-configuration for all three compounds. The synthesis of adenosine itself by this route proved more difficult, but was achieved14 in 1949. The glucopyranosides corresponding to the pyrimidine nucleosides uridine and cytidine had been synthesized by G. E. Hilbert and his colleagues in 1930 and 1936, and a similar comparison of their periodate-oxidation products with those from uridine and cytidine established the 웁 configurations here as well.13 The preparation of the 2,3,5-tri-O-acetylribofuranosyl halides enabled the synthesis of uridine and cytidine15 by the Hilbert route and adenosine and guanosine16 by the Fischer and Helferich method from 2,8-dichloroadenine. At this point the assignment of the 웁 configuration of
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the natural nucleosides depended on the mechanism of reaction of the glycosyl halides. Conclusive evidence for the 웁 configuration in the ribonucleosides was obtained when 5⬘-O-p-tolylsulfonyl derivatives of adenosine and cytidine were found to undergo intramolecular cyclization to give cyclonucleosides, a reaction only possible in the 웁-anomeric configuration and confirmed by X-ray crystallographic studies.17 Analogous structures were established for the 2⬘-deoxynucleosides. They were not oxidized by periodate18 and could be converted into cyclonucleosides,19,20 thus showing the 웁 configuration. In addition the ribonucleoside uridine was converted into 2⬘-deoxyuridine,21 obtained by deamination of the naturally occurring 2⬘-deoxycytidine, via O2,2⬘-cyclouridine,22,23 a versatile intermediate exploited in Cambridge and elsewhere for the synthesis of 3-웁-D-arabinofuranosyluracil (spongouridine) and other nucleosides.24 This and other cyclonucleosides are capable of a remarkable number of useful transformations. In the early 1940s the methods of phosphorylation were fairly primitive. C. Neuberg had used phosphorus oxychloride at the beginning of the century, and a major advance was the introduction of diphenyl phosphorochloridate by P. Brigl and H. Müller in 1939. Dibenzyl triesters, in which removal of benzyl protecting groups by hydrogenolysis occurred more readily, had been prepared in 1939 by L. Zervas by the reaction of silver dibenzyl phosphate with an appropriate bromo compound. Dibenzyl phosphorochloridate was a key compound, said by Zervas to be too unstable to be useful. The preparation of this relatively labile acid chloride was achieved by chlorination of the corresponding phosphite.25 In the longer term the choice of benzyl protecting groups was a happy one. Selective removal of one benzyl group in a triester could be achieved not only by partial hydrogenolysis25–27 but by acid hydrolysis,28 aminolysis,29 anionic displacement,30–32 or reaction with phenol.33 Reaction of a derived phosphate salt, originally a silver salt, with a phosphorochloridate afforded a pyrophosphate.24 The synthetic manipulation of phosphoric esters and pyrophosphates became for the first time a science and not a mystical art. Although many and improved protecting groups are now available, the benzyl ester still has its place in phosphorylation studies. The first application to a nucleotide was a new synthesis of adenosine 5⬘-phosphate and subsequently adenosine 5⬘-diphosphate (ADP).28 A major achievement was the synthesis of adenosine triphosphate (ATP),34 whose linear triphosphate structure had been confirmed by periodate oxidation.35 Uridine 5⬘-diphosphate,36 a degradation product of uridine diphosphate glucose (UDP-Glc), and uridine 5⬘-triphosphate37 were synthesized. Successful syntheses of the nucleotide coenzymes flavin adenine dinu-
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cleotide (FAD)38–40, UDP-Glc,41,42 and nicotinamide adenine dinucleotide (NAD)43–45 required the development of new methods for unsymmetrical P1P2 diesters of pyrophosphoric acid. A major contribution to pyrophosphate, and later phosphodiester, synthesis was the discovery by H. G. Khorana that carbodiimides, which he had prepared in connection with his work with G. W. Kenner on the peptide hormone ACTH, could be used as condensing agents for phosphates.46 Other imidoyl phosphates were prepared47–49 as potential intermediates for unsymmetrical pyrophosphates, together with mixed anhydrides50,51 and phosphoramidates.52–56 Benzyl phosphorochloridates51,57,58 derived from suitably protected nucleosides were also prepared via phosphite intermediates. Some of these methods were applicable to phosphodiester synthesis, as is described later. The synthesis of phosphates by reaction of a phosphate salt with a sugar-derived epoxide25,59 was also studied. It was found that oxidation of a quinol phosphate gave a reactive phosphorylating species which could be used to obtain pyrophosphates and in particular ADP.60,61 The speculation that this was related to biochemical oxidative phosphorylation was not borne out. In parallel with the research directed toward nucleotide coenzymes, Todd became increasingly interested in the nucleic acids. In 1949 C. E. Carter and W. E. Cohn, using ion exchange and paper chromatography, reported that the alkaline hydrolysis of ribonucleic acid (RNA) yielded two separable isomers (a and b) of adenosine monophosphate, neither of which was the 5⬘-phosphate, and in 1950 that the other mononucleotides also existed as mixtures of two isomers. The earlier work by Levene had apparently shown that alkaline hydrolysis of yeast RNA yielded only four mononucleotides, the 3⬘-phosphates of the corresponding nucleosides. Todd’s laboratory was in an ideal position to resolve the puzzle.62,63 It was eventually shown that adenylic acids a and b were the 2⬘- and 3⬘phosphates,64 respectively, and the conflict with Levene’s work could be explained by phosphate migration under the conditions of acid hydrolysis of the nucleotides. The structures of the other a and and b mixtures were also assigned.65–67 Most important was the realization by D. M. Brown and Todd68,69 that the alkaline hydrolysis of RNA was analogous to the behavior of esters of glycerol phosphates described by E. Baer and M. Kates and involved the formation of 2⬘,3⬘-cyclic phosphates which were further hydrolyzed irreversibly to give a mixture of the 2⬘- and 3⬘-monophosphates. The monobenzyl esters of the 2⬘- and 3⬘-phosphates were prepared and related to the parent nucleotides by hydrogenolysis, conditions which did not cause phosphate migration. The action pattern of various diesterases, particularly
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pancreatic ribonuclease70,71 and a spleen nuclease,72 on these monobenzyl esters showed that the phosphodiester linkage in RNA involved the 3⬘- and 5⬘-positions of adjacent ribofuranose units. This was consistent with an analogous (3⬘→5⬘)phosphodiester structure for DNA, which lacks a 2⬘-hydroxyl group and is therefore stable to dilute aqueous alkali. The primary structures of RNA and DNA were thus determined. The work was sufficiently advanced to be reported to the 75th Anniversary Meeting of the American Chemical Society in New York in the autumn of 1951 and provided a firm basis for the entirely independent X-ray structural work of Watson, Crick, Franklin and Wilkins on DNA in 1953. Todd then turned his attention to the synthesis of the remaining mononucleotides66,73 and the dinucleoside phosphates and dinucleotides. (5⬘→5⬘)Linked diesters of ribonucleosides were synthesised,74,75 but the crucial (3⬘→5⬘)-linkage was much more difficult and was first achieved in the deoxyribose series.76 The “unnatural” adenosine 2⬘-(uridine 5⬘-)phosphate was synthesised77 by the phosphorochloridate method and there were further studies on nucleoside phosphites.78,79 Although Todd himself did not fully exploit the methods for nucleotide phosphodiester synthesis, his work laid the foundation for the spectacular advances in the synthesis of polynucleotides, particularly the phosphate triester and H-phosphonate routes. He considered that that his natural successors in this field were A. M. Michelson, F. Cramer, H. G. Khorana, and C. B. Reese. Methods for sequence determination in oligonucleotides were developed.80,81 The 웁-elimination method,80 proposed independently by R. Markham and P. R. Whitfeld, has been developed and applied successfully to individual ribonucleic acids by these and other authors. In Cambridge Todd pursued new research interests. When vitamin B12 was isolated from liver by Lester Smith in Glaxo Laboratories in 1948 he was asked to undertake a chemical study. With A. W. Johnson the products of hydrolysis were shown to contain a benzimidazole nucleotide82,83 and later one of the crystalline degradation products84 gave an important lead in the X-ray studies of Dorothy Hodgkin, which finally solved the structure of the vitamin. Some synthetic work with V. M. Clark was directed toward the corrin ring system, but this was not pursued. A major project was the study of aphid pigments, a topic whose origins can be traced to Todd’s experience with anthraquinones in his Oxford days. The compounds, though quinonoid in character, were much more complicated and only with the advent of NMR were the structures finally solved. A. W. Johnson, S. F. MacDonald, and, later, D. W. Cameron, led an enthusiastic international group, whose work involved not only chemistry but the detection and harvesting of aphid infestations from the broad bean
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fields of Cambridgeshire. In Manchester, and later in Cambridge with A. W. Johnson, he attempted to isolate and identify the “hatching factor” of the potato eelworm. There were other related problems of obligate parasitism which were studied in Cambridge, but with little overall success, due mainly to problems of chromatographic fractionation and biological testing. He was also involved with tropolone natural products, some alkaloid chemistry, and peptide antibiotics of the actinomycin and ostreogrycin groups. Alex Todd was a master in the strategy of research. In his own words: “I always tell youngsters looking for a field of research that they should (1) choose an important one; (2) choose one large enough to give room for changes in direction; and (3) avoid fashionable fields and choose if possible one in which they themselves would be the authors of all or most of the relevant literature.” His view of natural product chemistry embraced biochemically important molecules, however intractable, and not just those immediately amenable to the experimental techniques currently available. He had a genius for organization and delegation, selecting the right person for a particular job, and, in the case of young men, giving them the confidence to succeed. When he moved to Cambridge from Manchester in 1944, at the age of 36, he found a Department requiring complete reorganization and renovation. He brought with him a band of enthusiastic colleagues and research students who helped him to achieve this transformation. In spite of the upheaval and the wartime conditions, the momentum of research was not lost. The material changes were brought about by the Laboratory Superintendent, A. R. Gilson, later responsible for much of the planning for the new University Chemical Laboratory in Lensfield Road. When Todd retired from the Chair of Organic Chemistry in 1971, the new University Chemical Laboratory had been in operation for 15 years and the Department had attained a high international reputation. Todd applied his managerial skills to all of his committee work. He had been elected a Fellow of Christ’s College, Cambridge in 1944 and became Master in 1963. During his Mastership (1963–1978) a major building program was undertaken and statutes changed to admit women students for the first time. In Cambridge he played a major part in founding Churchill College (including his proposal of the College motto “Forward”) and Darwin College. As Chairman of the Syndics of the Cambridge University Press he turned the Press into a profit-making organization. Todd played a full part in national and international affairs. From 1952–1964, under successive Conservative governments, he was Chairman of the Advisory Council on Scientific Policy and Chairman of the Royal
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Commission on Medical Education (1965–1968). He was president of the Chemical Society (1960–1962), of the Society of Chemical Industry (1981–1982), and of the British Association for the Advancement of Science (1969–1970). He was a managing trustee of the Nuffield Foundation (1950–1973) and its Chairman (1973–1979). He was a director of Fisons Ltd. (1963–1978) and a member of the National Research Development Corporation (1968–1976). He was much sought after as a consultant to major chemical and pharmaceutical firms. He was chairman (1980–1988) and later president of the Croucher Foundation in Hong Kong. He was president of the International Union of Pure and Applied Chemistry (1963–1965). While working in Edinburgh Todd met Alison Dale, who was doing postdoctoral research in the Department of Pharmacology of the University. They were married in London in 1937. In his autobiography, with characteristic understatement, he speaks of his marriage to Alison as “perhaps the best thing I ever did.” She gave up her own scientific career and was a great support to him in all of his later enterprises. They had a son and two daughters, and when Alison died in 1987, the year of their golden wedding, he felt the loss very deeply. Alison’s father was Sir Henry Dale, the physiologist and Nobel prizewinner, and both he and Sir Robert Robinson were very influential in advising Alex in his younger days. Alex Todd was a gregarious man, greatly encouraged by his wife, Alison. When Master of Christ’s he and his wife made a point of meeting every member of the College. The group that accompanied him to Cambridge from Manchester became the Toddlers, a dining club which met annually. He was a keen sportsman, a county-class tennis player in his youth, and an enthusiastic golfer and fisher. He eagerly participated in the annual laboratory cricket match, and the writer remembers the determination with which he took a running catch on the boundary in 1949. He enjoyed traveling, often with his wife, and had a wide circle of friends overseas. Alex Todd was a dominating figure, both in stature and in personality. He was never afraid, after due consideration, to take unpopular or unpalatable decisions. In 1943 he was given the opportunity to succeed F. Gowland Hopkins as Professor of Biochemistry in Cambridge, with the strong encouragement of Sir Henry Dale, Sir Robert Robinson, and Sir Charles Harrington. He analyzed the situation with great care and turned down the offer, to the great benefit of Organic Chemistry in Cambridge the following year. Although Todd left Scotland in 1929, apart from his period in Edinburgh in 1934–36, he remained a Scotsman in temperament and outlook. His appointment as the first Chancellor of Strathclyde University in his home city of Glasgow (1965–91) gave him particular pleasure. He received many honors, beginning with the Meldola Medal in
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1936. He was elected to the Fellowship of the Royal Society in 1942, became its president in 1975–80 and received three of its medals (Davy, Royal, and Copley). His work on nucleotides and nucleic acids led to the award of the Nobel Prize for Chemistry in 1957. He was knighted in 1954 and was made a Life Peer, Baron Todd of Trumpington, in 1962. In 1977 he was appointed to the Order of Merit. He was a member of several National Academies worldwide and the holder of many honorary degrees at home and overseas. Many of Alex Todd’s co-workers and students have taken up senior positions in academic life and industry in Britain and overseas. In Cambridge, Dan Brown developed his interests in phospholipid and nucleoside chemistry and later in molecular biology. Basil Lythgoe, who played an important part in the early stages of the nucleoside program, became Professor of Organic Chemistry in Leeds. James (later Sir James) Baddiley held the Chair of Organic Chemistry (and later Chemical Microbiology) in Newcastle upon Tyne; Alan Johnson in Nottingham and Sussex; George Kenner and later Ian Sutherland in Liverpool; Jan Michalski in –Lodz, Poland; Ted Corbett in Dunedin, New Zealand; Charles Dekker in Berkeley, California; Malcolm Clark and David Hutchinson in Warwick; Stuart Trippett in Leicester; Grant Buchanan in Heriot-Watt University, Edinburgh; Gordon Kirby in Loughborough and Glasgow; Don Elmore in Queen’s University, Belfast; Colin Reese in King’s College, London; Cedric Hassall in the University of the West Indies and Swansea; Len Haynes in the University of the West Indies and the Open University; Hugh Forrest in Austin, Texas; Ray Bonnett in Queen Mary and Westfield College, London; Rod Quayle in Sheffield and later Vice-Chancellor Bath University; Mike Blackburn in Sheffield; Neil Hughes in Newcastle upon Tyne. Franz Bergel, and some time later Cedric Hassall, became Director of Research at Roche Products in Welwyn Garden City, where Frank Atherton continued his pioneering work in organophosphate chemistry. Herchel Smith became Director of Research at Wyeth in Philadelphia. Following Alison’s death Alex Todd suffered several setbacks to his health. During that time Barbara Mann, his former secretary, who had moved to Cambridge from Manchester in 1944, looked after him with great care; he died on January 10, 1997. Although to some he appeared austere, the lasting impression of Alex Todd is one of directness, loyalty, and humanity. The world of science has lost one of its major figures. I am greatly indebted to Professor Sir James Baddiley and Dr. Daniel M. Brown for their helpful comments and suggestions in the preparation of this memoir. J. GRANT BUCHANAN
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REFERENCES 0(1) R. Robinson and A. R. Todd, J. Chem. Soc., (1932) 2293–2299; (1932) 2299–2303; (1932) 2488–2496. 0(2) A. R. Todd and F. Bergel, J. Chem. Soc., (1937) 364–367. 0(3) A. R. Todd, J. Chem. Soc., (1946) 647–653 (Pedler Lecture). 0(4) J. Baddiley, B. Lythgoe, D. McNeil, and A. R. Todd, J. Chem. Soc., (1943) 383–386. 0(5) J. Baddiley, B. Lythoge, and A. R. Todd, J. Chem. Soc., (1943) 386–387. 0(6) J. Baddiley, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1943) 571–574. 0(7) A. R. Todd, F. Bergel, and Karimullah, J. Chem. Soc., (1936) 1557–1559. 0(8) G. W. Kenner, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1944) 652–656. 0(9) G. A. Howard, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1945) 556–833. (10) J. Baddiley, G. W. Kenner, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1944) 657–659. (11) B. Lythgoe and A. R. Todd, J. Chem. Soc., (1944) 592–595. (12) B. Lythgoe, H. Smith, and A. R. Todd, J. Chem. Soc., (1947) 355–357. (13) J. Davoll, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1946) 833–838. (14) G. W. Kenner, C. W. Taylor, and A. R. Todd, J. Chem. Soc., (1949) 1620–1624. (15) G. A. Howard, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1947) 1052–1054. (16) J. Davoll, B. Lythgoe, and A. R. Todd, J. Chem. Soc., (1948) 967–969; (1948) 1685-1687. (17) V. M. Clark, A. R. Todd, and J. Zussman, J. Chem. Soc., (1951) 2952–2958. (18) D. M. Brown and B. Lythgoe, J. Chem. Soc., (1950) 1990–1991. (19) W. Andersen, D. H. Hayes, A. M. Michelson, and A. R. Todd, J. Chem. Soc., (1954) 1882–1887. (20) A. M. Michelson and Sir A. R. Todd, J. Chem. Soc., (1955) 816–823. (21) D. M. Brown, D. B. Parihar, C. B. Reese, and Sir A. Todd, J. Chem. Soc., (1958) 3035–3038. (22) D. M. Brown, Sir A. Todd, and S. Varadarajan, J. Chem. Soc., (1956) 2388–2393. (23) D. M. Brown, W. Cochran, E. H. Medlin, and S. Varadarajan, J. Chem. Soc., (1956) 4873–4876. (24) D. M. Brown, D. B. Parihar, and Sir A. Todd, J. Chem. Soc., (1958) 4242–4244. (25) F. R. Atherton, H. T. Openshaw, and A. R. Todd, J. Chem. Soc., (1945) 382–385. (26) V. M. Clark, G. W. Kirby, and Sir A. Todd, J. Chem. Soc., (1958) 3039–3043. (27) F. R. Atherton, H. T. Howard, and A. R. Todd, J. Chem. Soc., (1948) 1106–1111. (28) J. Baddiley and A. R. Todd, J. Chem. Soc., (1947) 648–651. (29) J. Baddiley, V. M. Clark, J. J. Michalski, and A. R. Todd, J. Chem. Soc., (1949) 815–821. (30) V. M. Clark and A. R. Todd, J. Chem. Soc., (1950) 2023–2030; (1950) 2030–2034. (31) J. Lecocq and A. R. Todd, J. Chem. Soc., (1954) 2381–2384. (32) R. J. W. Cremlyn, G. W. Kenner, J. Mather, and Sir A. Todd, J. Chem. Soc., (1958) 528–530. (33) G. W. Kenner and J. Mather, J. Chem. Soc., (1956) 3524–3531. (34) J. Baddiley, A. M. Michelson, and A. R. Todd, J. Chem. Soc., (1949) 582–586. (35) B. Lythgoe and A. R. Todd, Nature, 155 (1945) 695–696. (36) N. Anand, V. M. Clark, R. H. Hall, and A. R. Todd, J. Chem. Soc., (1952) 3665–3669. (37) G. W. Kenner, A. R. Todd, R. F. Webb, and F. J. Weymouth, J. Chem. Soc., (1954) 2288–2293. (38) H. S. Forrest and A. R. Todd, J. Chem. Soc., (1950) 3295–3299. (39) H. S. Mason, H. S. Forrest, and A. R. Todd, J. Chem. Soc., (1952) 2530–2535. (40) S. M. H. Christie, G. W. Kenner, and A. R. Todd, Nature, 170 (1952) 923; J. Chem. Soc., (1954) 46–52. (41) G. W. Kenner, A. R. Todd, and R. F. Webb, J. Chem. Soc., (1954) 2843–2847. (42) A. M. Michelson and Sir A. Todd, J. Chem. Soc., (1956) 3459–3463. (43) L. J. Haynes and A. R. Todd, J. Chem. Soc., (1950) 303–308.
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(44) L. J. Haynes, N. A. Hughes, G. W. Kenner, and Sir A. Todd, J. Chem. Soc., (1957) 3727–3732. (45) N. A. Hughes, G. W. Kenner, and Sir A. Todd, J. Chem. Soc., (1957) 3733–3738. (46) H. G. Khorana and A. R. Todd, J. Chem. Soc., (1953) 2257–2260. (47) B. H. Chase, G. W. Kenner, Sir A. R. Todd, and R. F. Webb, J. Chem. Soc., (1956) 1371–1376. (48) G. W. Kenner, C. B. Reese, and Sir A. Todd, J. Chem. Soc., (1958) 546–551. (49) R. J. Cremlyn, G. W. Kenner, and Sir A. Todd, J. Chem. Soc., (1960) 4511–4514. (50) H. S. Mason and A. R. Todd, J. Chem. Soc., (1951) 2267–2290. (51) S. M. H. Christie, D. T. Elmore, G. W. Kenner, A. R. Todd, and F. J. Weymouth, J. Chem. Soc., (1953) 2947–2953. (52) F. R. Atherton, H. T. Openshaw, and A. R. Todd, J. Chem. Soc., (1945) 660–663. (53) F. R. Atherton and A. R. Todd, J. Chem. Soc., (1947) 674–678. (54) V. M. Clark, G. W. Kirby, and Sir A. Todd, J. Chem. Soc., (1957) 1497–1501. (55) D. M. Brown, J. A. Flint, and N. K. Hamer, J. Chem. Soc., (1964) 326–335. (56) V. M. Clark, Lord Todd, and S. G. Warren, Biochem. Z., 338 (1963) 591–598. (57) N. S. Corby, G. W. Kenner, and A. R. Todd, J. Chem. Soc., (1952) 3669–3675. (58) G. W. Kenner, A. R. Todd, and F. J. Weymouth, J. Chem. Soc., (1952) 3675–3681. (59) W. E. Harvey, J. J. Michalski, and A. R. Todd, J. Chem. Soc., (1951) 2271–2278. (60) V. M. Clark, D. W. Hutchinson, G. W. Kirby, and Sir A. Todd, J. Chem. Soc., (1961) 715–721. (61) V. M. Clark, D. W. Hutchinson, and Sir A. Todd, J. Chem. Soc., (1961) 722–725. (62) D. M. Brown, L. J. Haynes, and A. R. Todd, J. Chem. Soc., (1950) 408; (1950) 3299–3304. (63) D. M. Brown and A. R. Todd, J. Chem. Soc., (1952) 44–51. (64) D. M. Brown, G. D. Fasman, D. I. Magrath, and A. R. Todd, J. Chem. Soc., (1954) 1448–1455. (65) D. M. Brown, D. I. Magrath, and A. R. Todd, J. Chem. Soc., (1952) 2708–2714; (1954) 1442–1447; (1954) 1442–1447; (1955) 4396–4401. (66) A. M. Michelson and A. R. Todd, J. Chem. Soc., (1954) 34–40. (67) F. Baron and D. M. Brown, J. Chem. Soc., (1955) 2855–2860. (68) D. M. Brown and A. R. Todd, J. Chem. Soc., (1952) 52–58. (69) D. M. Brown, D. I. Magrath, A. H. Neilson, and A. R. Todd, Nature, 177 (1956) 1124–1125. (70) D. M. Brown, C. A. Dekker, and A. R. Todd, J. Chem. Soc., (1952) 2715–2721. (71) D. M. Brown and A. R. Todd, J. Chem. Soc., (1953) 2040–2049. (72) D. M. Brown, L. A. Heppel, and R. J. Hilmoe, J. Chem. Soc., (1954) 40–46. (73) D. H. Hayes, A. M. Michelson, and A. R. Todd, J. Chem. Soc., (1955) 808–815. (74) D. T. Elmore and A. R. Todd, J. Chem. Soc., (1952) 3681–3686. (75) R. H. Hall, Sir A. Todd, and R. F. Webb, J. Chem. Soc., (1957) 3291–3296. (76) A. M. Michelson and Sir A. R. Todd, J. Chem. Soc., (1955) 2632–2638. (77) A. M. Michelson, L. Szabo, and Sir A. R. Todd, J. Chem. Soc., (1956) 1546–1549. (78) J. A. Schofield and Sir A. Todd, J. Chem. Soc., (1962) 2316–2320. (79) G. M. Blackburn, J. S. Cohen, and Lord Todd, J. Chem. Soc., (1966) 239–245. (80) D. M. Brown, M. Fried, and Sir A. Todd, J. Chem. Soc., (1955) 2206–2210. (81) G. P. Moss, C. B. Reese, K. Schofield, R. Shapiro, and Lord Todd, J. Chem. Soc., (1963) 1149–1154. (82) J. G. Buchanan, A. W. Johnson, J. A. Mills, and A. R. Todd, Chem. Ind. (London), (1950) 426; J. Chem. Soc., (1950) 2845–2855. (83) A. W. Johnson, G. W. Miller, J. A. Mills, and A. R. Todd, J. Chem. Soc., (1953) 3061–3066. (84) R. Bonnett, J. R. Cannon, A. W. Johnson, and Sir A. Todd, J. Chem. Soc., (1957) 1148–1158.
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
MELVIN CALVIN (1911–1997) Inspiration, competence, confidence, being in the right place at the right time and sheer luck can help toward success in any endeavor. In his unraveling of the path of carbon in photosynthesis, Melvin Calvin was blessed with them all. Born in 1911 to an immigrant family in St. Paul, Minnesota, Calvin became interested in natural phenomena early in life: he collected rocks, watched birds and, in the family grocery store, mused about the physical composition of all those products he saw on the shelves. Inevitably he became drawn to chemistry, earning his B.S. at the Michigan College of Mining and Technology in 1931 and a Ph.D. in 1935 from the University of Minnesota. There he worked with George Glockler on the electron affinity of halogens (initially iodine and later bromine and chlorine as well) from spacecharge effects—Calvin’s problem was to measure the amount of energy released when a halogen atom captures an electron and for that he had first to devise the methods for doing so. With personal savings and a postdoctoral fellowship from the National Research Council, he went to England to spend 2 years with Michael Polanyi at Manchester University. There he immersed himself in the interactions between quantum mechanical theory and chemical experimentation, starting with platinum–hydrogen activation systems. It was an important formative period for Calvin: his first experience of living in Europe, meeting new and different kinds of people and, via the activation of hydrogen by phthalocyanine and copper phthalocyanine, being introduced to pigment chemistry and light absorption which, 10 years later, was to lead him directly into biology and photosynthesis. While he was with Polanyi, Joel Hildebrand of the Berkeley Chemistry Department visited Manchester and Calvin’s future was discussed. Polanyi recommended him highly, letters passed and Gilbert Lewis invited Calvin to join the Berkeley faculty. His own inheritance and experience were the sources of Calvin’s inspiration, competence and confidence; he was soon to benefit from being in the right place at the right time, and good luck followed in due course. 0065-2318/00 $30.00
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Ingen-Housz in the late 18th century showed that, in the light, green plants fixed carbon dioxide. Sugars, including starch and sucrose, were later recognized as being among the main products of photosynthesis in different plants but the biochemical details of carbon dioxide fixation were entirely mysterious. Because the empirical formula for carbohydrates is (HCHO)n, one theory as late as the 1930s supposed a primary reduction of carbon dioxide to formaldehyde with subsequent polymerization. It was all supposition: there was no supporting evidence. Hope came with the discovery of radioisotopes. Here was a method that offered the opportunity of distinguishing between the carbon atoms of the substrate and those preexisting in the plant. Feeding radiolabeled carbon dioxide to green plants should allow the biochemical sequences leading to sugars to be monitored. Early attempts to do so were made in prewar Berkeley by Sam Ruben and Martin Kamen but the experimental difficulties were immense because the only radioisotope of carbon then available was 11C, with a half-life of little more than 20 min; experiments had to be completed within 2 or 3 h of manufacturing the nuclide. Their work attracted the attention of Ernest Lawrence, the founder and director of the Radiation Laboratory which was later to become pivotal in the Manhattan project and famous as a center for nuclear research and development. From his understanding of nuclear physics, Lawrence reasoned that there should exist a long-lived carbon isotope with a mass number of 14 which, if used as a tracer, would greatly aid such biochemical work. Early in 1940, in cans of ammonium nitrate solution used as a shield around Lawrence’s cyclotron, Ruben and Kamen discovered 14C with a half-life of 5700 years. Minute though the quantities were, the two scientists, joined later by Andy Benson, began to use it in an exploration of the path of carbon in photosynthesis until the events of December 7, 1941 put all such nonessential investigations on hold. By the end of the war, Ruben was dead and Kamen and Benson had both left Berkeley; Lawrence, however, had forgotten neither 14C nor the problem of photosynthesis. With radiocarbon now much more plentiful from nuclear reactors, Lawrence suggested to Calvin that he might like to undertake a twofold program: to develop the synthetic chemistry of 14Clabeled compounds and to resume the work on photosynthesis. Adequate supplies of 14C as well as a building (the Old Radiation Laboratory— “ORL” as it was eventually known round the world) were made available and funding was offered by the U.S. Atomic Energy Commission to take the project forward. Then an Associate Professor in the Chemistry Department, Calvin grasped the opportunity with both hands; acting as overall director himself, he invited Benson back to Berkeley to manage the photosynthesis laboratory.
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Calvin and Benson were both chemists and saw experimentation in chemical terms; their sort of chemistry was usually done in solution, accurately weighing or pipetting samples. Rather than using plant material in the form of excised portions of leaves, with all the implied variability between samples, they opted for a system based on microscopic algae cultured under constant conditions. Whenever an experiment was to be performed, algae would be taken from the culture vessel with the experimenters confident that the biological material would always be the same. Though they might not have been quite right about that in those early days, they were a lot closer than if they had used bits of leaf. In their standard experimental conditions, aqueous suspensions of algal cells in flat-sided vessels (the famous “lollipops”) were illuminated by spotlights and allowed to metabilize 14CO2 (supplied in solution as NaH14CO3) for short periods before the reactions were rapidly brought to a halt by dropping the reaction mixture into boiling ethanol. The identification of product molecules was difficult because their actual quantities in chemical terms were minute; it was the radioactivity label they carried which made possible their separation and characterization. It became clear that an early product of carbon dioxide fixation, perhaps the very first in the sequence, was acidic and, from its behavior on ionexchange resins, more likely to be a phosphoric than a carboxylic acid. (In the end it turned out to be both.) Intelligent guesses were made as to what it might be. Years later, Calvin told the story of how its identity came to him as he sat nervously in his car in a red zone at the corner of Cedar and Grove Streets in Berkeley, waiting for his wife who was buying supplies in the local frozen-food outlet. Using isotope dilution and reisolation, this first compound was unequivocally identified as 3-phosphoglyceric acid, the “PGA” of so many subsequent presentations. Had Calvin and his colleagues had forever to rely on ion exchange, it is doubtful whether they could have progressed very fast or very far. Luckily help was at hand—around 1948, Bill Stepka, then a graduate student in the Botany Department in Berkeley, introduced them to paper chromatography and radioautography. There was no looking back; analysis improved by leaps and bounds. Using both classical and novel methods, a whole range of compounds incorporating 14C from labeled bicarbonate was identified, always on minute chemical quantities which were revealed and made accessible by virtue of their 14C labeling. The kinetic relationships between these compounds was explored: how fast and in which order did these substances acquire 14C? Degradation methods were developed that allowed the accumulation of radiocarbon to be measured within the individual atoms of the product molecules. It soon became clear that carbon dioxide was converted into hexoses by
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a reversal of the glycolysis reactions, the reducing power necessary to drive the process deriving from the capture of sunlight by the energy-conversion mechanism of chloroplasts. A new problem arose which turned out to be rather more difficult to solve: if the first stable compound of carbon dioxide fixation was the 3-carbon molecule PGA, what was the 2-carbon acceptor with which carbon dioxide combined? Since, in short-term labeling experiments, this acceptor would not itself be labeled, there was no obvious way to find out. The clues came form the kinetics of the intramolecular distribution of 14C within many of the compounds already shown to be products of carbon dioxide fixation. As it gradually became clear that the biochemistry of carbon fixation was a cyclic process, Calvin and his colleagues moved toward the idea of a 5-carbon acceptor which, in accepting one molecule of carbon dioxide, would be split into two molecules of PGA, each identical with the other except for its labeling pattern. In two classic experiments in 1954 and 1955, Peter Massini from Switzerland and Alex Wilson from New Zealand showed that when the light was switched off and then on again, or the carbon dioxide concentration suddenly decreased, the kinetic behavior of compounds in the putative cycle was consistent with the operation of a cycle. By the late 1950s, the mystery of the path of carbon in photosynthesis had essentially been solved, save for some mopping-up activities. A detailed understanding of the enzymology, particularly of the primary fixation reaction, came later from work in a variety of laboratories. In 1961, Calvin was awarded the Nobel Prize in Chemistry for his work on photosynthesis. In many ways that changed his life. Until then he had been so totally dedicated to his scientific research and teaching that he had not had much contact with the other minor affairs of mankind. Naive in politics, with little time for culture, though having some industrial experience via consultancies, he had no need to concern himself with domestic matters or even his own health as his wife, Genevieve, took care of those things for him. Thus he had little to distract him from chemistry in general and photosynthesis in particular, and this was what he lived for. It was not to last; in 1962, invited by Kennedy to join the President’s Science Advisory Committee, Calvin discovered Washington and the big world outside Berkeley. He became drawn into more and more activities away from his laboratory and his scientific colleagues. However, things in Berkeley were not standing still. In 1959, ORL, which had been within yards of Calvin’s office in the Chemistry Department, was demolished to make room for a major new chemistry building. The photosynthesis group was displaced to a basement a quarter of a mile away down the hill and inevitably its link with Calvin weakened; no longer was he in the lab morning and evening, poring over chromatograms and graphs with
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the experimentalists, working out what it might all mean. The thematic drive that had been so important in keeping the group together had, in any case, grown fainter as the primary problem had been solved. It was an unsatisfactory state of affairs and time to try to develop a new home. Using his contacts and extensive power of persuasion, Calvin succeeded in raising the funding for a new building on the Berkeley campus reserved entirely for the use of his group which, for the first time since its founding in 1945, was to shelter under a common roof. The new building, styled the Laboratory of Chemical Biodynamics (LCB), was remarkable for its circular form and internal architecture intended, in a modern format, to recapture the intimacy and open informality of ORL. Occupied in November, 1963, the three floors were large enough to house some 90 people and the group inexorably grew to fill them. It was still a rosy time for science: for several years more, minimum effort kept the funding coming from the Atomic Energy Commission and its successors, the Energy Research and Development Agency and the Department of Energy. Calvin’s own horizons seemed to expand in step with the availability of space. While many of the earlier activities, including photosynthesis, continued to develop, new ones came (and sometimes went): more work on the physics of light absorption and energy transduction in photosynthesis; the biochemistry of learning in Planaria (including tests of those intriguing claims that cutting a trained worm in two would produce two trained individuals, or that naive worms fed the ground-up corpses of their trained fellows would themselves acquire training—leading to stories of a future in which students would be fed minced professors); genetic control of protein synthesis; the biochemistry of aging; and, eventually, the problems of cancer. But there was not the cohesion of the path of carbon days. Calvin himself could not keep up in detail with all this activity; nevertheless, such was the nature of the group and of his colleagues’ relationships both with him and among themselves, that there was virtually no tendency to fragmentation. That came later, mainly after Calvin retired from the directorship of the group in 1979. Never after the close of the 1950s did the group experience the constant excitement that participants in those early photosynthesis days still remember with such pleasure. In part this resulted from the ending of a unifying theme. The senior staff had, of course, grown older and the gap in age grew more pronounced between them and the graduate students and postdoctoral visitors who continued to flood into the group. (When the group was founded in 1945, Calvin, at 34, was by far the oldest member.) And, of course, the big unified biological sciences research group, which had been so extraordinary in the 1950s, was not longer quite such a novelty later on. Fragmentation of the Calvin group did begin to become more obvious
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when funding grew tighter in the 1970s and individual senior scientists started to acquire their own grants. Unfortunately, it has now progressed so far that, in that marvelous round building, the open spaces with common equipment which once expressed a unitary organization are now divided by screens and cabinets marking off individual territories. Calvin early recognized the value of publicity. With a splendid program going very well indeed, he made sure the world knew what was happening in his laboratory. Students and postdoctoral scientists from around the world began to be attracted to that old wooden building in Berkeley (and to the people who worked in it) as well as to the other wing of the group that had started out developing the chemistry of 14C and progressed into atomic recoil chemistry, brain biochemistry, the origin of life on earth and a host of other activities. While it is difficult now to be accurate, the records show that during the period of 1947–1971 at least 77 advanced degrees were awarded to students in the group and between 230 and 250 postdoctoral visitors came from all corners of the globe. Nor did the pace slacken subsequently. All this was achieved with the help of no more than 14 senior scientific staff, not all of them present during the whole of those 23 years. Benson, initially Calvin’s main collaborator in the photosynthesis studies, left Berkeley in 1954; he was replaced in that role by Al Bassham, who remained with the group for the rest of his working life. With his wide and deep knowledge of chemistry, his ebullient personality and his total dedication to his work, Calvin’s leadership qualities stood revealed. New ideas, not a few of them outrageous, flowed thick and fast. He showed a rare skill in choosing his collaborators and in inspiring all his colleagues with his own enthusiasm. An excellent coordinator, it was often unclear whether those new ideas were totally original or were derived by interaction of his chemical understanding with what he heard from the many people with whom he spoke or whose papers he read. Perhaps it did not matter. What he did was to provide and question, in private and in public, much to the discomfort of his junior colleagues at the ritual Friday morning seminars: many a graduate student cringed as only halfway through his first, carefully prepared sentence, Calvin popped up with the first searching query. He was never a man to stand on ceremony. A postdoc arriving with wife and child from another continent would be invited to stay in the Calvin household until they found their own place. And then Calvin might be seen carrying a sofa on his head into the new postdoc’s flat to help with its furnishing. There were always parties: parties for people leaving, parties for particular events, parties at Christmas, parties for skiing, parties for hiking—and just parties. But in the lab the talk was overwhelmingly of science, results and interpretations, invariably with enthusiasm.
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After stepping down from the directorship of LCB, Calvin maintained a small research group in the Chemistry Department where he continued his own explorations. He became interested in the supposed world shortage of hydrocarbons, proposing the mass cultivation in desert regions of Euphorbia from which, he claimed, an oil could be expressed usable in diesel engines without being refined. Whenever anyone visited, he wanted to know and to understand what they were doing, why they were doing it and could it not perhaps be done better some other way. In 1942 he married Genevieve Jemtegaard. She supported him marvelously as his career developed during the early years of their marriage, taking the domestic burdens off his shoulders so that he could get on with his work largely unencumbered. In some of his projects she became his professional collaborator and together they published a number of papers. Sadly, she died in 1987 and Calvin never recovered from his loss. Not physically robust and carrying the legacy of a severe heart attack that occurred when he was some 40 years old, he gradually became ever more frail and began to lose his intellectual vigor. Still, until the very last few days of his life, he spent several hours each working day in his office, assisted by Marilyn Taylor, that most remarkable of secretaries who had been with him since 1948. She was still there in the office when he died at the age of nearly 86 on January 8, 1997. VIVIAN MOSES
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
MARGARET A. CLARKE
1942–1998 Margaret Alice Clarke, the Managing Director of Sugar Processing Research Institute, Inc., died of cancer on June 18, 1998. Margaret was internationally known, not only within the specialized field of sugar processing, but in the much wider world of carbohydrate chemistry. Her outstanding ability to integrate and synthesize the industrial–technological aspects of carbohydrate chemistry with theoretical and basic carbohydrate research, to bring people together from these disparate worlds for meaningful exchanges, and her intense support of research in new uses of agricultural byproducts and search for new products distinguished her among her peers. Margaret was born in Northern Ireland on May 8, 1942, the oldest child and only daughter among four siblings. At an early age, around 12, her family emigrated to Canada. Her mother, Peggy, describes a little girl who loved to read and was able to do so as early as 3 years of age. She learned all of the domestic arts from her mother, including sewing, cooking, baking, gardening, and the fine craft of gift wrapping, skills she carried throughout her life, to great advantage. She also learned ballet, drama, and piano, skills she did not carry on with, but maintained a great love of each. From her father, she learned the love of socializing and the satisfactions of generosity toward others. Her visionary leadership qualities were demonstrated early on. When her family was leaving Ireland for Canada, Margaret wanted to leave a cup to be won by a pupil in her school, Cambridge House, and so she created an award of a silver cup, the Margaret Clarke Cup, to be won by a junior student who had striven to achieve a better grade. This was not for the student with the highest marks, but rather meant for a student who had shown the most improvement. She received a B.Sc. (Honors) in Chemistry form the University of Western Ontario in 1963 and her Ph.D. in physical inorganic chemistry at Tulane University in New Orleans in 1970. In 1980, she received an MBA from Loyola University. She often told the story of how she came to choose New Orleans for her graduate school. It happened toward the end of her term at 0065-2318/00 $30.00
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Western Ontario, on an icy winter day on campus, when she slipped for the third time. Upon picking herself up, she decided then and there that she would never again live in such a cold climate and set about finding a good school in a more hospitable climate. She chose New Orleans and Tulane. It was evidently a perfect fit, as she loved the city of New Orleans and the state of Louisiana, immersing herself in its culture and cuisine and quickly making lifetime friends. She was hired as a chemist with the Cane Sugar Refining Research Project in 1969 and in 1972 was named the administrator of the Project. In 1981, she became the Managing Director of the organization, which at the time expanded its scope and was renamed Sugar Processing Research Institute, Inc. She remained in this position until the time of her death. In 1991, she married Per J. Garegg. With her marriage to Per, a distinguished professor of chemistry at the Arrhenius Institute, University of Stockholm, came the full maturing of her unique talent for bringing together carbohydrate chemistry groups in small meetings and to make connections among diverse carbohydrate interests. Per encouraged and supported her in this and was also a source of advice in scientific matters. In 1984, during a Christmas visit to New Orleans, Margaret invited Per Garegg and Donald E. Kiely, University of Alabama at Birmingham, to give seminars at the Southern Regional Research Center, where SPRI is located. The twin seminars were repeated the next year. Thus were born the New Orleans Carbohydrate Symposia. In 1987, the program expanded to a day-and-a-half meeting called the Third New Orleans Carbohydrate Symposium. It was again held August 27–28 at the Southern Regional Research Center, utilizing a Gordon Conference format. The speakers at this first formalized meeting, which quickly became nicknamed “Carbo Days” and later became affectionately known as “Carbodaze,” included John Robyt of Iowa State University, Yu-Teh Li of Tulane University School of Medicine, Bertil Samuelsson of Astra AB, Geoffrey N. Richards of the University of Montana, Grant Taylor of the University of Louisville, Michael R. Ladisch of Purdue University, Roger Laine of Louisiana State University, Alfred D. French of the Southern Regional Research Center, and, of course, Per Garegg and Don Kiely, the “founding fathers.” In 1989, the meeting was held prior to the spring meeting of the American Chemical Society to take advantage of European carbohydrate chemists traveling to the United States, and this format continued until the Fourteenth New Orleans Carbohydrate Symposium, held April 2–4, 1998, the final meeting. The list of participants at the New Orleans Carbohydrate Symposia reads
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like a “Who’s Who” of carbohydrate chemistry, and the group photographs taken at the end of each session are an excellent archive of the prominent carbohydrate chemists of our time. Margaret expressed surprise and gratification when the meeting became so well considered that people traveled from Europe and other parts of the United States to New Orleans just to attend her meeting and not because they were then going on to attend the ACS meeting. These meetings were always by invitation only. A biography of Margaret Clarke is not complete without mention of the history of the company she helped to shape. The original incarnation of the Sugar Processing Research Institute, Inc. (SPRI, Inc.) was founded in 1939 under Dr. Victor R. Deitz in Washington, DC, as the Bone Char Research Project (BCRP) and under the auspices of the National Bureau of Standards (NBS). At the time, Mr. Frederick J. Bates (“Sugar“ Bates) was head of the Sugar and Polarimetry Divisions, and he encouraged the formation of an industry group operating in close cooperation with the government to work on industrial problems. In 1937, there were a total of 26 projects at the NBS working through its Research Associated Plan of Cooperation of Government with Industry. At the time, the charge of the BCRP was to research the chemistry and mechanisms of action of bone char, a newly developed adsorbent for decolorizing sugar. In 1948, Dr. Frank G. Carpenter joined the organization as a research chemical engineer. The reports and proceedings of the seven Technical Sessions on Bone Char are still important sources of information on decolorizing carbon and bone char in sugar refining. In 1963, NBS changed its policy and stopped housing industry-sponsored research. However, the sugar industry wanted to continue the profitable interaction with government and instituted a cooperative research effort with the U.S. Department of Agriculture in New Orleans at their Southern Regional Research Center. The BCRP was expanded in scope and renamed the Cane Sugar Refining Research Project, Inc. (CSRRPI), and Dr. Frank Carpenter moved to New Orleans as its new director. He remained there until his retirement in 1984. He hired Margaret Clarke as a research chemist in 1969. While technically a refiners group, the work of CSRRPI inevitably encompassed more and more work on raw cane sugar production and quality from both the refiners’ and producers’ viewpoints. In the early 1980s, beet sugar producers showed interest in membership, leading to a reorganization of the group into Sugar Processing Research, Inc. in 1981. (It became the Institute in 1984.) The organization is funded by annual subscriptions from sponsoring sugar companies, suppliers to the industry, and users of sugar, ranging from 35–45 industrial sponsors at any one time. One of Margaret’s major duties
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as Managing Director of SPRI, Inc. was to seek out new sponsors and, of course, to keep current sponsors on board. A major source of SPRI, Inc. support also comes from the USDA in the form of housing, supplies, equipment, and cooperation with resident scientists. The goals of SPRI are (a) To examine the fundamentals of sugar production and refining processes in order to gain understanding of the chemical and physical bases of these processes to improve operation and to develop new processes and products; (b) to study the chemical nature of sugars and nonsugars in sugar-producing plants to explain processing problems and product quality problems; (c) to develop new analytical methods for the sugar industry, to improve and expand methods in current use, and to apply rapid, practical methods to industrial needs; (d) to serve as an information resource and database on sugar production, process problems, sugar manufacturing byproducts, sweeteners, and associated areas for sponsoring companies of SPRI, Inc.; and (e) to assist in problem solving in research-related areas for sponsoring companies of SPRI, Inc. During her tenure as the Managing Director, Margaret had almost complete fiscal and operational responsibility for the operation of the Sugar Processing Research Institute, Inc. She sometimes chafed at working within a government bureaucracy and hated having SPRI, Inc. confused with a government agency and often lamented the financial constraints that kept the staff smaller than she would have liked, but she genuinely appreciated the cooperation with USDA scientists that allowed SPRI to be so productive. During her career with the sugar industry, Margaret authored or coauthored over 200 technical papers, magazine articles, encyclopedia articles, books, and proceedings. A review of her titles will show that she did, indeed, meet the goals of research enumerated above for SPRI, Inc. Among the most important of her contributions was her leadership in applying new analytical technology to the sugar industry; namely, she pioneered the use of high-performance liquid chromatography (HPLC) and ion chromatography (IC) systems in the 1980s and the use of Near Infrared (NIR) spectroscopy in the 1990s. She was indefatigable in her pursuit of these applications for the sugar industry, giving many talks all over the world on their use and carrying the instruments around with her to visit many cane and beet factories and refineries. Her able coauthors in much of the HPLC work were Mary Ann Brannan and, later, Dr. Charles Tsang. Her co-workers in the area of NIR were Dr. Charles Tsang until his early death and then Dr. Leslie A. Edye. Among other areas in which she made very important contributions to the sugar industry are the development, along with Earl Roberts and Mary
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An Godshall, of the now Official AOAC method for dextran in raw sugars.1,2 She also developed a rapid assay for dextran3 in cane juice which could be used in laboratories with very limited equipment and which is now in use throughout the Louisiana sugar industry as well as a quick test for starch in cane juice, also applicable in poorly equipped laboratories. She helped to educate the sugar industry on the dangers of dextran formation from the ubiquitous soil microorganism Leuconostoc mesenteroides and suggested ways to prevent or ameliorate it. She was very interested in elucidating the role of vegetative and microbial polysaccharides in causing processing problems for both cane and beet sugar producers. She developed a series of simple tests that could distinguish the type of colorant that was in a raw sugar,4 which could then be used to determine how it would refine and whether special attention would be needed in the refining of the sugar. Her most recent accomplishment was the elucidation of the role of oleanolic acid in the formation of acid beverage floc from beet sugar. She had also become intensely interested in new products and value-added products from sugar crops and had been involved in patenting a microbial levan from sucrose5 and a diethylaminoethyl derivative of bagasse with decolorizing properties.6 As already mentioned, the cooperation that SPRI, Inc., received from USDA scientists at the Southern Regional Research Center, where SPRI is housed, was very beneficial to SPRI. Margaret had successful and productive interactions with Frederick Parrish,7 Yuan W. Han,5,8 John R. Vercellotti,9 Wilton Goynes,7 Gillian Eggleston,10,11,15 and Armand Pepperman.15 A long-term working relationship was forged with Benjamin L. Legendre of the USDA Sugarcane Research Unit in Houma, Louisiana, in which work done at SPRI under Margaret’s direction was useful for the sugarcane breeding program.12–14 Additionally, she encouraged and mentored a number of young scientists and exchange students, both in SPRI and at SRRC. The tradition from the old Bone Char Research Project days was to organize a conference on the research every 2 years, a custom that continues to this day. Margaret edited the Proceedings of the Conference on Sugar Processing Research from about 1974 and was solely responsible for putting together the programs since about 1984. These proceedings contain a treasure trove of information about all aspects of sugar processing and are unparalleled for the scope of information they contain relating to the area of sugar processing. In 1984, Margaret instituted a series of workshops to be held following the Conferences on Sugar Processing Research. These also have been published and represent an excellent resource for practical areas of concern
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within the sugar industry. The workshops organized by Margaret Clarke were 1984 Workshop on Dextran, 1986 Workshop on Raw Sugar Quality, 1988 Workshop on White Sugar Quality, 1992 Workshop on Analysis of Sugars in Foods, 1994 Workshop on New Products of Sugarbeet and Sugarcane, 1996 Workshop on Separation Processes in the Sugar Industry, and 1998 Workshop on Sugar Around the World. It is worthwhile to include here a quote from Dr. Steve Clarke, which appeared in the July, 1998 Sugar Journal, “It is not possible to write about the work of the Sugar Processing Research Institute without referring to the recent death of Dr. Margaret Clarke. Her leadership transformed the rather narrowly focused Cane Sugar Refiners group into the more broadly-based SPRI. Others will write more detailed and formal accounts of her work, but one essential and constant feature was the importance of good science, or getting the chemistry right.” She served on the editorial boards of Sugar Industry Abstracts, Sugar Technology Reviews, and the recently started Seminars in Food Analysis. The June, 1998 issue of Seminars in Food Analysis on applications of near infrared spectroscopy in the food industry was put together by her and contained a comprehensive review of her activity in the field of NIR analysis in the sugar industry.14 She consulted for a number of organizations, including the United Nations Industrial Development Organization (UNIDO), the Food and Chemicals Codex Committee, the National Academy of Sciences, the Human Nutrition Service of the U.S. Department of Agriculture, Bioraf Denmark, and the Fauji Foundation. She had an espeically close working relationship with the Chinese sugar industry, making at least four trips to visit and consult, forging many personal and professional friendships and subsequently supporting several Chinese scientists in fellowship-type programs at SPRI. It was in her work with Bioraf Denmark that she began to conceive of an integrated system for utilization of agricultural materials, specifically to treat and fractionate key crops to isolate new products, especially for nonfood uses. During her career, Margaret Clarke received a number of prestigious awards and recognitions. In 1984 she received the Honorary Crystal Award of the Sugar Industry Technologists (SIT), given for contributions to sugar technology and the highest award given by this group of industrial peers. Perhaps her favorite honor was the Dyer Memorial Award, up until then known as the Sugar Man of the Year award, received in 1987, making her the only woman and youngest person to have received either award and the only recipient of both awards. She always insisted on calling it the Sugar Man of the Year award, since it was not until after she received it that the
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name was changed. She was the 1996 Melville L. Wolfrom awardee, which is given for service to the American Chemical Society Division of Carbohydrate Chemistry and outstanding contributions to the field of carbohydrate chemistry. In 1998 she received a Meritorious Service Award from ICUMSA (International Commission for Uniform Methods of Sugar Analysis) for her years of dedication to the organization. She was made an Honorary Lifetime Member of the American Society of Sugar Beet Technologists in 1997. Also in 1997, she was appointed an Honorary Member of the Italian Association of Sugar Technologists on the occasion of their 90th anniversary. She maintained active professional memberships in numerous organizations, among them, the American Chemical Society, the International Association of Official Analytical Chemists (AOAC Internationsl), Sigma Xi, the Honorary Scientific Research Society, the Institute of Food Technologists, the United States National Committee on Sugar Analysis (USNC), the International Commission for Uniform Methods of Sugar Analysis (ICUMSA), Commission Internationale Technique de Sucrerie (CITS), Sugar Industry Technologists, American Society of Sugar Beet Technologists, International Society of Sugar Cane Technologists, American Society of Sugar Cane Technologists, International Carbohydrate Society, and the Chemists’ Club of New York. Herein are some of her activities with several of these organizations. AOAC International: In 1994 she was appointed as a member of the newly formed committee, the AOAC Peer-Verified Methods Advisory Committee. This committee was set up to respond to the expressed need for many more analytical methods than could be routinely accommodated through the Official Methods Program and to avoid the perceived bureaucratic burden of the Official Methods Program. This was a good fit for Margaret, as she was especially interested in the peer-verified method as a possible route for incorporation of sugar industry-approved methods into AOAC. She updated and rewrote much of the chapter on Sugars and Sugar Products in the AOAC Official Methods Book. She had been the General Referee for Sugar and Sugar Products since 1985, the duties of which entailed coordinating numerous associate referees in areas as disparate as lactose purity testing, authenticity testing of honey, oligosaccharides in sugar products, sugars in cereals, sugar alcohols, stable isotope ratio analyses, screening of sulfites, and polarimetric methods, to name several. Margaret was able to use venues such as these to stay abreast of analytical technology as it may have related to the sugar industry. She also served as the Chair of the Methods Committee on Food Nutrition.
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American Chemical Society: She was a long-term member of the American Chemical Society and was especially active as a member of the Division of Carbohydrate Chemistry, including terms as Chairman of the Division and, at the time of her death, a Councilor of the Division. She was active in raising funds for speakers to attend symposia and in organizing the various Divisional social functions, especially those that involved banquets, as she could always find an elegant venue. She presented at many of the national meetings. In 1987, she organized two symposia for the Division of Carbohydrate Chemistry, at the spring meeting in Denver on the Chemistry and Processing of Sugarbeet and at the fall meeting in New Orleans on the Chemistry and Processing of Sugarcane. This resulted in a book, published in 1988, which was part of the Elsevier Sugar Series (Number 9), entitled Chemistry and Processing of Sugarbeet and Sugarcane, edited by M. A. Clarke and M. A. Godshall. Institute of Food Technologists: She became a member of IFT in 1988, the year she helped to organize a symposium, along with Mary An Godshall, on the role of carbohydrates in food. She was a member of four divisions, each reflecting an area of intense interest—the Biotechnology, Carbohydrate, International, and Food Laws and Regulations Divisions. USNC and ICUMSA: These sister organizations are involved with the development and collaborative testing of uniform methods of sugar analysis that can then be used in commerce, contracts, and governmental regulations. Margaret was involved in both, with the USNC as a long-time member of the Executive Committee and as a Referee or Associate Referee for various subjects, including Color and Turbidity and Oligosaccharides and Polysaccharides. She organized the workshop on The Role of the National Committee in 1986 and was the chair of the ICUMSA Working Group on Collaborative Studies, whose report in 1990 led to the ICUMSA’s acceptance of the IUPAC Harmonized Guidelines on Collaborative Studies, thereby making ICUMSA methods acceptable to other validating societies, such as AOAC and ISO. Along with her activities in international and U.S. organizations, she was also involved in the specific carbohydrate communities in other countries. Her activities with Italy and Portugal were especially dear to her heart. The First International Meeting of the Portuguese Carbohydrate Chemistry Group, which was nicknamed “Glupor 1,” was held in Lisbon, Portugal September 26–30, 1995. Margaret had been deeply involved in encouraging the organization of this group, which was formed in 1994. She presented the opening plenary lecture of the industrial session on September 28, 1995, with a talk entitled, “Sugar Crops: Food, Feed and Industrial Resources.” The second meeting of this organization, “Glupor 2” was held in Porto, Portugal, September 21–24, 1997, and Margaret again participated by present-
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ing the opening plenary lecture of the industrial session on September 23, “New Compounds from Microbiological Products of Sucrose,’’ coauthored by her, Earl J. Roberts, and Per J. Garegg. The third meeting, Glupor 3, scheduled for September, 1999, is dedicated to the memory of Margaret Clarke. Quoting from a letter from the coordinator of the Portuguese Carbohydrate Chemistry Group, Amelia Rauter, upon hearing of her death, “She was a dedicated friend, an enthusiast for all types of carbohydrate chemistry. Her scientific contribution was very important in stimulating a symbiosis between sugar chemists and industrial scientists.” She was also very involved with the Italian carbohydrate community. On October 20, 1990, she was invited by the Italian Association of Sugar Technologists (A.N.T.Z.A.) to give a lecture at Ferrara on research conducted at the Sugar Processing Research Institute, with emphasis on polysaccharides and coloring matter. On July 30th, 1996, she was invited by the Sugar School at the University of Ferrara to lecture on the microbiological formation of polysaccharides from sucrose. Upon her death, six different Italian carbohydrate groups sent condolences. Her prodigious activity was exhausting even to contemplate, yet seemed to invigorate her. In March and April of 1998, only months before her death, she organized three major international meetings simultaneously— the 1998 Sugar Processing Research Conference, the 1998 Workshop on Sugar Around the World, and the Fourteenth New Orleans Carbohydrate Symposium. All three meetings were very successful. To summarize her professional activities, it may be said that Margaret Clarke had a special ability to recognize the potential of a laboratory discovery and to encourage and develop it to its maximum potential and to then make it known to the scientific community. She moved easily between the practical, technological world of sugar processing and the academic world of scientific discovery and was able to bring items of that world into practical use within the more technological universe. The benefit to the sugar industry of this type of synergy was immense. A danger in writing about Margaret Clarke is that one can use up all the allotted space cataloguing her many activities and accomplishments without touching on the personal side. It should, however, be noted that for Margaret, her professional and personal lives, like those of many outstanding scientists, were indistinguishable one from each other—her work was her life and her professional colleagues were also her personal friends. Nevertheless, she also had many other friends who had nothing whatsoever to do with chemistry or carbohydrates, and they ranged from clerks in the French Quarter grocery store where she shopped, her hairdresser of many years, artists, jazz musicians and historians, and her beloved maid, Maggie,
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whom Margaret kept employed even when Maggie reached a quite advanced age and became somewhat infirm. She was a host with no parallel, giving small parties and receptions at her French Quarter apartment for her Board of Directors, members of the ACS Carbohydrate Division, and other distinguished groups who were in town in addition to an annual Christmas party for friends and colleagues. These parties were often entertained by a jazz trio, made up of personal friends in the New Orleans jazz scene, jazz being another of her interests. She also quite often threw a Christmas party at the Arrhenius Institute. An example was one held on December 8, 1995 in which a partial listing of the menu, all prepared by Margaret, consisted of eggnog, oyster patties in pastry shells (prepared and brought over from New Orleans), artichoke squares, Mexican corn bread, chicken salad, beer cheese, blue cheese spread, deviled ham sandwiches, curried eggs, homemade bread, bourbon balls, brownies, almond toffee, chocolate peanut butter squares, and heavenly hash. Margaret was very hospitable and always wanted to do something for everyone. She kept track of innumerable birthdays, and when she was in town, made home-baked cakes for many people, including those on the SPRI staff as well as for USDA friends. She had a tremendous repertoire of bakery items, including traditional hot cross buns that she would bring on Good Friday. The ICUMSA meeting, its 22nd Session and 100th Anniversary, held in May, 1998 in Berlin, was the last meeting Margaret attended. She was very ill at that time, certainly too ill to be traveling so much, but she was cheerful and involved, never admitting to anyone her condition. It was my impression in retrospect that she wanted to see as many of her dear “sugar people” as she could in the time allotted her. The outpouring of sympathy from all continents of the world upon Margaret’s death was stunning in its sheer volume and attested to the very personal impact she had on many hundreds of people during her professional life. ACKNOWLEDGMENTS The author is extremely grateful to Mrs. Margaret (Peggy) Clarke Sloane, Margaret’s mother, for the information on her early childhood. Much helpful information, encouragement, and advice were also received from her husband, Per Garegg, and her colleague, John R. Vercellotti.
MARY AN GODSHALL
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REFERENCES 0(1) E. J. Roberts, M. A. Clarke, and M. A. Godhsall. Proc. Internat. Soc. Sugar Cane Technol, 18 (1983) 104–126. 0(2) M. A. Clarke and M. A. Godshall. J. Assoc. Off. Anal. Chem. 71 (1988) 276–279. 0(3) M. A. Clarke, J. Bergeron, and F. Cole. Sugar y Azucar, 82 (1987) 23–24. 0(4) M. A. Clarke, R. S. Blanco, and M. A. Godshall. Proc. 1984 Sugar Process. Res. Conf., (1986) 284–303. 0(5) Y. W. Han and M. A. Clarke. U.S. Patent 5,547,863, August 20, 1996. 0(6) M. A. Clarke Garegg and E. J. Roberts. U.S. Patent 5,504,196, April 2, 1996. 0(7) F. W. Parrish, W. R. Goynes, E. J. Roberts, and M. A. Clarke. Proc. 1986 Sugar Process. Res. Conf., (1986) 53–59. 0(8) Y. W. Han and M. A. Clarke. J. Agric. Food Chem., 38 (1990). 393–396. 0(9) J. R. Vercellotti, M. A. Clarke, and L. A. Edye, Proc. 1996 Sugar Process. Res. Conf., (1996), 321–349. (10) G. Eggleston, J. R. Vercellotti, L. Edye, and M. A. Clarke. J. Carbohydr. Chem. 14 (1995) 1035–1042. (11) G. Eggleston, J. R. Vercellotti, L. A. Edye, and M. A. Clarke, J. Carbohydr. Chem. (1996) 81–94. (12) B. L. Legendre, W. S. C. Tsang, and M. A. Clarke. Proc. 1986 Sugar Process. Conf., (1986), 92–107. (13) B. L. Legendre, M. A. Clarke, M. A. Godshall, and M. P. Grisham. Proc. 1998 Sugar Process. Res. Conf., (1998), 160–175. (14) M. A. Clarke, B. L. Legendre, and L. A. Edye. Semin. Food Anal. 3 (1998) 141–153. (15) G. Eggleston, M. A. Clarke, and A. B. Pepperman. Proc. 1998 Sugar Process. Res. Conf., (1998), 212–232.
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
CHEMISTRY AND DEVELOPMENTS OF N-THIOCARBONYL CARBOHYDRATE DERIVATIVES: SUGAR ISOTHIOCYANATES, THIOAMIDES, THIOUREAS, THIOCARBAMATES, AND THEIR CONJUGATES BY JOSE⬘ MANUEL GARCI⬘A FERNA⬘ NDEZ AND CARMEN ORTIZ MELLET* Instituto de Investigaciones Químicas, CSIC, Américo Vespucio s/n, Isla de la Cartuja, E-41092 Sevilla, Spain, and * Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
IIIII. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IIIII. Energetics and Structure of N-Thiocarbonyl as Compared to N-Carbonyl Compounds: Implications for Reactivity, Conformations, and Electronic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IIIII. Sugar Isothiocyanates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Methods of Synthesis of Sugar Isothiocyanates . . . . . . . . . . . . . . . . . . . . . . . . 2. Reactions of Sugar Isothiocyanates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Spectroscopic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IIIV. Sugar Thioamides and Thiolactams. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Addition of Carbon Bases to Sugar Isothiocyanates . . . . . . . . . . . . . . . . . . . . 2. Thionation of N-Carbonyl Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Thioacylation of Amino Sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Miscellaneous Sugar Thioamide Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conformational Properties of Sugar Thioamides . . . . . . . . . . . . . . . . . . . . . . . IIIV. Sugar Thioureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Coupling of Sugar Isothiocyanates with Amine Nucleophiles . . . . . . . . . . . . . 2. Coupling of Amino Sugars with Isothiocyanates . . . . . . . . . . . . . . . . . . . . . . . 3. Coupling of Sugar Isothiocyanates with Amino Sugars . . . . . . . . . . . . . . . . . . 4. Sugar Thioureas from Sugar Carbodiimides . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Functional Group Transformations in Sugar Thioureas . . . . . . . . . . . . . . . . . . 6. Spectroscopic and Conformational Properties . . . . . . . . . . . . . . . . . . . . . . . . . IIVI. Sugar Thiocarbamates and Dithiocarbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Linear Sugar Thiocarbamates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Cyclic Sugar Thiocarbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Linear Sugar Dithiocarbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Cyclic Sugar Dithiocarbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IVII. Miscellaneous N-Thiocarbonyl Carbohydrate Derivatives . . . . . . . . . . . . . . . . . . VIII. Naturally Occurring N-Thiocarbonyl Carbohydrate Derivatives . . . . . . . . . . . . . IIIX. N-Thiocarbonyl Sugars in Molecular Recognition . . . . . . . . . . . . . . . . . . . . . . . . 1. Interactions with Membrane Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0096-5332/00 $30.00
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Copyright © 2000 by Academic Press. All rights of reproduction in any form reserved.
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2. Neoglycoconjugates, Glycodendrimers, and Glycoclusters. . . . . . . . . . . . . . . . 3. Enzyme Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Artificial Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IIIX. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
104 109 119 121 121
I. INTRODUCTION Investigations on N-thiocarbonyl carbohydrate derivatives go back almost a century. As early as 1903, Schoorl1 reported on the reaction of Dglucose and thiourea as a model system to understand the condensation of D-glucose and urea under physiological conditions. Although formation of the corresponding N-D-glucosylthiourea occurred, he did not succeed on isolating the pure product. Eleven years later, Emil Fischer2 described the synthesis of the first sugar isothiocyanate, namely 2,3,4,6-tetra-O-acetyl웁-D-glucopyranosyl isothiocyanate, and its transformation into sugar thiocarbamates and thioureas, including Schoorl’s thioureido sugar. Since then, a vast literature on N-thiocarbonyl sugar derivatives has accumulated and this continues to be a very active field in carbohydrate chemistry. A key reason for this activity is obviously the diversity of reactions and the availability of reactants. Moreover, thiocarbonyl compounds are close isosters of carbonyl compounds and may thus be useful for structure–activity studies in connection with naturally occurring, biologically active N-carbonyl amino sugars. The purpose of this chapter is to present the recent developments in the chemistry of N-thiocarbonyl-containing carbohydrate derivatives, including isothiocyanates, thioamides, thioureas, thiocarbamates, and dithiocarbamates. Emphasis has been placed on the mutual interactions between the various functional groups that may coexist in a given molecule; their consequences in the structural and chemical properties; and the synthetic, biological, and technical applications of these families of compounds. Glucosinolates,3 the precursors of the natural isothiocyanates and derived N-thiocarbonyl compounds in plants, have been omitted from this chapter since they constitute a rather homogeneous class of molecules in which the isothiocyanate functionality is masked by formation of a 웁-D-glucopyranosylthiohydroxamate O-sulfonate derivative. Nevertheless, we have included all types of glycoconjugates having these functional groups, either synthetic or isolated from natural sources, independent of the glyconic or aglyconic position of the N-thiocarbonyl segment. The chemistry of sugar isothiocyanates and their reactions has been the subject of a specialized article in this series by Witczak4 in 1986 with 143 references dating up to 1984. The reader is also referred to the earlier work of Goodman5 on ureido sugars for a thorough historical perspective. It should
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N-THIOCARBONYL CARBOHYDRATE DERIVATIVES
37
be noted that this chapter does not duplicate their material unless required for the sake of congruity. The literature has been surveyed up to April, 1998. The preparation, properties, and reactions of N-thiocarbonyl compounds have been the subject of valuable comprehensive6,7 as well as specialized accounts,8–14 which should be consulted for details. II. ENERGETICS AND STRUCTURE OF N-THIOCARBONYL AS COMPARED TO N-CARBONYL COMPOUNDS: IMPLICATIONS FOR REACTIVITY, CONFORMATIONS, AND ELECTRONIC PROPERTIES The exchange of oxygen by sulfur in a molecule in general, and in carbonyl compounds in particular, leads to close analogs which, however, may show notable differences in their physicochemical and biological properties because of the greater bulk and polarizability of the sulfur atom (covalent ratio: O, 0.66; S, 1.04 Å) and its decreased electronegativity (Pauling scale: O, 3.5; S, 2.4). Isothiocyanates, the esters of isothiocyanic acid, can be considered as the heteroallene representatives of N-thiocarbonyl compounds and their universal progenitors. In spite of their strong electrophilic character, isothiocyanates are less reactive and less hazardous to work with than the homologous isocyanates. Dipole moments, Raman spectra, and structural data indicate that the electron distribution in both families can be summarized in structures 1a–1d (Fig. 1).9,15 While structure 1d contributes little if anything in the case of isocyanates, it is a significant contributor in the case of the sulfur analogs. The higher contribution of structures 1b and 1c to the electron distribution of isocyanates probably accounts for the differences in the electron-withdrawing capacity of the central carbon atom, responsible for the reactivity toward nucleophiles. The coupling reactions of isothiocyanates with carbon, nitrogen, oxygen, and sulfur nucleophiles containing a labile hydrogen afford thioamides, thioureas, thiocarbamates, and dithiocarbamates, respectively. Since both the N and S atoms of the resulting N-thiocarbonyl adducts may act as new nucleophilic centers, subsequent intramolecular reactions may take place, and these have been used for the preparation of a plethora of heterocyclic derivatives.12,13 In addition, the NCS group reacts with suitable agents to form 1,2-, 1,3-, and 1,4-cycloadducts. It may be assumed that one of the po-
FIG. 1.
Resonance model for iso(thio)cyanates.
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET
lar resonance structures 1b or 1c is involved at the stage of chemical reaction in these cases.9 In N-thiocarbonyl compounds, conjugation of the 앟-system of the C苷S group and the lone pair of nitrogen can take place. This electron-donation effect of N-substituents at thiocarbonyl groups is quite important and stabilizing, more than in the related N-carbonyl derivatives.16 Consequently, and in contrast to many other thiocarbonyl compounds, thioamides, thioureas, and thiocarbamates are generally very stable and frequently characterizable as crystalline solids. All available X-ray data show unambiguously that the key atoms of N––C(苷S) functional groups are situated in a plane, as in the ligands at normal alkenic double bonds, suggesting large contributions from sp2-hybrid atomic orbitals of the central carbon and nitrogen atoms to the corresponding molecular orbital, that is, a preference for polar resonance structures such as 2b (Fig. 2).10 As a corollary, N-monosubstituted and unsymmetrically N-disubstituted derivatives are expected to exhibit (E)-(Z) geometrical isomerism. In the case of N,N⬘-unsymmetrically disubstituted thioureas, up to four different configurational arrangements can be envisaged, the (E,E) isomer being generally absent because of steric repulsion between the nitrogen substituents (Fig. 3). The typical activation energy values (Ea) for rotating the N-group out of the plane in N-thiocarbonyl derivatives fall in the range of 25–27 kcal mol⫺1 for thioformamides, 20–25 kcal mol⫺1 for other thioamides, 10–13 kcal mol⫺1 for thioureas, 16–18 kcal mol⫺1 for thiocarbamates, and 14–16 kcal mol⫺1 for dithiocarbamates.17 A further consequence is that the corresponding NMR spectra exhibit temperature dependence, with temperatures of coalescence (Tc) for the signals of the N-substituents ranging from 110–170⬚C for thioamides to 0–40⬚C for thioureas.17–20 Although the most widely accepted explanation for the hindered rotation in N––C(苷S) bonds employs the foregoing 2a–2b resonance model, this cannot satisfactorily explain the fact that the rotational barrier is greater, typically by 2–3 kcal mol⫺1, for N-thiocarbonyls than for the carbonyl analogs.16 It has been suggested that this traditional picture is actually more appropri-
FIG. 2.
Resonance model for N-(thio)carbonyl compounds.
4888 Horton Chapter 4 11/17/99 6:50 AM Page 39
N-THIOCARBONYL CARBOHYDRATE DERIVATIVES
39
FIG. 3. Possible rotameric forms about the N––C(苷S) bonds for N,N⬘-unsymmetrically disubstituted thioureas.
ate for N––C(苷S) systems, charge transfer from N to S being favored by the small difference in electronegativity between carbon and sulfur and the large size of the sulfur atom.21 In carbonyls, charge transfer from C to O (structure 2c) would be more important. A model based on the greater donation of charge from the softer C苷S group as compared to C苷O to the nitrogen atom has been proposed, based on theoretical calculations.22 The origin of the rotational barrier would be then in the cost of pyrimidalization of N, that is, rehybridation from sp2 (more electronegative) to sp3. The greater inherent ability of sulfur over oxygen to stabilize an anion is evident in the species derived from the amides on account of the weaker C苷S over the C苷O bond (by about 30 kcal mol⫺1). Consequently, replacement of oxygen by sulfur in carboxamides and ureas causes striking decreases23 in the N—H bond pKHA values. Conversely, the thiocarbonyl bases are, in water solution, weaker bases than the corresponding carbonyl bases on the pKBH⫹ scale by 1.5–2.0 pK units, the basic center being the sulfur atom.24–27 Notwithstanding, thiocarbonyl compounds have been shown to be consistently more basic than their carbonyl homologs in the gas phase.16,27,28 This variance has been ascribed to the strong attenuation of polarizability effects in water solutions and the poorer solvation of the protonated thiocarbonyl compounds. Regarding the nitrogen center, the thiocarbonyl group acts as a powerful electron sink which decreases the basicity by 14.1 pK units as compared to the parent amine.29 The diffuseness of the electronic charge in the lone pairs of sulfur leads to C苷S compounds being substantially weaker hydrogen-bonding acceptors than the homologous C苷O derivatives.16,24,28,30 In contrast, the higher acidity of NH protons in N-thiocarbonyl derivatives correlates, in general, with an enhanced hydrogen-bonding donor capability. The potential for hydrogen bonding is increased for thioureas because of the possibility to form trans-bidentated bonds (3, Fig. 4). An NMR investigation of this type of association, using acetate anion as acceptor, has indicated, however, that a fast equilibrium between monodentated complexes (4a–4b, Fig. 4) is also compatible with the present evidence.31
4888 Horton Chapter 4 11/17/99 6:50 AM Page 40
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET
FIG. 4. Bidentated (3) versus monodentated hydrogen bonds (4a–4b) between disubstituted thioureas and acetate anion.
