Carbohydrate Chemistry Volume 23
A Specialist Periodical Report
Ca r bohyd rate Che mist ry Monosaccharides, Disaccharides, and Specific Oligosaccharides
Volume 2 3 A Review of the Recent Literature Published during 1989 Senior Reporter R. J. Ferrier, Victoria University of Wellington, New Zealand Reporters R. Blattner, D.S.I.R., Petone, New Zealand R. H. Furneaux, D.S.I.R., Petone, New Zealand P. C. Tyler, D.S.I.R., Petone, New Zealand R. H. Wightman, Heriot-Watt University, Edinburgh N. R. Williams, Birkbeck College, University of London
ISBN 0-85 186-172-5 ISSN 09.5 1-8428 @ T h e Royal Society of Chemistry. 1991
All Rights Reserved No part of this book may be reproduced or transmitted in any form or bv any means-graphic, electronic. including photocop-ving, recording, taping, or information storage and retrieval systems-without written permission from The Ro-vaI Society of Chemistry
Published by T h e Royal Society of Chemistry Thomas Graham House, Science Park. Cambridge CB4 4WF Printed and bound in Great Britain by Bookcraft (Bath) Ltd
Preface
Our reviewing team has happily remained unchanged for Volume 23, and I acknowledge the great cooperation I have received from all members. Dr Neil Williams has continued to make his special contribution by again having done all of the drawings a service that is much appreciated in a project which requires clear, unambiguous art work and does not lend itself especially well to computerised methods. Despite our best intentions, the other responsibilities we hold have prevented our reducing the time required to produce the manuscript, and while continuing to aim to improve in this regard, we observe that for our own research purposes we place heavy reliance on back numbers as well as the most recent issue. It always, nevertheless, of course has particular significance. We have to concede that our coverage is becoming less comprehensive as carbohydrate chemistry on the one hand diffuses still further into neighbouring sciences, and on the other becomes manifestly more complex (compare early volumes of this Report), but we hope we offer a wide-ranging and almost complete record of work published in this field in 1989. We remain indebted to staff of the Royal Society of Chemistry and thank Dr P.G. Gardam and Mr A . G . Cubitt in particular for their cooperation and assistance. R.J.Ferrier April 1991
Contents
Chapter 1
Introduction and General Aspects
1
Chapter 2
Free Sugars
3
1
Theoretical Aspects
3
2
Synthesis Tetroses Pentoses Hexoses Higher Sugars Physical Measurements
9
Isomerisation
10
Oxidation
11
Other Aspects
12
References
13
Glycosides
16
0-Glycosides Synthesis of Monosaccharide Glycosides Synthesis of Glycosylated Natural Products 0-Glycosides Isolated from Natural Products Synthesis of Disaccharides and their Derivatives Hydrolysis and Other Reactions and Features
16 16
2
S-Glycosides
33
3
C-Glycosides Pyranoid Compounds Furanoid Compounds
35
References
44
Oligosaccharides
51
General
51
Chapter 3 I
Chapter 4 1
22 24 25 32
35 41
1..
Carbohydrrrre Chemistry
Vlll
2
Trisaccharides Linear Homotrisaccharides Linear Heterotrisaccharides Branched Hornotrisaccharides Branched Heterotrisaccharides
52 52 52 54 54
3
Tetrasaccharides Linear Homotetrasaccharides Linear Heterotetrasaccharides Branched Heterotetrasaccharides
54 55 55 56
4
Pentasaccharides Linear Pentasaccharides Branched Pentasaccharides
56 56 56
5
Hexasaccharides
57
6
Higher Oligosaccharides
58
References
59
Ethers and Anhydro-sugars
62
1
Ethers Methyl Ethers Other Alkyl and Aryl Ethers Silyl Ethers
62 62 62 64
2
Intramolecular Ethers (Anhydro-sugars) Oxirans Other Anhydrides
64 64 65
References
67
Acetals
69
1
Isopropylidene Acetals
69
2
Benzylidene Acetals
70
3
Other Acetals
71
References
73
Esters
74
Carboxylic Esters Synthesis and Reactions Isolation from Natural Sources
74 74
2
Phosphates and Related Esters
81
3
Sulphonates
84
4
Other Esters
86
References
88
Chapter 5
Chapter 6
Chapter 7 1
80
Contents
ix
Chapter 8 1
2
Halogeno-sugars
90
Fluoro-sugars
90
Chloro-,
92
Bromo-, and Iodo-sugars
References
93
Amino-sugars
95
1
Natural Products
95
2
Synthesis
95
3
Reactions
104
4
Diamino-sugars
106
References
106
Miscellaneous Nitrogen Derivatives
Chapter 9
1
Glycosylamines
ioa ioa
2
Azido-, Azi-, and Diazo-sugars
113
3
Nitro-sugars
115
4
Nitriles, Oximes, and Hydroxylamines
115
5
Hydrazones, Osazones, and Related Heterocycles
118
Other Heterocycles
119
References
120
Thio- and Seleno-sugars
122
References
125
Deoxy-sugars
127
References
132
unsaturated Derivatives
134
1
Glycals
134
2
Other Unsaturated Derivatives
138
References
143
Chapter 10
6
Chapter 11
Chapter 12
Chapter 13
Carbohydrate Chemistry
X
Chapter 14
Branched-chain Sugars
145
1
Compounds with an R-C-0 Branch
145
2
Compounds with an R-C-N Branch
147
3
Compounds with an R-C-H, R-C-R, or C=R Branch
147
References
154
Aldosuloses, Dialdoses, and Diuloses
156
1
Aldosuloses
156
2
Dialdoses
156
3
Diuloses
157
References
157
Sugar Acids and Lactones
158
Aldonic and Aldaric Acids
158
Ulosonic and Ulosaric Acids
160
Uronic Acids
165
Ascorbic Acids
166
References
168
Inorganic Derivatives
171
1
Carbon-bonded Phosphorus Derivatives
171
2
Other Carbon-bonded Derivatives
172
3
Oxygen-bonded Derivatives
173
References
175
Alditols and Cyclitols
177
Alditols Acyclic Alditols Anhydro-Alditols Branched-Chain Alditols Amino-Alditols Polyhydroxyalkyl-Heterocycles
177 177 177 179 179 182
Chapter 15
Chapter 16 1
Chapter 17
Chapter 18 1
Contents
xi Cyclitols
183
References
188
Antibiotics
191
1
Amino-Glycoside Antibiotics
191
2
Macrolide Antibiotics
192
3
Anthracycline and Related Polycyclic Antibiotics
193
4
Nucleoside Antibiotics
195
5
Glycopeptide Antibiotics
198
6
Miscellaneous Antibiotics
199
References
201
Nucleosides
205
Synthesis
205
Anhydro- and Cyclo-nucleosides
208
Deoxynucleosides
210
Halogenonucleosides
212
Nucleosides with Nitrogen-substituted Sugars
214
Thio- and Seleno-nucleosides
216
Nucleosides with Branched-chain Sugars
217
Nucleosides of Unsaturated Sugars, Ketosugars, and Uronic Acids
219
9
C-Nucleosides
219
10
Carbocyclic Nucleoside Analogues
221
11
Nucleoside Phosphates and Phosphonates
222
12
Ethers, Esters, and Acetals of Nucleosides
225
13
Miscellaneous Nucleoside Analogues
227
14
Reactions
227
15
Spectroscopic and Conformational Studies
229
References
229
2
Chapter 19
Chapter 20
xii
Carbohydrate Chemistry
Chapter 21
N.M.R. Spectroscopy and Conformational Features
237
Theoretical and General Considerations
237
Acyclic Systems
238
Furanose Systems
238
Pyranose Systems
240
Di- and Oligo-saccharides and Related Compounds
241
N.M.R. of Nuclei other than 'H and 13C
243
References
244
Other Physical Methods
246
I.R. Spectroscopy
246
Mass Spectrometry
246
X-Ray and Neutron Diffraction Crystallography
247
E.S.R. Spectroscopy
251
Polarimetry, Circular Dichroism, and Related Studies
251
References
251
Separatory and Analytical F-chods
254
1
Chromatogrphic Methods Gas-Liquid Chromatography Thin-Layer Chromatography High.-PressureLiquid Chromatography Column Chromatography Partition Chromatography
254 254 256 256 260 261
2
Other Analytical Methods
261
References
262
Synthesis of Enantiomerically Pure Noncarbohydrate Compounds
264
1
Carbocyclic Compounds
264
2
Y- and +Lactones
267
Chapter 22 1
Chapter 23
Chapter 2 4
...
Contenfs
Xlll
3
Macrolides, Macrocyclic Lactams, and Their Constituent Segments
267
4
Other Oxygen Heterocycles
270
5
Nitrogen Heterocycles
272
6
Acyclic Compounds
274
7
Carbohydrates as Chiral Auxiliaries
276
References
278
Author Index
281
R E P R I N T S
In response to several queries, the situation regarding reprints of chapters of Specialist Periodical Reports titles is that they are not made available because even a relatively small consequent decrease in sales would have a disproportionately large adverse effect on the precarious finances of this specialist series of books.
xiv
Abbreviations The following abbreviations have been used: Ac Ad AIBN A11 BBN Bn Boc Bz Cbz c.d. CI DAST DBU DCC DDQ DEAD DIBAL DMAP DMF DMSO EE e.s.r. FAB GC HMPT i.r. LAH LDA LTBH MCPBA MEM MOM m.s. Ms NBS NIS n.m.r. 0.r.d. PCC PDC PTC PY SIMS TASF
acetyl adenin-9-yl 2,2'-azobisisobutyronitrile ally1 9-borabicyclo[3,3,1]nonane benzyl t-butoxycarbonyl benzoyl benzyloxycarbonyl circular dichroism chemical ionization diethylaminosulphur trifluoride 1,5-diazabicyclo[5,4,O]undec-5-ene dicyclohexylcarbodi-hide
2,3-dichloro-5,6-dicyano-1,4-benzoquinone diethyl azodicarboxylate di-isobutylaluminium hydride 4-dimethylaminopyridine N,N-dimethylformamide dimethyl sulphoxide l-ethoxyethyl electron spin resonance fast-atom bombardment gas chromatography hexamethylphosphorous triamide infrared lithium aluminium hydride lithium di-isopropylamide lithium triethylborohydride 5-chloroperbenzoic acid methoxyethoxymethyl methoxymethyl mass spectrometry methanesulphonyl N-bromosuccinimide N-iodosuccinimide nuclear magnetic resonance optical rotatory dispersion pyridinium chlorochromate pyridinium dichromate phase transfer catalysis pyridine secondary-ion mass spectrometry tris(dimethy1amino)sulphonium difluorotrimethyl silicate
xv
Carbohydrate Chemistry
xvi
TBDMS Tf Tfa T FA THF
ThP TMS TPP TPS Tr Ts U
t-butyldlmethylsilyl trifluoromethanesulphonyl trifluoroacetyl trlfluoracetlc acid tetrahydrofuran tetrahydropyranyl trlmethylsilyl trlphenylphosphlne trl-lsopropylbenzenesulphonyl triphenylmethyl toluene psulphonyl uracil-1-yl
1
Introduction and General Aspects
The 1989 literature of mono- and oligo-saccharide chemistry illustrates continuing general advances on all fronts with strong emphasis on the development of synthetic methods and their application to problems with origins in biology. Many examples of this are clearly given in the Sections on oligosaccharides, nucleosides and antibiotics, while the role of carbohydrate chemistry in general organic chemistry is well illustrated by the many complex conversions of sugar derivatives into enantiomerically pure natural substances of a non-carbohydrate nature. Once again, however, biological issues - in this case medicinal - are commonly the driving forces behind the work. Relevant reviews have appeared on recent developments in modern aspects of synthetic carbohydrate chemistry,' stereoselective chemical syntheses of sugar derivatives,2 syntheses of unusual sugars by combinations of chemical and enzymic methods,3 and purely enzymic syntheses.4 Baer has surveyed recent synthetic studies of nitrogen-containing, deoxygenated sugars and related compo~nds,~ and more specifically, the use of allylboronates in the synthesis of carbohydrates," and the conversion of 7-oxanorbornenes to sugars and their derivatives' have been reviewed. The strategies for bonding sugars to proteins have been covered in a survey of neoglycoproteins,* and two Chinese reports have dealt with the applications of carbohydrates in the synthesis of other natural products,* and the effects of ultrasound on the reactions of derivatives of B-D-ribofuranose.lo References 1 2
1989, 2 (Stereosel. Synth., Pt. B), 209 (Chem. Abstr,, 189, 111,134 657). T. Mukaiyama, F.E.C.S. Int. Conf, Chem. Biotechnol. Biol. Act. Nat, prod.. i P r oc.1. 3rd, 1985 (Publ. 1987), 1, 1 (Chem. Abstr., 1989, 110, 75 8 9 8 ) . 2 . J . Witczak, Stud. Nat. Prod, Chem,,
Carholiydrate Chemistry
2 3
H. Wong, D. G. Drueckhammer, J . R. Durrwachter, B. Lacher, C. J. Chauvet, Y. F. Wang, H. M. Sweers, G. L. Smith, L. J. S. Yang, and W. J. Hennen, ACS SymD. Ser,, 1989, 386 (Trends Synth. Carbohydr. Chem.), 317 (Chem. Abstr,, 1989, 111,58 1 6 5 ) . G . M. Whitesides and M. J. Kim, New Methods Drug Res., 1988, 2, 1 (Chem. Abstr., 1989, 111,195244). H. H. Baer, Pure AD^. Chem., 1 9 8 9 , 61,1217 (Chem. Abstr., 1989, C.
m,
233 376) .
9
W. R. Roush, ACS S V ~ D .S e r . , 1989, 386 (Trends Synth. Carbohydr. Chem.), 242. (Chem. Abstr,, 1989, 111,58 1 6 2 ) . P. Vogel, Y. Auberson, M. Bimwala, E. De Guchteneere, E. Vieira, and J. Wagner, ACS SvmD. Ser., 1989, 386 (Trends. Synth. Carbohydr. Chem.), 197 (Chem. Abstr,, 1989, 97 621. F. J. Buchholzer and J. M. J. Tronchet, EDitheor. Klin. Farmakol, Farmakokinet., Int. Ed,, 1988, 2, 1 7 (Chem. Abstr . 1989, 110, 17 9 2 4 ) . C. Han and J. Du, Huaxue Shiii, 1988, lo, 224 (Chem. Abstr,, 1989, 110,
10
B. H. Han and G. M. Kim, Chunrrnam Kw-hak Yonmchi, 1987, 14,70 (Chem.
u,
8
57 9 2 6 ) .
Abstr,, 1989,
111,23
807).
2
Free Sugars
1 Theoretical Asuects The historic development of the understanding of carbohydrate stereochemistry has been briefly reviewed,' and a lecture with four references on the energetics and geometry of furanoid systems has been published. Two complementary descriptions of the conformational behaviour of furanose rings have been presented: (i) by quantum-mechanical energy calculations; and (ii) by a geometrical model of pseudorotation in five-membered rings.2 Molecular dynamic simulations of 8-D-ribofuranose and 2-deoxy-fl-D-erythropentofuranose in solution showed that their hydroxy groups are better hydrogenbond donors, but worse acceptors, than water and that the ring oxygen atoms accept even less hydrogen-b~nding.~ In a similar study with a-D-glucopyranose,solvation was found to have little effect on the preferred conformation of the sugar molecule! According to molecular dynamics simulation experiments both glucitol and mannitol have bent energy minima in vacuo; in aqueous solution mannitol is also bent, but glucitol prefers a planar zig-zag conformation? A computer program for molecular modelling which is part of the 3DMolmaster system has been used to carry out computations of the energetics of monosaccharide, polysaccharide and glycoside conformations.6 By use of the MM2 method a conformational energy map of 8-laminarabiose has been constructed which makes allowance for the presence of several inter-converting conformers ("structural relaxation"). The finding that this map differs from one based on a fixed structure indicates the importance of "structural relaxation" within the glucose residue? Newly developed computational methods for describing and understanding molecular motion and flexibility have been employed to describe the "relaxed" potential energy surface of maltose, which was chosen as a prototypical carbohydrate system? Calculations to give solvent-specific"relaxed" energy surfaces have been applied to carbohydrate molecules, in particular to a mannobiose, with the aim of providing new insights into the conformational properties of sugars in solution? By an examination of optical rotation and n.m.r. measurements, a picture has
Carbohydrate Chemisrry
4
been developed of the potential energy surfaces of cellobiose and maltose in aqueous solution."
2 Svnthesis The enzyme-catalysed synthesis of mono-, oligo- and poly-saccharides has been covered in a major review with 310 references," and a review has appeared on the synthesis of saccharides uniformly labelled with 14C,starting from D-[U-'4C]glucose.'2 The distribution of products of the formose reaction carried out in aqueous DMF has been studied. Considerable control was possible by adjustment of the water content. When, for example, formaldehyde was heated at 75°C for 1 hour with triethylamine and thiamine hydrochloride in 8:l DMF-H,O, DL-2-C-
Ho~2-& c -0
hydroxymethyl-3-pentulose,characterised as the tetraacetate (l), was produced in 28% yield. In the absence of water, the major products are dihydroxyacetone and DLglvcero-tetrulose (cf Shigemasa et al., Carbohvdr. Res., 1987,162, Cl).13 In the radiation-initiated formose synthesis in aqueous solution, pentaerythritol and ethylene glycol were the main products, their ratio depending on the initial formaldehyde ~0ncentration.l~ An efficient new procedure for the general ascent of the aldose series, which lends itself to repetitive application and gives an all-anticonfigurated chain, is
shown in Scheme l.15 The usefulness of this approach is further extended by the epimerisation referred to in Section 4, Scheme 11, of this Chapter. A new multigram method for trapping aldoses in their aldehydo-form is exemplified in
2: Frw Sugars
,
N.OMe
CHzOH
AcOf A C
i,u
___f
T ui
HO OAc OAc
OH
AcO
i"
5
OAc OA c
CH20Ac
CH~OAC
ReogW& : i, NH30MeCL, Py ;k , A c 2 0 , P y , d ,0, , Me2S
Scheme 2
Scheme 2. It exploits the discovery that oxime ethers are cleaved by ozone to give the parent aldehydes in high yields.16 In a study of the hydrolysis of cellulose to D-glucose by dilute sulphuric acid, the reversion products which represent 10% of the total yield have been analysed. and -furanose The main components (>50%) were 1,6-anhydro-fl-D-gluco-pyranose (7:3). Isomaltose and gentiobiose were the major disaccharides, and (1+2)- 2nd (1-.3)-linked a-disaccharides predominated over their 4-anomers.l7
2.1 Tetroses.- The D- and L-erythrose derivatives (3) and (4), respectively, are available from chlorobenzene by the enantiodivergent route shown in Scheme 3, 0
OH
0
(2)
Reagent6 i PseLLCLOmona5 iV,
cH2=PPh,,
V,
LAH
put&,
, VL, NODH4, V h ,
0
x
u ,M ~ ~ Y O M ~ ) ,TSOH, ,
LU,
(3)
,
DlBAL
Scheme 3
(4)
the optically pure microbial oxidation product (2)." Small but significant asymmetric induction was observed in the aldolisation of the glycolaldehyde derivative (5) bearing an enantiomerically pure acetal-type protecting group ROCH,CHO
(5)
ROc H ~ HC(0H)
cH (0R) CH o
(61 0-
RecLged L, E t 3 N or ca(OH]z
Scheme
4
(Scheme 4). The L-erythro-, D-erythro-, L-threo- and D-threo-isomers (6), present as a complex mixture of hemiacetals, were formed in a combined yield of 40-60% in the ratio 33:30:21:16. This was determined after reduction to the corresponding tetritols as mentioned in Chapter 18.19 2.2 Pentoses.- 3-Q-Hexopyranosyl-D-arabinoses, such as compound (7), have been prepared by Zemplen degradation of aldonobiononitrile octabenzoates with
Carbohydrate Chemistry
6
AcOQ2 CH20H
(10) R'= R4= H, R Z = O P r 1 , R 3 = B r
or R' = OPT', R'= R3= H , R4 = O r
(7)
R4
(1+4) glycosidic linkages. The products were obtained as 4)-pyranoselfuranose mixtures and were reduced and benzoylated to the corresponding hexopyranosy1-Darabinitol octabenzoates for easy characterisation by n.m.r. spectroscopy.m The conversion of derivatives of aldopentoses (e.g.,arabinose) to stereoisomeric derivatives of pentonolactones (e.g.,Clyxonolactone) is covered in Chapter 16. 2.3 Hexoses.- A convenient procedure for the synthesis of D-[1-"C]gluco- and D-[1-"C]galacto-pyranose from D-arabinose and D-lyxose, respectively, and H"CN uses diborane as highly effective and time saving reducing agent?l UDP-[6-3H]galactose of high specificity has been obtained by oxidation of the C-6 hydroxymethyl group of UDP-galactose by galactose oxidase and subsequent reduction with NaBT,. Radiolabelled UDP-N-acetylgalactosaminehas also been prepared by this method?2 Economical access to [6-3H]-labelled Ggalactose (8) and Gfucose (9) starting from D-galactose is offered by the reaction sequence CHO
CH"CH2
&+ Reaqents
i , C H = = PPh3,
u, HOAc,+O,
UL,
w , 03, MezS , v, MQ2CD, H2S04,GcS04,VL,
OH H O i CHTOH
NaBT4, TS CL, Py ,vd,
KSBz,DMF,
Vub,
Scheme 5
presented in Scheme 5.= A new tritiation method has been employed to synthesise [2,6,6 '-3H]-2-deoxy-D-glucose from a mixture of protected bromodeoxyglucose derivatives (lo).%
.'L/\CH20Bn
Bn0
0 Bn
Brio@
CHH* 0Bn
OBn
Rec~ger~ts : L, BbtOMgEr, CH2-
Scheme 6
(12)
2: Free Sugars
7
2,3,4,6-Tetra-Q-benzyl-D-glucopyranose (11) was converted to 1,3,4,5-tetra-Qbenzyl-L-sorbose (12) in 94% yield in the presence of bromomagnesium salts of certain phenols and alcohols in dichloromethane. This reaction for which there is no precedent involves, at least formally, a hydride transfer from C-5 to C-1of the starting material, a possible mechanism being indicated in Scheme 6.25 A selectively protected fucose derivative (14), suitable for use in oligosaccharide synthesis, has
OH
OH
(14)
(13)
been prepared from the known D-altrose derivative (13) in ten conventional steps (15) and 33% overall yield.% 3,4,5,6-Di-~-isopropylidene-2-~-methyl-quebrachitol served as the starting material for a multi-step synthesis of the peracetylated D- and Lgalactofuranosides (18) and (19), respectively, as outlined in Scheme 7. The key step was the high yielding (>94%) Baeyer-Villiger oxidation of ketone (16) to the hemiacetal-lactone (17).” BnO
OMe
‘ 0
OAc
(19)
Reagents L, B n B r , N a H , D M F , u , M e O H , T s O H VL,
OH LU,
BzCL,py,
W , PCC
, V, M C P Q A , N a H C 0 3
I
HC(OM&, McOH,TsOH, VLL, NaGH4
Scheme 7
In a newly patented process L-rhamnose has been produced from rhamnan sulphate by treatment with strong acid resin, followed by heating.= The enantiomerically pure oxabicycloheptane derivative (20) and its antipode, previously used in a total synthesis of D- and L-ribose (see Vol. 22, Chapter 2,
R e q d
L, F ~ C C O N M ~ S , u, L MCPBA ~
, a ,A(200’C).