III. SUGAR ISOTHIOCYANATES Sugar isothiocyanates are among the most versatile synthetic intermediates in carbohydrate chemistry. They play a pivotal role in the preparation of a broad series of functional groups such as amide, isonitrile, carbodiimide, and N-thiocarbonyl derivatives allowing, simultaneously, the covalent coupling of a quite unrestricted variety of structures to the saccharide part. Moreover, isothiocyanates are important reagents in heterocyclic chemistry, which may be exploited in the synthesis of nucleosides and other N-glycosyl structures. The development of several efficient general methods for the introduction of the isothiocyanate functionality at different positions of the carbohydrate molecule has translated these considerations into practical approaches. Nowadays, sugar isothiocyanates can be prepared routinely from inexpensive starting materials on the gram scale and some of them are commercially available. This has obviously contributed to the tremendous expansion of work on N-thiocarbonyl carbohydrate derivatives during the past decade, including both synthetic aspects and biomedical assays. For the purpose of this chapter, three types of isothiocyanate derivatives of sugars are considered, depending on the location of the NCS group in the molecule: glycosyl isothiocyanates, deoxyisothiocyanato sugars, and isothiocyanate conjugates. For a complete list of structures reported, see Tables I–III. 1. Methods of Synthesis of Sugar Isothiocyanates a. Reaction of a Glycosyl Donor with an Inorganic Thiocyanate.—The reaction of an O-protected glycosyl halide with an inorganic thiocyanate has been the most widely used procedure for the synthesis of glycosyl isothiocyanates.4,8 Problems with this synthesis arise from the ambident character of the thiocyanate anion. Whereas the use of silver thiocyanate
4888 Horton Chapter 4 11/17/99 6:50 AM Page 41
41
N-THIOCARBONYL CARBOHYDRATE DERIVATIVES TABLE I Glycosyl Isothiocyanates Rotation MP (⬚C) Monosaccharides 웁-D-Arabinofuranosyl 2,3,4-Tri-O-benzoyl 2-Deoxy-움-D-arabinohexopyranosyl 4,6-Di-O-acetyl-3-bromo3-deoxy 3,4,6-Tri-O-acetyl 3,4,6-Tri-O-benzoyl 3,4,6-Tri-O-(4nitrobenzoyl) 2-Deoxy-웁-D-arabinohexopyranosyl 4,6-Di-O-acetyl-3-bromo3-deoxy 3,4,6-Tri-O-acetyl 3,4,6-Tri-O-benzoyl 3,4,6-Tri-O-(4nitrobenzoyl) 움-D-Arabinopyranosyl 2,3,4-Tri-O-acetyl 2,3,4-Tri-O-benzoyl 웁-L-Arabinopyranosyl 2,3,4-Tri-O-acetyl 움-L-Fucopyranosyl 2,3,4-Tri-O-acetyl 웁-D-Fucopyranosyl 2,3,4-Tri-O-acetyl 웁-L-Fucopyranosyl 2,3,4-Tri-O-acetyl 2,3,4-Tri-O-benzoyl 웁-D-Galactofuranosyl 2,3,5,6-Tetra-O-benzoyl 움-D-Galactopyranosyl 2,3,4,6-Tetra-O-benzyl 웁-D-Galactopyranosyl 2,3,4,6-Tetra-O-acetyl 3,4,6-Tri-O-acetyl-2-deoxy2-iodo 3,6-Di-O-benzoyl 2,3,4,6-Tetra-O-benzoyl 2,3,6-Tri-O-benzoyl 2,3,4,6-Tetra-O-benzyl D-Glucosyl 2,3,4,5,6-Penta-O-acetyl
149–150
[␣]D
Solvent
—
—
Reference
40
Amorphous Syrup/70–72 Syrup
— ⫹168.8/⫹142 ⫹84.4
— CHCl3–CH2Cl2 CHCl3
50 49,50 49
Amorphous
⫹73.0
CHCl3
49
Amorphous 100–101/90–92 Syrup
⫹46 ⫺15.7/⫺26 ⫹11.0
CH2Cl2 CHCl3–CH2Cl2 CHCl3
50 49,50 49
Amorphous
⫺13.3
CHCl3
49
Syrup/175–178 Foam
— ⫺114
— CHCl3
40,161 34
Syrup
⫺45.5
CHCl3
39
102
⫺173.6
CH2Cl2
47
94
⫹20
CHCl3
152
102–104 58–60
— ⫺174
— CH2Cl2
152 65
Syrup
⫺36
CHCl3
53,54
Syrup
⫹103
CHCl3
48
92–94/97–99
⫹10
CHCl3
37,38,47,152
145–150 Amorphous 68–71 150–152 98–99
⫹110 — ⫹137 ⫹2 ⫹5.1
CHCl3 — CHCl3 CH2Cl2 CHCl3
57 69 63 69 48
132–135
—
—
162
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET TABLE I—Continued Rotation MP (⬚C)
움-D-Glucopyranosyl 2,3,4-Tri-O-acetyl-6-bromo6-deoxy 3,4,6-Tri-O-acetyl-2-deoxy2-thiocyanate 2,3,4,6-Tetra-O-benzyl 2,3,4,6-Tetra-O-benzyl-5acarba 2,3,4-Tri-O-benzyl-6-deoxy6-fluoro 3,4,6-Tri-O-benzyl 웁-D-Glucopyranosyl 2-Acetamido-2-deoxy 2-Acetamido-3,4,6-tri-Oacetyl-2-deoxy 2,3,4,6-Tetra-O-acetyl 2,3,4-Tri-O-acetyl 2,3,6-Tri-O-acetyl 3,4,6-Tri-O-acetyl-2-deoxy2-iodo 2,3,4,6-Tetra-O-benzoyl 2,3,4-Tri-O-benzoyl 2,3,6-Tri-O-benzoyl 2,3,4,6-Tetra-O-benzyl 2,3,4-Tri-O-benzyl-6-deoxy6-fluoro 2-Deoxy-움-D-lyxohexopyranosyl 3,4,6-Tri-O-acetyl 2-Deoxy-웁-D-lyxohexopyranosyl 3,4,6-Tri-O-acetyl 움-D-Mannopyranosyl 2,3,4,6-Tetra-O-acetyl 3,4,6-Tri-O-acetyl-2-deoxy2-iodo Methyl (움-D-glycero-Dgalacto-2nonulopyranosyl)onate 5-Acetamido-4,7,8,9-tetraO-acetyl-3,5-dideoxy 움-D-Quinovosyl 2,3,4-Tri-O-benzyl 웁-D-Quinovosyl 2,3,4-Tri-O-benzyl 웁-L-Quinovosyl 3,4-Di-O-acetyl-2-deoxy-2iodo
[␣]D
Solvent
Reference
164.5
⫹16.2
CCl4
163
94.5–96 Syrup
⫹249 ⫹73
CHCl3 CHCl3
56 34
103–104
⫹99
CHCl3
48,86
Syrup Oil Syrup Syrup
⫹125 ⫹20 ⫹72 ⫹25
CHCl3 CHCl3 MeOH MeOH
408 52 58,59,164 60
161 113–115 Amorphous Syrup
⫹9.5 ⫹4.4 ⫹5.0 ⫺46.0
CHCl3 CHCl3 CH2Cl2 CH2Cl2
34 2,34,37,38,63 70 70
103–105 147–148 Foam 197–199 Syrup
⫹4 ⫹17 ⫺16.2 ⫹46 ⫹12
CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3
57 64 70 69 34
109–110
⫺10.6
CHCl3
408
Syrup
⫹129
CH2Cl2
50
Syrup
⫹25
CH2Cl2
50
92–94 / Syrup
⫹132/⫹144
CHCl3
34,47,48
Syrup
⫹59
CHCl3
57
95–99
⫺17.06
MeOH
51
Syrup
⫹118
CHCl3
48
114–115
⫺2.6
CHCl3
48
62–65
⫺5
CHCl3
57
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43
N-THIOCARBONYL CARBOHYDRATE DERIVATIVES TABLE I—Continued Rotation MP (⬚C) 움-L-Rhamnopyranosyl 3,4-Di-O-acetyl-2-deoxy-2iodo 2,3,4-Tri-O-acetyl 웁-L-Rhamnopyranosyl 2,3,4-Tri-O-benzoyl 웁-D-Ribofuranosyl 2,3,5-Tri-O-acetyl 2,3,5-Tri-O-benzoyl 3-Deoxy-움-D-ribo-hexopyranosyl 2,3,4-Tri-O-benzyl 3-Deoxy-웁-D-ribohexopyranosyl 2,3,4-Tri-O-benzyl 움-D-Ribopyranosyl 2,3,4-Tri-O-benzoyl 웁-D-Ribopyranosyl 2,3,4-Tri-O-benzoyl 움-D-Talopyranosyl 3,4,6-Tri-O-acetyl-2-deoxy2-iodo 움-D-xylo-Hex-5(5a)enopyranosyl 5a-Carba-2,3:4,6-di-Oisopropylidene 웁-D-Xylofuranosyl 2,3,5-Tri-O-benzoyl 웁-D-Xylopyranosyl 2,3,4-Tri-O-acetyl Disaccharides 움-Cellobiosyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Obenzyl 웁-Cellobiosyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Oacetyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Obenzyl 웁-Chitobiosyl N,N’-Diacetyl-3,4,3⬘,4⬘,6⬘penta-O-acetyl 웁-D-Galp-(1→6)-웁-D-Glcp(1→NCS) 2,3,4,3⬘,4⬘,6⬘-Hexa-Oacetyl-2⬘-deoxy-2⬘isothiocyanato
[␣]D
Solvent
Reference
Syrup 106.7–107.3
⫺115 ⫺185
CHCl3 CHCl3
57 42
55–57
⫹182
CH2Cl2
65
Syrup Syrup/96–97
⫺3 ⫺91
CHCl3 CHCl3
34,41 53,165
Syrup
⫹110
CHCl3
48
65–66
⫹42.5
CHCl3
48
Syrup
⫺57
CH2Cl2
72
Syrup
⫺187
CH2Cl2
72
116–119
⫹110
CHCl3
57
Syrup
⫹260
CHCl3
48
Syrup
⫺36
CHCl3
53
72–73
⫺31.2
CHCl3
39
Syrup
⫹66.7
CHCl3
48
191–195
⫺9.0
CH2Cl2
4,47,66
114–115
⫹28.5
CHCl3
48
157–160
⫹9
CHCl3
42
Amorphous
0.0
CH2Cl2
67
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET TABLE I—Continued Rotation MP (⬚C)
웁-D-Galp-(1→4)-움-D-Manp(1→NCS)a 3,6,2⬘,3⬘,4⬘,6⬘-Hexa-Oacetyl-2-deoxy-2-iodo Gentiobiosyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Oacetyl 움-D-Glcp-(1→4)-움-D-Manp(1→NCS)a 3,6,2⬘,3⬘,4⬘,6⬘-Hexa-Oacetyl-2-deoxy-2-iodo 웁-D-Glcp-(1→4)-움-D-Manp(1→NCS)a 3,6,2⬘,3⬘,4⬘,6⬘-Hexa-Oacetyl-2-deoxy-2-iodo 웁-Lactosyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Oacetyl 움-Maltosyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Obenzyl 웁-Maltosyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Oacetyl 2,3,6,2⬘,3⬘,4⬘,6⬘-Hepta-Obenzyl 웁-Melibiosyl 2,3,4,2⬘,3⬘,4⬘,6⬘-Hepta-Oacetyl 2,3,4,3⬘,4⬘,6⬘-Hexa-Oacetyl-2⬘-deoxy-2⬘isothiocyanato Peracetyl trisaccharides 웁-Chitotriosyl 웁-D-GlcNAcp-(1→4)[움-LFucp-(1→6)]-웁-D-GlcNAcp(1→NCS) 움-D-Glcp-(1→4)-웁-D-Glcp(1→6)-웁-D-Glcp-(1→NCS) 웁-D-Manp-(1→4)- 웁-DGlcNAcp-(1→4)-웁-DGlcNAcp-(1→NCS) a
[␣]D
Solvent
Reference
57–59
⫹47
CHCl3
57
173–174
⫹3
CHCl3
68
60–62
⫹120
CHCl3
57
127–129 —
⫹33 —
MeOH —
57 62
157–159/167–169
-18.5
CHCl3
4,37,38,47,66
Syrup —
⫹3.1 —
CHCl3 —
48 58
120–123
⫹57.7
CH2Cl2
4,47,66
Syrup
⫹2.6
CHCl3
48
Syrup
⫹92.8
CH2Cl2
66
Amorphous
⫹60.0
CH2Cl2
67
Amorphous
⫺16.5
CHCl3
42
155–157
⫺74.2
CHCl3
44
Amorphous
⫹62
CHCl3
68
—
46
—
—
Erroneously named as glucopyranosyl isothiocyanate derivatives in the original reference.
4888 Horton Chapter 4 11/17/99 6:50 AM Page 45
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N-THIOCARBONYL CARBOHYDRATE DERIVATIVES TABLE II Deoxyisothiocyanato Sugars Rotation MP(⬚C) Monosaccharides 움-D-Allofuranose 5,6-Di-O-acetyl-3-deoxy-1,2-Oisopropylidene-3-isothiocyanato 3-Deoxy-1,2-O-isopropylidene-3isothiocyanato 3-Deoxy-1,2:5,6-di-Oisopropylidene-3-isothiocyanato 웁-D-Fructopyranose 4,5-Di-O-acetyl-1-deoxy-2,3-Oisopropylidene-1-isothiocyanato 1-Deoxy-2,3:4,5-di-Oisopropylidene-1-isothiocyanato 움-D-Galactofuranose 5,6-Di-O-acetyl-3-deoxy-1,2-Oisopropylidene-3-isothiocyanato 3-Deoxy-1,2-O-isopropylidene-3isothiocyanato 3-Deoxy-1,2:5,6-di-Oisopropylidene-3-isothiocyanato 움-D-Galactopyranose 6-Deoxy-1,2:3,4-di-Oisopropylidene-6-isothiocyanato 움-D-Galactopyranoside, methyl 2,3,4-Tri-O-acetyl-6-deoxy-6isothiocyanato 2,3,6-Tri-O-benzyl-4-deoxy-4isothiocyanato 6-Deoxy-6-isothiocyanato 6-Deoxy-6-isothiocyanato-2,3,4-triO-trimethylsilyl D-Glucitol 2,3,4,5,6-Penta-O-acetyl-1-deoxy-1isothiocyanato 움-D-Glucofuranose 5,6-Di-O-acetyl-3-deoxy-1,2-Oisopropylidene-3-isothiocyanato 3-Deoxy-1,2:5,6-di-Oisopropylidene-3-isothiocyanato 6-Deoxy-1,2:3,5-di-Oisopropylidene-6-isothiocyanato D-Glucopyranose 1,2,4,6-Tetra-O-acetyl-3-deoxy-3isothiocyanato 1,3,6-Tri-O-acetyl-4-O-benzyl-2deoxy-2-isothiocyanato
[␣]D
Solvent
Reference
Syrup
⫹183
CH2Cl2
84
60–62
⫹151
CH2Cl2
84
58–59
⫹151.1
CHCl3
84
107–109
⫺19.0
CHCl3
83
Oil
⫺65.8
CHCl3
83
Syrup
⫹10.0
CH2Cl2
84
Syrup
⫹31.3
CH2Cl2
84
Oil
⫺75.0
CHCl3
84
Oil
⫺83
CHCl3
81,82
Syrup
⫹105
CHCl3
75,82
Syrup 120–122
⫹71.0 ⫹110
CHCl3 MeOH
89 82
Syrup
⫹72.8
CH2Cl2
85
Syrup
⫹58.8
CH2Cl2
75
Amorphous
⫺60.0
CHCl3
84
64–65
⫺75.0
CHCl3
84
68
⫺45
Me2CO
80
Oil
⫹55.0
CHCl3
84
—
97
—
—
4888 Horton Chapter 4 11/17/99 6:50 AM Page 46
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET TABLE II—Continued Rotation MP(⬚C)
움-D-Glucopyranose 1,3,4,6-Tetra-O-acetyl-2-deoxy-2isothiocyanato 움-D-Glucopyranoside, methyl 2,3,4-Tri-O-acetyl-6-deoxy-6isothiocyanato 2,3,4-Tri-O-benzyl-6-deoxy-6isothiocyanato 2,3,6-Tri-O-benzyl-4-deoxy-4isothiocyanato 3,4,6-Tri-O-benzyl-2-deoxy-2isothiocyanato 6-Deoxy-6-isothiocyanato 6-Deoxy-6-isothiocyanato-2,3,4-triO-trimethylsilyl 웁-D-Glucopyranose 3-O-Acetyl-1,6-anhydro-4-O-benzyl2-deoxy-2-isothiocyanato 1,3,4,6-Tetra-O-acetyl-2-deoxy-2isothiocyanato 1,6-Anhydro-4-O-benzyl-2-deoxy-2isothiocyanato 1,6-Anhydro-4-O-benzyl-2-deoxy-2isothiocyanato-3-O-p-tolylsulfonyl 웁-D-Glucopyranoside, benzyl 2,3,6-Tri-O-benzyl-4-deoxy-4isothiocyanato 웁-D-Glucopyranoside, methyl 2,3,4-Tri-O-acetyl-6-deoxy-6isothiocyanato 6-Deoxy-6-isothiocyanato 움-D-glycero-L-gluco-Heptopyranose 1,3,4,6,7-Penta-O-acetyl-2-deoxy-2isothiocyanato 웁-D-glycero-L-gluco-Heptopyranose 1,3,4,6,7-Penta-O-acetyl-2-deoxy-2isothiocyanato D-arabino-Hex-1-enitol 3,4,6-Tri-O-acetyl-1,5-anhydro-2deoxy-2-isothiocyanato D-erythro-Hex-3-enopyranoside, ethyl 2,3,4-Trideoxy-2-isothiocyanato-6O-methylsulfonyl D-threo-Hex-3-enopyranoside, ethyl 2,3,4-Trideoxy-2-isothiocyanato-6O-methylsulfonyl
[␣]D
Solvent
Reference
65–66
⫹142
CHCl3
73
98–99
⫹129
CHCl3
75,82
Syrup
⫹86.8
CHCl3
89
Syrup
⫺7.0
CHCl3
89
75–77 52–53
⫹164 ⫹117
CHCl3 Me2CO
87 82
Syrup
⫹76.9
CH2Cl2
85
73–75
⫹200
CHCl3
97
72–73
⫹73
DMF
76
89–90
⫹115
CHCl3
97
82–84
⫹234
CHCl3
97
Syrup
⫺35.6
CHCl3
89
Syrup 108–110
⫺28 ⫺196
CHCl3 MeOH
82 82
75–76
⫺121
CHCl3
74
136–138
⫺23
CHCl3
77
Syrup
⫺60
CHCl3
166
68–69
⫺105
CHCl3
167,168
Syrup
⫹375
CHCl3
167,168
4888 Horton Chapter 4 11/17/99 6:50 AM Page 47
47
N-THIOCARBONYL CARBOHYDRATE DERIVATIVES TABLE II—Continued Rotation MP(⬚C) 움-D-Mannopyranoside, methyl 2,3,4-Tri-O-acetyl-6-deoxy-6isothiocyanato 2,3,4-Tri-O-benzoyl-6-deoxy-6isothiocyanato 6-Deoxy-6-isothiocyanato 6-Deoxy-6-isothiocyanato-2,3,4-triO-trimethylsilyl 움-D-Mannopyranoside, p-nitrophenyl 6-Deoxy-6-isothiocyanate D-Threose diethylacetal 2,4-O-Isopropylidene-3-deoxy-3isothiocyanato Disaccharides D-Cellobitol 2,3,5,6,2⬘,3⬘,4⬘,6⬘-Octa-O-acetyl-1deoxy-1-isothiocyanato 움-Gentiobioside, ethyl 3,4,2⬘,3⬘,4⬘,6⬘-Hexa-O-acetyl-2deoxy-2-isothiocyanato 2⬘,3⬘,4⬘,6⬘-Tetra-O-acetyl-3,4-di-Obenzoyl-2-deoxy-2-isothiocyanato 움-Kojibioside, methyl 2,4,6,3⬘,4⬘,6⬘-Hexa-O-benzyl-2⬘deoxy-2⬘-isothiocyanato 움-Melibioside, ethyl 3,4,2⬘,3⬘,4⬘,6⬘-Hexa-O-acetyl-2deoxy-2-isothiocyanato 2⬘,3⬘,4⬘,6⬘-Tetra-O-acetyl-3,4-di-Obenzoyl-2-deoxy-2-isothiocyanato 웁-D-Galp-(1→6)-웁-D-Glcp-(1→OEt) 3⬘,4⬘,6⬘-Tri-O-acetyl-3,4-di-Obenzoyl-2,2’-dideoxy-2,2⬘diisothiocyanato 움-D-Fructofuranose 웁-D-fructopyranose 1,2⬘:2,1⬘-dianhydride 3,4-Di-O-acetyl-6-deoxy-6isothiocyanato 3⬘,4⬘,5⬘-tri-O-acetyl 6-Deoxy-6-isothiocyanato Sucrose N-Acetyl-2,3,1⬘,3⬘,4⬘-penta-O-acetyl6-amino-6,6⬘-dideoxy-6⬘isothiocyanato 6,4-(cyclic thiocarbamate)
[␣]D
Solvent
Reference
114–115
⫹62
CHCl3
75,82
227 Syrup
⫺29.6 ⫹71
CHCl3 Me2CO
144 82
Syrup
⫹47.8
CH2Cl2
85
Amorphous
⫹85.2
MeOH
144
—
88
oil
—
Syrup
⫹25
CH2Cl2
75
151
⫹90.6
CH2Cl2
78
125
⫹48.3
CH2Cl2
78
Syrup
⫹93
CHCl3
87
—
—
—
67
—
⫹149
CH2Cl2
67
—
⫹42.9
CH2Cl2
67
Amorphous Amorphous
⫺34.0 ⫺16.0
CHCl3 MeOH
98 98
Syrup
⫺26.3
CHCl3
98
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET TABLE II—Continued Rotation MP(⬚C)
2,3,4,1⬘,3⬘,4⬘-Hexa-O-acetyl-6,6⬘dideoxy-6,6⬘-diisothiocyanato 6-Amino-6,6⬘-dideoxy-6⬘isothiocyanato 6,4-(cyclic thiocarbamate) 6,6⬘-Dideoxy-6,6⬘-diisothiocyanato 움,움⬘-Trehalose N-Acetyl-2,3,2⬘,3⬘,4⬘-penta-O-acetyl6-amino-6,6⬘-dideoxy-6⬘isothiocyanato 6,4-(cyclic thiocarbamate) 2,3,4,2⬘,3⬘,4⬘-Hexa-O-acetyl-6,6⬘dideoxy-6,6’-diisothiocyanato 6-Amino-6,6⬘-dideoxy-6⬘isothiocyanato 6,4-(cyclic thiocarbamate) 6,6⬘-Dideoxy-6,6⬘-diisothiocyanato 2,3,4,2⬘,3⬘,4⬘-Hexa-O(trimethylsilyl)-6,6⬘-dideoxy-6,6⬘diisothiocyanato Nucleosides Adenosine 3⬘-Azido-2⬘-O-t-butyldimethylsilyl3⬘,5⬘-dideoxy-5⬘-isothiocyanato Thymidine 5⬘-Amino-3⬘,5⬘-dideoxy-3⬘isothiocyanato-5⬘-Ntriphenylmethyl 3⬘-Azido-3⬘,5⬘-dideoxy-5⬘isothiocyanato 2⬘,3⬘-Dideoxy-3⬘-isothiocyanato Thymidine 3⬘-Deoxy-3⬘-isothiocyanato Thymidine 5⬘-O-t-Butyldimethylsilyl-3⬘-deoxy3⬘-isothiocyanato Uridine 2⬘,3⬘-Dideoxy-2⬘-isothiocyanato Uridine 2⬘-Deoxy-2⬘-isothiocyanato-3⬘,5⬘-diO-(1,1,3,3-tetraisopropyldisiloxyl) Oligosaccharides Cyclomaltoheptaose 6I-Deoxy-6I-isothiocyanato
[␣]D
Solvent
Reference
Syrup
⫹72.7
CHCl3
94
Syrup Syrup
⫹150.1 ⫹74.3
MeOH MeOH
98 98
Amorphous
⫹12.0
CH2Cl2
98
75–77
⫹113.8
CHCl3
98
Amorphous Amorphous
⫹10 ⫹100.7
MeOH MeOH
98 98
106–108
⫹85.1
CH2Cl2
100
Amorphous
—
—
269
—
—
—
270
Oil —
— —
— —
268 93
110–112
—
—
94,96
147–149
—
—
94
—
—
—
96
—
—
—
96
Pyridine
99
Amorphous
⫹112
4888 Horton Chapter 4 11/17/99 6:50 AM Page 49
N-THIOCARBONYL CARBOHYDRATE DERIVATIVES
49
TABLE II—Continued Rotation
Heptakis(6-deoxy-6-isothiocyanato) Cyclomaltohexaose Hexakis(6-deoxy-6-isothiocyanato) Cyclomaltooctaose Octakis(6-deoxy-6-isothiocyanato)
MP(⬚C)
[␣]D
Solvent
Reference
⬎255 (dec.)
⫹46
Me2SO
98
⬎255 (dec.)
⫹20
Me2SO
98
⬎240 (dec.)
⫹85
Me2SO
98
in apolar solvents following the classical Fischer method1 leads to the glycosylically linked isothiocyanate, the use of the (less expensive) alkali metal thiocyanate salts affords preferentially the kinetically favored thiocyanate isomer.32,33 This important drawback has been overcome by the use of phase-transfer catalysts that promote in situ thiocyanate→isothiocyanate conversion under mild conditions.34,35 Generally, per-O-protected glycosyl bromides in reaction with potassium or ammonium thiocyanate are used as precursors.36–43 The reaction is conducted in polar aprotic solvents (such as acetonitrile) in the presence of cyclic polyethers or tetraalkylammonium salts as catalysts (Scheme 1). In the case of glycopyranosyl donors bearing a participating group at C-2, glycopyranosyl isothiocyanates having a 1, 2-trans relative disposition are obtained in pure anomeric form. By this method, a broad series of isothiocyanate derivatives of per-O-acetylated and per-O-benzoylated aldohexoses, 2-amino-2-deoxyaldoses, and aldopentoses have been prepared in 60–80% yields. This approach has also been successfully applied to the synthesis of oligosaccharide glycosyl isothiocyanates
SCHEME 1
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET TABLE III Sugar Isothiocyanate Conjugates Sugar
Monosaccharides N-Acetylneuraminic acid 2-Aminoalditol-N→ 3-Deoxy-D-manno-2-octulosonic acid 2-Aminoalditol-N→ 움-L-Fucopyranoside 2-O-tert-Butyldimethylsilyl-3,4-Oisopropylidene 웁-L-Fucopyranoside 움-D-Galactopyranoside 2-Acetamido-2-deoxy 웁-D-Galactopyranoside 2-Acetamido-2-deoxy 2-Acetamido-2-deoxy, 1-aminoalditol-N→ 움-D-Glucopyranoside 움-D-Glucopyranoside, methyl 2-Amino-2-deoxy-N→ 웁-D-Glucopyranoside 2-Acetamido-2-deoxy 3-O-Methyl 움-D-Mannopyranoside 움-D-Mannopyranoside 6-Phosphate 웁-D-Mannopyranoside Methyl (움-D-glycero-D-galacto-2nonulopyranosid)onate 5-Acetamido-4,7,8,9-tetra-Oacetyl-3,5-dideoxy-2thio-(2S→ Nojirimycin 2,3,4,6-Tetra-O-benzyl-5-(N→ 움-L-Rhamnopyranoside Disaccharides 움-Abep- (1→3)-움-D-Manp (1→a Chitobioside N,N⬘-Diacetyl 움-D-Glcp-(1→6)-움-D-Manp-(1→ 웁-D-Glcp3OMe-(1→3)-움-L-Rhap-(1→ 웁-Lactoside 웁-Lactoside 웁-Maltoside 움-D-Manp-(1→6)-움-D-Glcp-(1→ 움-D-Manp-(1→2)-움-D-Manp-(1→ 움-D-Manp-(1→2)-움-D-Manp(1→
Bridging Arm
Reference
6-Isothiocyanatohexyl
137
6-Isothiocyanatohexyl p-Isothiocyanatophenyl
137 126
4-Isothiocyanatobutyl p-Isothiocyanatophenyl
131 117
p-Isothiocyanatophenyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl
126 103,126 126 135
p-Isothiocyanatophenyl
103,126
p-Isothiocyanatobenzoyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl 2-Isothiocyanatoethyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl
103 103,126 126 124 130 126 126 126
p-Isothiocyanatophenyl
116
2-Isothiocyanatoethyl p-Isothiocyanatophenyl
140 126
p-Isothiocyanatophenyl
120
Isothiocyanatoglycyl 2-(p-Isothiocyanatophenyl) ethyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenylthio) ethyl p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenyl)ethyl p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenyl)ethyl
138 127 125 126 129 126 127 114 127
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N-THIOCARBONYL CARBOHYDRATE DERIVATIVES TABLE III—Continued Sugar 움-D-Manp-(1→6)-움-D-Manp-(1→ 움-Parp-(1→3)-D-Manp-움-(1→b 움-L-Rhap-(1→2)-6-deoxy-움-L-Talp-(1→ 움-Tyvp-(1→3)-움-D-Manp (1→c Trisaccharides Chitotriose 1-Aminoalditol-N→ 2-O-(움-D-Glcp)isomaltoside 3-O-(움-D-Glcp)isomaltoside 4-O-(움-D-Glcp)isomaltoside 움-D-Neu5Ac-(2→6)-웁-D-Galp-(1→4)-웁-DGlcpNAc-(1→ 3⬘-O-움-Sialyllactose 1-Aminoalditol-N→ 1-Aminoalditol-N→ 6⬘-O-움-Sialyllactose 1-Aminoalditol-N→ 웁-D-Galp-(1→6)-웁-D-Galp-(1→6)웁-D-Galp-(1→ 웁-D-Glcp3OMe-(1→3)-움-L-Rhap-(1→2)6-deoxy-움-L-Talp-(1→ 움-D-Manp-(1→2)-[움-D-Manp-(1→6)]움-D-Manp-(1→ Higher oligosaccharides 웁-D-GlcpNAc-(1→2)-움-D-Manp-(1→3)-[웁-DGlcpNAc-(1→2)-움-D-Manp-(1→6)]웁-D-Manp-(1→4)--D-GlcpNAc(1→4)--D-GlcpNAc-(1N→ 웁-D-Galp(1→4)-웁-D-GlcpNAc-(1→2)움-D-Manp-(1→3)-[웁-D-Galp-(1→4)웁-D-GlcpNAc-(1→2)-움-D-Manp-(1→6)]웁-D-Manp-(1→4)-웁-D-GlcpNAc-(1→4)웁-D-GlcpNAc-(1N→ 움-D-Neu5Ac-(2→6)-웁-D-Galp-(1→4)-웁-DGlcpNAc-(1→2)-움-D-Manp-(1→3)-[움-DNeu5Ac-(2→6)-웁-D-Galp-(1→4)-웁-DGlcpNAc-(1→2)-움-D-Manp-(1→6)]-웁-DManp-(1→4)-웁-D-GlcpNAc-(1→4)웁-D-GlcpNAc-(1N→ 움-D-Neu5Ac-(2→3)-웁-D-Galp-(1→4)-웁-DGlcpNAc-(1→2)-움-D-Manp-(1→3)-[움-DNeu5Ac-(2→3)-웁-D-Galp-(1→4)웁-D-GlcpNAc-(1→2)-움-DManp-(1→6)]-웁-D-Manp-(1→4)-웁-DGlcpNAc-(1→4)-웁-D-GlcpNAc-(1N→ A-Tetrasaccharide 1-Aminoalditol-N→
Bridging Arm
Reference
2-(p-Isothiocyanatophenyl)ethyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl p-Isothiocyanatophenyl
127 121 125 118
p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenyl)ethyl 2-(p-Isothiocyanatophenyl)ethyl 2-(p-Isothiocyanatophenyl)ethyl
135 128 128 128
Isothiocyanatoglycyl
138
p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenyl)ethyl
135 134
2-(p-Isothiocyanatophenyl)ethyl p-Isothiocyanatophenyl
134 111
p-Isothiocyanatophenyl
125
2-(p-Isothiocyanatophenyl)ethyl
127
Isothiocyanatoglycyl
138
6-Isothiocyanatohexanoyl
139
6-Isothiocyanatohexanoyl
139
6-Isothiocyanatohexanoyl
139
p-Isothiocyanatophenyl
135
4888 Horton Chapter 4 11/17/99 6:50 AM Page 52
TABLE III—Continued Sugar Lacto-N-difucohexaose I 1-Aminoalditol-N→ 1-Aminoalditol-N→ Lacto-N-fucopentaose I 1-Aminoalditol-N→ Lacto-N-fucopentaose II 1-Aminoalditol-N→ 1-Aminoalditol-N→ Lacto-N-fucopentaose III 1-Aminoalditol-N→ Lacto-N-hexaose 1-Aminoalditol-N→ Lacto-N-tetraose 1-Aminoalditol-N→ Salmonella-specific oligosaccharides 1-Aminoalditol-N→ Polysaccharides Aeromonas-specific polysaccharides KDO-2-Aminoalditol-N→ Vibrio anguilarum polysaccharide Oxidized heptose-6-NH→ Cellulose-O→ Cellulose-O→ Cellulose-O→ Cellulose-O→ a
Abe, abequose (3,6-dideoxy-D-xylo-hexose). Tyv, tyvelose (3,6-dideoxy-D-arabino-hexose). c Par, paratose (3,6-dideoxy-D-ribo-hexose). b
d
e
f
Bridging Arm
Reference
p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenyl)ethyl
135 134
p-Isothiocyanatophenyl
135
p-Isothiocyanatophenyl 2-(p-Isothiocyanatophenyl)ethyl
135 134
p-Isothiocyanatophenyl
135
p-Isothiocyanatophenyl
135
p-Isothiocyanatophenyl
135
2-(p-Isothiocyanatophenyl)ethyl
106
6-Isothiocyanatohexyl
137
6-Isothiocyanatohexyl (CH2)2-NH-CS-NH-R-NCSd (CH2)2-NCS CH2-CO-NH-R-NCSe CO-NH-R-NCSf
137 141 141 141 141,143
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N-THIOCARBONYL CARBOHYDRATE DERIVATIVES
53
of biological importance, such as lactose, chitobiose, and chitotriose derivatives.36–38,42 Krepinski and coworkers44 have synthesized in a similar way the branched trisaccharide glycosyl isothiocyanate 웁-D-GlcpNAc(1→4)-[움-L-Fucp-(1→6)]-웁-D-GlcpNAc-(1→NCS), structurally related to the oligosaccharide core portion of N-glycoproteins. The synthetic scheme involved activation of the peracetylated trisaccharide with titanium tetrabromide and further treatment with potassium thiocyanate. The use of oxazolinium cations as glycosyl donors (such as 5) is an interesting alternative for the preparation of glycosyl isothiocyanate derivatives of 2-acetamido-2-deoxy-D-glucose and oligosaccharides thereof.45 Following this approach, Günther and Künz46 prepared the linear trisaccharide isothiocyanate 6, which was further used in the first synthesis of the core region unit of N-glycoproteins by coupling to the amino acid asparagine (Scheme 2). Recently, Lindhorst and Kieburg47 have reported a novel, solvent-free preparation of glycopyranosyl isothiocyanates by reaction of peracetylated glycosyl bromides with potassium thiocyanate in the molten state. In contrast to previous attempts of thermal isomerization of glycosyl thiocyanates, this procedure affords exclusively the thermodynamic isothiocyanate compounds. The method was effective with hexoses, 6-deoxyhexoses, pentoses, and disaccharides, with isolated yields ranging between 41 and 73% (Scheme 3). The 1,2-trans-configured glycosyl isothiocyanates were exclusively obtained in all cases, except for the D-galactopyranosyl derivative, where a 1 : 9 움 : 웁 anomeric mixture was formed. The readily available inexpensive reagents and the lack of a need for additives make this procedure very convenient for bulk preparation of glycosyl isothiocyanates from commercially available sugars. The preparation of 1,2-cis-configured glycopyranosyl isothiocyanates
SCHEME 2
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GARCÍA FERNÁNDEZ AND ORTIZ MELLET
SCHEME 3
requires the use of nonparticipating groups. Several perbenzylated monoand disaccharide glycosyl isothiocyanates have been thus obtained as 움,웁anomeric mixtures by treatment of the corresponding glycosyl chlorides with potassium isothiocyanate in the presence of a tetrabutylammonium salt.34,35,48 Analogously, peracetylated 2-deoxy-움-D-glycosyl bromides yielded mixtures of 2-deoxy-움- and 웁-D-glycosyl isothiocyanates upon reaction with either potassium thiocyanate–[18]-crown-6 or silver thiocyanate.49,50 In all cases, the 움 : 웁 ratio was close to 1 : 1, and both anomers were separated after column chromatography. A notable exception is the reaction of methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-움-Dglycero-D-galacto-2-nonulopyranosyluronate) chloride (7) with potassium thiocyanate under conditions of phase-transfer catalysis, which affords exclusively the 움-configured glycosyl isothiocyanate derivative of N-acetylneuraminic acid 8 (Scheme 4).51 To overcome the problems derived from formation of anomeric mixtures when O-benzylated glycosyl halides are used as precursors, Ledford and Carreira52 have disclosed an elegant synthesis of 2,3,4-tri-O-benzyl-움-Dglucopyranosyl isothiocyanate (10) based on the use of 1,6-anhydro-2,3,4tri-O-benzyl-웁-D-glucopyranose (9) as the glycosyl donor. Treatment of 9 with tetra-n-butylammonium thiocyanate and boron trifluoride–etherate complex provided 10 in 50% yield with total control of the anomeric configuration (Scheme 5). The reaction of fully acetylated glycofuranosyl halides with KSCN follows an analogous pattern to that just described for their pyranosyl counterparts, namely, glycofuranosyl thiocyanates are formed as the major
SCHEME 4
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N-THIOCARBONYL CARBOHYDRATE DERIVATIVES
55
SCHEME 5
reaction products,53 which can be isomerized to the corresponding isothiocyanates by using a phase-transfer catalyst.41 Remarkably, replacement of the acetyl protecting groups by benzoyl groups results in the direct formation of glycofuranosyl isothiocyanates with no need for any additive.53,54 The reaction is totally diastereoselective, affording the 1,2-trans-configured isothiocyanates as the sole reaction products under mild conditions (room temperature, 2 h). Fully benzoylated 웁-D-galacto- (14), 웁-D-ribo-, and 웁-Dxylo-furanosyl isothiocyanates were thus prepared in 80–90% yield. Crude glycofuranosyl chlorides (such as 12) or bromides (for example, 13), obtained from the perbenzoylated sugars (for instance, 11) by treatment with acetyl chloride–HCl or bromotrimethylsilane, respectively, were used as precursors (Scheme 6). The trimethylsilyl isothiocyanate–tin tetrachloride system has been proposed55 as an alternative to the use of inorganic thiocyanate salts for the synthesis of glycosyl isothiocyanates. By applying this reagent, 1,2,3,4,6penta-O-acetyl-␣-D-glucopyranose was directly transformed into the corresponding -isothiocyanate in 80% yield.
SCHEME 6
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b. Electrophilic Addition to Glycals.—The possibility of using glycals, namely 1,2-unsaturated sugars, as glycosyl isothiocyanate precursors was explored by Igarashi and Honma56 in the 1960s. However, formation of a complex mixture of diastereomers as well as of isothiocyanate– thiocyanate isomers was observed using thiocyanogen as reagent, and the approach was no longer investigated. In 1994, Santoyo-González et al.57 reported a very convenient route for the simultaneous introduction of the iodo and isothiocyanate functionalities in a sugar molecule starting from glycals. Electrophilic addition of iodine (I) thiocyanate, generated in situ from silica-supported KSCN and iodine, to the double bond leads exclusively to trans-2-deoxy-2iodoglycopyranosyl isothiocyanates. In the case of monosaccharide glycals, a mixture of the trans-diaxial (major) and trans-diequatorial product (minor) was obtained, whereas the trans-diaxial vic-iodoisothiocyanate was the sole product in the case of disaccharide glycals (Scheme 7). The high yield, good stereoselectivity, and simplicity of the method make it very attractive for the preparation of highly functionalized sugar derivatives. c. Isothiocyanation of Sugar Amines.—From the variety of preparative methods available for the synthesis of isothiocyanates, the reaction of a primary amine with an isothiocyanation reagent is probably the most generally useful. Formation of the C––N bond occurs here prior to generation of the isothiocyanate group and, therefore, formation of the isomeric thiocyanate is prevented. Depending on the location of the amine functionality in the sugar precursor, this approach allows access to glycosyl isothiocyanates, deoxyisothiocyanato, sugars, and isothiocyanate conjugates. Although the transformation of glycosylamines (such as 15) into fully unprotected glycosyl isothiocyanates by reaction with thiophosgene was already reported in the 1970s,58–61 these compounds were later shown to be unstable,62 and no further chemistry has been reported. The synthesis of stable, fully protected hexopyranosyl isothiocyanates by the thiophosgene reaction was first reported by Fuentes Mota and coworkers.63–65 The reaction sequence involves a glycosyl enamine (for example, 16) as key intermediate which, after O-protection (→17), is hydrolyzed under mild condi-
SCHEME 7
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SCHEME 8
tions using chlorine or bromine in moist chloroform (→18). By this procedure, peracetylated and perbenzoylated glycosyl isothiocyanates (such as 19) of several mono-63–65, di-66–68, and trisaccharides68 were obtained from the commercial sugars in five steps and 50–60% overall yields. Some partially acylated derivatives have been also prepared following an analogous strategy (Scheme 8).69,70 Since the preparation of glycosylamines from reducing sugars is under control of the reverse anomeric effect, the foregoing methodology affords 웁-configured glycopyranosyl isothiocyanates independent of the orientation of the acyloxy group at C-2, thus complementing the glycosyl halide– inorganic thiocyanate approach already mentioned. Following either one or the other method, both 2,3,4,6-tetra-O-acetyl-움- and 웁-D-mannopyranosyl isothiocyanates (22 and 23) may be prepared with total stereocontrol from the corresponding 움-bromide 20 or 웁-mannosylamine 21, respectively (Scheme 9).71
SCHEME 9
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Some deviations from this general pattern have been reported72 in the aldopentose series. Thus, 2,3,4-tri-O-benzoyl-웁-D-ribopyranosylamine hydrobromide partially anomerized on treatment with thiophosgene, leading to a 4 : 1 웁 : 움 anomeric mixture of the corresponding tri-O-benzoyl-Dribopyranosyl isothiocyanates 24 and 25. It is noteworthy that, in both anomers, the NCS group adopts an axial disposition, in accord with the anomeric effect. The synthetic value of the enamine strategy for temporary amine protection in the preparation of sugar isothiocyanates is further underlined by the possibility of access to peracylated derivatives bearing the NCS group at a nonanomeric secondary73,74 or primary position.75 No O→N acyl migration occurred, either in the halogenolysis or in the isothiocyanation steps, even in the case of the acyclic glucitol (26) and cellobiitol (27) derivatives. Other N-protecting methodologies applied to the synthesis of 2-deoxy2-isothiocyanatohexoses from D-glucosamine and oligosaccharides thereof include the formation of a Schiff base76,77 or a benzyloxycarbonyl derivative.67,78,79
Aldose and ketose derivatives bearing an isothiocyanate group at a primary carbon atom have also been obtained from cyclic acetal derivatives.80–83 In this case, introduction of the amino group follows hydroxyl protection and no N-protecting group is needed. 6-Deoxy-1,2 : 3,5-di-Oisopropylidene-6-isothiocyanato-움-D-glucofuranose,80–82 6-deoxy-1,2 : 3,4di-O-isopropylidene-6-isothiocyanato-움-D-galactopyranose,81,82 and 1-deoxy-2,3 : 4,5-di-O-isopropylidene-1-isothiocyanato-웁-D-fructopyranose83 have been thus prepared in three steps from the corresponding readily accessible selectively O-acetalated monosaccharides. An analogous synthetic pathway has been employed84 in the preparation of 3-deoxy-1,2 : 5,6-di-Oisopropylidene-3-isothiocyanato derivatives of kanosamine (3-amino-3deoxy-D-glucose) and of its C-3 and C-4 epimers (with the D-allo and D-galacto configurations, respectively). Although thiophosgene is generally preferred, since it provides clean and very fast reactions, other isothiocyanation reagents may also be employed for the transformation of amino sugars into sugar isothiocyanates. Carbon disulfide–N,N⬘-dicyclohexylcarbodiimide85 and N,N⬘-thiocarbonyldiimidazole48,85–88 have proved particularly useful in the case of derivatives bear-
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SCHEME 10
ing acid-sensitive silyl ether protecting groups.85 Other reported examples include Mukaiyama89,90 (CS2, Et3N, then 2-chloro-1-methylpyridinium iodide, Et3N) and Wadsworth–Emmonds89,91,92 [(EtO)2P(⫽O)Cl, Et3N, then NaH, n-Bu4NBr, carbon disulfide] isothiocyanation protocols. The synthesis, chemistry, and pharmacological properties of deoxyisothiocyanato ribonucleosides93–96 have been the subject of recent attention. Cech and coworkers96 examined different systems for the isothiocyanation of the aminodeoxy precursors. Thiophosgene in pyridine, N,N⬘-thiocarbonyldiimidazole, and CS2–HgO were found effective for the transformation of 3⬘-amino-2⬘,3⬘-dideoxythymidine 28 into the corresponding isothiocyanate 29, the later reagent having some practical advantages (Scheme 10). This was also the method of choice for the preparation of 2⬘-deoxy-2⬘-isothiocyanato derivatives in the uridine series. Interestingly, compound 29 was found to be cytotoxic to different mouse leukemic cell lines.94 The stability of monosaccharide derivatives bearing both isothiocyanate and free hydroxyl groups is dramatically dependent on the configuration and conformation of the sugar template. As a general rule, 웁- and 웂hydroxyisothiocyanates undergo spontaneous or base-induced annelation reaction to the corresponding five- and six-membered cyclic thiocarbamates, respectively.81–84, 96 Nevertheless, the partially protected derivatives 30–32 were stable compounds which could undergo further transformations (such as acylation) without affecting the NCS functionality.84, 97 In all these
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cases, the intramolecular nucleophilic cycloaddition would lead to a fivemembered–six-membered trans-fused bicyclic system, an unfavorable arrangement. Fully unprotected 6-deoxy-6-isothiocyanato aldopyranosides (33) have been found to be stable in the absence of base.82 Per-O-acyl and perO-trimethylsilyl derivatives were also prepared after conventional Oprotecting reactions,82,85 although some thiocarbamate formation was observed in the latter derivatization. The foregoing results have been expanded to the preparation of stable unprotected and O-protected sugar isothiocyanates of nonreducing oligosaccharides of economic and biological significance, such as sucrose (34), 움,움⬘-,trehalose (35), and cyclomaltooligosaccharides (움-, 웁-, and 웂-cyclodextrins; 36, 37) by reaction of the corresponding (poly)-amines with thiophosgene.98–100
Isothiocyanate and hydroxyl groups separated by three carbon atoms or more do not interfere between them, even in the presence of base catalysts or after prolonged heating. Consequently, homologation of primary aminodeoxy sugar methyl glycosides via the corresponding glycurononitrile (38), following the method reported by Defaye and Gadelle (→39),101 and fur-
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SCHEME 11
ther isothiocyanation resulted in very stable fully unprotected, 6,7-dideoxy7-isothiocyanatoheptose derivatives 40 (Scheme 11).102 The thiophosgene reaction has been broadly employed for the preparation of isothiocyanate conjugates, an important family of compounds in which the NCS group is located in a noncarbohydrate moiety covalently linked to the saccharide core. The isothiocyanate segment of the molecule is usually called the “handle’’ or “bridging arm’’ when such conjugates are generated as intermediates for the attachment of an oligosaccharide to a macromolecular carrier or solid matrix. In 1968, Buss and Goldstein103 reported a synthesis of monosaccharide–phenyl isothiocyanate conjugates (43) as convenient intermediates for coupling reactions with proteins, by analogy with the well-known use of phenyl isothiocyanate (Edman’s reagent) in protein analysis. The reaction scheme involved catalytic hydrogenation of the nitro group in commercially available p-nitrophenyl glycosides (41) and reaction of the resulting amine 42 with thiophosgene in aqueous ethanol (Scheme 12). Since this pioneering work, phenyl isothiocyanate conjugates have become very popular tools in the hands of glycobiologists for the preparation of neoglycoconjugate probes.104–117 The amine precursor can alternatively be liberated from suitable N-protected aminophenyl
SCHEME 12
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glycosides, such as 4-( p-toluenesulfonamido)118 or p-trifluoroacetamido derivatives (44).119–123 The isothiocyanation reaction may also be performed under mild alkaline conditions (pH 8) that would not affect the labile glycoside linkages of oligosaccharides containing deoxy sugar or sialic acid residues. By using this technique, several oligosaccharide–phenyl isothiocyanate conjugates related to the O-antigenic polysaccharide chains of the Salmonella119–123 and Mycobacterium124,125 bacteria have been prepared. The final sugar–isothiocyanate conjugates are usually employed for protein conjugation without further characterization, the presence of the NCS group being confirmed by chromatographic or spectroscopic (IR) techniques.126 In addition to the phenyl derivatives, a variety of aglycons have been proposed from which in a final synthetic step the reactive isothiocyanate functionality is generated. The choice of the arm and the mode of attachment to the sugar part of the conjugate depends mainly on the immunogenic requirements of the oligosaccharide to be coupled as a hapten to the protein. The reported examples include p-isothiocyanatophenethyl (45),127,128 2-(pisothiocyanatophenylthio)ethyl (46),129 2-isothiocyanatoethyl,130 4-isothiocyanatobutyl,131 and 6-isothiocyanatohexyl132,133 (47) glycosides.
If the terminal reducing sugar residue can be sacrificed, which is usually the case for large haptenic oligosaccharides, reductive amination becomes an attractive method for the coupling of the handle to the carbohydrate part. Several bifunctional diamine spacers, such as 4-aminophenetylamine,134 ptrifluoroacetamidoaniline (TFAN),135,136 and 1,6-hexanediamine137 have been employed for this purpose. The isothiocyanate group is generated after treatment of the adduct with thiophosgene (Scheme 13). This general strategy has proved useful for the preparation of isothiocyanate conjugates of complex oligosaccharides of biological importance, including those incorporating reducing ketose residues (for example, N-acetylneuraminic acid and 3-deoxy-D-manno-2-octulosonic acid).137 The (6-isothiocyanatohexyl)amino bridging arm has also been inserted into the core oligosaccharide of bacte-
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SCHEME 13
rial glycolipids allowing further conjugation to bovine serum albumin (BSA) protein. In this case, the isothiocyanate portion of the conjugate is linked to C-6 of a partially oxidized terminal heptosyl residue.137 The major drawbacks associated with the reductive amination coupling procedure are the loss of structural and biological information at the reducing end and the possibility of undesirable immunogenicity of the adducts. The reaction of 웁-glycosylamines with heterobifunctional reagents constitutes an interesting alternative. Importantly, oligosaccharide 웁glycosylamine derivatives have structural integrity and can be obtained very efficiently, thus making the method suitable for derivatizing complex oligosaccharides, either synthetic or from biological sources and available only in limited quantities. Two notable examples of this approach are the preparation of N-glycyl138 and N-(6-aminohexanoyl)139 glycosylamines, which were modified with thiophosgene to form the corresponding isothiocyanate conjugates 48. A further original version of the N-linked spacer strategy has been used in the preparation of deoxynojirimycin–trehalamine conjugates.140 The spacer arm was introduced by a reaction sequence involving the formation of an N-glycyl derivative, which was further reduced to the N-(2-aminoethyl)imino sugar. Isothiocyanation following the Mukaiyama methodology afforded the corresponding N-(2-isothiocyanatoethyl)-1-deoxynojirimycin derivative 49.
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Several macromolecular cellulose–isothiocyanate polyconjugates have been reported141–143 and characterized by their binding capacity with respect to amine and sulfur nucleophiles. Functionalization occurred at the cellulose fiber surfaces, and a variety of aromatic, aliphatic, and mixed-type spacers were used. d. Reaction of Sugar Iminophosphoranes with Carbon Disulfide.— Staudinger reaction of azido groups with a phosphine and subsequent azaWittig-type condensation of the resulting iminophosphorane with carbon disulfide is an attractive synthetic strategy for the direct transformation of sugar azides into sugar isothiocyanates (Scheme 14).144 Two main drawbacks for these routes are the high tendency of the forming isothiocyanate to react with the remaining iminophosphorane to give a carbodiimide145 and the separation of the final product from excess phosphine and phosphine thioxide. The use of polymer-bound triphenylphosphine, recently reported in the nucleoside series,96 constitutes a promising alternative to overcome such problems. By using this reagent, 3⬘azido-3-deoxythymidine (AZT) was transformed into the corresponding isothiocyanate 29 in 93% yield after a purification step that involved a simple filtration process. 2. Reactions of Sugar Isothiocyanates a. Reactions with C-, N-, O-, and S-Nucleophiles.—The reaction of sugar isothiocyanates with C-, N-, O-, and S-nucleophiles bearing a labile hydrogen atom leads, at least in a first stage, to N-monosubstituted adducts in which the electronegative residue is linked to the carbon atom of the heteroallene group. The resulting sugar thioamides, thioureas, thiocarbamates, and dithiocarbamates are of interest in view of their synthetic value, especially in heterocyclic chemistry, and their wide spectrum of technical and biological applications. Nucleophilic addition of amino, hydroxy, and mercapto groups to the NCS functionality also plays an important role in the conjugation of sugar isothiocyanates with biomolecules. The literature concerning this important aspect of sugar isothiocyanate reactivity has been discussed in part in several reviews.4,8,146 The growing interest in these reactions is further corroborated by the numerous new results reported in the past few years. A detailed survey of these results has been included in sections of this chapter.
SCHEME 14
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b. Condensation with Carboxylic Acids.—The triethylamine-catalyzed reaction of glycosyl isothiocyanates with carboxylic acids to give glycosylamides was first investigated by Khorlin and coworkers147,148 and further implemented149 for the construction of the N-glycosylic linkage between 2-acetamido-2-deoxy-웁-D-glucopyranosylamine and suitably protected L-aspartic acid derivatives, analogous to that existing in natural N-glycoproteins. Under optimal reaction conditions, which involve strict exclusion of water and the use of 0.1 molar equiv. of Et3N, yields higher than 70% of the desired glycosylamide are obtained,44,46 thus favorably comparable to other N-glycopeptide synthetic methodologies.150,151 The reaction has been applied to monoprotected dicarboxylic acids152–154 and to the selectively functionalized glycosyl isothiocyanate 51 (Scheme 15).155 The glycosylamides thus obtained incorporated a reactive group either in the aglycon (50) or in the sugar moiety (52), which was subsequently used in their coupling to 웁-cyclodextrin derivatives. c. Self-Condensation Reactions.—Bis(glycosyl)thioureas are often formed as secondary products during the synthesis and reactions of glycosyl isothiocyanates. Different mechanisms have been proposed to explain their formation, such as the coupling of unreacted amine with isothiocyanate during the isothiocyanation step or the hydrolysis of a mixed anhydride in the aforementioned condensation with carboxylic acids.149 The problem has been examined in detail71 and shown to involve two isothiocyanate molecules. In a first step, base-catalyzed addition of a water molecule to the NCS group takes place to give a thiocarbamic acid derivative. Subsequent addition to a second NCS group and elimination of COS affords the corresponding symmetric thiourea (Scheme 16). The reaction proceeds at room temperature in 10 : 1 pyridine–water in the case of glycosyl
SCHEME 15
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SCHEME 16
isothiocyanates or at 60⬚C in the case of deoxyisothiocyanato sugars and is of synthetic value for the preparation of a variety of symmetric sugar thioureas. d. Desulfurization Reactions.—Desulfurization of glycosyl isothiocyanates with tributyltin hydride at room temperature in the absence of a free-radical initiator affords glycosyl isocyanides (53) in 58–76% yields.39 The outcome of the reaction may strongly depend on the reagent ratio and the presence of moisture, since formation of the corresponding glycosyl thioformamides has been reported by other authors156 under apparently identical reaction conditions. Under more strenuous conditions and in the presence of azobis(isobutyronitrile) (AIBN) as a free-radical initiator, reduction of isothiocyanates leads to the formation of 1,5-anhydroalditols (54) via glycosyl isocyanide intermediates in virtually quantitative yield. Hassel and Müller157,158 have reported the preparation of glycosyl isocyanide dichlorides (55) by chlorination of mono- and disaccharide peracetyl glycosyl isothiocyanates. Interestingly, via these highly reactive intermediates, the isothiocyanate group can be transformed into a variety of other functionalities and heterocyclic derivatives, thus widening the already broad spectrum of synthetic applications of sugar isothiocyanates (Scheme 17). e. Aza-Wittig-Type Reactions.—The intermolecular aza-Wittig-type reaction of sugar isothiocyanates and sugar iminophosphoranes has been the subject of a detailed study159,160 aimed at the preparation of pseudooligosaccharide structures incorporating (1→6)-carbodiimide intersaccharide bridges. Coupling of glycosyl iminophosphoranes with 6-deoxy-6-isothiocyanato sugars afforded the desired compounds in
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SCHEME 17
25–35% yields. A converse strategy implying a one-pot Staudinger reaction of 6-azido-6-deoxy sugars (56) and triphenylphosphine and subsequent in situ aza-Wittig condensation with per-O-acetylated glucosyl (58) and cellobiosyl (59) isothiocyanates proved much more convenient, leading to the (1→6)-linked glycosyl carbodiimido sugars 60 in yields higher than 80% after 10 min of reaction time at room temperature. On the basis of kinetic considerations, the authors suggested a transient phosphazide (57), formed at the early stages of the Staudinger reaction, as the reactive intermediate (Scheme 18).160
SCHEME 18
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f. Cycloaddition Reactions.—The ability of the NCS group to react through the C苷S or the C苷N bond in cycloaddition reactions makes sugar isothiocyanates important precursors in the synthesis of heterocyclic derivatives of carbohydrates. From the body of results collected in the literature,4 it appears that cycloaddition reactions of glycosyl isothiocyanates show, preferentially, the more electron-rich thiocarbonyl double bond to afford glycosylamino heterocycles instead of the isomeric Nnucleosides. Accordingly, the cycloaddition of 2,3,4,6-tetra-O-acetyl-웁-Dglucopyranosyl isothiocyanate 58 and the 1-aza-2-azoniaallene ions 61 and 62 furnished glycosylimino-1,3,4-thiadiazoles 63 and 64, respectively (Scheme 19).55 The reactive heterocumulenic cations were generated in situ from the correspondig 움-chloro-azo compounds by treatment with antimony pentachloride. 3. Spectroscopic Properties The main spectroscopic features of sugar isothiocyanates are the characteristic strong IR absorption (VNCS 2100–1990 cm-1) and the 13C NMR chemical shift of the isothiocyanate functionality (웃NCS 145–135 ppm). The first one appears as a strong wide band and is extensively used both for structural confirmation and monitoring reactions involving sugar isothiocyanate derivatives. Its position is very characteristic and allows discrimination from the isomeric thiocyanates. Other NMR spectroscopic data show the upfield shift of the 13C resonance of the carbon atom directly attached to the heteroallene group (by 15 ppm) and the 1H resonance of the corresponding ␣-located protons (by 1 ppm) as compared to the parent sugar.4,8
SCHEME 19
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The UV spectra of acetylated sugar isothiocyanates show a low-intensity absorption at 250–254 nm, which allows UV detection in the course of chromatographic separations.50,70,78 The band is frequently overlapped when stronger chromophores (such as benzoyl groups) are present in the molecule.65,69,70,72 The main primary fragmentation of glycosyl isothiocyanates in electronimpact (EI) or chemical-ionization (CI) mass spectrometry consists in the loss of the NCS radical to give an oxocarbenium cation (m/z M ⫺ 58). The loss of thiocyanic acid (m/z M ⫺ 59) is also frequently observed, whereas the molecular peak is either absent or of very low intensity.50,57,65,70,78 Significantly, EI mass spectra of peracetyl 6-deoxy-6-isothiocyanato glycopyranosides show intense molecular peaks and losses of CH2NCS and MeNCS as the main primary fragmentation.82,83 An analogous fragmentation pathway was observed in the fast-atom bombardment (FAB⫹) mass spectra of the unprotected derivatives.82 These data probably reflect the higher stability of deoxyisothiocyanato sugars as compared to glycosyl isothiocyanates. IV. SUGAR THIOAMIDES AND THIOLACTAMS Despite the important role that N-acylated amino sugars play in many biological processes and the long-known influence that replacement of oxygen by sulfur may exert in the biochemical properties of a sugar molecule, only a few reports on the synthesis and reactivity of N-thioacylated amino sugars appeared4 before 1985. Since that time the chemistry of sugar thioamides has expanded significantly, fueled by both their synthetic potential, especially in nucleoside chemistry, and their biological applications. 1. Addition of Carbon Bases to Sugar Isothiocyanates Formally, the reaction of carbon nucleophiles and sugar isothiocyanates provides a general route to sugar thioamides. However, the instability of the NCS functionality under the strongly basic conditions needed for the generation of carbanions results, generally, in rather low to moderate coupling yields. The reported examples are limited to the use of enamines or active methylene compounds as carbanion precursors and glycosyl isothiocyanates as electrophiles. The reaction of monosaccharide isothiocyanates with enamines leads to the formation of 움,웁-unsaturated thioamides4,169 (67), which can be cyclized to isothiazole derivatives.4 Formation of additional products arising from attack of the amino group to the isothiocyanate functionality has also been observed, the outcome of the reaction being dependent on the nature of the enamine reagent and on reaction conditions. Thus, nucleophilic addition of a series of 3-amino-3-penten-2-ones (65) and ethyl 3-aminocroto-
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SCHEME 20
nates (66) to 2,3,4,6-tetra-O-acetyl-웁-D-glucopyranosyl isothiocyanate (58) proceeded through carbon (the hard site) in the case of N-aryl substituents, whereas it involved preferentially the amino group (soft site) for N-alkyl derivatives (Scheme 20).169 Nucleophilic addition of diethyl malonate derivatives 68 to the glucosyl isothiocyanate 58 in the presence of sodium hydride afforded the corresponding N-thioacylglucosylamines 69 in 40–60% yields.170 Adducts incorporting an 움-phenacyl substituent (68, R ⫽ Ar) were further cyclodehydrated using phosphoric acid and acetic anhydride to give N-nucleoside derivatives of 2-pyrroline 70. Under identical reaction conditions, the 움acetonyl derivative (68, R ⫽ Me) led to the tetrahydropyridine heterocycle 71 (Scheme 21). Carbanions derived from ethyl cyanoacetate, phenylthioacetonitrile, and cyanoacetamide likewise reacted with 58 to give a thioenolic sodium salt intermediate (72).170 Attempts to isolate the related thioamide were, how-
SCHEME 21
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ever, unsuccessful. After in situ reaction with phenacyl bromide the corresponding thioethers (such as 73, 74) were formed which, in some cases, underwent spontaneous cyclization to give glucosylamino-2-thioxopyrroline derivatives (such as 75–77; Scheme 22). 2. Thionation of N-Carbonyl Derivatives Thionation of N-acylated amino sugars is the method most frequently used for the preparation of sugar thioamides. The O→S exchange has been traditionally accomplished by using phosphorus pentasulfide as the thionation reagent.171–175 The procedure is of general applicability for O-protected carbohydrates, regardless of the anomeric or nonanomeric character of the amide substituent, and has been successfully applied to the preparation of N-thioformyl, N-thioalkanoyl, and N-thiobenzoyl derivatives.176–178 In recent years Lawesson’s reagent, namely, 2,4-bis(4-methoxyphenyl)1,3-dithiadiphosphetane-2,4-disulfide, has become the reagent of choice for thionation of carbonyl compounds. By this methodology, a series of glyconothiolactams (79), used as key synthetic intermediates in the preparation of a variety of glycosidase inhibitors, were obtained in high yield from the corresponding lactams 78 (Scheme 23).179–185 Thionation of N-acetylated amino sugars provides a convenient route for N-deacetylation in compounds sensitive to strongly basic conditions such as nucleosides, since the thioacetyl group can be removed under mild basic conditions using methanolic ammonia.171,172 Alternatively, S-methylation and subsequent mild acid hydrolysis of the resulting thioiminoether allows removal of the N-thioacetyl group in the presence of O-acetyl groups.173
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SCHEME 23
The reverse CS→CO transformation of N-alkyl thioacetamido sugars has been achieved by treatment with silver acetate.186 3. Thioacylation of Amino Sugars In contrast to the acylation of amines, for which acyl halides and acid anhydrides are the predominant reagents, direct introduction of a thioacyl substituent on an amino group is generally achieved by using thionocarboxylates or dithiocarboxylates as thioacylating reagents.187 Brossmer and Isecke188 have reported the direct thioformylation, thioacetylation, and thiopropanoylation of fully unprotected 2-amino-2-deoxyaldoses in the D-gluco, D-galacto, and D-manno series by reaction with O-ethyl thioformate, methyl dithioacetate, and methyl dithiopropionate, respectively (→80). The method was further extended to the preparation of sialic acid derivatives bearing thioamido groups at C-5 (81) or C-9 (82) as inhibitors of influenza virus hemagglutinin.189 Thioacetylation of O-protected amino
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sugars has alternatively been effected by treatment with dithioacetic acid in the presence of N,N⬘-dicyclohexylcarbodiimide.190 4. Miscellaneous Sugar Thioamide Syntheses O-Protected sugar thioformamides have also been prepared in 44–87% yields by tri-n-butyltin hydride reduction of isothiocyanate precursors in ether.156 For the preparation of 5-N-thioacylneuraminic acids (84), a chemoenzymatic route based on the N-acetylneuraminate pyruvate lyasemediated condensation of the corresponding N-thioacyl-D-mannosamine derivatives (83) and sodium pyruvate has been reported.189 The enzymecatalyzed aldol reaction was performed at pH 6.8 and afforded the desired compound in 55% yields (Scheme 24). Masson and co-workers191 have reported a different type of sugar thioamide in which the carbohydrate moiety forms part of the thioacyl radical, namely D-mannofuranosyl-ethanethioamides (87, 89). Their synthesis involved a Horner–Wadsworth–Emmons reaction of thiocarbamoylmethylphosphonates (86) with 2,3 : 5,6-di-O-isopropylidene-D-mannofuranose (85). The coupling yields were higher than 90% for N-alkyl and N,Ndialkylthioamides, while decreasing to 15% or even zero for amino acid derivatives. An alternative route for such compounds was devised consisting of the methylation–sulfhydrolysis of a preformed thioamide. The resulting methyl dithioate (88) was further used as thioacylating reagent for glycine and its methyl ester (Scheme 25). Though the prior formation of the C-glycosylic bond led to a mixture of the 움- and 웁-anomers, they could be readily separated by silica gel chromatography in all cases. 5. Conformational Properties of Sugar Thioamides The well-known rotational isomerism of thioamides has been studied in detail for monosaccharide derivatives bearing a thioacetamido substituent at a secondary or primary position.176,177,188,189 As common features,
SCHEME 24
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formamido and N,N-disubstituted thioamides exist at room temperature as a mixture of unequally populated Z and E rotamers at the N––C(苷S) bond, and two sets of signals can be seen in the corresponding 1H and 13C NMR spectra. In contrast, the Z rotamer exclusively occurs in the case of NHC(苷S)R substituents for R other than H. The relative disposition around the contiguous N––CH bond has been determined to be antiperiplanar for thioamide groups at secondary positions in a pyranose ring. Several useful rules for configurational assignment in these compounds have been given176 on the basis of 1H and 13C NMR spectral parameters (Fig. 5).
FIG. 5.
Spectral parameter relationships for (Z) and (E) rotamers of sugar thioamides.
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V. SUGAR THIOUREAS A large body of work in the area of N-thiocarbonyl carbohydrate derivatives has been directed toward the synthesis and applications of sugar thioureas. The early contributions focused on their use as synthetic intermediates in heterocyclic chemistry,4,8 an approach that continues to be explored intensively for the preparation of nucleoside and other N-glycosyl compounds. More recently, the extension toward glycobiology in the carbohydrate field and the promise of seminatural or unnatural carbohydratecontaining substances for basic biomedical research and practical medical applications has spurred an aggressive effort to design neoglycoconjugates, among which those incorporating thiourea linkers are of prime importance. Further uses of the thiourea technology include the attachment of saccharide portions to pharmaceuticals and the preparation of diastereomeric conjugates from enantiomeric mixtures for analytical purposes. 1. Coupling of Sugar Isothiocyanates with Amine Nucleophiles Sugar isothiocyanates are, probably, the most powerful starting materials for preparing sugar thioureas and derivatives. In a general manner, glycosyl isothiocyanates37,54,57,66,73,74 and deoxyisothiocyanato sugars97,192–194 react with ammonia, primary amines, and secondary amines to give 1-substituted, 1,3-disubstituted, and trisubstituted thioureas, respectively (Scheme 26). This reaction generally takes place with good yields and leads to welldefined, frequently crystalline compounds of high stability. One of the main advantages of the method is its versatility, being compatible with a wide range of protecting and functional groups both in the amine and in the sugar isothiocyanate reagents. The new examples reported include the preparation of antiviral, antibacterial, and antitumor agents by coupling sugar isothiocyanates and such biologically active amines as triazole derivatives,195 mitomycin,196 isothiazolopyrimidines,40 and also platinum compounds.197 Other N-nucleophiles such as hydrazine,37 isothiourea,198 and guanidine derivatives199 have been similarly coupled to sugar isothiocyanates. Isothiocyanate groups located at anomeric positions are distinctly more reactive than nonanomeric isothiocyanates toward addition of Nnucleophiles. Thus, whereas the reaction of glycosyl isothiocyanates with
SCHEME 26
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ammonia proceeds in ether or ethanol to give the corresponding N-glycosylthiourea in quantitative yield, no reaction was observed in the case of 6-deoxy-6-isothiocyanatoaldose derivatives under identical reaction conditions. Nevertheless, high coupling yields were obtained when the reaction was performed in pyridine as solvent and catalyst.85 Sugar thioureas containing an N-azolyl substituent, such as the thiazole, thiazoline, or benzoxazole rings, have been the subject of attention in connection with the interest in azole nucleoside analogs as antineoplastic and antiviral compounds.200–202 Their preparation involves the reaction of O-protected glycosyl isothiocyanates or 2-deoxy-2-isothiocyanatoaldoses with the corresponding 2-aminoheterocycles. A complete spectroscopic (UV, IR, NMR, and MS) study has shown the existence of six-membered intramolecular hydrogen bonding in chloroform solution, with the anomeric NH group acting, generally, as the donor (90). Notable exceptions are 4,4diphenyloxazoline derivatives, which exist as tautomeric mixtures of thiourea (91a), and isothiourea (91b) derivatives, with the thiocarbonyl and the thiol groups acting as hydrogen bond acceptor and donor, respectively.201
The reaction of 3⬘-deoxy-3⬘-isothiocyanatothymidine (29) with selectively protected diamines (→92) has been used96 to introduce thiourea spacers that allow further attachment with fluorescent dyes. Alternatively, 7-amino-4-methylcoumarin was added to 29 to give the fluorescent thiourea conjugate 93 (Scheme 27). The reaction is chemoselective and no protection of the primary OH group was needed. Amino acids and peptides have been coupled to glycosyl isothiocyanates to give N-(glycosylthiocarbamoyl)peptides which, in some cases, have shown immunoadjuvant and antitumor activities.42 The interest of this re-
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SCHEME 27
action for the chiral derivatization of 움-amino acid enantiomers was already realized by Nimura and co-workers in the early 1980s.203–205 Coupling of a glycosyl isothiocyanate with an enantiomeric mixture of D- and Lamino acids or the corresponding ethyl esters affords diastereomeric glycosylthiourea derivatives (Scheme 28), which can be separated using reverse-phase high-performance liquid chromatography (HPLC). The reaction is complete in 20–30 min in acetonitrile–water as the solvent at room temperature and the crude product can be injected directly into the chromatograph. 2,3,4,6-Tetra-O-acetyl-웁-D-glucopyranosyl isothiocyanate and 2,3,4-tri-O-acetyl-움-D-arabinopyranosyl isothiocyanate have been most widely used for this purpose, although other sugar isothiocyanates, such as 2,3,4,6-tetra-O-benzoyl-웁-D-glucopyranosyl,206 2,3,4,6-tetra-O-pivaloyl-웁206 D-galactopyranosyl, and 2,3,5,6-tetra-O-benzoyl-웁-D-galactofuranosyl54 isothiocyanates have been also proposed as chiral derivatization reagents. A porous graphitic carbon (PGC) column has proved to be a convenient alternative to the classic reverse-phase columns for the separation of the diastereomeric thioureas.207
SCHEME 28
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The same derivatization protocol has been applied to the optical resolution of other chiral physiologically active agents and pharmaceuticals containing amino groups, such as catecholamines,208 웁-adrenergic antagonists,206,209 adrenergic agents,210–212 amphetamines,213 amino alcohols,214 mexiletine,215 epinephrine,216 oxiranes,206,217 and unusual aromatic amino acids,218,219 thus illustrating the scope of glycosyl isothiocyanate-derived thioureas in HPLC analysis.220 Some problems related to the presence of an unidentified reactive impurity in commercial as well as locally prepared 58 have been pointed out.221 Nevertheless, the side reaction could be completely eliminated by pretreatment of the isothiocyanate reagent with another amine prior to the derivatization reaction. The thiourea adduct resulting from the addition of one equivalent of amine to a sugar isothiocyanate might still undergo a subsequent intramolecular cyclization if adequate functionalization is present. Amino aldehyde and amino ketone derivatives are among the many reagents employed for this purpose. The corresponding oxothioureas (94) may undergo spontaneous or acid-promoted cyclization to give imidazoline (95),50,70,72,222–226 thiazole (96),50,64,65,70,72,223–226 or tetrahydropyrimidine227–229 (97) heterocycles (Scheme 29). Closely related is the addition of semioxamazide to glycosyl isothiocyanates.230 Treatment of the adducts 98 with mercury(II) oxide affords glycosyloxadiazole derivatives 99 (Scheme 30). Although a rationalization of the ambident sulfur-versus-nitrogen nucleophilicity in thioureas is problematic, from the ensemble of results available in the literature it appears that nitrogen is generally involved in nucleophilic addition to carbonyl groups, whereas heterocyclic ring closures involving nucleophilic displacement generally proceed through sulfur. In agreement with this generalization, the reaction of glycosyl isothiocyanates with 2-chloroethylamine yielded 2-glycosylamino-2-thiazolines 101 via transient 2-chloroethylthioureas 10070,231–234 and not imidazolidine-2thiones as erroneously reported in a previous paper.235 Eventually, the
SCHEME 29
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SCHEME 30
adduct may be added to a second isothiocyanate molecule to give trisubstituted thioureas. Bicyclic thiazolines (103 and 105) have also been obtained by the spontaneous cyclization of 1,2-trans-2-deoxy-2-iodoglycopyranosylthioureas (102) and from 2-deoxy-2-thioureido sugars (104) after generating the corresponding glycosyl bromide (Scheme 31).73,194 The electron withdrawing -I effect of the pyranose ring decreases the nucleophilicity of the anomeric N-atom in glycosylthioureas, which is, consequently, less prone to participate in counterattack-type reactions. Thus, the attempted cyclization of N-(2-cyanoethyl)-N-ethyl-N⬘-(2,3,4,6-tetraO-acetyl-웁-D-glucopyranosyl)thiourea (106) to the corresponding 5,6dihydro-2-thiouracil has been reported236 to be unsuccessful, in contrast to what has been found for noncarbohydrate thioureas. Instead, hydrolysis of the cyano group to the corresponding amide 107 was observed (Scheme 32). 2. Coupling of Amino Sugars with Isothiocyanates Sugar thioureas can be prepared, conversely, by nucleophilic addition of the amino group of amino sugars to alkyl and aryl isothiocyanates. Since the
SCHEME 31
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reaction of amino alcohols with heterocumulenes is chemoselective, involving exclusively the amine functionality, fully unprotected amino sugars may be used as precursors. Following this approach, Plusquellec and coworkers237,238 have reported the preparation of amphiphilic di- and trisubstituted thioureas (109) by direct coupling of 웁-lactosylamine and its Noctyl derivative (108, R ⫽ H, n-octyl) with phenyl and long-chain alkyl isothiocyanates in N-methylpyrrolidine (NMP) (Scheme 33). Nonreducing amino sugars likewise afford sugar thioureas upon reaction with isothiocyanates. Reducing sugar thioureas, however, generally undergo further cyclization reactions entailing the acyclic carbonyl form to give heterocyclic compounds. Although the study of the reaction of unprotected 2amino-2-deoxyaldoses (such as 110) and 1-amino-1-deoxy-2-ketoses with isothiocyanates began almost 100 years ago, the structure of the adducts has been the subject of frequent controversy,239 being unequivocally established in later years by chemical and spectroscopic methods240–247 as well as by X-ray diffraction.248–250 The reaction mechanism has been also positively identified by isolation of the early intermediates and their transformation into the final reaction products.251,252 The thiourea formed in the first step spontaneously undergoes intramolecular nucleophilic attack of a nitrogen atom to the sugar carbonyl group to give an imidazoline-2-thione derivative (such as 111). When the reaction is carried out at acidic pH, further 웁-elimination of water and cyclodehydration reactions take place lead-
SCHEME 33
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ing, respectively, to imidazoline-2-thiones (for example, 112) and bicyclic (aldoses; such as 113) or spiro (2-ketoses) furanoid compounds (Scheme 34). The relative proportion of both types of compounds depends on reaction conditions. Bicyclic pyranoid derivatives were also obtained251 by blocking the hydroxyl group at C-4. An important exception to the foregoing reaction scheme is the reaction of 2-amino-2-deoxy-D-glucose (110) with benzoyl and ethoxycarbonyl isothiocyanates. Stable acylthioureas were isolated in these cases, probably because of the decreased nucleophilicity of the imide-type nitrogen atom.251 Despite their aforementioned instability, the adducts resulting from condensation of 2-amino-2-deoxy-D-glucose and 2-amino-2-deoxy-D-galactose with phenyl isothiocyanate have been proposed for the quantitative determination of these amino sugars in glycoproteins.253 The authors claimed to have developed conditions to avoid further transformation, preserving the stability of the phenylthiocarbamoyl derivatives by quenching the reaction mixture with acetic acid–triethylamine buffer. Nevertheless, it must be stressed that the structural characterization of the adducts was rather poor and that the thiourea structure is improbable in view of the whole literature background on this and related condensations.251,252 Alternatively, the amino sugars were reduced to the corresponding amino alcohols, which, after derivatization with phenyl isothiocyanate, yielded stable thioureas.253 The reaction of carbohydrate derivatives bearing amino groups with fluorescein isothiocyanate has been widely used to introduce a fluorescent dye into a sugar molecule. Several strategies have been proposed for the
SCHEME 34
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preparation of the amine precursors: reductive amination of reducing oligosaccharides,254 copolymerization of allyl glycosides with allylamine or acrylamine,255 incorporation of amine-containing spacers,256,257 replacement of hydroxyl by amino,258,259 or direct derivatization of natural amino sugars.258 Particularly noteworthy examples are the synthesis of thioureatethered fluorescein-labeled nucleotides256 (for instance 114) and sialic acid derivatives258–263 (for example, 115), which were enzymatically incorporated into DNA and oligosaccharide chains of glycoproteins, respectively. The use of 7-isothiocyanato-4-methylcoumarin has also been proposed for the identical purpose in the nucleoside series.96
3. Coupling of Sugar Isothiocyanates with Amino Sugars The reaction of O-acylated sugar isothiocyanates with selectively Oacylated amino sugars leads to pseudooligosaccharide derivatives in which both saccharide subunits are joined through a thiourea spacer. A variety of pseudodi-, pseudotri-, and pseudotetrasaccharide structures containing a single (1→1), (1→2), or (2→2) thiourea tether have been prepared in this way,4,63,77,78 but in no case were the final adducts deacylated. It is possible that solubility problems under standard Zemplén deacetylation conditions, rather than instability of the thiourea functionality in the presence of base, prevented the deprotection step, according to the experience of the authors. Unsymmetrical N,N⬘-bis(glycosyl)thioureas with benzylated and acetylated moieties have also been prepared in a similar way.264 2,3,4,6-Tetra-O-acetyl-웁-D-glucopyranosyl isothiocyanate (58) has been coupled with unprotected amino sugar derivatives of neuraminic acid265
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and daunorubicin266 to give the corresponding glucosylthiocarbamoyl adducts 116 and 117. Compound 116 exhibited immunomodulating activity, whereas compound 117 was successfully deacetylated using sodium carbonate in water–acetone to give 118, which showed antileukemic and antitumor activities with IC50 values in the submicromolar range.
To avoid the use of the somewhat problematic acyl O-protecting groups during the preparation of (1→6)-thiourea-linked pseudodisaccharides, the reactions of O-acetalated and O-trimethylsilylated 6-deoxy-6-isothiocyanato sugars (for example, 119 and 120, respectively) with 웁-D-glucopyranosylamine (15) were studied.85 The coupling yields ranged from 30 to 65%; in hydrolysis of 15 the splitting of ammonia which eventually reacted with NCS groups was identified as the main competing side-reaction. The final deprotection steps (on, for example, 121 and 122) were effected following standard protocols and afforded the reducing (for instance 123) or nonreducing derivatives (such as 124) in ⬃100% purity (Scheme 35). Upon further investigation, it was realized that a converse strategy, using a per-O-acetylated glycopyranosyl isothiocyanate (58, 126, 127) and fully unprotected methyl 6-amino-6-deoxy-움-D-glucopyranoside (125), afforded much higher coupling yields. Deacetylation of the thiourea adducts (128 → 129) was effected in quantitative yield by Zemplén (sodium methoxide in methanol) or mixed Zemplén–saponification (sodium methoxide in methanol and then water) methodologies. The latter was effective for compounds that precipitate in methanol on treatment with base (Scheme 36).267 A main interest of thiourea-linked pseudooligoaccharides stems from the structural analogy of the thiourea group and related pseudoamide functionalities with other groups of atoms, such as phosphate and urea, that occur in nature linking monosaccharide frameworks in biologically important compounds. This structural feature, together with the synthetic versatility of thioureas, has been notably exploited by Bruice and co-workers95,268–270 in the preparation of a series of antisense oligonucleotides with various back-
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SCHEME 35
bone modifications. Two basic strategies were developed for the synthesis of the (deoxy)ribonucleic thioureas. The first one involves 3⬘-azido-3⬘,5⬘dideoxy-5⬘-isothiocyanato nucleosides (130) as key building blocks.95,268,269 In every cycle, the amine nucleophile (as in 132) is generated by reduction of the 3⬘-azido group with hydrogen sulfide, chain extension occurring by subsequent coupling with 130, as depicted in Scheme 37, to give the DNA (133) or RNA analog (134). In a different approach, the 3⬘-deoxy-3⬘-isothiocyanatothymidyl derivative 135 was used as chain-extending intermediate, which in reaction with
SCHEME 36
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SCHEME 37
the 5⬘-amine 136 afforded270 the (3⬘→5⬘)-thiourea-linked dimer 137. Chain extension followed a cyclic two-step process involving deprotection of the amino group with acetic acid (→138) and coupling, in quantitative yield, with another equivalent of 135 to give, after three cycles, the thymidyl pentamer 139 (Scheme 38). The heterobifunctional oligosaccharide hapten 140, consisting of a group
SCHEME 38
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A-active tetrasaccharide (A-tetra) and a blood Lea-active pentasaccharide (lacto-N-fucopentaose II, LNF II) linked to each other with a phenylaminothiourea spacer, was prepared by reaction of the N-(p-isothiocyanatophenyl) derivative of the 1-amino-1-deoxyalditol of A-tetra with the 1-amino-1-deoxyalditol of LNF II.271 The hapten retained both blood group activities and was successfully applied to affinity purification of monoclonal anti-Lea and anti-A antibodies. Glycosyl isothiocyanates have also been allowed to react with unprotected 2-amino-2-deoxyaldoses and 1-amino-1-deoxy-2-ketoses.68 This reaction leads to the formation of heterocyclic derivatives resulting from cyclization involving the carbonyl group of the amino sugar moiety following the mechanistic pathway already discussed for similar condensation reactions with alkyl and aryl isothiocaynates. 4. Sugar Thioureas from Sugar Carbodiimides Carbodiimides are the main alternative to isothiocyanates for preparing thioureas, nucleophilic addition of hydrogen sulfide to the heteroallene functionality generating the thiocarbonyl group, usually in high yield. This approach has been, however, little exploited in the carbohydrate field, probably due to the lack of synthetic methodologies leading to the sugar carbodiimide precursors.272 Very recently, this transformation has been studied in 6-deoxy-
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6-carbodiimido sugars159 and (1→6)-carbodiimide-linked pseudodisaccharides.273 The process was accomplished by bubbling dry H2S through a solution of the carbodiimide in toluene, using silica gel as an acidic catalyst, and afforded the target thiourea in yields over 80% (Scheme 39). 5. Functional Group Transformations in Sugar Thioureas The thiourea group of linear and cyclic sugar thioureas can be transformed into other functional groups including urea,97,274,275 carbodiimide,276,277 guanidine,95,268,269 and isothiourea270,278–280 by classic standard procedures, thus opening a versatile route to a variety of other sugar derivatives (Scheme 40). The last two transformations are particularly efficient and have been successfully applied to the preparation of polycation analogs of DNA and RNA.268–270,276–278,281 6. Spectroscopic and Conformational Properties The more characteristic spectroscopic feature of sugar thioureas is the C NMR chemical shift of the thiocarbonyl carbon atom at 180–185 ppm.
13
SCHEME 40
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The UV 앟–앟* absorption of the C苷S group appears at 252–256 nm for monosubstituted thioureas and at 242–247 nm for N,N⬘-disubstituted derivatives. In the electron-impact mass spectra of glycosylthioureas, three basic group of ions are analytically significant: (a) rupture of the glycosylic C1––NH bond, (b) cleavage of the sugar NH––C(苷S) bond, and (c) cleavage of the (C苷S)––NH aglycon bond. The E-Z rotameric interconversion rates at the pseudoamide N––C(苷S) bonds in sugar thioureas fall in the range of the chemical-shift time scale, which generally results in large broadening of the NMR signals. Variabletemperature NMR studies have shown that the thiourea group in perO-acylated glycosylthioureas adopts the Z configuration at the sugar NH––C(苷S) bond, the only rotameric form in chloroform-d solution, with the NH proton and H-1 in anti relative disposition.77,78,176,273 A similar situation is found for thiourea groups located at secondary nonanomeric positions.77,78 In stark contrast, both Z and E rotamers are detected when the thiourea functionality is placed at a primary carbon atom, resulting in much more complex 1H and 13C NMR spectra.85,192 Examination of the temperature-dependence of the NMR chemical shifts of the thiourea proton and rotational barrier calculations supported a stabilization of the E rotamer by seven-membered intramolecular NH…O hydrogen bonding. This folding pattern seems to be a main structural feature of thioureido sugars, as seen from specifically designed models,193 probably favored by the inherent torsional preferences of the covalent bonds that connect the hydrogen-bond donor (N⬘H proton) and acceptor (endocyclic oxygen atom) centers. The existence of six-membered intramolecular hydrogen bonding in galactofuranosyl thioureas has also been suggested to explain the conformational preferences of the furanose ring (Fig. 6).54
FIG. 6 Postulated seven- (A) and six-membered intramolecular hydrogen bonds (B) in sugar thioureas.
VI. SUGAR THIOCARBAMATES AND DITHIOCARBAMATES The chemistry of sugar-derived thiocarbamic and dithiocarbamic esters was initially much less developed than that of the thiocarbamides already discussed, being limited to the condensation of reducing monosaccharides
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or amino sugars with thiocyanic acid282 or carbon disulfide,283 respectively. The reasons are mainly related to the lower nucleophilicity of alcohols and thiols as compared to amines and the reversible character of the nucleophilic addition of the derived anions to isothiocyanates. This situation significantly changed when Barton and McCombie conceived their radical deoxygenation of hydroxyl groups via thiocarbonyl esters.284,285 Many examples of the application of this procedure in the carbohydrate field, involving thiocarbamate derivatives, may be found in more general reviews.7,286–288 The ability of dithiocarbamates to form stable complexes with divalent metals and free-radical species has been a further stimulus for investigating the preparation, reactivity, and biological properties of sugar derivatives incorporating thiocarbamoyl and dithiocarbamoyl functional groups. 1. Linear Sugar Thiocarbamates The addition of alcohols to carbohydrate isothiocyanates is a general method for the preparation of linear N-sugar, O-alkyl thiocarbamates. This reaction is frequently used as a tool for structure confirmation.34,53,54 It requires the use of a large excess of the alcohol and reflux conditions to shift the reaction to the desired thiourethane. ˇ Elbert and Cern´ y97 have reported the condensation of 1,6-anhydro-4-Obenzyl-2-deoxy-2-isothiocyanato-3-O-p-tolylsulfonyl-웁-D-glucopyranoside (141) with methanol. The presence of a good leaving group vicinal to the thiocarbamate functionality resulted in spontaneous cyclization, the outcome of the reaction being dependent on the reaction conditions. Thus, with sodium methoxide in 1,4-dioxane the reaction involved the nitrogen atom to give an epimine (142) as the sole product. In contrast, with methanolic triethylamine a bicyclic thiazoline (143) was obtained (Scheme 41). The kinetics of the reaction of hydroxyl groups of monosaccharides and polyols with benzyl isothiocyanate has been checked by Augustín and Baláz using UV spectroscopy.289 However, because of the reversibility of the reaction, this procedure is not of synthetic utility. O-Sugar thiocarbamates have been more conveniently prepared by aminolysis of thiocarbonate derivatives290,291 or by thiocarbamoylation of free hydroxyl groups with 1,1⬘thiocarbonyldiimidazole.7,286–288 The main synthetic utility of O-sugar thiocarbamates is the aforementioned radical deoxygenation of secondary hydroxyl groups. The method is based on the radical-trapping ability of the thiocarbonyl group, leading to an intermediate carbon radical which fragments into a sugar radical and an S-thiocarbamate, as depicted in Scheme 42. In the presence of an H-donor, the corresponding deoxy sugar is formed, the energy gained on the change from thiocarbonyl to carbonyl driving the transformation.
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SCHEME 41
Several reports on the use of this methodology for the synthesis of deoxynucleosides292–295 as well as their carbocyclic analogs296,297 are on record. It is noteworthy that, unlike other procedures which involve an ionic mechanism, this radical process is not subjected to steric hindrance or electrostatic repulsion. Although N,N-diethylaminothiocarbonyl derivatives were originally employed, the O-(imidazolylthiocarbonyl) analogs have proved more efficient.7,286–288,298–301 The methodology is compatible with the presence of nitrogen and phosphorus functionalities in the molecule, as shown for the deoxygenation of the HO––C––P unit in the phosphinyl derivatives 144 and 145 (Scheme 43), a key step in the synthesis of xylopyranose mimics having phosphorus instead of oxygen in the ring (146 and 147).302,303
SCHEME 42
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SCHEME 43
In the case of vicinally disubstituted sugars with a pair of radical leaving groups, such as thiocarbamate and halogen (148), treatment with tri-n-butyltin hydride and 움,움⬘-azobis(isobutyronitrile) (AIBN) led to the corresponding unsaturated derivatives (for example, 149) in high yield without observed side products (Scheme 44).304 Thioacylimidazole esters have been found, however, less effective than thiocarbonates and xanthates in promoting radical Callylation, even in the presence of AIBN as radical initiator.305 Ley and co-workers306,307 have investigated the use of glycosyl thiocarbonylimidazolides as glycosyl donors using silver perchlorate as promotor. The method was successfully applied to the total synthesis of the antiparasitic agent Avermectin B1a by coupling of the oleandrose disaccharide thiocarbamate 150 with the monoacetylated aglycon 151 (Scheme 45). The 움glycoside 152 was isolated in 64% yield together with 11% of the corresponding 웁-anomer. 2. Cyclic Sugar Thiocarbamates The simultaneous presence of isothiocyanate and free hydroxyl groups in a sugar molecule may lead to formation of intramolecular cyclic thiocarba-
SCHEME 44
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mates, depending on their relative disposition and on conformational bias. The following rules apply when several isomeric structures can be foreseen: (a) formation of five-membered cyclic thiocarbamates is favored against six-membered analogs, (b) furanoid rings are more prone to afford bicyclic heterocycles than their pyranoid tautomers, and (c) hydroxyl groups in trans-diaxial orientation with respect to the NCS group or distant by five covalent bonds or more are, generally, unreactive. According to this general scenario, the recently revised275 reaction of reducing aldoses with thiocyanic acid provides furanoid bicyclic oxazolidine2-thiones (153) as the major reaction products, probably via an open-chain isothiocyanate (Scheme 46). Under the same reaction conditions, ketoses afforded mixtures of spiro- and bicyclic-thiocarbamate derivatives.308 When the isothiocyanate group is vicinal to the anomeric position in reducing monosaccharides, the more acidic hemiacetalic hydroxyl group is in-
SCHEME 46
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SCHEME 47
volved in thiocarbamate ring closure. Different sugar tautomeric structures can thus react with the corresponding loss of product purity. In the case of 1-deoxy-1-isothiocyanato-D-fructose (156), generated either from the corresponding amino sugar309 154 or from the diacetonated derivative83 155, a 5 : 1 mixture of the 웁-pyranoid and 웁-furanoid spironucleosides 157 and 158 was obtained (Scheme 47). If the cyclization process does not implicate the anomeric position, the regioselectivity of the reaction, regarding both the tautomeric form of the sugar and the functional groups involved, is self-controlled by the configuration of the sugar template. A variety of enantiomerically pure oxazolidine- and tetrahydrooxazine-2-thione heterocycles have been thus prepared by spontaneous or base-induced cyclization of carbohydratederived hydroxyisothiocyanates. The reported structures include 6,5-(159), 6,4-(160), 3,4-(161), 3,2-(162), 3,5-(163), and 5,6-(164) cyclic thiocarbamates.81,82,84,310 The sucrose derivative 165 illustrates the selectivity in the
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formation of 1,3-O,N-heterocycles from unprotected sugar isothiocyanates. Whereas the trans-decalin-type system at the glucopyranosyl moiety readily originates from the corresponding 웂-hydroxyisothiocyanate segment precursor (see 34) upon treatment with base, the NCS group at C-6 of the fructofuranosyl moiety remains unreactive98 even in the presence of triethylamine in N,N-dimethylformamide solution at 80⬚C. The formation of a seven-membered thiocarbamate ring system (168) in low yield has been observed during the attempted reduction156 of the selectively protected 웁-D-galactopyranosyl isothiocyanate 166 to the corresponding glycosyl thioformamide 167 (Scheme 48). Uzan and co-workers311 have reported an alternative route for the preparation of pyranose and furanose cis-1,2-fused oxazolidine-2-thiones that uses 1,2-O-sulfinyl sugar derivatives (169) as precursors. After treatment with sodium thiocyanate in DMF at 80⬚C, the bicyclic thiocarbamates (172) were isolated in 60–90% yield. The proposed mechanism involves formation of a 웁-configured thiocyanate (170) that isomerizes to the ␣isothiocyanate derivative (171) under the reaction conditions (Scheme 49). Five-membered cyclic thiocarbamates have also been reported to originate during the reduction of vic-azidothiocarbonates, nucleophilic attack of the intermediate amine to the thiocarbonyl group being faster than reduction of the ester.96,312 Recently, Pintér and co-workers313 have reported the use of cyclic thiocarbamates as precursors of cyclic isoureas by sequential S-p-chlorobenzy-
SCHEME 48
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lation and nucleophilic displacement of the p-chlorobenzylthio group with morpholine. Preparation of oxazoline heterocycles by desulfurization with Raney nickel has also been effected.308 3. Linear Sugar Dithiocarbamates The reaction of isothiocyanates with thiols is, in general, impractical for the preparation of dithiocarbamates, since N-monosubstituted derivatives readily decompose into the starting materials. Nevertheless, the method is synthetically useful in the case of aryl isothiocyanates. Thus, cellulose–aryl isothiocyanate conjugates exhibited a substantial thiol binding capacity which was absent for nonaromatic analogs.142,143 A valuable alternative for the preparation of N-sugar dithiocarbamates is the reaction of a sodium dithiocarbamate salt obtained from the condensation of an amino sugar with carbon disulfide in the presence of base, with an excess of alcohol97 or alkyl iodide190 (Scheme 50). To overcome the problems associated with purification of dithiocarbamate salts, Giboreau and Morin314 have disclosed a synthetic procedure that employs stannyl dithiocarbamates as precursors. The method is compatible with the presence of hydroxyl groups and has been applied to the high-yielding preparation of the sodium N-methyl-D-glucamine dithiocarbamate salt 175. Thus, treatment of the secondary amine 173 with carbon disulfide and bis(tri-n-butyltin)oxide achieved the stannyl dithiocarbamate 174 in 83% yield after purification on neutral alumina. Cleavage to the dithiocarbamate salt was effected in quantitative yield by using sodium hydrogensulfide (Scheme 51). N-Methyl-D-glucamine dithiocarbamate (175, MGD) was first conceived as a water-soluble metal chelating agent and both the sodium and ammonium salts were found to be effective antagonists of cadmium toxicity.315
SCHEME 50
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Closely related are the 1-benzylamino-1-deoxylactitol dithiocarbamate salts developed by Eybl and co-workers316,317 for the same purpose. However, the most important application of 175 is, probably, its use as a nontoxic, water-soluble nitric oxide probe in vivo. In view of the central importance that this gaseous free-radical species plays in regulating a broad range of important biological functions,* its detection and quantification near its site of production and action is of prime importance. For this purpose, the ferrous salt of MGD, which forms a stable water-soluble mononitrosyl iron–dithiocarbamate complex (176) with a characteristic electron spin resonance (ESR) spectrum at room temperature, is currently used.318–323 Cao and co-workers324 have reported the preparation of a 웁-cyclodextrin derivative containing an N-linked dithiocarbamate group at the C-2 position (177). The corresponding Mn(II) and Cu(II) complexes showed super-
* The discoverers of nitric oxide as a signal transmitter in the mediation of a variety of important cellular functions, in particular in the cardiovascular system, R. F. Furchgott, F. Murad, and L. J. Ignarro, were awarded the 1998 Nobel Prize in Physiology and Medicine.
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oxide dismutase mimetic activity, promoting the disproportionation of superoxide radical (O2˙⫺) into O2 and H2O2. S-Glycosyl-N,N-dialkyldithiocarbamates have attracted attention because of the known fungicidal, insecticidal, and anticarcinogenic properties of related dialkyldithiocarbamates. The classic synthetic methodology for their preparation relies on the reaction of a per-O-acyl protected glycosyl bromide with the sodium salt of a dialkyl dithiocarbamate.325 By this procedure, Bertram and co-workers326,327 prepared peracetylated N,N-diethyl and N,N-diallyl S-sugar dithiocarbamate derivatives of D-glucose, lactose, and cellobiose, which were further deprotected with methanolic ammonia. The S-glycosidic bond was found to be stable under physiological conditions in vitro and some of the compounds exhibited in vivo inhibition of nitrosamine-induced DNA damage. An original approach for the preparation of these types of compounds, developed by Szeja and Bogusiak,328 especially suited for acetal and benzyl protecting groups, involves in situgenerated glycosyl tosylates under phase-transfer conditions (Scheme 52). Mention should also be made of the application of Mukaiyama’s methodology to the synthesis of S-(2,3,4,6-tetra-O-acetyl-웁-D-glucopyranosyl)N,N-dimethyldithiocarbamate using a pyridinium derivative as the anomeric leaving group.329 Fügedi and co-workers330 have examined the potential of glycosyl 1piperidinecarbodithioates as glycosyl donors in oligosaccharide synthesis. Such thiophilic promotors as methyl or silver triflate were efficient activators for the glycosylation reaction, although other less expensive salts such as tin(IV) or iron(III) chloride also gave good yields. Of note is the fact that under conditions used by the authors, thioglycoside acceptors, which are
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themselves potential glycosyl donors, remained stable (Scheme 53). SGlycosyl-N,N-dimethyldithiocarbamate derivatives have been analogously used as glycosyl donors in the 2-amino-2-deoxyhexose series.331 Carbohydrate derivatives bearing S-linked dithiocarbamate functionalities at nonanomeric positions have been obtained by nucleophilic displacement of suitable leaving groups by N,N-dialkyldithiocarbamate anions.332 Interestingly, the glucose-derived bis(dithiocarbamoyl) esters 179 and 180, obtained from the 3-iodo-6-O-tosyl derivative 178 (Scheme 54), exhibited significant antifungal activity.333 4. Cyclic Sugar Dithiocarbamates The reaction of fully unprotected 2-amino-2-deoxyaldoses or 1-amino-1deoxyketoses with carbon disulfide leads to five-membered cyclic dithiocarbamates (182) involving the open-chain tautomeric form of the sugar (181), as unequivocally proved by Avalos and co-workers.251 N-Alkylglycosylamines undergo a similar transformation via an Amadori rearrangement. The monocyclic derivatives can be dehydrated to thiazoline deriva-
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tives (183), which were used as precursors of the 5-carbaldehyde structures 184 (Scheme 55).334 VII. MISCELLANEOUS N-THIOCARBONYL CARBOHYDRATE DERIVATIVES Bis(thiocarbonyl)hydrazide derivatives of galactaric acid (186, 187) have been prepared by reaction of 2,3,4,5-tetra-O-acetyl-D-galactaroyl dichloride (185) with 4-arylthiosemicarbazides335 or S-methyl(benzyl) hydrazinecarbodithioates336 (Scheme 56). The adducts were subsequently converted into a variety of bis(heterocyclic) compounds including thiadiazole, triazole, and oxadiazole derivatives. The tetraacetates 186 have been
SCHEME 56
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also reacted with different bifunctional amines (piperazine, tetraethyl- and tetramethyl-ethylendiamine, and tetramethyl-1,3-propanediamine) to give monomeric or polymeric bis(hydrazide) salts, depending on the ratio of the reagents.337 Opening of aldonolactons by thiosemicarbazide affords transient Nglyconoyl adducts that undergo spontaneous cyclodehydration to the corresponding acyclic C-nucleosides of 1,2,4-triazole (188, Scheme 57). Double-headed analogs were also prepared using diethyl D-galactarate as precursor.338 Tweeddale and co-workers339,340 have investigated the binding of sugars to a polymeric support through thiosemicarbazone spacers (190). Although thiosemicarbazones have been prepared in good yield by direct condensation of reducing carbohydrates with arylthiosemicarbazides, the reaction was found unsuitable in the solid phase because of the unfavorable thermodynamics. Nevertheless, coupling of glycosylhydrazines (189) with isothiocyanate-substituted polystyrene achieved good immobilization within a few hours at room temperature (Scheme 58). A main advantage of the method is that the bound sugar may be further released by reaction with either hydrazine hydrate or benzaldehyde. Sugar thiosemicarbazones have been the subject of further interest because of their capability to act as water-soluble tetradentated ligands for divalent transition-metal cations. Horton and co-workers341 reported the synthesis of 3-deoxyaldos-2-ulose bis(thiosemicarbazones) by the reaction of reducing aldoses with thiosemicarbazide in the presence of p-toluidine (Scheme 59). The authors observed in vivo antitumoral activity in the
SCHEME 57
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murine L-1210 assay for the copper(II) complex of the D-glucose derivative, namely 3-deoxy-D-erythro-hexos-2-ulose bis(thiosemicarbazone) (191). More recently, the bis(thiosemicarbazones) obtained from D-glucose, D-galactose, and D-ribose as well as their copper(II) and nickel(II) complexes were fully characterized by spectroscopic (1H and 13C NMR, UV, IR, ESR) methods.342 In order to preserve the cyclic form of the sugar, glycosyl derivatives of 2-hydroxyacetaldehyde (192) have been proposed as precursors of thiosemicarbazone ligands343 (193, Scheme 60). The corresponding copper(II) and manganese(II) complexes exhibited superoxide dismutase mimetic activity, with IC50 values ranging from 0.2 to 0.8 애M. VIII. NATURALLY OCCURRING N-THIOCARBONYL CARBOHYDRATE DERIVATIVES The only carbohydrate derivatives incorporating N-thiocarbonyl functional groups of natural origin appear to be isothiocyanate and thiocarbamate glycosides embodying 움-L-rhamnopyranose and 4-hydroxybenzyl
SCHEME 59
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isothiocyanate or thiocarbamate as the glyconic and aglyconic moieties, respectively. These compounds are mustard oil glycosides, which are very rare in nature and were isolated from plants of the Moringaceae family. The monosaccharide is found fully unprotected and as its 4-O-acetyl and 2,3,4tri-O-acetyl derivatives. The isothiocyanates 194 and 195 have been identified as the antibiotic elements of the plant,344,345 whereas the thiocarbamates 196–202, which exist in both E and Z configurations at the pseudoamide bond, showed hypotensive and spasmolytic properties.346–351 Recently, chemical synthesis of the niazinin (196), niazimicin (197), niazicin (198), and niaziminin (199) thiocarbamate glycosides has been achieved.352
IX. N-THIOCARBONYL SUGARS IN MOLECULAR RECOGNITION The critical role of carbohydrate recognition in cellular functioning has impelled aggressive research directed toward the understanding and control of the intermolecular processes involved in carbohydrate metabolism and signaling. Modified saccharide structures incorporating N-thiocarbonyl
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functionalities have proved to be very useful tools for such goals. A main factor is that attaching sugars to the amino groups of proteins, their putative receptors in biological systems, can be achieved very efficiently by means of N-thiocarbonyl linkers. This approach has been further extended to the new concepts of glycodendrimers and glycoclusters, highly ordered polyglycosyl structures whose preparation requires high-yielding coupling strategies. Moreover, the synthetic versatility of N-thiocarbonyl functional groups, allowing access to many other functionalities, and their particular structural and electronic properties, can be exploited in the preparation of sugar mimetics and artificial receptors useful for enzymatic and supramolecular studies aimed at elucidating the structural requirements for affinity and specificity in carbohydrate interactions. 1. Interactions with Membrane Receptors The ability of isothiocyanate groups to react with the amino group of lysine residues makes sugar isothiocyanates attractive candidates for labeling the specific proteins involved in the transport of carbohydrate substrates across cell membranes.59 Fully unprotected 웁-D-glucopyranosyl60 and 웁-maltosyl isothiocyanates61 were first used for this purpose. Both were found to behave as potent irreversible inhibitors of glucose translocation in the human erythrocyte. Using 웁-[14C]maltosyl isothiocyanate-labeled erythrocyte membranes, the question of carrier identity could be addressed.353 A main drawback for these applications is the low stability of fully unprotected glycosyl isothiocyanates under physiological conditions, so that results may be perturbed by decomposition of the reagent.62 6-Deoxy-6-isothiocyanato-D-glucopyranose was proposed as an alternative affinity reagent.80 However, it has been shown subsequently that this compound is actually unstable and undergoes spontaneous cyclization to give a furanoid 6,5-cyclic thiocarbamate.82 Stable fully unprotected phenyl isothiocyanate glycosides have been successfully used instead. Thus, pisothiocyanatophenyl 웁-D-glucopyranoside is a nontransported inhibitor of the Na⫹–glucose cotransporter and has found application in studies directed to elucidate the geometry and nature of the glucoside–transport protein interaction.117,354 Under mild conditions, not favorable for covalent linkage formation, p-isothiocyanatophenyl 2-acetamido-2-deoxy-웁-Dglucopyranoside reversibly inhibited N-acetyl-D-glucosamine countertransport in lysozomal membrane vesicles by 70%.355 Replacement of N-acyl and O-acyl by N-thioacyl groups in sialo-sugar chains of cell surface glycoproteins can influence certain biological functions mediated by sialic acids, such as cellular adhesion phenomena or virus specificity for host cells. Interestingly, sialyltransferases specific for different
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acceptor sequences exhibited a low enzyme specificity with respect to various N-thioacyl-modified neuraminic acid derivatives.189,356,357 This allowed, after sequential enzymatic desialylation–resialylation, substitution of Nacetyl-9-O-acetylneuraminic acid subunits by 9-deoxy-9-thioacetamido Nthioacetylneuraminic acid residues in intact erythrocytes.358 The synthetic analog was recognized by the receptor-destroying enzyme (acetylesterase) of this virus, so that the virus particles attached to the cells but were unable to infect them. N-Thioacetylneuraminic acid glycosides likewise are recognized by influenza virus hemagglutinin and have been used in the preparation of polymeric multisialylated structures (203–205) showing increased activity against different virus strains.359–361 Moreover, the thioglycoside polymer 204 was resistant to viral neuraminidase, which is an intrinsic advantage for the inhibitor efficiency.360
2. Neoglycoconjugates, Glycodendrimers, and Glycoclusters Neoglycoconjugates are synthetic compounds that emulate the behavior of the natural conjugates, being of direct application in practically every aspect of glycobiology. Those most often used are neoglycoproteins, obtained by covalent attachment of conveniently functionalized oligosaccharides to a carrier protein and are conceived as a way to remedy the lack of carbohydrate homogeneity in natural glycoproteins. Not surprisingly, generation of a thiourea bridge between the saccharide hapten and the protein is probably the most popular method to generate neoglycoproteins.104,114 Comparative descriptions of this technique and other conjugation methodologies can be found in several reviews.362–366 Sugar–isothiocyanate conjugates have been generally used as precursors because of their higher stability and the possibility of manipulating the spacer arm for optimal geometric or immunogenic properties. The major initial reaction that occurs under mild conditions at neutral or slightly alkaline pH is the formation of thiourea derivatives with terminal amino groups and with ⑀-amino groups of lysine residues (Scheme
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61). Bovine serum albumin (BSA),114,138,139 keyhole limpet hemocyanin (KLH),367 inmunoglobulin A (IgA),111 human serum albumin (HSA),368 and R-phycoerythrin,113 have been used as the conjugated proteins, frequently labeled with fluorescein residues. The technique has permitted the raising of antibodies against specific carbohydrate moieties; detection and quantification of oligosaccharide receptors in tissues, cells, or extracts; selection of a ligand structure for subsequent purification by affinity chromatography; and detailed analysis of carbohydrates and carbohydrate-binding proteins. In most cases, interactions involving carbohydrates in biological systems have a multivalent character, requiring a local density and a precise spatial orientation of the active saccharide epitopes that can be better achieved by using well-defined artificial templates. Application of the thiourea methodology for coating polyamine scaffolds and dendrimer carriers with carbohydrates has shown considerable promise in this respect.369–373 Lindhorst and co-workers374,375 have reported the synthesis of thiourea-bridged glycoclusters and glycodendrimers by coupling peracetylated glycosyl isothiocyanates with tris(2-aminoethyl)amine (→206) and dendritic multivalent cores of the polyamidoamine (PAMAM) family (→207–209). The adducts were further deacetylated in a final step. The strategy was also implemented for glycocoating other polyamine templates of different geometries, such as azamacrocycles376 (→210) and an 움-D-glucose-centered pentaamine337 (→211). In addition, protected and fully unprotected spacer-armed sugar isothiocyanate conjugates130,131 (→212, 213) as well as deoxyisothiocyanato sugars114 (→214) may be used as precursors. Fully unprotected thioureabridged glycodendrimers and glycoclusters with 움-D-mannopyranosyl residues were tested for their binding capacity to mannose-specific lectin on type 1 fimbriae of Escherichia coli,114,374,376 while the 2-acetamido-2-deoxy웁-D-glucopyranosyl derivatives were checked against the dimeric receptor of rat natural killer cells, sNKR-P1A protein.375
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Roy and co-workers have also used tetra-, octa-, hexadeca-, and 32-valent PAMAM cores to build 움-D-mannopyranosyl- and 움-Dthiosialodendrimers116 (217) by coupling them with the corresponding phenyl isothiocyanate glycoside (215) and thioglycoside378 (216), respectively. After deacetylation, these multivalent neoglyconjugates were shown to exhibit a high lectin-binding avidity and can be used as biochromatography materials for isolating carbohydrate-binding proteins (Scheme 62). Other reports from the same laboratory deal with the effect of shape, size, and valency of multivalent mannosides on their binding properties to concanavalin A and pea lectins.379–381 To optimize lectin–carbohydrate interaction, a series of thiourea-bridged di-, tri-, tetra-, and hexaantennaed clusters derived from different aliphatic and aromatic scaffolds were prepared. Coupling isothiocyanate 215 with mono-, di-, and hexaamines379,380 (→218–220) or reacting fully unprotected amine-functionalized mannosides with polyisothiocyanates381 (→221–223) afforded the target glycoclusters. Both the intramannosyl distance and valency were proved to be important factors for optimum protein binding. The use of cyclodextrins as biocompatible scaffolds for adjusting glycocluster molecular weight and topology using the thiourea technology has been explored by the groups of García Fernández and Defaye.382,383 Nucleophilic addition of cyclomaltoheptaose (웁-CD) derivatives bearing one or seven amino groups at the primary face to peracetylated 웁-D-glucopyranosyl, 웁-cellobiosyl, and 웁-lactosyl isothiocyanates provides efficient access to the corresponding mono- and heptaantennary conjugates. The reaction conditions (pyridine and water–acetone at pH 8, respectively) as well as the location of the reactive functional groups were found to be critical. Thus, a reverse strategy involving 웁-CD-derived isothiocyanates and glycosylamines proved much less satisfactory. The subsequent deacetylation step following a mixed Zemplén–saponification procedure was quantitative. A noteworthy exception to this general pattern was reported, however, for 움-D-mannopyranosylthiourea substituents.382 The authors observed an unprecedented anomerization reaction upon base treatment, which is in contrast with previously reported results on the preparation of 움-Dmannopyranosylthiourea glycoclusters and glycodendrimers. A thorough
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investigation of the anomeric behavior of ␣-configured glycosylthioureas in solution should throw some light onto this question. 3. Enzyme Inhibitors Even though the use of N-thiocarbonyl carbohydrate derivatives in enzyme studies was already devised in the mid-1970s, their prominent position both as precursors and as targets in the design and synthesis of glycosidase inhibitors was firmly established only in the beginning of the 1990s and runs parallel to the development of the concept of transition-state analogs. The unique properties of N-thiocarbonyl functional groups as versatile sources of planar resonance structures that resemble the incipient oxocarbenium cation postulated as the transition state in enzymatic glycoside cleavage is the main reason for this situation. Fully unprotected glycosyl isothiocyanates have been reported to act as specific irreversible inhibitors of glycosidases. Thus, 웁-D-glucopyranosyl isothiocyanate inactivated the action of sweet-almond 웁-glucosidase,384,385 while 2acetamido-2-deoxy-웁-D-glucopyranosyl isothiocyanate likewise inhibited the human and boar N-acetyl-웁-D-hexosaminidase.60 Competitive-inhibition assays indicated that covalent binding to the protein occurs at the active site. The structural analogy of glycosyl isothiocyanates and the 웁glycoside substrates suggested that the NCS groups would interact with one of
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the catalytic groupings of the enzyme. However, because of the instability and high reactivity of fully unprotected glycosyl isothiocyanates, decomposition and reaction at different positions in the protein may be a serious perturbation in these studies. Stable, unprotected deoxyisothiocyanato sugars might constitute an interesting alternative to overcome such drawbacks.82 Thioamides 226 and 227, resulting from replacement of the amide carbonyl by thiocarbonyl in p-nitrophenyl 2-acetamido-2-deoxy-웁-D-glucoand galacto-pyranosides, were shown to inhibit 2-acetamido-deoxy-웁-Dglucosidase from Turbatrix aceti.174 In contrast, the related p-nitrophenyl thioglycosides exhibited almost no inhibitory effect. In the light of the recent results of Knapp and co-workers,386 using the 4-methylumbelliferyl de-
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rivative 228, it is probable that the glycoside is converted in situ into a bicyclic thiazoline (229), which would be the real active species (Scheme 63). Structure 229 with D-gluco configuration was eventually prepared by refluxing 1,3,4,6-tetra-O-acetyl-2-deoxy-2-thioacetamido-웁-D-glucopyranose in toluene and proved to be a very potent inhibitor of jack bean Nacetylhexosaminidase.386 Since the first communication by Ganem and co-workers179 in 1990 on the broad-spectrum inhibition of glycosidases by amidine-type carbohydrate mimics, several reports on the synthesis of these derivatives using thiolactams as the key precursors have been published. The groups of Ganem,179,180,182,387,388 Vasella,181,184,185 and Tellier183,389,390 have been instrumental in developing these transformations that include access to amidine, amidrazone, amidoxime, and amidine N-arylcarbamate structures, which rank among the most potent competitive inhibitors of glycosylhydrolases reported. The approach has been extended to pentoses388,391 with the preparation of the D-ribonamidoxime 235 and the D-ribonamidhyrazones 236–238 from the corresponding thiolactam 234. Compound 237 is the most potent nucleoside hydrolase inhibitor known to date (Schemes 64 and 65).
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Closely related to the just-discussed transformation of sugar thiolactams into amidines is the preparation392 of the cyclic guanidinium glycomimetics 241 and 242 from the cyclic thiourea precursor 239. Replacement of the thiocarbonyl sulfur atom by nitrogen was effected after treatment with ethyl iodide and aminolysis or hydrazinolysis, respectively, of the corresponding S-ethyl derivative 240 (Scheme 66). Alternatively, analogs of glycosides (244) and disaccharides (245) containing a cyclic guanidinium
SCHEME 63
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structure have been obtained from acyclic 웂-aminothioureas (243) upon treatment with lead(II) oxide (Scheme 67).393–395 These two synthetic strategies are not compatible with the presence of a hydroxyl group contiguous to the guanidine functionality in the final glycomimetic. To overcome this limitation, Wong and coworkers88 have proposed a different approach involving thiourea derivatives of D-threose in the anchored acyclic form 246, which, after transformation into the guanidine analogs (247) and deprotection, afforded the target cyclic guanidinium hexose mimics 248 (Scheme 68). An impressive number of papers has appeared in the past few years based on the use of sugar thioureas as intermediates in the synthesis of the naturally occurring potent trehalase inhibitor trehazolin (251) and of several isomers.52,396–404 The key reaction step involved the cyclization of an N,N’-disubstituted 움-D-glucopyranosyl–aminocyclitol (움-D-glucopyranosyl-
SCHEME 68
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trehalosamine in the natural compound) thiourea (249) with participation of a 웁-located hydroxyl group. Either mercury(II) oxide or 2-chloro-3-ethylbenzoxazolium tetrafluoroborate promoted the desired transformation (→250) with generation of the aminoxazole ring (Scheme 69). The cyclocondensation reaction proceeds via a transient hydroxycarbodiimide that leads, selectively, to the cis-fused five-membered cyclic sourea. In addition to the preparation of a range of diastereomers, a thorough systematic modification of the sugar and aminocyclitol moieties hasbeen effected48,86,405–409 that allowed confirmation of the trehazolin structure, identification of new potent trehalase inhibitors, and determination of structure–inhibitory activity relationships. Some anomalous results have been reported, however, in the attempted preparation of tetrahydropyrano[2,3-d]oxazole analogs of trehazolin (e.g., 254) from N,N⬘-bis(Dglucopyranosyl)thioureas.264 Whereas the di-웁-configured derivative 252 afforded the expected cyclocondensation compound 253 in low yield, the 움,웁-isomer 255 yielded a furanose-fused structure (256) and the di-움epimer a complex mixture of unidentified products (Scheme 70). The reaction is not restricted to glycosylthioureas. Starting from carbohydrate derivatives bearing the cyclitolthioureido substituent at a nonanomeric position87,89,409 (for example, 258→259), new trehalozoid glycosidase inhibitors have been designed that, in some cases410 (260), exhibited aglycon selectivity (Scheme 71). Mixed 1-deoxynojirimycin–trehalamine inhibitors have also been prepared from the corresponding iminosugar 웁-hydroxythioureas 261–263.140 The versatility of this approach has been further illustrated by the synthesis of imidazoline analogs of trehazoline starting from sugar-derived 웁aminothioureas (263).408 The aminocyclitols allosamizoline (266) and demethylallosamizoline (267), which are found in the pseudotrisaccharide chitanase inhibitors known as allosamidin and demethylallosamidin, have been prepared from cyclic thiocarbamate411 (264) and 웁-hydroxythiourea412 (265) precursors,
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respectively. A glucosamine–aminothiazoline analog (269), obtained from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(3,3-dimethylthioureido)-웁-D-glucopyranose (268), has also been reported413 (Scheme 72). The glycosidase-inhibitory properties of sugar-shaped cyclic thioureas were first explored by Lehmann and co-workers,414 who obtained the hexahydropyrimidine-2-thione glucomimetic 271 by thiocarbonylation of the diamine precursor 270. Compound 271 was a very weak inhibitor of sweetalmond 웁-glucosidase, and this was ascribed to the lack of the OH group at the homologous position of C-3 in D-glucopyranosides. Moreover, an unexpected preference for the trans-diaxial conformation in deuterium oxide solution was observed (Scheme 73). García Fernández and co-workers415,416 have developed a different synthetic route to carbohydrate mimics having a cyclic thiourea structure based on the intramolecular nucleophilic addition of thiourea groups to the masked carbonyl group of reducing monosaccharides. Thus, starting from 3deoxy-3-thioureido sugars, the iminooctitol analogs 273 were obtained (Scheme 74). Likewise, a preference for structures with axial disposition of
SCHEME 73
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SCHEME 74
the carbon substituent was observed, a formal “deoxoanomeric effect’’ which seems to be a common feature to these azaheterocycles. On the other hand, the aminoketalic pseudoanomeric hydroxyl group adopted exclusively axial orientations in water solution, in accord with the anomeric effect. The possibility of controlling the conformation and configuration of anomeric hydroxyl groups by a vicinal N-thiocarbonyl functionality was further exploited in the design of bicyclic “azasugar’’ glycomimetics structurally related to the iminosugar (“azasugar’’) glycosidase inhibitor family.310 Acid hydrolysis of the isopropylidene group in the 5,6-(cyclic thiocarbamate) 274 resulted in tautomeric rearrangement to the bicyclic derivative 275 (Scheme 75). In contrast to data for reducing iminosugars, compound 275 is stable in water solution and exists exclusively in the 움anomeric configuration, probably due to a very efficient delocalization interaction between the 앟-type lone-pair orbital of the sp2-hybridized N-atom in the ground state of N-thiocarbonyl functionalities and the * antibonding orbital of the contiguous C––O bond. It is of note that this control of the anomeric configuration resulted in a dramatic increase (104-fold) in the yeast 움-glucosidase (Ki ⫽ 40 애M) versus sweet-almond 웁-glucosidase selectivity as compared with the parent 5-amino-5-deoxy-D-glucopyranose (nojirimycin).
SCHEME 75
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Monocyclic N-thiocarbonyl iminosugars are highly prone to undergo intramolecular glycosylation reactions when the resulting bicyclic structures can accommodate the anomeric effect at the aminoketalic center. Thus, the synthesis of inhibitors of the calystegine family has been accomplished by tandem tautomerization–intramolecular glycosylation of 5-deoxy-5thioureido-L-idose derivatives (276, Scheme 76).417 The resulting compounds (277) acted as specific inhibitors of 웁-glucosidases, analogous to the parent natural alkaloids. 4. Artificial Receptors Modification of cyclodextrins (CDs) with thioureido substituents is a very convenient way for conjugating these natural cyclooligosaccharide receptors with a variety of molecules. The resulting semisynthetic compounds (so-called second-generation cyclodextrins) may exhibit different inclusion, solubility, or toxicity properties as compared to their native counterparts. 웁Cyclodextrin derivatives bearing thiourea-bridged oligosaccharide– and glycopeptide–thiourea antennae at the primary face have been proposed as drug-carrier systems, endowed with the capability of molecular recognition at the cell membrane level.99,155,382,383,418 A significant increase in water solubility, initially ascribed to the hydrophilic saccharide branch, was measured for such adducts. However, the same behavior was observed when hydrophobic substituents such as peracetylated sugars or alkyl groups were incorporated. It was concluded that the increase in water solubility is actually imparted by the thiourea group, which probably forms hydrogen bonds with water molecules breaking the intercyclodextrin hydrogen-bond network, thus preventing aggregation. Moreover, thiourea-modified 웁-CDs exhibited an about fourfold decrease in their hemolytic properties without any significant modification of the inclusion capability as determined for the anticancer drug Taxotere. Thiourea segments have also been incorporated into macrocyclic 움,움⬘trehalose-based pseudocyclooligosaccharides (278–280) obtained100,419 by
SCHEME 76
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the coupling reaction of bifunctional isothiocyanate and amine precursors. The geometrical and conformational properties of the new host molecules were governed by the strong hydrogen-bond donor character of the thiourea NH protons and the presence of four slow rotating N––C(苷S) pseudoamide bonds. Low-temperature NMR experiments revealed the presence of two configurational patterns in solution, namely the Z,E : E,Z alternate conformation and the Z,E : Z,E parallel conformation, both having C2 symmetry and involving two intramolecular NH…O hydrogen bonds. The hydrogen-bonding donor capability of thiourea groups has been further exploited in the design of multitopic podantlike sugar thiourea receptors suitable for recognition and complexation of complementary functional groups such as carboxylate or phosphate (for instance, 281, 282). Preliminary results420–422 have shown association constants up to 105 M⫺1 for neuraminic acid derivatives as guests using the tritopic tris(glucopyra-
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nosylthiourea) receptor 282 in chloroform-d solution and above 102 M⫺1 in a polar competitive solvent such as dimethyl sulfoxide. X. CONCLUSIONS From the previous discussion, it is clear that the study of the chemistry of N-thiocarbonyl carbohydrate derivatives is at present experiencing a tremendous expansion, both quantitatively and qualitatively. In addition to the classic uses as synthetic intermediates in heterocyclic chemistry or in neoglycoprotein preparation, the new applications on record are of concern to virtually every aspect of glycobiology. A major reason is undoubtedly the possibility of access to highly functionalized complex derivatives with tailored structural properties employing relatively simple and very efficient synthetic procedures. The wide range of structures reported demonstrates that the basis for construction and manipulation of N-thiocarbonyl carbohydrate compounds is now well established, and further challenges are ready to be undertaken in the near future. Thus, the synthetic methodologies seem to be mature for solid-phase and combinatorial chemistry, which should allow preparation and testing of numerous novel linear and branched pseudooligosaccharides. The chelating and hydrogen-bonding capabilities of N-thiocarbonyl derivatives in combination with the chirality of carbohydrates remain almost unexplored and deserve thorough investigation in connection with molecular recognition and catalysis. ACKNOWLEDGMENTS The authors thank Dr. José L. Jiménez Blanco, Juan M. Benito, and M. Isabel García Moreno for assistance in obtaining references and in proofreading the manuscript. This work was supported by the Dirección General de Investigación Científica y Técnica of Spain under contract PB 97/0747.
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
SYNTHESIS OF CHIRAL POLYAMIDES FROM CARBOHYDRATE-DERIVED MONOMERS
OSCAR VARELA* AND HERNAN A. ORGUEIRA CIHIDECAR (CONICET), Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428-Buenos Aires, Argentina
IIII. IIII. IIII. I IV. IIIII II V. IVI. VII. IIIII IIIII
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chiral Polyamides: Properties and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . Chiral Polyamides Based on Diamino Saccharides. . . . . . . . . . . . . . . . . . . . . . . . . Chiral A,B-Type Polyamides (Nylons-n) Based on “Amino Acids” Derived from Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polyaldaramides: Polyhydroxy Chiral Analogs of Nylon-n,6 and Nylon-n,5 . . . . . Polytartaramides: Polyhydroxy Chiral Analogs of Nylon-n,4 . . . . . . . . . . . . . . . . . Chiral Analogs of Nylon-3 Prepared from Carbohydrate-Based Aspartic Acid-like Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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I. INTRODUCTION Polyamides are condensation products that contain recurring amide groups as integral parts. Polyamides are usually referred to as “nylons,” a generic term.1 The first polyamide was synthesized by Gabriel and Maas.2 Thirty years later, in 1929, this study was renewed by Carothers.3 Immediately after the first patents were issued,4 nylon stockings were introduced to the public in 1940 and were an immediate and outstanding commercial success. Since that time, the production of polyamides has greatly expanded throughout the world.1 However, in the near future, access to fossil raw materials is expected to become increasingly difficult and more expensive. The need for conservation of petroleum feedstocks and the increased awareness in recent years of the low biodegradability of petroleum-based polymers has drawn attention to the utilization of natural regrowing resources for the chemical synthesis of polymers.5 They are also promising materials with * E-mail:
[email protected]. 0096-5332/00 $30.00
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novel technical possibilities and improved properties, such as biocompatibility and biodegradability. Among the different natural sources that are inexpensive and readily available, carbohydrates, because of their great stereochemical diversity, stand out as highly convenient materials, especially for the synthesis of polymers containing several stereocenters in the main chain.6,7 In this chapter we discuss the synthesis of monomeric precursors derived from carbohydrates, their subsequent polymerization, and the physicochemical characterization of the resulting polyamides. A short introduction on the different types of polyamides and their common nomenclature is presented. Current and potential applications and properties of chiral polyamides derived from sugars are detailed. We have also included a comment on some of the requirements for control of the regio- and stereoregularity in the growing chains during the polymerization. The pioneering work on carbohydrate-based polymers is concisely described, although a more detailed historical overview can be found in the review article by Thiem and Bachmann.6 As the interest for new polyamides based on carbohydrates has steadily increased during the past 2 decades, we have focused attention mainly on the work published during this period. The subsequent sections of this chapter have been organized taking into account the class of carbohydrate-derived monomer (for example, a diamine, an amino acid, a dibasic acid, and so on) that is employed as precursor in the synthesis of a given type of polyhydroxy polyamide (analogs of nylon-3, nylon-5, nylon-6, nylon-n,5, nylon-n,6, and so on). Tartaric acids constitute the aldaric acid derivatives of tetroses and therefore polytartaramides have been included in this chapter. II. CHIRAL POLYAMIDES: PROPERTIES AND APPLICATIONS Linear polyamides are formed as the products of condensation of bifunctional monomers. If the monomers are amino acids or their lactams, the resulting polyamides are called the AB type, A representing amine groups and B, carboxyl groups. Polyamides formed by condensation of a diamine and a dicarboxylic acid are called AABB types. A common “shorthand” symbolism is the use of numbers that signify the number of carbon atoms in the respective monomers. For AABB polyamides, two numbers (m,n) are used. The first, m, gives the number of carbon atoms separating the amino groups of the diamine, and the second (n) gives the number of carbons between the acid groups in the dicarboxylic acid (including the carbonyl carbon). The self-condensation polymer derived from an amino acid or lactam (AB polyamide) is known as an n-type polyamide (nylon-n), where n gives the number of straight-chain carbon atoms separating the amine and the acid functions (Scheme 1).
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SCHEME 1
The physical properties of conventional nylons are essentially determined by the distance between the polar groups, namely, the length of the polymethylene chain. As a consequence of this constitutional uniformity, the nylons show a rather monotonous behavior, whereas peptides and proteins display a great diversity of physical and biological properties and functions. Therefore, conventional polymers are being replaced with high performance materials, designed to manifest improved biocompatibility, biodegradability, and other desired properties.7 These materials, useful for applications in medicine, include synthetic polymers that mimic natural substances, naturally occurring macromolecules, and chemically modified natural polymers.8 One advantage of using biodegradable polymers as drug delivery agents, suture filaments, ligature clamps, and the like is that the device does not have to be removed after its purpose has been fulfilled.9,10 Ideally, polymer degradation in an aqueous environment, such as the human body, should occur with the formation of natural metabolites or yield harmless degradation products.8 Polymer biodegradation includes various mechanisms, such as photodegradation, hydrolysis, enzymatic degradation, and thermooxidative degradation. Polyesters, polyamides, and polyester amides may undergo hydrolytic degradation because of the presence of hydrolytically unstable bonds, hydrophilic enough to allow for water access.9 Polyhydroxy alkanoates derived from glycolic (PGA), lactic (PLA), and 3-hydroxybutanoic acids (PHB) and from copolymers PGA–PLA are the most successful class of biodegradable polymers.11–14 Attempts have been made to synthesize biodegradable derivatives of nylon.15 Thus, some polyamides derived from
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natural amino acids have shown bioelastic properties and a certain degree of biodegradability.16,17 Polyamides containing methyl and hydroxyl groups are biodegradable,18 and hydroxypropyl methacrylamide polymers having peptide linkages are hydrolyzed by papain.19 Furthermore, the presence of electron-withdrawing groups vicinal to the carbonyl group of a polyamide enhances its rate of hydrolysis.20 In addition to chemical hydrolysis, hydrolysis by enzymes can operate as an alternative degradation process. It has become widely accepted that biodegradable synthetic polymers tend to be designed to mimic those structures prevailing in nature, since enzymes produced by microbial populations may not discriminate between polymers of similar structure.11 Synthetic nonpolypeptidic, chiral polyamides could mimic natural peptides or proteins, resulting in biodegradable products useful in biomedicine. Besides the aforementioned uses and promising potential developments for polyamides containing stereogenic centers, these materials are also envisaged as a class of polymers in which chiroptical and particularly desirable physical properties may be encompassed. In order to establish the relation existing between constitution and conformation in optically active polyamides, a fair number of them have been prepared and their optical properties studied in solution.21 It has been reported that the presence of a stereocenter in the polyamide chain may promote important conformational changes. For example, helical arrangements in the solid state, similar to those known as typical of polypeptides and proteins have been found.22,23 These helical nylons displayed particular properties such as liquid-crystalline behavior and piezoelectricity.24,25 From the synthetic point of view, the introduction of asymmetric carbons in the repeating unit of a polyamide makes it possible to adjust the physical properties by controlling the tacticity and also to study the effect of chirality on biological activity.9 In fact, stereo- and regioregularity are achieved in AB-type polyamides, regardless of the configuration of the monomer, as polycondensation is not restricted by the occurrence of directional isomerism. However, the stereo- and regioselectivity of chains of the AABB types rely upon the existence of C2 symmetry in the monomers from which the polymer is generated; otherwise regioisomerism will probably occur, giving rise to aregic polyamides. These topics are discussed in the next sections (Scheme 2). Carbohydrate-based synthetic polymers can be prepared by polymerization of small, activated carbohydrate-derived monomers. A pioneering study in this field was the preparation and polymerization26 of methyl 2,3,4,6-tetra-O-allyl-움-D-glucopyranoside (1). Under the influence of oxygen and heat, compound 1 gradually polymerizes, first to a viscous liquid and finally to a colorless, transparent resin. Similarly, acrylate and
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SCHEME 2
methacrylate derivatives of 1,4 : 3,6-dianhydro-D-glucitol (2) and 1,4 : 3,6dianhydro-D-mannitol (3) gave, on polymerization, transparent, colorless resins of the thermosetting type.27 Condensation of 1,2 : 5,6-dianhydro-3,4O-isopropylidene-D-mannitol (4) with phthalic acid gave, on heating, a solution that became thicker and finally set to a gel. If the heating is stopped before the gel stage is reached, brittle fibers of polyester could be drawn from the cooling melt.28 The first polyamides based on a carbohydrate were obtained from the crystalline salts of 1,6-diamino-2,3 : 4,5-dimethylene-Dmannitol (5) in reaction with such dibasic acids, as oxalic, hexanedioic (adipic), and decanedioic (sebacic) acids.29 These salts polymerized on heating above their melting points to afford polyamides, which did not give oriented fibers when cold-drawn. The preparation of salts of 5 with aldaric acid derivatives was somewhat difficult. Owing to the lack of thermal stability of the monomers derived from carbohydrates, the melt-polycondensation process led only to brittle fibers of low molecular weights and poor physical properties. As a consequence polymerization in solution came into practice. In an attempt to benzoylate 2,4 : 3,5-di-O-methylene-D-gluconic acid (6) with an equivalent amount of benzoyl chloride or benzoic anhydride in pyridine solution, rapid polymerization of the hydroxy acid was observed. The polyesterification of 6 under those conditions afforded a white, amorphous polymer in 57% yield.30 Condensation of 2,3,4,5-tetra-O-acetyl-galactaroyl dichloride (7) with ethylenediamine or piperazine, with subsequent acetylation, gave the corresponding polyamides, which decomposed above 250⬚C with no evidence of melting.31 Deacetylation was effected (with probable hydrolytic degradation) to yield polymers having 30–40 repeating units. A patent has described
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the condensation at high temperatures of diamines with acetals and ketals of galactonic acid, to give linear polyamides32 (Scheme 3). During the 1960s new polyamides were obtained employing the technique of interfacial polycondensation. This technique is well suited to carbohydrate monomers because of the low temperatures required for polymerization. Thus, Bird et al.33–36 synthesized carbohydrate polyamides with high inherent viscosities, comparable to those of commercial nylons. Two series of high-viscosity polyamides have been prepared35,36: (a) from 1,6diamino-1,6-dideoxy-di-O-methylenehexitols (such as 8) and decanedioyl (sebacoyl) or hexanedioyl (adipoyl) dichlorides and (b) from hexamethylenediamine (1,6-diaminohexane) or decamethylenediamine and a di-Omethylenehexaroyl dichloride (such as 9). A patent on these products has been issued.37 The following sections deal with the synthesis and properties of nylons derived from carbohydrates, work that has been published mainly during the past 2 decades (Scheme 4).
SCHEME 3
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SCHEME 4
III. CHIRAL POLYAMIDES BASED ON DIAMINO SACCHARIDES Diamino derivatives of carbohydrates have been employed for polycondensation reactions with carboxyl-activated aliphatic and aromatic dicarboxylic acids. The resulting polyamides are of the AABB type (nylons-m,n analogs), and therefore, the regio- and stereoregularity in the polyamide chain is determined by the configuration of the carbohydrate precursor. When such a molecule lacks a C2 axis of symmetry, random polymerization leads to nonstereoregular polyamides. As the presence of two amino groups in a natural sugar is rare, diamino saccharides are usually obtained by synthesis. However, the most common amino sugar, D-glucosamine, has been used as precursor of polymers having amide linkages. Thus, Kurita et al.38 prepared poly(ester amide)s by direct polycondensation of D-glucosamine and aliphatic and aromatic dicarboxylic acid chlorides. The polymerization took place in polar solvents, in the presence of pyridine, and involved the primary hydroxyl and the amino groups of glucosamine. The resulting poly(ester amide)s of the type 10 had inherent viscosities between 0.11 and 0.23 dL.g-1 and were soluble in polar solvents. Thermogravimetric analysis revealed that the polymers decomposed on heating, showing 10% weight loss at 180–197⬚C. Chitobiose, a disaccharide of glucosamine, possesses two amino functions, at C-2 and C-2⬘. These amino groups reacted with aliphatic and aromatic diacid chlorides to give linear polyamides (11).39 These polymers afforded transparent films, which showed high permeability, indicating probable utility as permeation-dialysis membranes (Scheme 5). Starting from D-glucosamine or common saccharides, diamino sugar derivatives may be prepared by conversion of hydroxyl groups into amines. The procedure usually employed involves sulfonylation of an OH group, followed by nucleophilic substitution by azide and subsequent hydrogenation. An alternative “one-pot” procedure for the conversion of a primary hydroxyl group into azide is the reaction with N-bromosuccinimide, triphenylphosphine, and sodium azide.40 From the nonreducing disaccharide sucrose, a diamino derivative (6,6⬘-diamino-6,6⬘-dideoxysucrose) was synthesized by means of the first-mentioned general procedure.
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SCHEME 5
This synthesis and the polycondensation of the resulting diamine with adipoyl dichloride has been patented.41 With oligosaccharides, the synthesis of bifunctional diamino monomers is more complicated. However, cyclodextrins have been successfully employed for the synthesis of polyamides. Cyclodextrins are cyclic oligosaccharides formed with glucose residues having 움-(1 → 4) linkages. The diamino derivatives of cyclodextrins were prepared from ditosylate precursors and polycondensed with dicarboxylic acid dichlorides in a mixture of N,N-dimethylformamide (DMF) and water. A patent concerning the synthesis and use of cyclomaltoheptaose (웁-cyclodextrin) polyamides as membranes has been issued.42 2,6-Diamino saccharides, obtained from D-glucosamine, have been used as monomers for polycondensation reactions with acid dichlorides. Methyl (12) and benzyl (13) glycosides of N-benzyloxycarbonyl-D-glucosamine were prepared and the primary hydroxyl groups converted into azides by the Appel procedure.40 Compounds 14 and 15 were the precursors of the diamino derivatives 16 and 17, respectively. Interfacial and solution polycondensations of these diamino derivatives 16 and 17 with aliphatic and aromatic acyl dichlorides yielded the corresponding polyamides (18). Employing the 3-O-pivaloyl and 3,4-di-O-pivaloyl derivatives of 16 as monomers, the corresponding pivaloylated polyamides were obtained.43 The partially substituted polyamides had similar properties as the unprotected polyamides (18). Number-average molecular weights for these materials, synthesized by interfacial polycondensation, ranged between 10,300 and 24,000, as determined by gel-permeation chromatography (GPC), with number-average degrees of polymerization up to Pn ⫽ 64. Polycondensation in solution afforded only higher oligomers. As the polycondensations
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were random, these AABB-type polyamides were nonstereoregular. However, their melting points were rather high (Tm ⬎ 200⬚C), and they melted with decomposition (Scheme 6). In order to synthesize a polyamide containing the more stable C-glycosyl linkage, instead of O-glycoside units in the polymer backbone, a C-glycosylic diamino saccharide (22) was prepared from D-glucal triacetate (19). Addition of trimethylsilyl cyanide to 19, with boron trifluoride etherate as catalyst, afforded the cyano compound 20 as the main product. Upon hydrogenation of the double bond and deacetylation, the OH group at C-6 was replaced by azide to give 21, which underwent hydrogenolysis, affording 22. In contrast with the other diamino saccharides (16 and 17), compound 22 had two primary amino groups, which are more reactive. Polycondensation of 22 with the same dicarboxylic acid dichlorides as before led to polymeric materials. However, neither structural determinations (except for the IR spectra) nor molecular-weight measurements for the polymers were reported43 (Scheme 7). Anhydroalditols, which are thermostable, proved to be suitable carbohydrate precursors for polymer synthesis. Thus chiral, cis-fused bicyclic
SCHEME 6
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SCHEME 7
1,4 : 3,6-dianhydrohexitols, having only two remaining hydroxyl groups in either exo or endo orientations, have been employed for the synthesis of polyesters44 and polyurethanes.45 1,4-Anhydroalditols have also been used for the synthesis of polyethers.46 Thiem and Bachmann47 reported the synthesis of polyamides stating from D-mannitol (23) and D-glucitol (26) via the corresponding 1 : 4,3 : 6-dianhydrohexitols of the D-manno (24), D-gluco (27), and L-ido (29) configurations. The three stereoisomeric dianhydroalditols were functionalized to their respective diamino derivatives 25, 28, and 30 by sulfonylation of the hydroxyl groups, azide substitution, and hydrogenolysis (Scheme 8). The same synthetic route was also applied to the transformation of 1,4anhydro-D,L-threitol (31) and 1,4-anhydroerythritol (33) into the corresponding diamines 32 and 34. The reaction of diamines 25, 28, 30, 32, and 34 with aromatic and aliphatic dicarboxylic acid dichlorides was performed by interfacial polycondensation in emulsions of organic solvents and water, with sodium carbonate as base and sodium dodecyl hydrogensulfate as emulsifier. The resulting polyamides (35–39), obtained in 60–80% yields, were characterized by IR and NMR spectroscopy. Number-average molecular weights were determined by gel-permeation chromatography and range between 5,000 and 25,000, corresponding to a number-average degree of polymerization up to Pn ⬃100. Inherent viscosities were measured and correlated with the observed average molecular weights. The thermal behavior of the polyamides was determined by differential scanning calorimetry (DSC) and indicated that many of the polyamides were crystalline (Scheme 9). The polyamides 35 and 37 are stereoregular, as the precursor diamines 25 and 30 posses a C2 axis of symmetry (a symmetric distribution of the stereocenters) and the two amino functions are topologically and stereochemi-
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SCHEME 8
cally equivalent. The polyamide 36 is nonstereoregular, as polymerization was random and the precursor 28 has two nonequivalent amino functions (one endo and the other exo). Polyamides 38 and 39, having tetrahydrofuran residues in the polymer backbone, were optically inactive, as 31 (precursor of 38) is racemic and 33 (precursor of 39) is a meso form (Scheme 10). Diamine derivatives 25, 28, 30, 32, and 34 were also condensed with 2,3,4,5-tetra-O-acetylgalactaroyl dichloride (7) employing the facial polycondensation technique.48 The conclusions from these studies are reported in Section V. IV. CHIRAL A,B-TYPE POLYAMIDES (NYLONS-n) BASED ON “AMINO ACIDS” DERIVED FROM CARBOHYDRATES The polyamides obtained by polycondensation of bifunctional monomers which contain the amino and the acid functions in the same molecule (“amino acids”) are stereoregular, regardless of the configuration of the
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SCHEME 9
SCHEME 10
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monomer. These polymers are also regioregular, as regioisomerism cannot occur in the formation of the amide linkage. Tokura et al.49 synthesized a polyamide of the Perlon type (40) starting from a 6-O-carboxymethyl-D-glucosamine derivative as monomer. This compound was obtained by carboxylmethylation of chitin with monochloroacetic acid, followed by hydrolysis of the glycosidic linkage. The molecular weight (Mw ⫽ 15,000) of the resulting water-soluble polyamide 40 was determined by gel-permeation chromatography and electrophoresis (Scheme 11). Galbis and co-workers50 reported the synthesis of stereoregular AB-type polyamides based on 움- and 웆-amino acids derived from carbohydrates. Thus, starting from N-acetyl-D-glucosamine (41), 2-amino-2-deoxy-3,4,5,6tetra-O-methyl-D-gluconic acid (43) was prepared51 via the lactone 42. Compound 43 was activated for the polycondensation with trichloromethyl chloroformate, to give the N-carboxy anhydride 44. The polymerization was conducted in N,N-dimethylformamide or dichlorometane and in the presence of N-ethyldiisopropylamine (EDPA). The resulting polyamide 45 is a chiral analog of nylon-2, having a polymethoxylated lateral chain in the repeating unit (Scheme 12). Methyl 움-D-glucopyranoside (46) was employed as a chiral template for the synthesis of 6-azido-6-deoxy-2,3,4,5,-tetra-O-methyl-D-glucono-1,5lactone (47), which was converted into the open-chain derivative 48. For the polymerization of 48, the active ester method was employed.52 The amino function was protected as the N-Boc derivative and the carboxylic acid was activated as the pentachlorophenyl or p-nitrophenyl ester to give 50. However, attempted polymerization of such a compound led to the lactam 51 instead of the polymer. In order to avoid this intramolecular reaction, the dimer 52 was prepared by condensation of 49 with the pentachlorophenyl ester 52 obtained from 48. Compound 53 was conveniently derivatized for the polymerization as the active ester 54. Thus, polycondensation of 54 under alkaline conditions afforded the chiral nylon-6 analog 58, having a tetramethoxypentamethylene chain spacing the amido groups along the polymer backbone50 (Scheme 13A).
SCHEME 11
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SCHEME 12
The molecular weights of the polyamides 45 and 55 were estimated as 25,000 and 67,000, respectively, on the basis of viscosimetric measurements. Both polyamides displayed high optical activity; they were highly hydrophilic and readily soluble in water and in organic solvents, including chloroform. Polyamide 55 was crystalline and yielded resistant films with a spherulitic texture (Scheme 13B). Derivatives of 5-amino-5-deoxy-L-arabinonic (58) and D-xylonic (59) acids were prepared from the respective per-O-methyl aldono-1,5-lactones (56 and 57). Opening of the lactone by alcoholysis followed by tosylation of HO-5, azide substitution, and hydrogenolysis led to the precursors of 58 and 59, respectively. Also, the (S)-5-amino-5-deoxy-4-methoxypentanoic acid (60) was prepared from D-ribono-1,4-lactone (via its 2-butenolide) and from L-glutamic acid, as depicted in Scheme 14.53 Compound 60 was N-protected and carboxylate activated to give 61. The
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SCHEME 13A
polymerization of 61 competed with the intramolecular lactamization and therefore the dimer of 62 was prepared by condensation of 60 and 61 in order to increase the distance between the reacting groups. The dimers of the amino acid derivatives having the L-arabino and D-xylo configuration were similarly prepared. Removal of the N-protecting groups under acidic conditions gave the corresponding hydrochlorides (for example, 63), which polymerized when the amino group was released with a base.54 The poly[(S)-5-amino-4-methoxypenathonic acid] (64), poly(5-amino-5-deoxy-2,3,4tri- O-methyl-L-arabinonic acid) (65), and poly (5-amino-5-deoxy-2,3,4-triO-methyl-D-xylonic acid) (66) were obtained in very good yields (⬃90%) and were characterized by elemental analysis, IR and NMR spectroscopies, and powder X-ray diffraction. They had a pronounced affinity for water, although they were not soluble in this solvent. Their intrinsic viscosities were measured in dichloroacetic acid at 25⬚C, and their molecular weights (Mw ⫽ 7.800–11.700) were determined by gel-permeation chromatography analysis. Polyamide 64 was highly crystalline and afforded films with a spherulitic texture (Scheme 15). Stereoregular, AB-type polyamides, containing a natural amino acid
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SCHEME 13B
(glycine) and a synthetic component (60), have been prepared by the active ester polycondensation procedure.55 Reaction of 60 with the N-Boc derivative of p-nitrophenyl glycinate (67) in N,N-dimethylformamide and Nethyldiisopropylamine afforded 68, which was readily converted into 69. The polycondensation reaction of 69 was carried out in N,N-dimethylformamide or dichloromethane and in the presence of N-ethyldiisopropylamine. The expected polyamide 70 was formed, accompanied by a considerable amount (⬃30%) of a cyclic product (71). The formation of the macrolactam 71 was attributed to the glycine moiety, which, being achiral, permits a broader range of allowable NH-C움H dihedral angles. For this reason, a conformation could be adopted that favors the fomation of cyclic 71 by bringing together the reactive groups located at the extremeties of the oligoamide chain (Scheme 16). The formation of cyclic by-products was avoided by introducing an additional molecule of 60 into the polymerizing unit. Therefore, the oligoamide
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SCHEME 14
72 was prepared by condensation of 60 with the pentachlorophenyl ester of 68, followed by usual functional group interconversions. Polymerization of 72 (N,N-dimethylformamide–N-ethyldiisopropylamine) gave the polyamide 73 in 85% yield, free of macrocyclic by-products. This polymer was spectroscopically characterized, and thermal studies and polarized optical microscopy indicated that it was crystalline. Films obtained by slow evaporation of formic acid solutions of 73 displayed birefrigence associated with a spherulitic texture (Scheme 17). Tri-O-methyl-L-arabinono-1,5-lactone (56), previosly used for the synthesis of 65, underwent ammonolysis to the corresponding amide, which on reduction gave the 1-aminoarabinitol derivative. The activated monomer 74 was obtained via blocking group manipulations, selective succinylation at C-5, and ester activation of the carboxyl group. Polymerization of 74 afforded the stereoregular poly(ester amide) 75, derived from a sugar
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SCHEME 15
SCHEME 16
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SCHEME 17
template.56 The polymerization was carried out in various polar solvents. The molecular weight of 75 was estimated by viscosimetry and gel-permeation chromatography. Poly(ester amide)s 77 and 79 were prepared by polycondensation of 1-amino-1-deoxy-5-O-glutaryl-L-arabinitol (76) and 1amino-1-deoxy-5-O-succinyl-D-xylitol (78) derivatives, respectively.57 The polymers were hydrophilic and exhibited moderate optical activity. Thermal and X-ray diffraction studies showed that they were slightly crystalline and stable up to 250⬚C under nitrogen. The hydrolytic degradation of poly(ester amide)s 75, 77, and 79 was studied and was shown to occur by hydrolysis of the ester linkages58 (Scheme 18). Replacement of the aliphatic acid residue in the 1-amino-1-deoxy-Larabinitol derivatives by an aromatic dicarboxylic acid gave the precursor 80. Attempted polymerization of 80 afforded, instead of the expected poly(ester amide), a mixture of oligomers (81) and the monomeric 1deoxy-1-phthalimido-L-arabinitol derivative 82. When the reaction was conducted in hexamethylphosphoric triamide, these products were obtained in 30 and 51% yields, respectively, indicating that intramolecular condensation competes with the intermolecular reaction.59 This case illustrates a limitation of the “active ester” method of polymerization (Scheme 19). V. POLYALDARAMIDES: POLYHYDROXY CHIRAL ANALOGS OF NYLON-n,6 AND NYLON-n,5 Polyaldaramides are hydroxylated, linear polyamides wherein the diacid monomer unit of a typical nylon copolymer, such as nylon-6,6, is replaced
SCHEME 18
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SCHEME 19
by an aldaric acid. As already described for other AABB-type polyamides, the regio- and stereoregularity in the construction of the polymer chain depends on the configuration of the comonomers. Thus, random polymerization of asymmetric aldaric acid derivatives with common aliphatic or aromatic diamines leads to nonstereoregular polyaldaramides. Although aldaric acid derivatives have been selected as monomers suitable for the synthesis of polyamides since the 1940s,29,31,32,35,36 polymerization processes employing active diesters of aldaric acids and diamines were not developed until the decade of 1970. Pioneer work of Ogata and coworkers established the order of reactivity of active esters of adipic acid with hexamethylenediamine60 or diols61 in a variety of solvents, and the conditions for the synthesis of the respective polyamides and polyesters were optimized. It was shown that heteroatom groups (such as ether or hydroxyl groups) greatly enhanced the reactivity of the diester in polycondensation reactions in polar solvents when they were located at the 움- or 웁-positions to the ester carbonyl group.62 The same authors also reported the polycondensation of diethyl galactarate with several diamines.63 These reactions were conducted in polar solvents such as methanol, dimethyl sulfoxide, and N-methylpyrrolidone under mild conditions. Polymerization of diethyl galactarate with hexamethylenediamine gave 83, a hydroxylated analog of nylon-6,6, which did not melt and decomposed at 200⬚C. The copolycondensation behavior of diethyl tartrate, diethyl galactarate, and diphenyl adipate with hexamethylenediamine was interpreted in terms of the solvent effect on the forming copolymer chain.64 The copolymerization of diethyl galactarate and diphenyl adipate with hexamethylenediamine in methanol yielded an almost homopolyamide of the former. The enhancement effect of the hydroxyl group on the reactivity of the ester toward aminolysis was
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attributed to hydrogen bonding of the OH group with the approaching amino group at an intermediate reaction stage. The polymerization of diethyl galactarate with 1,6-diaminohexane in dimethyl sulfoxide at 60⬚C and in the presence of poly(4-vinylpyridine) gave a polyamide having higher molecular weight than that prepared in the absence of the matrix65 (Scheme 20). Hoagland brought further understanding to the condensation of aldaric acid esters with diamines when he established the mechanism of aminolysis of six-carbon galactaric diesters66 and five-carbon xylaric acid diesters.67 Such a mechanism requires a two-step sequence at each diester function: a fast, base-catalyzed five-membered lactonization step followed by a slower step, the aminolysis of the lactone. From these studies it was clear that activation of five- or six-carbon aldaric acid diesters results from the facile formation and high reactivity of these five-membered aldarolactones. Thus, in the case of diethyl di-O-isopropylidenegalactarate, a lower rate of polycondensation with ethylenediamine was observed owing to the more difficult lactonization. Acetylation of D-galactaric acid afforded the 2,3,4,5-tetra-O-acetyl derivative (84), which was activated for condensation as the dichloride 7. Polyamides were obtained by solution polycondensation of 7 with various aliphatic and aromatic amines.68 Similar yields of polyamides were obtained by the interfacial polycondensation of the dichloride with diamines.48 When 1,6-diaminohexane was used, the resulting polyamide 85 resembles a nylon-6,6 in which half of the hydrogens have been substituted by acetoxy groups. However, the polycondensation of 7 with the diamino derivatives of dianhydrohexitols having the L-ido (25) and Dmanno (30) configurations afforded respectively the stereoregular polyamides 86 and 87, completely constructed from carbohydrate precursors. The polyamides derived from diamines 28, 32, and 34 were also prepared. These polymers showed molecular weights (Mn), determined by gelpermeation chromatography, between 4,000 and 17,000 and their inherent viscosities ranged between 0.05 and 0.34 dL.g-1. Polyamides having free hydroxyl groups were obtained by deacylation with aqueous ammonia (Scheme 21).
SCHEME 20
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SCHEME 21
The preparation of unprotected, activated D-glucaric acid esters monomers and their polymerization to poly(alkylene D-glucaramide)s were reported69,70 and patented71 by Kiely et al. D-Glucaric acid (monopotassium salt, 88) was esterified with alcohols, such as methanol, to give mixtures that contained varying amounts of dimethyl D-glucarate (89), methyl D-glucarate 1,4-lactone (90), and methyl D-glucarate 6,3-lactone (91). These ester forms of D-glucaric acid are also in equilibrium under the conditions of the polymerization with diamines. However, in order to obtain good stoichiometric control, which influences the degree of polymerization, compound 90 was isolated from the mixture in crystalline form, in 58% overall yield and employed for the polymerization (Scheme 22). The polycondensation of 90 with alkylenediamines was carried out in methanol solution and in the presence of triethylamine, at room tempera-
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SCHEME 22
ture, for several hours. Isolated yields of polyamides 92 ranged from 67% for poly(4⬘-azaheptamethylene D-glucaramide) to 96% for poly(m-xylenyl D-glucaramide). The linear aliphatic and arylalkylenediamines produced polyamides of higher crystallinity and high melting points. Heteroatom- or branch-containing poly(alkylene D-glucaramide)s were more soluble in water and alcohols, but they were not as crystalline as their straight-chain counterparts and had correspondingly lower melting points and higher molecular weights. Furthermore, the polymers of glucaric or xylaric acids with diprimary diamines containing at least one heteroatom in the main chain formed films when cast from aqueous solution and showed adhesive properties. The analogous polymers prepared from galactaric acid derivatives did not form satisfactory films and exhibited poor or no adhesive properties72 (Scheme 23). As D-glucaric acid is not a symmetrical diacid (2R, 3S, 4S, 5S), polycondensation of its esterified forms with diamines generated nonstereoregular polymers with randomly oriented glucaric acid units in the polymer chain. In order to prepare stereoregular polyglucaramides, the same authors described73 and patented74 a simple procedure starting from sodium Dglucarate 6,3-lactone (93). Compound 93 was synthesized in two steps from 88. The two carboxylic acid ends of 93 have different reactivities and hence they underwent regioselective aminolysis with diamines at the activated carbon (lactone), affording the N-(aminoalkyl)-D-glucaramide salts (94). The carboxylate group was converted into a mixture of ester 95 and lactone 96 on treatment with methanolic HCl. When the mixture was made basic the polymerization occurred spontaneously. The products, head-, tailpoly(alkylene D-glucaramide)s (97), precipitated from methanol, were
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SCHEME 23
isolated in 82–91% yields. The stereoregular polymers 97 exhibited similar properties to those of the random polymers 92, including high melting points (185–200⬚C), comparable solubilities, and also relatively low molecular weights (Mn average 2400, determined by NMR) (Scheme 24). Hashimoto and co-workers reported the use of hexaric-1,4 : 6,3dilactones as monomers in related polycondensations.75,76 Ring-opening polyaddition of D-glucaro-1,4 : 6,3-dilactone (98) with several alkylenediamines proceeded at room temperature in N,N-dimethylformamide or dimethyl sulfoxide, with no catalyst. The resulting polyamides (99) were more amorphous and hydrophilic than the corresponding nylons, having no hydroxyl groups, and were hydrolyzed more readily than the latter in acidic conditions. This fact was attributed to the neighboring-group effect of the hydroxyl groups of the chain upon protonation of the amide group (Scheme 25). Another hexarodilactone, D-mannaro-1,4 : 6,3-dilactone, underwent ringopening polyaddition when treated with diamines having two-, four-, and six-carbon chains.76 The polymerizations were conducted in dimethyl sulfoxide solution at 25⬚C. As the mannarodilactone has a symmetrical arrangement of hydroxyl groups (all S) along the backbone, the resulting polyamides were stereoregular. Therefore, their melting points were higher than those of nonstereoregular poly(alkylene D-glucaramide)s. However, both the polymer yield and the molecular weight of the polyamides from mannarodilactone were lower than those obtained from 98. In our laboratory,77 the yield of poly(alkylene D-mannaramide)s was markedly enhanced
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SCHEME 24
SCHEME 25
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by employing diamines having larger polymethylene chains and by conducting the polycondensations in methanol. We have reported78 a stereocontrolled synthesis of stereoregular, chiral analogs of nylon-5,5 and nylon-6,5. The key chiral intermediate in the synthesis of both polyamides was the pentachlorophenyl ester of (S)-2hydroxypentanedioic acid 5,2-lactone (100). This compound, prepared from D-ribonolactone or L-glutamic acid, possess a stereocenter at C-2 that impedes the construction of AABB-type polyamides, having ordered spatial configurations. However, stereocontrol in the synthesis of the polymers was achieved by chemoselective condensation of the ester group of lactone 100 with amino alcohols. The primary alcohol group of the resulting N-(hydroxyalkyl)amides (101) was converted into tosylate (102) and the sulfonate replaced by azide. Hydrogenolysis of 103 afforded the “amino lactone” 104, conveniently functionalized for the polycondensation. This reaction took place in N,N-dimethylformamide, after deprotonating the amino function with N-ethyldiisopropylamine, to give polyamides 105 and 106. As observed for other stereoregular polymers, these two polyamides displayed relatively high optical rotations compared with the monomers. Powder X-ray diffraction showed that they are highly crystalline products, having viscosimetric molecular weights of about 5000 (Scheme 26). VI. POLYTARTARAMIDES: POLYHYDROXY CHIRAL ANALOGS OF NYLON-n, 4 Polytartaramides are polyaldaramides deriving from tartaric (tetraric) acids. Stereoregular polytartaramides may be obtained, depending on the configuration of the starting tartaric acid derivative employed in the polycondensation. Since either of the chiral forms of tartaric acid (D- or L-threo) are disymmetric (containing a twofold axis normal to the backbone), they give on polymerization a stereoregular polymer, as the substituents will be equally oriented in every repeating unit of the polytartaramide chain. In contrast, if the meso (erythro) form is used for the polymerization, the substituents become oriented at random, and an aregic structure is formed. The synthesis of polytartaramides was first reported by Minoura and coworkers.79 During the 1970s, Ogata et al.80,81 described the polycondensation of tartaric acid itself or its 2,3-O-methylene derivative with diamines, by a variety of procedures. These authors also studied the copolymerizations of diethyl-L-tartrate with other diesters64 and reported that the rate of polymerization of dimethyl-L-tartrate with 1,6-diaminohexane in dimethyl sulfoxide at 60⬚C increased when the reactions were conducted in the presence of such polymer matrices as poly(vinyl pyrrolidone), pullulan, and poly(vinyl alcohol). The rate increased with increasing molecular weight of the matrix.82
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SCHEME 26
A renewed interest in polytartaramides has emerged in the past few years, mainly due to the work of Muñoz-Guerra and coworkers, who prepared a series of stereoregular polyamides by the polycondensation method developed by Katsarava et al.83 This procedure is based on activation of the diacid as the bis(pentachlorophenyl) ester and the diamine as the bis(trimethylsilyl) derivative, and the polymerization reactions may be conducted under very mild conditions, affording linear polyamides having acceptable molecular weights. Starting from L-tartaric acid, the bis(pentachlorophenyl) 2,3-O-methylene derivative (107) was prepared and polycondensed with the N,N⬘-bis(trimethylsilyl) derivatives of 1,9- and 1,12-alkanediamines.84 The polymerization was carried out in several solvents; the highest degree of polymerization was achieved for 1,12-dodecanediamine in chloroform. The polyamides 108 were soluble in chloroform and in warm dimethyl sulfoxide or N-methylpyrrolidone. Both viscosimetry and gel-permeation chromatography were used to estimate the molecular
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SCHEME 27
weights, which ranged between 6,000 and 44,000. Well-defined diagrams were obtained by powder X-ray diffraction for samples of the polyamides prepared by slow precipitation (or evaporation of solvents), indicating high crystallinity (Scheme 27). A series of poly(alkylene-2,3-O-dimethyl-L-tartaramide)s (110) of the nylon-n,4-type have been prepared by the same polymerization procedure as just described.85 The activated 2,3-di-O-methyl-L-tartaric acid derivative 109 was used to provide the two chiral backbone carbons. The number of methylene units in the polymethylene sequence of polyamides 110 ranged from 2 to 9 and 12. Polycondensations were conducted in chloroform at temperatures from ambient up to 60⬚C. By these means, polyamides having limiting viscosity numbers between 0.6 and 2.3 were obtained in yields exceeding 90% in most cases. Their optical activities were found to decrease with the length of the polymethylene chain, as the density of chiral centers also decreased. Number-average molecular weights, measured by gelpermeation chromatography, were between 8,000 and 50,000, with polydispersities ranging from 1,4 to 2,2. Polytartaramides 110 are hydrophilic and are hydrolyzed faster than conventional polyamides. Melting points fell within the range 185–312⬚C, with glass transitions (Tg) between 84 and 123⬚C (Scheme 28). The degradation of polytartaramides derived from alkanediamines having 6, 8, and 12 methylene groups was investigated. The polymers, in the form of disks, were placed in buffered solutions of pH 2.3, 7.4, and 10.6 at temperatures of 37, 55, and 70⬚C. The polytartaramides degraded slowly at 37⬚C, with the degradation rate depending on the number of methylene groups in the diamine unit.86 Thus, the polytartaramide derived from 1,6diaminohexane was degraded considerably faster than the others,87 showing a decrease of 30% in viscosity after 180 days of incubation in phosphate buffer (pH 7.4) at 37⬚C.