W, MeOH,OH-,
Scheme 8
v, MeOH,H+, vi,LAH, “ti, H30’
Curbohydrcrte Chemistry
8
Scheme l), were the starting compounds for new total syntheses of Ghexoses. the silyl enol ether (21) to Scheme 8 shows the steps leading from ketone (20) L-allose. By a slightly different reaction sequence the enantiomer of compound (20) was converted to L-tal0se.2~
2.4 (GD-Hepp) (23) was Higher Sugars.- L-glvcero-D-manno-Heptopyranose the main product of the hydroxymethylation of the mannose-derived aldehyde (22) with (isopropoxydimethylsily1)methylmagnesium chloride, followed by deprotection, the high stereoselectivity being consistent with the Cram cyclic model for 1,2asymmetric induction?' Further use was made of the 7-oxabornane silyl enol ether (21) of Scheme 8 in the crossaldolisation with 2,3-Q-isopropylideneD-glyceraldehyde to give octoses as shown in Scheme 9. Under catalysis by TiCl,
the condensation product (24) was formed exclusively. This was transformed, by methods similar to those depicted above in Scheme 8, to the octofuranose derivative (25) and hence in seven steps to a mixture (26) of D-erythro-D-m- and D-eIythroG&-octose derivatives. The enantiomer of silyl enol ether (21) gave analogously the D-threo-L-&- and D-threo-D-&-isomers (27)?'
OH
""0 OSL?
'
In accordance with Kishi's rule osmylation of the carbohydrate derived unsaturated ester (28) gave the D- and L-threo-D-gluco-confguratedproducts (29) and (30) in the ratio 9 1 (Scheme lo), and similar selectivity was observed in the
2: Free Sugars
9
osmylation of the manno analogue of alkene (28). In breach of Kishi's rule, however, methyl 3,5-~-benzylidene-6,7-dideoxy-1,2-~-isopropylidene-a-D-~luco-6octenofuranuronate (31) afforded the 4-L- and a-D-threo-derivatives (32) and (33) in the ratio l:2.32 The X-ray structure of the new compound (32) is referred to in Chapter 22. The selectivities of the osmylations represented in Scheme 10 and of
two similar examples were greatly enhanced on addition of the "matching" Sharpless chiral auxiliary, either dihydroquinine p-chlorobenzoate or dihydroquinidine p-chlorobenzoate [& (29):(30) = 20.5:1].33 3 Phvsical Measurements
As part of a study of the stability of enzymes in aqueous sugar solutions the solutesolvent interactions and water activities of small carbohydrates (D-glucose, D-galactose, D-fructose, D-glucitol, D-mannitol, sucrose and maltose) have been examined. D-Fructose was found to provoke the most noticeable perturbation of water structure, to cause denaturation (s, of lysozyme), and to lower the storage YADH).34 Based on the finding that the relative stability of enzymes (u, increments of the sound velocities in aqueous sugar solutions (ribose, sucrose, raffinose and six others) correlate with the number of equatorial hydroxy groups in the solute molecules, the suggestion was made that molecules with a large proportion of equatorial hydroxy groups are particularly effective in stabilising the structure of water?' The enthalpies of dilution at 25°C of binary and tertiary aqueous solutions containing the isomeric disaccharides cellobiose, maltose, and trehalose, were investigated, and an empitical relationship between saccharide solvation and solute solute interactions was deduced.% The thermochemical properties of aqueous solutions of small carbohydrates as glasses and rubbers at sub-zero temperatures have been measured by differential scanning calorimetry (DSC)?' and the thermodynamic properties of alcohols and monosaccharides in aqueous biuret solution at 25°C have been determined by flow microcalorimetry?s By use of DTG
10
Carbohydrate Chemistry
and DSC-DTA techniques endothermic and exothermic reaction temperatures and enthalpies between 25 and 700°C have been recorded for 24 typical sugars. These data yield important information pertaining to the relation between molecular structure and thermal behavi0ur.3~ The dehydration of xylose in aqueous solution catalysed by a Cp,TiCl,protoporphyrin complex immobilised in a polyacrylamide gel has been studied, and rate constants activation parameters for this process have been determined,m and a thermodynamic investigation of the hydrolysis cf sucrose by microcalorimetry and h.p.1.c. has been reported!l In an investigation of the kinetics of isotope exchange between [1-3H]saccharidesand hydrogen on Pd catalysts it was found that the compounds examined could be arranged in a sequence of decreasing hydrogen-exchange rate which agreed with the order of decreasing relative mobility coefficients for the 1-H atoms!2 Widely different polystyrene affinities are displayed by methyl glycopyranosides, deoxysugars and glucooligosaccharides as was demonstrated by measuring the coefficients for partition between polystyrene gel and aqueous solvent systems for these three groups of carbohydrates. In combination with the accessible surface data of sugar molecules, the &, values collected suggest that the hydrophobicity of sugars is determined, inter alia, by their surface area, the hydration effect of the hydroxy groups and molecular planarity and rigidity!3 The non-isothermal kinetic parameters for the kinetically possible thermal decomposition steps of hydrated iron(II1) and holmium(1II) gluconates were evaluated. The values obtained for the Fe(III) derivative were sensitive to the rate of heating? The association constants for the interaction of CaCl, and KCl with a number of standard monosaccharides are referred to in Chapter 17, and three kinetic studies of the anomerisation of D-glucose are covered in the next Section of this Chapter.
4 Isomerisation
A full report has been published on the newly discovered C-2 epimerisation of aldoses promoted by Ni(II) diamine complexes. The intermediate N i p ) complex containing both diamine and sugar was investigated by use of 13C-enriched A D-glucose and by extended X-ray absorption f i e structure ( E M S ) methods!' procedure has been described for the epimerisation and rearrangement of D1:l mixture of starting material and D-[2-'3C]mannose.46 [l-'3C]glucose to give a The isomerisation of epimeric pairs of aldohexoses and the related ketohexose by aqueous KOH has been examined in detail. It is proposed that structures with the
2: Free Sugars
11
hydroxy groups at C-1, -2 and -3 in ax/eq/ax or eq/ax/eq arrangements form particularly stable hydrogen-bonded ions or complexes, and that this influences the aldose ketose equilibrium:' Inversion a to the masked carbonyl group of sugar thiazoles by oxidation reduction, as exemplified in Scheme 11, promises to be a very useful extension of
-
-a&.$:
L, K:>SLMQ
; u ,lKMnO.+;'U, K-Seloctrcde
SGhWlle 11
the thiazole method of ascent in the aldose series which is described in Section 2 of this Chapter (see Scheme 1).48 The synthesis of 6-deoxy-L-arabino-hexulose by isomerisation of L-rhamnose is covered in Chapter 12. The "Glukometer GKM Ol", an analytical tool based on a 8-D-glucose-specific oxidase, has been used to measure the effects of pH, water content, water activity, and temperature on the mutarotation equilibrium of D-glucose. The equilibration rate showed a minimum value at pH 3 and increased with increasing water-content and -activity. The temperature dependence could be described by the Arrhenius equation, and an activation activity of 66.2 kJ mol-' was cal~ulated:~Similar experiments are reported in a Japanese publication?' The mutarotation of a- to 8D-glucose in DMSO over an alumina catalyst at 40°Chas been investigated under various pressures in the range 0.1-90 MPa and with initial a-D-glucose concentrations of 2.8-12.0 x lo2mol dm". The kinetic parameters (adsorption coefficients, rate constants for the surface reactions) were evaluated as a function of pressure. In sharp contrast to the negative adsorption volumes observed under homogeneous catalysis, fairly large positive activation volumes were found for the surface reactions, for which a formyl rotation step is thought to be responsible?* An n.m.r. study of the kinetics of anomerisation of D-talose is covered in Chapter 21. 5 Oxidation
The mechanism of oxidation of D-glucose in alkaline media at gold electrodes has been investigated. Experiments using cyclic voltammetry at a rotating disc electrode indicated that the mass-transport-limited reaction proceeds via an enediol intermediate hydrogen-bonded to catalytic hydrous gold oxide. The enediol is
Carbohydrate Chemistry
12
cleaved oxidatively and the primary hydroxy group is oxidised at the same time.52 In continuation of earlier work (Vol. 22, Chapter 2, ref. 53), three papers on the oxidation of monosaccharides and model compounds by vanadium(V) in the presence of perchloric acid have been published by Finnish researchers. From their results they conclude that the oxidations proceed in three steps and involve open chain forms. In the rate determining step a carbon-bound hydrogen atom is transferred from the substrate to V(0H);' as the main oxidising species. Oxidation is facilitated by a neighbouring carbonyl group which stabilises the initially formed carbon-centred carbohydrate radical. The experimental order of reactivity was acetoin>hydroxyacetone > >D-gluconic acid >standard ketohexoses> > standard aldopentoses>standard aldohexoses~D-glucit01;~~ D-fructose and L-sorbose gave dicarbonyl compounds as the primary products54and aldopentoses furnished aldotetro~es.5~ A spectrophotometric study of the oxidation of aldoses by Ce(IV) in dilute sulphuric acid showed that the reactions are first order in both Ce(1V) and sugar. Similar kinetics for D-glucose, D-ribose and D-erythrose indicate a common oxidation mechanism involving cyclic (furanoid or pyranoid) forms in the rate determining radical formation step. Dissimilar kinetic and thermodynamic data for glyceraldehyde, on the other hand, point to a different oxidation pathway for the t r i ~ s e .Formation ~~ of an intermediate free radical species in the rate determining step has also been proposed for the Ce(1V) oxidation of L-rhamn0se.5~ The kinetics of oxidation of D-glucose, D-galactose and D-fructose by K2Cr207have been studied by U.V. spectroscopy, and oxidation mechanisms were discussed. Whereas first order dependency in oxidant and substrate was readily demonstrated, the order with respect to [H+] was complex?* In the oxidation of monosaccharides by Mn(VI1) in acidic pyrophosphate solution the orders of reactivity were D-galactose>D-glucose>D-mannose and L-arabinose>D-xylose>Dribose in the aldo-hexose and -pentose series, respectively, and it is thought that the relative configurations at C-2 and C-3 affect the reaction rate.59 The oxidising action of hexachloroiridate on D-ribose, D-erythrose and DLglyceraldehyde has been studied and the results compared with those reported for D-glucose.60 6 Other Asuects
D - g l u c o - L - ~ - 3 - O c t u l o s e(34), the first naturally occurring 3-octulose reported, was identified as the main constituent in aqueous extracts from Laurus nobilis leaves and buds:* and evidence has been presented that 1-deoxy-D-threo-pentulose
2: Free Sugars
13
is a biosynthetic precursor of pyridoxal (vitamin B,).62 A review with 32 references has been published on capto-dative radical stabilisation and its importance in organic synthesis and especially in the radical halogenation of carbohydrate^.^^ The radiolysis-induced degradation of 2-deoxy-D-erythro-pentose has been investigated. In the presence of iron ions prolonged post-irradiation release of malondialdehyde, a major degradation product, was observed. It is thought that this is due to iron ions catalysing the formation of hydroxy radicals from H202 and stimulating the breakdown of intermediate carbohydrate-derived radical species.64 The conversion of fructose and glucose and their isopropylidene derivatives into hydrocarbons over zeolite catalysts at 2350°C has been examined,6’ and the decarbonylation - dehydration of ketoses mediated by complexes of rhodium and palladium has been reported.66 Procedures for the selective reductive cleavage of C - C bonds in sugars under catalysis by RuH2(PPh3), is referred to in Chapter 18.
HO
(34)
HO
The cyclic tetramer (35) acting as a lipophilic host solubilises certain sugars glucose) are not accepted at all. The relative affinities of various hexoses with compound (35) have been explained in terms of stereochemistry at C-3 and C-4 and lipophicility of the substituents at C-2 and C-6.6’@
(s, fructose) as polar guests in CCl,, whilst other sugars (e&,
References 1
2 3 4 5 6 7 8
9 10 11
R.S.Schallenberger and W.S. Wienen, J. Chem. Educ., 1989,~,67 (Chem. Abstr., 1989,110. 113 775). J. Wiorkiewicz-Kuczera, Zaeadnienia Biofiz. WsDolczesnei, 1987, 147 (Chem. Abstr., 1989,110. 154 699). B.P. van Eijck and J. Goon, J. Mol. Struct., 1989,195.133 (Chem. Abstr., 1989,111.233 391). J.W. Brady. J. Am. Chem. SOC, 1989,111.5155. J.R. Grigera, J. Chem. SOC.,Faradav Trans. 1, 1988,84- 2603 (Chem. Abstr., 1989,110.173 569). S. Abe, Kaiho-Kaeaku PC Kenkvukai, 1988, 83 (Chem. Abstr., 1989,110.135 604). H. Kobayashi, S. Kitamura, T. Ozaki, M. Yamaguchi, and T. Kuge, Chem. J3cDress, 1989,e 213 (Chem. Abstr., 1989,l&58 198). V. Tran, A. Buleon, and k Imberty, Biomlymers, 1989,28,679(Chem. Abstr., 1989,=,23 818). J. Jimenez-Barbero, 0.Noble, C. Pfeffer and S. Perez, New J. Chem., 1988,12,941 (Chem. AbStr., 1989,111.39 732). E.S. Stevens and B.K. Sathyanarayana,J. Am. Chem. SOC.,1989,111.4 149. E.J. Toone, E.S.Simon, M.D.Bednarski, and G.M.Whitesides, Tetrahedron, 1989, 5365.
14 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 35 36 37 38 39 40 41 42 43
44 45
46 47 48 49 50 51 52 53 54
55
Carbohydrute Chemistry
z,
L. Skala, Radioisotom, 1988, 49 (Chem. Abstr., 1989,110.213 184). Y. Shigemasa, T. Ueda,and H. Saimoto, J. Carbohvdr. Chem., 1989,S, 669. S. hie, Carbohvdr. Res., 1989,190.23. A. Dondoni, G. Fantin, M. Fogagnolo, A. Medici, and P. Pedrini, J. Ore. Chem., 1989, 693. D.J. Weitz and M.D. Bednarski, J. Ore. Chem., 1989, 4957. R.F. Helm, R.A. Young, and AH. Conner, Carbohvdr. Res.,1989,185,249. T. Hudlicky, H.Luna, J.D. Price, and F. Rulin, Tetrahedron Lett., 1989,g,4053. C.R. Noe, M.Knollmuller, and P. Ettmayer, Liebis Ann. Chem., 1989,637. N.B. D’Accorso and J.M.E. Thiel, J. Carbohvdr. Chem., 1989,8,743. M. Tada, A. Oikawa, T. Matsuzawa, M. Itoh, H. Fukuda, K. Kubota, H. Kawai, Y. Abe, H. Sugiyama, et al., J. Labelled Comud. Radiouharm., 1989,22, 1 (Chem. Abstr., 1989,111.39 692). B. Fudem-Goldin, P. Voulalas, and G. Orr, J. Biochem. Biouhvs. Methods, 1988, 199 (Chem. & 1989,110.91 605). H. Lay, J. Lehmann, L. Ziser, and W.Reutter, Carbohvdr. Res., 1989,195. 145. J. Deschamps, B. Rousseau, and J.P. Beaucourt, J. Labelled ComDd. Radiouharm., 1988, 1281 (Chem. Abstr., 1989,110.193 205). G. Casiraghi, G. Rassu, M. Cornia, and F. Nicotra, J. Chem. SOC..Chem. Commun., 1989,1242. A. Aqeel, K-I. Sato, H. Hashimoto, and J. Yoshimura, J. Carbohvdr. Chem., 1989,s405. N. Chida, M, Suzuki, M. Suwama, and S. Ogawa, J. Carbohvdr. Chem., 1989,S, 319. M. Takemura, Y. Tateno, M. Fuse, and H. Oba, Jm. Kokai Tokkvo Kaho JP 63,145,293.rS8.145.293L (Chem. Abstr., 1989,J l 173 691). Y. Auberson and P. Vogel, Helv. Chim. Acta, 1989,22,278. G.J.P.H. Boons, PAM. van der Klein, G.A. van der Mare1 and J.H. Boom, Recl. Trav. Chim. Pavs1988,107,507(Chem. Abstr., 1989,110.95653). S.Jeganathan and P. Vogel, J. Chem. Soc.. Chem. Commun., 1989,993. J.C. Barnes, J.S. Brimacombe, and G. McDonald, J. Chem. SOC..Perkin Trans. 1,1989,1483. J.S. Brimacombe and G. McDonald, Carbohvdr. Res., 1989,194,c4. M. Mathlouthi, V. Larreta-Garde, Z.F. Xu and D. Thomas, J. Carbohvdr. Chem., 1989,S, 233. H.Uedeira and M. Ishimura, Bull. Chem. SOC.Jun., 1989,62- 574. S.H. Gaffney, E.Haslam, T.H. Lilley, and T.R. Ward, J. Chem. SOC..Faradav Trans. 1, 1988,B 2545 (Chem. Abstr., 1989,110,24 176). H. Levine and L. Slade, J. Chem. Soc., Faraday Trans. 1, 1988, 2619 (Chem. Abstr. 1989,110.39 263). G. Barone, G.Castronuovo, P. Del Vecchio, V. Elia, and M.T. Tosto, J. Solution Chem., 1988, 925 (Chem. Abstr., 1989,109.238360). M.C. Ramos-Sanchez, F.J. Rey, M.L. Rodriguez-Mendez, F.J. Martin-Gil, and J. Martin-Gil, Thermochim. Acta, 1988,j34,55(Chem. Abstr., 1989,110,154 695). G.P. Potapov, V.I. Krupenskii, and M.I.Alieva, Izv. Uvssh. Vchebn. Zaved.. Khim. Khim. Tekhnol., 1987.30- 26 (Chem. Abstr., 1989,110. 173 566). R.N. Goldberg, Y.E. Tewari and J.C. Ahluwalia, J. Biol. Chem., 1989,264.9901 (Chem. Abstr., 1989, 111.195 275). G.P. Akulov, V.G. Kayumov, E.V. Snetkova, and Yu L. Kaminskii, Radioisotom 1988, 128 (Chem. Abstr., 1989,111.7 687). Y. Yano, K. Tanaka, Y. Doi, and M. Janado, J. Solution Chem., 1988,u 347 (Chem. Abstr.. 1989, 110, 154 739). 285 (Chem. Abstr., P.G. Schullerus,S. Plostinaru, and A. Contescu, Thermochim. Acta, 1988, 1989,110.127 454). T.Tanase, F. Shimizu, M. Kuse, S. Yano, M. Hidai, and S. Yoshikawa, Inora. Chem., 1988,2114085 (chem. Abstr., 1989,110,8 495). S.Yano and T. Tanase, Jun. Kokai Tokkvo Koho JP 63 77.893 (Chem. Abstr., 1989,110,173 689). H.S. El Khadem, S. Ennifar, and H.S. Isbell, Carbohvdr. Res., 1989,185,51. A. Dondoni, G. Fantin, F. Fogagnolo, k Medici, and P. Pedrini, J. Om.Chem., 1989, 702. J. Vogel, G.Westphal, and C. Pippig, Nahrung, 1988, 709 (Chem. Abstr., 1989,110.8 498). R. Nagata and S. Gondo, KaPaku Koeaku Ronbunshu, 1988,l4- 836 (Chem. Abstr., 1989,111,7 686). M. Sato, J. Nakatani, S. Ozawa, and Y. Ogino, m u o n Kaaaku Kaishi, 1988, 1794 (Chem. Abstr., 1989,Ilo. 115 202). LA.b r e w and D.C. Johnson, J. Electroanal. Chem. Interfacial Electrochem., 1989,262.167 (Chem. & 1989,110.239 089). P.O.I.Virtanen, E. Oikarinen, and H. Nevala, J. Carbohvdr. Chem., 1989,Q 313. P.O.I.Virtanen, E. Oikarinen, and A. Yli-Pyky, Finn. Chem. Lett., 188, fi 139 (Chem. Abstr., 1989, 110.213 202). P.O.I. Virtanen, H.Nevala, and S. Pohjola, Finn. Chem. Lett., 1988,& 109 (Chem. Abstr., 1989,110, 213 201).