SCHEME 28
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L-Tartaric acid was also used for the synthesis of (2S,3S)-2,3-dimethoxy1,4-butanediamine (113), which was employed in the preparation of polyamides of the 4,n-type.88 Diethyl L-tartrate (111) was reduced with lithium aluminium hydride to the corresponding diol 112, which was converted into 113 by conventional tosylation, azide substituion, and hydrogenation. The diamine 113 was activated as the bis(trimethylsilyl) derivative 114 and polycondensed with the pentachlorophenyl esters of even-numbered aliphatic diacids (ranging from 4 to 12 carbons) to give the stereoregular poly[(2S,3S)-2,3-dimethoxybutylenealkanamide]s (116). These highly crystalline polyamides melted over the range of 150–190⬚C, had a pronounced affinity to water, and exhibited moderate optical activity. These properties were investigated in relation to the molecular structure and compared with those of tartaramides of the type of 110 (Scheme 29). The polycondensation of the trimethylsilyl derivative of 1,6-hexanediamine with mixtures of bis(pentachlorophenyl)-2,3-di-O-methyl-D- and Ltartrates in chloroform at room temperature afforded a series of polytartaramides, such as 117, with enantiomeric D:L ratios ranging from 1 : 9 to 1 : 1.89 Polymerization of mixtures of enantiomers is a method frequently
SCHEME 29
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applied to generate stereochemical microheterogeneities in a polymer chain. By this means, the degree of crystallinity is depressed and related properties may be conveniently modified.9,90 In the absence of stereoselective catalysts or chiral solvents, atactic polymers following Bernouillian statistics are usually obtained. Thus, the microstructure of copolyamides, determined by NMR, appeared to consist of a statistical distribution of Dand L-configurations. The copolyamides were highly crystalline materials, with melting points close to that of the optically pure polymer 110 (x ⫽ 4), which is about 230⬚C. However, the Tg values steadily decreased from 106 to 68⬚C as the D:L ratio increased from 0 to 1. Powder X-ray diffraction indicated a crystal structure very similar to that described for the pure enanthiomer and that the replacement of L- by D-units is feasible over the whole range of enantiomeric compositions, without much distortion of the crystal lattice and properties. Consistent with the moderate decay in crystallinity of the stereocopolyamides, the susceptibility toward the hydrolytic degradation was not significantly enhanced with respect to that displayed by optically pure 110 (Scheme 30). As an efficient approach for increasing the degradability of a polyamide without losing good physical properties, poly(ester amide)s were prepared employing 1,6-diaminohexane, 1,6-hexanediol, 2,3-di-O-methyl-L-tartaric acid, and succinic acid as building blocks.91 The ester linkages were introduced in pairs, using as diacid compound 118, the product of the esterification of 1,6-hexanediol with 2 molar equivalents of succinic anhydride. The carboxyl groups of compound 118 were activated as the pentachlorophenyl esters, affording 119. The carboxyl-activated derivatives 109 and 119 were polycondensed with N,N⬘-bis(trimethylsilyl)-1,6-diaminohexane in chloroform at room temperature. The ester:amide content of the copolymer was adjusted by fixing the composition of the feed monomers 109 and 119. The resulting poly(ester amide)s 120 had number-average molecular weights in the range 10,000–40,000 and were found to be highly crystalline, with melting points above 200⬚C. They were degraded by aqueous buffer at pH 7.4 at a rate that increased with the content of succinic acid units in the copolymer (Scheme 31). The crystal structures of a series of polytartaramides, such as 110, derived from 2,3-di-O-methyl-L-tartaric acid and 1,n-alkylenediamines (n ⫽ 2, 4, 6,
SCHEME 30
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SCHEME 31
and 8), were studied by X-ray diffraction of powders and fibers as well as by electron diffraction of single crystals.92 The lattice parameters were established for each polymer. A triclinic unit-cell with space group P1 was found to be shared by the whole series. Semiempirical quantum-mechanical calculations revealed that the favored conformation for these polyamides involves the tartaric acid moiety in a gauche arrangement with the amide groups rotated out of the plane containing the all-trans polymethylene segment. Crystal models compatible with the crystallographic data suggested a favored structure consisting of hydrogen-bonded pleated sheets packed with a staggered arrangement similar to that found in nylon-6,6. In addition, the crystal structures of both the racemic copolyamide 117 and the equimolecular mixture of the two configurationally homogeneous D- and L-polyamides were studied and compared with that of optically pure 110.93 This study combined X-ray, electron microscopy, and 13C CP-MAS NMR measurements with computational methods. The two optically compensated and the optically pure polymers were shown to be highly crystalline systems; the melting point of the racemic mixture was 250⬚C, considerably higher than those of the homopolymer (232⬚C) and the racemic polymer (226⬚C). The crystal structure of the racemic mixture could be
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represented by a monoclinic unit-cell containing two enantiomeric chains related by a glide plane. A similar model appeared to be adequate for the racemic copolyamide, assuming that the crystal lattice was composed of configurationally averaged identical chains. This arrangement of the chains in the crystal seems to be substantially the same as that adopted in the triclinic structure of pure 110. Energy calculations corroborated the ability of D- and L-tartaric units to cocrystallize without altering the side-by-side packing of the chains of the three systems, which are of comparable energy. The potential development of polytartaramides such as 108 and 110 as degradable biomaterials has some limitations, since aliphatic diamines remain relatively toxic. In order to obtain fully biocompatible polytartaramides, Bou and Muñoz-Guerra94 employed L-lysine as a diamine of natural origin. Polycondensation of the L-tartaric acid derivative 109 with ethyl N,N⬘-bis(trimethylsilyl)-L-lysinate (121) in chloroform solution for 3 days afforded poly[(S)-1-(5)-ethoxycarbonyl-pentamethylene-di-Omethyl-L-tartaramide] (122) in almost quantitative yield (Scheme 32). Both optically active monomers behave in a different manner regarding the regioisomerism of the polymer chain being formed. As already explained, a unique arrangement is possible for the L-tartaric acid residue in the polymer chain. In contrast, two orientations are allowed for the L-lysine residue, depending on which of the two NH (움 or ) is implicated in each amide group and, as shown in the following scheme, the peptide linkage could be 움움, , or 움. Pure syndioregic chains will consist of an alternating sequence of 움움 and structures, but in an isoregic polymer only 움
SCHEME 32
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sesquiads should be present. The regioregularity of 122 was examined by 13 C NMR with the support of model compounds, which facilitated the assignment of the splitting resonances of the carbons of the diacid moiety. This study revealed that the chain is predominantly syndioregic. Polytartaramide 122 had a molecular weight of 6000 with a polydispersity of 1.9 (as determined by gel-permeation chromatography), displayed high optical activity, and was soluble in water (Scheme 33). Two stereoregular polyamides based entirely on tartaric acid have been synthesized.95 Tartaric acid derivatives having the D- and L-configuration were polymerized with (2S, 3S)-2,3-dimethoxy-1,4-butanediamine (113), affording respectively the polyamides 123 and 124. Each diastereoisomeric polymer posses two pairs of stereocenters in the repeating unit, one in the diamine and the other in the diacid counterpart (Scheme 34). Number-average molecular weights around 30,000 were estimated for compounds 123 and 124, by gel-permeation chromatography and viscosimetry. Circular dichroism and 1H NMR data in chloroform suggested the presence of definite secondary structures in this solvent. Crystals of both 123 and 124 were obtained upon annealing, and their structures were studied by X-ray diffraction of powders and oriented fibers. Polyamide 123 seemed to adopt a P1 triclinic structure as observed for
SCHEME 33
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other polytartaramides, whereas 124 crystallized in an orthorombic lattice in the space group P22121. In both cases, the polymer chain appeared to be in a folded conformation, but more contracted than in the 웂-form of conventional nylons. VII. CHIRAL ANALOGS OF NYLON-3 PREPARED FROM CARBOHYDRATE-BASED ASPARTIC ACID-LIKE DERIVATIVES Synthetic polyamides containing 웁-aspartyl moieties in the main chain have shown a character intermediate between those of polypeptides and nylons. In this way, such nylons as poly(움-isobutyl L-aspartate) (136), which bear an alkoxylcarbonyl group stereoregularly attached to the polymer backbone, are able to adopt helical conformations of the type commonly found in polypeptides and proteins.22,23 X-Ray diffraction of 136 indicated two crystalline forms, tetragonal and hexagonal, depending on the conditions used for preparation of the sample. In both forms, the polymer is arranged in intramolecular hydrogen-bonded helices, very similar to the 움helix of polypeptides. Polyamide 136 was first synthesized by polycondensation of active esters96 and then by polymerization of the 웁-lactam of 움-isobutyl-L-asparate (isobutyl 4-oxo-2-azetidinecarboxylate) (135).97,98 In this case, the polymerization was conducted either in solution or thermally. Anionic polymerization in solution, using potassium tert-butoxide as catalyst, yielded a polymer, of better quality having a higher molecular weight (intrinsic viscosity 3.0) than that obtained by the active ester method, although it showed lower optical activity, as it was partially racemized (Scheme 35). Just one example of an asparate-type polyamide derived from a carbohydrate precursor poly[isobutyl(2S,3R)-3-benzyloxyaspartate] (133), has
SCHEME 35
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been reported.99 Compound 133 was synthesized from the chiral 웁-lactam 132, which bears a new stereocenter at C-3. For preparation of 132, 2,3O-isopropylidene-D-glyceraldehyde (127), derived from D-mannitol, was converted into the Schiff base 128. This compound reacted with 2-benzyloxyacetyl chloride in the presence of triethylamine to give the lactam 130, as a unique diastereoisomer (45% yield), probably via the intermediate 129. The 웁-lactam 130 was readily converted, by successive removal of the ketal protecting group, oxidation, and esterification, into compound 181. The p-anisyl group was removed by oxidation with Ce(IV) under mild conditions, affording lactam 182. Polymerization of 182 was performed in dichloromethane with potassium tert-butoxide as catalyst, at room temperature for 3 days. The polyasparatate 133 was obtained as a colorless, powdery solid of high molecular weight (Mw ⫽ 232,000 as determined by gel-permeation chromatography) and of an intrinsic viscosity of 1.23 dL.g-1. No epimerization took place during the polymerization (Scheme 36). ACKNOWLEDGMENTS We thank the University of Buenos Aires (Project 01/TW70), the Agency for the Promotion of Science and Technology of República Argentina (ANPCYT-PICT 01698), and the National Research Council (CONICET) for financial support of the project on synthesis of chiral polyamides. O.V. is a Research Member of CONICET.
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(36) T. P. Bird, W. A. P. Black, E. T. Dewar, and J. B. Hare, J. Chem. Soc., (1963) 3389–3391. (37) W. A. P. Black, E. T. Dewar, and D. Rutherford, U.S. Patent 3,225,012 (1965); Chem. Abstr., 64 (1966) 11347f. (38) K. Kurita, K. Miyajima, T. Sannan, and Y. Iwakura, J. Polym. Sci., Polym. Chem. Ed., 18 (1980) 359–364. (39) K. Kurita, Y. Koyama, K. Murkami, N. Kato, and K. Katsuya, Kenkyu Hokoku-Asashi Garasu Kogyo Gijutsu Shoreikai, 52 (1988) 157–163; Chem. Abstr., 111 (1988) 25217z. (40) R. Appel, Angew. Chem. Int. Ed. Engl., 14 (1975) 801–811. (41) R. A. Khan, K. S. Mufti, and K. J. Parker, Brit. Pat. 1,431,559 (1976); Chem. Abstr., 85 (1976) 47008d. (42) M. Yoshinaga, Jpn. Kokai Tokkyo Koho, Jpn. Pat. 03,221,505; Chem. Abstr., 116 (1991) 8166t. (43) J. Thiem and F. Bachmann, Makromol. Chem., 194 (1993) 1035–1057. (44) J. Thiem and H. Lueders, Polym. Bull., 11 (1984) 365–369. (45) J. Thiem and H. Lueders, Makromol. Chem., 187 (1986) 2775–2785. (46) J. Thiem, W. A. Strietholt, and T. Haering, Makromol. Chem., 190 (1989) 1737–1753. (47) J. Thiem and F. Bachmann, Makromol. Chem., 192 (1991) 2163–2182. (48) J. Thiem and F. Bachmann, J. Polym. Sci. A, Polym. Chem., 30 (1992) 2059–2062. (49) S. Tokura, Y. Ikeuchi, S. Nishimura, and N. Nishi, Int. J. Biol. Macromol., 5 (1983) 249. (50) M. Bueno, J. A. Galbis, M. G. García-Martín, M. V. de Paz, F. Zamora, and S. MuñozGuerra, J. Polym. Sci. A, Polym. Chem., 33 (1995) 299–305. (51) M. G. García-Martín, M. V. de Paz-Bañez, and J. A. Galbis, Carbohydr. Res., 240 (1993) 301–305. (52) M. Bueno Martínez, F. Zamora Mata, M. T. Ugalde Donoso, and J. A. Galbis Pérez, Carbohydr. Res., 230 (1992) 191–195. (53) F. Zamora, M. Bueno, I. Molina, H. A. Orgueira, O. Varela, and J. A. Galbis, Tetrahedron Asym., 7 (1996) 1811–1818. (54) M. Bueno, F. Zamora, I. Molina, H. A. Orgueira, O. Varela, and J. A. Galbis, J. Polym. Sci. A: Polym. Chem., 35 (1997) 3645–3653. (55) H. A. Orgueira, M. Bueno, J. L. Funes, J. A. Galbis, and O. Varela, J. Polym. Sci. A, Polym. Chem., 36 (1998) 2741–2748. (56) I. Molina Pinilla, M. Bueno Martínez, and J. A. Galbis Pérez, Macromolecules, 28 (1995) 3766–3770. (57) I. Molina Pinilla, M. Bueno Martínez, F. Zamora Mata, and J. A. Galbis, J. Polym. Sci. A, Polym. Chem., 36 (1998) 67–77. (58) M. Bueno Martínez, I. Molina Pinilla, F. Zamora Mata, and J. A. Galbis Pérez, Macromolecules, 30 (1997) 3197–3203. (59) I. Molina Pinilla, M. Bueno Martínez, and J.A. Galbis, Carbohydr. Res., 302 (1997) 241–244. (60) N. Ogata, K. Sanui, and K. Iijima, J. Polym. Sci., Polym. Ed., 11 (1973) 1095–1115. (61) N. Ogata and S. Okamoto, J. Polym. Sci., Polym. Ed., 11 (1973) 2537–2545. (62) N. Ogata, K Sanui, T. Ohtake, and H. Nakamura, Polymer J., 11 (1979) 827–833. (63) N. Ogata, K. Sanui, Y. Hosoda, and H. Nakamura, J. Polym. Sci., Polym. Ed., 14 (1976) 783–792. (64) N. Ogata, K. Sanui, and Y. Kayama, J. Polym. Sci., Polym. Chem. Ed., 15 (1977) 1523–1526. (65) N. Ogata, K. Sanui, H. Nakamura, and H. Kishi, J. Polym. Sci., Polym. Chem. Ed., 18 (1980) 933–938. (66) P. D. Hoagland, Carbohydr. Res., 98 (1981) 203–208. (67) P. D. Hoagland, H. Pessen, and G. G. McDonald, J. Carbohydr. Chem., 6 (1987) 495–499. (68) E. M. E. Mansour, S. H. Kandil, H. H. A. M. Hassan, and M. A. E. Shaban, Eur. Polym. J., 26 (1990) 267–276.
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OSCAR VARELA AND HERNAN A. ORGUEIRA D. E. Kiely, L. H. Chen, and T. H. Lin, J. Am. Chem. Soc., 116 (1994) 571–578. L. Chen and D. E. Kiely, J. Carbohydr. Chem., 13 (1994) 585–601. D. E. Kiely and T. H. Lin, U. S. Pat. 4,833,230, 1989.; Chem. Abstr., 112 (1989) 8070. D. E. Kiely, L. Chen, and D. W. Morton, U.S. Pat. 5,434,233, 1995; Chem. Abstr., 123 (1995) 290272n. L. Chen and D. E. Kiely, J. Org. Chem., 61 (1996) 5847. D. E. Kiely, L. Chen, U.S. Pat. 5,329,044, 1994; Chem. Abstr., 122 (1994) 56785. K. Hashimoto, M. Okada, and N. Honjou, Makromol. Chem. Rapid. Commun., 11 (1990) 393–396. K. Hashimoto, S. Wibullucksanakul, M. Matsuura, and M. Okada, J. Polym. Sci. A, Polym. Chem., 31 (1993) 3141–3149. O. Varela and H. A. Ogueira, unpublished results. H. A. Orgueira and O. Varela, Tetrahedron Asym., 8 (1997) 1383–1389. Y. Minoura, S. Urayama, and Y. J. Noda, J. Polym. Sci., A-1, 5 (1967) 2441–2451. N. Ogata and Y. Hosoda, J. Polym. Sci, Polym. Chem. Ed., 13 (1975) 1793–1801. N. Ogata and Y. Hosoda, J. Polym. Sci., Polym. Lett. Ed., 14 (1976) 409–412. N. Ogata, K. Sanui, H. Nakamura, and M. Kuwahara, J. Polym. Sci., Polym. Chem. Ed., 18 (1980) 939–948. R. M. Katsarava, D. P. Kharadze, L. M. Avalishvili, and M. M. Zaalishvili, Makromol. Chem. Rapid Commun., 5 (1984) 585–591. A. Rodríguez-Galán, J. J. Bou, and S. Muñoz-Guerra, J. Polym. Sci. A, Polym. Chem., 30 (1992) 713–721. J. J. Bou, A. Rodríguez-Galán, and S. Muñoz-Guerra, Macromolecules, 26 (1993) 5664–5670. P. Ruiz-Donaire, J. J. Bou, S. Muñoz-Guerra, and A. Rodríguez-Galán, J. Appl. Polym. Sci., 58 (1995) 41–54. J. J. Bou, A. Rodríguez-Galán, and S. Muñoz-Guerra, Polymeric Materials Encyclopedia, Vol. 1 (A-B), J. C. Salomone (Ed.), CRC Press, New York, 1996, 561–569. J. J. Bou, I. Iribarren, and S. Muñoz-Guerra, Macromolecules, 29 (1996) 4397–4405. C. Regaño, A. Martínez de Ilarduya, I. Iribarren, A. Rodríguez-Galán, J. A. Galbis, and S. Muñoz-Guerra, Macromolecules, 29 (1996) 8404–8412. R. W. Lenz, Adv. Polym. Sci., 107 (1993) 1–40. A. Alla, A. Rodríguez-Galán, A. Martínez de Ilarduya, and S. Muñoz-Guerra, Polymer, 38 (1997) 4935–4944. I. Iribarren, C. Alemán, J. J. Bou, and S. Muñoz-Guerra, Macromolecules, 29 (1996) 4397–4405. I. Iribarren, C. Alemán, C. Regaño, A. Martínez de Ilarduya, J. J. Bou, and S. MuñozGuerra, Macromolecules, 29 (1996) 8413–8424. J. J. Bou, and S. Muñoz-Guerra, Polymer, 36 (1995) 181–186. J. J. Bou, I. Iribarren, A. Martínez de Ilarduya, and S. Muñoz-Guerra, personal communication. H. Yuki, Y. Okamoto, Y. Taketani, T. Tsubota, and Y. Marubayashi, J. Polym. Sci., Polym. Chem. Ed., 16 (1978) 2237–2251. J. Vives, A. Rodríguez Galán, S. Muñoz-Guerra, and H. Sekiguchi, Makromol. Chem., Rapid Commun., 10 (1989) 13–17. M. García Alvarez, A. Rodríguez Galán, and S. Muñoz-Guerra, Makromol. Chem., Rapid Commun., 13 (1992) 173–178. M. G. García Martín, M. V. de Paz, and J. A. Galbis, Macromol. Chem. Phys., 198 (1997) 219–227.
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
HYDRAZINE DERIVATIVES OF CARBOHYDRATES AND RELATED COMPOUNDS
BY HASSAN S. EL KHADEM AND ALEXANDER J. FATIADI* Department of Chemistry, The American University, Washington, DC. 20016, USA; and * Biotechnology Division, National Institute of Science and Technology, Gaithersburg, Maryland 20899, USA III. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Saccharide Azines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Saccharide Hydrazones and Glycosylhydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Formation of Saccharide Hydrazones and Glycosylhydrazines . . . . . . . . . . . . . 3. Structure of Saccharide Hydrazones and Glycosylhydrazines . . . . . . . . . . . . . . 4. Reactions of Saccharide Hydrazones and Glycosylhydrazines . . . . . . . . . . . . . . IV. Saccharide Osazones and Poly(hydrazones). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Formation of Osazones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Structure of Osazones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Reactions of Osazones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Saccharide Poly(hydrazones) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I V. Hydrazones of Carba-Sugars and Related Compounds. . . . . . . . . . . . . . . . . . . . . . 1. Importance of Carba-Sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Formation of Carba-Sugar Hydrazones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Structure of Carba-Sugar Hydrazones and Polyhydrazones . . . . . . . . . . . . . . . . 4. Reactions of Carba-Sugar Hydrazones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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I. INTRODUCTION1 Hydrazine (H2N-NH2), hydroxylamine (HO-NH2), and hydrogen peroxide (HO-OH) are highly reactive nucleophiles that add to carbonyl compounds to give N- and O-adducts, which are not usually isolated. The Nadducts of hydrazines and hydroxylamines readily undergo elimination to give condensation products of the type C苷N-NH-R and C苷N-O-R, whereas the O-adducts of hydroxylamine and of hydrogen peroxide do not do so because of valence considerations. Instead, the O-adducts of hydroxylamine remain in equilibium with the substrates and the O-adducts of peroxide adducts split up their weak O–O bonds to give oxidation products. 0096-5332/00 $30.00
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Hydrazines and hydrazones exhibit important biological activities; for example, arylhydrazines inhibit oxidases and redox systems such as hemoglobin,2 myoglobin,3 cytochrome P-450,4 and lactoperoxidase.5 The reaction seems to proceed via carbon-centered free radicals6,7 that lead to the formation of -aryliron(III) complexes,8–10 generated from diazenes11 and diazonium salts.12–14 Other hydrazines inhibit mitochondrial systems by acting as uncouplers of oxidative phosphorylation.15 Several hydrazones have been found to possess antiviral16 and antimicrobial activity.17–20 The hydrazine derivatives of saccharide are here discussed in sections on saccharide azines, which are formed when one hydrazine molecule reacts with two saccharide molecules; saccharide hydrazones and glycosylhydrazines, which are the tautomeric acyclic and cyclic products formed when one hydrazine molecule reacts with one sugar residue; saccharide osazones and poly(hydrazones), which are formed when two or more hydrazine molecules are linked to a saccharide residue; and, finaly, hydrazones of carbasugars and related compounds. II. SACCHARIDE AZINES Monosaccharides and reducing disaccharides react with unsubstituted hydrazine to give azines, such as 2, which on prolonged treatment with an excess of reagent yield hydrazones (3 see Scheme 1).21,22 Azines exist as equilibrated mixtures of tautomeric cyclic and acyclic forms, and on acetylation they yield acyclic acetates that possess ester, but no amide groups.22 Hydrazone azines (6) may be obtained by treating glycos-2-ulose Nmethyl-N-phenylhydrazone (4) with hydrazine and acetic acid or from mixed bis(arylhydrazone) (5) on treatment with acetic anhydride.23
SCHEME 1.
Formation of azines, hydrazones, and azine hydrazones.
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X-Ray crystallography has revealed that the N–N bonds of azines assume s-trans conformations and that phenyl rings, if present, are usually coplanar with the adjacent C苷N groups.24–26 However, bulky groups in the ortho position of phenyl rings may cause deviation from coplanarity. Thus the plane of the phenyl ring in (ZE)-o-nitroacetophenone azine was found by X-ray crystallography to deviate by some 38⬚ from coplanarity with the C苷N group.27 Photolysis of the azine of D-galactose regenerates D-galactose and yields some D-lyxose by chain degradation.28 III. SACCHARIDE HYDRAZONES AND GLYCOSYLHYDRAZINES29 1. General Aspects Originally, all condensation products formed by combination of one mole of hydrazine with one mole of a mono- or disaccharide were referred to as hydrazones, and when more than one form of the product was isolated, as in the case of D-glucose phenylhydrazone, the isomers were differentiated by the Greek letters 움, 웁, and so on. With the advent of modern methods of structure elucidation, and in particular of NMR spectroscopy and X-ray crystallography, more accurate structure determinations became possible. These revealed that hydrazones, like their parent saccharides, exist in acyclic and cyclic forms. The products that proved to be acyclic retained the name hydrazone (for example, D-galactose phenylhydrazone), whereas the cyclic isomers were designated as glycosylhydrazines [for example, 1-(웁-Dglucopyranosyl)-2-acetylhydrazine, depicted in Scheme 2 in the 4C1 conformation].30 Glycosylhydrazines may exist in pyranose or furanose forms and may possess 움- or 웁-configurations, although the equatorially substituted derivatives such as the 웁-D-hexopyranosyl-hydrazines depicted are usually favored. It must be emphasized that the term hydrazone is still used to designate products whose structures have not been fully established. For example, many of the arylhydrazones that have been used in the isolation and
SCHEME 2.
Acyclic hydrazones and cyclic glycosylhydrazines.
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characterization of mono- and disaccharides have never been subjected to rigorous structure elucidation, and yet they are refered to as hydrazones. It is to be expected that when the structure of all hydrazones have been determined, this ambiguity in terminology will vanish and only correct names will be used. Saccharide hydrazones have often been used to separate and characterize saccharides. Nowadays this is usually done by subjecting the free saccharides or their hydrazones to such chromatographic techniques as gas–liquid chromatography (GC), GC mass spectrometry (GCMS), and high-performance liquid chromatography (HPLC), which permit their separation identification, and estimation. In the last method, conversion of saccharide mixtures to hydrazones before analysis enables the use of ultraviolet (UV) detectors (which are much more sensitive than refractive-index ones).31–33 Similar conversions into hydrazones enable the separation of saccharide mixtures by electrophoresis (because, in buffered solutions, the electric charge on the nitrogen allows derivatives to migrate in electric fields).34,35 Nucleophilic addition of hydrazines to sugars is mostly used in the synthesis of cyclic and acyclic sugar derivatives and of amino and amido compounds,36–53 and ozonolysis has been used in the preparation of aldehydo sugars from hydrazones.54 Although the hydrazones of organic aldehydes have been studied more extensively than their saccharide counterparts, the use of Cu(II) salts to hydrolyze hydrazones and hydrazides efficiently (by decomposing the generated hydrazine to benzene, water, and nitrogen) was first introduced by carbohydrate chemists55 and used much later in terpene chemistry.56 The following organic reactions have rarely been performed on saccharide substrates and ought to receive more attention by carbohydrate chemists: (a) carbonyl-group reactions,57–59 such as in the Fischer indole synthesis,60 and other means of converting carbonyl compounds into hydrocarbons61 as well as the synthesis of 1,2,4-triazoles;62 (b) the conversion of 1,2-disubstituted hydrazines and hydrazones into the corresponding diazenes and diazonium compounds by two-electron oxidations;63 (c) hydrazines and hydrazones have been metallated and used in synthesis to make use of their reactivity, resistance to proton transfers, and propensity to alkylate exclusively on carbon64 (the complex with gold has been studied in detail65 and that with Ru3(CO)12 was found to cause fixation of the N–N unit and to bridge the ligand to the metal framework);66,67 (d) tosylhydrazones react with alkyllithiums to form anionic adducts,68 which decompose by sigmatropic rearrangement of allylic diazene intermediates to afford alkenes69–70 (similar sigmatropic rearrangements have been invoked in the reduction and elimination71 of tosylhydrazones as well as in the oxidation of alkylhydrazines);72 (e) the stereoselective synthesis of alkenes from sily-
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lated sulfonylhydrazones has been studied,73–75 and charge-transfer complexes of hydrazones have been examined by UV and infrared (IR) spectroscopy and by X-ray crystallography;76 and (f ) the photochromic properties of phenylhydrazones have been studied by laser flash spectroscopy,77 and 13C NMR spectroscopy has been used to study electron distribution in hydrazones, phenylhydrazones, oximes, and oxime ethers.78 Key papers and review articles detailing these reactions are presented here in the hope that some of the reactions mentioned might be applied to saccharide hydrazones and more spectroscopic studies would be directed toward carbohydrate derivatives. 2. Formation of Saccharide Hydrazones and Glycosylhydrazines Kinetic studies79,80 have clarified the mechanism of formation of phenylhydrazones of aromatic aldehydes. It was found that, during the formation of benzaldehyde phenylhydrazone,79 attack of the nucleophile is the ratedetermining step under slightly acidic conditions, whereas dehydration of the carbinolamine intermediate is the rate-determining step under neutral and basic conditions. Saccharide hydrazones are prepared by treating aldoses, ketoses, aldosuloses, or reducing disaccharides with unsubstituted hydrazine;81,82 with monosubstituted hydrazines having alkyl,81 acyl,30,83,84 aroyl,85 sulfonyl,36,39,40,86–88 aryl,89–93 or disubstituted N,N-dialkyl-,81 N,N-diaryl-,94 or N-alkyl-N-arylhydrazines39,40,43,95–99 or heterocyclic hydrazines;93,100–108 or with semicarbazide83 and thiosemicarbazide.109 Arylhydrazines have been extensively used for the characterization and identification of saccharides. In contrast, alkylhydrazines have been seldom used because the alkylhydrazones formed are difficult to crystallize and possess unfavorable equilibrium constants for their formation. Unsubstituted saccharide hydrazones are prepared by prolonged heating of sugars with an excess of hydrazine; the excess is needed to obviate the formation of azines.81,82 Substituted hydrazones are prepared by heating equimolar amounts of saccharide and substituted hydrazines in the freebase form36,39,40,42 or by treating cold, aqueous solutions of a sugar with a weakly acidic solution of hydrazine acetate. Aldosulose monohydrazones are prepared either by treating aldosuloses with one mole of hydrazine110 or by removing one hydrazone residue from osazones with nitrous acid111 or copper(II) sulfate (see Scheme 3).112 Both reactions must be performed under mild conditions to prevent formation of the bis(hydrazone) in the first case and the aldosulose in the second. Hydrazones are formed most rapidly in media that are slightly acidic (pH 4 to 5) in order to protonate the substrate. Kinetically, the reaction is
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SCHEME 3. Formation of aldosulose monohydrazones from aldosuloses and from osazones.
pseudounimolecular113,114 when acetate ions are present. Since saccharides exist in solution as equilibrium mixtures of various cyclic and acyclic forms, nucleophilic addition to the carbonyl groups of the acyclic form and nucleophilic substitution of the cyclic forms (움- or 웁-furanoses or 움- or 웁pyranoses) or on the hydrate of the acyclic form can occur concurrently, but the nucleophilic addition is usually faster. For example, it was found that the rate of nucleophilic addition to aldehydo-D-galactose pentaacetate is much higher than that of nucleophilic substitution of the two isomeric cyclic tetraacetates of D-galactose.113,114 This is why the preponderance of cyclic forms can only partly compensate for the rapidity of the nucleophilic addition reaction. Both reactions seem to be initiated by protonation. Protonation of the carbonyl group of the acyclic form of a saccharide (15), followed by nucleophilic addition of phenylhydrazine, results in the formation of a 1phenylhydrazine-1-ol (16), which, upon elimination, affords a protonated hydrazone (not shown) and then an acyclic hydrazone (17). The nucleophilic substitution reaction is also initiated by protonation of the anomeric hydroxyl group of the saccharide 12, which facilitates elimination of water and formation of a carbocation (13 in Scheme 4). The latter, when attacked by a substituted hydrazine, affords a cyclic hydrazone (14) having the same ring size as the starting cyclic sugar. It should be emphasized that, in solution, the acyclic hydrazones and all of the glycosylhydrazines, having various ring sizes, anomeric configurations, and different conformations, exist in equilibrium. They are interconvertible with one another and with the acyclic form by reactions quite similar to those of anomerization of free saccharides. It is not surprising therefore to find that the nature of the preponderant form of a hydrazone in solution and the structure of the solid isolated from this mixture is not determined by the mechanism of formation, but by the relative stability of the isomers. For example it is now known that D-glucose hydrazone is
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SCHEME 4.
181
Formation of phenylhydrazones from cyclic and acyclic saccharides.
formed initially when D-glucose is treated with aqueous hydrazine at room temperature and it then gradually cyclizes to afford predominantly 웁-Dglucopyranosylhydrazine30 (like the one depicted in Scheme 2). 3. Structure of Saccharide Hydrazones and Glycosylhydrazines Although saccharide hydrazones exist in solution as equilibrium mixtures of several forms, the crystalline hydrazones isolated from solution are usually composed of only one form, which is often the most stable one in the medium. It is to be expected that substituted hydrazines would afford two types of products, one formed by nucleophilic attack of N-1 and one by N-2. This expectation was confirmed when phenylazostyrene (18) was treated with phenylhydrazine (19) at low temperature and the ratecontrolled N-1 adduct (21) was isolated from the reaction mixture and converted into benzil bis(phenylhydrazone) (20) by heating. It may be assumed that the reaction proceeds by the conversion of the rate-controlled N-1 adduct to the equilibrium-controlled N-2 adduct (not depicted), followed by an oxidation step (Scheme 5).115,116 The hydrazones of sugars are capable of existing in various cyclic forms, whose presence is apparent from their nuclear magnetic resonance (NMR) spectra and from the complex mutarotation curves they exhibit110,111,117,118 (which seldom follow first-order kinetics). The principal structures encountered in saccharide hydrazones are the acyclic, Schiff base-type true hydrazones and the cyclic hydrazino forms, namely glycopyranosyl- and glycofuranosylhydrazines. For example, three isomeric forms of D-glucose phenylhydrazone have been isolated.119 The Schiff base derivatives can be
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SCHEME 5.
Formation of the rate-controlled adduct of a phenylhydazone.
recognized by polarographic120 and spectrophotometric (ultraviolet and infrared) analysis121–123 as well as by X-ray crystallography.124–126 Proton magnetic resonance can also distinguish between (cyclic) glycopyranosyl hydrazines and acyclic saccharide hydrazones.127–130 However, in the case of arylhydrazones, the IR spectra are difficult to interpret because the C⫽N absorption band at 1620 cm-1 may be masked by the phenyl ring absorptions.59,130,131 Similar difficulties may be encountered with NMR spectra, where some signals may be buried under aromatic multiplets.82 Despite these difficulties it was possible to show by 1H and 13C NMR spectroscopy that the conformation of arylhydrazones is syn129,132 and by X-ray crystallography that the product obtained by reacting D-glucose or L-arabinose with p-bromophenylhydrazine possesses a cyclic structure; both are glycopyranosyl-p-bromophenylhydrazines.124–126 A chemical method for establishing the cyclic or acyclic structure of hydrazones depends on their reaction with benzenediazonium chloride. Acyclic phenylhydrazones generally form crystalline diphenylformazans (see Scheme 17), whereas no well-defined product is obtained from the cyclic isomers.133 For example, the so called “웁-form” of D-glucose phenylhydrazone yields a crystalline diphenylformazan, whereas its two cyclic isomers do not. This reaction can be used to estimate the proportions of acyclic forms during mutarotation.133 Chemical evidence for the open-chain structure of D-galactose hydrazones was first provided by the reaction of N-methyl-N-phenylhydrazine with 2,3,4,6-tetra-O-acetyl-D-galactopyranose (22); 2,3,5,6-tetra-O-acetylD-galactofuranose (24); and penta-O-acetyl-aldehydo-D-galactose (27). The hydrazones (23 and 25) formed from 22 and 24 could be converted by acetylation into the same penta-O-acetyl-D-galactose N-methyl-N-phenyl-
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SCHEME 6. Formation of the same hydrazone from tetra-O-acetyl-웁-D-galactopyranose, tetra-O-acetyl-웁-D-galactofuranose and penta-O-acetyl-aldehydo-D-galactose.
hydrazone (26) obtained from 27, and so it was concluded that hydrazones 23 and 25 have open-chain structures (see Scheme 6).114 Acetylation of acyclic hexose arylhydrazones yields tetra-O-acetyl derivatives, whereas cyclic structures may afford derivatives acetylated on both nitrogen and oxygen.134 Benzoylation of acyclic hydrazones yields N- and O-benzoylated derivatives. The structures of several hydrazones and semicarbazones have been determined by studying the IR spectra of their acetates.135–142 The Schiff base structure of D-glucose semicarbazone was further confirmed when the same penta-O-acetyl derivative (29) was obtained by acetylating 28 and by treating penta-O-acetyl-aldehydo-D-glucose (30) with semicarbazide (Scheme 7). Aldosuloses react with substituted hydrazines to give mono- and bishydrazones. It is possible to remove one hydrazone residue from the latter to obtain aldosulose monohydrazones having the hydrazone residues attached to C-1. The position of substitution was established when D-arabinohexosulose mono-(N-methyl-N-phenyl)hydrazone (31) was converted into D-mannose N-methyl-N-phenylhydrazone (32) on catalytic hydrogenation (Scheme 8).143 The sign of optical rotation or of the Cotton effect is affected most strongly by the chiral center nearest to the chromophore. It is not surprising
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SCHEME 7. Formation of the same penta-O-acetyl semicarbazone from D-glucose, semicarbazone, and penta-O-acetyl-aldehydo-D-glucose
therefore that several rules have been formulated that correlate the configuration of the C-2 hydroxyl group of acyclic aldose hydrazones with their sign of rotation. Thus the “Benzyl Rule” states that if, in the Fischer projection formula, the C-2 hydroxyl group is to the right, the corresponding Nbenzyl-N-phenylhydrazone is levorotatory; if the group is to the left, the derivative is dextrorotatory.144–147 The circular dichroism (CD) and optical rotatory dispersion (ORD) spectra of benzoylhydrazones were also related in a similar manner to their configurations.148 Saccharide hydrazones can exist in several tautomeric forms, which include the phenylazo and enehydrazine forms. The glycosylhydrazines can exist in the furanose and pyranose forms and may possess 움- or 웁-configurations, although usually the equatorially substituted D-hexopyranosylhydrazines are favored.149 Most of these cyclic forms have not been isolated, but their amounts can be calculated from their NMR spectra and their mutarotation curves.150,151 4. Reactions of Saccharide Hydrazones and Glycosylhydrazines Because of the similarity between the C⫽O group of acyclic monosaccharides and the C⫽N group of their hydrazones, the latter exhibit many of the reactions of their parent saccharides; for example, they are susceptible
SCHEME 8. Formation of D-mannose N-methyl-Nphenylhydrazone by hydrogenating D-arabino-hexosulose mono-(N-methyl-N-phenyl)hydrazone.
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to nucleophilic attack and to the action of oxidizing and reducing agents. However, they behave differently in basic media; reducing saccharides undergo rapid epimerization, whereas saccharide hydrazones epimerize much more slowly. Furthermore, reducing saccharides undergo degradative oxidation in the presence of oxygen and base to give lower aldonic acids, whereas hydrazones do not undergo such oxidative degradation. These differences have been attributed to the ability of free saccharides to enolize in basic media and to the resistance of hydrazones to do so, as detailed next. a. Action of Alkalies.—It has already been noted that, in contrast to aldoses, ketoses, and reducing disaccharides, which undergo epimerization in dilute alkaline solutions and are degradatively oxidized in the presence of oxygen, saccharide phenylhydrazones do not epimerize and are not appreciably degraded during oxidation. The reason for the difference is the lower acidity of the 움-hydrogen of saccharide hydrazones, relative to the imino proton. This is because the hydrazone anion, formed by ionization of the imino group, is more stable, that is, it is stabilized by more resonance forms (33, 34, and 35) than is the ene-hydrazine anion, formed by abstraction of the 움-hydrogen (forms 36 and 37). In addition, the partial negative charge on the hydrazone carbon facilitates elimination of a leaving group (not a proton) from the adjacent carbon atom. The preferential ionization of the NH protons of phenylhydrazones suppresses enolization and slows epimerization and degradative oxidation of aldose phenylhydrazones.152–154 The fact that phenylhydrazones do not enolize in basic media does not preclude their enolization in acidic media. The acidcatalyzed enolization of hydrazones is initiated by protonation of the imino nitrogen of a hydrazone (38), followed by elimination of the 움-proton with water to give intermediate 39. Shifts of electrons then form a C苷C double bond and neutralize the charge on the nitrogen to give 40 (see Scheme 9). The ability of hydrazones to enolize in acid media explains why osazone formation (which requires enolization at one stage) occurs in acidic but not in basic media. The inability of aldose phenylhydrazones to enolize in basic media also explains why their acetates, which possess good leaving groups attached to C-2, undergo elimination in basic media to give azoalkenes (instead of eliminating a proton), and why the oxidation of aldose phenylhydrazones does not result in degradation, but leads instead to Nphenyl-N-aldonohydrazono-1,4-lactones,152–154 as is shown later. Literature surveys reveal several studies47,130,152–157 on the action of strong bases on sugar phenylhydrazones. These includes the isomerization of phenylhydrazones in akali to give alkyl phenyldiimides,158 the effect of alkali metals on nitrogen–nitrogen bond breaking in arylhydrazones,159 and the thermolysis of arylhydrazones in the presence of alkaline agents.160,161
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SCHEME 9. The resonance hybridization of an ionized NH group (upper) and an Ionized 움-CH group (lower) in hydrazones.
Generally, alkali causes homolytic fission of the saccharide chain adjacent to the hydrazone moiety to form two radicals (initiation). This is followed by combination of a radical (43) with another hydrazone molecule to form glyoxal bis(phenylhydrazone) (44) and a new radical (propagation).162–169 Another product of this free-radical reaction is 1-phenylpyrazole (41), formed by aromatization of a phenylhydrazone residue and a three-carbon sugar moiety (Scheme 10).165
SCHEME 10.
Homolysis of phenylhydrazones in alkali.
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Early studies in the sugar series reveal that glyoxal bis(benzoylhydrazone) is a major product when, for example, D-glucose is treated with benzoylhydrazine in aqueous alkali.161 Hydrogen–tritium exchange experiments reveal that, in alkaline medium, hydrazones undergo a series of rapid tautomerizations which may lead to degradation products.162–164 Experiments with D-[2-14C]glucose benzoylhydrazone show that, in forming glyoxal bis(benzoylhydrazone), a labeled entity derived from C-1 and C-2 competes with glycolaldehyde fragments (derived from the nonlabeled atoms C-3 and C-6) for reaction with the benzoylhydrazone group.170 This would suggest that fragmentation is achieved by a reversed aldol mechanism.170–172 b. Free-Radical Oxidation Reactions.—The autoxidation of aromatic phenylhydrazones at room temperature to produce phenylazohydroperoxides is well documented.173–175 It is also known176,177 that oxidative degradation of free sugars with oxygen in alkaline solution is a free-radical process and that anion radicals of the semiquinone type are formed during alkaline, oxidative degradation of saccharides, polysaccharides, and wood (ESR studies).178,179 Advances in free-radical chemistry make it possible to generate and to trap short-lived radicals,180 including free radicals of the anomeric carbon atom (whose behavior is influenced by stereoelectronic effects).181,182 Electron-transfer pathways that involve rearrangements by free radicals183,184 or radical ions185 can be inferred from the structure of rearranged products. Of the methods available for the detection of free radicals, spin trapping offers the opportunity to measure simultaneously and distinguish among a variety of important, biologically generated free radicals.186,187 A review on spin-labeled carbohydrates, including mono-, di-, and polysaccharides, glycoproteins, and nucleosides, has appeared.188 (i) Formation of Hydrazono Lactones.—It is known that aldehyde phenylhydrazones undergo oxidation by free-radical mechanisms when brought in contact with oxygen or air and are converted into phenylazohydroperoxides.173,175,189–191 The same reaction in basic media probably starts with ionization followed by removal of an electron by a radical (initiation) to give a resonance-stabilized radical. Reaction with oxygen affords a peroxide radical, which is needed for propagation. The latter is converted into a peroxy anion, which on protonation gives a phenylazohydroperoxide. Hydrazono-1,4-lactones have been isolated153,154 when solutions of aldose phenylhydrazones in aqueous ethanol containing potassium hydroxide were kept at room temperature in contact with air (bubbling air or oxygen into such solutions may lead to spontaneous explosion of
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peroxides). A plausible mechanism for this free-radical peroxidation starts with an attack by oxygen on C-1 of a phenylhydrazone (45) to give a hydroperoxide (not shown), which rearranges to a phenylazo-hydroperoxide form (46), which is tautomeric with the phenylhydrazono-hydroperoxide form (47). The latter then undergoes nucleophilic attack by O-4 and elimination of a hydroperoxide ion to give the isolated N-phenyl-aldonohydrazono-1,4-lactone (48). The electron-spin resonance (ESR) evidence reported in the literature192 and the explosive nature of the intermediates observed in this work suggest that a significant part of the peroxidation proceeds via a free-radical mechanism (Scheme 11).146,147 (ii) Formation of Oxadiazoles.—Saccharide benzoylhydrazones, semicarbazones, and thiosemicarbazones undergo free-radical oxidations, similar to the one just described, with iodine193 or Fe3+ to give 3acetoxyalkyl-5-aryl-oxadiazoles and thiadiazoles.194–199 The same compounds can be obtained from aldonic acids or aldonic acid chlorides. For example, D-galactose benzoylhydrazone pentaacetate (49) affords, on treatment with iodine, an acyclic 1,3,4-oxadiazole (50).193 This product, upon deacetylation, yields a cyclic hydrazono-lactone (52), which is an analog of compound 48. Analogous hydroximo- and hydrazino-1,5-lactones were obtained by Vasella and coworkers by oxidation of sugar oximes, sulfonylhydrazones and phenylsemicarbazones.200 These authors were able to convert the first compounds into diazirines, and then, by heating or irradiation, to carbenes, which were successfully used as intermediate in glycosidation reactions. Reviews of this last work have appeared.201 The electro-chemical oxidation of N-acylhydrazones to give oxadiazolines and oxadiazoles has been described202 and reviewed.203,204 Oxadiazolines have also been obtained by acetylation of aroylhydrazones (Scheme 12).205 c. Elimination Reactions (Formation of Azoalkenes).—One result of the relative acidity of the imino protons of hydrazones is the facile elimination of leaving groups (such as acetate esters located on C-2, which are
SCHEME 11. Formation of N-phenyl-aldonohydrazono-1,4-lactones by the action of air on phenylhydrazone in dilute alkali.
D-galactose
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SCHEME 12. drazones.
189
Formation of oxadiazoles and hydrazono lactones by oxidation of benzoylhy-
eliminated as acetic acid). Thus, the penta-O-acetyl derivatives of Dgalactose and D-mannose arylhydrazones (53), when warmed with pyridine, undergo elimination to give azoalkenes, for example, 3,4,5,6-tetraacetoxy-1phenylazo-trans-1-hexene (55). The structure of this and similar compounds has been confirmed by NMR spectroscopy.164,206–208 The reaction was explained by Wolfrom and Blair in terms of an ionic mechanism which starts with the ionization of the imino proton of a hydrazone acetate (53) in bases to give a resonance-stabilized anion (54). This anion readily undergoes elimination of the leaving group (OAc) to afford the azoethylene derivative 55. A free-radical mechanism was later proposed157 which starts with the formation of anion 54 in base. Initiation of the free-radical reaction is achieved with oxygen to generate a resonance-stabilized radical anion (forms 56 and 57) (deprotonation of hydrazobenzene by molecular oxygen in alkaline solution proceeds via a dianion which also loses an electron to oxygen).209–211 Reaction of oxygen with the resonance form 57, having the radical on C-1,212,213 affords a peroxide radical (not shown)29,173–175 that is needed for propagation and to produce a peroxide anion (58) by addition of an electron. The peroxy anion attacks the carbonyl group of the acetate on C-2 to form a six-membered ring (59). Finally, fission by electron shifts affords the observed product 60 (Scheme 13). The reaction of phenylhydrazine with phenylazoalkenes at low temperature yields labile 1-phenylhydrazino-phenylhydrazones, which are converted at higher temperature to the thermodynamically more stable (2phenylhydrazino)-phenylhydrazones.115 In the saccharide series, treatment of 3,4,5,6-tetraacetyl-1-phenylazo-trans-1-hexenes (61) with phenylhydrazine was shown to yield the free osazones (63), denoting that oxidation of the addition product (62) must have occured during the reaction. It should be noted that the ester groups are eliminated by transamidation to form acetic phenylhydrazide.152,214 Several azoalkenes and azoalkene intermediates have been subjected to conjugate nucleophilic additions (Scheme 14).215–217
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SCHEME 13.
Formation of azoalkenes by ionic and free-radical mechanisms.
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SCHEME 14.
191
Nucleophilic addition of phenylhydrazine to azoalkenes.
d. Derivatives of Saccharide Hydrazones and Glycosylhydrazines.— Acetylation of saccharide hydrazones (65) with acetic anhydride in pyridine affords per-O-acetylated derivatives (such as 66) with acyclic hydrazones and N-acetyl-O-acetyl derivatives with the cyclic ones.85,114, 134,165 In the last case, the NH group attached to the aryl moiety is not acetylated, but the more basic NH group attached to the sugar moiety is acetylated. The O-acetyl groups are split off by base more readily than the N-acetyl groups,218 and methods for selective saponification have been devised. With acetyl chloride in N,N-dimethylaniline, the NH group attached to the aryl residue becomes acylated and acyclic hexose hydrazones give N-acetyl-penta-O-acetyl derivatives (64);165 similarly, benzoylation with benzoyl chloride in pyridine affords N-benzoyl-Obenzoyl derivatives (Scheme 15).219 e. Electrophilic Substitution—(i) Formation of Bromino and Dibromo Derivatives.—Arylhydrazones having electron-attracting groups such as pnitro that deactivate the aromatic ring may undergo electrophilic substitution on the hydrazone residues by an SE2⬘ mechanism.213,214 The products are tautomeric (azo-hydrazono) pairs of monobromo derivatives, such as 68 and 69. With an excess of bromine a gem dibromo phenylazo derivative (72) having the E configuration is isolated (Scheme 16).220–222 (ii) Formation of Formazans.223—Aldose phenylhydrazones undergo electrophilic substitution with aryldiazonium salts to give brilliant red,
SCHEME 15.
Acetylation and benzoylation of hydrazones.
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SCHEME 16.
Bromination of hydrazones.
crystalline formazan derivatives.98,134 Two structural features are required to form formazans: the presence of an aldehyde arylhydrazone (a Schiff base type of structure) and the presence of a free methine hydrogen atom on the arylhydrazone group. In consequence, aldose phenylhydrazones in the cyclic hemiacetal forms, ketose phenylhydrazones, and N,Ndisubstituted hydrazones fail to yield formazans. Formazans are known to have a chelated structure which permits the equilibration of monosubstituted isomers.224–227 For example, the tautomeric pair structure of N-phenyl-N⬘-p-bromophenylformazan (74 and 76) can be formed from either the p-bromophenylhydrazone 73 and a benzenediazonium salt or from a phenylhydrazone (75) and a p-bromobenzenediazonium salt.228 The neutral D-mannose diphenylformazan229 molecule has a chelate structure in which the imino proton spans the phenylhydrazono and the phenylazo groups (Scheme 17).230 Treatment of a formazan such as 77 with a strong acid, such as perchloric acid, results in a color change from orange-red to purple-blue. Apparently, the strong acid ruptures the chelate ring and forms a resonance-stabilized cation. Delocalization of the positive charges over the resonance system (78a and 78b) may account for the bathochromic shift observed in the spectrum of on protonation.230 Saccharide formazan acetates, upon deacetylation, undergo some epimerization (Scheme 18).231
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SCHEME 17.
SCHEME 18.
Formation of formazans.
Protonation of formazans.
193
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Circular dichroism studies of saccharide formazans and their acetates were used to establish the configuration at the C-2 atom and the conformation of the sugar chain.232 Formazans react with salts of heavy metals to give stable complexes;233 and they are also oxidized by N-bromosuccinimide or (after acetylation) by lead tetraacetate to yield tetrazolium salts.234–236 Reduction of the latter give back the formazans. Reductive decomposition of sugar formazans (79) with hydrogen sulfide leads to aldothionic acid phenylhydrazides (82).237–240 Treatment of these with benzaldehyde in the presence of hydrochloric acid yields sugar thiadiazolines (83) (Scheme 19).237 Because of their sharp melting points, sugar formazans can be used to identify aldoses233 (ketoses do not give formazans) and to purify them after conversion to the thioaldonic phenylhydrazides.241,242 Fluoroboric acid in acetic anhydride transforms penta-O-acetyl-D-galactose diphenylformazan into mono-N-acetyl-penta-O-acetyl-D-galactose diphenylformazan, which, on saponification, yields 2,6-anhydro-D-galactose diphenylformazan.231 f. Cycloaddition.—Aldose aryl and alkylhydrazones react with acetylenic compounds to give pyrazole derivatives.243–246 If the reaction is
SCHEME 19.
Action of hydrogen sulfide on formazans.
HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
195
carried out with 2,5-anhydropentose 1-bromo-arylhydrazones (84), it affords C-nucleoside analogs, such as 86 (Scheme 20).247,248 g. Reduction.—In theory, reduction of hydrazones should yield hydrazino derivatives and then, under more vigorous conditions, the corresponding aminodeoxy derivatives. However, most aldose hydrazones afford the aminodeoxy derivatives directly. For example, reduction of hydrazone 87 yields the 1-amino-1-deoxyalditol (88).249 The hydrazino derivatives of carbohydrates can be obtained by nucleophilic substitution, for example, by hydrazinolysis of sulfonic esters of monosaccharides,250 oligosaccharides,251 and polysaccharides.252,253 The following two examples illustrate the use of hydrazone reductions in the preparation of amines. (a) Formation of 5-amino-5-deoxy-D-ribofuranose, a so-called “aza-sugar,” so named because its furanose ring exists in equilibrium with the more stable six-membered azacyclohexane ring. This group of amino and imino sugars has attracted considerable attention because many examples exhibit interesting biologically properties; some act as enzyme inhibitors,254–256 such as glycosidase inhibitors,257 others have potential antidiabetic properties,258 and a few show anticancer259 or anti-HIV activity.260 As noted, 5-amino-5-deoxy-D-ribofuranose (93) is in equilibrium with its six-membered isomer 94. Its synthesis starts with the periodate oxidation of 1,2-O-isopropylidene-D-allofuranose (89) to form aldehyde 90, which is converted into a phenylhydrazone 91 and reduced to 92 and then deblocked to give a mixture of the desired 5-amino-5-deoxy-D-ribofuranose (93) and the 움- and 웁-anomers of 5-amino-5-deoxy-D-ribopyranose (94).255 The other example (b) involves stereoselective amination of the monohydrazone (96) of glyoxal. This synthon is converted into a chiral aminal (97)
SCHEME 20.
Cycloaddition to hydrazones.
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SCHEME 30.
Conversion of squaric acid bis(phenylhydrazone) to a dianilide.
SCHEME 31.
Fischer structure of D-arabino-hexulose phenylosazone.
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FIG. 1. Electron-density projection in the direction of the b axis of D-erythro-pentulose pbromophenylosazone. Note that C-1 is linked two bulky atoms only (C and N).
tris(phenylhydrazones). For example, squaric acid (163), upon treatment with phenylhydrazine, yields a tris(phenylhydrazone), which exists preponderantly in the azoenehydrazine form (165) rather than in the tautomeric tris(hydrazone) form (164) (Scheme 34).314 b. Chelated Structures of Osazones.—Fieser and Fieser315 predicted, on theoretical grounds, that sugar arylosazones exist as equilibrium mixtures of four tautomeric forms (166–169). However, only one pair of tautomers could be detected, namely the chelated pair (166 and 167), which is clearly evident by X-ray crystallography (see Fig. 1).307,308,313 It is probable that the other pair (168 and 169) is not formed because its members would be
SCHEME 32. osazone.
Periodate oxidation and acetylation products of a hexulose
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SCHEME 33.
Tautomeric forms of osazones.
destabilized by the close proximity of the bulky saccharide residue and the anilino group (Scheme 35). It should be noted that the members of the chelated pair have never been separated in the case of saccharide osazones, but this has been achieved with noncarbohydrate bis(phenylhydrazones). In at least one case they were found to be interconvertible, either by irradiation with light (photochromism) or by treatment with acids or bases (see Fig. 2).316 Further evidence for the chelated structure of osazones was obtained by physical methods,317 such as polarography318 and ultraviolet317,319–327 and 1 H NMR307–312,326 spectroscopy, which clearly showed that the two NH groups (attached to C-1 and C-2) were not in identical environments. Similarly 15N NMR spectroscopy revealed significant differences in the chemical shifts of the two H-coupled nitrogen atoms, attributable to chelation.328,329 The presence of stable chelated rings in osazones is also evident from the slowing down, and sometime inhibition, of certain reactions. Thus, the formazan reaction223 requires potassium hydroxide to break the chelated ring of osazones and to effect coupling with the diazonium ion.319,320 Similarly, the formation of polyhydrazones is inhibited by chelation accross the C-1
SCHEME 34.
Tautomeric structures of squaric acid tris(phenylhydrazone).
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SCHEME 35. Two pairs of tautomeric chelated osazones are possible, but only the top pair is formed.
and C-2 hydrazone residues. This is the reason why N,N-disubstituted hydrazines, which lack the imino protons necessary for cheation, afford trisand tetrakis-arylhydrazones, whereas monosubstituted arylhydrazines which can form osazones with a chelated ring do not yield such polyhydrazones. c. Mutarotation of Osazones.—It is agreed that during mutarotation, the initial form of the saccharide osazone is the chelated pair of tautomeric bis(phenylhydrazones) (170) and their tautomers. However, different structures have been suggested for the final form(s).324–336 These include unchelated azoenehydrazine forms and C-3 chelated forms (171).325,337–342 The following observations regarding mutarotation of osazones have been made: (a) osazones mutarotate in basic solvents by a first-order process, differing in this respect from phenylhydrazones (see Section III.3); (b) base-catalyzed mutarotation is shown by sugar osazones having a chelated structure and not by bis N-alkyl-N-phenyl bis(hydrazones), which lack chelated ring structures; (c) mutarotation is accompanied by a hypsochromic shift in the ultraviolet absorption maximum; (d) mutarotation is reversible, and the product recovered from solution at equilibrium is identical to the starting osazone; and (f ) the NMR spectra of osazones undergoing mutarotation exhibit325 changes expected by the conversion of N-chelated structures such as 170 to O-chelated structures such as 171. Rules have been fomulated to corrolate the configuration at C-3 with the sign of optical rotation311 and the sign of the Cotton effect at 250–270 nm (Scheme 36).325,326
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FIG. 2. Ultraviolet absorption spectra of two tautomeric bis(phenylhydrazones), taken at different intervals to show their interconversion.
3. Reactions of Osazones a. Nucleophilic Substitution (Hydrolysis and Transhydrazonation).— Fischer110 was the first to report that sugar osazones (172) are hydrolyzed by the action of hydrochloric acid. This hydrolysis is an example of
SCHEME 36. The starting and ending chelated structures of osazones in basic media.
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nucleophilic substitution; it is initiated by protonation of the hydrazone, followed by attack of a molecule of water to give an adduct. The latter loses phenylhydrazine to give first the corresponding aldos-2-ulose 1phenylhydrazone (173) and then the aldos-2-ulose (originally termed a glycosone) (174). The bis(hydrazone) residues may also be removed by transhydrazonation with an aldehyde such as benzaldehyde343,344 or a keto acid such as pyruvic acid.345 In addition, the groups may also be removed completely or partially by the oxidative action of nitrous acid346 or Cu2+ salts,112 which decompose the hydrazine generated and afford, first, aldos-2-ulose 1-phenylhydrazones (173) and then aldosuloses (174) (Scheme 37). Aldos-2-ulose 1-phenylhydrazones react with differently substituted hydrazines to yield mixed arylosazones.347–352 In addition, they react with ophenylenediamine to give quinoxalines (as seen in Scheme 29).347,352 It seems that the phenylhydrazone residue undergoes nucleophilic substitution with o-phenylenediamine, either directly or after hydrolysis to the aldosulose, to give a quinoxaline lacking a hydrazone residue. If the hydrazone residue is stabilized by chelation, as in the case of compound 175, the reaction proceeds with retention of the hydrazone residue in the quinoxaline formed (176) (Scheme 38).314 b. Electrophilic Substitution.—D-arabino-Hexulose phenylosazone (177) reacts with diazotized aniline to give a formazan (178). The same compound is obtained by treating D-arabino-hexosulose 1-phenylhydrazone formazan (179) with phenylhydrazine (Scheme 39).319,347,350 Because of the chelated structure of sugar osazones, the osazone formazan 181, obtained by coupling diazotized [14C]aniline to a saccharide phenylosazone (180) loses 42% of the label (as aniline) upon conversion to an osotriazole (182), whereas the formazan of an unchelated osazone, such as pyruvaldehyde osazone loses exactly half of the radioactivity as aniline during osotriazole formation (Scheme 40).168 c. Action of Bases (Formation of Free Radicals and Degradation).— Treatment of a solution of glyoxal bis(phenylhydrazone) with base causes
SCHEME 37.
Stepwise hydrolysis of bis(phenylhydrazones).
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SCHEME 38.
Formation of a quinoxaline with retention of the hydrazone residue.
SCHEME 39.
SCHEME 40.
Formation of formazans.
Reaction of formazans.
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ionization of the imino proton and produces a deep-purple color.29 The presence of oxygen causes such solutions to become paramagnetic353 because of the formation of resonance-stabilized anionic free radicals. The dianionic character of these radicals was shown by their conversion into N,N-dimethyl and N,N-dibenzoyl derivatives with dimethyl sulfate and with benzoyl chloride. The resolution of the ESR spectrum of glyoxal bis(phenylhydrazone) is greatly enhanced when certain positions of the benzene rings are substituted. For example, the spectrum of glyoxal bis[(2,5-dichlorophenyl)hydrazone] in the presence of tert-butoxide gives a 44-line ESR spectrum (see Fig. 3). The hyperfine structures are attributed to the interaction of unpaired electrons with equivalent nitrogen atoms,353 as in the case of a hydrazine cation radical.354 Saccharide phenylhydrazones and phenylosazones do not show evidence of the paramagnetic species that are characteristic of glyoxal bis(phenylhydrazone). Instead they show 3-line ESR spectra characteristic of nitroxide radicals having 움-hydrogen atoms,157 unlike nitroxide radicals having no 움-hydrogen atoms.355 The nitroxide radicals are generated by oxidation of the phenylhydrazine liberated by hydrolysis. Saccharide osazones (183) are relatively stable in cold concentrated alkalies, but degrade progressively with time. The degradation starts at the
FIG. 3.
Radical anion from glyoxal bis[(2,5-dichlorophenylhydrazone)] in base.
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hydroxyalkyl chain of saccharide phenylosazones and gives rise to glyoxal bis(phenylhydrazone) (184) (Scheme 41).162,163,168 d. Oxidation of Bis(hydrazones)—(i) Formation of 1,2-Bis(phenylazo)ethene.—Oxidation of glyoxal bis(phenylhydrazone) with Fe3+, Cu2+, or Cr3+ yields an intense red-colored compound, 1,2-bis(phenylazo)ethene (185). This compound has an extended, conjugated 앟-electron system that is disrupted by protonation in some of the resonance forms of the ion 186, causing a hypsochromic shift (Scheme 42).230 (ii) Formation of Dehydroosazones.—Treating saccharide phenylosazones in alkaline media with atmospheric oxygen gives rise to dehydroosazones,356 which are very similar in appearance to the parent osazones. Structural investigations357,358 have shown that the dehydro derivative obtained from D-arabino-hexulose phenylosazone has a pyranoid ring (it consumes one mole of periodate to give a dialdehyde and does not afford a formazan). The NMR spectrum of its tri-O-acetyl derivative suggests that the hydroxyl group attached to C-3 is not equatorial, as would be expected from the D-arabino configuration (187), but axial (D-ribo configuration) (188). D-Glucose gives the same dehydro-osazone as D-allose and Dgalactose gives the same derivative as D-gulose, suggesting that an inversion at C-3 occurs in one of each pair (Scheme 43). (iii) Formation of Phenylazo-Phenylhydrazones.—This oxidation was first observed359 with dehydroascorbic acid bis(phenylhydrazones) (189). It proceeds by cyclization of the side chain to give a bicyclic hydrazinohydrazone (190). A facile hydrazino-azo oxidation then takes place with Cu2+ or iodine to give a phenylazo-phenylhydrazone (191). The reaction is reversible and the product may be reduced to the starting bis(phenylhydrazone) (Scheme 44).359–364
SCHEME 41. Degradation of saccharide phenylosazones in alkali to glyoxal bis(phenylhydrazone).
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HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
SCHEME 42. Effect of protonation on the resonance forms of 1,2bis(phenylazo)ethene.
215
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216
KHADEM AND FATIADI
SCHEME 42.
Continued
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HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
SCHEME 43.
217
Dehydro-osazone derived from D-glucose.
e. Aromatization of the Bis(phenylhydrazone) Residues.—The hydrazone residues of bis(hydrazones) readily undergo conversion into aromatic heterocycles. If one hydrazone residue is involved in aromatization, a pyrazole results, but if two hydrazone residues are involved a phenyltriazole is usually formed. (i) Formation of Pyrazoles from Bis(hydrazones).—Mesoxaldehyde bis(phenylhydrazone) (193), obtained by periodate oxidation of saccharide osazones (192) is readily cyclized in the presence of acids to give 1-phenyl-4phenylazo-pyrazole (195).162,365 Hexulose phenylosazones (192) are also disproportionated in the presence of acidic salts of carbonyl reagents, such as hydroxylamine hydrochloride, to give 1-phenyl-4-phenylazo-pyrazolin5-one (196). The reaction probably proceeds via mesoxalic acid 1,2bis(phenylhydrazone) (194).365 The hydroxalkyl derivatives of 196 are produced from dehydroascorbic acid bis(phenylhydrazone) by treatment with base to open the lactone ring and permit the conversion of 197 to 199.351, 366 Another type of pyrazole that is formed by dehydrating osazones with acetic anhydride is discussed later under anhydroosazones (see Schemes 45, 53). (ii) Formation of Saccharide Triazoles.367,368—Two types of 1,2,3triazoles are obtained by treatment of saccharide bis(hydrazones) with mild
SCHEME 44.
Formation of a phenylazo-phenylhydrazone from a bis(phenylhydrazone).
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218
SCHEME 45.
KHADEM AND FATIADI
Different types of pyrazoles formed by aromatization of hydrazone residues.
oxidants. The first are the 2-aryl-4-(hydroxyalkyl)-1,2,3-triazoles, also known as saccharide osotriazoles, and the other are the 1-arylamino-4(hydroxyalkyl)-1,2,3-triazoles, obtained from saccharide bis(aroylhydrazones). Other types of carbohydrate triazoles can be prepared by cycloaddition of azides to acetylenic sugars.
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219
Saccharide Phenylosotriazoles. These 2-aryl-1,2,3-triazoles (201) are by far the most extensively studied triazoles. They were first prepared by Hann and Hudson369 by refluxing arylosazones (200) with aqueous copper (II) sulfate. Subsequently, numerous osotriazoles have been prepared to characterize the osazones of monosaccharides,369–379 disaccharides,380–386 and anhydroosazones.387–391 The conversion of arylosazones into the corresponding osotriazoles and aniline necessitates the presence of an oxidizing agent, which suggests that the process is not as the structure of the reactants and products might suggest, a simple elimination of aniline from an osazone. Apart from copper(II) sulfate, which is the regent most commonly used, other oxidizing heavy-metal salts, such as mercuric acetate392 and ferric sulfate and choride,393 have been used. In addition, halogens394 and nitrososulfonates have also been used.395 The acetylated osazones are converted by nitrous acid into osotriazoles,396 and this reagent decomposes unacetylated osazones to give aldosuloses.397 The structure of saccharide osotriazoles was confirmed by oxidation of the hydroxyalkyl chain with periodate to yield 2-phenyl-1,2,3-triazole-4-carboxaldehyde (202) and with permangante, giving 2-phenyl-1,2,3-triazole-4-carboxylic acid (203) (Scheme 46). Mechanism of Osotriazole Formation. A mechanism was proposed by El Khadem398 to explain (a) why the triazole reaction requires oxidizing agents, (b) why the formation of an osazone–Cu(II) complex must precede triazole formation, (c) how aniline is eliminated to form a triazole, and (d) how Cu(II)2+ is converted to Cu0 during the reaction. The first step is the reaction of the osazone (204) with Cu(II) ions to form an osazone–Cu(II)
SCHEME 46.
Formation and structure of saccharide phenylosotriazoles.
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220
KHADEM AND FATIADI
complex, such as 205, which undergoes a one-electron shift from the nitrogen atom of the ligand to the metal in the complex. It should be noted that a monomeric complex such as 206 in Scheme 47 would achieve the same re-
SCHEME 47.
Mechanism of formation of osotriazoles.
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221
sult. In either case the intramolecular oxidation–reduction results in reduction of the Cu(II) complex to a Cu(I) complex (208) and formation of a ligand radical (207). This undergoes a set of one-electron shifts to form the triazole (209) by elimination of a phenylimine radical (Ph-NH); which is quickly converted in water to aniline. The Cu(I) complex 208 obtained from the dimer 205 decomposes to regenerate 1 mole of osazone and Cu(I)+, whereas the Cu(I) complex from the monomer yields directly the triazole, aniline, and Cu(I)+. The Cu(I)+ produced in either way is converted to Cu(II)2+ and Cu0 by disproportionation. This is a well-known reaction of Cu(I) ions,399 which undergo disproportionation upon boiling in acidified water to give Cu(II)2+ and Cu0. It should be noted that the exact amount of copper precipitated depends of the ratio of at least two competing reactions, triazole formation and hydrolysis to the glycosulose.400 The role of Cu(II) complexes in triazole formation is to facilitate the oxidation by bringing the electron-rich part of the ligand (nitrogen) next to the oxidant. Stronger oxidizing agents, such as chlorine or bromine in water, can directly attack the hydrogen-bonded chelated ring of osazones and do not require metal-complex intermediates. The oxidation of labeled osotriazoles has been used to determine the position of 14C-label in aldoses401 and to ascertain that the unchelated aniline of the C-1 phenylhydrazone residue (and not that of C-2) is eliminated during triazole formation. Similar results were obtained by using 82Br-labeled 291 D-arabino-hexulose p-bromophenylosazone, mixed arylosazones,397 and 402 1-phenylazo-osotriazoles. The nitrogen atom of the triazole ring activates the phenyl ring by resonance and electrophilic substitution occurs mainly in the para position393,394 because the ortho positions are crowded. Correlations have been made between the configuration of the hydroxyl group attached to C-3 of sugar osotriazoles and the sign of their optical rotation403,404 and the sign of their Cotton effect.405,406 Comparative NMR studies of osotriazoles as a function of the configuration of the side chain demonstrated that the chain adopts a “sickle” conformation such as 210 if the planar zig-zag arrangement of carbon atoms would have given rise to a paralled 1,3interaction between hydroxyl37 or acetoxyl groups (Scheme 48).38
SCHEME 48.
The sickle conformation of saccharide osotriazoles.
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KHADEM AND FATIADI
Saccharide 1-benzamidotriazole enolbenzoates (212) have been obtained by the free-radical oxidation of bis(benzoylhydrazone) acetates (211), with iodine and hydrolysis of the ester groups of the resulting 1-움-benzoyloxybenzylideneamino-1,2,3-triazoles (213).407,408 The structure of these triazoles was determined by periodate oxidation, which gave 1-benzamido-4formyl-1,2,3-triazole (214), and by NMR spectroscopy (Scheme 49). f. Reduction of Bis(phenylhydrazones).—Fischer409 obtained 1-amino1-deoxy-D-fructose (215) by reduction of D-arabino-hexulose phenylosazone (216) with zinc and acetic acid and called it “iso-D-glucosamine.” The yield of this product was increased when hydrogenation over a palladiumon-carbon catalyst was used.310,410 When D-arabino-hexulose phenylosazone (216) was reduced over Raney nickel in 2M alcoholic potassium hydroxide (added to open the chelated ring), the reduction proceeded to the alditol stage and yielded 1,2-diamino1,2-dideoxy-D-mannitol and -D-glucitol (217 and 218).249,411,412 Similar reductions have been carried out on disaccharide phenylosazones244,393,394, 413 and dehydroascorbic acid osazone (Scheme 50).414,415 g. Formation of Anhydroosazones.—The formation of anhydroosazones is initiated by an elimination reaction, followed by a cyclization. The latter involves nucleophilic attack by a chain oxygen or a suitably located hydrazone nitrogen atom. Three types of anhydroosazones have been isolated, namely (i) monocyclic 3,6-anhydroosazones, (ii) monocyclic dianhydroosazones, and (iii) bicyclic dianhydroosazones. All three types of anhydroosazone are formed from a common intermediate, a 2-phenylazo1-phenylhydrazono-1-alkene (220).168 These intermediates are similar to
SCHEME 49.
Formation and reactions of 1-움-benzoyloxybenzylideneamino-1,2,3-triazoles.
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HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
SCHEME 50.
223
Reduction of osazones.
the azoalkenes formed from hydrazones. It is postulated that, in the presence of acids or bases, such osazones as 219 undergo conjugate elimination to afford 2-phenylazo-1-phenylhydrazono-1-alkenes (220). In the presence of acids the reaction is initiated by protonation of the OH group attached to C-3 to facilitate the elimination of water and in basic media by ionization of the imino protons to shift electrons toward the leaving group (Scheme 51). (i) Formation of 3,6-Anhydroosazones.—These compounds were first discovered by Fischer286, 416 and were later obtained by boiling osazones in methanol containing some sulfuric acid as catalyst.417 Their structure (for example, compound 223) was studied by many investigators,162,418 and they were finally shown to be 3,6-anhydrohexulose phenylosazones.419–421 Mechanistically, they are formed by nucleophilic attack of O-6 of the sugar chain on the double bond at C-2 of 2-phenylazo-1-phenylhydrazono-1alkenes (221). During the formation of 3,6-anhydroosazones, two 3-epimers
SCHEME 51.
Formation of azoalkene intermediates.
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224
KHADEM AND FATIADI
are produced. The major product usually has the hydroxyl groups at C-3 and C-4 cis to each other, and the minor product has these hydroxyl groups trans oriented.388 However in the case of heptulose osazones,422–424 this rule is not so strictly observed. 3,6-Anhydroosazones are also formed when osazones are boiled with acetic anhydride169,425–427; the products in this case are accompanied by dianhydroosazones having pyrazole rings such as, for example, compound 225, discussed in the next section (Scheme 52). (ii) Dianhydroosazones of the Pyrazole Type.—These dianhydroosazones are obtained by boiling saccharide phenylosazones in acetic anhydride. They are formed from the same intermediate, 2-phenylazo-1phenylhydrazono-1-alkenes (224), by migration of the double bond, followed by nucleophilic attack by nitrogen to give an acetoxy-pyrazoline (226), which is aromatized by elimination of the acetoxy group to yield the pyrazole (228). The structure of this type of dianhydroosazone (228) was established by degradation, including oxidation to a known pyrazoledicarboxylic acid (227), and by NMR spectroscopy.219,312, 425–427 An analog of pyrazole was obtained by heating 3,4,5-tri-O-acetyl-pentulose phenylosazones with pyridine (Scheme 53).169,427 (iii) Bicyclic Dianhydro-Osazones.—This third type of anhydroosazone was first prepared by Percival when deacetylating a hexulose phenylosazone tetraacetate with sodium hydroxide. Two enantiomeric compounds are otainable from hexose precursors, one from D-hexoses and the other from 166 L-hexoses. Tricyclic structures were first assigned to these compounds, but were later revised.428 Finally, NMR data provided evidence for a chelated bicyclic structure 231 which possesses one imino proton.429 These dianhydroosazones are formed from the same intermediate, 2-phenylazo-1phenylhydrazono-1-alkenes (229) by conjugate elimination to give 230, followed by nucleophilic attack of O-6 to afford the product 231 (Scheme 54).
SCHEME 52.
Formation of 3,6-anhydroosazones.
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HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
SCHEME 53.
225
Dianhydroosazone of the pyrazole type.
h. Derivatives—(i) Esters.—The fully acetylated and benzoylated sugar phenylosazones have acyclic structures. Mild acetylation of D-arabino- and D-lyxo-hexulose phenylosazones leads to tetra-O-acetyl derivatives (232).218,294,313 Stronger acetylating agents, such as acetyl chloride, yield a 1-N-acetyl-tetra-O-acetyl derivative (234).313 To acetylate the chelated
SCHEME 54.
Formation of Percival’s dianhydroosazonee.
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226
KHADEM AND FATIADI
NH group on C-2, the acetylation requires the presence of Lewis acids (Scheme 55).215,216 Benzoylation of hexulose osazones with benzoyl chloride in pyridine affords crystalline pentabenzoates312,326 which possess one N-benzoyl and four O-benzoyl groups. (ii) Ethers.—Methylation of D-arabino-hexulose phenylosazone (174) under mild conditions yields preferentially the 6-methyl ether.430,431 Vigorous methylation leads to a mixture of methylated products. Mixed 1N-methyl-N-phenyl-2-phenylosazones are obtained either by direct methylation of the unchelated nitrogen432,433 or by transhydrazonation of bis(N-methyl-N-phenyl)osazones with phenylhydrazine.434 Two mono-Nmethyl derivatives of D-arabino-hexulose phenylosazone, designated mixed osazones A and B, have been described in the literature. Mixed osazone A was later identified as 1-(N-methyl-N-phenyl)-2-phenylosazone, whereas mixed osazone B proved to be a mixture of compound A and D-arabinohexulose phenylosazone.157,317,320 When treated with acetone in the presence of an acidic catalyst, the osazone 235 yields a 5,6-isopropylidene acetal (236), which is converted into the O-isoprophylidene-N-methyl-di-O-methyl derivative (237) on methylation with dimethyl sulfate.432 These reactions also provide evidence in favor of the acyclic structure of the sugar osazones. (Scheme 56). 4. Saccharide Poly(hydrazones) If the assumption is correct that the chelated ring in osazones prevents the osazone-forming reaction from proceeding beyond C-2, it would be expected that osazones incapable of forming such chelated rings would undergo an extended reaction which ultimately would involve the whole poly(hydroxyalkyl) chain. This expectation was realized in the
SCHEME 55.
O-Acetylated and O,N-acetylated osazones.
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HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
SCHEME 56.
227
Isopropylidene derivatives of osazones.
case of the N-methyl-N-phenylosazones, which are incapable of forming chelated rings. Treating trioses, tetroses, and pentoses with N-methyl-Nphenylhydrazine afforded tris-, tetrakis-, and pentakis-hydrazones. The resulting polyhydrazones (238) were given the generic name of alkazones (Scheme 57).435,436 Triose tris(hydrazones) may also be obtained from periodate-oxidized saccharide bis(hydrazones)313,365 (239) by treating the resulting mesoxaldehyde bis(benzoylhydrazone) (240) with benzoylhydrazine. Mesoxalaldehyde tris(benzoylhydrazone) (241) was found to react with iodine in a manner similar to that of hexosulose bis(benzoylhydrazones) to give a triazole derivative408 242 (Scheme 58). Alkazones are very reactive compounds; they readily cyclize and aromatize. This renders alkazones of hexoses and higher sugars difficult to isolate from the dark products they form. Other highly reactive species of bis(hydrazones) are the derivatives of mesoxaldehyde and of ascorbic acid, which
SCHEME 57.
Structure of an alkazone.
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228
KHADEM AND FATIADI
SCHEME 58.
Formation and reactions of mesoxaldehyde tris(hydrazones).
contain additional carbonyl groups. Most monosaccharides contain more nucleophiles than nucleophile acceptors (they contain several OH groups and only one C苷O group at the anomeric carbon). The reactivity of their derivatives is greatly enhanced by the presence of additional C苷C, C苷N, or C苷O groups to which nucleophiles can add. An empirical rule has been developed398 to quantitate the reactivity of polyfunctional molecules such as sugars and measure their susceptibility to cyclize by nucleophilic addition. According to this rule, sugars and their oximes and hydrazones have a nucleophilicity quotient of about 1, the (more reactive) osazones and bis(hydrazones) have a quotient of 2, and alkazones and ascorbic acid bis(hydrazones), which are still more reactive, have a quotient of about 3. This rule would predict that esters of phenylosazones and bis(benzoylhydrazones) should exhibit higher reactivities because of the additional C苷O groups that they contain. This is indeed the case; the osazone acetates form two types of aromatized dianhydroosazones (see Schemes 53 and 54) which cannot be formed without acetylation, and benzoylhydrazones show many reactions not given by osazones (see Schemes 49 and 58). V. HYDRAZONES OF CARBA-SUGARS* AND RELATED COMPOUNDS 1. Importance of Carba-Sugars Carbocyclic analogs of monosaccharides in which the ring-oxygen atom is replaced by a methylene group were first synthesized by McCasland and co-workers437 and named “pseudo-sugars”; today, they are termed “carbasugars.”* Some members of this important group of compounds occur naturally,438–440 others inhibit enzymes441,442 or possess antibacterial properties (for example, carba-움-D-galactopyranose).443 Interest in the use of carba-sugars as artificial sweeteners444,445 led to the synthesis of
*
IUPAC-IUBMB, Nomenclature of Carbohydrates, Adv. Carbohydr. Chem. Biochem., 52 (1997) 43–177; see also Nomenclature of Cyclitols, Eur. J. Biochem., 57 (1975) 1–7.
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carba-웁-D-fructopyranose. At first, only racemic mixtures were synthesized,440 but later the synthesis of enantiomerically pure carba-sugars was achieved.442,445–448 Carba-웁-D-fructopyranose was synthesized from a chemically resolved Diels–Alder adduct of furan445 and carba-움-Dmannopyranose from L-(⫺)-quebrachitol (1-L-2-O-methyl-chiro-inositol).449 (⫺)-Quinic acid was converted into optically active carba-웁-Dfructopyranose and carba-웁-D-mannopyranose,450 and the synthesis of carba-움-D-glucopyranose and carba-움-D-mannopyranose has been reported.451 Keto intermediates derived from L-(⫺) quebrachitol were utilized to synthesize an antifungal metabolite, (⫺)-isoavenaciolide,452 and related products,453–456 and the first total synthesis of simondsin, a cyanoglucoside, was achieved.454 A free-radical cyclization of sugar derivatives to chiral aminodeoxy carba-sugars has been described,457 and valiolamine (an aminodeoxy carba-sugar that is a strong 움-D-glucosidase inhibitor) has also been synthesized.458 Synthesis of (⫹)-pinitol, a natural product that possesses hypoglycemic activity,459 and of related compounds was achieved via microbial oxidation of benzene460 or halobenzenes461 with Pseudomonas putida and other microorganisms.461–464 Azidoinososes, intermediates for the sythesis of aminoglycoside antibiotics, have also been synthesized.465,466 A method introduced by Ferrier,467 involving mercury salt-mediated ring transformations of 6-deoxy-5-enopyranosides into deoxyinososes, has been used in the synthesis of cyclitols, aminocyclitols,468,469 and carba-sugars470,471 as well as enantiomerically pure inositols and inososes.472–482 2. Formation of Carba-Sugar Hydrazones a. Preparation and Uses of Phenylhydrazones.—The chemistry of carba-sugars is quite similar to that of cyclitols. Both groups lack the latent carbonyl groups of their saccharide counterparts and therefore do not exhibit many of the reactions characteristic of monosaccharides. Thus, carba-sugars and cyclitols do not form hydrazones or osazones when treated with hydrazines,439 nor do they mutarotate or reduce heavy-metal salts in base. Their hydrazones are prepared from hydroxycyclohexanones (inososes, ketocyclitols) by procedures analogous to those used for the preparation of saccharide hydrazones. The hydrazones of inososes,483–488 like those of monosaccharides,47,130,155,156 may be used to isolate and purify substrates. For example, 2,4,6/3,5-pentahydroxycyclohexanone (myo-inosose-2) is purified by treatment with phenylhydrazine, recrystallization of the resulting phenylhydrazone, and regeneration of the inosose with benzaldehyde489 or with a sulfonic acid-type cationexchange resin.490 Table I lists some protected inososes and hydroxycyclohexanones that have been converted into phenylhydrazones to produce carba-sugars.
230 carba-웁-DLgalactopyranose
carba-웁-DL-allopyranose
carba-움-DLaltropyranose
DL-talopyranose
carba-움
Carba-Sugar
carba-움-D-allopyranose
Keto-Cyclohexane
439, 440
439, 440
439
437
Reference
Keto-Cyclohexane
carba-웁-Dglucopyranose
carba-움-Lidopyranose
carba-웁-D-mannopyranose
carba-움-D-galactopyranose
carba-움-D-mannopyranose
Carba-Sugar
TABLE I Keto-Cyclohexane Derivatives Purified by Conversion to Hydrazones and Used to Prepare Carba-Sugars
447
449
449
438
Reference
4888 Horton Chapter 6-3 11/17/99 2:39 PM Page 230
carba-웁-DLtalopyranose
carba-움-DLgalopyranose
439, 463
439, 448
439, 440
carba-웁-Dmannopyranose
carba-움-Dglucopyranose
carba-웁-Dfructopyranose
carba-웁-L-idopyranose 450
447
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231
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232
KHADEM AND FATIADI
b. Formation of 1,2-Bis(phenylhydrazones).—Inosose phenylhydrazones, such as myo-inosose-2 phenylhydrazone,491 are converted with difficulty into bis(phenylhydrazones); for this reason, many cyclitol osazones are prepared directly from cyclic 1,2-diketones.485,488,492 Investigation of the rate of formation of cyclohexane-1,2-dione bis(phenylhydrazone) from 2-hydroxycyclohexanone phenylhydrazone and of the corresponding 2-methoxy-, 2-acetoxy-, and 2-chloro-derivatives revealed that azoalkenes, formed by 1,4-elimination, are key intermediates in the reaction.299 Other studies299,493 have confirmed the formation of azoalkene intermediates during the conversion of 움-acetoxycyclohexanone and of 움substituted oxosteroids into the corresponding bis(phenylhydrazones) (Scheme 59).494 c. Formation of 1,3-Bis- and 1,2,3-Tris(phenylhydrazones).—Reaction of cyclohexane-1,3-dione (251–252) with phenylhydrazine yields cyclohexanetrione bis- and tris-(phenylhydrazones). The formation of bis(phenylhydrazone) 256 and tris(phenylhydrazone) 257 proceeds by an ionic mechanism (see Scheme 60), whereas that of cyclohexanetrione bis(phenylhydrazone) (263–264) from the enol form of 1,3-cyclohexanedione (259) involves freeradical intermediates (see Scheme 61). The formation of free radicals in the first reaction became evident when a solution containing the cyclohexane1,3-dione (251–252) and phenylhydrazine revealed a five-line ESR spectrum.495,496 The presence of a paramagnetic species, identified as a
SCHEME 59.
Formation of inosose 1,2-bis(phenylhydrazones).
HYDRAZINE DERIVATIVES OF CARBOHYDRATE COMPOUNDS
SCHEME 60.
Formation of 1,2,3-tris(phenylhydrazones) by an ionic mechanism.
233
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237
(phenylhydrazone) structure, for instance 265, and the red one has an enolic phenylhydrazono-phenylazo structure (266 and 267). The deep red color of 2-oxo-1,3-bis(phenylhydrazones) and the strong 앟 → 앟* absorptions they display suggest that they have conjugated phenylhydrazono-phenylazo groups, similar to the diphenylformazans of sugars.223,240 The latter were studied by 15N NMR on 15N-labeled formazans,527 which confirmed the formazan ring structure.528 The marked similarity in the absorption spectra of the 2-oxo-1,3bis(phenylhydrazones) and of formazans clearly supports the phenylhydrazono-enol-phenylazo structures (266–267) assigned to these compounds. This was confirmed by 1H NMR studies, which reveal the presence of both chelated and nonchelated imino protons in the tautomeric forms 265–267 (Scheme 62).526 An analogous structure for 2-oxo-1,3-bis(phenylhydrazono)cyclopentane (268) was likewise based on spectroscopic evidence.526 Quantummechanical calculation (HMO) of the bonding energies of various tautomers (such as 268, 269, and 270) indicates505 that the most stable tautomeric structure is the chelated bis(phenylhydrazone) 269. It seems that interconversion of the tautomers 268, 269, and 270 occurs in polar solvents and that the dichelated structure 271 is preponderant in the solid state or in nonpolar solvents (Scheme 63).526 b. Structure of Tris(phenylhydrazones).—Tris(phenylhydrazones) resemble 2-oxo-1,3-bis(phenylhydrazones) in possessing chelated ring structures. The NMR spectra of 1,2,3-tris(phenylhydrazono)cyclopentane (272), 1,2,3-tris(phenylhydrazono)cyclohexane (273), and 2,3,4-tris(phenylhydrazono) cyclohexanecarboxylic acid (274) all show the presence of two chelated rings. Similarly, the NMR spectra of the tris(phenylhydrazono)propane (275–276) show no low-field NMR signals immediately after
SCHEME 62. Chelation and resonance forms of enolic, phenylhydrazono-phenylazo structures of cyclohexanetrione bis(phenylhydrazones).
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238
SCHEME 63.
KHADEM AND FATIADI
Chelation and resonance forms of cyclopentanetrione bis(phenylhydrazones).
dissolution, but only after a few minutes of equilibration.526 These results were later substantiated (Scheme 64).365 4. Reactions of Carba-Sugar Hydrazones a. Action of Acids and Bases—(i) Protonation and Formation of Anions.—Protonation of 2-oxo-1,3-bis(phenylhydrazones), diphenylformazans, and 1,2-bis(phenylazo)ethene produces purple, blue, or green
SCHEME 64.
Chelated structures of tris(phenylhydrazones).
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cations.230 On the other hand, cyclitol phenylosazones and bis(phenylhydrazones) that cannot form resonance-stabilized cations on protonation do not usually give a blue coloration. For example, when perchloric acid is added to a solution of 2-oxo-1,3-bis(phenylhydrazono)cyclohexane in acetic acid, a protonated, blue, crystalline salt is obtained.230 The observed bathochromic shift and the intense color were found to arise from the formation of a conjugated, resonance-stabilized cation having structure 277. Electron-spin resonance measurements of solutions of colored 2oxo-1,3-bis(phenylhydrazones) and diphenylformazans do not show the presence of radical species, thus indicating the ionic character of the products formed on protonation. Treatment of 1-phenylhydrazino-3-phenylazo-2-cyclohexene with a strong base also produces a blue coloration. The amphoteric character of this compound and of other formazan vinylogs has been ascribed502 to the formation of such resonance-stabilized anions as 278a,b. The absorption spectrum of this anion resembles the spectrum of the resonance-stabilized cation of 2-oxo-1,3-bis(phenylhydrazones), indicating some amphoteric character in these compounds (Scheme 65). (ii) Formation of Stable Free-Radicals.—The ESR probe can be used to distinguish between the hydrazine derivatives of saccharides and nonsaccharides. Saccharide phenylhydrazones, which are much less stable in basic media than inosose phenylhydrazones, exhibit 3-line ESR patterns
SCHEME 65. Resonance-stabilized structures of 2-oxo-1,3-bis(phenylhydrazono)cyclohexane in acid and in base.
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characteristic of nitroxide radicals, produced by oxidation of the phenylhydrazine moiety generated by hydrolysis. On the other hand, inosose phenylhydrazones and, in particular, their esters, exhibit welldefined spectra. For example, 2,4,5,6/3-pentahydroxycyclohexanone phenylhydrazone pentapropanoate (DL-epi-inosose-2 phenylhydrazone pentapropanoate) (280c), shows a 30-line ESR spectrum.157,353 The hyperfine structure observed in the spectrum of 280c has been attributed to the great stability of this inosose phenylhydrazone ester toward alkali. Elimination (Formation of Phenylazo-Cycloalkenes). Eliminations, similar to the Wolfrom reaction of acylated saccharide phenylhydrazones, have been observed with some, but not all, inosose phenylhydrazone acetates.Thus, acetylation of 2,4,6/3,5-pentahydroxycyclohexanone phenylhydrazone (myoinosose-2 phenylhydrazone) (279a) with pyridine–acetic anhydride at 10–15⬚C yields a pale yellow elimination product, namely 6-phenylazo-5-cyclohexeneDL-ido-1,2,3,4-tetrol tetraacetate (281a). In contrast, treatment of the same phenylhydrazone with propanoic anhydride and pyridine gives the pentapropanoate 279c without elimination. Similarly, treatment of 2,4,5,6/3pentahydroxycyclohexanone phenylhydrazone (DL-epi-inosose-2 phenylhydrazone, (280a) with acetic or propanoic anhydride gives pentaacetate 280b or propanoate 280c without elimination. However, if the reaction temperature for 279a or 280a is raised, elimination occurs, with formation of aromatic azo compounds. The major factors influencing the course of the reaction seem to be (i) thermodynamic stability, (ii) the nature of the acyl group (acetyl, propanonyl, benzoyl, and the like), and (iii) temperature (Scheme 66).529 b. Nucleophilic Substitution.—When a leaving group present in the 움position relative to a hydrazone residue undergoes elimination, the resulting azo-cycloalkene is able to add a nucleophile in the same position. Thus if a 2-benzoyloxyinosose p-nitrophenylhydrazone is treated with azide anions, the benzoyloxy group is replaced by an azide group.207,472–474 For example, when 2L-(2,4,5/3)-4-benzamido-2,3-dibenzoyloxy-5-hydroxycy-
SCHEME 66.
Formation of phenylazo-cycloalkenes.
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clohexanone (283a), prepared from 282 via a Ferrier transformation, is treated with p-nitrophenylhydrazine it gives a p-nitrophenylhydrazone (283b);475,476 this compound, upon treatment with sodium azide, affords the azide 286. An analogous product is obtained from the corresponding oxime (283c) by treatment with tetrabutylammonium azide. The product in this case is a mixture of the epimers of 2-azido-4-benzamido-3-benzoyloxy-5hydroxycyclohexanone (E)-oxime (284 and 285), which are conveniently separable by column chromatography.475 In this situation, the hydroximino group shows477,478 an activating effect similar to that of the arylhydrazone group, and affords a nitroso-cycloakene intermediate. Preparation of azidoinososes from derivatives 284–286 may be achieved by use of a cationexchange resin490 or by acid hydrolysis (Scheme 67).
SCHEME 67.
Nucleophilic substitution.
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c. Aromatization—(i) Aromatization of the Cyclohexane Ring.—The base-catalyzed acetylation of 279a shown in Scheme 66 is accompanied by elimination to give an arylazocyclohexene derivative (281a).529 However, the thermodynamically less stable 4,6/5-trihydroxy-1,3-bis(phenylhydrazono)cyclohexanone (287), shown in Scheme 68, upon similar treatment undergoes complete aromatization at ambient temperature to give a substituted benzene (291).530 Compound 287 is prepared from 4,6/5trihydroxy-1,2,3-cyclohexanetrione by treatment with phenylhydrazine at room temperature.531 The formation of 291 from 287 probably proceeds via an ionic pathway that involves (i) acetylation of the hydroxyl groups to give 288, (ii) ionization of the imino hydrogen atom with base and formation
SCHEME 68.
Aromatization of the cyclohexane ring.
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of an enol (289), (iii) sequential cleavage of the acetoxy group to give 290, and, finally, (iv) aromatization with acetic anhydride to give the product 291. (ii) Aromatization of the Hydrazone Residues, Formation of Phenylosotriazoles.—A number of cyclitol phenylosotriazoles have been prepared from the corresponding bis(phenylhydrazones). For example, 1D (292a), 1532 L-chiro (293), and DL-inositol phenylosotriazoles have been prepared 492 from the corresponding inosose phenylosazones by using mercuric acetate as the oxidant.532 Unlike sugar phenylosotriazoles which possess a flexible side chain,130 some cyclitol phenylosotriazoles possess symmetrical structures, as indicated by the simplicity of their proton-decoupled 13C NMR spectra.392,532 Thus the 1H NMR spectra of inositol phenylosotriazoles, 292a, and their esters revealed the presence of a simple, twofold axis of symmetry and the ring protons were symmetrical about a midpoint (see 294), making them examples of four-nucleus AA⬘BB⬘ systems. In solution, the favored conformation for the osotriazole tetra-isobutanoate 292c is 5H4, as depicted in structure 295. A small coupling-constant for H-3–H-6 is attributed to the influence of the neighboring planar osotriazole ring and is consistent with a half-chair conformation.392,532 The NMR spectra of alkyl-substituted inositol phenylosotriazoles [from D-(⫹)pinitol (1-D-3-O-methyl-chiro-inositol, 296a) or L-(⫺)-quebrachitol (1L2-O-methyl-chiro-inositol, 297a)] or those from (⫹)-quercitol [(⫹)-protoquercitol (1 D-1,3,4/2,5-cyclohexanepentol), 298a] or their acetates (296b, 297b, and 298b), which are not symmetric, show the ring-proton signals as part of an ABX system (Scheme 69).392 d. Oxidation and Reduction.—In an early investigation, Magasanik and Chargaff533 showed that cyclitol osazones, for example, 1-D-chiro-inositol phenylosazone (299) consume the expected amount of periodate (three moles), but that the product, namely, 2,3-bis(phenylhydrazono) succindialdehyde (300), cyclized to give a pyrazole (301). Similarly, the oxidation of such cyclitol phenylhydrazones533 as the 2-oxo-1,3-bis(phenylhydrazone) 303 (prepared upon the reaction of 302 with phenylhydrazine),531 upon treatment with sodium periodate, yields 3-oxo-2,4-bis(phenylhydrazono)glutaraldehyde (304), which was not isolated, but was directly converted into the methyl hemiacetal of 4-oxo-1-phenyl-5-(phenylazo)-3-pyrazinecarboxaldehyde (307).225 This conversion presumably involves formation of 305, followed by dehydration to aldehyde 306 and reaction with methanol to give 307 (Scheme 70). The oxidation of 308 by periodic acid provides a synthetic route to
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SCHEME 69.
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Aromatization of the hydrazone residues, formation of phenylosotriazoles.
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SCHEME 70.
Periodate oxidation.
245
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interesting pyrazine derivatives. However, reduction with sodium amalgam in ethanol gives534 streptamine (309), a degradation product of the antibiotic streptomycin. The synthesis of 309 offers an additional proof of the structure of 308. When 308 is reduced catalytically,534 the product is the antibiotic actinamine 310. The exclusive formation of a 1,3-diamine (310), with two equatorial amino groups, by catalytic hydrogenation over platinum is noteworthy because phenylhydrazones of inososes535,536 or hexuloses537 generally form products having axial amino groups. The difference may be due to the fact that compound 308 exists514 mainly in the phenylhydrazono-phenylazo form and not the bis(phenylhydrazono) form526 or that the phenyl group plays a directing role during catalytic hydrogenation.534 The rotation of the phenyl group in the chair conformers has been the subject of numerous studies (Scheme 71).538–540 VI. CONCLUSION The study of the hydrazine derivatives of sugars has played an important role in the development of carbohydrate chemistry since its inception. Phenylhydrazine, first described in Emil Fischer’s doctoral thesis, was al-
SCHEME 71.
Reduction of 2-oxo-1,3-bis(phenylhydrazones).
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lowed to react with sugars to form hydrazones and osazones. The latter compounds proved invaluable in establishing the configuration of Dglucose, which won Fischer the Nobel Prize in 1902, and in the synthesis of L-ascorbic acid, which won Sir Norman Haworth the prize in 1937. Hydrazones and osazones have been extensively used in analysis to separate and characterize mono- and disaccharides and in the preparation of new sugars such as glyculoses (ketoses), aldos-2-uloses (“osones”), and amino- and imino-deoxy sugars as well as countless aromatic nitrogen heterocycles. As in other fields of chemistry, research in the area of carbohydrates has benefited from the advent of such instrumental methods of structure elucidation, as NMR, MS, and X-ray crystallography. The impact of these tools can be realized by considering the time it took chemists to determine the structure of two hydrazine derivatives of about equal complexity, before and after the advent of NMR spectroscopy: it took 65 years (from 1887 to 1952) and the efforts of four of the best chemists to prove by classic methods that the anhydro derivative obtained in acid media from what was then called “glucosazone” was 3,6-anhydro-D-ribo-hexulose phenylosazone and only a few months in 1990 to determine that the oxidation products obtained from saccharide phenylhydrazones in basic media were in fact N-phenylaldonohydrazono-1,4-lactones (see schemes 52 and 11, respectively). In this chapter an attempt has been made to present an account of the rich chemistry of the hydrazine derivatives of sugars, the versatility of their structures, and their availability, which makes them valuable enantiomerically pure synthons for chiral products. For example, reduction of aldose hydrazones affords an important class of chiral amino- and iminodeoxy sugars which contain nitrogen in place of the oxygen present in the rings of natural sugars. These imino sugars exhibit a wide spectrum of biological activities, mainly attributable to their ability to act as enzyme inhibitors. Also of considerable interest are the carba-sugars, the carbocyclic analogs of monosaccharides, which are readily available from inosose phenylhydrazones. Members of both these classes of compounds, the carba-sugars and the imino sugars (“aza sugars”) are capable of inhibiting enzymes because they mimic the enzyme’s natural substrates (the sugars). For the same reason they, and other members of both groups, often exhibit antibacterial, antiviral, or antitumor properties. It is not surprising, therefore, to find that the study of these compounds is attracting the interest of numerous researchers from the field of carbohydrate chemistry as well as from other disciplines. This area of research is under rapid development and is producing an ever-increasing number of papers that enrich the chemical literature. Another area currently attracting great interest is the enantioselective synthesis of 움-aminoaldehydes and 웁-lactam intermediates, obtained by reduction or conjugate reduction of hydrazine derivatives.
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T. K. M. Shing, Y. Cui, and Y. Tang, Tetrahedron, 48 (1992) 2349–2358; S. Ogawa, K. Sato, and Y. Miyamato, J. Chem. Soc. Perkin Trans., 1 (1993) 691–696; L. Lay, F. Nicotra, C. Pangrazio, L. Panza, and G. Russo, J. Chem. Soc. Perkin Trans., 1 (1994) 333–338; L. Pingli and M. Vandewalle, Tetrahedron, 50 (1994) 7061–7074; D. F. McComsey and B. E. Maryanoff, J. Org. Chem., 59 (1994) 2652–2654; H. A. J. Carless and Sh. S. Malik, J. Chem. Soc. Chem. Commun. (1995) 2447–2448. N. Chida, T. Tobe, M. Suwama, M. Ohtsuka, and S. Ogawa, J. Chem. Soc. Chem. Commun. (1990) 994–995. N. Chida, M. Suzuki, M. Suwama, and S. Ogawa, J. Carbohydr. Chem., 8 (1989) 319–332. N. Chida, K. Yamada, and S. Ogawa, J. Chem. Soc. Chem. Commun. (1991) 588–590; N. Chida, T. Tanikawa, T. Tobe, and S. Ogawa, J. Chem. Soc. Chem. Commun. (1994) 1247–1248. H. Paulsen and F. R. Heiker, Liebigs Ann. Chem. (1981) 2180–2203. H. Paulsen and W. von Deyn, Liebigs Ann. Chem. (1987) 133–140. J. Marco-Contella, C. Pozuelo, M. I. Jimeno, L. Martnez, and A. Martinez-Grav, J. Org. Chem., 57 (1992) 2625–2631. H. Fukase and F. Horii, J. Org. Chem., 57 (1992) 3642–3650, 3651–3658; T. K. M. Shing and L. H. Wan, J. Org. Chem., 61 (1996) 8468–8479. C. R. Narayanan, D. D. Joshi, A. M. Miyumdar, and V. V. Dhekne, Curr. Sci., 56 (1987) 139–141. S. V. Ley and F. Sternfeld, Tetrahedron, 45 (1989) 3463–3476; S. V. Ley, Abstr. Pap., 200th Natl. Meet. Am. Chem. Soc. Washington, DC, 1990 ORGN 123; T. Hudlicky and A. J. Thorpe, Chem. Commun. (1996) 1993–2000. T. Hudlicky, J. D. Price, F. Rulin, and T. Tsunoda, J. Am. Chem. Soc., 112 (1990) 9438–9439. T. Hudlicky and J. D. Price, Synlet, 159 (1990) 309–310. T. Hudlicky, H. Luna, J. D. Price, and F. Rulin, J. Org. Chem., 55 (1990) 4683–4687; see also S. M. Roberts, N. J. Turner, A. J. Willetts, and M. K. Turner, Introduction to Biocatalysis Using Enzymes and Microorganisms, Cambridge Univ. Press, Cambridge, 1995; H. J. M. Gijsen, L. Qiao, W. Fitz, and C.-H. Wong, Chem. Rev., 96 (1996) 443–473; W. D. Fessner and C. Walters, Top. Current Chem., 184 (1997) 97–153. D. R. Boyd, M. V. Hand, N. D. Sharma, J. Chima, H. Holton, and C. N. Sheldrake, J. Chem. Soc. Chem. Commun. (1991) 1630–1632. H. Umezawa, Trends in Antibiotic Research, H. Umezawa (Ed.), Japan Antibiotic Research Assoc., Tokyo, 1982, 1–15. M. Awata, N. Muto, M. Hayashi, and S. Yaginuma, J. Antibiot., 39 (1986) 724–726. R. J. Ferrier, J. Chem. Soc. Perkin Trans., 1 (1979) 1455–1458; R. Blattner, R. J. Ferrier, and S. R. Haines, J. Chem. Soc. Perkin Trans., 1 (1984) 2413–2414; R. J. Ferrier and S. R. Haines, Carbohydr. Res., 130 (1984) 135–146; R. J. Ferrier and S. Middleton, Chem. Rev., 93 (1993) 2779–2831; see also S. M. Weinreb, J. Org. Chem., 56 (1991) 5010–5012. M. Madi-Puskas, I. Pelyvas, and R. Bognár, J. Carbohydr. Chem. 4 (1985) 323–331. G. Vass, P. Krausz, B. Quiclet-Sire, J.-M. Delaumney, J. Cléophax, and S. D. Gero, C. R. Acad. Sci., Ser. II (1985) 1345–1346. A. S. Machado, A. Alesker, S. Castillon, and G. Lukas, J. Chem. Soc. Chem. Commun. (1985) 1399–1401. D. H. R. Barton, S. D. Gero, S. Augy, and B. Quiclet-Sire, J. Chem. Soc., Chem. Commun. (1986) 1399–1401. P. M. Collins, D. Gardiner, S. Kumar, and W. G. Overend, J. Chem. Soc., Perkin Trans., 1 (1972) 2596–2610.
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(473) G. S. Hajivarnava, W. G. Overend, and N. R. Williams, J. Chem. Soc., Perkin Trans., 1 (1982) 205–214. (474) I. Pinter, J. Kovacs, A. Messmer, G. Toth, and S. D. Gero, Carbohydr. Res., 116 (1983) 156–161. (475) P. Meszaros, I. Pinter, A. Messmer, G. Toth, and S. D. Gero, Carbohydr. Res., 197 (1990) 302–309. (476) G. J. Martin and M. L. Martin, Prog. Nucl. Magn. Res. Spectrosc., 8 (1972) 163–259. (477) R. U. Lemieux, T. L. Nagabushan, and K. James, Can. J. Chem., 51 (1973) 1–6. (478) Z. Smiatacz, R. Szweda, and J. Drewniak, Carbohydr. Res., 143 (1985) 151–159. (479) P. Laszlo, I. F. Pelyvas, F. Sztaricskai, L. Szilagyi, and A. Somogyi, Carbohydr. Res., 175 (1988) 227–239. (480) S. L. Bender and R. J. Budhu, J. Am. Chem. Soc., 113 (1991) 9883–9884. (481) V. A. Estevez and G. D. Prestwich, J. Am. Chem. Soc., 113 (1991) 9885–9887. (482) S. K. Chung and S.-H. Moon, J. Chem. Soc. Chem. Commun. (1992) 77–79. (483) H. G. Fletcher, Jr., Adv. Carbohydr. Chem., 3 (1948) 45–77. (484) S. J. Angyal and L. Anderson, Adv. Carbohydr. Chem., 14 (1959) 135–212. (485) T. Posternak, The Cyclitols (Fr. ed.), Herman, Paris, 1962; Engl. ed. (updated), Herman, Paris, and Holden-Day, San Francisco, California, 1965. (486) L. Anderson, The Carbohydrates, Chemistry, and Biochemistry, Vol. 1A, W. Pigman and D. Horton (Eds.), Academic Press, New York, 1972, Chapter 15, 519–579. (487) T. Hudlicky and M. Cebulak, Cyclitols and Derivatives, VCH, New York, 1993. (488) B. Magasanik and E. Chargaff, J. Biol. Chem., 174 (1948) 173–188. (489) T. Posternak, Biochem. Prep., 2 (1952) 57–64. (490) A. J. Fatiadi, Carbohydr. Res., 1 (1966) 489–491. (491) H. E. Carter, C. Belinskey, R. K. Clark, Jr., E. H. Flynn, B. Lyttle, G. E. McCasland, and M. Robins, J. Biol. Chem., 174 (1948) 415–426. (492) A. J. Fatiadi, Carbohydr. Res., 8 (1968) 135–147. (493) L. Caglioti, G. Rosini, and F. Rossi, J. Am. Chem. Soc., 88 (1966) 3865–3866; L. Caglioti and A. G. Giumanini, Bull. Chem. Soc. Jpn., 44 (1971) 1048–1050; A. G. Giumanini, L. Caglioti, and W. Nardini, Bull. Chem. Soc. Jpn., 46 (1973) 3319–3320. (494) J. Buckingham and R. D. Guthrie, Chem. Commun. (1966) 781–782; J. Buckingham and R. D. Guthrie, J. Chem. Soc. C (1968) 3079–3084. (495) A. J. Fatiadi, Carbohydr. Res., 25 (1972) 173–186. (496) A. J. Fatiadi, Chem. Ind. (London) (1973) 38–40. (497) S. Terabe and R. Konaka, J. Am. Chem. Soc., 91 (1969) 5655–5657. (498) A. B. Forrester, J. M. Hay, and R. H. Thompson, Organic Chemistry of Free Radicals, Academic Press, New York, 1968, 195–217. (499) F. L. Scott and J. A. Barry, Tetrahedron Lett. (1968) 2461–2462. (500) A. J. Fatiadi, J. Org. Chem., 35 (1970) 831–833. (501) A. J. Fatiadi, Synthetic Reagens, Vol. 4, J. S. Pizey (Ed.), Ellis Horwood, Chichester, 1981, 147–335. (502) B. Eistert, G. Kilpper, and J. Goring, Chem. Ber., 102 (1969) 1379–1396. (503) E. S. Gould, Mechanism, and Structure in Organic Chemistry, Henry Holt, New York, 1959, 376. (504) L. Eberson and S. S. Shaik, J. Am. Chem. Soc., 112 (1990) 4484–4489. (505) P. Smith and K. R. Maples, J. Magn. Reson., 65 (1985) 491–496. (506) H. C. Yao and P. Resnick, J. Org. Chem., 30 (1965) 2832–2834. (507) G. E. Lewis and G. I. Spencer, Aust. J. Chem., 28 (1975) 1733–1739. (508) E. Friedrich, W. Lutz, H. Eichenauer, and D. Enders, Synthesis (1977) 893–914. (509) Y. Ito, K. Kyono, and T. Matsuura, Tetrahedron Lett. (1979) 2253–2256.
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(510) A. A. Frime. (Ed.), Singlet Oxygen Reaction Modes and Products, Vol. II, Part 1, CRC Press, Boca Raton, FL, 1985. (511) J. H. Boyer, Chem. Rev., 80 (1980) 495–561. (512) H. H. Wasserman and R. W. Murray (Eds.), Singlet Oxygen, Academic Press, New York, 1979. (513) E. L. Clennan, L. J. Noe, E. Szneler, and T. Wen, J. Am. Chem. Soc., 112 (1990) 5080–5085. (514) C. Castro, M. Dixon, I. Erden, P. Ergonenc, J. R. Keeffe, and A. Sukhovitsky, J. Org. Chem., 54 (1989) 3732–3738. (515) For review of the chemistry of vicinal polyketones, see M. B. Rubin, Chem. Rev., 75 (1975) 177–202. (516) E. M. Tanner, Spectrochim. Acta V15. (1959) 20–26. (517) J. Elguero, R. Jaquier, and G. Tarrago, Bull. Soc. Chim. Fr. (1966) 2981–2989. (518) N. Thankarajan and K. M. Nair, J. Indian Chem. Soc., 53 (1976) 1156–1157. (519) A. Mitchell and D. C. Nonhebel, Tetrahedron, 35 (1979) 2013–2019. (520) H. H. Wasserman, J. D. Cook, and C. B. Vu, J. Org. Chem., 55 (1990) 1701–1702; H. H. Wasserman, Abstr. Pap., 200th Natl. Meet. Am. Chem. Soci., Washington, DC, (1990) ORGN 160. (521) G. A. F. Roberts, J. Chem. Soc., Perkin Trans., 1 (1979) 603–605. (522) J. M. Rao and P. M. Nair, Tetrahedron, 26 (1970) 3833–3838. (523) H. S. El Khadem and B. Coxon, Carbohydr. Res., 89 (1981) 321–325. (524) P. Pollet and S. Gelin, Tetrahedron, 36 (1980) 2955–2959. (525) A. S. Shawali, I. M. Abbas, N. F. Abdelfattah, and C. Parkanyli, Carbohydr. Res., 110 (1982) 1–9. (526) A. J. Fatiadi and H. S. Isbell, Carbohydr. Res., 5 (1967) 302–319. (527) R. P. Larsen and L. E. Ross, Anal. Chem., 31 (1959) 176–178; E. D. Marshall and R. R. Rickard, Anal. Chem., 22 (1950) 795–797. (528) A. Hutton, H. M. N. H. Irving, K. R. Koch, L. R. Nassimbeni, and G. Gafner, J. Chem. Soc. Chem. Commun. (1979) 57–58. (529) A. J. Fatiadi, Carbohydr. Res., 7 (1968) 89–94. (530) A. J. Fatiadi and H. S. Isbell, Abstr. Pap., 145th Natl. Meet. Am. Chem. Soc. N.Y. (1963) CARBOHYD 2. (531) A. J. Fatiadi and H. S. Isbell, J. Res. Natl. Bur. Std., 68A (1964) 287–299. (532) A. J. Fatiadi, Carbohydr. Res., 20 (1971) 179–184. (533) B. Magasanik and E. Chargaff, J. Am. Chem. Soc., 70 (1948) 1928–1929; see also B. Magasanik, in Essays in Biochemistry, S. Graff (Ed.), Wiley, New York, 1956, 180–190. (534) F. W. Lichtenthaler, H. Leiner, and T. Suami, Chem. Ber., 100 (1967) 2383–2388. (535) L. Anderson and H. A. Lardy, J. Am. Chem. Soc., 72 (1950) 3141–3147. (536) T. Posternak, Helv. Chim. Acta, 33 (1950) 1597–1604. (537) C. F. J. Chittenden and R. D. Guthrie, J. Chem. Soc. (1966) 1508–1510. (538) M. Oki, Top. Stereochem., 14 (1983) 1–81; M. Oki, Applications of Dynamic NMR Spectroscopy to Organic Chemistry, VCH, Deerfield Beach, FL., 1985. (539) C. Jaime, M. Rubiralta, M. Feliz, and E. Giralt, J. Org. Chem., 51 (1986) 3951–3955; D. Kost, K. Aviram, and M. Raban, J. Org. Chem., 54 (1989) 4903–4908. (540) For more on conformational and steric factors, see J. March, Advanced Organic Chemistry, 4th Edition, Wiley, New York, 1992, pp. 143, 275; E. Juaristi, Introduction to Stereochemistry and Conformational Analysis, Wiley, New York, 1991, Chapter 3.
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
A FRESH UNDERSTANDING OF THE STEREOCHEMICAL BEHAVIOR OF GLYCOSYLASES: STRUCTURAL DISTINCTION OF “INVERTING” (2-MCO-TYPE) VERSUS “RETAINING” (1-MCO-TYPE) ENZYMES
BY EDWARD J. HEHRE Department of Microbiology and Immmunology, Albert Einstein College of Medicine, New York, USA
III. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. The Extraordinary Catalytic Abilities of Glycosylases. . . . . . . . . . . . . . . . . . . . . . . 1. Use of Minisubstrates of Forbidden Configuration . . . . . . . . . . . . . . . . . . . . . . . 2. Nonretaining Reactions Catalyzed by Retaining Enzymes, Noninverting Reactions by Inverting Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Glycosyl Transfer by “Inverting” Glycosidases . . . . . . . . . . . . . . . . . . . . . . . . . . III. X-Ray Findings That Support Catalytic Group Versatility and Identify the Structures Controlling Stereochemical Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Residues Potentially Able to Protonate Minisubstrates of “Improper” Configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Structures That Limit the Stereochemical Outcome in GlycosylaseCatalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Structural Basis for Separating Glycosylases into 1-MCO (“Retaining”) and 2-MCO (“Inverting”) Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Relation of Stereochemical Behavior to Catalytic Mechanism . . . . . . . . . . . . . . . . 1. Do 1-MCO (“Retaining”) Glycosylases Invariably Act via Double Displacements? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Relationship of Transition-State Structure to the Stereochemistry and Mechanism of Glycosylase Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Structures That May Help Keep Solvent from the Catalytic Center in Glycosylase–Substrate Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Unresolved Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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I. INTRODUCTION This is a time of an unprecedented merging of different broad streams of novel findings that are reshaping the traditional understanding of the relation of protein structure to the stereochemical behavior and catalytic 0096-5332/00 $ 30.00
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workings of glycosylases. Reported crystallographic studies reveal the overall active-site geometry of some 30 glycosyl mobilizing enzymes and identify, with differing degrees of certainty, the nature and disposition of components deemed important to the catalytic process.1–3 Gene and amino acid sequencing with analysis for homology4–6 has allowed the assembly of many glycosidase families whose members share structural features and the stereochemical outcome of their catalyzed reactions.5 Again, computational treatment of multiple kinetic isotope-effect data has allowed the derivation of highly refined transition-state structures for a number of hydrolytic reactions.7 Finally, studies of reactions promoted with small glycosyl (but nonglycosidic) substrates have yielded much evidence at odds with traditional views about the catalytic scope and stereochemical behavior of glycosylases.8–10 The origins of this approach, and the ways in which results obtained with it depart from long accepted assumptions, form a preface to the main present theme, which is to examine the reported crystal structures of various glycosylases in an effort to identify the structural features that underlie the stereochemical behavior of “inverting” and “retaining” enzymes. Such findings could be significant in terms of mechanistic functioning. In the traditional view, the catalytic groups of an individual glycosylase act always to invert (or always to retain) substrate configuration and possibly do so by effecting single (or double) nucleophilic displacements. However, the key question of how a given enzyme’s catalytic groups “know” which way they are to function has only recently begun to be addressed experimentally through (a) studies of reactions catalyzed with small nonglycosidic substrates8–10, (b) by measurements of the average distance between the catalytic carboxyl oxygens of glycosidases11, and (c) by present observations on the contribution of structures in addition to the catalytic groups to the stereochemical behavior of individual enzymes. Glycosidases and glycosyltransferases are here considered together as catalysts of glycosylation (glycosylases) despite their formal assignment to separate the hydrolase [EC 3.2] and transferase [EC 2.4] classes; all of their reactions are assumed to effect, by one means or another, a simple type of chemical change whereby the glycosyl moiety of a substrate replaces a proton of a cosubstrate and is itself replaced by a proton.12–14 The stoichiometry predicts something long overlooked—that a compound may need only to bind appropriately at an active site and to yield a glycosyl group in exchange for a proton in order to serve as a substrate. This is abundantly confirmed; many well-known enzymes can use an appropriate glycosyl fluoride and/or enolic glycosyl donor as substrate (see reviews8–10,14–18).
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II. THE EXTRAORDINARY CATALYTIC ABILITIES OF GLYCOSYLASES Glycosyl fluorides of appropriate structure and anomeric configuration serve as substrates for diverse glycosylases, and the catalyzed reactions usually are closely similar in kind and in rate to those promoted with the enzyme’s best substrates. Yet, on occasion, large departures from this closeness do occur. Thus alpha-amylases, which usually are thought of as lacking significant glycosyl transferring ability, convert 움-maltosyl fluoride to maltooligsaccharides in great preference to hydrolyzing this substrate, demonstrating that alpha-amylases have a large latent potential for glycosyl transfer.19,20 Again, glucoamylase hydrolyzes 움-D-glucosyl fluoride much faster than it cleaves the nonreducing-end D-glucosyl group from maltosaccharides, suggesting that release of the bulky residual saccharide may perhaps limit the latter substrate’s rate of hydrolysis.21 Finally, cyclodextrin glycosyltransferase, which produces cyclo-dextrins from maltosaccharides and starch, does so more effectively from 움-maltosyl fluoride than from maltoteraose; it also transfers all of the glucosyl units of 움maltoheptaosyl fluoride in forming the cyclic heptaose, a “total transfer” capability not demonstrated with natural substrates.22 These and other comparable observations offer clues as to possible types of structures that may have a role in the process of catalysis by glycosylases. The present main focus, however, is not on reactions with anomerically correct glycosyl donors, but on those catalyzed with nonglycosidic substrates lacking proper configuration. These unusual reactions reveal aspects of catalytic behavior long thought to be forbidden for particular types of glycosylases.8–10 Traditional views of the catalytic scope of glycosidases and glycosyltransferases arose from decades of studies of reactions with glycosidic type substrates (saccharides, glycosides, nucleosides, glycosyl phosphates, sugar nucleotides, and so on). The accumulated findings gave rise to three confidently accepted rules about the limits of catalytic activity, namely (a) a given glycosidase uses substrates only of 움- (or only of 웁-) anomeric configuration23, (b) a glycosidase or transferase always retains (or always inverts) substrate configuration15,16, and (c) glycosidases which hydrolyze substrates with inversion never promote glycosyl transfer to compounds other than water.10,15,24 These confidently assumed limits of catalytic scope and steric course can be of practical usefulness when applied to reactions with glycosidic substrates. However, the lack of generality of each of the rules is evident in their failure to hold for many reactions promoted with small nonglycosidic substrates. Although the latter reactions are not found in living matter and generally show a very low order of catalytic efficiency,
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their occurrence in contradiction to long-standing belief recalls experiences in other disciplines where unusual effects of very small magnitude have altered basic understanding and opened new opportunities for progress. 1. Use of Minisubstrates of Forbidden Configuration Various glycosidases react slowly with small substrates lacking the particular 움- (or 웁-) anomeric configuration required of their glycosidic substrates. Some use a glycosyl fluoride whose configuration is opposite that of the enzyme’s natural substrates (reviewed in refs.8,9, see also25); among these, 움- and 웁-glucosidase,26–28 for example, also use an enolic glycosyl donor of one or more structural type lacking the anomeric
I 웁-D-glycoside
II 웁-D-glycosyl fluoride
III D-glycal
IV “D-glycoheptenitol”
V “D-glycooctenitol”
configuration and ring conformation of glycopyranosides. Others such as 움and 웁-galactosidase29–35 and cellulases of several types36,37 act on appropriate enolic glycosyl donors; still others, including a 웁-xylosidase38 and the amylo-(1 → 6)-glucosidase component of glycogen-debranching enzyme,39 use the wrong anomer of an appropriate glycosyl fluoride. In most cases, the forbidden substrate is protonated from a different direction and by a different catalytic source than the enzyme’s glycosidic substrates. How is it that such familiar enzymes as 움- and 웁-glucosidases,26 웁galactosidase,29 beta-amylase,40 and glycogen phosphorylase41 use very small glycosyl compounds lacking correct anomeric configuration and/or ring conformation as substrates (albeit poor ones), whereas they never act on glycosidic compounds of the wrong configuration, and only in rare cases use furanosides?a Appropriate glycosyl fluorides (both anomers), glycals, and exocyclic enitols presumably have the potential to bind productively at an a
One laboratory group has reported that almond 웁-glucosidase hydrolyzes aryl 웁-Dglucofuranosides as well as the corresponding 웁-D-glucopyranosides42; that limpet 웁-glucosiduronase hydrolyzes 2-naphthyl 웁-D-glucofuranosiduronic acid as well as 2naphthyl 웁-D-glucopyranosiduronic acid43; and that almond 웁-galactosidase (but not E. coli or bovine liver) 웁-galactosidase hydrolyzes various 웁-D-galactofuranosides.44
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enzyme’s donor site because they lack an unsuitably oriented bulky substituent at C-1, in contrast to glycosides of the wrong configuration. For example, various 움-glucosidases hydrolyze compounds of types II–V such as 웁-D-glucopyranosyl fluoride, D-glucal, 2,6-anhydro-1-deoxy-D-gluco-hept-1enitol (“D-gluco-heptenitol”), and (Z)-3,7-anhydro-1,2-dideoxy-D-glucooct-2-enitol (“D-gluco-octenitol”), whereas no 움-glucosidase is known to act on a compound of type I. Even the smallest of the latter, methyl 웁-Dglucopyranoside, carries a sizeable equatorial substituent at C-1 that presumably precludes the productive binding of I to 움-glucosidases by clashing with protein residues lining the active-site cavity. Finally, the means whereby an enzyme activates a suitably bound minisubstrate of forbidden configuration is suggested by the finding noted earlier that, in most cases, the protonation of such substrates involves a different catalytic source than that which protonates natural substrates. Presumably, an enzyme’s paired catalytic carboxyl groups, one of which acts on glycosidic substrates as general acid with the other as a base or nucleophile, would function in the reverse way—with the latter carboxyl group (uncharged) serving to protonate a bound minisubstrate of forbidden anomeric configuration. 2. Nonretaining Reactions Catalyzed by Retaining Enzymes, Noninverting Reactions by Inverting Enzymes Glycosylases are commonly referred to as inverting or retaining enzymes based on whether the reaction–product configuration is opposite to or the same as that of the enzyme’s glycosidic substrates.15 Yet, these neat characterizations of the two types of enzymes are not free from ambiguity. They imply that a given glycosylase catalyzes all reactions with inversion (or all with retention) and that product configuration derived from that of substrates by the number of displacements effected by the catalytic groups is the only way the steric course of reactions can be effected. However, glycosylases cannot be considered to catalyze retaining or inverting reactions with glycals or exocyclic enolic glycosyl donors, as these substrates have no 움- or 웁-anomeric configuration to retain or invert. Beginning with the first NMR studies of the hydration of D-glucal promoted by an 움- and a 웁-glucosidase, carried out with Fred Brewer,26 the stereochemistry of more than 25 such reactions by various “retaining” or “inverting” enzymes with different enolic substrates has been elucidated by work in our own and other laboratories, particularly that of Jochen Lehmann.The latter’s syntheses of the heptenitol and octenitol analogs of Dgalactal and D-glucal opened the way to stereochemical studies of a critically widened range of glycosylation reactions catalyzed with prochiral substrates.
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Table I shows that, in every reaction examined, the hydration (or transfer) products formed from an enitol have the same configuration as the hydrolytic (or transfer) products formed by the same enzyme from its more reactive chiral substrates. The conservation of stereochemical outcome holds whether the enzyme protonates the enitol from the same or opposite direction than its glycosidic substrates. The finding that a given glycosylase can create, de novo, a particular product configuration from a prochiral substrate indicates that the stereochemical outcome of all its reactions could be under topological control. This possibility is further suggested by the finding that hydrolysis of a glycosyl fluoride of the wrong configuration is catalyzed by certain enzymes. For example, 움-glucosidases of several origins slowly hydrolyze 웁-D-glucosyl fluoride to form 움-D-glucose,52,53 while sweet almond 웁TABLE I Stereochemical Course of Reactions Catalyzed by Various “Retaining” and “Inverting” Glycosylases With Prochiral Glycosyl Donors
Enzyme Candida tropicalis, buckwheat, rice, Aspergillus niger 움-glucosidase Candida tropicalis, rice 움-glucosidase Rice, Aspergillus niger 움-glucosidase Sweet almond 웁-glucosidase Sweet almond 웁-glucosidase Coffee bean 움-galactosidase Escherichia coli 웁-galactosidase Escherichia coli 웁-galactosidase Escherichia coli 웁-galactosidase Iapex lacteus Ex-1, Trichoderma reesei CBH I cellulase Trichoderma reesei CBH I cellulase Muscle, potato, Escherichia coli phosphorylase Muscle, potato phosphorylase Sweet potato, soybean, 웁-amylase Trichoderma reesei trehalase Arthrobacter globiformis glucodextranase
Prochiral Donora
Configuration of Product(s)b
Reference
␣H
26,45
Cellobialc
움H, 움T 움H 웁H 웁H 움H 웁T 웁H 웁H 웁H
28,46 47 26 28 33 31 30 32 36,37
Lactalc D-Glucal
웁H 움T
D-gluco-Heptenitol
움T 웁H 웁H 웁H, 움T
D-Glucal
a,c
D-gluco-Heptenitol D-gluco-Octenitol D-Glucal
c
c
D-gluco-Heptenitol D-galacto-Octenitol c
D-Galactal
D-galacto-Heptenitol D-galacto-Octenitol
Maltalc c D-gluco-Octenitol D-gluco-Heptenitol
37 41 48,49 50,51 47 28,46
a The “enitol” names refer to 2,6-anhydro-1-deoxyhept-1-enitol or (Z)-3,7-anhydro-1,2-dideoxyoct-2enitol. b H, anomeric configuration of the hydration product; T, configuration of the mobilized glycosyl unit in the transfer product(s). c Substrate found to be protonated from a direction opposite to that generally assumed for glycosidic substrates.
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glucosidase very slowly hydrolyzes 움-D-glucosyl fluoride to form 웁-Dglucose.53 These inverting reactions obey Michaelis–Menten kinetics and show no evidence of transfer-product formation. In a related situation, the CBH II cellulase of Trichoderma reesei (which hydrolyzes substrates of 웁configuration with inversion)54 is found to hydrolyze 움-cellobiosyl fluoride to form 움-cellobiose with no evidence of transfer-product formation or departure from Michaelian kinetics.25 A minimal mechanism whereby 움-glucosidases hydrolyze 웁 D-glucopyranosyl fluoride, 움-D-glucopyranosides, and D-glucal (in each case yielding the product as the 움-anomer) is illustrated53 in Fig. 1. This mechanism assumes that in each case the lone pair on the substrate’s ring oxygen assists cleavage of the C-1 glycosyl bond to form an oxocarbonium ionlike transition state and that this is stabilized by negatively charged carboxylates and finally attacked by water from a structurally restricted (움) direction to provide an SN1-type mechanism. For the CBH II-catalyzed hydrolysis of 웁glycosidic substrates with inversion and of 움-cellobiosyl fluoride with retention, Konstantinidis et al.25 suggested a different mechanism. They considered that the reported crystal structure of the catalytic domain of cellulase CBH II (of family 6)55 shows no plausible candidate for a catalytic base and that hydrolysis of 움-cellobiosyl fluoride by the enzyme involves merely a pattern of electrostatic fields that indiscriminantly stabilize a
FIG. 1. Proposed mechanisms of reactions catalyzed by rice ␣-glucosidase with substrates of different anomeric configuration. Reproduced from H. Matsui et al., Carbohydr. Res., 250 (1989) 45–56, with permission from Elsevier Science, Ltd.
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cationlike transition state for SNi displacement of the (small) departing fluoride ion.b Regardless of the mechanism(s) involved, these examples of “retaining” enzymes promoting hydrolysis with inversion and “inverting” enzymes promoting hydrolysis with retention again point to the existence of protein structural features that control the stereochemical outcome of reactions independent of substrate configuration. 3. Glycosyl Transfer by “Inverting” Glycosidases The literature records a consistent failure of such hydrolytic enzymes as beta-amylase,58,59 mold glucoamylase,60,61 glucodextranase,62 trehalase,63,64 and Bacillus pumilus 웁-xylosidase65 to promote glycosyl transfer.c These negative results of tests using glycosidic substrates led to the widely held view that “inverting” glycosidases are unable to form transfer products, as the latter would lack the anomeric configuration required of the enzyme’s substrates. Were glucoamylase, for example, to transfer the 움-D-glucosyl residue of maltose to the 4-OH group of D-glucose, one would expect formation of cellobiose, which is not a substrate for the enzyme.15,10 Yet, maltose phosphorylase—which, like glucoamylase, acts on maltose but not on cellobiose—catalyzes D-glucosyl transfer from maltose to inorganic phosphate in a reaction that proceeds with inversion of configuration.68,69 Actually, each of the five just cited hydrolytic enzymes acts with inversion on both 움- and 웁-anomers of a glycosyl fluoride—hydrolyzing the correct anomer and catalyzing glycosyl transfer with the wrong anomer21,38,40,70,71; the glycogen debranching enzyme of rabbit muscle [specifically, its amylo(1 → 6)-glucosidase (EC 3.2.1.33) component] behaves similarly,39 catalyzing D-glucosyl transfer from 웁-D-glucosyl fluoride to cyclomaltoheptaose as acceptor. Rhizopus nireus glucoamylase acts on 웁-D-glucosyl fluoride plus methyl 움-D-glucopyranoside (a nonsubstrate) as acceptor b
c
Rouvinen et al.55 considered that Asp401 of cellulase CBH II might possibly serve as a general base in cellodextrin hydrolysis, but presented no data on the distances from its carboxyl group to the reaction center or to the carboxyl group of the putative general acid residue. The possibility that Asp401 might serve as the catalytic base appeared to be supported by the tentative assignment of this function to its counterpart Asp265 in family 6 Thermomonospora fusca cellulase E2.56,24 New findings with a mutant of Asp265, however, are not consistent with this residue’s role as a catalytic base in E2.57 The first report proposing the glycosyl moiety to be a functional group of biochemical significance12 introduced the term “transglycosylation” for nonhydrolytic reactions catalyzed by enzymes subsequently classed as glycosyltransferases [EC 2.4]. The more general stoichiometric view of grouping together all enzymes that catalyze glycosyl–proton interchange (or glycosylation)13,66,14 further covers hydrolytic reactions and their reversals as well as reactions promoted with small nonglycosidic glycosyl donors. At present, some authors use “glycosyl transfer” in this broad sense.15
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to yield methyl 움-maltoside and a little methyl 움-isomaltoside.21 Glucodextranase acts similarly to form mainly methyl 움-isomaltoside; in addition, it catalyzes both the hydration of “D-gluco-heptenitol” to form 웁-D-gluco-heptulose and transfers a glycosyl group from the enitol to form 움-D-gluco-heptulosyl-“2,7-heptenitol” and 움-D-gluco-heptulosyl-“2,728,46 D-gluco-heptulose.” Thus, it is not that “inverting” glycosidases lack the ability to catalyze nonhydrolytic glycosylation reactions but that small substrates having an “anomeric” configuration other than that of hydrolyzable glycosidic substrates often allow the ability to be demonstrated. How they do so is suggested by the behavior of Rimiveus glucoamylase. The catalytic groups of this enzyme promote transfers from 웁-D-glucosyl fluoride in a way that parallels their actions in condensing two tandemly bound D-glucose molecules to form maltose. In condensation, 웁-D-glucose (the anomer-specific donor substrate)66 is protonated at the si-face by the same catalytic group (now uncharged) that functions as a base in the hydrolysis of maltose—as required by the principle of microscopic reversibility. However, since the stereocomplementary hydrolysis and transfer reactions catalyzed by glucoamylase with 움- and 웁-D-glucosyl fluoride are not reversals of each other, the reactions observed clearly indicate that the enzyme’s catalytic groups are functionally flexible beyond needs of the principle of microscopic reversibility.21 The small size of 웁-D-glucopyranosyl fluoride, which is comparable to that of the 웁-D-glucose that undergoes condensation, would permit it to bind productively and to allow a second molecule (or other acceptor) to bind simultaneously in tandem at the reaction center. In contrast, the equatorial aglycon group at C-1 of any 웁-glucoside would clash with protein residues at the active site, preventing 웁-glucosides such as cellobiose from achieving the productive binding alignment required of glucoamylase substrates. That “inverting” glycosidases catalyze complementary hydrolysis and transfer reactions with the opposed anomers of a glycosyl fluoride has been considered15,72,73 to be strong evidence for Koshland’s74 single nucleophilic displacement mechanism. However, the large intrinsic secondary 3H kinetic isotope effects obtained by Matsui et al.75 for 움-D-glucopyranosyl fluoride hydrolysis with inversion, catalyzed by glucoamylases of different biological origins, do not support the inversion mechanism proposed by Koshland74 in which: “the significant feature is that the covalent bond between B and X [of substrate] is broken simultaneously with or after the nucleophilic attack on B by molecule A.” The large secondary kinetic isotope effects point instead to a mechanism in which substantial glucosyl bond breaking and development of a carbonium ionlike enzyme transition state occur before appreciable product is formed.
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III. X-RAY FINDINGS THAT SUPPORT CATALYTIC GROUP VERSATILITY AND IDENTIFY THE STRUCTURES CONTROLLING STEREOCHEMICAL OUTCOME Interest centers on the extent to which the reported crystal structures of individual glycosylases (a) are able to identify an active-site residue which, by nature and spatial disposition, might serve to protonate a bound enolic substrate or wrong glycosyl fluoride anomer and (b) are able to identify protein structural features that could dictate the direction of approach of acceptor cosubstrates to the reaction center. 1. Residues Potentially Able to Protonate Minisubstrates of “Improper” Configuration The catalysis of reactions by glycosidases acting on glycosidic substrates is commonly considered to depend on a pair of spatially fixed carboxyl groups disposed across the reaction center from each other—one acting as a general acid, the other as a general base or nucleophile. That many glycosidases use enolic substrates or the wrong glycosyl fluoride anomer, protonating them from a direction opposite that for glycosidic substrates, suggested that their carboxyl groups are able to function flexibly and to activate such disfavored substrates.9,40 Recent crystal structure studies confirm the presence of two fixed and opposed active-site carboxyl groups in nearly all glycosidases, including 웁galactosidase;77 cellulasesd of families 6,7,9,10, and 45;56,80–88 xylanases;89–93 alpha-amylases;94–100 beta-amylase;101,102 and glucoamylase.103,104e Hevamine, a chitinase from Hevea braziliensis, is exceptional in lacking a catd
e
A cellulase is classed either as an endo 웁-glucanase [EC 3.2.1.4] or a 웁-glucan cellobiohydrolase [EC 3.2.1.91] distinguished by cleaving mostly cellobiose from the chain ends. Each is made up of a set of genetically distinct families characterized by the steric course of its reactions. Thus an “endoglucanase” of family 10 hydrolyzes cellulosic linkages with retention; one of family 9 does so with in version.5,6 Likewise, a “cellobiohydrolase,” CBH I, of family 7 hydrolyzes cellulosic chains from the reducing end with retention78–80; CBH II of family 6 does so from the nonreducing end with inversion.55,80 A point to be noted is that the anomeric configuration of a cellobiose molecule released on hydrolysis by CBH I is not created by the reaction, whereas, the 움-anomeric configuration of the cellobiose released on hydrolysis by CBH II is so created; CBH II is found to use cellobiose (presumably the 움-form) as a glycosyl donor to the terminal 4-OH group of cellulose.67 Independent evidence for the highly frequent presence of a pair of oppositely disposed carboxyl groups at the catalytic center of glycosidases has come from hydrophobic cluster analysis.105 Motifs formed by contiguous Val, Ile, Leu, Met, Phe, Trp, and Val residues, corresponding to 움-helical or strand structures, indicate that a pair of glutamic acid residues characterizes all (⬎150) members of families 1, 2, 5, 10, 23, 30, 35, 39, and 42, which hydrolyze 웁105 D-glycosidic substrates with retention of configuration. These motifs are not observed for enzymes that hydrolyze 움-D-glycosidic substrates, whether with retention (alpha-amylases) or inversion of configuration (beta-amylases).
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alytic base.106,107 Possibly, as previously noted, this lack may also characterize cellulase CBH II.55,25 Among glycosyltransferases, this arrangement of opposed carboxyl groups across the reaction center appears not to be the norm. It is found Bacillus circulans cyclodextrin glucanosyltransferase (an alpha-amylase family member),108–110 but not in orotate 5⬘-phosphoribosyl transferase,111,112 purine nucleoside phosphorylase,113 NAD⫹ nucleosidase (oxidized nicotinamide adenosine diphosphate ribosylase),114 or glycogen phosphorylase.115–119 In learning how glycosylases may protonate a substrate lacking correct anomeric configuration it is of note that opposing catalytic carboxyl groups exist at the active site of two inverting glycosidases (glucoamylase and betaamylase), which use a glycosyl fluoride of disfavored (웁) configuration, protonating it differently than their 움-linked substrates21,40; likewise, in two retaining glycosidases—cellulase CBH I, which hydrates cellobial and lactal,37 and 웁-galactosidase, which hydrates D-galactal31—each enzyme protonating these glycals differently from its 웁-linked substrates. a. Glucoamylase and Beta-Amylase.—That the probable source of protonation of 웁-D-glucosyl fluoride by glucoamylase is Glu400, which normally functions as the catalytic base in hydrolyzing 움-linked maltosaccharides, is evident from the crystal structure of Aspergillus awamori glucoamylase complexed with 1-deoxynojirimycin.103 The carboxyl group of Glu400, presumably uncharged in some protein molecules, appears properly positioned to assist departure of fluoride from 웁-D-glucosyl fluoride with formation of a transient oxocarbonium iontype–enzyme complex.103 Likewise, the crystal structure of soybean betaamylase complexed with 웁-maltose shows the catalytic site with Glu186 and Glu380 suitably disposed to serve as general acid and base catalyst, respectively, in maltosaccharide hydrolysis (Fig. 2, see color plate). The carboxyl group of Glu380, presumably present in the uncharged state in some molecules, is properly located to serve as the source of protonation101 in reactions catalyzed by beta-amylase with 웁-maltose, 웁-maltosyl fluoride, and maltal. b. CHB I and -Galactosidase.—Similarly, the structure of cellulase CHB-I of T. reesei complexed with o-iodobenzyl 1-thio-웁-cellobioside contains two opposed glutamic acid residues. Glu217, near the labile 웁glycosidic oxygen bridge atom, is judged to be the general acid catalyst with Glu212, across the reaction center, the probable nucleophile in the retaining reactions catalyzed with 웁-glucosidic substrates.79 Glu212 appears to be suitably spatially disposed to account for the observation that CBH I protonates cellobial and lactal from a direction opposite that for
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protonating the glycosidic bridge oxygen of cellulose chains.37 It would appear likely that Glu212 exists in uncharged form in some protein molecules, possibly with its pKa elevated by proximity of the double bond of a bound glycal, providing it with the flexibility to function as a general acid with prochiral substrates. Again, the crystal structure of the very large tetrameric Escherichia coli 웁-galactosidase molecule shows the active site located in a deep pocket present at the end of the TIM-like barrel of each monomer.77 The conserved catalytic residues found in the walls of this pocket comprise Glu461, the presumed acid catalyst, and Glu537, the catalytic nucleophile.120,121 The latter residue appears suitably positoned to function as the general acid catalyst in the observed protonation of the double bond of D-galactal from a direction opposite that for protonating 웁31 D-galactosides. In sum, each of these four glycosidases possesses a suitably disposed glutamic acid carboxyl group which, in the uncharged state, could potentially activate a small glycosyl donor of disfavored configuration. Figure 2 illustrates the geometry of the catalytic site in one of these enzymes, soybean beta-amylase, complexed with 웁-maltose. The latter binds both as as donor substrate (violet and green glucose units) and cosubstrate (red and yellow units).101 2. Structures That Limit the Stereochemical Outcome in Glycosylase-Catalyzed Reactions The different anomeric configuration of products formed from starch by alpha- and beta-amylase led to the early proposal that these and other enzymes catalyzing reactions with retention or inversion act by clearly different direct nucleophilic displacement mechanisms74 and later to the idea that they might act by a common carbonium-ion mechanism if they vary the direction whereby water approaches the reaction center.122–124 Experimental indications that glycosidases may, indeed, control product configuration topologically first emerged from studies of reactions of such enzymes with enolic glycosyl substrates (Table I). The enzymes 움- and 웁-glucosidase, for example, both catalyze hydration of D-glucal; each leads to a product of the same anomeric configuration as formed from its usual substrates, even though each enzyme protonates D-glucal differently from maltosaccharides.26 Again, certain “retaining” 움-glucosidases and the “inverting” glucodextranase of Arthrobacter globiformis act on D-gluco-heptenitol, yielding both D-gluco-heptulose and D-gluco-heptulosyl transfer products. In each case the anomeric configuration of the hydration product and that of the transfer products matches the configuration of the corresponding hydrolysis and transfer products formed from chiral substrates.28,46 The stereo-
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chemical outcome of these reactions catalyzed with heptenitol, created without guidance from substrate configuration, indicates that the 움-glucosidases must somehow direct all incoming cosubstrates to the catalytic center in the same (움) orientation; whereas the glucodextranase must ensure that water approaches the center from the 웁 direction, carbohydrate cosubstrates from the opposite (움-) direction.28,46 Although the tertiary structures of the 움-glucosidases and the glucodextranase used have not yet been described, those reported for various other “retaining” and “inverting” enzymes add independent new information concerning the structural basis of the stereochemical behavior of these enzymes. a. Reported Findings with “Retaining” Glycosylases.—The central question now to be asked regarding reported crystallographic findings for individual (ligand complexed) glycosylases of this type is whether the activesite cavity orients all acceptor cosubstrates (water, carbohydrates, and others) to reach the catalytic center (namely, C-1 of the reactive glycosyl moiety) from the same direction. This is a narrower and more realistic goal than seeking to derive a mechanism from extended time-averaged X-ray crystal structures that may or may not reveal the disposition of all ordered water molecules and that do not resolve proton positions. For example, in the case of hen’s egg-white lysozyme, where the proposed oxycarbonium ion-stabilizing role of Asp52 has been questioned,73,125,126 subsequent X-ray findings show not only that that Asp52 and its interactions with bound substrate help strain the pyranose ring into a more reactive conformation but that this residue’s interactions with neighboring residues block all acceptors from approaching the center from the 움-side. (i) Hen’s Egg-White Lysozyme.—The active site is located in a cleft in the protein surface. Glu35 functions as the general acid, with Asp52 possibly implicated in stabilizing the transition state.1,76 The structure of the enzyme complexed with a reaction product, N-acetyl-웁-muramic acid– N-acetyl-웁-D-glucosamine—N-acetyl-웁-muramic acid (MurNAc-GleNAcMurNAc) shows the trisaccharide bound at subsites B, C, and D in the active-site cleft.1 The reducing MurNAc unit in subsite D has a sofa-type conformation and 웁-anomeric configuration; its equatorial O-1 atom is Hbonded to the OE1 atom of Glu35. There is no room for binding the 움anomer of this MurNAc, as its axially oriented 1-OH would clash with Asp52 and other closely interacting components in the region. These features indicate that water and other cosubstrate molecules can only approach the reaction center from the 웁 (Glu35)-side. Studies with a ⬎99% inactive Asp52Ser mutant, cocrystallized with 웁-(1 → 4)-N-acetyl-Dglucosamine hexasaccharide, confirm the importance of the position of the
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side chain of Asp52 in relation to substrate in blocking an 움-directed approach of acceptors.127 (ii) CBH I Cellulase, -Galactosidase, and Glycogen Phosphorylase.— X-Ray structures have been reported for these three “retaining” glycosylases, which convert enolic substrates into products of the same configuration as formed from their glycosidic substrates. The reported crystallographic findings are consistent with the view that the conserved stereochemical outcome of reactions catalyzed by each enzyme is due to substrate and cosubstrate-binding structures in the active-site cavity that orient all reactants, including water, to the catalytic center from the same direction with no cosubstrate access to the center from the opposite direction. The structure of cellulase CBH I of Trichoderma reesei complexed with o-iodobenzyl 1-thio-웁-cellobioside shows the active site to be located in a long tunnel flattened to accomodate glucose units in subsites A to G.79 This tunnel directs all reactants, including water, toward the presumed general acid catalyst, Glu217, on the 웁-side of the reaction center. In the enzyme–ligand complex, Glu217 is H-bonded to the O-4 atom of cellobioside’s O-glycosidic linkage between subsites B and C; Glu212, across the center and proximate to it, is assumed to be the nucleophile. The data are highly suggestive of water entry from the 웁-side, even though bound water is not found near the nucleophile and reaction center. Whether residues on the 움-side of the center (around Glu212) have zero access to solvent is not established. The authors concluded that the catalytic groups necessary for a double displacement reaction are present,79 but the data do not establish that a covalent 움-glycosyl–Glu217 intermediate is necessarily formed. The entry of water via the active-site cavity is consistent with the enzyme’s observed creation of a hydration product of 웁-configuration from cellobial by way of a carbonium ion type-mediated reaction.37 The crystal structure of the very large tetrameric E. coli 웁-galactosidase molecule has been reported77 at relatively low (3.5 Å) resolution and only for the unliganded enzyme; it does not inform as to whether the catalytic site has access to solvent from the 움- as well as from the 웁-side of the reaction center. However, the data are consistent with the idea that all acceptors, including water, gain access to the center from the 웁-side, which ensures that products of 웁-configuration are formed from various enitols30–32 as they are from 웁-D-galactosides. Crystallographic studies of the structures of rabbit muscle glycogen phosphorylase b, complexed with D-gluco-heptenitol or a maltosaccharide plus inorganic phosphate (Pi), confirm that the 움-anomeric configuration of the product of these phosphorolytic reactions is dictated topologically. As illustrated in Fig. 3, the enitol binds at the catalytic site of phosphorylase in a
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FIG. 3. Reported mechanism of catalysis by glycogen phosphorylase for the phosphorolysis of D-gluco-heptenitol to form 움-D-heptulosyl phosphate (above) and the phosphorolysis of malto-oligosaccharides to form 움-D-glucosyl phosphate (below). Adapted from McLaughlin et al., Biochemistry, 23(1984) 5862–5873, with permission of the American Chemical Society.