a
a,
a
-
a
2: Free Sugars 56 57 58 59
60 61 62 63
64 65 66 67 68
15
KK Sen Gupta, S. Sen Gupta, and A. Mahapatra, J. Carbohvdr. Chem., 1989,& 713. A. Kale and R.C. Nand, Acta Cienc. India. Chem., 1987-3l 178 (Chem. Abstr., 1989,111.154 242). M.P. Alvarez Macho, An. Quin.. Ser. A, 1989,85, 72 (Chem. Abstr., 1989,111. 195 258). R. Lindroos-Heinanen and P.O.I. Vinanen, Finn. Chem. Lett., 1988,lS- 117 (Chem. Abstr, 1989, 110, 213 236). C K Sen Gupta, U. Chatterjee and A. Mahapatra, J. Chem. Res. Svnop., 1988, 260 (Chem. Abstr., 1989,110,24 166). K. Sakata, H. Hagiwara, k Yagi, and K. h a , Aeric. Biol. Chem., 1989, 53, 2539. R.E. Hill, B.G.Sayer, and LD. Spenser, J. Am. Chem. SOC.,1989,111, 1916. L. Somsak, Maw. Kem. Lapia, 1988,43,219 (Chem. Abstr., 1989,110, 135 570). K.H. Cheeseman, A. Beavis, and H. Esterbauer, Biochem. J., 1988,252.649 (Chem. Abstr., 1989,110. 173 568). M.I. Haniff and L.H. Dao, Apul. Catal., 1988,39,33 (Chem. Abstr., 1989,110, 8 490). M.A. Andrews, Oreanometallics, 1989,8, 2703 (Chem. Abstr., 1989,111,214 830). Y. Tanaka, Y. Ubukata, and Y. Aoyama, Chem. Lett., 1989, 1905. Y.Aoyama, Y. Tamaka, and S. Sugahara, J. Am. Chem. SOC., 1989,111. 5397.
3
GIycos ides
1
0-Glvcosides
1.1 Svnthesis of Monosaccharide G1vcosides.- A new procedure for glycosylatinq unreactive alcohols or phenols involves the treatment of perbenzylated S-phenyl 1-thioglycoside sulphoxides with triflic anhydride followed by the hydroxy compounds at -78°C. The a,@ ratios depend strongly on the solvent, and the procedure appears to be the first to allow the direct N-glycosylating of amides An entirely novel approach to glycosylation uses glycosylideneaziridines which can be oxidised to the relatively unstable diazirines from which glycosylidene carbenes are produced on warming to room temperature. In the presence of alcohols these give glycosides by insertion reactions (Scheme 1); attempts to
.
Reaged3
L, MSCL,Et3N
,iL, N H 3 , MeOH, iu, Dr2,Et3N, MeOH ,LV, PrLOH
Scheme 1
repeat these processes with furanoid analogues were not Glycosyl carbonates treated with alcohols in the presence of g-toluenesulphonic acid afford a new way of making qlycosides,3 and a more sophisticated, related method for making cyclic glycosides involves acylation of anomeric hydroxyl groups followed by Tebbe methylenation of the resultant esters and ring closures (Scheme 2).4 l-Q-Acetyl-2,3,5-tri-Q-benzyl-~-D-ribofuranose can be converted into a-glycosides with good stereoselectivity (Scheme 3 ).5
2-Chloro-1,1,2-trifluoroethyl a-D-glucopyranoside was prepared and found to inhibit yeast a-glucosidase irreversibly, probably because the released 2-chloro-1,1,2-trifluoroethanol
3: Glycosides
17
decomposed to hydrogen fluoride and 2-chloro-2-fluoroacetyl fluoride which acylates the nucleophilic centre of the enzymic
R e a g d i, (c~),T'(u)[uI,-ALMc)
;i i,
x2, K
O B ~
Scheme 2
active site.' Tetra-Q-benzyl-a-D-glucopyranosyl chloride has been used to prepare (1R12R_) and (1~,2S_)-2-hydroxylcyclohexyla-D-
-
I 6n0 R Q , ~ ~ W & S : ,.i
I OBn ROTPlS,SnCL+, S ~ - L ( O T F ) ~ , L C L O ~
Scheme 3
glucopyranoside (from tran~-1,2-dihydroxycyc1ohexane),' and 3iodopropyl a-D-glucopyranoside tetrabenzoate has been made from the corresponding pentabenzoate and converted into the uridine diphosphate glucose analogue (l).'
A reviet on free r dical reactions has included a description of the synthesis of 2-deoxy-p-D-glycosides,' and an extension of work referred to above' has used an interesting new glycosylation method involving thionoaldonates to obtain a 2,6dideoxy steroidal glycoside (Scheme ,).lo A further novel and general route to 2-deoxyglycosides starts with 2-deoxy-2-
18
Cmbohydrute Chemistty
M=otJ .
05iPh,l3~~'
_ ,
L u .
'cozn
__L_+
'S &O-Sterold
(4
0M e
R e a gents : i, DCC, steroid ; u , M
Q
Z,S.5
Meo~o-~,,,
iri-v
OMe
~ b a O M e ; &, LiBHEtJ , M e 1 ; &, D a 4 N f ;v, AqBF4
4
Scheme
formamido-compounds and proceeds by reduction of derived isocyanides (Scheme 5)." In related work Ogawa's synthesis of
0'' :yR 0' CH~OAC
i,ii
iii
~
,
\
AcO
CH~OAC
CH20Ac
iv
A co
AcO
NC
NHCHO
ReagwLt~: i, A c C l , HCl ; ii, ROH, AgOTF ;'&, POCL3, N E t 3 , Scheme 5
LV ',
EugSnH
2-deoxy-p-glycosides from glycals by addition of arylsulphenyl esters of the aglycone has been modified by use of the less volatile 2-naphthylsulphenyl chloride and extended to the synthesis of ( Z ) , a model of aureolic acid antibiotics (Scheme
A further route to 2-deoxy-glycosides involves the specific
6).12
6,
Rq&:
L
+J ..
HQ
i
DnO
T o
(J&
(
. 5 \
/
Scheme
6
H Q
0 2
(21
,Me&OTf;
,
Ll R M y
k;
ring opening of 1,2-orthoacetates and the subsequent reductive cleavage of the ester group at C-2 (Scheme 7).13 A route to CH208n
CH~06n
L 0 >h "0@
O nQ 0o
CH20Bn
D nOQR OAG
,+OB&
Me Rec~g&S'
i, ROH, CoLLicLine p
e r b d e ;u
, MeO-;
u,NaM;iv,
CS, ; v, Me1 ; V L , 0u3SnH, AIBN
Scheme 7
2-deoxy-D-lvxo-hexopyranosides from ulosonic acid glycosides is mentioned below. In the field of glycosides of 2-amino-2-deoxy sugars Mootoo and Fraser-Reid have found an ingenious method for controlling the
19
stereochemistry at the anomeric position by opting for specific amino-protecting groups. With monohydroxy sugar derivatives they were able to obtain yields of about 65% and 80-90% of Q- and plinked disaccharides respectively (Scheme 8 ) . 1 4
RecqenLs
L,
I(cou~~L~=),cto,,L, Ron ;.u, H + Scheme 8
A novel method of synthesis of p-glycosides (including disaccharides) of 2-acetamido-2-deoxy-D-glucose uses 2-deoxy-2iodo-D-mannosyl azide (prepared from tri-Q-acetyl-D-glucal) which gives access to the glycosides (via aziridine intermediates) on treatment with triphenylphosphine and alcohols in dichloromethane. In similar fashion, the D-alucQ-iodoazide affords the 2-acetamido2-deoxy-a-D-mannopyranosides." When 2-acetamido-2-deoxy-D-glucose or -galactose was dissolved in anhydrous hydrogen fluoride, the oxazolinium ions (3) and ( 4 ) were produced: addition of methanol gave the methyl pglycopyranosides (5) and (6) in high yield. The former glycoside was also obtained by treating chitin under the same conditions. If, instead of treating the intermediates with methanol, the acid was allowed to evaporate, p-(l-+6)-linked oligomers ranging from the di- to hexa-saccharides were formed.15 Some N-acrylyl derivatives from which p-glycosides can also be produced are referred to in Chapter 9. Specific 2-amino (or 2-acetamido-)-2deoxy-p-D-glucopyranosides or -galactopyranosides have been made from the "spacer arm" compound 3,6-dioxa-non-8-en-l-01,~~6aminohexanol bonded through the amino-group to 2'-deoxyuridine," and 4-methylumbelliferol." In this last report the a-anomer was also isolated, and analogous 2-acetamido-2-deoxy-a-D-glucosides and -galactosides having "spacer arm" aglycones were made following Wittig reactions applied to 3-hydroxyacraldehyde glyco~ides.'~ In the area of ulosonic acid glycosides a stereospecific route to a-glycosides of KDO derivatives has been described (Scheme 9),'O and a related route involves addition of hydrogen chloride to the glycal, conversion of the adduct via the phenyl thioglycoside to the sulphone and C-1 carboxylation of the latter. The products could be reduced to the ulosonic acid thioglycosides and
20
Curbohydrute Clietnistry CH20H
(3) R 1 = H, R2=Oti (4)
CH ~
AGO
4
R ‘ r OH, R3= H
OAC
R e a g d s : I, PhSeTf,
ROH;L,Bu3SnH
Scheme -9 hence converted to glycosides; radical decarboxylation of these last products afforded a novel route to 2-deoxy-Dgalactopyranosides.” The sodium salts of the phenyl, g-nitrophenyl and
4-
methylumbelliferyl a-glycosides of 3-deoxy-D-glvcero-D-ualact~-2nonulopyranosonic acid have been synthesised using compound (7),22 as have the 4-methylumbelliferyl a-glyCOSideS of N-acetylneuraminic acid, its 7-, 8- and 9-deoxy and 4,7-dideoxy-analogues and its 7-, 8- and 7,8- epimers, also from the corresponding glycosyl chlorides.23 a- and p-Thioglycosides if N-acetylneuraminic acid have been made from the acetylated p-glycosyl chloride and from the p-glycosyl acetate, r e s p e c t i ~ e l y ,and ~ ~ the p-chloride was used in the preparation of anomeric sialyl glycerol lipids (8) from
yL
OA c.
AcHNpo)olQ;;%
CH20Ac C 0 2 B n
CH~OAC
OAc
OAc
(7)
toH
CH20R
R
= CO(CH~),M~ n = 6,10,I4
(S)
both (B)- and (2)-glycerol-lipid precursors. The products, after deacetylation, especially those incorporating the palmitoyl residue, are inhibitors of phospholipase A, and
c.,’ Continuing their studies on acetal glycosides Tietze and coworkers have made various compounds with general structure (9) (R, alkyl or chloromethyl) by treatment of trimethylsilyl tetra-pacetyl-p-D-glucopyranoside with different ketones and (trimethylsily1)methyl ether.,‘ Related aldehyde methyl acetals (10) have been tested as substrates for p-D-glucosidase from sweet almond emulsin. Some of the amino-compounds were particularly
3: Glycosides
21
resistant to hydrolysis
-
especially (R)-3-amino-l-methoxypropyl
p-
D-glucopyranoside. The significance of the findings was discussed in terms of the special orientation of functional groups in the active site. 27 Condensation of protected glycosyl fluorides with phenols in the presence of Cp,HFCl, and silver perchlorate generally affords the thermodynamically favoured aryl glycosides, but in some cases such factors as solvent can determine which anomers are favoured.” Specific aryl glycosides to have been made and studied the p-Dare the p-glucopyranoside of g-hydr~xybenzaldehyde,~~ mannopyranosides of p-nitrophenol, methylumbelliferol and Onaphthol (Mitsunobu c o n d e n ~ a t i o n ) ,the ~ ~ a-D-xylopyranoside of Rchloro-5‘-bromosalicylanil~de’1and the ,&D-glucuronide of fluorescein (enzymic procedure).” A series of tetra-Q-acety1-p-Dglucopyranosides of hydroxy-substituted benzaldehydes have been made and condensed with 3-methylpyrazolin-5-(4H)-ones to give potential anti-inflammatory product^.'^ Several biologically significant products which are alkaryl glycosides have been synthesised: the metabolite (11) of the diabetes therapeutic ciamexon;” potassium lespedezate (12) which is involved with the circadian rhythm in plants,” and salidroside (13).36
z:Me
J-(
AcO
.N
OAc
(9)
CH20H
OH (1 3)
Further interesting work has continued on the synthesis of glycosides of functionalised cyclohexanes formed by Diels-Alder reactions of glycosyloxybutadienes. The detailed structure of (14) was examined crystallographically and in solution by n.0.e. methods, and its reactions with various dienophiles, e.g. quinones, N-methyl maleimide and tetracyanoethylene, were reported. The final product (Scheme lo), formed after a specific cycloaddition process, was again structurally characterised by crystallography.37 Results obtained in an extension of this work
22
Carbohydrate Chemistry Me
OTMS
0 w e m t x
i, 0
0
0
0
0 ; iL, H +
S c h e m e 10
are summarised in Scheme 11."' An important related study was carried out with 2-methylbutadienyl a-D-glucopyranoside and 2methylacrolein to give (15) using aqueous media and no catalyst. The reaction proceeded with 20:l endo:exo selectively. The
Scheme 1 1
0
effects of substitution of a benzyl group at 0-2 and 0-6 were also examined.'' A reverse type of Diels-Alder reaction involving a
vinyl glycoside is illustrated in Scheme 12." CH200n
Q
BnO
0-CH=C!-I*
OBn
R V d S:
a:-,,, :401f,,m CH(Orle),
. ..
L,w
+
NHDNP
'., W 0 3 , MeOH ;
U
, MeOH, Dower H
-+
Scheme 12
In the area of glycosylinositols, l-Q-(1,2-di-Q-palmitoyl~-glvcer~-3-phosphoryl)-2-~-a-D-mannopyranosyl-D-~-inositol has been synthesised by way of a substituted derivative of the corresponding 2-Q-a-D-mannopyranosyl-D-~-inositol.40' 2.2 Svnthesis of G l v c o s m t e d Natural Products.- Several of the compounds mentioned above have biological chemical significance: this section notes the synthesis of natural glycosides (or related
3: Glycosides
23
substances) grouped according to the type of aglycone employed. A review has appeared on the total synthesis of neutral glycosphingolipids, one of the topics being the preparation of optically active ceramide from D-glucose." The first total synthesis of optically active cerebroside B,, (16) and its aglycone stereoisomers used the trichloroacetimidate method^,'^ as did the preparation of the hydroxy analogue (17),43and the related phosphonophingoglycolipid (18)has been reported, the aglycone as was the having been derived from 2,4-Q-benzylidine-D-threose,'' case for (17).4' Palmityl p-D-glucosiduronic acid and p-Dglucopyranoside have been produced in connection with studies of liposome stability,'" and compound (19)was coupled with a 3aminopropylthioglycolate and the product condensed via the terminal amino group with fluorescein isocyanate to give a compound used for fluorescence studies of membrane lectin~.'~ In the field of anthracycline chemistry the alcohols ( 2 0 ) ( 2 2 ) were glycosylated by use of derivatives of 2,6-dideoxy-Llvxg-hexopyranose,"' 2,6-dideoxy-2-iodo-L-hexoses4" and 3-amino-2,6dideoxy-L-lvxo-hexopyranose," respectively. Likewise daunosamine and related sugars have been bonded to the dihydropyran analogues (23)-( 2 5 )
.
t-19LO-
0 - D - G L c p - 0V
"'0
(cH~),~M~ C \
.(
ou P-
QH H
-
&
CH20- P*N+H~F?~
M
e
R
(16) R - H
OH
(17) R = O H
HO
W2),pe
CH20Ac
R'
R2
R3
(20) H
NH,
COMe
R'
RZ
R3
(21) OH
OH
Et
(23)
H
H
OR
(22) OH OH
Et
(24)
H
(25) M e
CHZOH
H
CHzOH
H
R4
R5
H
H
OH
H
C02Me OH
In the area of simple terpene glycoside farnesyl p-Dgalactopyranoside and Q- and p-D-mannopyranoside have been reporteds1 as have eighteen monoterpene p-D-glucopyranosides for an investigation of p-glucosidase specificity. The soluble silver trifluoroacetate gave appreciably enhanced
24
Curbohydrute Chemistry
Glycosylation of various steroids by use of tri-Q-acetyl-2deoxy-2-fluoro-a-D-glucopyranosyl fluoride gave predominantly the p - g l y c ~ s i d e s ,and ~ ~ p-galactosylation of ethyl cholate at 0-7 was most effective with trimethylsilyl triflate as catalyst.s5 A review has been produced on the preparation of potent unnatural
-
digitalis derivatives cardioactive steroid glycosides improved safety margins."""
- having
A review has been published on flavone and flavonol g l y c ~ s i d e s . ~Specific ~ reports have appeared on the preparation of several sets of a- and 0-4-trifluoromethylumbelliferone g l y c o s i d e ~ ,and ~ ~ on the p-D-glucopyranosides of several isof lavones
."
Ally1 esters have been used for carboxyl group protection in Q-glycopeptide synthesis. Standard glycosylation procedures were used to substitute the hydroxyl groups of serine and threonine p C b z esters, and the peptide chains were extended following dealkylation using Pd(0)-catalysed ally1 transfers.59 Specifically, glycosylated threonine derivatives have been extended by solid phase peptide methodology to glycosylated hexapeptides related to oncofetal fibronectin; the sugars involved were p-D-GlcNAc and the (l-3)-linked 8-D-Gal derivative of it.'O Complex polycyclic compounds to have been glycosylated are several gibberellins (p-D-glucosylation),61 pseudopterosin (26) (aL-fucosylation),62 normorphine (27) (3- and 6-p-D-glucuronide~),~~ 9a-methoxymitosane (28) (7-substitution by p-D-glucopyranose, plactose, p-D-E-acetyl-glucosamine and -galactosamine)f 6 ' and streptazoline (29) (p-D-gluc~sylation).~~
k=
(f" 0 %
OH
0
2.3 O-Glvcosides Isolated from Natural Products.- Four flavan-301 8-D-allopyranosides and three proanthocyanidin allopyranosides have been isolated from a fern,=" and the 6-benzoate (30) and the glucoside (31) have been obtained from a g ~ o t e aand ~ ~ from strawberries,'* respectively. In the latter case a mixture of diastereomers was found and the mixture was also produced by
3: Glycosides
25
synthesis. 2 - Q - p - L - A r a b i n o p y r a n o s y l - ~ - ~ n o s i t o l is a main, and tasteless, constituent of tea."* Svnthesis of Disaccharides and their Derivatives.- In the area of non-reducing disaccharides bis-4,6-Q-benzylidene-~,~trehalose has been used to give, by way of the dibutylstannylene intermediate, the 2,2'-di-Q-benzyl and 2,2'-di-Q-allyl ethers; 1.4
Bisfrom the latter the 3,3'-di-Q-benzyl compound was derived." 2-acetamido-2-deoxytrehalose compounds having long chain fatty acid esters at 0-6,6' and pepti.de substituents at 0-3, 0-3' have been reported." A newly isolated fructosyl transferase from *
.