position essentially occupied by the glucose of bound 움-D-glucopyranosyl phosphate.115 The attacking inorganic phosphate (Pi) binds between the enolic bond of heptenitol and the 5⬘-phosphate of the pyridoxal 5⬘phosphate catalytic cofactor; that is, as is found for the axial 1-PO4 group of 움-D-glucosyl phosphate and related compounds.115–118 Figure 3 illustrates that the active-site cavity of phosphorylase provides for the conserved (움-)
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binding orientation to the catalytic center of all cosubstrates, including the inorganic phosphate (or arsenate) in lytic reactions and the maltosaccharide acceptors in syntheses from 움-D-glucosyl phosphate.115,117–119 Since glycogen phosphorylase has no ionizable group near the catalytic center,115,117 neither binding nor activation of Pi can occur on the 웁-side of the center. (iii) Pancreatic Alpha-Amylase and Cyclodextrin Glycosyltransferase.— Active-site structures have been described for these related glycosylases whose reactions with maltosidic substrates and 움-maltosyl fluoride proceed with retention of configuration. Their stereochemical behavior with minisubstrates of improper configuration has not been described. The active center of porcine pancreatic alpha-amylase (family 13) is found in a long cleft in the protein surface that provides easy access to solvent and dissolved ligands. The crystal structure of the enzyme soaked with 1 mM acarbose (A,B,G1,G2), an 움-linked inhibitor in which A,B ⫽ acarvioside and G1,G2 ⫽ maltose, shows cyclic units bound in five subsites. These are identified as G,G,A,B,G with G,G representing maltose 움-(1 → 4)-linked to A, the nonreducing end unit of acarbose. The catalytic center, located between units A and B, comprises a trio of conserved carboxylates. Those of Glu233 and Asp300, each on the 움-side of the active-site cleft and 3 Å from the glycosidic bridge N-atom of the acarvioside moiety, presumbly provide for the protonation of the anomeric carbon atom of an 움-linked moiety of a substrate. The presumed base or nucleophile, Asp197, lies opposite in the cleft, across the reaction center.98,99 An ordered water molecule is not observed in the region of Asp197, suggesting that solvent as well as carbohydrate ligands can reach the reaction center only from the 움-direction via the active-site cavity. The authors found OD2 of Asp197 and OE2 of Glu233 to be located 3.3 and 3.5 Å from the anomeric C-I atom of cyclitol A—distances ⬃1.8 Å longer than expected for covalent bonds. They considered that the crystal structure does not provide evidence for a covalent 웁-linked glycosyl–enzyme intermediate99 but supports, instead, a mechanism for porcine alpha-amylase involving a carbonium-ion transition state as proposed for lysozyme.1,76 For the alpha-amylase of Asperillus oryzae, a water molecule is found hydrogen bonded to the presumed acid catalyst, each oriented alpha to the reaction center.95 Cyclodextrin glycosyltransferases [EC 2.4.1.19] share family 13 with alphaamylases, although the latter are formally classed as hydrolases [EC 3.2.1.1]. The CGTases utilize starch, maltodextrins, and 움-maltosyl fluoride to synthesize cyclic compounds of six, seven, or eight 움-(1 → 4)-linked glucopyranose units as well as related noncyclic dextrins. The Bacillus circulans strain 251 enzyme complexed with acarbose shows an active-site structure
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with the inhibitory ligand bound in the same orientation as maltosaccharides.110 Glu257, found within H-bonding distance of the glycosidic oxygen between the B and C units of acarbose, is considered to be the proton donor; Asp229, on the opposide (웁-) side of the reaction center, is the presumed general base or nucleophile. It interacts closely with a water molecule in a pocket formed by the main-chain atoms of residues 139 and 229, but this water does not appear to be catalytically significant as it is not in close contact with the reactive C-1 atom of the B unit of acarbose. Though proof is lacking that this C-1 atom lacks access to solvent from the 웁-side, the crystallographic data strongly suggest that water, as well as carbohydrate cosubstrates, approach the catalytic center from only one (움-) direction, by way of the active-site cavity. (iv) Cex -Cellulase/Xylanase.—Crystallographic studies have been reported for the catalytic domain of the Cex 웁-glycanase of Cellulomonas fimi, which hydrolyzes cellulase and xylan with retention of configuration. The active-site structure of the complex of this enzyme with 2,4dinitrophenyl 2-deoxy-2-fluoro-웁-cellobioside shows the presence of bound 2-deoxy-2-fluorocellobiose, with C-1 covalently 움-linked to the nucleophilic residue, Glu233.88 The intermediate is catalytically competent. Bound water is not observed in proximity to Glu233, but measurement of the accessibility of the nucleophile to solvent is not reported. An ordered water molecule within H-bonding distance of the acid catalyst Glu127 and of residue Gln203 is considered to be the likely nucleophile in the terminal step of catalysis. This water has the same (웁-) orientation to the catalytic center as the enzyme’s substrates.87,88 b. Reported Findings with “Inverting” Glycosylases.—(i). Cellulase CBH II, Beta-Amylase, and Glucoamylase.—X-Ray diffraction findings have been reported for these three glycosidases, which had been found, through studies of their reactions with minisubstrates, to control product configuration topologically. Their crystal structures provide significant insights into how protein structural features control the stereochemical outcome of reactions by enzymes of this type. Trichoderma reesei cellulase CBH II directly hydrolyzes cellodextrins and both 움-and 웁-cellobiosyl fluoride to form 움-cellobiose in each case.25,73 The crystal structure of the catalytic domain shows the active site to be located in a tunnel-like cavity of restricted volume, affording four subsites in tandem.55 After the nonreducing end-unit of a cellulose chain has entered and traversed the tunnel, hydrolysis of the penultimate 웁-(1 → 4) linkage occurs at the reaction center; the 움-cellobiose product is then extruded into solvent. Rouvinen et al.55 reported that a narrow tubular passage, roughly
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orthogonal to the tunnel, channels water from the protein surface to the reaction center specifically from the 움-direction. It is not evident whether a water molecule needs to be bound to be activated, but no ordered water molecule is found near (and alpha) to the reaction center. A catalytic residue serving to help water attack is not apparent, but the presumed acid catalyst, Asp221, is reportedly buried and inaccessable to solvent. Hence, the structure of CBH II is consistent with the view that formation of 움cellobiose from 웁-cellobiosyl fluoride54 and from methyl 웁-cellotetraoside37 results from a structure-limited 움-orientation of water to the reaction center.55 A different specific mode is envisioned for beta-amylase, based on the crystal structures of soybean enzyme, unliganded or treated with 웁-maltose or with maltal.101 Beta-amylase does not hydrolyze maltose but uses 웁maltose as a glycosyl donor, condensing it to a small extent with a second maltose to form maltotetraose and water, as expected from the principle of microscopic reversibility.66 Beta-amylase also catalyzes the slow hydration of maltal [움-D-glucopyranosyl-(1 → 4)-D-glucal] to form 2-deoxy-웁maltose.50,51 The crystal structure locates the catalytic site in a deep pocket in the protein surface. The 웁-maltose-treated enzyme shows two molecules of the substrate/cosubstrate bound in tandem, with some maltotetraose condensation product detectable in the same subsites. The maltal-treated enzyme shows two molecules of the 2-deoxymaltose hydration product bound in tandem (the nonreducing end of each saccharide points to the base of the active-site pocket).101 In unliganded beta-amylase the pocket is open for substrate binding or product release, but one of its walls is formed by a mobile hinged loop that closes down on bound substrates (Fig. 4, see color plate). The closed loop’s Asp101 residue interacts with the two most deeply positioned glucose units in the active-site pocket and also (indirectly) with its Val99 residue; Asp101 is too far removed from the reaction center to be part of the catalytic chemistry.f Through contacts between the methyl groups of Val99 and those of Leu383 the closed loop also forms a hydrophobic surface across the reaction center, shielding it from solvent (Fig. 5, see color plate). In the 웁-maltose-treated enzyme this surface extends over the area between the two bound maltose molecules (or middle 움-D-glucosidic linkage of f
Totsuka et al. initially proposed, based on finding site-directed mutants of Asp101 and Glu186 to be nearly inactive, that these two moieties are the essential catalytic residues for beta-amylase.128 However, later reports confirm the crystallographic evidence that Glu186 and Glu380 are suitably disposed to function as the catalytic residues,101 since activity is lost in mutants of these residues.129,130 The importance of Asp101 and of Leu383 (whose Leu383Ser mutant shows remarkably decreased activity)130 lies in their demonstrated roles in binding or recognizing substrate and in their contributions, via interactions with Val99, that allow the closed loop to form a hydrophobic surface over the reaction center.101
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maltotetraose) and over both catalytically active carboxyl groups, namely of Glu186 on the 움-side of the reaction center and of Glu380 on the 웁side.101 There is then no measurable solvent access to the side chains of the catalytic residues or to the potentially reactive carbon and oxygen atoms of the sugars at the catalytic center. This means that the water molecule involved in starch hydrolysis or maltal hydration must exist beneath this hydrophobic surface. In unliganded beta-amylase an ordered water molecule (H2O 866) is indeed found within H-bonding distance of OE2 of Glu380, the presumed nucleophile, and the main-chain O of Asn381. In the enzyme treated with maltal, this water molecule is displaced by the equatorial O-1 atom of the 2-deoxy-웁-maltose hydration product. Moreover, when maltotetraose is formed by the enzymic condensation of maltose, the byproduct appears as an ordered water in the same position as occupied by H2O 866 in the unliganded enzyme, H-bonded to the carboxyl group of Glu380 and main-chain O of Asn 381. No ordered water is found near Asp221, the general acid catalyst in maltosaccharide hydrolysis, located on the 움-side of the reaction center. An apparently similar situation is found with fungal glucoamylase, which catalyzes the hydrolysis of 움-D-glucosyl fluoride and maltosaccharides to yield 웁-D-glucose, but forms 움-linked transfer products from 웁-D-glucose66 or 웁-D-glucosyl fluoride.21 The crystal structure of Aspergillus awamori glucoamylase complexed with 1-deoxynojirimycin103 shows the active site to be located in a pocket. A water molecule (water500) is found hydrogenbonded to OE1 of Glu400, the putative general base located across the reaction center from the presumed general acid catalyst, Glu179, indicating that hydrolysis of an 움-D-glucosylic substrate will yield 웁-D-glucose. On binding 웁-D-glucose or 웁-D-glucosyl fluoride as substrates, the equatorial 1OH or 1-F would displace water500.103 Glucosyl transfer from these two donors would then occur by reversal of the catalytic roles of the two carboxylate side chains; 움-linked products would be formed as the 4-OH group of a D-glucosyl acceptor molecule would face the reaction center in the same orientation as that of the second 움-D-glucosyl unit of a maltosaccharide substrate. Although the mode whereby solvent is purged from the active-site pocket (and kept from Glu179 in particular) is not clear, Harris et al.103 suggested that a transient compression of the active-site structure may allow water to slide by the substrate (or inhibitor) as it enters the close-fitting recess of the active-site pocket. Perhaps water in the deepest part of the pocket may be displaced through lateral diffusion as substrate enters.104 (ii) Cellulases of Families 9 and 45.—Crystal structures are reported for two different endocellulases that hydrolyze 웁-(1 → 4)-linked substrates with inversion but whose actions on minisubstrates are not known. The
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structural findings strongly suggest that product configuration is controlled topologically, although they do not fully establish that reactant water reaches the reaction center only from the 움-direction or that it binds close to both the nucleophile and the center. The active-site structure of each enzyme is an open cleft with two oppositely disposed catalytic carboxyl groups reported to resemble the arrangement in such groups at the reaction center of hen’s egg-white lysozyme. In CelD (family 9) of Clostridium thermocellum, the presumed nucleophile Asp201 is located too far from the catalytic center to react directly with a positively charged reaction intermediate.83 The authors suggested that a pocket occupied by the -amino group of Lys38 from an abutting molecule in the crystal could accomodate a water molecule between Asp201 and the reaction center.83 With the enzyme in solution the open pocket might allow water to bind near Asp201 and to be activated by it so as to become a specifically 움-directed nucleophile. However, the data do not indicate how the reaction center might be shielded from solvent present in the active-site cavity. The crystal structure of endocellulase EGV (family 45) from Humicola insolens, with cellobiose in the leaving-group site, shows an ordered water molecule near Asp10, the proposed general base.85 The authors indicated that this water, if moved ⬍1 Å, would be suitably positioned to make a nucleophilic attack leading to inversion of configuration. Were it bound to Asp10 and sufficiently near C-1 of the glucosyl unit at the reaction center (distances not noted) it could attack without need for prior product departure. The structure of an inactive Asp10Asn mutant of EGV complexed with cellohexaose is almost isomorphous to the native enzyme; but a local conformational change involving a loop segment (disordered in the apoenzyme) moves residues Asp114 and Leu115 some 7Å to enclose the active site at the point of cleavage. The authors considered that the data show a water molecule suitably disposed to participate in a single-displacement reaction,85 with loop closure possibly preventing access of other potential nucleophiles to the active site.86 (iii) Orotate Phosphoribosyltransferase.—A different example is provided by the inverting orotate phosphoribosyl transferase of Salmonella typhimurium, representative of the various phosphoribosyl transferases involved in nucleotide synthesis. This enzyme catalyzes the reversible transfer of the 5⬘-phosphoribosyl moiety from 움-phosphoribosyl pyrophosphate (움-PRPP), the light-atom structure at the bottom of Fig. 6, to orotic acid (light-atom structure at the top of the figure), acting as specific base, to form 웁-phosphoribosyl orotate (dark atoms) plus pyrophosphate, PPi. The position of reactants, plotted directly from the crystal structures by Scapin
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FIG. 6. Diagram from Scapin et al. (Biochemistry, 34 (1995) 10744–10754) illustrating the location of bound orotic acid (light atoms), of orotic acid glycosidically linked in orotidyl 5⬘-phospho-웁-D-riboside (dark atoms), and of pyrophosphate (light atoms) oriented to form the ␣-5⬘-phosphoriboside in orotate 5⬘-phosphoribosyl transferase.
et al.111,112 shows both the free orotate and 5⬘-웁-phosphoryl orotate bound far from pyrophosphate and 움-PRPP. In the reverse (lytic) reaction, dashed lines mark the 웁-D-ribosyl C–N bond cleaved and the 움-D-ribosyl C–O bond formed with the PPi consubstrate. In either direction, the bound orotate and PPi cosubstrates are thus oriented oppositely to C-1 of the ribosyl moiety. The 5⬘-phosphoribosyl unit, upon being transferred between O-1⬘ of PPi and N-1 of orotate, rotates about 60⬚ around the pivot of its 5⬘phosphate—with the C-1 atom moving about 7 Å between the two cosubstrates. Figure 7 shows the electrostatic potential surface of the active-site region for the enzyme complexed with orotate 웁-phosphoriboside. The orotate ring is deep in its binding site, with the 웁-ribosyl unit near the surface and
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FIG. 7. Electrostatic potential surface of the active-site region of orotate 5⬘-phosphoribosyl transferase complexed with orotidyl 웁-5⬘-phosphoriboside. Reproduced from Scapin et al., (1995) Biochemistry 34, 10744–10754, with permission of the American Chemical Society.
its 5⬘-phosphate group visible on the surface.111,112 The binding site for the PPi cosubstrate molecule is evident as a separate depression in the surface. In short, although the organic orotate and inorganic pyrophosphate cosubstrates reach their binding sites via a common active-site cavity, they become oppositely oriented to the ribosyl C-1 atom by the different dispositions of their binding sites. Details of the catalytic mechanism, and of how water is kept out, are not known. 3. Structural Basis for Separating Glycosylases into 1-MCO (“Retaining”) and 2-MCO (“Inverting”) Types As noted earlier (compare Table I), studies made using small prochiral substrates gave the first concrete indications that product configuration in some glycosylase-catalyzed reactions does not depend on that of the substrate but is determined topologically by protein structures which determine how incoming cosubstrates approach the catalytic center.26,32,36,45–48
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Reported crystal structures of the liganded enzymes already reviewed here expand this conclusion by identifying the probable controlling structures in a number of “lytic” glycosylases. The observations summarized in Table II indicate that the cosubstrates of a particular “retaining” enzyme all approach the catalytic center only from its 움- (or only from its 웁-) side. Examination of the available structures of such enzymes gave no indication that water or phosphate is directed to the center differently from carbohydrate or nitrogenous cosubstrates. On the other hand, the findings with the “inverting” glycosylases in Table III provide evidence for, or at least strongly suggestive of, the presence of a special structural feature which ensures that the inorganic or lytic cosubstrate (water, phosphate, or pyrophosphate) is positioned so as to reach the reaction center from a direction opposite that required for carbohydrate or nitrogenous cosubstrates. Both soybean beta-amylase101 and A. awamori glucoamylase103 show an ordered water molecule at a specific site closely proximate to both a nucleophilic residue and the C-1 atom defining the reaction center. This water not only is positioned to attack from the 웁-side, opposite the direction of approach of carbohydrate acceptors but, most significantly, it is poised for activation and preemptory attack on substrate, whereas organic cosubstrates can bind and react only after prior release of the substrate’s aglycone. A specific water-binding site would appear to exist in several other “inverting” glycosidases (Table III). Structural evidence also is found for a comparable special pyrophosphate binding site in orotate phosphoribosyl transferase and, presumably, in various other inverting PRtransferases. This site, which is part of a common PRPP binding motif, places O-1⬘ of the inorganic acceptor close to and on the 움-side of the 5⬘-phosphoribosyl C-1 atom. It is far separated from the binding site for orotate (or other specific nitrogenous bases used by different PRtransferases) whose N-1 atom is oriented to the 웁-side of the 5⬘-phosphoribosyl C-1 atom. Although the pyrophosphate and orotic acid cosubstrates gain access to their specific binding sites from a common cavity, their selective binding affinities position them at sites which orient them oppositely with respect to the C-1 atom of the phosphoribosyl moiety. Kinetic studies indicate that a special binding site, this time for inorganic phosphate, likely exists in maltose phosphorylase, which catalyzes the phosphorolysis of maltose to form 웁-D-glucosyl phosphate plus glucose as well as maltose synthesis from 웁-D-glucosyl phosphate plus glucose.68 A crystal structure has not been reported for this enzyme but, as found in kinetic studies68 and illustrated in Fig. 8,69 Pi most likely binds on the 웁-side of C-1 of the maltose undergoing phosphorolysis. In contrast, in the reverse reaction with 웁-D-glucosyl phosphate as substrate, the glucose cosubstrate
The structure of PPA treated with acarbose shows no ordered water between the presumed nucleophile Asp197, on the 웁-side of the catalytic center, and the C-1 atom of the cyclitol unit. Access of the center to solvent from the 웁-side, though not measured, appears unlikely.99 Asp229, the presumed nucleophile on the 웁-side of the reaction center, is stabilized by a 2.8 Å interaction with a water molecule. The latter, located in a pocket formed by residues 139 and 229, is not near the reaction center. Although the data do not establish that the catalytic center lacks access to solvent from the 웁-side, all incoming cosubstrates appear able to reach the center from the ␣-side only.110 Crystal structure of the enzyme complexed with ␣-D-glucosyl phosphate indicates that Pi binds only on the axial (␣-) side of the catalytic center. No phosphate site is observed on the 웁-side and no ionizable residue exists in that region to serve as a nucleophile to help activate a phosphate group.115–117
␣-Side
␣-Side
␣-side
Porcine pancreatic Alpha-amylase Cyclodextrin glycosyl transferase
Glycogen phosphorylase
Enzyme
No Indication of a Special Structure That Directs Small Inorganic Cosubstrates (Water or Phosphate) to the Catalytic Center With a Different Orientation Than Carbohydrate Acceptors
Active-site Residues Direct All Incoming Cosubstrates to the Catalytic Center From One Sidea
Observed Features of the Crystal Structures of “Retaining” Enzymes That Provide but One Mode of Approach of All Cosubstrates to the Enzyme–Substrate Reaction Center
TABLE II
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웁-Side
웁-Side
웁-Side HEWL complexed with a product, MurNAc-GlcNAc-MurNAc, shows the ligand bound at subsites B–D. There is no room at subsite D for the ␣anomer of MurNAc as its axial 1-OH would clash with Asp52 and other residues in the region. These structural features confirm that water and other acceptors reach the reaction center only from the 웁-side.1 The complex with o-iodobenzyl 1-thio-웁-cellobioside shows no ordered water between the presumed nucleophile Glu212 and the reaction center. The data suggest but do not establish that the center lacks access to solvent from the ␣-side. The catalytic group positions are consistent with a double-displacement mechanism,79 but they also can account for cellobial hydration by a different mechanism.37 The complex with 2,4-dinitrophenyl-2-fluoro-웁-cellobioside shows88 bound 2fluorocellobiose with C-1 covalently ␣-linked to the OE1 of the nucleophilic residue Glu233. No measurements of the accessibility of Glu233 to solvent are reported.
a This would account for the observation that all reactions by a given “retaining” enzyme have the same steric outcome. The structural findings in several instances do not suffice to establish that incoming cosubstrates can reach the catalytic center only from the side specified, but they are consistent with this view.
Cellulomonas fimi Cex cellulase– xylanase
T. reesei cellulase CBH I
Hen’s egg-white lysozyme (HEWL)
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움-Side
웁-Side
웁-Side
웁-Side
A. awamori glucoamylase
T. reesei cellulase CBH II
C. thermocellum cellulase CelD
H. insolans cellulase EGV
a The structure of each enzyme indicates that organic (carbohydrate, alcoholic, nitrogenous) cosubstrates reach the reaction center from one (움- or 웁-) side by one route only, by way of a common binding site or similarly oriented binding-sites. b Any hydrolytic, phosphorolytic, or pyrophosphorolytic product formed by a listed enzyme would thus have a configuration opposite to that of transfer products formed with organic cosubstrates.
Orotate 5⬘phosphotribosylransferase 웁-Side
Water866 is found H-bonded to OE2 of Glu380 (the nucleophile), to the O atom of Asn381, and to C-1 of the reaction intermediate. Loop closure on bound substrate shields the Glu186 (acid catalyst) region and all potentially reactive atoms from solvent.101 An inhibitor complex shows ordered water500 in proximity to OE1 of Glu400 (general base) and to N5 of the inhibitor (equivalent to C-1 of a maltosaccharide). Water is presumably purged from the Glu179 (acid catalyst) region by closely fitting into the active site.103,104 A narrow tube conveys H2O to the 움-side of the catalytic center; but residues on the 웁-side lack access to solvent. Structural control of steric outcome is clear, yet no ordered water is found between the reactive C-1 atom and a potential nucleophilic residue.55 Water apparently reaches the catalytic center only from the 움-side. The Asp201 base is too far from the center to react directly with C-1. Between them is a site occupied by the ε-group of Lys38 from a nearby protein in the lattice, which perhaps could in solution become a H2O activating site.83 The active-site structure of the complex with cellobiose shows an ordered H2O near to but not H-bonded to Asp10 (general base). The authors stated that an inactive cellohexaose complex has water suitably bound to participate in a single displacement reaction.85,86 Pyrophosphate binds in a PPRP site on the 움-side of the ribosyl C-1 atom. Orotate bids in a separate site on the 웁-side of the center, tailored to the binding of specific nitrogenous bases in other such transferases.111,112
움-Side
Soybean Beta-amylase
Enzyme
Through a Special Structural Feature, Inorganic Cosubstrates (H2O, Pi, PPi) Approach the Catalytic Center From a Direction Oopposite to That Required for Organic Acceptorsb
Organic Cosubstrates Approach the Reaction Center From One Direction Onlya
Observed Features of the Crystal Structures of “Inverting” Glycosylases That Provide Two Modes of Approach of Different Cosubstrates to the Enzyme–Substrate Reaction Center
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FIG. 8. Stereochemistry of reactions catalyzed by maltose phosphorylase with inversion of configuration. (A) ␣-Maltose synthesis from 웁-D-glucopyranosyl phosphate and the reverse phosphorolysis of ␣-maltose; (B) ␣-maltose synthesis from 웁-D-glucopyranosyl fluoride plus 움D-glucose. X represents a protein component whose interaction with the axial 1-OH of 움-Dglucopyranose is required to activate all reactions promoted by the enzyme. Reproduced from Tsumuraya et al., Arch. Biochem. Biophys., 281 (1990) 58–65, with permission of Academic Press.
binds at a separate site with its O-4 atom 움-oriented to the reaction center. This contrasts with glycogen phosphorylase, where both phosphate and the nonreducing-end glucose unit of dextrin cosubstrates bind in the same orientation to the reaction center and lead to reaction products of 움-anomeric configuration. X-Ray studies of human purine nucleoside phosphorylase, an inverting D-ribofuranosylase, show that the Pi cosubstrate is bound in an 움orientation, purines in the opposite (웁-) orientation to the reaction center.113 Carboxyl groups apparently are not involved in the catalytic event. As summarized in Table IV, the evidence thus far obtained with various glycosidases, phosphorylases, and pyrophosphorylases indicates that “retaining” glycosylases would probably be more precisely characterized as proteins with a 1-MCO type of structure, which restricts both substrates and cosubstrates to one mode of orientation to the reaction center. The structurally directed approach of all incoming cosubstrates, either always from the 움- or always from the 웁-side of the center, can account for the constancy
Purine nucleoside phosphorylase S. typhimurium orotate 5⬘-phosphoribosyltransferase
T. reesei CBH II ellulase C. thermocellum Cel D cellulaseb H. insolans EGV cellulase B. pumilus 웁-xylosidase
Alpha to the Center
Maltose phosphorylase
Soybean Beta-amylase A. awamori glucoamylase ␣-glucosidase component of glycogen debranching enzyme
Beta to the Center
Glycogen phosphorylase Sucrose phosphorylase
Hen’s egg-white lysozyme C. fimi Cex cellulase White mustard seed myrosinase
Cyclodextrin glycosyl transferase A. niger 움-glucosidase
E. coli 웁-galactosidase
T. reesei CBH I cellulase
Beta to the Center
A. oryzae Alpha-amylase
Alpha to the Center
Structure Allows One Mode of Orientation of All Incoming Cosubstrates to the Reaction Center; Organic and Inorganic Cosubstrates May Have Specific Binding Sites, Each Located:
1-MCO-Type (“Retaining”) Glycosylases
Assignments in bold are based on evidence or strong indications from the reported crystal structure for the individual ligand-complexed enzyme. Others are tentatively assigned on the basis of stereochemical and kinetic findings for reactions with nonglycosidic as well as glycosidic substrates. b Thermomonospora fusca cellulase E4-68 (in the same family 9 as Cel D cellulase) complexed with cellohexaose shows evidence of a water molecule bound close to the carboxyl group of the catalytic base and the reaction center, 움-oriented to the latter.120
a
PPi
Pi
H2O
Inorganic (Lytic) Cosubstrate
Structure Provides Two Opposed Modes of Cosubstrate Orientation to the Reaction Center— One Mode Via a Specifically Located Binding Site for the Inorganic Cosubstrate:
2-MCO-Type (“Inverting”) Glycosylases
TABLE IV Proposed Subdivision of Glycosylases Based on Structural Features That Dictate the Stereochemical Outcome of Catalyzed Reactionsa
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of product configuration in all reactions promoted by the lytic 1-MCO enzymes in Table IV, including the hydration of enitols and slow hydrolysis of 웁-D-glucosyl fluoride by 움-glucosidases to form 움-products. In contrast, the lytic 2-MCO glycosylases are distinguished by the possession of a second structural feature which ensures that the inorganic cosubstrate approaches the center from a direction opposite that of incoming organic cosubstrates. In CBH II cellulase, a narrow channel restricts the approach of water so that the hydrolytic product(s) are of 움-configuration55; in other enzymes, a binding site positions the appropriate inorganic cosubstrate (H2O, Pi, or PPi) proximate to both the catalytic nucleophile and reaction center. That the findings with representative phosphorylases and pyrophosphorylases are comparable to those obtained with glycosidases is a sign of the potential generality of the subdivision presented in Table IV. Whether the same structural distinction extends to all enzymes classed as glycosyltransferases [EC 2.4]c is not known. Evidence on this point must await description of the positioning of cosubstrates in crystal structures of relevant enzyme–ligand complexes. However, one can envision, for example, that the many enzymes which act on uridine 5⬘-(움-D-glucopyranosyl diphosphate) (UDP-움-D-glucose) plus a cosubstrate to form transfer products of 움-configuration may have a 1-MCO structure—with the UDP leaving group and the cosubstrate binding separately but with each 움-oriented to the reaction center. Lactose synthase, which acts on UDP-움-D-galactose to catalyze an inverting transfer reaction to glucose to form lactose plus UDP, may well have a 2-MCO structure with the UDP leaving-group (inorganic at its reactive pyrophosphate end) and D-glucose cosubstrate bound in opposite orientations to the reaction center. The evidence summarized in Tables II and III and presently used to characterize certain individual glycosidases as having a 1-MCO or 2-MCO structure is enhanced by, and further extends, Withers’ observation3,11 that a simple parameter derived from crystal structures distinguishes “inverting” from “retaining” glycosidases. The authors found a greater average distance between the opposed catalytic carboxyl groups in enzymes of the first type and assumed that this provides room for a water molecule to intervene.3,11 A separation between the opposed carboxyl oxygens (average of four possible distances), amounting to 4.8 ⫾ 0.5 Å for four 움-amylases and 5.3 ⫾ 0.2 Å for several “retaining” 웁-glycosidases, is recorded; in contrast, a combined distance of 9.0 ⫾ 1 Å is reported for beta-amylase and glucoamylase and 9.5 Å for a third “inverting” enzyme, the E2 cellulase of Trichoderma fusca. In glycosidases, the calculated distance between the catalytic carboxyl oxygen atoms correlates well with their stereochemical behavior in reacting with glycosidic substrates. The averaged distance between the opposing
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carboxyl oxygen atoms does not, however, necessarily represent the distance between the two oxygens actually involved in catalyzing a reaction. For example, in soybean beta-amylase, OD2 of the nucleophile Glu380 and OD2 of the acid catalyst Glu186 on the opposite (움-) side of the reaction center are well positioned for catalyzing hydrolysis. However, whereas the calculated average of possible distances between the carboxyl oxygens of Glu380 and of Glu186 is 7.5 ⫾ 1.0 Å, the measured distance between the OE2 atoms presumably involved in catalysis is only 5.7 Å.101 Again, in the recently reported crystal structure of cellulase CelA of Clostridium thermocellum,81 shorter distances of 5.8 Å (or 7.5 Å) separate the carboxyl group of the acid catalytic residue, Glu95, from that of the likely nucleophile, Asp152 (or Asp278) respectively, than projected3 for “inverting” enzymes. Nevertheless, an averaged distance extending across the center evidently does identify “inverting” glycosidases, even though the measurements include some less directly relevant parts. The present interpretation (Tables II and III) emphasizes the location, in several inverting glycosidases, of an ordered water molecule between and closely proximate to the nucleophile and the reaction center. This supports the assumption3 that the greater distance between the carboxyl oxygen atoms in enzymes of this type is associated with the positioning of reactant water. In a further study of broad significance, Withers and his associates11 examined the activity of two mutants of Agrobacterium fecalis 웁-glucosidase in which the nucleophile Glu358 was replaced by Asp or Ala. The Glu358Asp mutant, which presumably increased the average separation of the enzyme’s active-site carboxylate atoms by 1 Å, lowered by 2500-fold the activity for 2,4-dinitrophenyl 웁-D-glucopyranoside but did not change the stereochemistry. The activity of the Glu358Ala mutant was some 107-fold lower than that of the wild-type enzyme, but the addition of an azide or formate nucleophile increased kcat 105-fold, that is, most of the way back toward the wild-type value. The reaction product was identified as 움-D-glucosyl azide. Further checks confirmed the change-of-reaction stereochemistry from one of retention to one of inversion: wild-type 웁glucosidase failed to release fluoride from 움-D-glucopyranosyl fluoride, whereas the Glu358Ala mutant rapidly catalyzed an inverting D-glucosyl transfer reaction from one 움-fluoride molecule to a second serving as cosubstrate, to yield a product identified as a cellobiose derivative, presumably 움-cellobiosyl fluoride.11 The observed change in the stereochemical behavior of the A. fecalis 웁glucosidase mutant acting on an aryl 웁-D-glucoside11 does not arise solely from the elimination of assistance to a 웁-directed attack by water, but depends also on the creation of a new site of access located as to permit an 움directed attack by azide. One would wish to know the relative proportion
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of transfer product formation to hydrolysis in the altered reaction and whether wild-type A. fecalis 웁-glucosidase forms detectable glucopyranosyl azide from the glycosidic substrate in presence of azide. A similar modification of the catalytic nucleophile, Glu233, of the Cex xylanase/cellulase of Cellulomonas fimi in the mutant Glu233Ala eliminates this enzyme’s ability to hydrolyze (with retention) 2,4-dinitrophenyl 웁cellobioside. Catalytic activity is restored in the presence of azide, with the formation of a transfer product of inverted configuration, 움-cellobiosyl azide.133 A probable (obverse) example involves a covalent glycosyl–enzyme adduct isolated from a digest of E. coli cell wall by the Thr26Glu mutant of phage T4 lysozyme.134,135 The authors considered this adduct to be a stabilized intermediate (움-linked to Glu26) in a double displacement involving final water attack from the 웁-side of the reaction center. On direct structural comparison, native unliganded T4 lysozyme shows a water molecule close to both Thr26 and the center. The authors suggested that natural T4 lysozyme is an “inverting” enzyme which is converted by the Thr26Glu mutation into one acting with retention.134,135 Direct establishment of the steric course of hydrolysis catalyzed by native T4 lysozyme would appear desirable, though difficult to achieve. The enzyme does not use the simple chito-oligosaccharides that allow the observation of hydrolysis with inversion by papaya lysozyme.136 In short, there is now a merging of basic information on the relation of structural elements to stereochemical behavior. The degree of separation of the two catalytic carboxyl groups of a glycosidase correlates with such behavior,3 as does replacing the carboxyl group of the catalytic base by a small space open to solvent.11,133 The stereochemical behavior of a glycosidase or glycosyltransferase further correlates with its 1-MCO or 2-MCO type structure (Table IV), even when the substrate lacks the proper configuration. The notable point is that the structural findings for several enzymes of 2MCO type (Tables III and IV) confirm the assumption3 that the wider catalytic carboxyl-group separation in “inverting” glycosidases provides for the intervention of a water molecule; it also confirms the significance of the altered stereochemical behavior of mutant 웁-glycosidases whose nucleophilic carboxyl group is replaced by a space for a small entering nucleophile.11,133 The correspondence of these different observations about the disposition of these several significant structural features, relative to each other, is strongly supportive when other evidence shows that a glycosidasecatalyzed reaction occurs through a single or double “displacement” mechanism. However, the findings assembled in Table IV can also accomodate other mechanisms, and this would encourage further investigation of reactions whose features do not readily accord with the view that “retaining” enzymes act only by way of a double-displacement mechanism.
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IV. RELATION OF STEREOCHEMICAL BEHAVIOR TO CATALYTIC MECHANISM 1. Do 1-MCO (“Retaining”) Glycosylases Invariably Act via Double Displacements? Over the past few decades the reactions of a number of “retaining” glycosylases have been reported to involve an oxocarbonium ion rather than a covalent intermediate. During the same period, however, a revised version of the traditional double-displacement mechanism has become widely accepted as the way “retaining” glycosidases function. Here, the required covalent intermediate is reached via an oxocarbonium ionlike transition state in which the anomeric C-1 atom remains partly bonded to its original axial or equatorial substituent, with a second transition state intervening between the intermediate and cosubstrate. According to this model, the idea of an ion-pair intermediate is untenable—with the questionable exception of hen’s egg-white lysozyme.137,15 The existence of a covalent intermediate has been inferred for a number of reactions.15 Clear direct evidence has been presented by Withers and his associates, who recovered a covalent 움-D-glucopyranosyl–enzyme adduct in the hydrolysis of 2,4-dinitrophenyl 2-deoxy-2-fluoro-웁-D-glucopyranosyide by the 웁-glucosidase of Agrobacterium fecalis138,139 and in the hydrolysis of similar 웁-D-glycosides by the Cex cellulase/xylanase of C. fimi.133,140 Crystallographic studies confirm the structure of the intermediate in the latter case87,88 and of a comparable intermediate observed for the complex of white mustard seed myrosinase with 2-deoxy-2-fluoro-웁-D-glucotropeolin.141 Further covalent intermediates are demonstrated in reactions of Saccharomyces cerevisiae 움-glucosidase with 5-fluoro-움-D-glucopyranosyl fluoride142,143 and in a reaction catalyzed by the 움-D-glucanotransferase part [EC 2.4.1.25] of glycogen debranching enzyme using 4-deoxy-움maltotriosyl fluoride as a probe.144 The recovery of covalent intermediates in reactions involving transitionstate destabilizing substrates provides clear evidence of the nucleophile’s identity and mode of functioning in the reactions studied. Probes that drastically perturb the catalytic process through carbonium ion destabilization allow the possibility that the catalytic nucleophile might act differently with ordinary substrates. Thus far, however, kinetic studies and 2H kinetic isotope effects of reactions catalyzed with a range of aryl 웁-D-glucosides by the A. fecalis and C. fimi 웁-glycosidases give findings consistent with the presence of a covalent intermediate.145,146 Yet, a number of investigators report the catalysis of reactions by various “retaining” enzymes that they consider to be inconsistent with a mechanism requiring a covalent glycosyl–enzyme intermediate. For lysozyme, the crystallographic data show that OE2 of Asp52 and C-1 of 웁-MurNAc-GlcNAc-
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MurNAc cannot approach one another closer than 2 Å and that the syn lone pair orbitals on the Asp52 carboxylate are not favorably oriented to form a covalent bond with of C-1 of MurNAc. These findings appear to make it most unlikely that a covalent 움-linked glycosyl–enzyme intermediate is formed.1,127,147,148 The counterargument that Asp52 is catalytically unimportant since the equivalent residue in bacteriophage-T4 lysozyme is replaceable with little loss of activity73 appears fragile, since the stereochemical behavior of T4 lysozyme evidently differs from that of the hen’s egg-white enzyme.134, 135 For glycogen phosphorylase, kinetic findings and crystallographic evidence of the lack of a suitably disposed carboxylate group that might act as a nucleophile have led to the view that catalysis occurs via an ion pair that collapses without involving a covalent 웁-D-glucosyl intermediate117 or by a concerted mechanism without requiring a sequential double inversion of configuration.119 The Glu461 mutant of E. coli lacZ 웁-galactosidase lacking the ionizable side chain of the catalytic residue, Glu46, has been reported to vigorously catalyze galactosyl transfer from 2-nitrophenyl 웁-D-galactopyranoside to azide to form 웁-D-galactopyranosyl azide (second-order rate constant 4900 M⫺1 s⫺1). Wild-type enzyme gives no detectable reaction. The equilibrium constant for galactosyl transfer by the mutant is ⬎8000-fold higher than for the wild-type enzyme.149 These findings demonstrate the predominant reactivity of azide as nucleophile over water. In the presence of formate ion, the galactosylated Glu461Gly mutant gives only D-galactose, suggesting that carboxylate anions can provide general base catalysis of reaction intermediates with water. These and other findings indicate that replacement of the anionic side chain of Glu461 by hydrogen exposes an enzyme-stabilized oxocarbonium ion to approach and attack by an external nucleophile and that 웁-galactosidase acts via an ionic rather than a covalent intermediate.149 Again, the structure of porcine pancreatic 움-amylase, in complex with the pseudotetrasaccharide acarbose shows the OD2 of Asp197 and the OE2 of Glu233 (the presumed catalytic components) to be located 3.3 and 3.5 Å, respectively, from the cleavable glycosyl bond. These are much greater distances than the length of a glycosylic bond and are reported to be supportive of an ionic mechanism.99 On the other hand, a nuclear magnetic resonance study of a pancreatic alpha-amylase–[1-3H] maltotetralose mixture, set up in cold (⫺20⬚) buffer containing 40% dimethyl sulfoxide and examined under cryoscopic conditions, gave findings pointing to the presence of a 웁-linked covalent adduct.150 Several other “retaining” glycosidases promote reactions where the findings are reported to be unsupportive of a mechanism requiring a covalent intermediate. For example, the 움-glucosidases of A. niger, ungerminated rice, and sugar beet seed catalyze the slow hydrolysis of the wrong (웁) D-
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glucopyranosyl fluoride anomer with the formation of 움-D-glucose.52,53 One may argue that, on protonation of the disfavored (웁-) substrate, a carbonium ionlike structure is formed which interacts with the catalytic nucleophile to form the same (웁-linked) covalent intermediate as in the case of 움-linked substrates. However, such an intermediate is not expected to arise via a transition state where C-1 remains weakly bonded to the original 웁oriented fluorine substituent. The suggested (and more likely) mechanism involves one of the lone pairs on the pyranose ring oxygen assisting in cleavage of the C-1–F bond to form a stabilized carbonium ion intermediate, with attack by the structurally positioned water cosubstrate (움oriented to the reaction center in 1-MCO 움-glucosidases) assisted by the general base catalyst (Fig. 1).53 Again, it is possible that the hydration of glycals and other prochiral glycosyl donors catalyzed by various “retaining” glycosidases (Table I) also may not require a covalent intermediate. A glycosyl carbonium ion transition-state structure arising on protonation of a glycal would have neither an 움- nor a 웁-substituent at C-1, unlike the transition state specified15 for bimolecular reactions with chiral glycosyl donors. In the hydration of cellobial by CBH I cellulase, for example, an 움-linked covalent intermediate might be reached via a carbonium ion or ion-type structure—although the enzyme’s catalytic nucleophile, presumably having just protonated the glycal, may be ionized. Alternatively, an oxycarbonium ion intermediate could be stabilized and attacked by a structurally positioned water, assisted by the acid–base catalyst, to give a product of 웁configuration as found for the hydration of cellobial or lactal.37 Finally, intestinal sucrase/isomaltase shows large secondary 2H isotope effects for hydrolysis of p-chlorophenyl 움-D-glucopyranoside and a nearly zero 웁1g value for p-substituted phenyl 움-D-glucopyranosides, 151,152 suggesting the essentially complete protonation of the leaving group at the transition state.15 Other examples of hydrolytic reactions showing an extremely high ratio of bond breaking to bond formation at the transition state are discussed next. 2. Relationship of Transition-State Structure to the Stereochemistry and Mechanism of Glycosylase Reactions Transition-state structures computed from multiple kinetic isotope-effect data have provided important information on the catalytic mechanisms of glycosylases. This is exemplified by the refined transition-state structures derived by Schramm and his associates and used to probe the hydrolytic reactions catalyzed by nucleosidases and the ADPR (adenosine diphosphoribosyl) transferase toxins of Vibrio cholerae and Corynebacterium diphthe-
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riae.153–156 The methods employed in these studies153,154 were used by Tanaka et al.157 to derive refined transition-state structures for the hydrolysis of 움-D-glucopyranosyl fluoride by two enzymes that differ in stereochemical behavior. The aim was to determine the relationship of transitionstate character to the steric course of each reaction as well as to gain information about the catalytic mechanism(s). The hydrolysis promoted by the 움-glucosidase of sugar beet seed yields 움-D-glucose; that catalyzed by Rhizopus niveus glucoamylase yields 웁-D-glucose and shows large and equivalent 움-secondary 3H and 2H kinetic isotope effects.75 To determine the transition state for each enzyme, [1-3H, 6-14C]-, [2-3H, 6-14C]-, [6-3H, 614 C]-, and [1-14C, 6-3H]-움-D-glucopyranosyl fluoride were hydrolyzed by each; near-intrinsic 움-, 웁-, and remote-secondary 3H and primary 14C kinetic isotope effects were concurrently determined and subjected together to bond energy–bond order analysis.157 The modeled transition-state structures for hydrolysis by the 움-glucosidase and the glucoamylase show significant oxocarbonium ion character with the D-glucosyl unit of each having a flattened 4C1 conformation consistent with a C-1–O-5 bond order of 1.92, even though opposite D-glucose anomers are formed from the substrate. The transition-state structures show modest differences but they do not predict the stereochemical outcome of the catalyzed reactions.157 Table V lists transition-state features of special relevance to the mechanism of hydrolysis with fluoride release by the 움-glucosidase and TABLE V Features of the Anomeric Carbon Atom at the Transition State for the Hydrolysis of -DRibofuranosyl–N and ␣-D-Glucopyranosyl–F Bonds Bond Order (Bond Length, A)
Glycosylase Glucoamylase, R. niveus 움-Glucosidase, sugar beet seeds ADPRibosyltransferase, V. cholerae
Substrate Hydrolyzed
Stereochemical Course
C-1–F or C-1‘–N
C-1‘–O’
Reference
움-Glucosyl fluoride 움-Glucosyl fluoride NAD⫹
움→웁
0.045 (2.3)
0.010 (2.8)
(157)
움→움
0.27 (1.7)
0.001 (3.5)
(157)
웁 → ?a
0.107 (2.2)
0.002 (3.3)
(155)
a ADP-D-Ribosyl transfer products formed from NAD⫹ are of 웁-configuration.158 Configuration of the ADP-D-ribose hydrolysis product has not been established.
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glucoamylase as well as to that of the hydrolysis of oxidized nicotinamide adenine dinucleotide (NAD⫹) with cation release catalyzed by the V. cholerae toxin. The findings for each of the three reactions appear most consistent with an SN1 rather than an SN2 mechanism. The independently derived transition states for the sugar beet seed 움-glucosidase157 and ADPRtransferase-catalyzed reactions155 have a notable point in common, namely, a barely detectable (0.001 or 0.002) C-1–O bond order and a too-great C–O “bond length” (3.5 or 3.3 Å) to constitute a bond. In each case, the extent of bond formation relative to substrate bond breaking is miniscule, ⬍0.25%. Considering that each transition-state structure represents the average of a range of structures for individual reactant complexes, a fair proportion of these may represent sufficiently stabilized oxocarbonium ions to have a real existence until they undergo attack by a structurally positioned water molecule. Kinetic isotope-effect findings157 for hydrolysis of 움-D-glucopyranosyl fluoride by the sugar beet seed 움-glucosidase indicate that the reaction occurs by other than the concerted SN2 mechanism found by Banait and Jencks159 for the nonenzymatic and nonhydrolytic reactions of the same substrate in water containing added anionic nucleophiles as well as released fluoride. For this model, these authors found159 that an intimate ion pair could not exist as an intermediate species as its lifetime would be too short. The refined transition-state structure derived for hydrolysis of this substrate in hot water also indicates that the D-glucopyranosyl cation is too unstable to exist in solution contact with the fluoride leaving group.160 Yet, it is not entirely appropriate to dismiss the mechanism reported for the hydrolysis catalyzed by the sugar beet seed 움-glucosidase157 on the basis of its departure from the findings of respected nonenzymic solvolysis models. For one thing, this particular enzymic reaction is but one of a cluster of mechanistically extreme reactions catalyzed by a group of closely related enzymes and not an isolated example. Later studies show that the 움glucosidase of sugar beet seed shares the conserved amino acid sequences of the aspartic acid catalyst region with A. niger and rice 움-glucosidase as well as with rabbit intestinal sucrase and isomaltase.161–163 As previously noted, the three 움-glucosidases slowly hydrolyze the wrong (웁-) Dglucopyranosyl fluoride anomer via a mechanism unlikely to involve a covalent intermediate;52,53 each also catalyzes the slow hydration of Dglucal by a reaction where the possibility of an ion-pair intermediate is not excluded.45 Further, the large 움-secondary kinetic 2H isotope effects observed for hydrolysis of [1,1-2H]-isomaltose by A. niger and sugar beet seed 움-glucosidase under optimal-rate conditions are reported to support the presence of a carbonium-ion intermediate at the transition state.10 In addition, reactions promoted by the closely related mammalian sucrase and iso-
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maltase with p-substituted aryl 움-D-glucopyranosides also appear unusual in showing essentially complete protonation of the leaving group at the transition state.151,152 As to the V. cholerae toxin-catalyzed hydrolysis of NAD⫹, the kinetic isotope-effect findings point to a mechanism providing nearly unimolecular N-glycosylic bond cleavage with minimal nucleophilic participation at the transition state.155 These findings, when compared with a nonenzymic solution model,164 also suggest that a glycosyl carbonium ion would be on the borderline of having a short but significant lifetime in water.155 A quantum study of the hydrolysis of 웁-D-ribofuranosyl nicotinamide⫹ in the gas phase165 finds that the C-1–N glycosylic bond must be broken almost entirely before solvent can react with the oxocarbonium-ion intermediate. Further, the transition state for hydrolysis with inversion shows a lower C1–O bond order than that for hydrolysis with retention, contrary to indications that inverting and retaining reactions pass through a single activated complex.166 This distinction, however, is not observed in the enzymically catalyzed hydrolysis of 움-D-glucopyranosyl fluoride (Table V).157 Indications exist that the hydrolysis of 움-D-glucosyl fluoride by sugar beet 움-glucosidase157 and of NAD⫹ by V. cholerae toxin155,167 may involve a relatively desolvated reaction center at the transition state. The view also has been expressed that solvation may be critical to the stability of the 웁-Dribosyl–nicotinamide linkage in solution since rapid dissociation into oxocarbonium ion and nicotinamide occurs in the gas phase.167 The question arises whether the findings of studies of nonenzymic reactions in aqueous solution are always directly applicable to glycosylase-catalyzed reactions. Careful studies are needed to determine whether the structures of some glycosylase–substrate complexes may possibly shield the reaction center from solvent during the catalytic process. 3. Structures That May Help Keep Solvent from the Catalytic Center in Glycosylase–Substrate Complexes Glycosidases are extensively hydrated during their formation. Final structures contain many individual water molecules hydrogen-bonded to various amino acid residues and also may show localized pools of disordered solvent. Further, the catalytic groups of unliganded glycosidases generally are sufficiently exposed to solvent to allow slow replacement of their reactive carboxyl protons by deuterons in enzyme dissolved in 2H2O. Yet, all hydrolysis reactions catalyzed by a given glycosidase with whethever substrate yield product(s) of the same anomeric configuration. This result indicates that the reaction center of a glycosidase–substrate complex is accessible to a water molecule positioned to attack C-1 from one structurally
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specified direction. The key question is whether C-1 and the catalytic carboxyl groups of an enzyme–substrate complex are as exposed to bulk solvent as the catalytic groups of the unliganded enzyme. One can envision that, in some complexes, the close apposition of substrate and the many interactive protein residues may transiently displace disordered water from proximity to those atoms involved in the catalytic chemistry. One apparent example has been observed crystallographically. The structure of soybean beta-amylase complexed with 웁-maltose shows two tandem maltose molecules and some maltotetraose condensation product bound at the same subsites. A mobile hinged loop at the active site, present mainly in an open conformation in the unligated enzyme, is found in closed conformation in the complex. It participates in ligand binding and also in sequestering the reaction center from bulk solvent (Figs. 4 and 5).101 Measurements on the structure of the complex made with a 1.4-Å-diameter spherical probe168 show values of O Å2 (zero access to solvent) for the anomeric carbon atom and equatorial O-1 atom of the 웁-maltose donor; likewise, zero access to solvent for the reactive O-4 atom of the adjacent maltose cosubstrate; also for the side chain of each of the catalytic residues. In unliganded beta-amylase (loop open), the side chain of each catalyst residue has free access to solvent. Thus far, few other glycosidase active sites have been found to include a mobile loop that closes on the ligand and adds to its binding. Porcine pancreatic alpha-amylase shows such a loop sequence. On binding to acarbose, it moves toward the ligand and narrows the breadth of the active site cleft. One loop residue binds to a unit of the ligand from the solvent side, partly protecting the bound fragment from solvent.99 In other glycosidases, simpler structural means, such as the narrow close-fitting substrate binding pocket in glucoamylase,103,104 could have a role, not yet critically evaluated, in displacing solvent from the reaction center. Phosphorylases offer other examples of how the catalytic process may be protected from solvent. In glycogen phosphorylase, water cannot act as a cosubstrate since the phosphate of 움-D-glucopyranosyl phosphate or that used as D-glucosyl acceptor, when bound to the enzyme, has an essential catalytic role,117,119 which water bound in its place cannot assume. In the case of maltose phosphorylase, only the 움- but not the 웁-anomer of maltose (or analogs lacking an axial 1-OH group) serves as a donor substrate. Also, in reversal, the enzyme uses 웁-D-glucopyranosyl phosphate or fluoride as the donor only when the D-glucose cosubstrate is the 움-anomer.69 The axial 1-OH required of a disaccharide substrate, and of the cosubstrate in reversal, binds to an unidentified protein component, X, located remote from the catalytic center (Fig. 8). This required binding interaction limits the enzyme to the synthesis and phosphorolysis (arsenolysis) of 움-maltose-type disac-
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charides. Hydrolysis is negligible, as water bound at X is too far removed to attack C-1 at the reaction center. 4. Unresolved Issues Analysis of the structures of various liganded glycosylases indicates that specific structural features of an enzyme limit the stereochemical outcome of its reactions and provide a rational basis for distinguishing glycosylases differing in stereochemical behavior. Glycosylases of the 1-MCO type structurally orient all cosubstrates to C-1 at the reaction center in one particular way; those of 2-MCO type provide one mode of orientation to C-1 for water (or other appropriate inorganic cosubstrate) and a second, opposite, orientation mode for organic cosubstrates. Although present evidence falls short of establishing the complete generality of this structural subdivision, the assumption is not unreasonable. Both 1-MCO and 2-MCO enzymes correspond to “retaining” and “inverting” glycosidases, respectively, when the comparison involves reactions where other evidence demonstrates nucleophilic substitution(s) to be effected by the catalytic groups. According to the latter (mechanistic) subdivision,15 reaction-product configuration derives from that of the substrate via the action(s) of the enzyme’s catalytic groups. That the stereochemical outcome of a retaining reaction catalyzed via a double-displacement mechanism corresponds to the outcome required by an enzyme’s 1-MCO structure does not mean that this particular mechanism is needed to meet the enzyme’s structural constraint as to cosubstrate orientation. The latter allows for the possibility that the reactions of some “retaining” glycosylases may not proceed via a covalent glycosyl–enzyme intermediate. As discussed earlier, such reactions are reported to be catalyzed by lysozyme, 웁-galactosidase, pancreatic alpha-amylase, glycogen phosphorylase, and several genetically related 움-glucosidases. Proposals that these reactions may proceed by way of an oxycarbonium-ion intermediate have been opposed in general on the basis that the reactions are bimolecular and that the very short lifetime of oxocarbonium ions in water precludes their existance as transient intermediates in enzymecatalyzed reactions.15,169 One observation raises the question of whether enough is known about the carbonium-ion lifetime in enzymic sites to be certain that it is always as short as estimated for reactions in water. The crystal structure of soybean beta-amylase complexed either with 웁-maltose or maltal shows features strongly suggesting that the reaction center is shielded from solvent.101 A mechanism involving a carbonium-ion transition state with C-1 unsubstituted and subject to attack by a structurally positioned water molecule, to form a product of 웁-configuration, is likely for the inverting reactions
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catalyzed by this enzyme. Studies of the structures of “retaining” enzyme complexes would appear desirable in order to gain some insight into the extent to which ligand binding may displace solvent from the catalytic center in such complexes. Techniques are available for measuring access to solvent of the reactive groups at the catalytic center169 as well as for investigating the electrostatic fields generated at the protein surface that might, as reported for lysozyme170 and suggested for cellulase CBH II,25,73 help stabilize a transient carbonium ion. Among the glycosidase-substrate complexes which might be studied are several showing noncovalently bound ligand with the reactive glycosyl unit in a distorted (sofa-type) conformation1,127,132,171 and others showing a covalently linked glycosyl–enzyme intermediate.88,132,141 A final point concerns the progress made on aspects of stereochemistry uncovered in earlier studies. The findings showed that small nonglycosidic (especially enolic) glycosyl donors are protonated by certain glycosidases from a different direction than the enzyme’s glycosidic substrates, yet provide reactions having the same stereochemical outcome as similar reactions catalyzed with “normal” substrates.26,31 The indication from these findings that an enzyme’s catalytic groups can function flexibly but that reaction product configuration is ultimately controlled topologically is presently confirmed. The reported active-site structures of representative “inverting” and “retaining” glycosidases show that a residue identified as the catalytic nucleophile in the tested enzymes is suitably positioned to protonate a nearby double bond. The overall crystal structures further show features that specifically orient cosubstrates to the catalytic groups and reaction center in ways consonant with the stereochemical outcome of reactions catalyzed with substrates of either disfavored or proper configuration. Whether the presently established mechanisms for some glycosylasecatalyzed reactions are applicable to all reactions to the point of excluding other mechanisms is not yet settled, and further investigations are to be encouraged in efforts to do so. At least the time has come for the terms “retaining” and “inverting” enzymes to be put in quotation marks. REFERENCES (1) N. C. J. Strynadka and M. N. G. James, J. Mol. Biol., 220 (1991) 401–424. (2) N. G. Oikonomakos, K. R. Acharya, and L. N. Johnson, in Post-Translational Modifications of Proteins J. J. Harding and M. J. C. Crabbe (Eds.), CRC Press, London, 1991, 81–151. (3) J. D. McCarter and S. G. Withers, Curr. Opin. Struct. Biol., 4 (1994) 885–892. (4) B. Svensson FEBS Lett., 230 (1994) 72–76. (5) J. Gebler, N. R. Gilkes, M. Claeyssens, D. B. Wilson, P. Beguin, W. W. Wakarchuk, D. G. Kilburn, R. C. Miller, Jr., R. A. J. Warren, and S. G. Withers, J. Biol. Chem., 267 (1992) 12,559–12,561.
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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 55
INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY AND INTERNATIONAL UNION OF BIOCHEMISTRY AND MOLECULAR BIOLOGY JOINT COMMISSION ON BIOCHEMICAL NOMENCLATURE NOMENCLATURE OF GLYCOLIPIDS* (Recommendations, 1997)
Prepared for publication by M. Alan Chester, Blodcentralen, Universitetssjuhuset i Lund, Sweden
GL-1. General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GL-2. Generic Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Glycolipid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Glycoglycerolipid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Glycosphingolipid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Glycophosphatidylinositol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Psychosine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Other names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GL-3. Principles of Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Number of Monosaccharide Residues . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* These
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are recommendations of the IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN), whose members are A. Cornish-Bowden (Chairman, France), A. J. Barrett (UK), R. Cammack (UK), M. A. Chester (Sweden), D. Horton (USA), C. Liébecq (Belgium), K. F. Tipton (Ireland), and B. J. Whyte (Secretary, Switzerland). JCBN thanks a panel convened by C. C. Sweeley (USA), whose members were S. Basu (USA), H. Egge (Germany), G. W. Hart (USA, co-opted), S. Hakomori (USA), T. Hori (Japan: deceased 1994), P. Karlson (Germany), R. Laine (USA), R. Ledeen (USA), B. Macher (USA), L. Svennerholm (Sweden), G. Tettamanti (Italy), and H. Wiegandt (Germany), for drafting the recommendations; and other present or former members of the Nomenclature Committee of IUBMB (NC-IUBMB), former members of JCBN, and invited observers, namely A. Bairoch (Switzerland), H. Berman (USA), C. R. Cantor (USA), H. B. F. Dixon (UK), M. A. C. Kaplan (Brazil), K. L. Loening (USA), A. McNaught (UK), G. P. Moss (UK), J. C. Rigg (The Netherlands), W. Saenger (Germany), N. Sharon (Israel), P. Venetianer (Hungary), and J. F. G. Vliegenthart (The Netherlands). Acknowledgement. This document was first published in Pure Appl. Chem. 69, 2475–2487 (1997): © 1997 IUPAC. A World Wide Web version, prepared by G. P. Moss, is available at http://www. chem.qmw.ac.uk/iupac/misc/glylp.html.
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GL-4.
GL-5.
GL-6.
GL-7.
NOMENCLATURE OF GLYCOLIPIDS 3.2. Naming of Monosaccharide Residues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Use of Symbols for Defining Oligosaccharide Structures . . . . . . . . . . . . . . 3.4. Ring Size and Conformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of Glycolipids Based on Their Lipid Moieties. . . . . . . . . . . . . . . . 4.1. Glycoglycerolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Glycophosphatidylinositols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Glycosphingolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neutral Glycosphingolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Monoglycosylceramides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Diosylceramides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Neutral Glycosphingolipids with Oligosaccharide Chains . . . . . . . . . . . . . . Acidic Glycosphingolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Gangliosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Glycuronoglycosphingolipids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Sulfatoglycosphingolipids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Phosphoglycosphingolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Phosphonoglycosphingolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Short Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Recommended Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. The Svennerholm Abbreviations for Brain Gangliosides . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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GL-1. GENERAL CONSIDERATIONS Glycolipids are glycosyl derivatives of lipids such as acylglycerols, ceramides, and prenols. They are collectively part of a larger family of substances known as glycoconjugates. The major types of glycoconjugates are glycoproteins, glycopeptides, peptidoglycans, proteoglycans, glycolipids, and lipopolysaccharides. The structures of glycolipids are often complex and difficult to reproduce in the text of articles and certainly cannot be referred to in oral discussions without a nomenclature that implies specific chemical structural features. The 1976 recommendations1 on lipid nomenclature contained a section (Lip-3) on glycolipids, with symbols and abbreviations as well as trivial names for some of the most commonly occurring glycolipids. Since then, more than 300 new glycolipids have been isolated and characterized, some having carbohydrate chains with more than 20 monosaccharide residues and others with structural features such as inositol phosphate. The nomenclature needs to be convenient and practical as well as extensible to accommodate newly discovered structures. It should also be consistent with the nomenclature of glycoproteins, glycopeptides, and peptidoglycans,2 oligosaccharides,3 and carbohydrates in general.4 This chapter supersedes the glycolipid section in the 1976 Recommendations on lipid nomenclature.1
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GL-2. GENERIC TERMS GL-2.1. Glycolipid The term glycolipid designates any compound containing one or more monosaccharide residues bound by a glycosidic linkage to a hydrophobic moiety such as an acylglycerol, a sphingoid, a ceramide (N-acylsphingoid), or a prenyl phosphate. GL-2.2. Glycoglycerolipid The term glycoglycerolipid is used to designate glycolipids containing one or more glycerol residues. GL-2.3. Glycosphingolipid The term glycosphingolipid designates lipids containing at least one monosaccharide residue and either a sphingoid or a ceramide. The glycosphingolipids can be subdivided as follows. A. Neutral glycosphingolipids 1. Mono-, oligo-, and polyglycosylsphingoids 2. Mono-, oligo-, and polyglycosylceramides B. Acidic glycosphingolipids 1. Sialoglycosphingolipids (gangliosides, containing one or more sialic acid residues) 2. Uronoglycosphingolipids (containing one or more uronic acid residues) 3. Sulfoglycosphingolipids (containing one or more carbohydratesulfate ester groups) 4. Phosphoglycosphingolipids (containing one or more phosphate mono- or diester groups) 5. Phosphonoglycosphingolipids [containing one or more (2aminoethyl)hydroxyphosphoryl groups] GL-2.4. Glycophosphatidylinositol The term glycophosphatidylinositol is used to designate glycolipids which contain saccharides glycosidically linked to the inositol moiety of phosphatidylinositols (e.g., diacyl-sn-glycero-3-phosphoinositol), inclusive of lyso- (Lip-2.6 in ref. 1) species and those with various O-acyl-, O-alkyl-, O-alk-1-en-1-yl- (e.g., plasmanylinositols5), or other substitutions on their glycerol or inositol residues.
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GL-2.5. Psychosine Psychosine was coined historically to designate a monoglycosylsphingoid (i.e., not acylated). The use of this term is not encouraged (Lip-3.4 in ref. 1). GL-2.6. Other Names Other terms such as fucoglycosphingolipid, mannoglycosphingolipid, xyloglycosphingolipid, and so on may be used when it is important to highlight a certain structural feature of the glycolipid. GL-3. PRINCIPLES OF NOMENCLATURE GL-3.1. Number of Monosaccharide Residues The number of monosaccharide residues in an oligosaccharide is indicated by suffixes such as “diosyl,” “triaosyl,” “tetraosyl,” and so on.1,6 Thus, the general name for the oligosaccharide residue of all glycosphingolipids containing 10 monosaccharide residues is “glycodecaosyl”; it might be a glycodecaosylceramide or a 3-glycodecaosyl-1,2-diacyl-snglycerol. Note 1: “diosyl” not “biosyl” is the correct suffix. Note 2: The “a” in “tetraosyl,” and so on is not elided in order to differentiate a tetrasaccharide residue (tetraosyl) from a four-carbon sugar (tetrose), and so on. The “a” in “triaosyl” is added for a similar reason. Recommendations have been made for the nomenclature of oligosaccharides.3,4 GL-3.2. Naming of Monosaccharide Residues Monosaccharide residues are named and abbreviated (Table I) according to the proposed nomenclature recommendations for carbohydrates4 (see also the nomenclature of glycoproteins2). The D- and L-configurational symbols are generally omitted; all monosaccharides are D with the exception of fucose and rhamnose, which are L unless otherwise specified. GL-3.3. Use of Symbols for Defining Oligosaccharide Structures Using the condensed system of carbohydrate nomenclature (ref. 2, section 3.7: ref. 4, 2-Carb-38.5), positions of glycosidic linkages and anomeric configurations are expressed in parentheses between the monosaccharide residues that are thus linked. This principle should be adhered to with full names as well as with the abbreviated structures. A “short form” for repre-
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TABLE I Recommended Abbreviations for Some Monosaccharides, Derivatives, and Related Compounds Name
Symbol
N-Acetylgalactosamine N-Acetylglucosamine N-Acetylneuraminic acida 5,9-N,O-Diacetylneuraminic acida Fucose (6-deoxygalactose) Galactitol Galactosamine Galactopyranose 3-sulfate Galactose Galacturonic acid Glucitol Glucosamine Glucose Glucose 6-phosphate Glucuronic acid N-Glycoloylneuraminic acida myo-Inositolb Mannose 4-O-Methylgalactose Rhamnose Xylose
GalNAc GlcNAc Neu5Ac or NeuAc Neu5,9Ac2 Fuc Gal-ol GalN Galp3S Gal GalA Glc-ol GlcN Glc Glc6P GlcA Neu5Gc or NeuGc Ins Man Gal4Me Rha Xyl
a Acylated neuraminic acids and other derivatives of neuraminic acid may also be called sialic acids (abbreviated Sia) when the nature of the N-acyl substituent(s) is not relevant or is unknown.7 b myo-Inositol with the numbering of the 1D-configuration.8
senting sequences more briefly can be used for specifying large structures. Positions of glycosidic linkages are still given, but the number of the anomeric carbon is omitted, since this is invariable for each monosaccharide, i.e., C-1 for Glc, and so on; C-2 for Neu5Ac, and so on. Example 움-D-Galp-(1 → 3)-움-D-Galp- (extended form) or Gal(움1-3)Gal(움- (condensed form) or Gal움3Gal움- or Gal움-3Gal움a- (short form) GL-3.4. Ring Size and Conformation Ring size and conformation should be designated only when firmly established from NMR or other experimental data. Previously published
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recommendations on the specification of conformation should be consulted.9,10 Example 움-D-galactopyranosyl-4C1-(1 → 3)-움-D-galactopyranosyl-4C1or Galp4C1움3Galp4C1움Subsequently, examples will usually be in the more traditional form with parentheses and both anomeric locants, as, for example, Gal(웁1-4)Glc-, but it is understood that the short form (i.e., Gal웁4Glc-) is also acceptable. GL-4. CLASSIFICATION OF GLYCOLIPIDS BASED ON THEIR LIPID MOIETIES GL-4.1. Glycoglycerolipids Esters, ethers, and glucose derivatives of glycerol are designated by a prefix, denoting the substituent, preceded by a locant. As previously discussed in detail1, the carbon atoms of glycerol are numbered stereospecifically, with carbon atom 1 at the top of the formula shown below. To differentiate this numbering system from others that have been used, the glycerol is always accompanied by the prefix sn (for stereospecifically numbered, Lip1.13 in ref. 1) in systematic and abbreviated names.
Example
1,2-di-O-acyl-3-O-웁-D-galactosyl-sn-glycerol
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GL-4.2. Glycophosphatidylinositols 4.2.1.—Glycophosphatidylinositol (GPI) nomenclature should incorporate the accepted IUB-IUPAC recommendations1,2 for the naming of phospholipids and the glycan portions of glycolipids or glycoproteins. While the diversity of glycophosphatidylinositol structures is only beginning to be realized (for reviews see refs. 11 and 12), many appear to have a common “core.” “Core” structure of glycophosphatidyinositols
Xaa ⫽ C-terminal residue R ⫽ acyl, alkyl, etc., side chains
4.2.2.—Glycophosphatidylinositols covalently attached to polypeptides are termed “GPI-anchors.” Generally, such anchors are covalently attached to the C-terminus of a polypeptide via an amide linkage to 2-aminoethanol, which is linked to the terminal core mannose residue via a phosphodiester bond on O-6 of the mannose. A core Man움2Man움6Man움4GlcN움6 glycan structure is attached to the inositol (generally D-myo-inositol) of phosphatidylinositol. The nonacetylated GlcN is a characteristic feature of glycophosphatidylinositols. Anchor structures appear to vary considerably both in terms of modifications on the core glycan and with respect to additional modifications of the inositol residue. Free glycophosphatidylinositols have generically been termed “glycoinositolphospholipids” to distinguish them from those covalently attached to proteins or larger glycan structures.
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GL-4.3. Glycosphingolipids 4.3.1.—A glycosphingolipid is a carbohydrate-containing derivative of a sphingoid or ceramide. It is understood that the carbohydrate residue is attached by a glycosidic linkage to O-1 of the sphingoid. 4.3.2.—Sphingoids are long-chain aliphatic amino alcohols. The basic chemical structure is represented by the compound originally called “dihydrosphingosine” [2S,3R)-2-aminooctadecane-1,3-diol]. This sphingoid should now be referred to1 as sphinganine (I). The terms sphinganine, sphing-4-enine, and so on imply a chain length of 18 carbon atoms. Chain-length homologs are named by the root chemical name of the parent hydrocarbon. For example, the sphingoid with 20 carbon atoms is icosasphinganine and the sphingoid with 14 carbon atoms is tetradecasphinganine. Unsaturated derivatives of sphinganine and other sphingoids should be defined in terms of the location and configuration of each olefinic center. The most commonly occurring unsaturated sphingoid was originally called “sphingosine” [(2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol]. It should now be referred to as (E)-sphing-4-enine (II). The trivial name “sphingosine” can be retained. As a second example, a C18 sphingoid with two trans double bonds at 4,14 should be called (4E,14E)-sphinga-4,14-dienine. Substituents such as hydroxy, oxo, methyl, and so on are referred to by appropriate suffixes that denote the position of each substituent. The sphingoid containing a hydroxyl group at C-4 of sphinganine was originally called phytosphingosine. According to the nomenclature adopted in 19761, it should be called (2S,3S,4R)-2-aminooctadecane-1,3,4-triol. A trivial (but incorrect) name is (R)-4-hydroxysphinganine (III).
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4.3.3.—Ceramides are N-acylated sphingoids. The fatty acids of naturally occurring ceramides range in chain length from about C16 to about C26 and may contain one or more double bonds and/or hydroxy substituents at C-2. The complete chemical name for a specific ceramide includes the sphingoid and fatty acyl substituents. For example, a ceramide containing 2-hydroxyoctadecanoic acid and sphing-4-enine should be called (E)-N-(2hydroxyoctadecanoyl)sphing-4-enine. GL-5. NEUTRAL GLYCOSPHINGOLIPIDS GL-5.1. Monoglycosylceramides The trivial name “cerebroside” was historically used for the substance from brain, 웁-galactosyl(1 ↔ 1)ceramide, and was later modified to include 웁-glucosyl(1 ↔ 1)ceramide from the spleen of a patient with Gaucher’s disease. It has become a general term for these two kinds of monoglycosylceramides. However, since other monosaccharides are found in this class, the more structurally explicit terms such as glucosylceramide (GlcCer or, better, Glc웁1Cer), galactosylceramide (GalCer), xylosylceramide (XylCer), and so on should be used. GL-5.2. Diosylceramides Diosylceramides may be named systematically, e.g., 웁-D-galactosyl(1 ↔ 4)-웁-D-glucosyl-(1 ↔ 1)-ceramide. However, it is often more convenient to use the trivial name of the disaccharide and call the structure given above lactosylceramide (LacCer). GL-5.3. Neutral Glycosphingolipids with Oligosaccharide Chains 5.3.1.—Systematic names for glycosphingolipids with larger oligosaccharide chains become rather cumbersome. It is therefore recommended to use semisystematic names in which trivial names for “root” structures are used as a prefix. The recommended root names and structures are given in Table II. The name of a given glycosphingolipid is then composed of (root name)(root size)osylceramide. Thus, lactotetraosylceramide designates the second structure listed in Table II linked to a ceramide. When referring to particular glycose residues Roman numerals are used (Lip-3.9 in ref. 1), counting from the ceramide (see Table II). The use of the prefix “nor-” for unbranched oligosaccharide chains should be abandoned since this prefix has a well-defined meaning (“one carbon atom less”) in organic chemistry nomenclature.
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NOMENCLATURE OF GLYCOLIPIDS TABLE II Root Names and Structures Root
Symbol
Root Structure
Ganglio Lactoa Neolactob Globo Isoglobob Mollu Arthro
Gg Lc nLc Gb iGb Mu At
IV III II I Gal웁3GalNAc웁4Gal웁4GlcGal웁3GlcNAc웁3Gal웁4GlcGal웁4GlcNAc웁3Gal웁4GlcGalNAc웁3Gal움4Gal웁4GlcGalNAc웁3Gal움3Gal웁4GlcGlcNAc웁2Man움3Man웁4GlcGalNAc웁4GlcNAc웁3Man웁4Glc-
a
Lacto as used here should not be confused with lactose. The prefix “iso-” is used here to denote a (1 → 3) versus (1 → 4) difference in the linkage position between the monosaccharide residues III and II, while the term “neo-” denotes such a difference [(1 → 4) versus (1 → 3)] between residues IV and III. This scheme should be used also in other cases where such positional isomers occur and only in such cases. b
5.3.2.—The root name applies also to structures that are shorter than the root given in Table II. Thus, gangliotriaosylceramide is the name for the structure GalNAc웁4Gal웁4GlcCer, where the fourth, terminal residue is missing. The trisaccharides obtained from the lacto and neolacto series are identical and in this case the former (shorter) name should be used. 5.3.3.—In the lacto series, the residues III and IV can form a repeating unit. Thus, names like neolactohexaosylceramide (not recommended) have been used, even though the chemical nature of the two glycose residues at the nonreducing end are not explicit in the name. Example 웁-D-Galp-(1 → 4)-웁-D-GlcpNAc-(1 → 3)-웁-D-Galp-(1 → 4)웁-D-GlcpNAc-(1 → 3)-웁-D-Galp-(1 → 4)-웁-D-Glcp-(1 ↔ 1)Cer or Gal웁4GlcNAc웁3Gal웁4GlcNAc웁3Gal웁4GlcCer or Galb-4GlcNAcb-3Galb-4GlcNAcb-3Galb-4GlcCer The correct name is 웁-(N-acetyllactosaminyl)-(1 → 3)-neolactotetraosylceramide, where N-acetyllactosaminyl is 웁-D-Galp-(1 → 4)-D-GlcNAc-. 5.3.4.—Substances containing glycose residues that are not part of a root structure should be named by referral to the root oligosaccharide and locating the additional substituents by a Roman numeral designating the position of the substituent in the root oligosaccharide (counting from the ceramide end) to which the substituent is attached, with an arabic numeral
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superscript indicating the position on that residue which is substituted. The anomeric configuration should also be specified. Examples (i) III2-움-fucosylglobotriaosylceramide or Fuc움2Gal움4Gal웁4GlcCer or III2-움-Fuc-Gb3Cer (ii) II2-웁-xylosylmollutetraosylceramide or GlcNAc웁2Man움3(Xyl웁2)Man웁4GlcCer or II2-웁-Xyl-Mu4Cer 5.3.5.—Branched structures should be designated in a systematic manner, locating substituents in correlation with the Haworth structure of the multiply substituted monosaccharide. This principle should be applied in full structures as well as linear formulations, wherein substituents are in one or more sets of square brackets. Such names and abbreviations should refer to the substituent on the highest carbon number of the branched monosaccharide first and proceed toward the substituent on the lowest carbon number.This recommendation is consistent with the nomenclature of glycoproteins, glycopeptides, and peptidoglycans,2 although not explicitly stated therein. Note: When root names (see GL-5.3.1) are used, the branches should be treated as side chains and named accordingly even when linked to a carbon atom with a higher number than the member of the root oligosaccharide. In oligosaccharide nomenclature4 the longest chain is the parent structure. If two chains are of equal length the one with lower locants at the branch points is preferred, although some oligosaccharides are traditionally depicted otherwise—frequently NeuAc and Fuc derivatives. Example GalNAc웁4Gal웁4Glc| Neu5Ac움3 or GalNAc웁4(Neu5Ac움3)Gal웁4Glc-. Otherwise in ref. 4: Neu5Ac움3(GalNAc웁4) Gal웁4Glcor II3-움-Neu5Ac-Gg3GL-6. ACIDIC GLYCOSPHINGOLIPIDS GL-6.1. Gangliosides Gangliosides are sialoglycosphingolipids.They are named as N-acetyl- or Nglycoloyl-neuraminosyl derivatives of the corresponding neutral glycosphingolipid, using the nomenclature given in GL-5.3. The position of the sialic acid residue(s) is indicated in the same way as is the case of a branched structure.
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Example IV3-움-N-II3-움-N-acetylneuraminosylgangliotetraosylpceramide or Neu5Gc움3Gal웁3GalNAc웁4Gal웁4GlcCer | Neu5Ac움3 or IV3-움-Neu5Gc,II3-움-Neu5Ac-Gg4Cer Gangliosides containing neuraminic acid residues (with O-acyl or other substituents) should be named accordingly, with the positions of the substituents given. Example IV3-움-N-N-acetylneuraminosylgangliotetraosylceramide or Neu5,9Ac2움3Gal웁3GalNAc웁4Gal웁4GlcCer | Neu5Ac움3 or IV3-움-Neu5,9Ac2,II3-움-Neu5Ac-Gg4Cer. GL-6.2. Glycuronoglycosphingolipids These are best named according to the guidelines of GL-5.2 and GL-5.3. Special root names have not yet been assigned. GL-6.3. Sulfoglycosphingolipids These are glycosphingolipids carrying a sulfate ester group, formerly called “sulfatides.” They are sometimes termed sulfatoglycosphingolipids. Sulfoglycosphingolipids may also be named as sulfate esters (sulfates) of the neutral glycosphingolipids (see GL-5). Example II3-sulfo-LacCer or lactosylceramide II3-sulfate GL-6.4. Phosphoglycosphingolipids Two types of glycosphingolipids containing phosphodiester bonds are known: (i) those containing a 2-aminoethyl phosphate residue esterified to a monosaccharide residue, and (ii) those with a phosphodiester bridge between an inositol residue and the ceramide moiety. Those of the first type can be easily named by analogy to the sulfoglycosphingolipids. Example III6-(2-aminoethanolphospho)arthrotriaosylceramide or 6(EtnP)-GlcNAc웁3Man웁4GlcCer or III6-Etn-P-At3Cer
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The second type can be named as inositolphosphoceramide derivatives Example 움-(N-acetyllactosaminyl)-(1 → 4)-움-glucuronosyl-(1 → 2)inositolphosphoceramide or Gal웁4GlcNAc움4GlcA움2Ins-1-P-Cer GL-6.5. Phosphonoglycosphingolipids These are glycolipids esterified with an alkylphosphono acid, i.e., a compound containing a C–P bond. Their nomenclature is best derived using the prefix phosphoryl that denotes the trivalent radical O⫽P←. The residue
may be termed (2-aminoethyl)hydroxyphosphoryl. The location of this group is given in the same way as other ester groups. Example (4-O-methyl-웁-D-galactopyranosyl)-(1 → 3)-(2-acetamido2-deoxy-웁-D-galac-topyranosyl)-(1 → 3)-[움-L-fucopyranosyl(1 → 4)]-(2-acetamido-2-deoxy-웁-D-glucopyranosyl)-(1 → 2)움-D-mannopyranosyl-(1 → 3)-[움-D-xylopyranosyl-(1 → 2)]6-[(2-aminoethyl)hydroxyphosphoryl]-웁-D-mannopyranosyl(1 → 4)-웁-D-glucopyranosyl-(1 ↔1 )-ceramide or Gal4Me웁3GalNAc웁3(Fuc움4)GlcNAc웁2Man움3(Xyl움2)-6(NH2-CH2CH2-P(OH)⫽O)Man웁4GlcCer or OH | NH2CH2CH2-P⫽O | 6 Gal4Me웁3GalNAc웁3GlcNAc웁2Man움3Man웁4GlcCer | | Fuc움4 Xyl움2 GL-7. SHORT ABBREVIATIONS There are no easy solutions to the dilemma that has arisen from the discovery of so many (nearly 300) glycosphingolipids of diverse structures. Short abbreviations are so attractive that a logical system, with broad application to more complex compounds, is desirable.
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NOMENCLATURE OF GLYCOLIPIDS
GL-7.1. Recommended Abbreviations A system already used (GL-5.3) is based on the abbreviated root names of the oligosaccharide structures. The full root structures are tetrasaccharides, and sequential removal of terminal monosaccharide residues gives smaller, precisely defined structures. Elongation of root tetrasaccharides is, on the other hand, undefined and hence ambiguous. The root name may be used, followed by an arabic number indicating the total number of monosaccharide residues. A lowercase letter can be added to differentiate between particular compounds. Example (i) Gal웁3GalNAc웁3Gal움4Gal웁4GlcCer or IV3-웁-Gal-Gb4Cer (ii) GalNAc움3GalNAc웁3Gal움4Gal웁4GlcCer or IV3-움-GalNAc-Gb4Cer. Either of these compounds could, after definition, be referred to as Gb5Cer. In the presence of both structures the abbreviations Gb5a and Gb5b may be defined and used. It is recommended that the use of “Ose,” as in GbOse4Cer, be discontinued. Since this short form sometimes leads to ambiguities, the full structure should be given once in a paper or in a footnote, using the abbreviated from according to GL-5.3. GL-7.2. The Svennerholm Abbreviations for Brain Gangliosides In this system, the fact that we are dealing with gangliosides is indicated by the letter G and the number of sialic acid residues is stated by M for mono-, D for di-, T for tri-, and Q for tetra-sialoglycosphingolipids. A number is then assigned to the individual compound which referred initially to its migration order in a certain chromatographic system.13 Though these designations are far from being systematic, and it is impossible to derive the structure from them, they have the advantage of being short and well understood since they have been in use for a long time. A list of these abbreviations is given in Table III. Since there is no clear-cut system in these abbreviations, it is not recommended to extend the list by coining new symbols of this kind.As a result, the following two cases are examples of abbreviations that should not be used. 1. A disialoganglioside, Neu5Ac움3Gal웁3(Neu5Ac움6)GalNAc웁4Gal웁4Glc Cer, has been abbreviated GD1움. This practice should be discontinued. The recommended abbreviation for this compound is IV3-움-Neu5Ac,III6-움Neu5Ac-Gg4Cer.