Bacillus subtilis has exceptionally high propensity to form a range of a-1+2 linked disaccharides; by its use ffxylosucroseff, "galactosucroseqfand 6-deoxysucrose have been prepared.72 The 5amino-5-deoxy-D-glucose derivative (32), which has structural similarities to non-reducing disaccharides, and which acts as an aglucosidase inhibitor, has been rep~rted.~' The synthesis, n.m.r. studies and conformational analysis of several 1,3- and 1,4-linked disaccharide methyl glycosides and related trisaccharide methyl glycosides have been ~ndertaken.~' Reducing disaccharides are now treated according to their non-reducing moieties. p-D-Glucopyranosyl disaccharides can be synthesised in high yield by use of tetra-Q-benzy1-a-Dglucopyranosyl fluoride together with Cp,HFCl, AgC10, in the proportions l:2;" further studies of disaccharide synthesis using
-
tetra-Q-benzyl-a-D-glucopyranosyl chloride have been reported.'" Reaction of the cyanoethylidene reagent (33) with methyl
2,4,6-tri-~-acetyl-3-Q-trityl-p-D-glucopyranoside under the catalytic effect of trityl perchlorate at high pressure gave a 95:5 ratio of p:a-3-linked disaccharides." In the area of 4-linked glucobioses the a-compound (34) was prepared in 82% yield as indicated in Scheme 13;7* an analogous
26
Curbohydrate Chemistty CH20Bn
CH20Bn
CH20Bn
QSQ
BnO
$-
Q + OMe
l-40
05n
0130
CH20Bn
b0QO
81-10
0Bn
OBn
(s 9)
R q e d L,MeI S c h e m e 13
synthesis is depicted in Scheme 14, starting from the more novel glycosyl thiocyanate as glycosylating agent.79 Several perfluoroalkyl maltosides have been reported to have abilities to stabilise emulsions." CflzOAc
CH20Ac
p?;CN
Q
AcO
CH~OAG
+
Tr 0@Me_,
0Bn
AGO QoQue
OAc
OAc
OMe
S c h e m e 14
Reaction of the glycosyl imidate (35) with the receptors disaccharide when the protecting group at 0-3 was benzyl whereas, unexpectedly, the Qlinked analogue was the main product when the acetyl group was present .'* Tetra-Q-benzyl-a-D-glucopyranosyl (dipheny1)phosphate and methyl 2,3,6-tri-Q-benzyl-~-D-glucopyranoside, condensed in the presence of trimethylsilyl triflate, afforded the substituted cellobioside in high yield and with an u : p ratio of 7:93. This is an unusual use of phosphate esters and is of particular interest since the glycosyl phosphate used is claimed to have appreciable shelf life.02 Compound (37) is an active-site directed inhibitor of (36) led to the correspond B-(l+4)-linked
CH20Bn
ODn
CH 2 0 R'
OAc
OH
OH
cellulase of u h v 1 1 sommu ~ ne;a3tritiation at C-1' aided the isolation of a complex of the inhibitor and the inactivated cellulase.04 A new method of synthesising 1,6-linked compounds affords The mutagenicity products with m. 70% efficiency (Scheme 15)." and lethal toxicity of chemically synthesised lipid A analogues having 2,3-acyloxyacylglucosa1n~ne4-phosphate with
3: Glycosides
27
CH20Ac
AcO@m5
OAc
CH205;Ph2But
@"-
Ac 0 t
0 Q"' CH20Ac
L
AcO
/ CH2 Ac 0
0 fu
OAc
OAc
S c h e m e 15
Seaged. ;,TMSOTf
tetraacetylhexose substituents bonded at 0-6 vary according to the hexose."6 The bromoacetate group can be used, by selective primary substitution, as a route to sets of 1,6-linked oligosaccharides." Epoxidation of tri-Q-benzyl-D-glucal with dimethyldioxirane gave the 1,2-anhydro-D-aluco-sugar in good yield and with 20:l stereoselectivity. (Other glycal derivatives afforded the 2,3trans-adducts with similar selectivity). Use, in glycoside synthesis, of the glucal adduct, is illustrated in Scheme 16.'"
The endo-isomer (38) is more reactive than the
exo-
(39)
CH~OAC
towards tritylated sugars in the presence of trityl perchlorate. Both have been used to make 6-p-linked glucosylgalactose. A related set of disaccharides was made in the course of this study."' Other hetero-glucosyl-disaccharides to have been reported are 6-Q-p-D-glucopyranosyl-D-fructose (leucrose) (and the a-linked is~mer),'~2-Q-a-D-glucopyranosyl-L-rhamnose" and various derivatives of methyl a-D-galactopyranoside having 0-3 or 0-4 (or both) substituted by a glucopyranosyl group in either anomeric configuration.92 The unusual C-linked disaccharide analogue (40) has been made as illustrated in Scheme 17.93 In the series of galactobiosides the 6-pa- and p-linked compounds have been made as their methyl glycosides by the orthodox Koenigs-Knorr approa~h,'~and the analogous photolabile Cglycoside (41), which was used in immunological studies related to
28
Curb0hydrate Chemistry
O0n R q & s
!
L, LLN(TMS)~;U
(M?
BnO
om Scheme 17
IgAX24, has been made by chemical and enzymatic method^.^' GlyCOSylatiOn of 3- and 6-trityl ethers of methyl p-D-
galactopyranoside with 1,2-Q-cyanoalkylidene derivatives of galactopyranose afforded routes to 1,3- and 1,6-linked galactobiosides." Syntheses have been reported of the 3'-Qmethyl, 4'-deoxy-4'-fluoro and 4'-epi-derivatives of methyl 4-Q-p-
D-galactopyranosyl-p-D-galactopyranoside as well as the 2'-, 3'-, 4'-, 6'-deoxy and 6'-deoxy-6~-fluoro-analogues. Calculations by molecular mechanics showed only small deviations for the conformations of these compounds from that of the parent disaccharide glycoside." The procedure illustrated in Scheme 18
,.
0
provides a convenient method for preparing p-D-galactofuranosides and D-galactofuranosyl disac~harides.~' 1-Q-p-D-Lactosyl-(It,S)-glycerol and 1,3-di-Q-p-D-lactosylglycerol have been prepared to study their binding to the asialoglycoprotein receptor site of mammalian an extension of the work has afforded the a-linked monosubstituted compound and the 1-a, 3-p-linked disubstituted derivative.'00 A lactose ether
3: Glycosides
29
substituted at all positions except 0-4’ has been prepared as an acceptor in the synthesis of glycolipids, and various 2-azido-2deoxylactosyl trichloroacetimidates have been made as glycosyl donors in the course of related work.’” Various 6°-octylmelibiose-based aldehydes ( e A . 42) and related hemiacetals (e,g. 43) have been made by reductive ozonolysis of corresponding alkenyl glycosides for reductive coupling to amino-acid derivatives.102 A 2’-deoxylactose derivative has been obtained as outlined in Scheme 19.’’’ CH20C8H17
CH20C0
‘YQo/@c OAc H2AcO
CHO
Q o -f,Q /o “
OAc
(421
OH
HO
\W / 2)n o-CH~OH)
(43)
n =1,2
The 2-amino-2-deoxy-D-galactose-conta~n~ng disaccharide glycoside (44) was coupled with various proteins to give CH20Bn
M..;
f
LIiL
OyoMe
Me
“OQyOQ
CHrOBo
@m e ,
R a z z p a k S : L,AcOH;uuo
CH200n
OMe
OAc
CH2OBn
CHzOBn
~*Bno$JqoQo
0 Dn
0011
q O T M S ; G ,MeO-;iv,NaH,CS,,MeI;v, B U ~ S ~ H , A I B N
0th
Scheme 19
neoglycoproteins (45) carrying teratocarcinoma-specific carbohydrate chains.”’ The related 2-acetamido-2-deoxy-3-Q-(p-Dgalactopyranosy1)-D-galactose was prepared enzymically from b(- O -Ga L-p -(l+ 3 )-c c -D -
(++)
=
COCF3
GaLmpNAc-0-NHR
; (45)R = CO-COR‘
, R ’ = s e r u m albumk, or cytoChrome C
lactose and 2-acetamido-2-deoxy-D-galactose.’”” Other work has described similar preparation of the ethyl p-glycosides of this compound as well as the Q,U- and p,a-linked isomers.’06 Tetra-Q-benzyl-a-D-mannopyranosyl fluoride, used together with bis(cyclopentadieny1)zirconium chloride and silver tetrafluoroborate, affords an effective means of preparing a-linked mannopyranosyl disaccharide~,’~’ and plinked analogues can be made by way of 2-Q-imidazolsulphonates of p-D-glucose linked compounds as can 2-amino-2-deoxy-p-D-mannopyranosyl The synthesis of the dermatan sulphate disaccharides ( 4 5 a ) and (45b)
30
Curb0hvdrrrrr Chemisrry
has been reported; the paper also describes a new route to the azido-compound ( 4 5 c ) . lo*a
0
“0
COz Na
CH20l-J
(450.)
NQs030@M‘
R-
CH20Bn
(456) R =
HO NH Ac
@
‘.le
HO
OH
(45 4
N3
Interest continues in the synthesis of deoxydisaccharides. simple route to 2‘-deoxy-D-arabino-hexosyl compounds proceeds from 1,2-di-Q-acetyl-3,4,6-tri-Q-benzyl-~-D-glucose, the glycosylation being catalysed by trimethylsilyl triflate and the deoxygenation at C-2‘ effected by radical induced reduction of derived xanthate esters.lo9 Compounds ( 4 6 ) and ( 4 7 ) , obtainable A
CH20Dn
(46)
&LJ
BnO
CH20Bz
(47)
0x0
from glycal derivatives, can be used for 2,2‘-dideoxy disaccharide production or in the production of related tri- and higher saccharide analogues and hence 2-deoxyhexose oligomers.l‘O Several fucosyl derivatives of methyl a-D-glucopyranoside, having the substituent sugar at 0-3 or 0-4 or 0 - 3 , 4 and in both anomeric configurations, have been prepared and subjected to indepth conformational analysis.** In an attempt to synthesise the geranyl glycoside of rutinose (6-Q-a-L-rhamnopyranosyl-D-glucose) by use of the acetylated a-glycosyl chloride in pyridine with silver carbonate, the corresponding carbonate ( 4 8 ) was obtained instead.’11 Ozonolysis of a silylated avermectin B, derivative gave improved access to oleandrosyloleandrose ( 4 9 ) , ” * and the compound AcoQ----
AcO
0 0 C0,- G ~ r a n y L
OAc AGO OAc
Ho”,’oo OMe
(4 8)
OMe
(49)
has been synthesised in good yield by use of the 2-pyridylthioglycoside method.113 The related a-1+4 linked 2,6-dideoxy-L-lvxohexose disaccharide, related to anthracycline components, has been made using the glycal, N-iodosuccinimide procedure.”* The 3-Q-aparatosyl, abequosyl and tyvelosyl a-D-mannopyranoses have been
3: Giycosides
31
prepared as their alkyl and 2-acrylamidoethyl glycosides for conversion into artificial antigens related to those oE the Sa1m0nella.l~~ Several selectively substituted derivatives of the p-(l+3)linked dimer of 2,6-dideoxy-D-xvlo-hexose have been made by specific removal of benzyl, benzoyl and tosyl groups in turn.'16 Additions to glycal derivatives were used to obtain the pentadeoxyamino compounds ( 5 0 ) '17 and ( 51) '* 3-0-(3,6-D~deoxy-a-D-xvlo-hexopyranosyl)-L-rhamnopyranose was prepared as its a- and B-2-acrylamidoethyl glycosides for
.
A
C
OO
~
~
M
vopoH
ti0 OH
NHCOCF3
OAc
~
(50)
(51)
R = NMe,,
NYCOCF~
development of polyacrylamide copolymers with Salmonella antigen specific ity 'I9 Use of a specific, immobilised hydrolase which cleaves a-1+4 bonds of sodium pectate gave access to the correspondingly linked di-D-galactosiduronic acid.'20 The 5-deoxy derivative (52) of a KDO disaccharide has been synthesised,121and a review has appeared on various glycosylating reagents derived from N-acetylneuraminic acid.122 Specifically, in this area, compounds (53) and ( 5 4 , n = 12 or 16) have been
.
OAc
OH
OH
OH (54)
prepared synthetically.123r124 In the area of disaccharides having 2-acetamido-2-deoxy-p-Dglucopyranose glycosidically bonded to other sugars, the 1-6 linked methyl p-D-galactopyranoside and the methyl a-Dmannopyranoside compounds have been made by use of glycosidases.'"" Chemical procedures have been applied to obtain the disaccharides having the amino-sugar 1+4 and 1+6 linked to methyl a-Dg l u c ~ p y r a n o s i d e methyl , ~ ~ ~ pD-glucopyranoside and methyl Q-Dmannopyranoside.126 Similarly it has been coupled 1-6 to 2-amino-
32
Cnrbohydrate Chrmistry
2-deoxy-D-glucose,”’ 1-4 linked to N-acetylmuramic acid,‘*’ 1-4 and 1+6 linked to ~-acetylmuramoyl-L-alanyl-D-isoglutamine12g and 1+4 linked to fJ-acetylnormuramoyl-L-a-aminobutanoyl-Disoglutamine.’”” Chitobiose octa-acetate has been obtained in improved yields by acetolysis of chitin (12-16% yield) and following microbial degradation of the polymer (31%); derived glycosides were re~0rted.l~’ In the pentose series methyl 4-Q-p-D-xylopyranosyl p-Dxylopyranoside has been synthesised by glycosylation of a methyl 4-Q-trityl-p-D-xylopyranoside derivative.”’,”’ Detailed ‘”C n.m.r. studies of the methyl 8-D-xylopyranosyl-p-D-xylopyranosides have been reported.134 1.5 Hvdrolvsis and Other Reactions and Features.- E.b initio calculations on the protonation of dimethoxymethane have confirmed that a m-periplanar alignment of a lone pair with a leaving group is on the pathway to the transition state and is energetically favoured relative to an anti-periplanar arrangement. These results were correlated with the optimal stereochemical requirements for glycoside hydr~lysis.’~’ 2-Methoxyethyl glycosides bearing such protecting groups as acetyl, benzyl and ally1 may be cleaved by treatment with TiC1, in dichloromethane followed by hydrolysis on a column of silica gel.136 In a study of the relative rates of hydrolysis of conformationally restrained Q- and p-4-pentenyl glucosides under neutral conditions, it was concluded that the Deslongchamps theory for glycoside hydrolysis (the anti-periplanar lone pair hypothesis) was not consistent with the results obtained.13’ In work on variously substituted 4-pentenyl glycosides compound ( 5 5 , either anomer) gave the amide ( 5 6 ) on treatment with Nbromosuccinimide in aqueous acetonitrile, whereas the benzylated analogue (57) underwent hydrolysis in these conditions (Scheme 20). The first result was attributed to the strain imposed by the ring fusions on the pyranose system.”’ Reductive cleavage of the acetal groups in some methyl 4 , 6 Q-benzylidene-a-D-hexopyranosides with sodium cyanoborohydride has been shown to depend upon subtle structural features as illustrated in Scheme 21. In the first two examples, the products shown were the only ones Liberation of the sensitive aglycone ptaquilosin ( 5 8 ) from its glucoside has been achieved as illustrated in Scheme 22, the key step being the opening of the pyranosyl ring triggered by
3: Glyrosides
33
PI
- -o&DnO -!(
L
O h
R e 9 e n . k : i,NDS,MeCN,H20
(57)
Scheme 20
attack at the C-6 iodo-group with zinc.”” The configuration of the glycerol moiety of glycosylglycerols can be determined by perbenzylation followed by
ph
J-/
CI 0
L ,
OMe OH
*
R&a.g&
OH
OH
: L, NaBH3CN, UC1
OOn
0Bn
OH
3 : 2
OH
Scheme 21
hydrolysis and ORD/CD examination of the dibenzylglycerols produced.14’
8811
?
OAG
L-LV
__t
Foi; “ b S $ I 1
1111
v-vu
~
OH
p - D- G l c - p Ac 0 L o A J
(50 ) OAc
R ~ & s
L.,
B u ~ S ~ O , U , T S C L , U , A ~ ZL O v r, KP I,~ D, M F , v, Z n , N H 4 t L , E t O H , VL, K~t03,MeOH ,VIA,,
PCC
S c h c m e 22
A I3C n.m.r. spin-lattice relaxation study of solvent effects on the rotational dynamics of methyl a- and p-glycosides has been reported. Rotation rates for both anomers follow the order MeOH-DMF-D,O
S-Glvcosides
Further applications of sugar peracetates to the synthesis of
ethyl and phenyl l-thio-1,2-trans-D-glycopyranosides have used iron(II1) chloride as catalyst and have led to 2-amino-2-deoxy-p-Daluco- and a-D-manno-c~mp~~nd~.'"~ A related report described Enitrophenyl l-thioglycosides made from 1,2-trans-related glycosyl fluorides, the products having the p-D-Xylf, p-D-Glcp, p-D-Galp, aL-Rhap and a-L-Arap structures.'"4 Compound ( 5 9 ) , readily made according to Scheme 23, has clear value for the synthesis of
.
0
oligosaccharides 145 CH~OAC
@Ac
CH20Ac
>
OTflS
u.
A c0
AcO
OAc Rq&S
Ph
OAc
(59)
i , T M S O T f > P h STNS; u, Py
S c h e m e 23
When penta-Q-acetyl-p-D-glucopyranose was treated with ethanethiol and zirconium tetrachloride at 0°C in dichloromethane, the p-thioglycoside was obtained in 74% yield; at higher temperatures a , p mixtures were formed as the kinetically controlled product equilibrated with its anomer. Related studies were carried out in the D-yvlo-, D-aalacto- and D-mannQ-series.146 Various l-thio-a-D-aluco-compounds having long chain aglycons were prepared directly from the penta-acetate by use of boron trifluoride as catalyst and were studied as liquid crystals.'"' Compound (60) was prepared as a carrier for introducing anti-hepatitis drugs, so that they concentrate on the hepatocytes, by reaction of bovine serum albumin with compound (61),14' and fluorescent diastereomeric l-isoindolyl l-thio-p-D-glucoside derivatives (62) were made from amino acids and o-phthalaldehyde in the presence of l-thio-p-D-glucose for the HPLC resolution of enantiomeric amino acids.'"' l-Thioglycosides remain of importance in the synthesis of O-glycosides and Q-disaccharides. Dimethyl(methy1thio)sulphonium triflate acts as a potent activator for such purposes; glycoside esters with participating groups at 0-2 give l,2-trans-related products, those with non-participating groups usually afford 1,2&-anomers. The latter selectively can be enhanced by addition of tetra-alkylammonium bromide."" Specifically, compound (63) has been used to glycosylate suitably protected 16-membered macrolides in the synthesis of 3-Q-a-cladino~ides,~~' and the ganglioside GM, thioanalogues ( 6 4 , n = 12 or 16) have been prepared.'"
3: Glycosides 3
35
C-Glvcosides
3.1 Pvranoid Compounds.- Giese has published two important reviews on the use of glycosyl radicals in the synthesis of C-glycosides and C-disaccharides ’53r154 Methods for the determination of C-glycoside stereochemistry, based on l&-l,R-l values, have been reported.155
.
*
R = -CH C02H
I
OH
OH
(64) A further report of the addition of glycosyl radicals to acrylonitrile has appeared,156and a set of intramolecular addition reactions, illustrated in Scheme 24, have been rep~rted.~”’,’”~
R e o g e d s , i, B u , S ~ HA,IDN
Scheme 24
Several syntheses of aryl C-glycosides have appeared, and the use of metal phenolates for the production of compounds of this series has been reviewed.’”’ Features of the use of acylated glycosyl halides with aryl Grignard reagents have been described, a , p ratios increasing with the leaving properties of the halide and when the reagent is less nucleophilic and more sterically hindered.’“” The use of a glycosyl fluoride is illustrated in Scheme 25, anomeric ratios of the products being controlled by the selection of reaction conditions.161 A related reaction leading to the preparation of the C-aryl part of the vineomycins is shown in mass spectra of a- and B-DScheme 26.16’ The FAB glucopyranosylbenzene and their methyl ethers are referred to in Chapter 2 2 . Tetra-Q-benzyl-a-D-glucopyranosyl trifluoroacetate reacts
-
36
Carbohydrate Chemistry CHZOBn
OF+ 6 Me0
Bn 0
'
.j~oMe
OMe
Me0
OBn
Reagcnte : i, Q2ZrCL,
,A g c q Scheme 25
with electron rich benzene derivatives in the presence of boron trifluoride to give mainly p-linked aryl g l y ~ o s i d e s , ~and ~ " similar
bF +
BzO
OH
Rcage*Lts
L,
CpHFCL2, AgCL04,
p
OMe OM@
/
/
i-iii
'
~
OMc U,
04C 0
A C ~ OPy , ;Li, CAN, MeCN
S c h e m e 26
compounds may be made by the less orthodox route shown in Scheme 27. This method was then extended to the synthesis of 5,7,4'-triCHO
OAc
Scheme 27
Q-methylvitexin.16'
A similar acyclic starting material (65) was
converted into the nitropropyl glycoside (66) as indicated in Scheme 28,'"' and related methodology was applied to obtain the
B no V
f
alkenoic acid glycoside (67) (Scheme 29).lS6 Free radical addition reactions which lead to further, related G-glycosides and chain extended aldonic acid derivatives are referred to in Chapter 16.
37
3: Glycosides
i, TBDWSCL,DBU
R,=a.gent;S:
0Ac
; u, O3 ; i r i , P h ~ P P H ~ C 0 2 E t
(67)
Scheme 2 9
further novel approach to aryl pglycosides starts with aldonolactone derivatives (Scheme 30),16' and another provided A
0-J
CH~OAC
CH20Bn
( &
AcO
BnO
OAc
OBn R a ~ j e n t s i, : A r L i ; u, E t g S i H , BF3 ; iii, P&/C ; iv, AczO, Py
S c h e m a 30
access to 8-linked alkyl and aryl tetra-Q-acetyl-D-C-glucosides by treatment of Brigl's anhydride with organocuprates. 1,2-Anhydro3,4,6-tri-Q-benzyl-pD-mannose similarly gave the 2-hydroxy a-mannoside (68) from which the 2-deoxy compound (69) was prepared. 16'
bR, R
BnO
R'
(68)
OH
Me,Ph
(69)
H
Me,Ph
The allyl glycoside (70) has been used for the elaboration of the interesting €-linked sucrose derivative (71) which exists as a mixture of furanoid and pyranoid forms (Scheme 31).'69 CH200n L-v
08n
~
:
v
-
& o
VL-XL
1
DnO
CX
-D -GLc-p
I
HOCwCH2
-
HO
(?OjlQn
0
OH (71)
S e a g e n t s L, Mg(OAc),, H l O ,a,12 , U, PCC , W , PPh3.Et3N ( . x , Flonsd., N, K I C o g EWU X L , I+, PWC
, V,
Eix
,VL,
OH OSO, ,v u , A+,
Py , v w , F a U 3 ,5t.01,
Scheme 31
An alternative method for making 3'-oxygenated C-alkyl ethers is illustrated in Scheme 32; the a,p-anomeric ratio was
a :1
.
m.
170
The very stable (_E)-isomer (72) and the allyl compounds (73) were obtained as shown in Scheme 33. While the former product
38
Carbohydrate Chemistly
&*&=
4
A.
P.fiMe3
Bn 0
OBn
Go c
BnO R ~ & L :Li, B F 3 . E t Z O
;k
‘
OAG
\
OAc CHzOH
H
y O.CO,E~ M e ,
OBn
i BnO & \ -0Et OBil
Scheme 32
underwent Diels-Alder reaction with maleic anhydride, the latter (and the analogue activated by having a E-toluenesulphonyl
substituent on the terminal alkene carbon atom) failed to react with dienes.17’ The ethynyl C-glycoside ( 7 4 ) was prepared from the
corresponding 2,4-dimethoxybenzoyl ester by use of ethynylmagnesium bromide in the presence of zinc chloride,’” and the tllineartt glycosyl, glycosid-4-yl alkyne (75) has been synthesised as shown in Scheme 34.’73 A useful brief survey of methods for making C-glycosides is contained in a paper describing the reaction of 2,3,4,6-tetra-Qbenzyl-D-glucose with silyl enol ethers in the presence of acid catalysts. The products bear a carbonyl group at C-2 of the aglycone and, in base, epimerise very efficiently to mixtures having a , p ratios of m. 4:96 (Scheme 35).174 The Horner-Wittig products (glycosyl-CH2C0,Et) derived from 2,3,4,6-tetra-Q-benzyl-D-glucose and D-mannose had the following
3: Glycosides
Reage&:
4
39
L3uL.i; i,EtS H ,D F 3
; k,,EC35iH,BF3
Scheme 3 4
configurations: From the D-glucose ether: From the D-mannose ether:
8
1
&
p-manno 1
21
CHzOBn
CH2COR
BnO
~ - ~ l u c o a-manno 5.6 2.3
a - w o 13.2 2.3
9 CH206n
ii--.. -+ 0
Bn 0
BnO
OEn 2CoR
O0n
OBn
R c a g d :i, base
R = Me, CHzOMe, P I T , O M ~
Scheme 35
In each case 86% yields were obtained overall. The Wittig reaction proceeded much less satisfactorily.’” Discussion of the use of the Tebbe reagent for the synthesis of methylene sugars from which C-linked disaccharides can be prepared is contained in a review of some Du Pont re~earch.”~In related work, the C-methyl a-D-glucosamine derivative ( 7 6 ) was obtained, together with minor proportions of the B-anomer, by use of vinylmagnesium bromide (Scheme 36),177 but CH200n
Y O h R-enL.5:
B
47 - QNe CH205n
OH
0 ..\. ~
I
FL
’~
~
CHZOH
ii-V
~ NHBn~
I , W M g o r ;L, H ~ ( O C O C F , ) , ; ~ , K C L ; ~ V , N Q B H + ; V ,
HO
NH2
(76)
H~,PCL/C
Scheme 36
the p-anomer predominated on hydrogenation of the difluoromethylene compound ( 7 7 ) (Scheme 37).17’ Michael addition of hydrogen cyanide to a glycal-3-ulose, followed by reduction with CeC1,-NaBH, and acetylation, gave compounds ( 7 8 ) and ( 7 9 ) in 64 and 15% yield, respectively. The ratio of products was reversed when L-Selectride was used for the reduction, and the work was repeated with the D-eEythrQ-UlOSe starting materia1.17’ 1,2-Unsaturated glycosyl cyanides are referred to in Chapter 13.
40
Carbohydrate Chemistry CH,OR
CH20R
b 3 c l g d 6 ' L , (Et N),P;CBrIF~,
; u., H 2 , P d c
,'u, SMSU., Py
S c h e m e 37
The acylated glycal to 2,3-unsaturated pglycoside rearrangement reaction continues to be used. Thus, tri-Q-acetylD-glucal was converted in good yield into compound (80) and several related products by use of the bromomagnesium phenolates. Alternatively, tri-isopropoxytitanium and diethylaluminium phenolates gave exclusively the corresponding Q-linked aryl glycosides.l'O The C-ally1 compound (81) was obtained with high selectivity from di-Q-acetyl-D-xylal, which contrasts with the preference found for the a-anomer when tri-Q-acetyl-D-glucal was treated with allyltrimethylsilane in the presence of titanium tetrachloride. Compound (81) was used to prepare a conformationally restricted analogue of LTD,."' The related (82) and (83) were the products formed when the analogous glycosyl
w
AcO Ac
-
phenylsulphone and the phenyl glycoside were treated respectively with bromobenzene in the presence of butyllithium, zinc bromide and magnesium bromide,''* and with pentane-2,4-dione in the presence
of tetrakis(tripheny1phosphine)palladium. In the latter case different active methylene compounds and phosphorus ligands were examined. Phenyl 2,3-unsaturated p-linked glycosides reacted with retention of configuration, whereas the a-anomers gave mixed products. '03 Further, with unsaturated sugar derivatives, the 2phenylsulphinyl-D-glucal (84) was used as indicated in Scheme 38 to prepare 1'-hydroxyalkyl ~-glyc~sides,''~and this approach was developed to synthesise (via 4-deoxy-4-~-formyl-D-glucose and Dgalactose derivatives) the C-linked cellobiose analogue (85) and the 1,4-p-linked glucosylgalactose isomer ( 8 6 ) . ' "
3: Glycosides
41
OH
OH
R e a g m :i,LDA ; ii,R W O ;iii, Rancy
Ni
;&, MezS.8t4.13;v, N(aon,u20,
Scheme 38
A range of C-glycosides, e.g. ( 8 7 ) - ( 8 9 ) , have been prepared from the corresponding glycosyl carboxylic acid,"' and compound
(-JC{GOH It;r'"QOH CHpOH
CH2OH
CH20H
HO
CH2OH
HO
OH
OH
(95)
OH
(86)
OH
(41) with a photolabile C-1 substituent has been mentioned previously. '' The cyanogenic C-glycoside (90) containing the rare 2,6-
I OH
(90)
dideoxy-D-xvlo-hexopyranose has been isolated from passiflora caDsularis '*' Further references to pyranoid C-glycosides are contained in Chapter 24.
.
3.2 Furanoid Compounds.- Treatment of the benzylated glycosyl fluoride (91) with boron trifluoride gave the product (92) of intramolecular c-glycosylation (cf. Carbohvdr. Res 1987, XU, 211). The 2,3-di-Q-benzyl-5-Q-methyl fluoride afforded the analogous pglycoside, but the 5-Q-benzyl-2,3-di-Q-methyl triether did not react, establishing that in compound (92) the aglycone was derived from the ether group at 0-2 of the starting material. Sugar ring opening of the tricyclic (92) was effected as indicated in Scheme 39. la'
42
Carbohydrare Chernisiry
2,3,5-Tri-Q-benzyl-p-D-ribofuranosyl acetate with allyltrimethylsilane and the trimethylsilyl enol ether of acetophenone, together with tin(1V) tetrachloride, tin(I1) triflate and lithium perchlorate, gave only the a-:-glycosides (93) and ( 9 4 ) , respectively,' and the radioactively labelled selenazolecarboxylate (95) has been elaborated from 2,3,5-tri-Qbenzoyl-p-D-ribofuranosyl acetate by way of the labelled glycosyl
S c h e m e 39
nitrile.'"' The aryl C-glycoside (96) (in 1:l mixture with the a-anomer) was prepared by direct substitution using tetra-Q-acetylD-ribose,'90 and compounds (97) ( a , @ 82:18) were synthesised by use
m p
CHZOBn
b u
S\I4
I P-0-Rk.b f
013n 0Bn
P 0
y$
Ac 0
'E t
(95)
(93) R = @ (94) R = q
0 s L ( P rL)3
h
0Bn
-
OAc
c H* co Ph
OAC
(96)
(97)
of the glycosyl acetate and the acetophenone en01 silyl ether.'91 Two methods based on the use of aldonolactones, mentioned in the above section on pyranoid pglycosides, can be used to obtain furanoid aryl :-glycosidesl"' and difluoromethyl analogues."" The D-ribose derivative (98) was converted into the Cglycosides (99) and (100) via the 2- and E-alkenes as indicated in Scheme 4 0 , the former product being used to prepare the 2,7anhydride (101).19* In a related study the effects of different groups and electrophiles on the electrophilic ring closure of compound (102) and related substances to Q- and pfuranoid and pyranoid products were The furanoid glycal (103), treated with g-anisylmercury acetate in acetonitrile in the presence of palladium(I1) acetate, gave the C-glycoside (104), whereas reaction in chloroform led to the unusual ring opening and silyl migration reaction shown in
3: Glycosides
43
CH20Tr
The pyrrole and carbazole compounds (105) and (106) were prepared from the dihydrofuran derivative (107) as indicated in
L
(103) R e v d s
L,
Pd(OAc),,
M d N
,k , PclC(OAd),,W U J S c h e m e 41
Scheme 42.1g5 Singlet oxygen addition to the furan (108) afforded the peroxide (109) which could be reduced to the diketone (110) and hence, with ethyl diazoacetate, converted into the pyrazolines (111) (Scheme 43).lq6 Reaction with boron trifluoride of the 1-deoxy-Dfructofuranose (112), available from the lactone by reaction with methyllithium, gave the isomeric C-disaccharides (113) in 9 3 % yield. An indication of the possible mechanism of reaction is given in Scheme 44.1g7
44
Carbohydrate Chemistry
L
-& 3
BzO
Bz 0
/
L -
S c h e m e 44
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5 6 7 8
9 10
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s,
3: G1yroside.s 81 82 83 84 85 86 87
88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103
104 105 106 107 108 108a 109 110 111
112 113
114 115 116 117
47
T.Takano, F.Nakatsubo, and K.Murakami, Cellul. Chem. Technol.. 1988, 22, 135 (Chem. Abstr., 1989, 110, 57 955). S.Hashimoto, T.Honda, and S.Ikegami, J . Chem. S o c . , Chem. Commun.. 1989, 685. A.J.Clark, Biochem. Cell Biol., 1988, 66. 871 (Chem. Abstr., 1989. 110. 71 788). A.J.Clarke and H.Strating. Carbohvdr. Res.. 1989, 188,245. E.M.Nashed and C.P.J.Glaudemans,J. O n . Chem., 1989, s , 6116. T.Shimizu, T.Masuzawa, Y.Yanagihara, T.Itoh, S.Nakamoto, and K.Achiwa, Chem. Pharm. Bull., 1989, 37, 2535. T.Ziegler. P.Kovac, and C.P.J.Glaudemans.Carbohydr. Res., 1989. 194, 185. R.L.Halcomb and S.J.Danishefsky.J. Am. Chem. SOC.. 1989, 111,6661. C.Vincent, J.-M.Coteron,J.Jimenez-Barbero,M.Martin-Lomas. and S.Penedes, Carbohvdr. Res., 1989, 194, 163. J.Thiem, M.Kleeberg, and K.-H.Klaska,Carbohvdr. Res., 1989, 189, 65. P.Ciuffreda, F.Ronchetti, and L.Toma, J. Carbohpdr. Chem., 1989, 8 , 805. H.Baumann, B.Erbing, P.-E.Jansson,and L.Kenne, J. Chem. SOC. Perkin Trans. 1, 1989, 2145, 2153, 2167. S.Jarosz and B.Fraser-Reid, Tetrahedron Lett., 1989, 30, 2359. J.Hlavati, S.Karaksonyi, and J.Alfoeldi, Chem. Pau,, 1988, 42, 519 (Chem. Abstr., 1989. 110. 154 728). C.- S .Kuhn, C.P.J.Glaudemans, and J.Lehmann, Liebigs Ann. Chem. , 1989, 357. V.I.Betaneli, I.A.Kryazhevskikh,A.Ott, and N.K.Kochetkov, Bioore. Khim., 1989, 15,217 (Chern. Abstr., 1989, 111,174 5 4 8 ) . J.Kihlberg, T.Frejd. K.Jansson, S.Kitzing, and G.Magnusson, Carbohydr. Res., 1989, 185, 171. C.Marino. O.Varela, and R.M.De Lederkremer, Carbohvdr. Res,. 1989, 190, 65. I.J.J.Hronowski,W.A.Szarek, G.W.Hay,A.Krebs, and W.T.Depew, Carbohydr. Res., 1989, 190,203. L.J.J.Hronowski,W.A.Szarek. G.W.Hay, A.Krebs, and W.T.Depew, Carbohvdr. Res., 1989, 193, 91. K.-H.Jung,M.Hoch, and R.R.Schmidt, LiebiEs Ann. Chem,, 1989, 1099. D.Cabaret and M.Wakselman, Carbohydr. Res., 1989, 189, 341. M.Trumte1, P.Tavecchia, A.Veyrieres. and P.E.Sinay, Carbohpdr. Res., 1989, 191,29. T.V.Zemlyanukhina,N.V.Bovin, and N.E.Bairamova, Dokl. Akad. Nauk SSSR. 1988, 299. 129 (Chem. Abstr., 1989, 110,8509). L.Hedbys, E.Johansson, K.Mosbach, P.-O.Larsson, A.Gunnarsson, and S.Svensson, Carbohydr. Res.. 1989, 186,217. K.G.I.Nilsson,Carbohydr. Res,, 1989, 188,9. K.Suzuki, H.Maeta. T.Suzuki. and T.Matsumoto, Tetrahedron Lett., 1989, 30, 6879. S.David. A.Malleron, and C.Dini, Carbohydr. Res., 1989, 188,193. A.Marra, X.Dong, M.Petitou, and P.Sinay, Carbohydr. Res., 1989, 195, 39. M.Trumte1, A.Veyrieres, and P.Sinay, Tetrahedron Lett., 1989, 30, 2529. R.W.Friesen, and S.J.Danishefsky,J . Am. Chem. S o c . , 1989, 111,6656. R.L.Baumes, C.L.Bayonove, R.E.Cordonnier. Y.Z.Gunata, R.Wylde, and A.Heitz, Carbohvdr. Res., 1989, 189, 331. T.A.Blizzard. G.Marino, H.Mrozik, and M.H.Fisher. J. Ore. Chem., 1989, 54, 1756. D.Ravi, V.R.Kulkarni, and H.B.Mereyala, Tetrahedron Lett., 1989, 30, 4287. J.Thiem and W.Klaffke, J . Ore. Chem., 1989, 54, 2006. A.Ya Cherniak, A.B.Levinskii, and N.K.Kochetkov, Bioore. Khim., 1988, &, 1047 (Chem. Abstr., 1989. 110, 154 725). R.W.Binkley and D.J.Koholic, .J. Ore. Chem., 1989, 54, 3 5 1 7 . B.Abbaci. J.-C.Florent,and C.Monneret. J. Chem. S O C . , Chem. Commun.,
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15, 223
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G . X u , D.Zhang. and T . G u , Shanehai Yike Daxue Xuebao, 1 9 8 8 , (Chem. Abstr.. 1 9 8 9 , 120. 8 6 9 0 ) .
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111, 7703). 151 152 153 154 155 156
15 7 158 159 160 161 162 163 164 165 166
167 168 169 170 171 172
173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189
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u,
a,
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Carbohydrate Chew isfry D.-I Kwok and G.D.Daves,J. Ore. Chem., 1989, 2 . 4496. Y.-i.Ichikawa,H.Kubota. K.Fujita, T.Okauchi, and K.Narasaka, Bull. Chem S O C . J m . , 1989, 845. F.J.Lopez Herrera, M.S.Pino Gonzalez, M.Nieto Sampedro, and R.M.Dominguez Aciego, Tetrahedron, 1989, 45. 269. F.Freernan and K.D.Robarge, J . Orz. Chem., 1989, 54, 346. 29. R.A.Outten and G.D.Daves, L o r e . Chem., 1989, I.Maeba, T.Takeuchi, T.Iijima, K.Kitaori, and H.Muramatsu, J. Chem. S O C . Perkin Trans. 1. 1989. 649. R.Robles Diaz, F.Garcia Calvo-Flores, L.Alvarez Guardia, and F.J.Lopez Aparicio, Carbohydr. Res., 1989, 191,209. A.Boschetti, F.Nicotra, L.Panza. G.Russo, and L.Zucchelli, J. Chern. Sot., Chern. Commun., 1989, 1085.
u.
s,
4
01igosacc harides
1
General
As before, this Chapter deals with specific tri- and higher oligosaccharides; most references relate to their syntheses by specific chemical methods. It does not deal with compounds made by the oligomerisation of monosaccharide derivatives, nor does it cover the cyclodextrins. The synthesis of, e.a. pentasaccharides is dealt with under that heading, and the required preparations of constituent parts are assumed and are not covered in their
respective sections. Frequently, specific derivatives of the basic compounds are involved and this fact is often not recorded in the structural formulae used. Examples of modified oligosaccharides, which include for example non-carbohydrate spacer units between the sugars, are included for the first time in this section. A review containing 32 references has been published on sequencing methods applicable in the structural analysis of oligosaccharides.' A further review by Whitesides and coworkers has dealt with the enzymic in vitro synthesis of mono-, oligo- and poly-saccharides,' and the effects of several parameters on the yields and selectivities of glycosidase-catalysed formation of oligosaccharide glycosides have been discussed.' The synthesis of structural components of glycopeptides with emphasis on the use of selective protecting groups has been published (in German),' and a further review, also in German, has dealt with the synthesis of "neoglycoproteins" - artificial analogues in which mono- and oligo-saccharides are chemically bound to proteins. The strategies for coupling the sugars to proteins and the applications of the products as drug carriers, antigens and receptor probes are covered.' Methods available for the synthesis of deoxyoligosaccharides found as parts of antibiotics and cytostatics have been described and illustrated for four different trisaccharides of aureolic acids.'
Carbohydrate Chemistry
52 2 2.1
Trisaccharides
Linear H0motrisaccharides.-
1,6-Anhydro-p-maltotriose (1) has
been prepared in 3 3 % overall yield from the polysaccharide pullulan by enzymic degradation followed by conversion to pentachlorophenyl deca-Q-acetyl-p-maltotrioside. A range of derivatives was then described.’ Chemical synthesis of the antigen of Pseudomonas aerogenosa was achieved by polycondensation of the D-rhamnose trimer derivative (2),’ and in related work the 6-aminohexyl glycoside of a-L-Rha~-(1+3)-O-a-L-Rhap-(l+2)-a-L-Rhap was produced.’