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NOMENCLATURE OF GLYCOLIPIDS TABLE III Some Abbreviations Using the Svennerholm System Structure
Abbreviationa
Neu5Ac움3Gal웁4GlcCer GalNAc웁4(Neu5Ac움3)Gal웁4GlcCer Gal웁3GalNAc웁4(Neu5Ac움3)Gal웁4GlcCer Neu5Ac움3Gal웁3GalNAc웁4Gal웁4GlcCer Neu5Ac움8Neu5Ac움3Gal웁4GlcCer GalNAc웁4(Neu5Ac움8Neu5Ac움3)Gal웁4GlcCer Neu5Ac움3Gal웁3GalNAc웁4(Neu5Ac움3)Gal웁4GlcCer Gal웁3GalNAc웁4(Neu5Ac움8Neu5Ac움3)Gal웁4GlcCer Neu5Ac움8Neu5Ac움3Gal웁3GalNAc웁4(Neu5Ac움3)Gal웁4GlcCer Neu5Ac움3Gal웁3GalNAc웁4(Neu5Ac움8Neu5Ac움3)Gal웁4GlcCer Gal웁3GalNAc웁4(Neu5Ac움8Neu5Ac움8Neu5Ac움3)Gal웁4GlcCer Neu5Ac움8Neu5Ac움3Gal웁3GalNAc웁4(Neu5Ac움8Neu5Ac움3)Gal웁4GlcCer
GM3 GM2 GM1a GM1b GD3 GD2 GD1a GD1b GT1a GT1b GT1c GQ1b
a
Previously written using subscripts, e.g., GM3, and so on.
2. The system has been extended to gangliosides of other “root” types, such as those derived from lactotetraosylceramide. An example of this kind is the widely distributed ganglioside called sialoparagloboside, Neu5Ac움3Gal웁4GlcNAc웁3Gal웁4GlcCer, which has at times been abbreviated LM1, but should be referred to as IV3-움-Neu5Ac-nLc4Cer. Attempts to abbreviate more complex glycosphingolipids derived from these examples have resulted in other illogical abbreviations, such as Fuc-3⬘-LM1 for Neu5Ac움3Gal웁4(Fuc움3)GlcNAc웁3Gal웁4GlcCer (IV3-움Neu5Ac,III3-움-Fuc-nLc4Cer). More information on the structures of various glycolipids and the biological material from which they were obtained may be found in several reviews.14–16 REFERENCES (1) IUPAC-IUB Commission on Biochemical Nomenclature (CBN). The nomenclature of lipids (Recommendations 1976). Eur. J. Biochem., 79 (1977) 11–21; Hoppe-Seylers Z. Physiol. Chem., 358 (1977) 617–631; Lipids, 12 (1977) 455–468; Mol. Cell. Biochem., 17 (1977) 157–171; Chem. Phys. Lipids, 21 (1978) 159–173; J. Lipid Res., 19 (1978) 114–128; Biochem. J., 171 (1978) 21–35. (2) IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycoproteins, glycopeptides and peptidoglycans (Recommendations 1985). Eur. J. Biochem., 159 (1986) 1–6; Glycoconjugate J., 3 (1986) 123–134; J. Biol. Chem., 262 (1987) 13–18; Pure Appl. Chem., 60 (1988) 1389–1394; Royal Society of Chemistry Specialist Periodical Report, Amino Acids and Peptides, Vol. 21, 1990, 329. (3) IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Abbreviated terminology of oligosaccharide chains (Recommendations 1980). Eur. J. Biochem., 126
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(4)
(5) (6) (7) (8) (9)
(10)
(11) (12) (13) (14) (15) (16)
NOMENCLATURE OF GLYCOLIPIDS (1982) 433–437; J. Biol. Chem., 257 (1982) 3347–3351; Pure Appl. Chem., 54 (1982) 1517–1522; Arch. Biochem. Biophys., 220 (1983) 325–329. IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of carbohydrates (Recommendations 1996). Pure Appl. Chem., 68 (1996) 1919–2008; Carbohydr. Res., 297 (1997) 1–90; Adv. Carbohydr. Chem. Biochem., 52 (1997) 43–177; J. Carbohydr. Chem., 16 (1997) 1191–1280. W. L. Roberts, S. Santikarn, V. N. Reinhold, and T. L. Rosenberry, J. Biol. Chem., 263 (1988) 18776–18784. C. C. Sweeley and B. Siddiqui, in The Glycoconjugates, Vol. 1, M. I. Horowitz, and W. Pigman (Eds.), Academic Press, New York, 1977, 459–540. G. Reuter and R. Schauer, Glycoconjugate J., 5 (1988) 133–135. Nomenclature Committee of IUB (NC-IUB). Numbering of atoms in myo-inositol (Recommendations 1988). Biochem. J., 258 (1989) 1–2; Eur. J. Biochem., 180 (1989) 485–486. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Conformational nomenclature for five- and six-membered ring forms of monosaccharides and their derivatives (Recommendations 1980). Eur. J. Biochem., 111 (1980) 295–298; Arch. Biochem. Biophys., 207 (1981) 469–472; Pure Appl. Chem., 53 (1981) 1901–1905. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Symbols for specifying the conformation of polysaccharide chains (Recommendations 1981). Eur. J. Biochem., 131 (1983) 5–7; Pure Appl. Chem., 55 (1983) 1269–1272. M. G. Low and A. R. Saltiel, Science, 239 (1988) 268–275. M. A. J. Ferguson and A. F. Williams, Annu. Rev. Biochem., 57 (1988) 285–320. L. Svennerholm, J. Neurochem., 10 (1963) 612–623. H. Wiegandt, in New Comprehensive Biochemistry: Glycolipids, A. Neuberger, and L. M. van Deenen (Eds.), Vol. 10, Elsevier, New York, 1985, 28. S. Hakomori, in Handbook of Lipid Research, Vol. 3, J. N. Kanfer, and S. Hakomori (Eds.), Plenum, New York/ London, 1983, 1–165. C. L. M. Stults, C. C. Sweeley, and B. A. Macher, Methods Enzymol., 179 (1989) 167–214; see also B. A. Macher and C. C. Sweeley, Methods Enzymol., 50 (1978) 236.
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Author Index
Abashev, Yu. P., 43, 44, 75, 122(42) Abass, T. M., 97, 98, 104, 131(336; 337) Abbas, I. M., 234, 261(525) Abboud, J.-L. M., 38–39, 121(16; 27) Abdallah, A. A., 186, 251(195; 198) Abdelfattah, N. F., 234, 261(525) Abdel Rahman, M. M., 184, 186, 196, 215, 225, 236, 250(167), 251(195; 196; 201), 254(283), 256(365) Abelson, J. N., 226, 227, 258(442) Acharya, K. R., 264, 273, 277, 278, 286, 295, 300, 302(2), 306(117) Adachi, H., 226, 227, 258(442) Adachi, M., 280, 306(129) Aebersold, R., 274, 294, 306(121), 307(140) Afanas’ev, V. A., 41, 74, 122(37; 38) Aftab, K., 101, 131(346–350) Ágoston, K., 50, 51, 61, 124(125) Ahnoff, M., 77, 127(221) Akiya, S., 224, 258(432) Albers-Schonberg, G., 226, 258(443) Al-Daher, S. S., 193, 253(257) Alemán, C., 165, 172(92; 93) Aleshin, A. E., 272, 273, 281, 285, 288, 300, 306(103; 104) Alesker, A., 227, 259(470) Alexis, A., 194, 253(261) Alfes, H., 217, 257(396) Alföldi, J., 180, 249(129) Algrim, D. J., 39, 121(23) Ali, M. A., 96, 131(332) Ali, R. S., 177, 249(101) Alizari, P. M., 272, 292, 305(81) Alla, A., 164, 172(91) Allan, Z., 182, 186, 250(146) Allen, A., 183, 185, 250(154)
Allgire, J. F., 77, 127(216) Allison, W. S., 174, 246(5) Almarsson, Ü., 86, 129(278) Al-Masoudi, N., 55, 66, 122(55) Al-Soud, Y. A., 55, 66, 122(55) Alzari, P. M., 272, 282, 288, 305(83) Amaral, L., 177, 248(79) Ambartsumova, R. F., 75, 127(200) Amer, A., 55, 66, 122(55) Ames, M. M., 77, 127(213) Amit, A. G., 272, 282, 288, 305(83) Amyes, T. L., 295, 307(149) Anand, N., 6, 13(36) Andersen, W., 6, 13(19) Anderson, L., 227, 230, 244, 260(485; 486), 261(535) Ando, O., 45, 46, 58, 113, 114, 123(89), 133(407) Ando, T., 270, 304(61) André, S., 51, 62, 103, 125(139) Andres, C. J., 193, 253(256) Andronova, T. M., 43, 44, 75, 122(42) Angulo, M., 68, 69, 126(169) Angyal, S. J., 227, 260(484) Antonopoulos, C. A., 176, 247(31) Anumula, K. R., 80, 128(253) Anzeveno, P. B., 193, 253(258) Apel, R., 177, 249(93) Aplin, J. D., 102, 132(363) Appel, R., 141, 142, 171(40) Arai, M., 113, 133(402; 403) Aravind, S., 106, 132(379) Archer, D. B., 276, 295, 302, 306(127) Ardagh, E. G. R., 176, 247(42) Areces, P., 86, 129(280) Areces Bravo, P., 79, 86, 128(247), 129(279)
327
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328
AUTHOR INDEX
Arison, B. H., 226, 258(443) Armand, S., 273, 306(107) Armstrong, A., 89, 130(307) Armstrong, E. F., 209, 256(343) Armstrong, R. K., 193, 220, 253(249) Arndt, F., 194, 254(263) Arnold, A., 174, 177, 246(22), 248(81) Arrese, F., 175, 246(25) Arya, D. P., 82, 83, 86, 129(270) Asano, N., 193, 253(258) Ashare, R., 37, 121(13) Ashiura, M., 46, 47, 58, 114, 123(87) Ashry, S. H., 212, 256(360) Atherton, F. R., 6–7, 13(25; 27), 14(52; 53) Atta, K., 212, 256(364) Aubert, J.-P., 272, 282, 288, 305(83) Augé, C., 102, 132(357) Augustín, J., 37, 38, 52, 62, 88, 94, 121(9), 125(141–143), 129(289) Augusto, O., 174, 246(7) Augy, S., 227, 259(471) Avalishvili, L. M., 161, 172(83) Avalos, M., 46, 58, 65, 70–73, 77, 79–81, 86–87, 90, 92, 97, 123(77), 125(156), 126(176; 186), 128(233; 234; 251), 129(275; 280) Avalos González, M., 46, 58, 74, 77–79, 86, 123(73; 74), 126(194), 128(231; 243; 246), 129(274) Aviram, K., 244, 261(539) Awad, L. F., 98, 131(338) Awata, M., 227, 259(466) Ayad, M., 206, 255(322) Aymamí, J., 138, 170(22; 23) Aymes, T. L., 299, 308(164) Azimov, V. A., 183, 250(159)
Babiano, R., 43, 46, 58, 65, 68, 70–73, 77, 79–81, 86–87, 90, 92, 97, 123(72; 77), 125(156), 126(176; 186), 128(233; 234; 251), 129(275; 280) Babiano Caballero, R., 41, 42, 56–57, 68, 77, 81, 122(63), 123(69), 127(224), 128(231) Bachmann, F., 142–145, 155, 171(43; 47; 48) Backinowski, L. V., 61, 125(132; 133) Baddiley, J., 5–6, 13(4–6; 10; 28; 29; 34) Badicke, G., 209, 222, 256(348), 258(428) Baehler, B., 189, 252(220–222) Bahl, O. P., 70, 109, 126(174)
Bairoch, A., 264, 272, 303(6) Baker, J. D., 176, 248(70) Bakina, E. V., 81, 129(266) Baláz, S., 88, 129(289) Balding, P., 60, 103, 124(113) Ballesteros, E., 39, 121(27) Balmér, K., 77, 127(221) Bamba, T., 137, 170(12) Bamford, W. R., 194, 254(281) Banait, N. S., 298, 307(159) Bandas, E. M., 198, 254(302), 255(303; 304) Banoub, J. H., 50, 52, 61, 125(137) Baptista, J. A. B., 44, 64, 122(44) Barawkar, D. A., 86, 129(277) Barbalat-Rey, F., 193, 253(247) Barker, H. A., 217, 256(381), 257(382) Barker, R., 194, 254(266) Baron, F., 7, 14(67) Barr, B. K., 272, 305(80) Barrett, D. A., 76, 127(207) Barrows, T. H., 137, 170(13) Barry, J. A., 232, 233, 260(499) Barry, V. C., 197, 254(290) Barton, D. H. R., 87–89, 129(284; 286), 226–227, 258(442), 259(471) Barzilay, M., 60, 124(110) Bastos, M. P., 177, 248(79) Batley, M., 98, 131(339) Batta, G., 50, 51, 61, 124(125) Battioni, P., 174, 246(11) Baudat, A., 193, 253(256) Bauer, C., 209, 256(352) Baum, H., 174, 246(15) Baxter, E. W., 193, 253(256) Bayne, S., 209, 217, 256(344), 257(389) Beaupère, D., 92, 130(311) Becker, R. S., 177, 248(77) Beckwith, A. L. J., 185, 251(184) Bedi, G. S., 70, 109, 126(174) Beguin, P., 264, 272, 282, 288, 302(5), 305(83) Behrend, R., 181, 189, 190, 250(134) Beintema, J. J., 273, 306(106) Belaich, A., 272, 305(82) Belaich, J.-P., 272, 305(82) Belal, S., 206, 255(322) Belinskey, C., 230, 260(491) Bellamy, A. J., 185, 187, 251(173; 190) Benárquez Fonseca, F., 79, 128(244) Bender, D. R., 176, 248(60) Bender, H., 273, 306(108)
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AUTHOR INDEX Bender, S. L., 227, 260(480) Bendiak, B., 175, 177, 179, 247(30), 248(83) Bendnyagina, N. P., 189, 206, 235, 252(223) Benitez, L. V., 174, 246(5) Benito, J. M., 57, 60, 64, 82, 106, 107, 118, 120, 123(71), 124(102), 129(267), 132(382), 133(417), 134(421) Bennani, Y. L., 194, 253(261) Bensen, D., 183, 185, 250(153; 154) Berad, B. N., 74, 127(198) Beraldo, H., 100, 131(342) Beránek, J., 70, 71, 126(171) Bergel, F., 3, 5, 13(2; 7) Bergeron, J., 27, 33(3) Bergfors, T., 269, 270, 272, 273, 279, 280, 288, 291, 304(55) Berkebile, J. M., 194, 254(271) Berliner, L. J., 185, 251(188) Bernstein, J., 181, 250(141) Berthelot, M., 39, 121(24) Berthod, T., 80, 81, 128(256) Berti, P. J., 297, 307(156) Bertram, B., 95, 131(326; 327) Bezouska, K., 104, 132(375) Bhattacharjee, A. K., 51, 60, 103, 124(111) Biely, P., 272, 305(78) Billault, I., 226, 227, 258(442) Binkley, R. W., 175, 247(28) Binkley, W. W., 175, 247(28) Binte, H. J., 174, 206, 246(23), 255(321) Bird, T. P., 140, 154, 170(33–35), 171(36) Bjamer, K., 180, 202, 205, 206, 249(125), 255(307) Black, W. A. P., 140, 154, 170(33–35), 171(36; 37) Blackadder, D. A., 187, 252(209) Blackburn, G. M., 8, 14(79) Blair, H. S., 180, 249(121; 122) Blair, M. G., 187, 252(206) Blake, C. C. F., 295, 307(147) Blanchard, J. S., 268–269, 271, 296–299, 304(53), 305(75), 307(157) Blanco, R. S., 27, 33(4), 68 Blanke, S. R., 297, 307(156) Blasco López, A., 91, 97, 130(309), 131(334) Blattner, R., 227, 258(446), 259(467) Blériot, Y., 70, 110, 126(183), 133(389; 390) Bloom, S. H., 177, 248(74) Blummel, F., 176, 177, 247(36) Bobrova, N. I., 183, 250(160)
329
Bocelli, G., 176, 177, 248(69; 76) Bock, W., 181, 250(142) Bode, G., 220, 257(414) Bodenheimer, T. S., 217, 256(375) Bodley, J. W., 307(131) Boel, E., 272, 305(96) Bognár, R., 71, 94, 126(190), 227, 259(468) Bogusiak, J., 95, 131(328) Boink, G. J., 197, 198, 223, 254(294) Bols, M., 193, 253(256) Bommuswamy, J., 298, 307(160) Bonaly, R., 64, 125(154) Bonfils, E., 60, 124(115) Bonnett, R., 8, 14(84) Borders, L. L., Jr., 293, 307(136) Bordwell, F. G., 39, 121(23) Bou, J. J., 161–163, 165–167, 172(84–88; 92–95) Bouab, W., 39, 121(27) Boutellier, M., 110, 133(391) Bovin, N. V., 70, 102, 126(175; 178), 132(361) Bowden, C. R., 74, 127(199) Boyd, D. R., 227, 259(464) Boyer, J. H., 234, 260(511) Bracke, B. R. F., 39, 121(30) Brady, L., 272, 305(96; 97) Brandi, A., 193, 253(256) Brannon-Peppas, L., 137, 170(14) Braude, E. A., 197, 254(289) Braun, C., 266, 270, 294, 303(39), 307(144) Braun, W., 176, 177, 247(39) Brauns, O., 193, 253(250) Brenken, H., 176, 177, 247(39) Brewer, C. F., 265–276, 280, 281, 284, 285, 287, 296, 298, 300, 302, 303(21; 26; 28; 33; 36–38; 40; 45–47; 50–53; 69–71; 75) Brock, J., 177, 189, 248(85) Brockhaus, M., 266, 268, 276, 303(30) Broder, S., 89, 130(292; 293) Brossmer, R., 71–72, 81, 102, 126(188; 189), 129(258–262), 132(356; 358–360) Brown, D. M., 6–8, 13(18; 21–24), 14(55; 62–65; 67–72; 80) Brown, E., 79, 128(237; 238) Brown, R. L., 194, 254(272; 273; 275; 276) Browne, K. A., 58, 82–83, 86, 123(95), 129(268; 281) Brozozowski, A. M., 308(172) Bruice, T. C., 58, 82–83, 86, 123(95), 129(268–270; 276–278; 281)
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AUTHOR INDEX
Brull, L., 209, 256(345) Bruni, P., 176, 248(69) Bruse, G., 60, 61, 124(122) Brzozowski, A. M., 272, 302, 305(96), 307(132) Buchanan, J. G., 8, 14(82), 192, 220, 253(244–246) Buchmann, F., 136, 170(6) Buckingham, J., 175, 182, 187, 211, 230, 247(29), 250(150), 260(494) Buckley, N., 299, 308(165) Budhu, R. J., 227, 260(480) Buehner, M., 273, 278, 295, 300, 306(119) Bueno, M., 147–150, 171(50; 53–55) Bueno Martínez, M., 147, 153, 171(52; 56; 57; 59) Buisson, G., 272, 278, 286, 295, 300, 305(99) Bunin, B. A., 226, 227, 258(442) Burgess, K., 193, 253(254) Burke-Laing, M., 175, 246(24) Burneister, W. P., 294, 302, 307(141) Buss, D. H., 50, 60, 124(103) Butler, C. L., 179, 249(118) Butler, K., 140, 154, 170(32) Butters, T. D., 193, 253(259) Buzykin, B. I., 189, 206, 235, 252(223) Buzykin, B. J., 176, 180, 247(59) Byramova, N. E., 102, 132(361) Byranova, N. E., 70, 126(178)
Caglioti, L., 230, 260(493) Callebaut, I., 272, 306(105) Camarasa, M. J., 41–43, 54, 55, 88, 122(34; 41) Camarasa Rius, M. J., 54, 122(35) Cameron, L. M., 39, 121(22) Campadelli-Fiume, G., 174, 246(16) Campbell, R. L., 272, 305(91) Cañada, F. J., 92, 117, 130(310) Canard, B., 80, 81, 128(256) Cane, D. E., 176, 248(71) Cannon, J. R., 8, 14(84) Cantoni, A., 176, 248(69) Cao, R., 95, 100, 131(342; 343) Cardellini, L., 177, 248(76) Cardillo, B., 176, 248(69) Carless, H. A. J., 227, 259(451) Carnovskii, A. D., 189, 206, 235, 252(223) Caro, H. N., 106, 107, 118, 132(382) Carothers, W. H., 135, 170(3; 4)
Carpenter, N. C., 193, 253(257) Carreira, E. M., 42, 54, 113, 122(52) Carroll, P. J., 193, 253(256) Carson, J. F., 217, 256(380) Carter, H. E., 230, 260(491) Cascio, D., 272, 305(100) Casiraghi, G., 193, 253(256) Castillon, S., 227, 259(470) Castro, C., 234, 244, 261(514) Catar, G., 174, 246(18) Cavallaro, C. L., 176, 247(54) Cebulak, M., 227, 260(487) Cech, D., 48, 58, 63, 81, 92, 123(96) Ceni de Bello, J., 193, 253(257) Cerny, M., 45, 46, 59, 74, 86, 88, 94, 123(97) Cert Ventulá, A., 79, 128(240; 242; 245) Chaby, R., 80, 128(257) Chacon-Fuertes, M. E., 192, 220, 253(244; 245) Chamberlin, A. R., 177, 248(74) Chan, A. W.-Y., 111, 133(392) Chan, W. C., 76, 127(207) Chandler, J. H., 176, 248(70) Chaney, A., 139, 154, 170(31) Chang, Y.-T., 226, 227, 258(442) Chaplin, A. F., 185, 251(191) Chaplin, D. A., 193, 253(254) Chapman, O. L., 206–207, 225, 255(325; 332), 258(435) Chargaff, E., 202, 206, 227, 230, 241, 255(309), 260(488), 261(533) Charon, D., 80, 128(257) Chase, B. H., 7, 14(47) Chatterjee, M., 193, 253(259) Chen, D., 193, 253(256) Chen, L., 156–157, 172(69; 70; 72–74), 193, 253(257) Chernyak, A. Ya., 102, 132(364) Chiba, H., 96, 131(331), 177, 249(108) Chiba, S., 264, 265, 268, 270, 280, 284, 298, 303(10), 304(45; 47; 51), 307(161; 163) Chiba, T., 176, 186, 206, 248(63), 251(202), 255(316) Chida, N., 227, 259(452–454) Chilton, W. S., 182, 219, 250(148), 257(405) Chima, J., 227, 259(464) Chittenden, C. F. J., 244, 261(537) Chmurski, K., 82, 106, 107, 118, 129(267), 132(382) Chow, H.-F., 104, 132(373)
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AUTHOR INDEX Christ, D. D., 77, 127(211; 212) Christie, S. M. H., 7, 13(40), 14(51) Chung, S. K., 226–227, 258(442), 260(482) Churn, S. C., 176, 247(32) Ciajola, M. R., 175, 246(26) Cintas, P., 46, 58, 77, 79–81, 86, 87, 90, 97, 123(77), 128(233; 234; 251), 129(275) Cintas Moreno, P., 74, 77, 78, 86, 126(194), 128(231), 129(274) Claeyssens, M., 264, 266, 268, 270, 272, 273, 276, 280, 282, 287, 288, 296, 302(5), 303(37; 38), 305(83) Clark, R. K., Jr., 230, 260(491) Clark, V. M., 6–7, 13(17; 26; 29; 30; 36), 14(54; 56; 60; 61) Clarke, A. E., 264, 303(18) Clarke, M. A., 27, 28, 33(1–5; 7–10), 34(11–15), 68 Clarke Garegg, M. A., 27, 33(6) Clennan, E. L., 234, 261(513) Cléophax, J., 227, 259(469) Cluss, E., 212, 256(356) Cochran, W., 6, 13(23) Cogoli, A., 296, 299, 307(151) Cohen, J. S., 8, 14(79) Cole, F., 27, 33(3) Coleman, A. W., 41, 64, 125(152; 153) Collins, P., 176, 247(54) Collins, P. M., 227, 238, 259(472) Colman, P. M., 193, 253(258) Compton, J., 178, 181, 189, 249(114) Conde, A., 79, 128(248–250) Conde, C. F., 79, 128(248; 249) Conn, R. S. E., 176, 248(60) Connerton, I., 272, 305(90) Connolly, M. L., 300, 308(168) Cook, J. D., 234, 261(520) Cooper, P. W., 194, 197, 254(274) Corby, N. S., 7, 14(57) Cordona, F., 193, 253(256) Corey, E. J., 176, 248(71; 72) Corley, E. G., 176, 248(60) Cortesi, R., 36, 120(3) Coste-Sarguet, A., 47–49, 60, 92, 124(98) Cottaz, S., 294, 302, 307(141) Cotton, F. A., 38, 121(20) Courtois, J. E., 270, 304(63) Cox, R. A., 39, 121(25) Coxon, B., 199, 201, 205, 209, 234, 255(306; 314), 261(523)
331
Cremlyn, R. J., 6, 7, 13(32), 14(49) Cretcher, L. H., 179, 249(118) Crich, D., 37, 88, 89, 121(7), 186, 187, 189, 251(203), 252(213) Crossman, A., 183, 185, 187, 250(152–154) Crum, J. D., 194, 254(266; 269) Cuevas Lorite, T., 75, 127(201) Cueves, T., 47, 58, 68, 81, 87, 123(78; 79) Cui, Y., 227, 258(451) Cumming, D. A., 177, 248(83) Cummings, N., 272, 305(90) Czarnik, A. W., 226, 227, 258(442) Czjzek, M., 272, 305(82) Czubarow, P., 219, 257(400) Czyzewski, Z., 209, 256(346)
Dahlquist, F. W., 293, 295, 307(136; 148) Dahm, S., 202, 205, 206, 255(307) Dahmén, J., 50, 61, 124(129) Dakour, J., 84, 129(271) Daley, L., 92, 130(312) Dalko, P., 226, 227, 258(442) Dalton, D. R., 193, 253(256) Damo, C. P., 77, 127(216) Daniel, J. K., 193, 253(258) Dao-Pin, S., 302, 308(170) Dauter, M., 302, 307(132), 308(172) Dauter, Z., 272, 282, 288, 302, 305(85), 308(171) Davidis, E., 174, 246(21) Davies, G., 272, 282, 288, 300, 302, 305(82; 85; 86), 306(105), 307(132), 308(169; 172) Davoll, J., 5, 13(13; 16) Davoodi, J., 272, 305(91) Day, J., 272, 305(100) Debacher, N. A., 39, 121(29) de Bernardo, S., 89, 130(298) De Bruyne, C. K., 270, 304(65) De Clercq, E., 74, 127(195) Defaye, J., 47–49, 60, 65, 82, 92, 106, 107, 118, 124(98; 99; 101), 125(155), 129(267), 132(382; 383), 133(418), 270, 304(64) Degano, M., 272–274, 280, 281, 285, 288, 292, 300, 301, 306(101) Dekker, C. A., 8, 14(70) de las Heras, F. G., 41–43, 54, 55, 88, 89, 122(34; 41), 130(299) de las Heras Martín Maestro, F. G., 54, 122(35)
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332
AUTHOR INDEX
Delaumney, J.-M., 227, 259(469) de Lederkremer, R. M., 41, 43, 55, 74, 75, 87–88, 122(53; 54) de Marco, A. M., 176, 248(60) Demchenko, A. V., 41, 54, 121(33), 122(49) Demes, P., 174, 246(18) Dempcy, R. O., 58, 82–83, 86, 123(95), 129(268; 269; 278; 281) de Paz, J. L. G., 39, 121(27) de Paz, M. V., 147, 169, 171(50), 172(99) de Paz-Bañez, M. V., 147, 171(51) Derdall, G. D., 39, 121(26) Derewenda, U., 272, 305(89) Derewenda, Z. S., 272, 305(89; 96; 97) de S. Sierra, M. M., 39, 121(29) Deshmukh, S. P., 74, 127(198) de Vries, G. E., 273, 306(109) Dewar, E. T., 140, 154, 170(33–35), 171(36; 37) Deyn, W., 227, 258(447; 449) Dhekne, V. V., 227, 259(459) Diánez, M. J., 74, 79, 80, 87, 126(193), 128(252) Días-Martín, D., 89, 130(307) Díaz, A., 100, 131(342; 343) Díaz Arribas, J. C., 92, 117, 130(310) Díaz Pérez, V. M., 45–47, 58, 59, 65, 66, 75, 81, 85, 87, 92, 117, 123(85), 125(159; 160), 129(273), 130(310) Diels, O., 184, 185, 212, 215, 221, 250(162), 256(356), 257(417) Dijkhuizen, L., 273, 279, 286, 306(109; 110) Dijkstra, B. W., 273, 279, 286, 306(106; 107; 109; 110) Dijong, I., 197, 198, 201, 219, 254(291) Dintinger, T., 110, 133(389; 390) Divne, C., 272, 273, 276, 287, 305(79) Dixon, M., 234, 244, 261(514) do Amaral, L., 177, 248(80) Doane, W. M., 89, 130(290; 291) Dobson, C. M., 276, 295, 302, 306(127) Dodson, E. J., 272, 305(97) Dodson, G. G., 272, 282, 288, 305(85; 96) Dominguez, R., 272, 292, 305(81) Dong, X., 51, 62, 103, 125(139) Dorman, L. C., 207, 255(331) Doudoroff, M., 217, 256(381), 257(382), 270, 285, 304(68) Douglas, A. W., 176, 248(60) Doyle, M. P., 174, 246(13)
Drewniak, J., 227, 239, 260(478) Driguez, H., 270, 294, 302, 304(64), 307(141) Driscoll, J. S., 89, 130(292; 293; 296) Drobnica, L., 37, 38, 52, 62, 94, 121(9), 125(141–143) Druet, L. M., 39, 121(25) Drumright, R. E., 185, 251(185) Dubber, M., 104, 132(377) Dubose, R. F., 272, 274, 276, 305(77) Ducros, V., 272, 305(82) Duddeck, H., 176, 247(54) Duee, E., 272, 278, 286, 295, 300, 305(99) Duke, E. M. H., 273, 277, 278, 306(118) Duke, J., 60, 124(105) Dukefos, T., 180, 249(124) Duplishcheva, A. P., 77, 128(229) Durán, C. J., 70–73, 87, 126(176; 186) Durham, L. J., 226, 258(437) Dursun, K., 177, 249(106) Duus, F., 37, 121(6) Dwek, R. A., 50, 51, 62, 103, 125(138), 193, 253(259)
Ealick, S. E., 273, 289, 306(113) Eberson, L., 233, 260(504) Ebisu, S., 60, 124(107) Eby, R., 50–51, 61, 124(127; 128) Eckhart, E., 190, 192, 252(228; 234) Edvabnaya, L. S., 61, 125(132) Edward, J. T., 39, 121(26) Edye, L. A., 27, 28, 34(9–11; 14) Eggleston, G., 27, 33(10), 34(11; 15) Ehlers, S., 47, 63, 125(144) Eichenauer, H., 233, 260(508) Eilert, U., 101, 131(345) Eistert, B., 194, 233, 237, 254(263), 260(502) Ekborg, G., 51, 60, 61, 103, 124(111; 119) Eklind, K., 50, 60, 61, 124(120) Ekwall, E., 60, 61, 124(122) El Adl, S., 206, 255(322) El Ashry, E. H., 186, 251(195–201) El Ashry, E. S. H., 98, 131(338), 196, 254(283) El Ashry, H., 212, 256(363) El Ashry, S., 184, 189, 212, 215, 250(165), 256(359; 361; 366) El Badry, S. M., 177, 249(101) Elbein, A. D., 110, 133(387), 193, 253(254; 258) Elbert, T., 45, 46, 59, 74, 86, 88, 94, 123(97) El Ghomari, M. J., 39, 121(24)
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AUTHOR INDEX Elguero, J., 234, 261(517) Elion, M. D., 273, 289, 306(113) El Khadem, H. S., 176, 177, 180, 183, 184, 185, 186, 187, 189, 193, 196, 199, 201, 202, 205–207, 209, 212, 215, 217, 219– 220, 222–228, 233–234, 236, 241, 247(37; 38; 47; 48), 249(112; 130), 250(152–154; 165; 167), 251(193), 252(219), 253(251), 255(306; 311–314; 326; 341), 256(359–363; 365–368; 378), 257(388; 393; 394; 396; 398; 400; 403; 407; 408; 413; 422), 258(425; 426; 429) 261(523) El Kheir, A. A., 206, 255(322) El Kilany, Y., 186, 251(196; 198–200) El-Menshawi, B., 101, 131(344) El Meslouti, A., 92, 130(311) Elmore, D. T., 7, 8, 14(51; 74) El-Mouhtadi, M., 39, 121(27) El Sadek, M., 212, 256(363) El Sayed, 212, 256(363) El-Sekeli, M. A., 212, 256(361) El Sekily, M., 220, 257(415) El Shadem, H., 220, 257(415) El-Shafei, Z. M., 184, 189, 202, 206, 212, 217, 219, 222, 224, 234, 250(165), 255(312), 256(363), 257(393; 394; 422), 258(425) El-Toukhy, A. A., 97, 98, 104, 131(336; 337) Emoto, S., 70, 71, 126(173) Enders, D., 233, 260(508) Engel, L. L., 207, 255(336) Enholm, E. J., 89, 130(305) Entwhistle, D. A., 193, 253(257) Erden, I., 234, 244, 261(514) Ergonenc, P., 234, 244, 261(514) Ermolaev, K. E., 198, 255(303) Ermolaev, K. M., 198, 254(302; 304) Esposito, E., 36, 120(3) Esseffar, M., 39, 121(27) Estabrook, R. W., 174, 246(4) Estevez, V. A., 227, 260(481) Estrada, M. D., 74, 79, 87, 126(193), 128(250) Estrwan, E. I., 222, 258(423) Estupinan, B., 297, 307(154) Ettel, V., 217, 256(377) Evans, E. F., 194, 254(267; 268; 272) Evans, W. L., 185, 250(171) Ewing, D., 91, 93, 130(308) Eybl, V., 94, 130(316; 317)
333
Fabrega, S. E., 272, 306(105) Fadeeva, N., 137, 170(8) Faillard, H., 42, 54, 68, 122(51) Fairbanks, A. J., 193, 253(257) Faizi, S., 101, 131(346–351) Falk, I., 176, 177, 247(39) Fasman, G. D., 7, 14(64) Fatiadi, A. J., 177, 180, 183, 186, 187, 190, 199, 201, 205, 209, 211, 212, 217, 224, 227, 230, 233–241, 248(75), 250(131; 157), 251(192), 252(225; 230), 255(306; 314), 256(353), 257(392), 260(490; 492; 495; 496; 500; 501; 526), 261(526; 529–532) Feather, M. S., 196, 254(284) Fechtner, E., 176, 177, 247(39) Feizi, T., 193, 253(257) Félix, C., 64, 125(154) Feliz, M., 244, 261(539) Ferguson, M. A. J., 315, 324(12) Fernandez, R., 176, 247(54) Fernández-Bolaños, J., 79, 80, 91, 97, 128(239–245; 252), 130(309), 131(334) Fernández-Bolaños Guzmán, H, 79, 80, 128(252) Fernández García-Hierro, J. I., 79, 86, 128(247), 129(279) Fernández-Resa, P., 41–43, 54, 88, 122(34; 35) Fernández-Santín, J. M., 138, 170(22; 23) Ferrier, R., 46, 126(167; 168), 176, 227, 247(54), 258(446), 259(467) Fessner, W. D., 227, 259(463) Fiandor, J., 89, 130(299) Fierobe, H.-P., 272, 305(82) Fieser, L. F., 205, 255(315) Fieser, M., 205, 255(315) Figueroa Pérez, S., 106, 132(381) Filippatos, E. C., 74, 127(195) Fink, C., 51, 62, 103, 125(139) Finkelstein, E., 185, 211, 251(187), 256(355) Finney, N. S., 176, 248(72) Firsov, L. M., 272, 273, 281, 285, 288, 300, 306(103; 104) Fischer, E., 36, 42, 120(2), 126(163), 176, 177, 179, 196, 197, 202, 208, 209, 220–221, 247(52), 249(110), 254(285; 286), 256(343), 257(409; 416) Fischer, P. B., 190, 252(227) Fishman, M. L., 135, 170(5) Fitting, C., 270, 285, 304(68) Fitz, W., 227, 259(463)
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334
AUTHOR INDEX
Fleet, G. W. J., 193, 253(257) Fletcher, H. G., 227, 260(483) Flint, J. A., 7, 14(55) Flowers, H. M., 265, 303(23) Flynn, E. H., 230, 260(491) Forbes, E. C., 197, 254(289) Ford, M. J., 89, 130(306; 307) Forrest, H. S., 7, 13(38; 39) Forrester, A. B., 232, 233, 260(498) Fox, H. H., 181, 250(140) Fox, J. J., 70, 71, 126(171) Fraenkel, G., 187, 252(208) Fragoso, A., 95, 100, 131(324; 343) Franck, R. W., 193, 253(257) Franco, J. D., 39, 121(29) Frank, N., 95, 131(326) Frank, V., 174, 246(19) Frazier, J., 89, 130(295) Frejd, T., 50, 61, 124(129) Freudenberg, K., 176, 177, 193, 247(36), 253(250) Fricke, T., 104, 132(376) Fried, M., 8, 14(80) Friedberg, F., 198, 254(296) Friedman, H. A., 70, 71, 126(171) Friedrich, E., 233, 260(508) Friendman, R. B., 135, 170(5) Frime, A. A., 234, 260(510) Fritz, H., 268, 271, 274, 275, 284, 304(46) Fuentes, J., 41–48, 54, 57–60, 64, 65, 68–70, 72, 74, 75, 77, 81, 84, 85, 87, 92, 101, 102, 108, 117–119, 122(50), 123(66–68; 70; 71; 75; 77; 79; 81; 84; 85), 124(100), 125(159), 126(169; 170; 177; 192), 128(233), 130(310), 133(415–417), 134(419) Fuentes Mota, J., 41–43, 45–49, 56–60, 68, 74, 75, 77–79, 81, 86, 87, 91–92, 97, 122(63–65), 123(69; 72–74; 78; 83), 124(98), 126(194), 127(201; 222–226), 128(231; 240; 242; 244; 245; 247), 129(274; 279), 130(309), 131(334) Fügedi, P., 95, 131(330) Fukase, H., 193, 227, 253(258), 259(458) Fukazawa, C., 280, 306(128) Fukui, K., 78, 128(236) Fukui, S., 176, 247(56) Fukuzawa, C., 280, 307(130) Funes, J. L., 150, 171(55) Furberg, S., 180, 202, 205–206, 249(125; 126), 255(307; 308)
Furuhata, K., 81, 129(265) Furukawa, Y., 113, 133(403) Furuta, S., 226, 258(437) Fuska, J., 174, 246(19) Fuskova, A., 174, 246(19)
Gaafar, A. E. M., 55, 66, 122(55) Gabius, H.-J., 51, 62, 103, 125(139) Gabriel, S., 135, 170(2) Gadelle, A., 47–49, 60, 92, 124(98; 101) Gafner, G., 235, 261(528) Gal, J., 77, 127(209; 213; 214; 217; 220) Galbis Pérez, J. A., 41, 43, 56–58, 68, 77, 79, 81, 86, 122(63), 123(72), 128(241; 243; 246; 247), 129(279), 147–150, 153, 163, 169, 171(50; 51; 52; 53–55; 56; 57–59; 89; 99) Galons, H., 64, 125(153) Gambaryan, A. S., 70, 102, 126(178), 132(361) Ganem, B., 70, 110, 111, 113, 115, 126(179; 180; 182), 133(387; 388; 391; 392; 404; 411), 272, 305(80) Gao, Z., 109, 110, 133(386) García, I., 100, 131(342) García Alvarez, M., 168, 172(98) Garcia-Blanco, S., 175, 246(25) García-Calvo-Flores, F., 41–44, 56, 68, 74, 122(57) García Fernández, J. M., 37, 40–49, 56–60, 63–66, 68, 70, 72, 74–75, 77, 81, 82, 87, 91–92, 102, 106–108, 117–120, 121(8), 122(64), 123(66; 69; 71; 72; 75; 81–85), 124(98–100; 102), 125(155; 159; 160), 126(177; 192; 193), 127(201; 223–226), 129(267), 130(310), 132(382; 383), 133(415–418), 134(419–421) García Gómez, M., 42, 56, 57, 77, 122(64) García González, F., 79, 128(239) García-López, M. T., 41–43, 54, 55, 88, 122(34; 35; 41) García-Martín, M. G., 147, 169, 171(50; 51), 172(99) García-Mendoza, P., 41–44, 56, 68, 74, 122(57) Garcia-Mina, M., 175, 246(25) García Rodríguez, S., 79, 80, 128(252) García-Verdugo, C., 65, 71, 125(156) Gardiner, D., 227, 238, 259(472)
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AUTHOR INDEX Garegg, P. J., 50–52, 60–61, 95, 103, 124(106; 107; 118–121; 123), 131(330), 132(367) Garg, H. G., 64, 125(150) Gätzi, K., 194, 254(264) Gaudin, C., 272, 305(82) Gaudino, J. J., 226, 227, 258(442) Gautheron-Le Narvor, C., 102, 132(356) Gebler, J., 264, 272, 274, 302(5), 306(121) Gelin, S., 234, 261(524) Gemeiner, P., 52, 62, 94, 125(141–143) Genghof, D. S., 264–268, 270–274, 280–281, 284, 302, 303(14; 19–21; 26), 304(40; 66) Genre-Grandpierre, A., 70, 110, 126(183) Genre-Granpierre, A., 110, 133(389) Georges, L. W., 181, 250(137; 138) Gero, S. D., 226–227, 238, 239, 258(442), 259(469; 471; 474), 260(475) Gibas, J. T., 181, 250(140) Giboreau, P., 94, 130(314) Gibson, S. T., 137, 170(13) Giese, B., 185, 251(180; 181) Gijsen, H. J. M., 227, 259(463) Gilani, A. H., 101, 131(346–350) Gilbert, H. J., 272, 305(90) Gilding, D. K., 137, 170(10) Gilkes, N. R., 264, 272, 279, 294, 302(5), 305(87), 307(140) Gillet, G., 174, 246(11) Gingsburg, V., 51, 52, 61, 125(134) Giorgioni, E., 176, 248(69) Giralt, E., 244, 261(539) Giumanini, A. G., 230, 260(493) Glaudemans, C. P. J., 51, 60, 103, 124(111) Gliemann, J., 44, 56, 101, 122(62) Gnewuch, T., 185, 251(188) Godshall, M. A., 27, 33(1; 2; 4), 34(13), 68 Goering, B. K., 115, 133(411) Goldstein, I. J., 50, 60, 102–104, 124(104; 105; 107; 108; 114) Gomez Guillen, M., 192, 252(243) Gómez Monterrey, I. M., 46, 58, 74, 77–78, 86, 123(73; 74), 126(194), 127(225), 129(274) Gonsalves, K. E., 136, 137, 170(7) González, L., 86, 100, 129(280), 131(342) Goodman, I., 36, 121(5) Gordon, M. S., 177, 248(78) Goring, J., 233, 237, 260(502) Goti, A., 193, 253(256) Goto, R., 176, 247(31)
335
Gottammar, B., 50, 51, 60–61, 124(119–121) Gould, E. S., 233, 260(503) Goynes, W. R., 27, 33(7) Graham, R. W., 264, 270, 291–293, 303(11) Graham Shipley, G., 273, 306(114) Grandberg, I. L., 183, 250(160) Grech-Bélanger, O., 77, 127(215) Greemer, L. J., 193, 253(258) Green, D. C., 74, 127(197) Green, J. W., 185, 251(177) Green, R., 272, 305(89) Greenwood, A., 272, 305(100) Greenwood, C. T., 270, 304(58) Gregory, H., 139, 170(27) Grice, P., 89, 130(307) Griffin, T. S., 37, 121(11) Grisebach, H., 198, 254(295) Grisham, M. P., 27, 34(13) Gross, B., 220, 257(415) Gross, H. J., 81, 102, 129(258–263), 132(357) Grossman, A., 187, 189, 252(214) Groullier, A., 91, 93, 130(308) Grubmeyer, C., 273, 283–284, 288, 306(111; 112) Grussing, D. M., 137, 170(13) Guerreiro, C., 80, 81, 128(256) Guida, W. C., 273, 289, 306(113) Guile, G. R., 50, 51, 62, 103, 125(138) Guillo, N., 110, 133(390) Guilloux, E., 270, 304(63) Günther, W., 44, 64, 122(46) Guthrie, R. D., 182, 185, 187, 230, 244, 250(150), 251(173; 190), 260(494), 261(537) Gyorgydeak, Z., 176, 247(54)
Haas, H. J., 198, 255(305) Haas, J. W., Jr., 180, 249(120) Hadfield, A. T., 273, 276–278, 295, 302, 306(118; 127) Hadzic, A., 177, 249(106) Hadzic, M., 177, 249(106) Haering, T., 144, 171(46) Hagneav, F., 177, 248(77) Hague, C., 176, 247(34) Hahner, E., 176, 177, 247(39) Haines, S. R., 227, 259(467) Hajivarnava, G. S., 227, 238, 259(473) Hakomori, S., 323, 324(15)
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336
AUTHOR INDEX
Hall, R. H., 6, 8, 13(36), 14(75) Hamer, N. K., 7, 14(55) Hammer, C. F., 74, 127(197) Han, O., 176, 248(61) Han, Y. W., 27, 33(5; 8) Hand, M. V., 227, 259(464) Hanessian, S., 194, 253(261) Hanisch, G., 217, 257(391) Hann, R. M., 176, 217, 247(55), 256(369; 370; 374) Hansen, A., 193, 253(256) Hantschel, H., 181, 250(143) Hanzawa, H., 81, 113, 114, 129(264), 133(407) Hara, H., 226, 258(441) Harada, N., 266, 304(42) Harada, W., 272, 305(94) Hardegger, E., 217, 221, 222, 256(378), 257(387; 388; 390; 419) Hardy, L. W., 275, 306(126) Hare, J. B., 140, 154, 170(34; 35), 171(36) Harrelson, J. A., Jr., 39, 121(23) Harris, E. M. S., 272, 273, 281, 285, 288, 300, 306(103; 104) Harris, G. W., 272, 305(90) Hartwig, W., 88, 89, 129(287) Haruyama, H., 50, 62, 81, 113–114, 125(140), 129(264), 133(402; 403; 407) Harvey, D. J., 276, 295, 302, 306(127) Harvey, W. E., 7, 14(59) Hase, S., 80, 128(254), 176, 247(33) Haselhorst, M., 198, 254(295) Haser, R., 272, 278, 286, 295, 300, 305(82; 98; 99) Hashimoto, K., 158, 172(75; 76) Haskins, W. T., 217, 256(370) Hassan, H. H. A. M., 155, 171(68) Hassan, N. A., 55, 66, 122(55) Hassel, T., 65, 122(43), 125(157; 158) Hassid, W. Z., 217, 256(381), 257(382) Hassner, A., 87, 129(285) Hatano, K., 206, 255(316) Haushalter, K. A., 39, 121(31) Havukainen, R., 272, 305(93) Hawkins, E. G. E., 185, 187, 251(175) Haworth, W. N., 139, 154, 170(27; 29), 207, 255(335) Hay, J. M., 232, 233, 260(498) Hayashi, M., 227, 259(466) Hayashi, T., 138, 170(16)
Hayauchi, Y., 193, 253(254) Hayes, C. E., 50, 60, 102–104, 124(114) Hayes, D. H., 6, 8, 13(19), 14(73) Haynes, L. J., 7, 13(43), 14(44; 62) Hazalwood, G. P., 272, 305(90) Hearn, M. J., 176, 247(58) Heath, R. L., 139, 154, 170(29) Heaton, B. T., 176, 248(67) Hefnawy, M. M., 77, 127(219) Hegendus-Vajda, J., 190, 252(231) Hehre, E. J., 264–276, 280–281, 284, 285, 287, 296–300, 302, 303(8; 9; 12–14; 19–22; 26; 28; 33; 36–38), 304(40; 45–47; 50–53; 66; 69–71), 305(75), 306(102), 307(157) Heightman, T. D., 70, 110, 126(185) Heiker, F. R., 227, 259(455) Helferich, B., 42, 126(163), 177, 248(83) Helmreich, E. J., 266, 268, 273, 278, 284, 295, 300, 304(41; 48), 306(119) Henderson, G., 185, 187, 251(174) Henderson, I., 193, 253(254) Henre, E. J., 272–274, 280, 281, 285, 288, 292, 300, 301, 306(101) Henrissat, B., 264, 270, 272, 273, 282, 288, 294, 302, 303(6), 304(64), 305(86), 306(105; 107), 307(141) Henseke, G., 174, 177, 179, 181, 206–207, 209, 217, 219, 222, 246(23), 249(111), 250(143), 255(321; 339; 340), 256(346–349; 352), 257(391; 397), 258(428) Heo, C., 295, 307(149) Heppel, L. A., 8, 14(72) Herczegh, P., 71, 94, 126(190) Hernández-Mateo, F., 41–44, 56, 68, 74, 122(57) Herreros, M., 39, 121(27) Herrier, G., 102, 132(358) Hester, M. R., 174, 246(13) Hetterich, P., 102, 132(359; 360) Hetzheim, A., 177, 249(104) Heubach, G., 198, 254(300) Hey, D. H., 185, 251(191) Heyns, K., 46, 126(166) Hickmott, P. W., 176, 248(64) Hida, N., 177, 249(105) Hilditch, C. M., 60, 103, 124(113) Hill, H. A. O., 174, 246(6) Hill, M. L., 89, 130(294) Hilmoe, R. J., 8, 14(72)
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AUTHOR INDEX Hinselwood, D., 187, 252(209) Hintz, P. J., 211, 256(354) Hiramaya, B. A., 50, 60, 102, 124(117) Hirose, M., 272, 306(102) Hirst, E. L., 177, 189, 248(85) Hjort, C., 272, 282, 288, 305(85; 86) Hoagland, P. D., 155, 171(66; 67) Hodder, H. J., 50, 52, 61, 125(137) Hohlweg, R., 46, 126(166) Hojo, K., 95, 131(329) Hojo, M., 176, 247(57) Holker, J. R., 180, 249(128) Hollender, J., 273, 306(108) Holman, G. D., 44, 56, 101, 122(62) Holmberg, B., 177, 189, 248(85) Holton, H., 227, 259(464) Holzach, V., 224, 258(431) Homan, H., 39, 121(27) Homma, I., 176, 248(71) Honda, S., 177, 249(88; 108) Honeyman, J., 185, 251(191) Honjou, N., 158, 172(75) Honma, M., 298, 307(161) Honma, T., 42, 56, 122(56) Honzatko, R. B., 272, 273, 281, 285, 288, 300, 306(103; 104) Hoos, R., 70, 110, 126(181; 184) Hoque, A. K. M. M., 176, 248(62) Horenstein, B. A., 110, 133(391), 264, 297, 303(7), 307(154) Horii, F., 227, 259(458) Horii, J., 193, 253(258) Horton, D., 99, 131(341), 176, 185, 193–194, 196, 202, 206–207, 219, 224, 247(37; 38; 48), 251(177), 253(252), 254(279; 280), 255(311; 326) Hoshino, M., 227, 258(448) Hosoda, Y., 154, 160, 171(63), 172(80; 81) Hough, L., 96, 131(332), 176, 177, 247(40) Houptmann, S., 212, 256(364) Howard, F. B., 89, 130(295) Howard, G. A., 5, 13(9; 15) Howard, H. T., 6, 13(27) Howard, S. T., 39, 121(30) Hsieh, Y.-L., 272, 305(80) Hsu, L.-Y., 175, 246(27) Huang, S. J., 135, 170(5) Huang, Y., 193, 253(256) Hubbard, F. E., 272, 282, 288, 305(85) Huber, R. E., 295, 307(149)
Hudlicky, T., 193, 227, 253(257), 259(460–463), 260(487) Hudson, C. S., 176, 182, 217, 247(55), 250(144), 256(369–374) Hughes, D. L., 176, 248(60) Hughes, N. A., 7, 14(44; 45) Hull, S. R., 176, 247(31) Humeres, E., 39, 121(29) Husain, S., 101, 131(351) Hutchins, R. O., 176, 248(70) Hutchinson, D. W., 7, 14(60; 61) Hutton, A., 235, 261(528)
Igaki, S., 298, 307(163) Igarashi, K., 42, 56, 122(56) Ignatova, L. A., 77, 127(227–229) Ihlo, B., 177, 249(91) Iijima, K., 154, 171(60) Iimo, N., 266, 304(44) Iimura, Y., 227, 258(448) Ikeda, S., 74, 127(195) Ikemoto, N., 48, 58, 123(93) Ikeuchi, Y., 147, 171(49) Illig, H.-K., 266, 303(27) Im, M. J., 268, 304(49) Imoto, I., 272, 275, 278, 305(76) Ingold, K. U., 185, 251(184) Iori, R., 36, 120(3), 294, 302, 307(141) Iribarren, I., 163, 172(88; 89; 92; 93; 95) Irving, H. M. N. H., 235, 261(528) Irwin, D., 265, 270, 272, 274, 290, 303(24), 305(84), 306(120) Isac-García, J., 41–44, 56, 68, 74, 122(57) Isbell, H. S., 176, 185, 190, 212, 234–237, 240–241, 247(49; 51; 53), 251(176), 252(225; 230), 261(526; 530; 531) Isecke, R., 71–72, 102, 126(188; 189), 132(358–360) Ishiguro, S., 95, 131(325) Ishihara, T., 177, 249(107) Ishikawa, Y., 193, 253(256) Ismailov, N., 41, 74, 122(37) Isogai, A., 273, 306(107) Itano, H. A., 174, 246(2; 3) Ito, H., 96, 131(331), 298, 307(161) Ito, M., 81, 129(265) Ito, Y., 234, 260(509) Itoh, M., 102, 132(360) Itoh, Y., 280, 306(128)
337
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338
AUTHOR INDEX
IUPAC-IUB Commission on Biochemical Nomenclature, 226, 310, 312, 314–317, 319, 323(1–3), 324(4; 9; 10) Iversen, T., 60, 124(107) Iwaisaki, T., 113, 133(406) Iwaisaki, Y., 113, 114, 133(408) Iwakura, Y., 141, 171(38) Iwanami, S., 298, 307(161) Iwatsuki, M., 138, 170(16) Izumi, M., 193, 253(256)
Jackman, L. M., 38, 121(20) Jacob, C., 176, 248(67) Jacob, G. S., 193, 253(260) Jacobi, H., 179, 249(117) Jacobs, W. A., 207, 255(333) Jacobson, G., 293, 307(136) Jacobson, R. H., 272, 274, 276, 305(77) Jaime, C., 244, 261(539) Jambor, B., 206, 224, 255(317) James, K., 227, 239, 260(477) James, M. N. G., 264, 275, 278, 287, 295, 302, 302(1) Jamieson, J. C., 193, 253(259) Janzen, E. G., 185, 251(186) Jaquier, R., 234, 261(517) Jardine, F. H., 219, 257(399) Jayamma, Y., 193, 253(259) Jayaraman, N., 104, 132(370) JCBN, 310, 312, 319, 324(4) Jeanloz, R. W., 64, 125(150) Jeenes, D. J., 276, 295, 302, 306(127) Jellinek, G., 217, 257(395) Jencks, W. P., 298, 299, 307(159), 308(164; 166) Jenke, B. T., 176, 248(66) Jenkins, J. A., 272, 305(90) Jenkins, R., 60, 103, 124(113) Jensen, V. J., 272, 305(96) Jeong, J.-H., 47, 58, 112, 123(88) Jermyn, M. A., 270, 304(60) Jiménez, J. L., 46, 58, 65, 70–73, 77, 79–81, 86–87, 90, 97, 123(77), 125(156), 126(176; 186), 128(233; 234; 251), 129(275; 280) Jímenez-Barbero, J., 119, 134(419) Jiménez Blanco, J. L., 43–49, 57–60, 64, 68, 74, 75, 81, 87, 91–92, 117, 119, 123(66; 71; 75; 83–85), 124(98; 100), 126(192; 193), 130(310), 133(415; 416), 134(419)
Jiménez Requejo, J. L., 46, 58, 74, 77–79, 86, 123(73; 74), 126(194), 128(231; 243; 246), 129(274) Jimeno, M. I., 227, 259(457) Jiricek, R., 115, 133(414) Jobe, H., 60, 102, 124(112), 132(355) Jochims, J. C., 46, 55, 58, 66, 87, 122(55), 123(76), 129(282; 283) Johns, B. A., 193, 253(256) Johns, K., 272, 279, 287, 294, 302, 305(88) Johnson, A. W., 8, 14(82–84) Johnson, C. R., 193, 253(256) Johnson, J. D., 137, 170(13) Johnson, L. M., 273, 277–278, 286, 295, 300, 306(115–117) Johnson, L. N., 264, 272, 275, 276, 278, 295, 302, 302(2), 305(76), 306(127), 307(147) Jonas, A. J., 60, 102, 124(112), 132(355) Jonen, H. G., 174, 246(4) Jones, J. K. N., 176–177, 189, 247(40), 248(85) Jones, M. M., 94, 130(315–318) Jones, S. G., 94, 130(315) Jones, T. A., 269, 270, 272–273, 276, 279, 280, 287, 288, 291, 304(55), 305(79) Jordan, A. D., Jr., 74, 127(199) Jordan, M. D., 273, 277, 278, 286, 295, 300, 306(117) Joshi, D. D., 227, 259(459) Jotterand, A., 189, 252(222) Jourdan, F., 176, 247(52) Juaristi, E., 244, 261(540) Judkins, B. D., 89, 130(294) Juenge, E. C., 77, 127(216) Jung, S.-H., 193, 253(257) Junqua, S., 60, 124(110) Just, E. K., 194, 254(280) Juy, M., 272, 282, 288, 305(83)
Kabalka, G. W., 176, 248(70) Kacher, M., 176, 248(70) Kadowaka, H., 280, 306(128) Kahlenberg, A., 45, 58, 102, 123(80) Kakehi, K., 177, 249(88; 108) Kakudo, M., 272, 278, 305(94; 95) Kalk, K. H., 273, 279, 286, 306(106; 107; 109; 110) Kallin, E., 50–52, 61, 84, 103, 125(135; 136), 129(271), 132(368) Kalyanaraman, B., 95, 131(321)
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AUTHOR INDEX Kamada, T., 266, 304(42; 44) Kameda, Y., 193, 253(258) Kamitori, Y., 176, 247(57) Kamiya, H., 176, 247(31) Kanaya, E. N., 89, 130(295) Kanda, T., 266, 268, 270, 284, 303(36), 304(70) Kandil, S. H., 155, 171(68) Kaplan, L., 198, 254(296) Karabinos, J. V., 217, 256(374) Karaday, S., 176, 248(60) Karamanos, N. K., 176, 247(31) Karimullah, 5, 13(7) Karlson, G. B., 193, 253(259) Karpellus, P., 179, 187, 249(115; 116) Karplus, A., 265, 270, 272, 303(24), 305(84) Karplus, P. A., 270, 272, 274, 290, 304(56), 306(120) Kasahara, Y., 75, 76, 127(204; 208) Kassab, R., 64, 125(154) Kassem, A. A., 97, 98, 104, 131(336; 337) Kasube, Y., 272, 306(102) Kasumi, T., 266, 270, 303(38), 304(71) Kasuya, A., 113, 133(403) Kato, K., 206, 255(316), 266, 304(42–44) Kato, N., 141, 171(39) Katsarava, R. M., 161, 172(83) Katsuya, K., 141, 171(39) Kaul, B. L., 190, 252(227) Kaushal, G. P., 110, 133(387) Kayama, Y., 154, 160, 171(64) Kayser, K., 51, 62, 103, 125(139) Keck, G. E., 89, 130(305) Keeffe, J. R., 234, 244, 261(514) Kegel, W., 177, 249(94) Keil, K. D., 198, 254(298) Kelley, J. A., 89, 130(292) Kempton, J. B., 294, 307(139; 145) Kenner, G. W., 5–7, 13(8; 10; 14; 32; 33; 37; 40; 41), 14(44; 45; 47–49; 51; 57; 58) Kenner, J., 197, 254(288) Kenny, D. H., 175, 246(27) Keopsel, H. J., 217, 257(385) Kerékgyártó, J., 50, 51, 61, 124(124; 125) Kerr, D. E., 174, 246(9) Kersters-Hilderson, H., 266, 270, 303(38), 304(65) Kettner, M., 174, 246(19) Khan, R. A., 142, 171(41) Khan, S. H., 226, 227, 258(442) Kharadze, D. P., 161, 172(83)
339
Kharitonenkov, I., 102, 132(359) Kholodova, E. V., 61, 125(132) Khorana, H. G., 7, 14(46) Khorlin, A. Ya., 42–44, 56, 64, 70, 75, 108, 122(36; 42; 60), 125(147–149), 126(164; 175), 132(384), 133(385) Kieburg, C., 41–44, 50, 53, 61, 104, 122(47), 124(130), 132(374; 375; 377) Kiely, D. E., 156, 157, 172(69–74) Kihlberg, J., 102, 132(364) Kilburn, D. G., 264, 272, 294, 302(5), 307(140) Kilpper, G., 233, 237, 260(502) Kim, C.-H., 89, 130(293) Kim, C.-S., 280, 306(128) Kim, Y., 104, 132(372) Kimber, S. J., 103, 132(368) Kimura, A., 298, 307(161–163) Kimura, H., 89, 113, 114, 130(301), 133(405; 406; 409) King, C. H. R., 193, 253(258) King, R. W., 206, 207, 225, 255(325), 258(435) Kinoshita, T., 75, 76, 127(203–205; 208) Kirby, G. W., 6, 7, 13(26), 14(54; 60) Kirchhoefer, R. D., 77, 127(216) Kirchner, K. D., 198, 254(295) Kirk, B., 109, 110, 115, 133(386; 413) Kirsch, J. F., 275, 306(125) Kirschenlohr, W., 220, 257(412) Kishi, H., 155, 171(65) Kitaev, Yu. P., 176, 180, 247(59) Kitahashi, H., 41–44, 54, 58, 113, 114, 122(48), 133(408) Kitahata, S., 265, 268, 270, 271, 273, 280, 281, 303(21; 22), 304(50; 51) Kjær, A., 101, 131(344) Klapötke, T. M., 39, 121(28) Klausner, A. E., 39, 121(25) Klayman, D. L., 37, 121(11) Klebe, J., 198, 233, 254(297) Klein, C., 273, 306(108) Klein, H. W., 266, 268, 273, 277–278, 284, 286, 295, 300, 304(41; 48; 49), 306(115; 119) Klein, R. A., 102, 132(359) Klenk, H.-D., 102, 132(359; 360) Klimov, E. M., 41, 54, 122(49) Klimov, E. V., 61, 121(33) Kline, P. C., 264, 303(7) Klobusiky, M., 174, 246(18) Klock, J. C., 176, 247(34) Klockow, A., 176, 247(35)
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340
AUTHOR INDEX
Kluepfel, D., 272, 305(89) Knapp, S., 58, 109, 110, 114, 115, 123(91), 133(386; 410; 413) Knecht, E., 197, 254(287) Knight, E. C., 197, 254(288) Knight, J. G., 89, 130(306; 307) Knirel, Yu. A., 61, 125(132) Knowles, J. K. C., 269, 270, 272–273, 276, 279–280, 287, 288, 291, 304(54; 55), 305(79) Knutsen, L. J. S., 89, 130(294) Kobayashi, H., 137, 170(12) Kobayashi, J., 89, 130(303) Kobayashi, Y., 45, 46, 58, 113, 114, 123(89), 133(396; 399; 401–403; 407) Koch, K. R., 235, 261(528) Kocharova, N. A., 61, 125(132) Kochetkov, N. K., 61, 121(33), 125(132; 133) Kocourek, J., 80, 128(255) Koepsel, H. J., 217, 257(383) Kohler, H., 207, 255(339) Kojima, S., 51, 62, 103, 125(139) Kolb, H. C., 89, 130(307) Kolkaila, A. M., 217, 219, 257(394) Kollmam, P. A., 299, 308(165) Komarov, A. M., 95, 130(318; 319), 131(323) Komitsky, F., Jr., 187, 252(208) Konaka, R., 232, 233, 260(497) Kondo, S., 226, 227, 258(442) Kong, C.-T., 102, 132(354) König, B., 104, 132(376) Konig, R., 212, 256(356) Konigsberg, M., 189, 202, 223, 252(218) Kononov, L. D., 102, 132(364) Konstantinidis, A. K., 266, 269, 271, 273, 279, 302, 303(25), 304(72) Kopecek, J., 138, 170(19) Koshinen, A. M. P., 194, 254(262) Koshland, D. E., Jr., 271, 274, 304(74), 306(123) Kost, D., 244, 261(539) Kötter, S., 47, 63, 125(144) Kotyzová, D., 94, 130(316; 317) Koutensky, J., 94, 130(316; 317) Kovác, P., 51, 60, 103, 124(111) Kovacik, V., 176, 247(31) Kovác˘s, J., 65, 66, 85, 93, 125(159; 160), 130(313), 227, 238, 259(474) Koyama, Y., 141, 171(39) Krahn, R. C., 219, 257(405)
Krallmann-Wenzel, U., 47, 63, 104, 125(144), 132(376) Kramer, J. H., 95, 131(323) Kraus, A., 183, 184, 207, 209, 212, 220, 225, 227, 233, 234, 250(156; 168), 256(342), 258(436) Krause, J. G., 177, 248(78) Krausz, P., 227, 259(469) Kren, V., 104, 132(375) Krepinsky, J. J., 44, 64, 122(44) Kristian, P., 37, 38, 121(9) Kubrina, L. N., 95, 131(322) Kucar, S., 174, 246(20) Kuhn, R., 220, 257(412) Kukkola, P., 177, 248(73) Kumar, G. S., 138, 170(20) Kumar, S., 227, 238, 259(472) Kunz, H., 44, 64, 101, 122(46), 125(151), 131(352) Kunze, K. L., 174, 246(8) Kuo, E. Y., 176, 248(72) Kuppusamy, P., 95, 131(320) Kurita, K., 141, 171(38; 39) Kuroki, R., 293, 295, 307(134; 135) Kusunoki, M., 272, 278, 305(94; 95) Kuwahara, M., 160, 172(82) Kuznetsov, M. A., 183, 250(158) Kuzuhara, H., 70, 71, 115, 126(173), 133(412) Kyono, K., 234, 260(509)
Lai, C.-S., 95, 130(318; 319) Laidig, K. E., 39, 121(22) Laing, M., 175, 246(24) Laitinen, T., 272, 305(93) Lakhtina, O. E., 42, 56, 108, 122(60), 126(164), 132(384) Lamprecht, H., 177, 249(90) Lang, F., 113, 133(404) Langdon, R. G., 42, 44, 56, 101, 102, 122(58; 59; 61), 132(353) Lantos, I., 39, 121(26) Larcheveque, M., 194, 254(262) Lardy, H. A., 244, 261(535) Larner, J., 274, 306(122) Larsen, R. P., 235, 261(527) Larson, A., 272, 305(100) Lassaletta, J.-M., 176, 247(54) Laszlo, P., 227, 260(479)
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AUTHOR INDEX Lau, J., 39, 121(31) Laurence, C., 39, 121(24) Laurie, J. I., 272, 305(90) Laus, G., 77, 127(218) Law, H., 82, 106, 107, 118, 129(267), 132(382) Lawrence, D. R., 140, 154, 170(32) Lawson, C. L., 273, 306(109) Lawson, S. L., 272, 305(92) Lawson, T., 174, 246(12) Lay, L., 227, 258(451) LeBlay, K., 80, 128(257) Lebold, S. A., 176, 247(58) Lecocq, J., 6, 13(31) Ledford, B. E., 42, 54, 113, 122(52) Lee, B.-H., 95, 131(326; 327) Lee, H. H., 44, 64, 122(44) Lee, P. H., 193, 253(256) Lee, R. T., 102, 132(365) Lee, Y. C., 63, 102, 125(146), 132(362; 365) Lefeuvre, M., 79, 128(238) Legendre, B. L., 27, 28, 34(12–14) Legler, G., 193, 253(257), 264–266, 303(16; 27) Lehmann, G., 177, 249(94) Lehmann, J., 112, 115, 133(393–395; 414), 266, 268, 271, 273–276, 284, 302, 303(28–33), 304(46; 47) Lehn, P., 272, 306(105) Le-Hong, N., 189, 252(220) Leiner, H., 244, 261(534) Lelièvre, Ph., 92, 130(311) Lemieux, R. U., 185, 227, 239, 250(172), 260(477) Leminger, O., 182, 250(145) Len, C., 96, 131(333) Lenaz, G., 174, 246(15) Lensen, N., 194, 253(261) Lentovaara, P., 269, 280, 304(54) Lenz, R. W., 164, 172(90) Leong, K.-W., 137, 170(15) Leoni, O., 36, 120(3) Le Questel, J.-Y., 39, 121(24) Leray, E., 41, 64, 125(152) Le Roy-Gourvennec, S., 71, 126(191) Leuck, M., 101, 131(352) Leupold, F., 193, 253(255) Levene, P. A., 194, 207, 254(278), 255(333) Lever, J. E., 102, 132(354) Lewis, G. E., 233, 260(507) Ley, S. V., 89, 130(306; 307), 227, 259(460)
341
Li, J., 113, 133(404), 193, 253(256) Liao, D.-I., 302, 308(170) Libit, L., 176, 248(71) Lichtenthaler, F. W., 244, 261(534) Liebenow, W., 177, 179, 249(111) Liebster, J., 217, 256(377) Lin, J. K., 176, 247(31) Lin, S., 295, 307(149) Lin, T. H., 156, 172(69; 71) Lin, T.-S., 89, 130(304) Lindberg, A. A., 51, 52, 60, 61, 103, 124(106; 109; 118; 122), 132(367) Lindenberg, S., 103, 132(368) Lindhorst, T. K., 41–44, 47, 50, 53, 61, 63, 104, 122(47), 124(130; 131), 125(144), 132(374–377), 294, 307(144) Lindman, Y., 77, 127(221) Lineback, D. R., 187, 238, 252(207; 208) Linek, K., 174, 176, 180, 246(17–20), 247(31), 249(129) Linkletter, B., 86, 129(276; 277) Lipunova, G. N., 189, 206, 235, 252(223) Little, N., 60, 124(105) Liu, H., 176, 248(61) Liu, M.-C., 89, 130(304) Liu, P. S., 193, 253(258) Liu, W., 266, 270, 303(39) Livio, P. F., 189, 252(220) Ljunggren, A., 52, 60, 124(106) Lloyd, D. M. G., 207, 255(330) Lobell, M., 75, 127(206) Lohray, B. B., 193, 253(259) Lo Leggio, L., 272, 305(90) Lolsing, M., 181, 250(141) Lönn, H., 50–52, 61, 125(135) Loo, D. D. F., 50, 60, 102, 124(117), 132(354) López Aparcio, F. J., 79, 128(239) López-Barba, E., 41, 43, 56, 57, 68, 77, 122(65) López-Castro, A., 74, 79, 80, 87, 126(193), 128(252) López-Mardomingo, C., 39, 121(27) Losee, K., 181, 250(141) Lostao, M. P., 50, 60, 102, 124(117) Lou, J., 109, 110, 133(386) Lovell, A. V., 176, 248(60) Low, M. G., 315, 324(11) Lowe, G., 276, 295, 302, 306(127) Lubineau, A., 226, 227, 258(442)
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342
AUTHOR INDEX
Luckas, G., 227, 259(470) Ludewig, M., 50, 61, 104, 124(131) Lueders, H., 144, 171(44; 45) Luna, H., 227, 259(463) Lund, H., 176, 248(63) Lundblad, A., 84, 129(271) Luo, J., 82, 83, 86, 129(269) Lutz, W., 233, 260(508) Lycka, A., 206, 207, 255(329) Lyle, G. G., 219, 257(406) Lyons, R., 185, 250(170) Lythgoe, B., 5, 6, 13(4–6; 8–13; 15; 16; 18; 35) Lyttle, B., 230, 260(491)
MacCleod, A. M., 293, 294, 307(133) MacDonald, D. L., 194, 254(266) Machado, A. S., 227, 259(470) Macharadze, R. G., 64, 122(36), 125(147–149) Macher, B. A., 323, 324(16) Machida, H., 48, 58, 123(94) Machón, Z., 41, 74, 122(40) Machytka, D., 102, 132(359) Maciejewski, S., 48, 60, 65, 118, 124(99), 125(155), 133(418) Mackawy, K., 186, 251(197–199; 201) MacKenzie, D. A., 276, 295, 302, 306(127) Mackenzie, G., 91, 93, 130(308) MacKenzie, L., 302, 307(132), 308(172) Madhavan, G. V. B., 89, 130(297) Madin, A., 89, 130(307) Madi-Puskas, M., 227, 259(468) Madsen, N. B., 266, 270, 294, 303(39), 307(144) Madson, M. A., 196, 254(284) Maeda, H., 227, 258(448) Maetinez-Ripoll, M., 175, 246(25) Magasanik, B., 202, 206, 227, 230, 241, 255(309), 260(488), 261(533) Magnusson, G., 50, 61, 102, 124(129), 132(364) Magrath, D. I., 7, 14(64; 65; 69) Mahapatro, S. N., 174, 246(13) Mahmoud, M. A., 186, 251(201) Mahuteau, J., 64, 125(153) Mahy, J. P., 174, 246(11) Maimind, V. I., 198, 254(301; 302), 255(303; 304) Mair, G. A., 295, 307(147)
Major, A., 180, 192, 206, 207, 209, 221, 224, 235, 250(133), 252(240), 255(320; 337), 256(350), 257(420) Mak, I. T., 95, 131(323) Makarenko, T. A., 61, 125(132) Malik, Sh. S., 227, 259(451) Mal’kova, V. P., 43, 44, 75, 122(42) Malver, O., 101, 131(344) Malysheva, N. N., 41, 54, 121(33), 122(49) Manasek, Z., 185, 251(178; 179) Mancy, S., 220, 257(415) Mangeney, P., 194, 253(261) Manger, I. D., 50, 51, 62, 103, 125(138) Manners, D. J., 270, 304(59) Mansour, E. M. E., 97, 98, 104, 131(336; 337), 155, 171(68) Mansuy, D., 174, 246(11) Maples, K. R., 233, 235, 260(505) Marby, C. A., 89, 130(307) March, J., 244, 261(540) Marchione, C. S., 74, 127(199) Marco-Contella, J., 227, 259(457) Margolis, S. A., 174, 246(15) Marino, C., 41, 43, 55, 74, 75, 87–88, 122(53; 54) Marino, S., 55, 66, 122(55) Markley, J. L., 222, 258(423) Márquez, R., 79, 128(248–250) Marquez, V. E., 89, 130(292; 293; 296) Marsden, I., 266, 269, 273, 279, 302, 303(25) Marshalkin, M. F., 183, 250(159) Marshall, D. R., 207, 255(330) Marshall, E. D., 235, 261(527) Martin, G. J., 227, 239, 260(476) Martin, J. C., 89, 130(297) Martin, J. L., 273, 277, 286, 306(116) Martin, M. L., 227, 239, 260(476) Martínez de Ilarduya, A., 163–165, 167, 172(89; 91; 93; 95) Martinez-Grav, A., 227, 259(457) Martín-Pastor, M., 119, 134(419) Martins, J., 181, 250(141) Martnez, L., 227, 259(457) Marubayashi, Y., 168, 172(96) Maryanoff, B. E., 74, 127(199), 176, 227, 248(70), 259(451) Masada, R. I., 176, 247(34) Mason, H. S., 7, 13(39), 14(50) Mass, T. A., 135, 170(2) Masson, S., 71, 126(191)
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AUTHOR INDEX Masuda, R., 176, 247(57) Mather, J., 6, 13(32; 33) Matrosovich, M. N., 70, 102, 126(178), 132(361) Matsuda, A., 48, 58, 123(94) Matsui, H., 266, 268–269, 271, 284, 296, 298, 303(33), 304(45; 52; 53), 305(75), 307(161) Matsui, K., 193, 253(258) Matsumura, I., 275, 306(125) Matsuo, T., 193, 253(258) Matsuura, M., 158, 172(76) Matsuura, T., 234, 260(509) Matsuura, Y., 272, 278, 305(94; 95) Matsuzaki, K., 78, 128(236) Matteson, J. L., 174, 246(2) Matthews, B. W., 272, 274, 276, 293, 295, 305(77), 307(134; 135) Mattson, D., 95, 130(318) Maurer, K., 202, 206, 220, 255(310) Mayer, F. C., 274, 306(122) Mayer, R., 37, 121(14) McBroom, C. R., 60, 102, 124(104) McCarter, J. D., 264, 291–294, 302(3), 307(142; 143) McCasland, G. E., 226, 230, 258(437), 260(491) McCombie, S. W., 87, 129(284) McComsey, D. F., 227, 259(451) McDonald, G. G., 155, 171(67) McGlynn, S. P., 37, 121(15) McLaughlin, M. A., 193, 253(256) McLaughlin, P. J., 273, 277–278, 286, 295, 300, 306(115; 117) McNeil, D., 5, 13(4) McPherson, A., 272, 305(100) McPherson, E., 74, 127(196) Medlin, E. H., 6, 13(23) Meeks, J. L., 37, 121(15) Meguso, T., 217, 256(379) Mehltretter, C. L., 139, 170(30) Mellies, R. L., 139, 170(30) Mendes, C., 60, 124(115) Méndez-Castrillón, P. P., 41–43, 54, 88, 122(34; 35) Menegatti, E., 36, 120(3) Mentch, F., 297, 307(153) Merle-Subrey, L., 138, 170(21) Meshreki, M. H., 176, 196, 212, 217, 219, 247(48), 256(361), 257(394)
343
Messmer, A., 63, 85, 125(145), 129(272), 177, 190, 192, 206, 224, 227, 238, 239, 249(98), 252(228; 231; 235–239; 241), 255(318; 320), 259(474), 260(475) Mester, L., 177, 180, 182–183, 189–190, 192, 194, 202, 206–207, 209, 212, 219, 221, 224, 227, 233–235, 241, 249(98; 127; 130), 250(133; 151; 155), 252(223; 226; 228; 232; 242), 254(282), 255(311; 317–320; 323; 324; 327; 328; 337; 338; 341), 256(350; 357; 358), 257(402; 420) Mester, M., 192, 235, 252(232; 233–240) Mészáros, P., 93, 130(313), 227, 239, 260(475) Meuwly, R., 89, 130(300) Meyer, R., 184, 185, 212, 215, 221, 250(162), 257(417) Meyers, A. I., 193, 253(256) Michalski, J. J., 6, 7, 13(29), 14(59) Micheel, F., 197, 198, 201, 219, 220, 254(291), 257(414) Michelson, A. M., 6–8, 13(19; 20; 34; 42), 14(66; 73; 76; 77) Micklewright, R., 76, 127(207) Mickova, V., 94, 130(317) Middleton, S., 227, 259(467) Midoux, P., 50, 61, 124(110; 115; 126) Mielczarek, I., 41, 74, 122(40) Mikami, B., 272–274, 280, 281, 285, 288, 292, 300, 301, 306(101; 102; 129) Mikkelsen, J. M., 272, 282, 288, 305(85) Mikoyan, V. D., 95, 131(322) Milde, K., 177, 249(92) Miles, H. T., 89, 130(295) Mileski, C. A., 176, 248(70) Mil’grom, Yu. M., 75, 127(200) Millan, M., 79, 128(248; 249) Miller, G. W., 8, 14(83) Miller, J. B., 194, 254(268; 269; 277) Miller, K. J., 77, 127(213) Miller, R. C., Jr., 264, 272, 302(5) Miller, T. W., 226, 258(443) Miller, V. P., 176, 248(61) Mills, J. A., 8, 14(82; 83), 219, 257(404) Mino, T., 176, 247(56) Minor, J. L., 220, 257(411) Minoura, Y., 160, 172(79) Miocque, M., 64, 125(153) Mitchell, A., 234, 261(519) Mitchell, P. W. D., 197, 254(290) Mitchell, W. L., 89, 130(294)
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344
AUTHOR INDEX