The spacer-inserted D-galactose trisaccharide (3) was made for affinity labelling of the “antigalactan“ 2gA x 24” and the similarly p-(1-+6), p-(1+6) linked simple trisaccharide was prepared by use of the glycosylating agent ( 4 ) generated in situ from the corresponding D-pent-4-enyl glycoside.” cH
OH
*
OH
i3)
0s L + :
OALL I
OH
(4;
Isomeric Q-n-D-KDOp-(2-4)-Q-a-D-KDOp-2~2-+4)-~-~-D-KDO~-All and Q - ~ - D - K D O Q - ( ~ - ~ ) - Q - P - D - K D O ~ - ( ~ - + ~ ) - Q - ~ - D -have K D O ~ been -A~~ prepared and copolymerised with acrylamide to afford artificial antigens. 2.2 Linear - Heterotrisaccharides.The passage of D-galactose and sucrose through a column carrying immobilised a-D-galactosidase
_.___
gave access to raffinose - Q-fi-D-Galp-(l-6)-_O-cr-D-Glcp-(1-+2)-P-DFruf - in 17% yield. Similarly, immobilised n-D-galactosidase gave the a,a-linked isoraffinose in 10% yield.” Q-a-D-NeupNAc-(2-~3)-0~ - D - G ~ ~ ~ - ( ~ - ~ ) - ~ - Q - D - G ~ ~ E - O C H ( N , ) C H ( N ~ ) C H ( O B Z )has C H = Cbeen H(CH~)~~M~ converted into gangliosides GM, with three different fatty acids on
4: Oligosaccharides
53
the ceramide moiety.'" Q - B - D - G ~ ~ Q N A ~ - ( ~ + ~ ) - Q - B - D - G ~ ~ E - N A ~ - ( ~ - ~ ) a-D-Glcp-(CH,),CO,Me, carrying a sulphate substituent at 0-3", has been prepared as a 'H nmr standard to demonstrate the absence of 3"-sulphated D-Galp-NAc groups in bovine lutropin." The spacer phosphate - containing trisaccharide derivative (5), a fragment of polysaccharide C of StreDtococcus meumoniae, has been synthesised using 1,6:2,3-dianhydro-p-D-talo~e.~~ The capsular polysaccharides of types 6 A and 6B are potentially available using Q-a-D-Galp(1+3)-Q-a-D-Glcp-(l-+3)-Q-~-L-Rhap which has been prepared for the purpose.'7 The D-glucosamine-containing sialyl glycopeptide Q-a-DNeu~NAc-(2-+6)-Q-p-D-Gal~-(l-+4)-~-~-D-GlcpNAc-(l+4)-L-Asp has been made by successive specific glycosylations from the glucosaminyl amino acid.'" A more complex but related compound (6) CH20H
no
OH
(6)n-4or7
was synthesised by the condensation of 6-deoxy-6-mycolylamino-alatrehalose and an N-acetylmuramyl dipeptide; the product exhibited the biological properties of both its component parts.19
O-~-D-G~C~~NAC-(~-+~)-O-L-~-D-H~~E-(~~~)-Q-L-~-D-H~~~
O(CH,),NH,, containing two units of L-glvcero-D-manno-heptose and related to the core region of Neisseria meninaitides polysaccharide, was made using chain extension with PhSiMe,-CH,MgCl applied to a D-manno dialdose derivative. The oxidative unmasking of the hydroxymethyl groups was carried out at the trisaccharide stage.2o 2-Deoxyhexosyl-containing oligosaccharides can be made from benzylated glycals by the use of phenylselenyl chloride and sugar alcohols followed by radjcal reduction of the carbon-selenium bonds. A derivative of compound (7) was made in this manner."'
54
Carbohydrate Cliemistiy
eNHoO~o/J--!o Me
(7)
2.3 Branched H0motrisaccharides.- Oligosaccharide fragments of Salmonella kentucky Q-antigenic polysaccharides in the form of p-methyl glycosides having D-galactosyl units at 0 - 2 and 0-3 have been synthesised.22 Likewise, the trisaccharide branching point (6-Q-a-D-glucopyranosylmaltose) of starch and glycogen (Vol. 18, p. 2 4 , ref. 21) has been made as the (4-carboxy-2-nitro)benzyl glycoside for linking to polymers or for photorelease.23 The trisaccharide of the inner core region of Citrobacter PCM 187 lipopolysaccharide consists of a (3,7-di-Q-heptosyl)heptose with L-glvcero-D-manno-heptose as the sugar; its synthesis by the method referred to in reference 20 has been reported.24 Branched Heter0trisaccharides.- Transglycosylation of lactose by use of the 8-galactosidase of Asperuillus orvzae gave O-p-D-Galp-(l+4)-Q-[p-D-Galg-(l+6)]-D-G1~.~~ Q-a-D-Galp-(1+3)-Q-[pD-Gl~pUA-(1+2)1-D-Man~~ and eight trisaccharides of methyl a-Dgalactopyranoside having 0 - 3 and 0 - 4 substituted with either Lfucose or D-galactose or D-glucose units2’ have been prepared. In the latter work detailed nmr and theoretical conformational analyses (HSEA and GESA methods) were reported., O-p-D-Galg-(1+4)-Q-[pD-Gl~pUA-(l+3)]-L-Rha~~ and Q-a-D-Galp NAc-(l-3)-Q-[@-D-Glc@JA-(l~4)]-L-Fuc having methyl ether groups at 0-3 and 0-4 of the two substituent sugars, respectively, have been synthesised.29 With aminosugars at the reducing termini Q-p-D-Galp-(1-3)-Q[a-D-Neu5Ac-(2+6)]-Q-a-D-GalNA~-(1+3)Ser~~ and 0-p-D-Galp-(and Q-aL-Fuc~)-(1-+3)-Q-[p-D-GlcpNAc-(1+6)]-D-GalpNA~~~ have been prepared as has the trisaccharide of the inner core region o f lipopolysaccharides: Q - L - ~ - D - H ~ ~ E - ( ~ - + ~ ) - [ ~ - D - K D O Q - ( ~ + ~ ) ] - D - K D O where the heptose is L-glv~ero-D-manno-heptose.~~ 2.4
3
Tetrasaccharides
As with the trisaccharides, the following tetrasaccharides are
classified according to whether they have linear or branched
4: Oligosaccharides
55
structures, and then by the nature of the sugars at the reducing termini. Linear Homotetrasaccharides.- Cyclo-oligomerisation of the isomeric ( 8 ) and ( 9 ) under Helferich conditions gave the unbranched tetramers (10) and (ll), respectively, as well as the dimer and trimer from the latter trityl ether.33 3.1
4
3.2 Linear Heter0tetrasaccharides.Compounds of this category having D-glucose as the reducing terminal sugar are as follows:
O-~-D-G~~~NA~-(~~~)-~-~-D-M~~~-(~-~)-Q-~-D-G~C~-(~+~)
All,34Q - ~ - D - G ~ ~ ~ - ( ~ - ~ ) - Q - ~ - D - M ~ ~ E N A C ( ~ + ~ ) - ~ - B - D - G ~ C E - ( ~ ~ ~ ) - Q Gl~g-(CH,).C0pe,~*Q-,3-D-Galp(l-t3)-Q-p-D-GalgNAc-(l+4)-Q-p-D-Galg(1+4)-O-8-D-GlcgCH,CH,TMS,36 o-a-L-FUCg-(1+3)-Q-8-D-GlcgNAc-(l+3)-Q-
8-D-Galg-( 1+3 ) -Q-~-D-Glc~CH,CH,C,H,NHCOCF,,
37
Q-a-D-NeuENAc-( 2+8 ) -Q-a-
D-NeugNAc-(2+3)-Q-~-D-Gal~-(l-4)-Q-~-D-Glcg-~eramide,~~ and Q-p-DGalg-(1-4)-Q-~-D-GlcgNAc-(l-3)-~-p-D-Galg-(l-4)-Q-p-D-Glc~-
ceramide.39 Analogues containing a pseudo-sugar (h. the tetramer dihydroacarbose) and a phosphate spacer group have been synthesised and are illustrated in (12)40and (13),a1respectively.
OH I
OH
OH
OH
OH
The ribitol-containing analogue (14) has also been prepared.12 Other tetramers to have been synthesised
Curbohydrate Chemistty
are: ~-a-D-KDO-(2+4)-~-a-D-KDO-(2-r6)-Q-B-D-GlcpNH,-(1-6)-D-G1CpNH,43 and ~ - ~ - D - G ~ ~ ~ N A ~ - ( ~ + ~ ) - Q - ~ - D - G ~ ~ ~ - ( ~ ~ ~ ) - Q - ~ - D - G ~ C ~ N A C Gal,44the latter being sulphated at 0-6 of all the sugars other than that of the reducing moiety. The following 6-deoxyhexose tetramer was isolated from the tuber of Merremia mammosa and also synthesised: o-a-L-Rhae-(1+4)-Q-a-L-Rhap-(l+4)-o-a-L-Rhae-(l+2)-pD-Fucp.45 3.3 Branched Heter0tetrasaccharides.- Syntheses of the following compounds have been reported: Q-p-D-Galp(1+4)-Q-[a-L-Fucp-(l+3)]O - ~ - D - G ~ C ~ N A ~ - ( ~ - ~ ~ ) - Q - ~ - D - G ~ ~ ~ -Q-p-D-Galp-(1+4)-Q-p-DC~H~NHCOCF~,~~ GlcpNAc-Q-[p-D-Gl~pNAc-(l-+3)]-Q-a-D-Galp-Ser,~~ Q-B-D-Xylp-(1+2)-Q[a-D-Manp-(1-3)]-o-[~-D-Man~-(l+6)]-Q-p-D-ManpMe,~~ Q-L-Fucp-(1+2)O - D - G ~ ~ ~ - ( ~ - ~ ) - Q - [ L - F U C ~ - ( ~ + ~ ) ] - D and - G ~ Q-a-D-NeUpNAC-(2-3)~NH,,~~
~-B-D-G~~~-(~+~)-Q-[Q-D-N~U~NAC-(~+~)]-~-D-G~~~NAC-S~~.~~
The branched tetrasaccharide lactones calonyctin A, (15) and A, (16) have been reported, their structures having been established by 2D 'H and 'C n.m.r. methods and by FAB mass spectrometry."' A related 6-deoxyhexose tetrasaccharide lactone is noted in Chapter 7. 4
Pentasaccharides
4.1 Linear Pentasaccharides.- The total synthesis of the Forssman glycolipid, Q - Q - D - G ~ ~ ~ N A c - ( ~ + ~ ) - Q - ~ - D - G ~ ~ Q N A c - ( ~ - + ~ ) - Q - ~ Gal~-(1-r4)-~-~-D-Galp-(l~4)-Q-~-D-Glcp-ceramide,"z and the ParaForssman isomer, which has the same structure but with the nonreducing terminal unit p-lir~ked,~~ have been reported. Similarly, the pentasaccharide sialyl lactotetraosyl ceramide, Q-a-D-NeuNAc( 2 + 3 ) - ~ - p - D - G a l p - ( 1 - 3 ) - ~ - ~ - D - G l c e N A c - ( I - ~ - D -
Glcp-~eramide,~" and the isomeric sialyl neolactotetraosyl ceramide, which has a 1+4 linkage between the D-galactose and the N-acetylglucosamine have been synthesised. A pentasaccharide comprising five a-(1+2) linked 4-deoxy-4formamido-D-rhamnose units has been prepared as a potential antigenic determinant of the Brucella A polysaccharide,""and
57
4: Oligosaccharides
likewise isomers composed of the same a-D sugar (1+3), (1-2), (1-2), (1-2) and (1+2), (1+2), (1+2), (1+3) linked have been made for similar purposes related to the Brucella M polysaccharide.” Synthesis of the N-acetylated heparin pentasaccharide (17) has been completed, the compound having 600 times less and anticoagulant activity than does the N-sulphated several sulphated and non-sulphated pentasaccharides corresponding to units of E. coli K5 glycosaminoglycan have been synthesised.59 Compound (18), a highly reactive glycosylating agent, was used to prepare the pentasaccharide analogue which is the core oligosaccharide of the surface glycoprotein of TrvDanosoma brucei
u. O-a-D-Mang-(1+2)-O-a-D-Man~-(l+6)-O-a-D-Mang-(l+4)-Q-~-D-GlcgNH,-l-m-inositol . 6 0 4.2
Branched Pentasaccharides.-
Q-@-D-Galg-(1-4)-Q-p-D-Glc~NAc-
(1+6)-~-[~-D-Ga1~-(1-3)]-Q-p-D-Galg-(l-4)-D-Glc has been isolated
from horse colostrum,61and a-D-Neug-NAc-(2+3)-Q-p-D-Galg-(l-3)-Q-
CH,OSO,-
CH2 0 5 03-
CO;
HO~
o NHAc
OH
CH*050j-
~ NH Ac
NH Ac
o
~
oso;
[~-D-Fuc~-(1-4)]-~-~-D-Glcg-NAc-(l+X)-p-D-Gal~-oR, where X = 3 or 6 and R = O(CH,),CO,Me, have been made by consequential use of porcine (2-3)-a-sialyltransferase and human milk a-L-fucosyltransferase on chemically prepared trisaccharides.62 A branched pentasaccharide containing a macrocyclic lactone ring related to that in compounds (15) and (16) is mentioned in Chapter 7.
o
58
Carbohydrate Chemistry 5
Hexasaccharides
This section does not aim to cover the cyclodextrins comprehensively; the following however, are some references observed: a monograph has been published on the compounds covering their structures, derivatives, inclusion compounds and methods of preparation"' and a collection of invited papers dealing mainly with inclusion complexes has appeared.64 Cyclodextrin glucosyltransferase applied to 6'-Q-methyl-a-maltosyl fluoride yielded 6A,6C,6E-tri-Q-methylcy~lomaltohexaose.65 Chemical approaches to the cyclodextrins have been reviewedIs6and a synthesis of cyclomannohexaose has been The linear hexasaccharide Q-a-L-Rhag-(1-2)-Q-a-L-Rhap-(l+3)~-a-L-Rha~-(1-3)-~-p-D-Glc~NAc-(l~2)-~-~-L-Rhap-(l-2)-~-a-L-Rha~Pr, the hapten of Shisella flexneri variant Y polysaccharide, has been
characterised by 2D NMR and synthesised. In the series of branched hexasaccharides the ganglioside O-~-D-G~~~-(~-~)-~-~-D-G~~~NAC-(~~~)-~-[~-N~UNAC-(~~~
(2-3)]-Q-p-D-Galp-(1-4)-O-8-D-Glce-ceramide has been synthesised as a dilactone." Several complex hexasaccharides have been isolated as triterpene glycosides from the bulbs of Muscari armeniacum71 and others as diosgenin glycosides from a Liliaceae member."
6
Hiuher Oliaosaccharides
Compound (19) has been isolated from human milk" and compound ( 2 0 ) , a core glycoheptaose of I1bisected" complex glycans of a glycoprotein, has been synthesised.'" Octasaccharides comprising a pcyclodextrin having 1-thio-aand p-D-glucopyranose bonded to C-6 have been made via the 6-deoxy6-iodo and 7-cyclodextrins substituted at 0-2 and 0-6 with arylsulphonate esters, when cleaved with Taka-amylase A , gave a set of acyclic monosubstituted oligosaccharides which led to proposals regarding the binding of various hydroxyl groups to the enzyme.76 A nonasaccharide corresponding to compound (19) with a-L-fucopyranosyl units bonded to 0 - 2 of the terminal p-Dgalactosyl moiety and to 0 - 3 of the neighbouring unit has been isolated from human milk," and the tumour-associated compound (21) has been synthesised.'" T. Ogawa and Nakahara have made the propyl glycoside of a(1+4)-linked decagalacturonic acid, an endogenous phytoalexin
4: 01igosaccharides
59
elicitor substance, by a process involving C-6 oxidation of the decagalactose ana10gue'~ and these workers have also described the synthesis of the analogous dodecamer.'' Phytochemical studies have also led t o the synthesis of 32,3",36-tri-Q-p-D-
glucopyranosylgentioheptaose by block synthetic strategy."' ~-NeupNAc-(2-6)-~-~-D-GalE-(l-r4)-Q-~-D-Glc~NAc-(l-3)-~-~-D-Gal~-(1-4)-D-Glc 6
t 1
Q-j3-D-Galp-(1-+4)-Q-#?-D-Glc~NAc (19)
a - D -Mane 1
1 6
~ - ~ - D - G ~ ~ ~ N A ~ - ( ~ - * ~ ) - ~ - ~ - D - M ~ ~ ~ - ( ~ - ~ ) - ~ - ~ - D - G ~ ~ ~ - N A ~ - ( ~ ~ 1
6
t
t 1
1
a - D -Man2
a -LFucp
[ ~ - ~ - D - G ~ ~ ~ - ( ~ ~ ~ ) - ~ - ~ - D - G ~ C ~ N A ~ - ( ~ - ~ ~ ) ] ~ - ~ - ~ - D - G ~ ~ ~ - ( 3
3
t
t
1
a-L-Fucp
1
a-L-F
uc~
References J.K.Welply, Trends Biotechnol., 1 9 8 9 , 1, 5 (Chem. Abstr,, 1 9 8 9 ,
u, 150
625).
E.J.Toone, E.S.Simon, M.D.Bednarski, and G.M.Whitesides, Tetrahedron, 1 9 8 9 ,
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K.G.I.Nilsson, Ann. N. Y. Acad. Sci., 1 9 8 8 , 542 (Enzyme Eng. 9 ) , 3 8 3 (Chem. Abstr., 1 9 8 9 , 111,22 100). C.Unverzagt and H.Kunz, GIT Fachz. Lab,, 1 9 8 8 , 2 , 5 9 9 (Chem, Abstr., 1 9 8 9 ,
110,8 5 9 5 ) . F.J.Buchholzer and J.M.J.Tronchet,Epitheor. Klin. Farmakol. Farmakokinet., Int.Ed., 1 9 8 8 , 2, 17 (Chem, Abstr., 1 9 8 9 , 110,1 7 9 2 4 ) . J.Thiem, ACS Svmo. Ser., 1 9 8 9 , 3 8 6 (Trends Svnth. Carbohvdr. Chem,), 1 3 1 (Chem. Abstr., 1 9 8 9 , 111,7 7 0 4 ) . N.Sakairi, M.Hayashida, and H.Kuzuhara, Carbohydr. Res., 1 9 8 9 , 185,9 1 . Y.E.Tisvetkov, L.V.Backinowsky, and N.K.Kochetkov, Carbohydr. Res., 1 9 8 9 ,
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Yu.E.Tsvetkov, A.V.Bukharov, L.V.Bakinovsky, and N.K.Kochetkov, Bioore. Khim., 1 9 8 8 , l4, 1 4 2 8 (Chem. Abstr., 1 9 8 9 , 111,7 7 0 1 ) .
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Cnrboliydrnte Clwmimy
10
C.P.J.Glaudemans,J.Lehmann, and M.Scheuring, Aneew. Chem. Int. Ed. Envl,, 1989, 28, 1669. P.Konradsson and B.Fraser-Reid, J. Chem. SOC., Chern. Commun,, 1989, 1124. P.Kosma, G.Schulz, F.M,Unger, and H.Brade, Carbohvdr. Res., 1989, 190,191. K.Ajisaka and H.Fujimoto, Carbohvd-, 1989, 185,139. T.Murase, H.Ishida, M.Kiso, and A.Hasegawa, Carbohydr. Res., 1989, 188,71. V.Srivastava and O.Hindsgau1, Carbohvdr. Res,, 1989, 185,163. J.P.G.Hermans,G.E.Dreef, P.Hoogerhout, G.A.van der Marel, and J.H.van Boom, Recl. Trav. Chim. Pavs-Bas, 1988, 107, 600 (Chem. Abstr,, 1989, 110, 231 986). T.M.Slaghek,M.J.van Vliet, A.A.M.Maas,J.P.Kemerling, and J.F.G.Vliegenthart,Carbohvdr. Res,, 1989, 195,75. C.Auge, C.Gautheron, and H.Pora, Carbohvdr. Res., 1989, 193,288. H.Ishida, Y.Ogawa, Y.Imai, M.Kiso, A.Hasegawa, T.Sakurai, and I.Azuma, Carbohydr. Res., 1989, 194,199. G.J.P.H.Boons,M.Overhand, G.A.van der Marel, and J.H.van Boom, Anvew. Chem. Int. Ed. End,, 1989, 28, 1504. M.Perez and J.-M.Beau,Tetrahedron Lett,, 1989, 0, 75. O.A.Nechaev,V.I.Torgov, and V.N.Shibaev, Bioore. Khim,, 1988, 14,1224 (Chem. Abstr., 1989, 111,7692). S.Kopper and V.Zehavi, Carbohvdr. Res., 1989, 193, 296. G.J.P.H.Boons,M.Overhand, G.A.van der Marel, and J.H.van Boom, Carbohvdr, Res., 1989, 192, C 1 . E.Deya, S.Yanahira, and S.Igarashi, Yukiiirushi NVUFVO Kenkyusho Hokuku, 1988, 133 (Chem. Abstr., 1989, 110,213 222a). A.K.Sarkar, A.K.Ray, and N.Roy, Carbohydr. Res., 1989, 190, 181. H.Baumann, B.Erbing, P.-E.Jansson,and L.Kenne, J. Chem. SOC,, Perkin Trans. 1 , 1989, 2145, 2153, 2167. A.K.Ray, A.K.Sarkar, and N.Roy, J. Carbohydr. Chem., 1989, 8 , 357. O.Kanie, T.Takeda, and Y.Ogihara, Carbohvdr. Res., 1989, 190, 53. H.Iijima and T.Ogawa, Carbohvdr. Res,, 1989, 186,95. R.L.Thomas, J.F.Rutan,S.A.Abbas, and K.L.Matta,Carbohpdr. Res., 1989, 189, 21. H.Paulsen and A.C.Heitmann, Liebivs Ann. Chem., 1989, 655. L.V.Bakinosky, S.A.Nepogod'ev, and N.K.Kochetkov, Bioorg. Khim., 1988, 14, 1122 (Chem. Abstr,, 1989, 110, 154 727). S.H.Khan, S.A.Abbas, and K.L.Matta, Carbohvdr. Res., 1989, 193, 125. H.Paulsen, and B.Helpap, Carbohvdr. Res., 1989, 186, 189. K.P.R.Kartha,A.Kameyama, M.Kiso, and A.Hasegawa, J. Carbohydr. Chem., 1989, 8 , 145. T.Norberg and M.Walding, GlvcoconiuPate J . , 1988, 5 , 137 (Chem. Abstr., 1989, 110,24 195). Y.Ito, M.Numata, M.Sugimoto, and T.Ogawa, J. Am. Chem. SOC,. 1989, 111, 8508. R.Bommer and R.R.Schmidt,LiebiPs Ann, Chem., 1989, 1107. M.Hayashida, N.Sakairi, H.Kuzuhara, and M.Yajima, Carbohvdr. Res., 1989, 194, 233. G.H.Veeneman, L.J.F.Gomes,and J.H.van Boom, Tetrahedron, 1989, 45, 7433. J.P.G.Hermans,D.Noort, G.A.van der Marel, P.Hoogerthout, and J.H.van Boom, Recl. Trav. Chim. Pavs-Bas, 1988, 107, 635 (Chem. Abstr., 1989, J J Q , 231 988j) . H.Paulsen and C.Kragrnann,Liebigs Ann. Chem., 1989, 1203. M.Kobayashi, F.Yamazaki, Y.Ito, and T.Ogawa, Tetrahedron Lett., 1989, 3 0 , 4547. I.Kitagawa, N.I.Baek, K.Ohashi, M.Sakagami, M.Yoshikawa, and H.Shibuya, Chem. Pharm. Bull., 1989, 1131. B.Classon, P.J.Garegg,and A.C.Helland, J. Carbohydr. Chem,, 1989, 8 , 543. W.Kinzy and R.R.Schmidt, Carbohvdr. Res,, 1989, 193,33. J.Kerekgyarto, J.P.Kamerling, J.B.Bouwstra,J.F.G.Vliegenthart.and A.Liptak, Carbohydr. Res., 1989, 186, 51. S.Nilsson, H.Loenn, and T.Norberg, Glvcoconiueate J,. 1 9 8 9 , 6 . 21 (Chem, Abstr., 1989, 111, 174 559).
11 12 13 14 15 16
17 18 19 20 21 22
23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
x,
4: Oligosucchurides 50 51 52 53 54 55
H.Iijima and T.Ogawa, Carbohvdr. Res,, 1 9 8 9 , 186,107. Y.Hu, Q.Guo, R.Pastor, G.Serratrice, A.Cambon, and C.Bosso, Youii Huaxue, 1 9 8 9 , 9 , 1 4 6 (Chem. Abstr,, 1989, IJJ, 214 8 3 1 ) . S.Nunomora, M.Mori, Y.Ito, and T.Ogawa, Tetrahedron Lett., 1989, 30, 6713. S.Nunomura, M.Mori, Y.Ito, and T.Ogawa, Tetrahedron Lett,, 1989, 30, 5619. A.Kameyama, H.Ishida, M.Kiso, and A.Hasegawa, Carbohvdr. Res,, 1 9 8 9 , 193, c1. A.Karneyama, H.Ishida, M.Kiso, and A.Hasegawa, J. Carbohvdr. Chem., 1989, 8 , 799.
56 57 58 59
61
a,
60
T.Peters and D.R.Bundle, Can. J. Chem., 1989, 491. T.Peters and D.R.Bundle, Can. J. Chem,, 1989, fl, 497, H.P.Wesse1, L.Labler, and T.B.Tschopp, Helv. Chim. Acta, 1989, 1268. N.A.Kraaijeveld and C.A.A.van Boeckel, Recl. Trav. Chim. P a w - B a s , 1989, 1 0 8 , 39 (Chem. Abstr., 1989, 111,1 7 4 5 4 7 ) . D.R.Mootoo, P.Konradsson, and B.Fraser-Reid, J. Am. Chem. Sac,, 1989, 111,
61
T.Urashima, T.Sakamoto, H.Ariga, and T.Saito, Carbohydr. Res, , 1989,
a,
8540.
194,
280, 62 63 64 65 66 67 68 69
M.M.Palcic, A.P.Venot, R.M.Ratcliffe, and O.Hindsgau1, Carbohvdr. Res,, 1 9 8 9 , 190,1. Monograph "Cyclodestrins Their Industrial Uses", Ed: D. Duchene Ed. Sante, Paris, Fr. Carbohydr. Res,, 1989, 192, 1 - 3 6 9 . S.Cottaz and H.Driguez, J. Chem. SOC., Chem. Commun., 1989, 1 0 8 8 . Y.Takahashi and T.Ogawa, ACS Symp. S er,, 1989, (Trends Svnth. Carbohydr. Chem,), 150 (Chem. Abstr,, 1989, 111,23 8 2 2 ) . M.Mori, Y.Ito, and T.Ogawa, Carbohydr. Res,, 1989, 192, 1 3 1 . M.Mori, Y.Ito, and T.Ogawa, Tetrahedron Lett., 1989, 30, 1273. B.M.Pinto,K.B.Reimer, D.G.Morissette, and D.R.Bundle, J. Orp. Chem,, 1989,
54,
2650.
70
G.Fronza, G.Kirschner, D.Acquotti, and S.Sonnino, Carbohydr. Res,, 1 9 8 9 ,
71
M.Adinolfi, G.Barone, M.M.Corsaro,L.Mangoni, R.Lanzetta, and M.Parilli, Can. J. Chem., 1988, 66, 2187. S.Chen and J.K.Snyder, J. Ore. Chem,, 1989, 2 , 3679. M.T.Tarrago, H.K.Tucker, H.van Halbeek, and D.F.Smith, Arch. Biochem, BioDhys,, 1988, 267, 353 (Chem. Abstr., 1989, 110, 92 4 6 7 ) . F.Yamazaki, T.Nukada, Y.Ito, S.Sato, and T.Ogawa, Tetrahedron Lett,, 1989, 30, 4417. S.Cottaz and H.Driguez, Synthesis, 1989, 755. K.Fujita, T.Tahara, T.Koga, and T.Imoto, Bull. Chem. SOC. JDn., 1989, 62,
195, 51. 72 73 74 75 76
3150. 77 78 79 80 81
G.Gronberg, L.Lipniunas, T.Lundgren, K.Erlansson, F.Lindh, and B.Nilsson, Carbohydr. Res,, 1989, 191, 261. M.Nilsson and T.Norberg, J. Carbohydr. Chem,, 1989, 8 , 613. Y.Nakahara and T.Ogawa, Carbohvdr. Res,, 1989, 194,9 5 . Y.Nakahara and T.Ogawa, Tetrahedron Lett,, 1989, 30, 87. W.Birberg, P.Fugedi, P.J.Garegg, and A.Pilotti, J. Carbohvdr. Chem., 1989,
8,
47.
5
Ethers and Anhydro-sugars
1 Ethers Methyl Ethers. - A short synthesis from L-arabinose of 2,6-dideoxy-3-Q-methyl-Larabino-hexose, suitable for large scale work, features the selective methylation (CH,N,,SnCl,,DME) of the 5-deoxy-arabinosederivative (1) giving a 94% yield of the 2-@methyl ether (2).' Acyl migration was observed during methylation (Ag,O, MeI, CHC1,) of 2,5-di-Q-benzoyl-L-rhamnono-1,4-lactone so that 3,5-di-Q-benzoyl-2O-methyl-L-rhamnono-l,4-lactone was the product obtained. This was converted into 2-Q-rnethyl-L-rhamno~e.~ A five step synthesis of methyl 2,6-di-Q-methyl-a-Dglucofuranoside from 1,2-Q-isopropylidene-a-D-glucofuranose has been described., Methyl ethers of methyl a-L-arabinofuranoside have been synthesised in a partial methylation study which employed standard reagents., The methyl ether (3) has
qoR (1)
CI 0
Me
R= H
(2) R = Me
oaz
(3) R = Me (4) R =
H
been selectively deprotected to the parent alcohol (4) by use of BF,.OEt, and Bu,M.' Some Q-methyl derivatives of methyl j?-D-galactobiosidehave been and the synthesis of a tri-Q-methyl-cyclomaltohexaoseis discussed in Chapter 4. Other Alkvl and ATyl Ethers. - The reagent system of allyl ethyl carbonate and a Pd( 0) catalyst, applied to carbohydrate alcohols, has been utilised for making allyl ethers under neutral conditions.' The synthesis of benzyl ethers from the parent alcohols under non-basic conditions has been achieved using phenyldiazomethane and HBF,? Dibutylstannylene compounds derived from benzyl 8-D-lactoside and its derivatives have been regioselectively benzylated." Similarly, 2,2 '-di-Q-alkylhave been prepared by regioselective 4,6:4 '6 '-di-0-benzylidene-@,a-trehaloses alkylation of a dibutylstannylene derivative." Phase transfer catalysed benzylation
5: Ethers and Anhydro-sugars
63
of benzyl 4,6-Q-benzylidene-/?-D-galactopyranoside afforded predominantly the corresponding 3-benzyl ether.12 Alkylation and subsequent hydrolysis of oxazoIine (5) has given access to 2acetamido-3-Q-alkyl-2-deoxy-D-glucose derivatives such as the corresponding 3benzyl ether and &I-acetylmuramic acid.13 A D-glucose ether of a hydroporphyrin has been synthesised and shown to have improved in vivo activity as a tumour photo~ensitiser.'~Some 6-~-(2-alkoxycarbonylallyl)-1,2:3,4-di-~-isopropylidene-a-Dgalactopyranoses have been synthesized and co-polymerised with maleic anhydride to yield poly(viny1saccharides) after removal of the acetonide protecting groups by hydrolysis. l5 "'0-&o \
K
o
H
Jo\/ x - H,Me
x
b%-
The alkoxy dienes ( 6 ) containing a chiral carbohydrate auxiliary each undergo a highly stereoselective Diels-Alder reaction with naphthoquinone affording adducts (7).16 The vinyl ether (8), on treatment with tosyl isocyanate, stereoselectively produced the /?-lactam derivative (9).17 (10)
R'=R7=R3=
(11)
R'= R3= B n , RZ= Me
(12) R1=R2= Bn
On
R3=
~
H
(13) R ' C B n , RZ=Me, R 3 = H
(9 )
(14) R1- R3= Bn
~
R 3 = Me
(15) H ' = B n , R 2 = H , R3= Me.
Some benzyl ether derivatives of 1,6-anhydro-fl-D-mannopyranose have been selectively debenzylated using stannic chloride. Thus, both the tribenzyl ether (10) and the 3-0-methyl derivative (11) afforded seIectively the 2-mono-01s (12) and (13) respectively, whereas the 2-methyl ether (14), under the same conditions, generated the 3-mono-01 (IS).'' Some sugar 3,4-dimethoxybenzyl ethers and and 4,8dimethoxynaphthylmethyl ethers have been selectively cleaved to generate the sugar alcohols in moderate to good yield by a photochemical single-electron transfer reaction, using dicyanonaphthalene and anthraquinone as electron acceptors." Macrocycles (16) and (17) have been prepared from diol (18), and their binding with ammonium salts and use as catalysts in asymmetric Michael additions has been studied.20 Treatment of methyl 2,3-anhydro-4,6-Q-benzylidene-a-Dallopyranoside with ethanolamine gave a product that was converted into the mono-
Carbohydrate Chemistry
64
aza crown ether (19).21
&
('9)
Silvl Ethers; Attempted preparation of trimethylsilylmethyl ethers of sugar alcohols by their treatment with Me,SiCH2T and sodium hydride has led only to mixtures of trimethylsilyl ethers and methyl ethers.22 A series of papers reporting the synthesis and hydrolytic stability of a number of 3 ',5 '-Q(dialkylsilanediy1) derivatives of uridine, adenosine and thymidine is discussed in Chapter 20. 2 Intramolecular Ethers (Anhvdro-Sugars) Oxirans. - Glycal derivatives have been treated with dimethyl-dioxiraneaffording 1,2-anhydro-sugarswith the stereo-chemistry determined by the orientation of the substituent at C-3. 3,4,6-Tri-Q-tert-butyldimethylsilyl-D-glucal afforded the 1,2anhydride (20) as the only product, and 4,6-Q-benzylidene-3-Q-tert-
butyldimethylsilyl-D-allal gave only (21) (Scheme 1).= Glycosylation reactions of these epoxides and the reaction of some analogous 1,2-epoxides with organocuprates are covered in Chapter 3. Separate syntheses affording unambiguously 1,2-anhydro3,4:5,6di-Q-isopropylidene-D-glucitol, and -D-mannitol from D-glucono-1,5-lactone have been carried 0ut.2~Phase-transfer conditions have been utilised for the monotosylation of a 1,2-dioland then the in situ formation of an epoxide.25 An unexplained reversal in the ratio of secondary to primary alcohol product, from 151
5: Ethers and Anhydro-sugars
05
using GI, to 1:5 using MgI,, was observed in the one-pot reductive cleavage of
Reage&
L, L L I ,B u 3 5 n H , A I B ~ u,M91L,Du3SnY,H18N ,
Scheme 2
epoxide (22) (Scheme 2), which is presumed to proceed via initial opening of the epoxide with halide.% The formation of some anhydro derivatives in low yield during the treatment of sucrose under Mitsunobu chlorinating conditions (DIAD, PPh,, ZnCl,(Py),) has been noted.27 Enzymic hydrolysis of racemic epoxide (23) with microsomal epoxide hydrolase gave, with 50% conversion, the L-sugar (24) and recovered D-epoxide (25) in >96% ee.=
0 Me
o
B
U
L
R 2 R': 6 R3 R 4
o&N3
OH O5uL (23) D,L ( 2 5 ) D
HO
'**4
R3
(241
(26)
,:
N ( 2-9
(26) (R'=OBn, R2=H, R3=H, The treatment of some azidoepoxides, R4=Me; or R'=H, R2=OBn, R3=Me, R4=H; or R'=OBn, R2=H, R3=OBn, R4=H) with triphenylphosphine under aprotic conditions affords l-azabicyclo[3.l.0]hexanes, (27):' The conversion of a 3,4-anhydro-fructose derivative into 4-deoxy-fructose is covered in Chapter 12. A total synthesis of the a-glucosidase inhibitor acarbose, featuring a nonregioselective opening of a 3",4"-anhydro-l,6-anhydro-maltotriose derivative is outlined in Chapter 18, while the Sharpless epoxidation of an octose nucleoside allylic alcohol is discussed in Chapter 20. The selectivity of some carbon nucleophiles in opening some 1,6:2,3-and 1,6:3,4- dianhydro-hexose derivatives is mentioned in Chapter 14 as is the opening of an epoxide by a reagent bearing an electrophilic carbon atom. Other Anhvdrides.- Procedures for the large scale synthesis of 1,6anhydrohexopyranoses have been outlined whereby the free sugars are selectively tosylated at 0 - 6 and the products are treated with base.3oi31The heating of starch or other (1+4)-glucansin a conventional microwave oven yields 1,6-anhydro-fl-D-
66
Carbohydrate Chemistry
glucopyranose within a few minutes?2 Some partially protected 1,6-anhydrosugars have been prepared as synthons for oligosaccharide synthesis by acid catalysed anhydride formation of the respective 6-hydroxy methyl gly~osides.3~ 1,6-anhydro-bmaltotriose has been synthesized in 33% overall yield from the polysaccharide pullulan by way of enzymic degradation followed by chemical manipulation pentachlorophenyl deca-Q-acetyl-p-maltotrioside.34Calculations on the chair-boat equilibrium for 1,6-anhydro-~-D-glucopyranose have been de~cribed.3~ Controlled oxidation of penta-Q-acetyl-D-glucose diethyldithioacetalgave the mono-sulphoxide (28) which, on treatment with sodium methoxide in methanol gave, after acetylation, the 2,5-anhydro-D-mannosederivative (29) which was converted into the diethyl acetal (30)?6 Attempted nucleophilic displacements applied to the a-L-fucopyranoside triflate (31) and its b-anomer with a variety of nucleophiles
AcO OAc
OAc
(29) X = SOEt,SEt CH20Ac
(3’) ( 3 2 ) X = F, OMe,OBz, N3, H
(30) X = O E t
(29
under mild conditions led to the 2,5-anhydro-sugarcompounds (32), the nucleophiles having attacked the anomeric carbon and the sulphonyloxy group having been displaced by the C-1-0-5 bond. The same type of ring contraction occurred with methyl 4-Q-benzyl-3-Q-(4-methoxybenzyl)-2-Q-trifluoromethanesulphonyl-cr-L-fucopyranosideand with methyl 4,6-dideoxy-3-Q-(4-methoxybenzyl)-2O-trifluoromethanesulphonyl-a-L-~&-hexopyranoside.~’ In an attempt to prepare 2,5-anhydro-sugar derivatives, 5-Q-ptoluenesulphonyl dialkyl dithioacetals (33) of Garabinose were heated under basic conditions. Moderate yields of the desired compounds (34)were formed together with the thioglycosides (35) produced following participation of sulphur in the displacement p r o c e s s e ~ .Tosylation ~~ of C H (SR);!
G0q
coy
CH20T.S
C H(5R)2
@ H O T =
OR,
HO CHzOTS
(34)
( 33)
RSCH2
OH
(35)
(36) R =R‘=
H
(37) R = T ~ , R ‘ = H
(39) R=R’=TS
5: Ethers and Anhydro-sugurs
67
pyridine solutions of xylitol has given selectively either the mono-(36), di-(37), or tritosylate (38) 2,5-anhydro-D,Gxylitol derivatives depending on the quantities of toluenesulphonyl chloride and the temperatures used.39 Photolysis of the benzyl ether (39) produced a 5:l ratio of the cyclised
'
(39)
products (40)and (41).40 While conventional partial esterification of 1,4:3,6dianhydro-D-glucitolis directed towards the 5-endo position, the 2 - a position has been regioselectively esterified by forming the dialkoxide and subsequent treatment with pivaloyl chloride!' Standard tritylation of the above starting material has also afforded 1,4:3,6-dianhydro-2,5-di-Q-trityl-D-gl~citol.~~ A periodate oxidation/reduction sequence applied to (6s)-(6-2H)-1,6-anhydro-J-Dgalactopyranose has been used to prepare (I$)-( l-2H)-~-glycerol~3 References 1 2
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
23 24 25
R.L. Tolman and L.H. Peterson, Carbohvdr. Res.,1989,189. 113. LO. Jeroncic, M.L. Smaidman, AF. Cirelli and R.M. de Lederkremer, Carbohvdr. Res., 1989,191. 130. k Mukherjee and N. Roy, Indian J. Chem., Sect. B, 1988,27B, 1037 (Chem. Abstr, 1989,111.7 695). EV. Evtushenko, S.E. Kraeva and Yu S. Ovodov, Bioore. Khim., 1989,15,534 (Chem. Abstr.. 1989, 111.233 395). S.V. Ley and F. Sternfeld, Tetrahedron, 1 9 8 9 , s 3463. J. Kihlberg, T. Frejd, K Jansson, S. Kitzing and G. Magnusson, Carbohvdr. Res., 1989,185. 171. J. Kihlberg, SJ. Hultgren, S. Normack and G. Magnusson, J. Am. Chem. Soc., 1989,111.6364. R. Lakhmiri, P. Lhoste and D. Sinou, Tetrahedron Lett., 1989.304669. LJ.Liotta and B. Ganem, Tetrahedron Lett., 1 9 8 9 , a 4759. T. Yoshino, M. Sadamitsu, M. Minagawa, G. Reuter and R. Sichauer, Glvcoconiupate J., 1988, 377 (Chem. Abstr., 1989,111. 23 819). C.Vicent, M. Martin-Lomas and S. Penades, Carbohvdr. Res.. 1989,194.308. G. Garcia-Fernandez, V. Verez Bencomo, M.T. Campos Valdes and C.S. Perez, Rev. Cubana Quim., 1987,L 73 (Chem. Abstr., 1989,110,8 499). H. Merten and R. Brossmer, C a r b o h v d r a 1989,191. 144. R. Bonnet, AN. Nizhnik and M.C. Berenbaum, J. Chem. SOC..Chem. Commun., 1989, 1822. J. Klein and K Blumenberg, Makromol. Chem., 1988,189,805 (Chem. Abstr., 1989,110, 8 516). C.W. Bird and k Lewis, Tetrahedron Lett., 1 9 8 9 , a 6227. Z Kaluza,W. Fudong, C. Belzecki and M. Chmielewski, Tetrahedron Lett., 1 9 8 9 , a 5171. H. Hori, Y. Nishida, H. Ohrui and H. Meguro, J. Ore. Chem., 1 9 8 9 , s 1346. A Nishida,S. Oishi and 0. Yonemitsu, Chem. Pharm. Bull., 1989,37- 2266. C. Vincent, M. Martin-Lomas and S.Penades, Tetrahedron, 1989.453605. P. Bako, L. Fenichel, L Toke and B.E. Davison, J. Chem. SOC.,Perkin Trans. 1, 1989,2514. T.K.Chakraborty and G.V. Reddy, J. Chem. Soc., Chem. Commun, 1989,251. R.L. Halcomb and S.J. Danishebky, J. Am. Chem. SOC.,1989,111.6661. H. Regeling and G.J.F. Chittenden, Caorbohvdr. Res, 1989,190.313. Yu A Zhpanov, Yu E. Alekseev, V.G. Alekseeva, V.A. Polenov, E.L. Korol, T.P. Sudareva, V.M. Khar'kovskii and N.N. Samarskova, Zh. Obshch. Khim., 1 9 8 8 , s 2612 (Chem. Abstr. 1989,111.39
Carbohydrate Chemisrry
68 689).