Mitsuya, H., 89, 130(292; 293) Miwa, I., 226, 258(441) Miyajima, K., 141, 171(38) Miyamato, Y., 227, 258(451) Miyamoto, S., 113, 133(403) Miyazaki, H., 113, 133(396; 401; 407) Miyumdar, A. M., 227, 259(459) Mizokami, K., 265, 303(22) Mó, O., 38–39, 121(16; 17) Mochalova, L. V., 70, 126(178) Mochizuki, T., 81, 114, 129(264) Moczar, E., 182, 206, 207, 212, 250(151), 255(323; 324), 256(357; 358) Modro, T. A., 39, 121(25) Mohammed, M. A. A., 186, 251(201) Mohammed, Y. S., 217, 219, 257(394) Mohammed-Ali, M. M., 222, 258(425; 426) Mokhlisse, R., 39, 121(27) Moldenhauer, H., 184–185, 187, 212, 250(163; 164) Moldenhauer, W., 198, 225, 230, 254(299), 258(436) Molina, I., 148, 149, 171(53; 54) Molina, J. L., 43–44, 47, 57, 58, 68–70, 84, 123(67; 68), 126(169; 170) Molina, M. T., 38, 39, 121(16) Molina Molina, J., 41, 43, 56, 57, 68, 77, 122(65) Molina Pinilla, I., 153, 171(56–59) Mondange, M., 80, 128(257) Mong, T. K.-K., 104, 132(373) Monneret, 92, 130(312) Monsigny, M., 50, 60, 61, 124(110; 115; 126) Montserrat, J. M., 138, 170(24) Moon, S.-H., 227, 260(482) Moorhouse, S. J., 192, 253(246) Mooser, G., 264, 303(17) Mordarski, M., 41, 74, 122(40) Moreda, W., 42, 57, 68, 77, 123(70) Moreno Marín, A., 70, 72, 74, 87, 126(177; 192) Mori, H., 298, 307(161) Mori, O., 70, 71, 126(173) Morin, C., 94, 130(314) Morita, E., 217, 256(379) Morita, S., 96, 131(331) Morita, Y., 272, 306(102) Mornon, J.-P., 272, 306(105) Morosoli, R., 272, 305(89) Morton, D. W., 157, 172(72) Moss, G. P., 8, 14(81)
Mostad, A., 180, 249(124) Motherwell, W. B., 88, 89, 129(286), 186, 187, 189, 251(203), 252(213) Mousaad, A., 186, 251(200) Mufti, K. S., 142, 171(41) Mukaiyama, T., 58, 95, 123(90), 131(329) Mukerjee, A. K., 37, 121(13) Mukherjee, S., 89, 130(307) Müller, H. P., 65, 122(43), 125(158) Muller, V., 222, 258(428) Mullins, R. E., 56, 101, 102, 122(61), 132(353) Mungara, P. M., 136, 137, 170(7) Muñoz-Guerra, S., 138, 147, 161–168, 170(22–24), 171(50), 172(84–89; 91–95; 97; 98) Murali Dhar, T. G., 58, 123(91) Muramoto, K., 176, 247(31) Murkami, K., 141, 171(39) Murphy, R. C., 77, 127(220) Murphy, T. J., 206, 207, 225, 255(325), 258(435) Murray, B. W., 47, 58, 112, 123(88) Murray, M., 269, 280, 304(54) Murray, R. W., 234, 260(512) Muto, N., 227, 259(466) Myers, A. G., 176, 177, 248(72; 73)
Nagabushan, T. L., 227, 239, 260(477) Nagano, H., 177, 249(107) Nagy, Z., 61, 124(124) Nahrstedt, A., 101, 131(345) Nair, K. M., 234, 261(518) Nair, P. M., 234, 261(522) Nair, V., 177, 249(87) Naito, T., 43, 126(165), 177, 249(107) Najib, B., 91, 93, 130(308) Nakahashi, G., 193, 253(257) Nakajima, M., 113, 133(407) Nakamura, H., 154, 155, 160, 171(62; 63; 65), 172(82) Nakamura, S., 176, 248(71) Nakano, M., 270, 304(70) Nakata, K., 177, 249(105) Nakhla, N. A., 50, 52, 61, 125(137) Nance, S., 273, 306(114) Narayanan, C. R., 227, 259(459) Nardini, W., 230, 260(493) Nashed, M. A., 176, 196, 247(48)
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AUTHOR INDEX Nasr, A. Z., 97, 131(335) Nasr, M. A. M., 97, 98, 104, 131(336; 337), 177, 186, 220, 225, 249(102), 251(193; 194; 200; 201), 257(408) Nassimbeni, L. R., 235, 261(528) Nastruzzi, C., 36, 120(3) Naughton, A. B., 58, 70, 110, 123(91), 126(181) Neilson, A. H., 7, 14(69) Neilson, T., 220, 257(410) Neimann, W., 177, 249(109) Nelson, S. F., 211, 256(354) Nemogova, E., 174, 246(18) Nepogodiev, S. A., 104, 132(370) Nesmzmelyi, A., 190, 252(231) Neuberg, C., 177, 249(109) Newton, R. F., 89, 130(294) Nguyen-Xuan, T., 193, 253(247) Nichols, P. L., Jr., 138, 170(26) Nicholson, L. K., 270, 304(57) Nickol, R. G., 99, 131(341) Nicotra, F., 227, 258(451) Nieforth, K. A., 193, 253(257) Nikolajewski, H. E., 177, 249(96) Nimura, N., 41, 75, 76, 126(162), 127(203–205; 208) Nishi, N., 147, 171(49) Nishimura, S., 147, 171(49) Nishimura, Y., 177, 226, 227, 249(108), 258(442) Noda, Y. J., 160, 172(79) Noe, L. J., 234, 261(513) Nomenclature Committee of IUB, 313, 324(8) Nong, V. H., 280, 306(128) Nongrum, M. F., 104, 132(373) Nonhebel, D. C., 234, 261(519) Noor, F., 101, 131(351) Noori, G., 50, 61, 124(129) Norberg, T., 50–52, 61, 84, 125(135), 129(271) Nordman, C. E., 175, 246(27) North, A. C. T., 272, 275, 278, 295, 305(76), 307(147) Notario, R., 38–39, 121(16; 27) Novotna, Z., 174, 246(20)
Obereigner, B., 138, 170(19) Ochoa, E., 100, 131(342) O’Connor, R., 185, 187, 251(174)
345
Ogata, N., 154, 155, 160, 171(60–65), 172(80–82) Ogawa, S., 41–44, 46, 47, 54, 58, 89, 113–114, 122(48), 123(86; 87), 130(301), 133(397; 398; 400; 405; 406; 408; 409), 226–227, 258(439–441; 444; 451), 259(452–454) Ogawa, Y., 96, 131(331) Ogueira, H. A., 158, 160, 172(77; 78) Ogura, H., 41, 75, 77, 81, 125(161), 126(162), 127(203), 128(232; 235), 129(265), 177, 249(105) Oguri, S., 177, 249(88) Ohara, S., 176, 247(57) Ohashi, T., 89, 130(301) Ohle, H., 209, 215, 256(346; 351) Ohta, K., 78, 128(236) Ohtake, T., 154, 171(62) Ohtsuka, M., 227, 259(452) Ohya, T., 270, 304(62) Oikonomakos, N. G., 264, 302(2) Okada, G., 264–266, 268, 270, 271, 280, 281, 284, 298, 303(14; 19; 20; 36), 304(45; 66) Okada, M., 158, 172(75; 76) Okamoto, S., 154, 171(61) Okamoto, Y., 168, 172(96) Oki, M., 38, 121(18), 244, 261(538) Okimoto, M., 176, 186, 248(63), 251(202) Okuda, J., 226, 258(441) Olano, D., 44, 57, 84, 123(68) Olejniczak, B., 58, 123(92) Olin, S. M., 194, 254(267) O’Neill, R. A., 226, 227, 258(442) Onnen, O., 184, 185, 212, 215, 221, 250(162) Openshaw, H. T., 6–7, 13(25), 14(52) Oppenheim, A., 302, 308(171) Oppenheimer, N. J., 299, 307(131; 158), 308(165; 167) Orgueira, H. A., 148–150, 171(53–55) Oritz de Montellano, P. R., 174, 246(7–10) Orning, A., 176, 247(44) Ortiz, C., 42, 57, 68, 77, 123(70) Ortiz de Montella, P. R., 187, 252(210) Ortiz Mellet, C., 37, 40–49, 56–60, 63–66, 68, 70, 72, 74–75, 77, 81, 82, 85, 87, 91–92, 102, 106–108, 117–120, 121(8), 122(64), 123(66; 69; 71; 72; 75; 81–85), 124(98–100; 102), 125(155; 159; 160), 126(177; 192; 193), 127(201; 222–226), 129(267), 130(310), 132(382; 383), 133(415–418), 134(419; 420)
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346
AUTHOR INDEX
Ortiz Mellet, M. C., 46, 58, 74, 78, 123(73) Oscarson, S., 95, 131(330) Oshikawa, T., 89, 130(303) Osipov, C. A., 189, 206, 235, 252(223) Ostmann, P., 42, 126(163) O’Sullivan, M. L., 106, 107, 118, 132(382) Ottembrite, R. M., 137, 170(8) Ouchi, T., 137, 170(12) Overend, W. G., 227, 238, 259(472; 473) Oztruk, D. H., 273, 283, 284, 288, 306(112)
Padrines, M., 110, 133(389) Pagé, D., 103, 104, 106, 132(378–381) Page, P., 176, 248(67) Page, T. F., Jr., 176, 219, 247(38) Pakulski, Z., 121(32) Palacios, J. C., 46, 58, 65, 70–73, 77, 79–81, 86–87, 90, 97, 123(77), 125(156), 126(176; 186), 128(233; 234; 251), 129(275; 280) Palacios Albarrán, J. C., 46, 58, 74, 77–79, 86, 123(73; 74), 126(194), 128(231; 243; 246), 129(274), 192, 252(243) Palm, D., 266, 268, 273, 278, 295, 300, 304(41; 49), 306(119) Palmieri, S., 36, 120(3), 294, 302, 307(141) Palovcik, R., 180, 249(129) Pan, Y.-T., 110, 133(387), 193, 253(254) Panayotova-Heiermann, M., 102, 132(354) Pangrazio, C., 227, 258(451) Panza, L., 227, 258(451) Papadaki-Valirki, A. E., 74, 127(195) Papandreou, G., 70, 110, 126(179; 180; 182), 133(387) Paranjpe, M. G., 74, 127(198) Parello, J., 190, 206, 207, 252(226), 255(323; 324; 328) Parihar, D. B., 6, 13(21; 24) Parkanyi, C., 234, 261(525) Parker, K. J., 142, 171(41) Parkin, D. W., 297, 307(153; 154) Parrish, F. W., 27, 33(7) Parrot-Lopez, H., 41, 64, 125(152–154) Patai, S., 176, 248(63) Paulsen, H., 22, 58(449), 72, 177, 193, 227, 249(100), 253(254; 255), 258(447), 259(455; 456) Paulus, A., 176, 247(35)
Pausacker, K. H., 185, 197, 198, 223, 251(189), 254(294) Pavlisko, A., 138, 170(18) Paxton, J., 211, 256(355) Payen, F., 272, 278, 286, 295, 300, 305(98; 99) Pazur, J. H., 270, 304(61) Peciar, C., 180, 249(129) Pegorier, L., 194, 254(262) Pelyvas, I., 176, 227, 247(54), 259(468), 260(479) Penadés, S., 120, 134(420; 421) Penninga, D., 273, 279, 286, 306(109; 110) Pepperman, A. B., 27, 34(15) Percheron, F., 270, 304(63) Percival, E. E., 224, 258(430; 433) Percival, E. G. V., 173, 184, 221, 222, 224, 246(1), 250(166), 257(418), 258(430; 433) Pérez, R., 138, 170(25) Pérez-Garrido, S., 74, 87, 126(193) Perrakis, A., 302, 308(171) Perret, F., 189, 193, 252(221; 222), 253(247; 248) Perry, F. M., 181, 250(141) Pessen, H., 155, 171(67) Péter, A., 77, 127(218) Peter, B., 177, 189, 248(85) Petersen, C. S., 180, 202, 205, 206, 249(125; 126), 255(307) Petersen, S. B., 272, 305(96) Petit, Y., 194, 254(262) Petsko, G. A., 174, 246(9) Pettersson, G., 272, 273, 276, 287, 305(79) Philips, K. D., 194, 254(279) Phillips, D. C., 272, 275, 278, 295, 305(76), 307(147) Piazza, M. J., 219, 257(406) Picasso, S., 193, 253(256) Pickersgill, R. W., 272, 305(90) Pierozynski, D., 121(32) Pigman, W., 185, 251(177) Pihko, P. M., 194, 254(262) Pilo, M. D., 86, 129(280) Pingli, L., 227, 259(451) Pinkus, G., 183, 185, 250(161) Pinna, L., 193, 253(256) Pintér, I., 63, 65, 66, 85, 93, 125(145; 159; 160), 129(272), 130(313), 190, 192, 227, 238, 239, 252(231; 241), 259(474), 260(475) Pitzer, K. K., 193, 253(257) Placek, J., 185, 251(178; 179) Platt, R. M., 193, 253(259)
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AUTHOR INDEX Platts, J. A., 39, 121(30) Pleshkova, A. P., 75, 127(202) Ploven, S., 190, 252(224) Plusquellec, D., 79, 128(237; 238) Poljak, R. J., 272, 282, 288, 305(83) Pollet, P., 234, 261(524) Poncet, J., 189, 252(221; 22) Pons, J.-F., 80, 128(257) Porco, J. A., Jr., 193, 253(257) Portal Olea, D., 41, 43, 56, 57, 68, 77, 122(65) Postel, D., 96, 131(333) Posternak, T., 227, 230, 244, 260(485; 489), 261(536) Postovskii, I. Y., 189, 206, 235, 252(223) Potapova, N. P., 81, 129(266) Poteete, A. R. E., 275, 306(126) Potter, A. L., 217, 257(382) Povarov, L. S., 81, 129(266) Pozuelo, C., 227, 259(457) Pradera, M. A., 41–44, 47, 54, 57–58, 68–70, 77, 81, 84, 87, 101, 122(50), 123(67; 68; 78; 79), 126(169; 170) Pradera Adrián, M. A., 41–43, 56–58, 68, 75, 77, 122(64), 123(69; 72), 127(201; 222–226) Pratt, J. S., 217, 256(373) Prean, M., 179, 187, 249(115; 116) Preobrazhenskaya, M. N., 81, 129(266) Prestwich, G. D., 227, 260(481) Price, J. D., 227, 259(461–463) Prieto, A., 138, 170(25) Prough, R. A., 174, 246(4) Provencher, D. H., 193, 253(257) Purandare, A., 114, 133(410)
Qian, M., 272, 278, 286, 295, 300, 305(98; 99) Qiao, L., 227, 259(463) Quiclet-Sire, B., 227, 259(469; 471) Quintanilha, A., 174, 246(7) Quintero, L., 37, 88, 89, 121(7)
Raban, M., 244, 261(539) Rablen, P. R., 39, 121(21) Rademacher, T. W., 50, 51, 62, 103, 125(138) Radford, S. E., 276, 295, 302, 306(127) Raftery, M. A., 295, 307(148) Rahman, M. A. A., 202, 205, 206, 222–225, 234, 255(312; 313), 258(429)
347
Rakhmatullaev, I., 41, 74, 122(37; 38) Ramaiah, M., 88, 89, 129(288) Ramamuroothy, V., 176, 248(65) Ramirez, J., 193, 253(256) Ramjeesingh, M., 45, 58, 102, 123(80) Ramos Montero, M. D., 79, 128(246) Ramsden, N. G., 193, 253(257) Rand-Meir, T., 295, 307(148) Rao, J. M., 234, 261(522) Rashed, N., 186, 196, 251(195; 196; 201), 254(283) Rashkes, Ya. V., 75, 127(200) Rasmussen, G., 272, 282, 288, 305(85) Rassau, G., 193, 253(256) Rauckman, E. J., 211, 256(355) Ravenscroft, P., 89, 130(294) Rebolledo Vicente, F., 79, 86, 128(247), 129(274; 279) Reckhaus, M., 197, 198, 254(293) Redmond, J. W., 98, 131(339; 340) Rees, W. D., 44, 56, 101, 122(62) Reese, C. B., 6–8, 13(21), 14(48; 81) Reese, E. T., 270, 304(71) Regaño, C., 163, 172(89) Regna, P. P., 217, 256(376) Rehpenning, W., 176, 247(46) Reichert, C. M., 50, 60, 102–104, 124(108; 114) Reichstein, T., 194, 254(264) Reidez, P., 176, 248(60) Reilly, P. J., 295, 307(150) Reinhold, V. N., 311, 324(5) Reinikainen, T., 272, 273, 276, 287, 305(79) Reinsberg, W., 181, 189, 190, 250(134) Reisch, J., 101, 131(344) Reitz, A. B., 74, 127(199), 193, 253(256) Remington, S. J., 302, 308(170) Repte, E., 177, 249(89) Resek, J. E., 193, 253(256) Resnick, P., 233, 260(506) Reuben, J., 185, 251(188) Reuter, G., 313, 324(7) Richard, J. P., 295, 307(149) Richardson, A. C., 96, 131(332) Richtmyer, N. K., 217, 256(371–373; 375), 257(386) Rickard, R. R., 235, 261(527) Rienäcker, C. M., 39, 121(28) Ringe, D., 174, 246(9) Rising, K. A., 297–299, 307(155)
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348
AUTHOR INDEX
Rist, C. E., 89, 130(290) Rob, B., 112, 115, 133(393–395; 414) Roben, W., 227, 258(449) Roberts, E. J., 2, 27, 33(1; 6; 7) Roberts, G. A. F., 180, 234, 249(122; 123), 261(521) Roberts, G. P., 180, 249(121) Roberts, J. D., 39, 121(31) Roberts, S. M., 227, 259(463) Roberts, W. L., 311, 324(5) Robina, I., 41–43, 54, 56–57, 68, 77, 101, 122(50; 65), 123(70) Robina Ramírez, I., 79, 128(244) Robins, M., 230, 260(491) Robinson, B., 176, 248(60) Robinson, E. A., 174, 246(3) Robinson, R., 2, 13(1), 176, 248(60) Robles-Díaz, R., 41–44, 56, 68, 74, 122(57) Robyt, J. F., 295, 307(150) Roche, A.-C., 50, 60, 61, 124(110; 115; 126) Rodríguez-Galán, A., 138, 161–164, 168, 170(22; 23), 172(84–87; 89; 91; 97; 98) Roeser, K. R., 266, 303(27) Roger, P., 92, 130(312) Rogers, L. J., 60, 103, 124(113) Rollin, P., 71, 126(191) Ronco, G., 96, 131(333) Rose, D. R., 272, 279, 287, 294, 302, 305(87; 88) Rosén, G., 95, 131(330) Rosen, G. M., 185, 211, 251(187), 256(355) Rosenberg, L. T., 52, 60, 124(106) Rosenberry, T. L., 311, 324(5) Rosenfeld, D. A., 217, 256(371) Rosini, G., 230, 260(493) Ross, L. E., 235, 261(527) Rossi, F., 230, 260(493) Rossi, M. H., 177, 248(80) Roth, J. S., 89, 130(292) Rothermel, J., 42, 54, 68, 122(51) Roulleau, F., 79, 128(237; 238) Rouvinen, J., 269, 270, 272, 273, 279, 280, 288, 291, 304(55), 305(93) Roy, R., 50, 60, 102, 104, 106, 124(116), 132(366; 369; 371; 378–381) Rozeboom, H. J., 273, 279, 286, 306(109; 110) Rozynov, B. V., 81, 129(266) Rua, L., 176, 248(70) Rubin, M. B., 234, 261(515) Rubiralta, M., 244, 261(539) Ruiz-Donaire, P., 162, 172(86)
Rulin, F., 227, 259(461; 463) Ruohonen, L., 272, 273, 276, 287, 305(79) Rupitz, K., 70, 110, 114, 126(181; 184), 133(410), 293, 294, 307(133) Rupley, J. A., 272, 275, 278, 305(76) Rupley, M. A., 293, 307(136) Rusinova, L. I., 189, 206, 235, 252(223) Russell, C. R., 89, 130(290) Russell, C. S., 185, 250(170) Russo, G., 227, 258(451) Rutherford, D., 140, 170(33), 171(37), 217, 257(386) Rutherford, F. C., 176, 247(42)
Sacchettini, J. C., 272–274, 280, 281, 283–285, 288, 292, 300, 301, 306(101; 102; 111; 112) Saeed, M., 177, 248(84) Saitz Barría, C., 57, 64, 123(71) Sakaguchi, M., 177, 249(105) Sakon, J., 274, 290, 306(120) Salberg, M. M., 100, 131(342) Saleem, R., 101, 131(346–351) Sallaiova, Z., 174, 246(20) Sallam, A. E. M., 222, 258(423; 424) Sallam, M., 222, 257(422) Salminen, O. M., 270, 304(57) Saltiel, A. R., 315, 324(11) Samanen, C. H., 60, 102, 124(104) Sandrinelli, F., 71, 126(191) Sandsted, C., 219, 257(400) Sandström, J., 38, 121(19) Sandterova, R., 176, 247(31) San Félix, A., 41–43, 54, 88, 122(34; 35) Sannan, T., 141, 171(38) Sano, M., 43, 126(165) Santikarn, S., 311, 324(5) Santoyo-González, F., 41–44, 56, 57, 64, 68, 74, 122(57), 123(71) Sanui, K., 154, 155, 160, 171(60; 62–65), 172(82) Sarfati, R. S., 80, 81, 128(256) Sarma, V. R., 295, 307(147) Sasaki, N., 226, 227, 258(445) Sasaki, T., 48, 58, 123(94) Sasso, G. J., 89, 130(298) Sato, K., 227, 258(451) Sato, M., 272, 306(102) Sato, O., 77, 128(235) Sato, S., 96, 131(331)
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AUTHOR INDEX Sato, T., 176, 248(71) Satoh, M., 48, 58, 123(94) Sawai, T., 265, 270, 271, 273, 281, 303(21), 304(62; 70) Sawyer, D. T., 187, 252(211) Scapin, G., 273, 283–284, 288, 306(111; 112) Schaffer, R., 176, 247(50) Schantl, J. G., 179, 187, 249(115; 116) Scharnow, H.-G., 174, 177, 246(22), 248(81) Schauer, R., 313, 324(7) Schaukellis, H., 177, 189, 248(85) Schaumann, E., 71, 126(187) Schein, P. S., 74, 127(196; 197) Scheithauer, S., 37, 121(14) Scheuring, M., 115, 133(414) Schiedt, B., 202, 206, 220, 255(310) Schinzel, R., 273, 278, 295, 300, 306(119) Schirp, H., 177, 248(83) Schlesselmann, P., 266, 268, 271, 274–276, 284, 303(28; 32), 304(46) Schmezer, P., 95, 131(326; 327) Schmidt, E. W., 174, 246(14) Schmidt, O. T., 224, 258(431) Schmidt, P., 55, 66, 122(55) Schneider, M. P., 75, 127(206) Schoch, A., 55, 66, 122(55) Schofield, J. A., 8, 14(78) Schofield, K., 8, 14(81) Schoorl, M. N., 36, 120(1) Schramm, V. L., 110, 133(391), 264, 297–299, 303(7), 307(153–156) Schreiber, S. L., 48, 58, 123(93) Schreier, E., 217, 221, 222, 256(378), 257(387–390; 419) Schrörder, S., 299, 308(165) Schuerch, C., 50–51, 61, 124(127; 128) Schülein, M., 272, 282, 288, 302, 305(85; 86), 307(132), 308(172) Schultz, G. E., 273, 306(108) Schutz, A., 39, 121(29) Schwartz, J., 176, 247(54) Scopes, D. I. C., 89, 130(294) Scott, D. L., 273, 306(114) Scott, F. L., 232, 233, 260(499) Scott, M., 272, 305(90) Searles, S., 190, 252(224) Sedman, A. J., 77, 127(209) Seeliger, A., 46, 58, 87, 123(76), 129(282), 198, 255(305) Sekiguchi, H., 168, 172(97)
349
Selegny, E., 138, 170(21) Semenyaka, A., 110, 133(391) Semenza, G., 296, 299, 307(151; 152) Seo, K., 89, 130(302; 303) Serafini-Cessi, F., 174, 246(16) Serezhenkov, V. A., 95, 131(322) Serrano, J. L., 175, 246(25) Shaban, M. A. E., 97, 131(335), 155, 171(68), 177, 186, 220, 225, 249(101–103), 251(193; 194; 204), 257(407; 408) Shafizadeh, F., 193, 220, 253(249) Shah, R. H., 70, 109, 126(174) Shaik, S. S., 233, 260(504) Shalaby, M. A., 199, 201, 205, 209, 255(306; 314) Shapiro, R., 8, 14(81) Sharma, N. D., 227, 259(464) Sharma, S., 37, 121(12) Sharon, N., 60, 124(110), 265, 303(23) Sharp, P. R., 176, 248(65) Sharpe, E. S., 217, 257(383; 385) Sharshira, E. M., 186, 251(204) Shasha, B. S., 88–89, 130(290; 291), 193, 253(253) Shateil, F., 272, 305(89) Shaw, A. N., 89, 130(307) Shaw, D. H., 50, 52, 61, 125(137) Shaw, G., 91, 93, 130(308) Shawali, A. S., 234, 261(525) Sheldrake, C. N., 227, 259(464) Shemyakin, M. M., 198, 254(301; 302), 255(303; 304) Shibanuma, T., 58, 123(90) Shidori, Y., 81, 129(265) Shine, H. J., 176, 248(62) Shing, T. K. M., 227, 258(150; 451), 259(458) Shinkai, I., 176, 248(60) Shinobu, L. A., 94, 130(315) Shinozaki, M., 113, 133(396) Shiono, M., 58, 123(90) Shiozaki, M., 45, 46, 50, 58, 62, 81, 113–114, 123(89), 125(140), 129(264), 133(399; 401–403; 407) Shiyan, S. D., 42, 108, 126(164), 132(384), 133(385) Shröter, E., 266, 303(29) Shulman, M. L., 42, 56, 108, 122(60), 126(164), 132(384), 133(385) Shutalev, A. D., 77, 127(227), 128(228; 229) Siddall, T. H. III, 38, 121(17) Siddiqui, B. S., 101, 131(346–351), 312, 324(6)
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350
AUTHOR INDEX
Siddiqui, S., 101, 131(346–350) Siebert, R., 220, 257(414) Silwanis, B. A., 95, 131(330) Simkovic, I., 185, 251(178; 179) Simon, H., 183–185, 187, 198, 207, 209, 212, 219, 220, 225, 227, 230, 233, 234, 250(156; 163; 164; 168), 254(297–300), 256(342), 257(401), 258(436) Singh, A., 176, 248(72) Singh, P. K., 94, 95, 130(316–318) Sinha, A., 176, 247(58) Sinilova, N. G., 77, 128(229) Sinnott, L. M., 193, 253(257) Sinnott, M. L., 264–267, 269–271, 273, 275, 279, 280, 294–296, 298, 299, 301–302, 303(15; 25), 304(54; 67; 72; 73), 307(137; 160), 308(166; 169) Sinnwell, V., 193, 253(254) Sirigu, A., 175, 246(26) Skop, E., 176, 247(34) Skraup, Z. H., 179, 249(119) Slawing, A. M. Z., 89, 130(307) Smiatacz, Z., 227, 239, 260(478) Smith, A. J., 60, 103, 124(113) Smith, D. F., 51, 52, 61, 125(134) Smith, H., 5, 13(12) Smith, P., 233, 235, 260(505) Smith, P. A. S., 176, 247(60) Snobl, D., 206, 207, 255(329) Sohn, K.-H., 226, 227, 258(442) Sojka, S. A., 177, 248(78) Soliman, F. M., 192, 252(241) Soliman, R., 186, 251(197) Soltzberg, S., 181, 189, 202, 223, 250(137; 139), 252(218) Somogyi, A., 227, 260(479) Somogyi, L., 184, 186–187, 221–222, 224, 250(169), 252(205; 215–217), 257(421), 258(427) Soro, P., 193, 253(256) Sorokina, I. B., 43, 44, 75, 122(42) Sosnovsky, G., 185, 251(188) Souchon, H., 272, 292, 305(81) Spangler, B. D., 273, 306(114) Spanu, P., 193, 253(256) Spearman, M. A., 193, 253(259) Spencer, G. I., 233, 260(507) Spencer, R. P., 176, 247(54) Spezio, M., 265, 270, 272, 303(24), 304(56), 305(84)
Stachissini, A. S., 177, 248(80) Stahlberg, J., 272, 273, 276, 287, 305(79) Stanislavski, E. S., 61, 125(132) Starr, C. M., 176, 247(34) Stbie, A., 192, 253(245) Steensma, D. H., 193, 253(257) Steffen, J., 219, 257(401) Stempel, G. H., Jr., 176, 177, 247(43; 44) Stephan, H. J., 212, 256(356) Stephen, A., 190, 206, 207, 252(226), 255(328) Sternfeld, F., 227, 259(460) Sternlicht, H., 266–268, 274, 284, 302, 303(26) Stevens, T. S., 194, 254(281) Stewart, J. T., 77, 127(219) Stewart, L. C., 217, 256(372) Stewart, W. E., 38, 121(17) Sticher, U., 81, 129(261) Stock, H. W., 177, 249(104) Stöckl, W. P., 49, 122(45) Stoddart, J. F., 104, 132(370) Stodola, A. H., 217, 257(385) Stodola, F. H., 217, 257(383) Stoeckler, J. D., 273, 289, 306(113) Stoeckli-Evans, H., 176, 248(66) Stohr, G., 217, 222, 257(388; 390) Stolle, W. T., 176, 248(68) Stone, B. A., 264, 303(18) Stout, E. I., 89, 130(290) Stowell, C. P., 63, 102, 125(146), 132(362) Stoye, D., 177, 249(100) Street, I. P., 294, 307(138; 139) Strietholt, W. A., 144, 171(46) Stroh, H.-H., 174, 176–178, 189, 246(22), 247(41; 45), 248(81; 85), 249(89–97; 113) Strokopytov, B., 273, 279, 286, 306(109; 110) Strynadka, N. C. J., 264, 275, 278, 287, 295, 302, 302(1) Stuart, D. J., 273, 277, 278, 286, 306(115) Stukan, R. A., 95, 131(322) Stults, C. L. M., 323, 324(16) Stumer, C., 87, 129(285) Suami, T., 226–227, 244, 258(438; 439; 441; 444; 445; 448), 261(534) Subirana, J. A., 138, 170(22–25) Sugar, A., 226, 258(444) Suhaza, Y., 193, 253(256) Sukhovitsky, A., 234, 244, 261(514) Sullivan, G. M., 77, 127(216) Sung, W. L., 272, 305(91) Sunia, A., 101, 131(349)
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AUTHOR INDEX Suss-Fink, G., 176, 248(66) Suvorov, A. A., 183, 250(158) Suwama, M., 227, 259(452; 453) Suzuki, M., 227, 259(453) Svennerholm, L., 322, 324(13) Svenson, S. B., 60, 61, 124(109; 122) Svensson, B., 264, 302(4) Svensson, S., 52, 60, 124(106) Swain, L. C., 174, 246(5) Swanson, B. A., 174, 187, 246(10), 252(210) Sweeley, C. C., 312, 323, 324(6; 16) Sweeney, W., 135, 154, 170(1) Sweilem, N. S., 270, 271, 304(67) Swenson, L., 272, 305(89) Swift, G., 137, 138, 170(11) Swift, H. J., 272, 305(96; 97) Sy, K., 176, 247(58) Sysoeva, L. P., 189, 206, 235, 252(223) Szabo, L., 8, 14(77) Szegö, F., 63, 85, 125(145), 129(272) Szeja, W., 95, 131(328) Szilagyi, L., 176, 227, 247(54), 260(479) Szneler, E., 234, 261(513) Sztaricskai, F., 227, 260(479) Szurmai, Z., 50, 51, 61, 124(124; 125) Szweda, R., 227, 239, 260(478)
Tagmose, T. M., 193, 253(256) Taha, A. M., 186, 251(204) Taha, M. A. M., 97, 131(335), 177, 186, 249(102; 103), 251(194) Taha, M. I., 193, 253(252) Taigel, G., 87, 129(282) Takahashi, H., 41, 77, 125(161), 126(162), 128(235) Takahashi, S., 115, 133(412) Takata, M., 226, 258(444) Takayama, S., 47, 58, 112, 123(88) Takayama, T., 113, 133(403) Takayanagi, H., 77, 128(232) Takeda, K., 41, 77, 126(162), 128(232) Takeda, T., 206, 255(316) Takeda, Y., 182, 250(149) Takei, K., 226, 258(444) Taketani, Y., 168, 172(96) Takeuchi, H., 177, 249(105) Takeuchi, T., 226, 227, 258(442) Talebian, A., 74, 127(197)
351
Tanaka, Y., 268–269, 296–299, 304(53), 307(157) Tandano, K., 227, 258(448) Tang, P. W., 177, 248(83) Tang, Y., 227, 258(450; 451) Tanikawa, T., 227, 259(454) Tanko, J. M., 185, 251(185) Tanner, E. M., 234, 261(516) Tao, B. Y., 295, 307(150) Tao, W., 297–299, 307(157) Tarrago, G., 234, 261(517) Tashpulatov, A. A., 41, 74, 122(37) Tashpulatov, O. A., 41, 122(38) Tauber, H. J., 217, 257(395) Taverna, R. D., 42, 44, 56, 122(58) Taylor, C. W., 5, 13(14) Taylor, J., 265, 270, 272, 303(24), 305(84) Taylor, P. B., 80, 128(253) Teeri, T., 269, 270, 272–273, 276, 279, 280, 287, 288, 291, 304(55), 305(79) Teijima, S., 224, 258(432) Tejima, S., 95, 131(325), 206, 255(316) Tellier, C., 70, 110, 126(183), 133(389; 390) Tengi, J. P., 89, 130(298) Tengler, H., 177, 189, 248(85) Terabe, S., 232, 233, 260(497) Terayama, H., 115, 133(412) Terwisscha van Scheltinga, A. C., 273, 306(106; 107) Tesler, I. D., 122(36) Tews, I., 302, 308(171) Thankarajan, N., 234, 261(518) Thiel, W., 70, 110, 126(181) Thiem, J., 50, 61, 104, 124(131), 136, 142–145, 155, 170(6), 171(43–48) Thim, L., 272, 305(96) Thoma, J. A., 274, 306(122–124) Thompson, A., 187, 194, 217, 238, 252(207), 254(271), 257(384) Thompson, F. P., 197, 254(287) Thompson, R. H., 232, 233, 260(498) Thornally, P. J., 174, 246(6) Thorpe, A. J., 193, 227, 253(257), 259(460) Tichá, M., 80, 128(255) Tiers, G. V. D., 190, 252(224) Tino, J., 185, 251(178; 179) Tipson, R. S., 177, 180, 248(82) Tobe, T., 227, 259(452; 454) Todd, A. R., 2–8, 13(1–17; 19–43), 14(44–66; 68–71; 73–84)
4888 Horton Auth Index 11/17/99 3:21 PM Page 352
352
AUTHOR INDEX
Todoulou, O. G., 74, 127(195) Tokura, S., 147, 171(49) Tolley, S. P., 272, 282, 288, 305(85; 86) Tomme, P., 266, 268, 273, 276, 280, 287, 296, 303(37) Tong, M. K., 70, 110, 126(179; 182) Török, G., 77, 127(218) Törrönen, A., 272, 305(93) Tosi, G., 176, 177, 248(69; 76) Toth, B., 174, 246(12) Toth, G., 77, 93, 127(218), 130(313), 227, 238, 239, 259(474), 260(475) Totsuka, A., 280, 306(128), 307(130) Tourwé, D., 77, 127(218) Toy, M. S., 139, 154, 170(31) Toyama, A., 75, 127(205) Tracy, S. M., 174, 246(5) Tran, S. V., 174, 246(13) Trancier, J.-P., 194, 253(261) Treanor, S. P., 89, 130(296) Trimbue, D., 264, 270, 291–293, 303(11) Tronchet, J. M. J., 189, 193, 252(220–222), 253(247; 248) Trujillo Pérez-Lanzac, M., 79, 128(240; 242; 245) Tsang, W. S. C., 27, 34(12) Tsegenidis, T., 176, 247(31) Tseng, C. K. H., 89, 130(292; 296) Tsubota, T., 168, 172(96) Tsukamoto, H., 266, 304(42) Tsumuraya, Y., 266, 270, 285, 300, 303(38), 304(69) Tsunoda, T., 227, 259(461) Tsvetkov, Yu. E., 61, 125(132; 133) Tull, D., 272, 279, 287, 293–294, 302, 305(88), 307(133; 140; 146) Tuman, R. W., 74, 127(199) Turco, S. J., 176, 247(31) Turgeon, J., 77, 127(215) Turkenburg, J. P., 272, 305(97) Turner, M. K., 227, 259(463) Turner, N. J., 227, 259(463) Tuzi, A., 175, 246(26) Tuzikov, A. B., 70, 102, 126(178), 132(361) Tweeddale, H. J., 98, 131(339; 340)
Ubukata, O., 50, 62, 114, 125(140) Uchida, C., 41–44, 46, 47, 54, 58, 89, 113–114, 122(48), 123(86; 87), 130(301), 133(397; 398; 400; 405; 406; 408; 409)
Uchiyama, T., 266, 268, 271, 274–275, 284, 303(28), 304(46) Uedo, T., 48, 58, 123(94) Uematsu, Y., 226, 227, 258(444; 445) Uemura, M., 217, 256(379) Ugalde Donoso, M. T., 147, 171(52) Ulbrich, K., 138, 170(19) Umezawa, H., 227, 259(465) Umezawa, Y., 226, 227, 258(442) Unkovskii, B. V., 77, 127(227), 128(228; 229) Uno, T., 206, 255(316) Unverzagt, C., 51, 62, 103, 125(139) Uppugunduri, S., 84, 129(271) Urayama, S., 160, 172(79) Urry, D. W., 138, 170(17) Uspenskaya, M. N., 75, 127(202) Utsumi, S., 280, 306(129) Uzan, R., 92, 130(311)
Valencia, C., 79, 80, 86, 90, 97, 128(251), 129(275) Valent, M., 174, 246(18) Valentin, F., 182, 250(145) Valenza, S., 193, 253(256) Van Den Nest, W., 77, 127(218) van der Haar, A. W., 177, 249(99) Vandewalle, M., 227, 259(451) van Doorslaer, E., 270, 304(65) Vanin, A. F., 95, 131(322) van Montfort, R., 273, 306(109) Van Zyl, C. M., 174, 246(13) Varadarajan, S., 6, 13(22; 23) Varela, O., 41, 43, 55, 74, 75, 87–88, 99, 122(53; 54), 131(341), 148–150, 158, 160, 171(53–55), 172(77; 78) Varrot, A., 302, 307(132), 308(172) Vasella, A., 70, 89, 110, 126(181; 184; 185), 130(300) Vass, G., 180, 182, 192, 206–207, 227, 249(127), 250(151), 252(232), 255(328; 341), 259(469) Vasu, S., 177, 249(87) Vazquez de Miguel, L. M., 192, 252(243) Vedejs, E., 176, 248(68) Vercellotti, J. R., 27, 33(9; 10), 34(11), 193, 220, 253(251), 257(413) Vérez, V., 100, 131(343) Vérez Bencomo, V., 106, 132(381) Vert, M., 137, 170(9)
4888 Horton Auth Index 11/17/99 3:21 PM Page 353
AUTHOR INDEX Vethaviyasar, N., 46, 126(167; 168) Viguera Robio, F. J., 79, 128(242) Vile, S., 89, 130(306; 307) Villa, P., 96, 131(333) Villalonga, R., 95, 131(324) Viratelle, O. M., 266, 303(35) Vives, J., 168, 172(97) Vocadlo, D., 109, 110, 115, 133(386; 413) Vogel, P., 193, 253(256) Volkovich, S. V., 75, 127(202) von Deyn, W., 227, 259(456) Vondracek, R., 224, 258(434) Vonhoff, S., 70, 110, 126(185) von Pechmann, H., 190, 252(229) Vorgias, C. E., 302, 308(171) Voss, J., 37, 38, 121(10) Votoc˘ek, E., 182, 186, 224, 250(145–147), 258(434) Vranesic, B., 51, 60, 103, 124(111) Vr¯sanskà, M., 272, 305(78) Vu, C. B., 234, 261(520)
Wacker, H., 198, 254(300) Wagenknecht, H.-A., 112, 133(395) Waisbrot, S. W., 194, 254(265; 273; 275) Wakarachuk, W. W., 272, 305(91; 92) Wakarchuk, W. W., 264, 272, 302(5) Wakatsuki, S., 273, 277, 278, 306(118) Walle, T., 77, 127(211; 212) Walle, U. K., 77, 127(211) Wallin, N.-H., 52, 60, 124(106) Walling, C., 187, 252(212) Walter, R. L., 273, 289, 306(113) Walter, W., 37, 38, 121(10) Walters, C., 227, 259(463) Waltuch, R., 207, 255(334) Wan, C.-W., 104, 132(373) Wan, L. H., 227, 259(458) Wan, P., 39, 121(25) Wander, J. D., 176, 219, 247(37) Wang, P., 95, 131(320) Wang, P. G., 193, 253(256) Wang, Q., 264, 270, 291–293, 303(11) Wang, Y.-F., 193, 253(257) Warren, A. J., 293, 294, 307(133) Warren, R. A. G., 264, 270, 291–294, 303(11), 307(140) Warren, R. A. J., 264, 272, 302(5) Warren, S. G., 7, 14(56)
353
Wasserman, H. H., 234, 260(512), 261(520) Wassmann, A., 104, 132(376) Watanabe, K. A., 70, 71, 126(171) Watanabe, S., 41–44, 54, 58, 113, 122(48) Weaver, L. H., 293, 295, 307(134; 135) Webb, R. F., 6–8, 13(37; 41), 14(47; 75) Weber, B., 42, 54, 68, 122(51) Weber, W., 70, 110, 126(181) Weglicki, W. B., 95, 131(323) Wehrmuller, J. O., 193, 220, 253(249) Wei, Y., 272, 305(89) Weidmann, H., 49, 122(45) Weigel, T. M., 176, 248(61) Weigele, M., 89, 130(298) Weinber, H. R., 176, 248(63) Weinberg, N. L., 176, 248(63) Weinreb, S. M., 227, 259(467) Weisblat, D. I., 194, 254(265; 268; 269) Weiser, W., 266, 268, 284, 303(33), 304(47) Welsh, C., 42, 57, 64, 123(70), 7768 Welstead, W. J., Jr., 206, 207, 225, 255(325), 258(435) Wen, T., 234, 261(513) Weng, M., 55, 66, 122(55) Wentworth, D. F., 266, 303(34) Werringloer, J., 174, 246(4) Wess, G., 176, 248(72) West, D. X., 100, 131(342) Westbrook, E. W., 273, 306(114) Westbrook, M. L., 273, 306(114) Westphal, G., 176, 247(41) Weygand, F., 197–198, 219, 233, 254(292; 293; 295; 297; 298), 257(402) Weymouth, F. J., 6, 7, 13(37), 14(51; 58) Whistler, R. L., 193, 222, 253(253), 258(423) White, A., 272, 279, 287, 294, 302, 305(87; 88) White, A. D., 89, 130(307) Wiberg, K. B., 39, 121(21) Wibullucksanakul, S., 158, 172(76) Wichterle, O., 182, 186, 250(147) Wieczorek, J., 41, 74, 122(40) Wiegandt, H., 323, 324(14) Wiessler, M., 95, 131(326; 327) Wiggins, L. F., 139, 154, 170(27–29) Wightman, R. H., 192, 220, 253(244–246) Wilcox, C. S., 226, 227, 258(442) Wilde, H., 212, 256(364) Wiley, M. R., 89, 130(305) Wilkinson, A. J., 272, 305(97) Willetts, A. J., 227, 259(463)
4888 Horton Auth Index 11/17/99 3:21 PM Page 354
354
AUTHOR INDEX
Williams, A. F., 315, 324(12) Williams, D. J., 89, 130(307) Williams, J. M., 177, 180, 248(83; 84), 250(132) Williams, N. R., 185, 227, 238, 251(182), 259(473) Wilson, D. B., 264, 265, 270, 272, 274, 290, 302(5), 303(24), 304(56; 57), 305(80; 84), 306(120) Wilson, K. S., 272, 282, 288, 302, 305(85), 308(171) Wilson, M. J., 77, 127(211) Wilson, S. R., 226, 227, 258(442) Wilt, J. W., 185, 251(183) Winchester, B. G., 193, 253(257) Winkley, M. W., 70, 71, 126(172) Winter, M., 209, 217, 219, 256(347; 349), 257(397) Witczak, Z. J., 36, 40, 41, 43, 44, 63, 65, 66, 74, 81, 120(4), 122(39), 193, 253(257) Withers, S. G., 70, 109–110, 114, 115, 126(181; 184), 133(386; 410; 413), 264, 266, 270, 272–274, 277, 279, 286, 287, 291–294, 301–302, 302(3; 5), 303 (11; 39), 305(87; 88; 92), 306(116; 121), 307(132; 133; 138–140; 142–146), 308(169; 172) Wittel, K., 37, 121(15) Wojtowicz, M., 77, 128(230) Woldike, H. F., 272, 305(96) Wolfenden, R., 266, 303(34) Wolff, H., 177, 189, 248(85) Wolfgang, D. E., 270, 304(57) Wolfrom, M. L., 70, 71, 126(172), 139, 154, 170(31), 178, 181, 184, 187, 189, 193–194, 197, 202, 206, 207, 217, 220, 223, 224, 238, 249(114), 250(135–139; 165), 252(206–208; 218), 253(249; 251; 252), 254(265; 267–277), 255(326), 257(384; 396; 411; 413) Wollin, R., 60, 61, 124(122) Wolters, B., 101, 131(345) Wong, C.-H., 47, 58, 112, 123(88), 193, 227, 253(257), 259(463) Wong, R., 193, 253(257) Wong, S. C., 39, 121(26) Wong, S. Y. C., 50, 51, 62, 103, 125(138) Wood, H. B., 194, 254(270) Wood, H. C. S., 220, 257(410) Woodall, C. C., 193, 253(256)
Woods, E. A., 177, 189, 248(85) Woods, M., 89, 130(307) Woods, T. S., 37, 121(11) Wright, E. M., 50, 60, 102, 124(117), 132(354) Wright, J. A., 193, 253(259) Wriston, J. C., Jr., 102, 132(363) Wu, S. S., 176, 247(31) Wu, Z., 176, 248(65)
Xiang, Y. B., 176, 248(72)
Yaginuma, S., 227, 259(466) Yaguchi, M., 272, 305(91) Yakhontov, L. N., 183, 250(159) Yale, H. L., 181, 250(141) Yamada, K., 176, 227, 247(57), 259(454) Yamagishi, T., 113, 114, 133(398; 400; 406; 408) Yamaki, T., 270, 304(62) Yamamoto, I., 78, 128(236) Yamamoto, S., 78, 128(236) Yamashita, H., 177, 249(86) Yamashita, M., 89, 130(303), 176, 177, 247(56), 249(86) Yáñez, M., 38–39, 121(16; 27) Yang, D., 176, 248(61) Yang, D. T. C., 176, 248(70) Yang, J.-H., 89, 130(304) Yankeelov, J. A., Jr., 274, 306(123) Yanovsky, E., 138, 170(26) Yao, H. C., 233, 260(506) Yasuda, K., 226, 258(444) Yasui, T., 177, 249(107) Yates, J. B., 89, 130(305) Yates, K., 39, 121(25) Yi, Y., 176, 248(65) Yon, J. M., 266, 303(35) Yoshida, K., 266, 304(42–44) Yoshida, S., 226, 227, 258(445) Yoshida, T., 176, 247(57) Yoshiike, R., 50, 62, 114, 125(140) Yoshikawa, N., 176, 247(57) Yoshinaga, M., 142, 171(42) Yoshino, H., 95, 131(329) Yu, H. K. B., 176, 247(54) Yu, L., 193, 253(256) Yu Cui, U., 227, 258(451) Yuki, H., 168, 172(96)
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AUTHOR INDEX Zaalishvili, M. M., 161, 172(83) Zach, K., 221, 257(416) Zacharieva, E. I., 138, 170(19) Zamojski, A., 121(32) Zamora, F., 147–149, 171(50; 53; 54) Zamora Mata, F., 79, 128(241; 244), 147, 153, 171(52; 57; 58) Zanini, D., 50, 60, 124(116) Zehl, A., 48, 58, 63, 81, 92, 123(96) Zemek, J., 174, 246(17; 20) Zemplén, G., 190, 192, 206, 224, 252(228; 234; 237), 255(320) Zerner, E., 207, 255(334) Zhang, R.-G., 273, 306(114) Zhang, X.-J., 272, 274, 276, 305(77) Zhang, Y., 298, 307(160) Zhao, D., 176, 248(60) Zhu, J.-L., 89, 130(304)
355
Zhu, Y.-H., 193, 253(256) Ziegler, B., 266, 268, 273, 274, 276, 302, 303(31) Zimmermam, S. C., 104, 132(372) Zimmerman, J., 135, 154, 170(1) Zinardi, F., 193, 253(256) Zinke-Allmang, G., 224, 258(431) Zinner, H., 176–177, 181, 189, 247(39; 46), 248(85), 250(142) Zollinger, H., 190, 252(227) Zopf, D. A., 51, 52, 61, 84, 125(134), 129(271) Zophy, W. H., 194, 254(265) Zsolldos-Mady, V., 190, 252(231) Zurabyan, S. E., 43, 44, 64, 70, 75, 122(36; 42), 125(147–149), 126(175) Zussman, J., 6, 13(17) Zweier, J. L., 95, 131(320) Zwierzak, A., 58, 123(92)
4888 Horton Sub Index 11/17/99 3:07 PM Page 357
Subject Index
Acetylation, D-galactaric acid, 155 Acetylenic compounds, reactions, 192–193 Acid dichlorides, polycondensation reactions with, 142–143 Acids, action in carba-sugar hydrazones, 236–238 Aldose arylhydrazones, reaction with acetylenic compounds, 192–193 Aldoses, for saccharide hydrazone preparation, 177 Aldosuloses, for saccharide hydrazone preparation, 177 Alexander Robertus Todd aphid pigment research, 8–9 2⬘-deoxynucleosides, 6 dibenzyl phosphorochloridate, 6–7 education, 1–3 glucopyranoside research, 5–6 managerial skills, 9 marriage, 10 nucleic acids, 7–8 nucleotide coenzymes, 4–7 personality and achievements, 10–11 professorships, 3 research strategy, 9 role in national and international affairs, 9–10 student careers, 11 thiamine work, 5 vitamin B12 , 8 Alkalies glycosylhydrazine reactions, 183–185 saccharide hydrazone reactions, 183–185 Alkylenediamines, polycondensation, 156–157 Alkylhydrazones, reaction with acetylenic compounds, 192–193
Alpha-Amylase, pancreatic, structure, 278–279 Amine nucleophiles, coupling with sugar isothiocyanates, 74–78 Amino acids carbohydrate-derived, for chiral A, B-type polyamides, 145–153 coupling to glycosyl isothiocyanates, 75–76 2-Amino-2-deoxyaldose reactions with carbon disulfide, 97 with glycosyl isothiocyanates, 84 5-Amino-5-deoxy-L-arabinonic acid, derivative preparation, 148 2-Amino-2-deoxy-D-glucose, reaction with isothiocyanates, 80 1-Amino-1-deoxyketose, reaction with carbon disulfide, 97 1-Amino-1-deoxy-2-ketose, reaction with glycosyl isothiocyanates, 84 4-Aminophenethylamine, reductive amination, 61 Amino sugars derivatives of neuraminic acid, 81 –isothiocyanate coupling, 78–81 –sugar isothiocyanate coupling, 81–84 thioacylation, 71 Ammonolysis, tri-O-methyl-L-arabinono-1,5lactone, 151–153 Anhydroalditols, for polymer synthesis, 143–144 1, 6-Anhydro-4-O-benzyl-2-deoxy-2isothiocyanato-3-O-p-toliylsulfonyl-웁-Dglucopyranoside, condensation with methanol, 88 1,4-Anhydroerythritol, transformation, 144 Anhydroosazones, formation, 220–222 357
4888 Horton Sub Index 11/17/99 3:07 PM Page 358
358
SUBJECT INDEX
3,6-Anhydroosazones, formation, 221–222 1, 4-Anhydro-D,L-threitol, transformation, 144 1, 6-Anhydro-2,3,4-tri-O-benzyl-웁-Dglucopyranose, as glycosyl donor, 54 Anions, formation in carba-sugar hydrazone reactions, 236–237 Antineoplastic compounds, azole nucleoside analogs as, 75 Antiviral compounds, azole nucleoside analogs as, 75 Aphid pigments, research by Lord Todd, 8–9 Aromatization bis(phenylhydrazone) residues, 215–220 cyclohexane ring, 240–241 hydrazone residues, 241 Artificial receptors, N-thiocarbonyl sugars, 118–120 Aspartic acid, carbohydrate-based derivatives, 168–169 Aza-Wittig-related reactions, sugar isothiocyanates, 65–66 6-Azido-6-deoxy-2,3,4,5-tetra-O-methylD-glucono-1,5-lactone, synthesis, 147 3⬘-Azido-3⬘,5⬘-dideoxy-5⬘-isothiocyanato nucleosides, in (deoxy)ribonucleic thiourea synthesis, 82–83 Azoalkenes, formation, 186–188 Azole nucleoside, analogs, 75
Bases, action in carba-sugar hydrazones, 236–238 Benzoylisothiocyanates, reaction with 2amino-2-deoxy-D-glucose, 80 Benzylisothiocyanates, reaction with hydroxyl groups, 88–89 Beta-Amylase residues for protonation, 273 X-ray studies, 279–281 Bicyclic dianhydro-osazones, preparation, 222 Biocompatible scaffolds, cyclodextrins as, 106–107 Biodegradation, polymer, 137–138 Bis(glycosyl)thioureas, as secondary products, 64–65 Bis(hydrazones) oxidation, 212 pyrazole formation, 215
2,4-Bis(4-methoxyphenyl)-1,3dithiadiphosphetane-2,4-disulfide, see Lawesson’s reagent 1, 2-Bis(phenylazo)ethene, formation, 212 Bis(phenylhydrazone) reduction, 220 residue aromatization, 215–220 1,2-Bis(phenylhydrazones), formation, 230 1,3-Bis(phenylhydrazones), formation, 230–234 Bis(thiocarbonyl)hydrazide, derivatives of galactaric acid, 97–100
Carba-sugar hydrazones acid and base action, 236–238 aromatization, 240–241 1,2-bis(phenylhydrazones), 230 1,3-bis(phenylhydrazones), 230–234 importance, 226–227 nucleophilic substitution, 238–239 oxidation, 241, 244 phenylhydrazone preparation, 227 phenylhydrazones, 227 reduction, 241, 244 structure, 234–236 1,2,3-tris(phenylhydrazones), 230–234 Carbohydrate derivatives amino acids, for chiral A,B-type polyamides, 145–153 aspartic acid-like derivatives, 168–169 reaction with fluorescein isothiocyanate, 80–81 Carbon-14, Melvin Calvin research, 16–18 Carbon bases, addition to sugar isothiocyanates, 68–70 Carbon disulfide reactions with deoxyaldoses, 97 with deoxyketoses, 97 with sugar iminophosphoranes, 63 N-Carbonyl compounds comparison to N-thiocarbonyl compounds, 37–39 thionation, 70–71 Carboxylic acids, condensation with sugar isothiocyanates, 64 Cellulase, X-ray studies CBH-I, 273–274, 276–278 CBH-II, 279–281 family 9, 281–282 family 45, 281–282
4888 Horton Sub Index 11/17/99 3:07 PM Page 359
SUBJECT INDEX Cex 웁-cellulase, X-ray studies, 279 Chiral polyamides A,B-type, from carbohydrate-derived amino acids, 145–153 based on diamino saccharides, 141–145 properties and applications, 136–140 Chitobiose, amino functions, 141 Circular dichroism glycosylhydrazines, 182 saccharide hydrazones, 182 Condensation polycondensation with alkylenediamines, 156–157 with 2,6-diamino saccharides, 142–143 with hexaric-1,4:6,3-dilactones, 158 interfacial, polyamides, 140 self-condensation, 64–65 sugar isothiocyanates with carboxylic acids, 64 Conformations N-carbonyl compounds, 37–39 glycolipids, 313–314 sugar thioamides, 72–73 sugar thiourea, 86–87 N-thiocarbonyl compounds, 37–39 Cyclic guanidinium glycomimetics, preparation, 111–112 Cyclic sugar dithiocarbamates, synthesis, 97 Cyclic sugar thiocarbamates, synthesis, 90–93 3,2-Cyclic thiocarbamates, preparation, 92–93 3,4-Cyclic thiocarbamates, preparation, 92–93 3,5-Cyclic thiocarbamates, preparation, 92–93 5,6-Cyclic thiocarbamates, preparation, 92–93 6,4-Cyclic thiocarbamates, preparation, 92–93 6,5-Cyclic thiocarbamates, preparation, 92–93 Cycloaddition as glycosylhydrazine reaction, 192–193 as saccharide hydrazone reaction, 192–193 sugar isothiocyanates, 66 Cyclodextrin glycosyltransferase, pancreatic, 278–279 Cyclodextrins as biocompatible scaffolds, 106–107 modification, 118–120
359
Cyclohexane, ring aromatization, 240–241 Cyclohexane bis(phenylhydrazone), free radical mechanism, 233–234 Cyclohexane 1,2,3-trione tris(phenylhydrazone), ionic mechanism, 233
Degradation osazones, 209–212 polymer, 137–138 Dehydroosazones, formation, 212 6-Deoxy-6-isothiocyanato aldopyranosides, stability, 59–60 3⬘-Deoxy-3⬘-isothiocyanatothymidyl derivative, in (deoxy)ribonucleic thiourea synthesis, 83–84 Deoxynucleosides, synthesis, 89 2⬘-Deoxynucleosides, research by Lord Todd, 6 (Deoxy)ribonucleic thiourea synthesis with 3⬘-azido-3⬘, 5⬘-dideoxy-5⬘isothiocyanato nucleosides, 82–83 with 3⬘-deoxy-3⬘-isothiocyanatothymidyl derivative, 83–84 Desulfurization reactions, glycosyl isothiocyanates, 65 Diamino saccharides, chiral polyamides based on, 141–145 2,6-Diamino saccharides, for polycondensation reactions, 142–143 Dianhydroosazones, pyrazole type, 222 Diazo derivatives, reactions, 194 Dibenzyl phosphorochloridate, research by Lord Todd, 6–7 Dimethyl D-glucarate, preparation, 156 Diosylceramides, nomenclature, 317 Disaccharides, for saccharide hydrazone preparation, 177 Dithiocarbamates cyclic sugar dithiocarbamates, 97 linear sugar dithiocarbamates, 94–96
Electron affinity, halogens, 15 Electronic properties N-carbonyl compounds, 37–39 N-thiocarbonyl compounds, 37–39 Electrophilic addition, to glycals, 56
4888 Horton Sub Index 11/17/99 3:07 PM Page 360
360
SUBJECT INDEX
Electrophilic substitution as glycosylhydrazine reactions, 189–192 osazones, 209 as saccharide hydrazone reactions, 189–192 Elimination in azoalkene formation, 186–188 in carba-sugar hydrazone reactions, 238 Enzymatic degradation, polymer, 137–138 Enzyme inhibitors, studies with Nthiocarbonyl sugars, 107–118 Enzymes inverting, catalysis of noninverting reactions, 267–270 retaining, catalysis of nonretaining reactions, 267–270 Esters, derivatives of saccharide osazones, 223–224 Ethers, derivatives of saccharide osazones, 224 Ethoxyisothiocyanates, reaction with 2amino-2-deoxy-D-glucose, 80
Flurescein isothiocyanate, reaction with carbohydrate derivatives, 80–81 Formazans, formation, 189–192 Free radicals formation, 209–212 formation in carba-sugar hydrazone reactions, 237–238 in mechanism of cyclohexane bis(phenylhydrazone), 233–234 oxidation glycosylhydrazines, 185–186 saccharide hydrazones, 185–186 Furanose cis-1,2-fused oxazolidine-2-thione, preparation, 92
Galactaric acid, bis(thiocarbonyl)hydrazide derivatives, 97–100 D-Galactaric acid, acetylation, 155 웁-Galactosidase residues for protonation, 273–274 X-ray structure, 276–278 Gangliosides brain, Svennerholm abbreviations, 322–323 nomenclature, 319–320 D-Glucaric acid esters, preparation, 156
Glucoamylase residues for protonation, 273 X-ray studies, 279–281 Glucopyranosides, research by Lord Todd, 5–6 Glycals, electrophilic addition to, 56 Glycofuranosyl halides, acetylated, reaction with KSCN, 54–55 Glycogen phosphorylase, X-ray structure, 276–278 Glycoglycerolipids classification, 314 definition, 311 Glycolipids acidic glycosphingolipids, 319–320 classification by lipid moiety, 314–317 definition, 311 monosaccharide residue naming, 312 monosaccharide residue number, 312 neutral glycosphingolipids, 317–319 oligosaccharide structure definition, 312–313 other names, 312 recommended abbreviations, 322 ring size and conformation, 313–314 Svennerholm abbreviations, 322–323 Glycophosphatidylinositols classification, 315 definition, 311 Glycopyranosyl donors, in sugar isothiocyanate synthesis, 49 Glycopyranosyl isothiocyanates 1, 2-cis-configured, preparation, 53–54 solvent-free preparation, 53 Glycosidases glycosyl isothiocyanates as inhibitors, 108 inverting, in glycosyl transfer, 270–271 X-ray studies, residues for protonation, 272–274 Glycosphingolipids classification, 316–317 definition, 311 nomenclature acidic glycosphingolipids, 319–320 neutral, with oligosaccharide chains, 317–319 neutral glycosphingolipids, 317–319 Glycosylamines preparation, 57 transformation, 56–57
4888 Horton Sub Index 11/17/99 3:07 PM Page 361
SUBJECT INDEX Glycosylases catalyzed reactions inverting glycosylases, 279–284 retaining glycosylases, 275–279 glycosyl transfer by inverting glycosidases, 270–271 1-MCO and 2-MCO types, separation, 284–293 1-MCO type, stereochemical behavior, 294–296 minisubstrates of forbidden configuration, 266–267 noninverting reactions by inverting enzymes, 267–270 nonretaining reactions by retaining enzymes, 267–270 role of transition-state structure, 296–299 –substrate complexes, catalytic center, solvent proximity, 299–301 S-Glycosyl-N,N-dialkyldithiocarbamates, synthesis, 95 Glycosyl donor, in sugar isothiocyanate synthesis, 41, 49, 53–55 Glycosylhydrazines alkali action, 183–185 bromo and dibromo derivative formation, 189 characteristics, 175–177 cycloaddition reactions, 192–193 derivatives, 189 diazo derivative reactions, 194 elimination reactions, 186–188 formation, 177–179 formazan formation, 189–192 hydrazono lactone formation, 185–186 oxadiazole formation, 186 reduction reactions, 193–194 structure, 179–182 Glycosyl isothiocyanates coupling reactions, 75–76 desulfurization reactions, 65 as glycosidase inhibitors, 108 reaction with 2-amino-2-deoxyaldoses, 84 reaction with 1-amino-1-deoxy-2ketoses, 84 N-(Glycosylthiocarbamoyl)peptides, by glycosyl isothiocyanates coupling, 75–76 Glycosyl transfer, by inverting glycosidases, 270–271
361
Glycuronoglycosphingolipids, nomenclature, 320
Halogens, electron affinity, 15 Hapten, preparation, 84 Hen’s egg-white lysozyme, structure, 275–276 1, 6-Hexanediamine, reductive amination, 61 Hexaric-1,4:6,3-dilactones, in polycondensations, 158 Hexarodilactones, polyaddition, 158–160 Hydrazones carba-sugar, see Carba-sugar hydrazones residue aromatization, 241 saccharide, see Saccharide hydrazones Hydrazono lactone, formation, 185–186 Hydrolysis osazones, 208–209 polymer, 137–138 Hydroxyl groups, reaction with benzyl isothiocyanate, 88–89
Infrared spectroscopy glycosylhydrazines, 181 saccharide hydrazones, 181 sugar isothiocyanates, 66 Inorganic thiocyanate, in sugar isothiocyanate synthesis, 41, 49, 53–55 Isothiocyanate conjugates, preparation, 60–61 Isothiocyanates coupling with amino sugars, 78–81 energetics and structure, 37–39 Isothiocyanation reagents, 58 sugar amines, 56–62 Isotopes, radioisotopes, Melvin Calvin research, 16
Ketoses, for saccharide hydrazone preparation, 177
Laboratory of Chemical Biodynamics, Melvin Calvin leadership, 19 Lawesson’s reagent, for thionation, 70–71 LCB, see Laboratory of Chemical Biodynamics
4888 Horton Sub Index 11/17/99 3:07 PM Page 362
362
SUBJECT INDEX
Linear sugar dithiocarbamates, synthesis, 94–96 Linear sugar thiocarbamates, synthesis, 88–90 Lipid, in glycolipid classification, 314–317 Lord Todd, see Alexander Robertus Todd Lysozyme, hen’s egg-white, structure, 275–276
D-Mannaro-1,4:6,3-dilactone,
polyaddition, 158–160 Margaret Alice Clarke awards and recognitions, 28–29 consulting work, 28 early years, 23 education, 23–24 friendships, 31–32 marriage, 24 New Orleans Carbohydrate Symposia, 24–25 professional memberships, 29–30 role in international carbohydrate communities, 30–31 Sugar Processing Research Institute, Inc., 25–26 Mass spectrometry, sugar isothiocyanates, 68 Melvin Calvin carbon-14 research, 16–18 early years, 15 generosity, 20–21 LCB leadership, 19 Nobel Prize in Chemistry, 18 radioisotope research, 16 use of publicity, 20 Membrane receptors, interaction with Nthiocarbonyl sugars, 101–102 Methanol, condensation with 1,6-anhydro-4O-benzyl-2-deoxy-2-isothiocyanato-3O-p-toliylsulfonyl-웁-Dglucopyranoside, 88 Methyl 6-amino-6-deoxy-움-Dglucopyranoside, coupling reactions, 81–82 Methyl D-glucarate 1, 4-lactone, preparation, 156 Methyl D-glucarate 6,3-lactone, preparation, 156 Methyl 움-D-glucopyranoside, for lactone synthesis, 147
Methyl 2,3,4,6-tetra-O-allyl-움-Dglucopyranoside, preparation and polymerization, 138–139 Molecular recognition, N-thiocarbonyl sugars artificial receptors, 118–120 enzyme inhibitors, 107–118 glycoclusters, 102–107 glycodendrimers, 102–107 interactions with membrane receptors, 101–102 neoglycoconjugates, 102–107 Monoglycosylceramides, nomenclature, 317 Monosaccharides hydroxyl groups, reaction with benzyl isothiocyanate, 88–89 residue naming, 312 residue number, 312 Mutarotation, osazones, 207
Neuraminic acid, amino sugar derivatives, 81 New Orleans Carbohydrate Symposia, and Margaret Alice Clarke, 24–25 Nobel Prize, Melvin Calvin, 18 Nuclear magnetic resonance glycosylhydrazines, 179–180 saccharide hydrazones, 179–180 sugar isothiocyanates, 66–68 sugar thiourea, 86–87 Nucleic acids, research by Lord Todd, 7–8 Nucleophiles, amine, coupling with sugar isothiocyanates, 74–78 C-Nucleophiles, reactions with sugar isothiocyanates, 63 N-Nucleophiles, reactions with sugar isothiocyanates, 63 O-Nucleophiles, reactions with sugar isothiocyanates, 63 S-Nucleophiles, reactions with sugar isothiocyanates, 63 Nucleophilic addition, in sugar thiourea synthesis, 78–81 Nucleophilic substitution carba-sugar hydrazones, 238–239 osazones, 208–209 Nucleotide coenzymes, research by Lord Todd, 4–7 Nylons nylon-3, chiral analogs, preparation, 168–169
4888 Horton Sub Index 11/17/99 3:07 PM Page 363
SUBJECT INDEX nylon-n, based on carbohydrate-derived amino acids, 145–153 nylon-n, 4, polyhydroxyl chiral analogs, 160–168 nylon-n, 5, polyhydroxyl chiral analogs, 153–160 nylon-n, 6, polyhydroxyl chiral analogs, 153–160 physical properties, 137
Oligosaccharides neutral glycosphingolipids with chains, 317–319 structure definition, 312–313 Optical rotatory dispersion glycosylhydrazines, 182 saccharide hydrazones, 182 Orotate phosphoribosyltransferase, X-ray studies, 282–284 Osazones action of bases, 209–212 chelated structures, 205–207 electrophilic substitution, 209 formation, 194–196 formation mechanism, 196–197 mutarotation, 207 nucleophilic substitution, 208–209 tautomeric structures, 202–205 Osotriazole, mechanism of formation, 217–220 Oxadiazole, formation, 186 Oxazolidine-2-thione heterocycles, preparation, 92 Oxazolinium cations, as glycosyl donors, 49, 53 Oxidation, free radical glycosylhydrazines, 185–186 saccharide hydrazones, 185–186 Oxidation–reduction carba-sugar hydrazones, 241, 244 intermolecular, saccharide osazones, 197–198 intramolecular, saccharide osazones, 198–202 2-Oxo-1,3-bis(phenylhydrazones), structure, 234–235
Peptides, coupling to glycosyl isothiocyanates, 75–76
363
Phenylazo-cycloalkenes, formation in carba-sugar hydrazone reactions, 238 Phenylazo-phenylhydrazones, formation, 212 1-Phenylhydrazino-phenylhydrazones, preparation, 187 Phenylhydrazones, preparation, 227 Phenylosotriazoles, formation, 241 Phosphoglycosphingolipids, nomenclature, 320–321 Phosphonoglycosphingolipids, nomenclature, 321 Photodegradation, polymer, 137–138 Photosynthesis, Melvin Calvin research, 16–19 Pigments, aphid, research by Lord Todd, 8–9 Polyaddition, hexarodilactones, 158–160 Polyaldaramides, polyhydroxy chiral analogs, 153–160 Polyamides chiral A,B-type, from carbohydrate-derived amino acids, 145–153 based on diamino saccharides, 141–145 properties and applications, 136–140 from interfacial polycondensation, 140 Polycondensation with alkylenediamines, 156–157 with 2,6-diamino saccharides, 142–143 with hexaric-1, 4:6, m3-dilactones, 158 interfacial, polyamides, 140 Polyhydroxy chiral analogs nylon-n, 4, 160–168 nylon-n, 5 and nylon-n, 6, 153–160 Polymers biodegradation, 137–138 synthesis, with anhydroalditols, 143–144 Polyols, hydroxyl groups, reaction with benzyl isothiocyanate, 88–89 Polytartaramides, polyhydroxy chiral analogs of nylon-n, 4, 160–168 Potassium thiocyanate, reaction with acetylated glycofuranosyl halides, 54–55 Protonation in carba-sugar hydrazones, 236–237 glycosidase residues for, 272–274 Psychosine, definition, 312 Pyranose cis-1, 2-fused oxazolidine-2-thione, preparation, 92
4888 Horton Sub Index 11/17/99 3:07 PM Page 364
364
SUBJECT INDEX
Pyrazoles formation from bis(hydrazones), 215 type of dianhydroosazones, 222
Radioisotopes, Melvin Calvin research, 16 Reduction glycosylhydrazines, 193–194 saccharide hydrazones, 193–194 Reduction–oxidation carba-sugar hydrazones, 241, 244 intermolecular, saccharide osazones, 197–198 intramolecular, saccharide osazones, 198–202 Reductive amination, for isothiocyanation, 61–62
Saccharide azines, synthesis, 174–175 Saccharide hydrazones alkali action, 183–185 bromo and dibromo derivative formation, 189 characteristics, 175–177 cycloaddition reactions, 192–193 derivatives, 189 diazo derivative reactions, 194 elimination reactions, 186–188 formation, 177–179 formazan formation, 189–192 hydrazono lactone formation, 185–186 oxadiazole formation, 186 reduction reactions, 193–194 structure, 179–182 Saccharide osazones action of bases, 209–212 anhydroosazone formation, 220–222 bis(hydrazone) oxidation, 212 bis(phenylhydrazone) reduction, 220 bis(phenylhydrazone) residue aromatization, 215–220 chelated structures, 205–207 electrophilic substitution, 209 ester derivatives, 223–224 ether derivatives, 224 formation, 194–196 intermolecular oxidation–reduction, 197–198 intramolecular oxidation–reduction, 198–202
mutarotation, 207 nucleophilic substitution, 208–209 saccharide poly(hydrazones), 224–226 tautomeric structures, 202–205 Saccharide phenylosotriazoles, formation, 217 Saccharide poly(hydrazones), preparation, 224–226 Saccharide triazoles, formation, 215–220 Self-condensation reactions, sugar isothiocyanates, 64–65 Solvent, proximity to catalytic center, 299–301 SPRI, Inc., see Sugar Processing Research Institute, Inc. Sugar amines, isothiocyanation, 56–62 Sugar carbodiimides, in sugar thiourea synthesis, 84–85 Sugar iminophosphoranes, reaction with carbon disulfide, 63 Sugar isothiocyanates addition of carbon bases, 68–70 aza-Wittig-type reactions, 65–66 condensation with carboxylic acids, 64 coupling with amine nucleophiles, 74–78 coupling with amino sugars, 81–84 cycloaddition reactions, 66 desulfurization reactions, 65 reactions with C-nucleophiles, 63 with N-nucleophiles, 63 with O-nucleophiles, 63 with S-nucleophiles, 63 self-condensation reactions, 64–65 spectroscopic properties, 66–68 synthesis by electrophilic addition, 56 by isothiocyanation, 56–62 by reaction of glycosyl donor, 41, 49, 53–55 by reaction of sugar iminophosphoranes, 63 Sugar Processing Research Institute, Inc., and Margaret Alice Clarke, 25–26 Sugar thioamides conformational properties, 72–73 synthesis by carbon base addition, 68–70 miscellaneous methods, 71–72
4888 Horton Sub Index 11/17/99 3:07 PM Page 365
SUBJECT INDEX by thioacylation, 71 by thionation, 70–71 Sugar thiocarbamates cyclic sugar thiocarbamates, 90–93 linear sugar thiocarbamates, 87–90 Sugar thiosemicarbazones, synthesis, 99–100 Sugar thiourea conformational properties, 86–87 functional group transformation, 86 spectroscopic properties, 86–87 synthesis by amino sugar coupling, 78–81 from sugar carbodiimides, 84–85 by sugar isothiocyanate coupling, 74–78, 81–84 Sulfoglycosphingolipids, nomenclature, 320 Svennerholm abbreviations, brain gangliosides, 322–323
Tautomers, osazones, 202–205 2,3,4,5-Tetra-O-acetyl derivative, from Dgalactaric acid acetylation, 155 S-(2,3,4,6-Tetra-O-acetyl-웁-Dglucopyranosyl) N,Ndimethyldithiocarbamate, synthesis, 95 2,3,4,6-Tetra-O-acetyl-웁-D-glucopyranosyl isothiocyanate, coupling reactions, 81 Tetrahydrooxazine-2-thione heterocycles, preparation, 92 Thermooxidative degradation, polymer, 137–138 Thiamines, research by Lord Todd, 5 Thioacylation, amino sugars, 71 N-Thiocarbonyl carbohydrate derivatives, synthesis, 97–101 N-Thiocarbonyl compounds, comparison to N-carbonyl compounds, 37–39 N-Thiocarbonyl sugars artificial receptors, 118–120 enzyme inhibitors, 107–118 glycoclusters, 102–107 glycodendrimers, 102–107
365
interaction with membrane receptors, 101–102 neoglycoconjugates, 102–107 Thionation, N-carbonyl derivative, 70–71 Thioureido substituents, in cyclodextrin modification, 118–120 Tin tetrachloride–trimethylsilyl isothiocyanate system, 55 Transformation, sugar thiourea functional groups, 86 Transhydrazonation, osazones, 208–209 Transition state, glycosylase reaction, 296–299 Tri-O-benzoyl-D-ribopyranosyl isothiocyanates, preparation, 58 2,3,4-Tri-O-benzyl-움-D-glucopyranosyl isothiocyanate, synthesis, 54 p-Trifluoroacetamidoaniline, reductive amination, 61 Tri-O-methyl-L-arabinono-1, 5-lactone, ammonolysis, 151–153 Trimethylsilyl isothiocyanate–tin tetrachloride system, 55 Tris(phenylhydrazones), structure, 235–236 1, 2, 3-Tris(phenylhydrazones), formation, 230–234
Ultraviolet spectroscopy, sugar isothiocyanates, 68
Vitamin B12, research by Lord Todd, 8
X-Ray studies glycosidases, residues for protonation, 272–274 inverting glycosylases, 279–284 retaining glycosylases, 275–279 Xylanase, X-ray studies, 279 D-Xylonic acid, derivative preparation, 148