26 27 28
C Bonini, R. Di Falsio, G. Sotgiu and S. Cavagnero, Tetrahedron, 1989,
2895.
G. Descotes, J. Mentech and S. Veesler, Carbohvdr. Res., 1989,190.309.
P.L Barili,G. Berti, G. Catelani, F. Colonna, E. Mastrocilli and M. Paoli, Tetrahedron, 1989, & 1553.
29
30 31 32 33 34 35
J. Mulzer, R. Ekcker and E. BruMer, J. Am. Chem. Soc., 1989,111.7500. M.A.Zottola, R. Alonso, G.D. Vite and B. Fraser-Reid, J. Ore. Chem., 1989, 6123. D. Lafont, P. Boullanger, 0. Cadas and G. Descotes, Svnthesis, 1989, 191. A.J.J. Straathof, H. Van Bekkum and A.P.G. Kieboom, Red. Trav. chi. Pas-Bas, 1988,107.647 (Chem. Abstr., 1989, 130.213 195). RR. Schmidt, J. Michel and E. Rucker, Liebies AM. Chem., 1989,423. N. Sakairi, M. Hayashida and H. Kuzuhara, Carbohvdr. Res., 1989,185.91. A.J.J. Straathof, k van Estrik, A.P.G.Kieboom, J.M.k Baas and B. van de Graaf, Carbohvdr. Res., 1989,&2%.
41
J.A. Lopez, J.M. Molina, D.P. Olea and C. Romero-Avila,Can. J. Chem., 1988, @, 2975. H.H. Baer, F.H. Mateo and L. Siemsen, Carbohvdr. Res., 1989,187.67. E.T. Jarvi and B.W. Metcalf, Carbohvdr. Res.,1989,187. 159. D.Miljkovic, S. Velimirovic, J. W a d i and V. Popsavin, J. Carbohvdr. Chem., 1989,g 457. Y. Araki, Y. h i , T. Endo and Y.Ishido, Chem. Lett., 1989.1. G. Le Lem, P. Boullanger, G. Descotes and E. Wimmer, Bull. Soc. Chim. Fr., 1988,567 (Chem.
42 43
Y.Nishida, H. Uzawa, S. Hanada, H. Ohrui and H. Meguro, Aeric. Biol. Chem., 1 9 8 9 , s 2319.
36 37 38 39
40
Abstr., 1989,130.213 k).
P.A. Finan and J.P. Reidy, J. Chem. Res. SV~OD., 1989, 69.
6
Acetals
1 IsoDrouvlidene Acetals An improved procedure for the direct synthesis of 1,2-Q-isopropylidene-cr-D-
glucofuranose has been published; treatment of D-glucose monohydrate with acetone in the presence of sulphuric acid gave, after filtration of unreacted starting material and neutralisation with NaOH, a product mixture consisting to 83% of the 1,Zacetonide. The contaminants, mainly a- and 8-D-glucopyranose, were readily removed by fractional crystallisation.' D-Glucose has been converted to the synthetically useful diacetonide dimethyl acetal (1) by exposure to 2,2dimethoxypropane and sulphuric acid in methanol? The transformation of compound (1) to 2-azido-2-deoxy-D-mase and hence to neuraminic acid is covered in Chapter 16.
From the reaction of D-galactitol with 2,2-dimethoxypropane in dimethyl sulphoxide catalysed by pyridinium ptoluenesulphonate the diacetonides (2) and (3) have been isolated. From the latter, the 1,3 : 2,4 : 5,6-tri-Q-isopropylidene derivative (4) was obtained on treatment with fresh reagents. The structures of these new acetals were established spectrometricallyand their possible role in the conventional isopropylidenation of D-galactitol has been assessed? The isopropylidenation of maltitol with 2,2-dimethoxypropane and p-toluenesulphonic acid in &,a-dimethylformamide at ambient temperature for 15 h gave the 1,2 : 5,6 : 4 ',6 ' and 2,3 : 5,6 : 4 '6 '-triacetals and the 1,2 : 5,6- and 1,3 : 5,6-diacetals in 14, 40, 4 and 12% yield, respectively. Use of excess of reagent and prolonged reaction times led to 1,2 2,3 acetal migration! +
70
Carbohydrate Chemistry
2 Benzvlidene Acetals The effect of ultrasound on the conventional Freudenberg benzylidenation (ZnC1,methyl Q- and 8-Dbenzaldehyde) of some alkyl D-glucopyranosides (s glucopyranoside) has been described. Considerable enhancement in the rate of formation of the 4,5-Q-acetals was observed and pure products were obtained in good yields (67-70%) after reaction times of ca 1 h.5 The configuration at the acetal centre of 2,3-Q-benzylidene-L-arabinitol(6), obtained from Larabinose the di-Q-benzylidene dithioacetal (5) was deduced to be (l3) following its conversion to the 1,4-di-Q-benzoyl-2,3-Q-benzylideneerthritol derivative (7) with trans-disposed benzyloxymethyl and phenyl groups, as indicated in Scheme 1.6
The reductive opening of the dioxane ring in the 4,6-Q-benzylidene acetal (8) with sodium cyanoborohydride in the presence of hydrochloric acid was accompanied by deoxygenation at the anomeric centre giving the products (11) and (14) in 3:2 ratio as outlined in Scheme 2. In the case of benzylidene derivatives (9) and (10) the 1,6-anhydroalditols(12) and (13) respectively were the only products isolated? CH2 OBn L
R2
(9)
R' = Me, R2= OH
(11) R'
R2 ('4)
(9) R1= Me, R2= O h (12) (10)R1= H
Reage&:
, R2=
OH
(13)
L8 N a D H 3 C N , H C L
Scheme 2
71
6: Acetals
3 Other Acetals The use of a range of protecting groups which incorporate the n-pentenyl acetal moiety (e.g.the 4-pentenyloxymethyl group) is discussed in a review on novel carbohydrate transformations discovered en route to natural products.8 The 4,6-Q-methylidene acetal (17) was obtained in a.30% yield from the reaction of methyl a-D-glucopyranosidewith dimethoxymethane in the presence of ptoluenesulphonic acid and lithium bromide. As indicated in Scheme 3, a mixture of products (15) and (16) was initially formed. Treatment with acid resin and molecular sieves ensured complete conversion to the 4,6-acetals (16). Under similar conditions methyl j-D-glucopyranoside suffered partial anomerisation. Reaction of methyl a-D-glucopyranoside or D-glucose with formaldehyde and hydrochloric acid gave in 20% yield the furanose dimethylidene derivative (lS)?
Ultrasound-accelerated Freudenberg acetalisation was used to prepare the amphiphilic 4,6-Q-n-aLl@dene-D-glucopyranose derivatives (19); only the 11heptylidene and 11-octylidene acetals were sufficiently water-soluble to attain critical miceue concentrations."
The 4,6-Q-pyruvate acetals (20)-(25) have been synthesized from the ratios corresponding bis-Q-(trimethylsily1)ethers in yields of 50-75% and with of 25-1:l. An example is given in Scheme 4. The configurations at the acetal centres were assigned with the help of 13C-n.m.r. spectroscopy; axial methyl groups
(R/s)
72
Carbohydrate Chemistry CHzOTMS
1
‘M50@ph
OBn RecLgcnts: L,
“y’;r ““reY?’Me{-
Me ~
Me02C
3
I*lfiCOC02M~,TMS0Tf, CH2U,
OBn
Ph
+
J
md2c
0
OBI7
(5)- (20)
OR2
(s)-(20)
(21) R1==~-OMe,R2=R’=On
(22)
Q I
I?‘
J’
RZ= R3= Bz
(26) X = H ,Br,OMe
Mild and rapid conversion of sugar dithioacetals into dimethyl acetals has been effected with N-bromosuccinimide in methanol. The unstable tetra-Q-mesylD-arabino diethyl dithioacetal(27) of Scheme 5, for example, gave the dimethyl acetal (28) in high yie1~1.l~
The use of an enantiomerically pure acetal protecting group to achieve asymmetric induction in the aldolysation of glycoladehyde is referred to in Chapters 2 and 18.
73
6: Acetals
REFERENCES 1
2 3 4 5
6 7 8
9 10 11 12 13
D.P. Fel'dman, AD. Voitenko, M.V. Shimamskaya, and M.Yu. Lidak, Khim. - Farm. Zh., 1989,a 326 @em. Abstr., 1989,111.195 254). C. Auge, S. David, and A. Malleron, Carbohvdr. Res., 1989,188.201. G.J.F. Chittenden, Recl. Trav.Chim.Pas-Bas, 1989,108.14 (Chem. Abstr., 1989,110.213 235). Y.Shinohara, M.Mori, and S.Tejima, Yakueaku Zasshii 1988,108.1046 (Chem. Abstr., 1989,111. 97 633). G.J.F. Chittenden, Recl. Trav. Chim. Paw-Bas, 1988,107.607 (Chem. Abstr., 189,110. 173 a00). M.H. Qadir and J.M. Webber, J. Chem. SOC. Pak, 1988,J M 55 (Chem. Abstr., 1989,110.57929). Y.Chapleur, P. Boquel, and F. Cdtien, J. Chem. Soc. Perkin Trans. 1, 1989,703. B. Fraser-Reid, D.R Mootoo, P. Kouradsmn, U.E. Udodong, C.W. Andrews, A.J. Ratcliffe, Z Wu, and K L Yu,pure ADDLChem., 1989, 1243 (Chem. Abstr.. 1989,111.233377). R Nougier and J.-LGras, Teuahedron. 1 9 8 9 , s 3423. R Miethchen, and D. Peters, Z Chem., 1988, 298 (Chem. Abstr., 1989,110.193202). A. Liptak and L Szab6, J. Carbohvdr. Chem., 1989,& 629. V.I. Betaneli, L A Kryazhevskikh, k Ya. 0 t h and N.K Kochetkov, Bioore. Khim., 1988,l4- 664 (Chem. Abstr., 1989,110.24168). D.Miljkovic, M.Popsavin, V. Popsavin, N. Vakojevic, J. Harangi, and M. Mak, Carbohvdr. Res., 1989,194.300.
a
7
Esters
1 Carboxylic Esters 1.1 Svnthesis and Reactions.- The Q- and /I-penta-Q-acetates(1) and (2), respectively, and the B-tetra-0-acetate (3) of a-acetylneuraminic acid methyl ester have been prepared in good to excellent yields by use of the reagents indicated in Scheme 1. Direct acetylation of methyl N-acetylneuraminatewith acetic anhydridepyridine gave a 1:3 mixture of the anomeric peracetates (1) and (2).' The selective synthesis of mono- and di-Q-acetates of an aryl glycoside of g-acetylneuraminic acid benzyl ester is covered in Chapter 16.
Exposure of 2-(trimethylsily1)ethyl glycosides to acetic anhydride and iron(III) chloride (substrate : FeCl, = 3:1, w/w) led to acetylation of all free hydroxy groups and concommitant acetolysis of the glycosidic function. With catalytic quantities of the iron salt (substrate : FeC13 = 201, w h ) acetylation of the free hydroxy groups proceeded with retention of the 2-(trimethylsilyl)ethyl group. Examples are given in Scheme 2. Benzyl ethers, but not pmethoxybenzyl or benzyloxymethyl ethers, were stable under both sets of conditions? Treatment of methyl a-D-gluco- and a-Dgalacto-pyranosidewith acetic anhydride-FeC1, (substrate : FeCl, = 12.5:1, w/w) produced mixtures of peracetylated pyranoses, furanoses and acyclic sugars?
^"'NT 'YAC
t A
OAc
CHZOAC
~
CO,Me
CHIOH
OAc
R e v k
L, A+O,FeCLj(l
C H N F )'COzMe OSE
OH 3,w/w);G,
A c ~ O , ~ C (I IJ ~ O , W / W ) .
Scheme 2
tA
d
)':;
N OAc F
CH~OAC OAC
SE= Mc35rCH*U.1*+
7: Esters
75
In a study of the regioselective benzoylation of N-2,2-(diethoxycarbonyl)vinyl0-D-hexopyranosylamines with 2-3 mol equivalents of benzoyl chloride in pyridine, the gluco isomer (4)afforded the 2,6-di-, 3,6-di-, 2,3,6-tri-, and 2,3,4,6-tetra-0benzoates in 19,19,27, and 5% yield, respectively. From the galacto analogue (5) the 3,6-diester was obtained as the main product in 54% yield, accompanied by minor amounts of the 2,3,6-tri- and 2,3,4,6-tetra-Q-benzoates(11 and 6%, respective~y).~ The six mono- and di-Q-bum1 derivatives of 1,6-anhydro-fl-D-glucopyranose and the six corresponding palmitic acid esters have been prepared from the tributyrate and tripalmitate respectively, by partial methanolysis and hydrazinolysis. The experimental findings regarding the regioselectivity of the deesterification reactions were related to polar and steric effects identified by quantum-chemical calculations (PCILO).~ Preferential hydrolysis at the anomeric centres of peracetylated a-D-gluco-, galacto-, and -manno-, and fl-D-gluco-,-galacto-, and -xylo-pyranose has been achieved with ammonium carbonate in DMF in yields of 63-95%, and the same base in THF-methanol was used for the preferential anomeric deacylation of a-D-glucose pentabenzoate (60% yield)? CH*0 WCH,X
R’ = H, R ~ OH = or
OH (4) R1= H, R2=OH (5)
R’= OH,R z = H
( 6 ) X = Br, R 4 =
H
(7) X = C L , R 4 = B z
The 6-Q-bromoacetates (6) obtained selectively by reaction of methyl Q- or 4D-gluco- or -galacto-pyranoside with 1.3 mol equivalents of bromoacetyl bromide underwent halogen exchange during conventional benzoylation of the secondary hydroxy groups to give chloroacetyl derivatives (7). Removal of the chloroacetyl groups by use of thiourea proceeded without acyl migration in contrast to previous experiences with acetyl protection (see Vol. 19, Chapter 4, refs. 15 and 16).7 The application of this procedure to the synthesis of (1+6)-linked disaccharides is referred to in Chapter 3. Selective primary protection has also been effected under Mitsunobu conditions as exemplified in Scheme 38 The primary benzyl groups of perbenzylated fl-C-glucosides (8) were selectively acetolysed on treatment with acetic anhydride in the presence of boron trifluoride etherate in ether. Phenolic hydroxy groups were acetylated in the process. Under identical reaction conditions, a-anomers were stable?
Carbohydrate Chemistry
76
x
X
Rag@&
i, ROH , PPhJ, D E A b
Scheme 3
their The glycal diols (9) and (10) were selectively acetylated at 0-3 11) dibutylstannylene derivates,1° and 1,5-anhydro-4,6-Q-benzylidene-D-galactitol( reacted preferentially at 0-3 with benzoyl or ptoluenesulphonyl chloride in pyridine at -15°C. Activation of this position by intramolecular hydrogen bonding is thought to be responsible."
WR
C H2 O T r
DnOCH2
Btl
R=
&J
H,OH,or OMe
O "Q
OBn
OH
c9
(8)
(10)
Rhodomycins I(12) and 11(13), and iremycin(l4) were esterified at the hydroxy groups of the sugar moiety (OH-4') only, on exposure to pmethoxybenzoyl chloride (1 mol. equiv. per daunosamine residue) and sodium hydrogen carbonate in a two-phase system (CHC13-H20).'2 0
Ph-(
pp&yH OH
Q ('9
OH
OH
0
OH
(12) R ' = O H , (13)
R - d S
z
0
1OMe
N3 : L, DBU ,C6H6
>
R2
Ch&&=
R ~ d=-
qJ
HO
NM e2
R'= d a u , R2= ti
(14) R'= R2=
B
R'
&LL
Bz;DoMe
N3
OR2
(15) R'= R2= H
(161 R'=H, R ~ copr =
77
7: Esters
Further examples of selective acylations and deacylations by means of enzymes, especially lipases, have been reported. Acetylation at the primary centre of N-acetylneuraminic acid was performed by acyl transfer from 2,2,2-trichloroethyl acetate under catalysis by porcine pancreatic lipase in pYfidine,l4and use of an immobilised microbial lipase in a solvent-free process allowed selective 6-0esterification of ethyl a-D-glucopyranoside with long-chain fatty acids. Under the same conditions methyl a-D-glucopyranoside and D-glucose reacted similarly but at much slower rates." Sucrose was acylated at 0-1' preferentially by subtilisin-catalysed transesterifkation from the trifluoro- or trichloro- ethyl esters of acetic, propionic, octanoic, benzoic, and acrylic acid in DMF. Subsequent hydrolysis of the glycosidic bond with a-glucosidase gave D-fructose l-esters.16 For the selective deacetylation of sucrose octaacetate various lipolytic enzymes have been employed. Purified wheat germ lipase, for example, liberated the free hydroxy groups at 0-1 0-4 ' and 0-6 addition of calcium ions or cosolvents (udi-pbutyl ether) had little effect on the activity or selectivity of the enzyme, but lowering of the reaction temperature or immobilisation on agarose decreased the activity drastically without improving the selectivity. With candzkiz cyZindracea lipase in aqueous phosphate buffer-toluene (9:1) deacetylation occurred selectively at 0 - 4 '; in the absence of toluene complete, non-selective hydrolysis was observed.l7 The lipase-mediated selective hydrolysis of peracylated 1,6-anhydro-hexoses has been studied. Lipase from candida cyZidracea deesteri€ied 1,6-anhydro-2,3,4-tri0-butyryl-8-D-glucopyranose at 0-2 and 0-4, whereas lipases from several other and -butyrylsources cleaved only the 4-ester.'' For 1,6-anhydro-2,3,4-tri-Q-acetylfi-D-galactopyranose the relative rates of hydrolysis by a number of soluble and immobilised lipases were in the order 0-2> 0-4> 0-3. The $mono- and the 3,4di-0-acyl derivatives could be isolated in moderate to excellent yields by choice of suitable condition^.'^ Twenty enzymes were tested for selectivity in the butyrylation of the 1,5anhydro-D-arabinitolderivative (15). Good results were obtained with lipases from rhizopus japanicus [ratio (16)/(17) = 86:14, combined yield 71%] and from humicuZu hwginosa [ratio (16)/(17) = 3:97, combined yield 71%].20 The enzymatic synthesis of acylated glucals is covered in Chapter 13. A convenient synthesis of 1-Q-bcnzoyl-8-D- [I4C]- glucose esters uses acyl transfer from unlabelled 1-Q-benzoyl-glucose esters to 14C-labelledglucose by an acyl transferase from young oak leaves?' I,
I;
78
Carbohydrate Chernistry
The acrylates and methacrylates of several di-Q-isopropylidene hexoses have been prepared, as shown in Scheme 5, in yields of 2550% for use in the synthesis of hydrogels by radical-induced polymerkation.z
r
Me
ro
In the course of a surface activity study the decanoate (18) and the laurate (19) were synthesised by treatment of diacetone glucose with the respective acyl chlorides under phase transfer conditions followed by removal of the acetal groups. The corresponding 6-esters were similarly obtained from 1,2-Q-isopropylidene-a-Dglucofuranose.23 Conventional acylation (acid anhydride-pyridine)and subsequent hydrolysis were used to prepare the succinate (20) and the phthalate (21) from diacetone glucose, and the 6-succinate and 6-phthalate of D-galactose from diacetone galactose." Base-catalysed acylation with succinic and phthalic anhydride has also been applied to methyl a-D-glucopyranoside and to a,a '-trehalose. Primary esters were mainly formed, phthalylation being more regioselective than succinylation.= The conversion of these esters to potential herbicides is covered in Chapter 17.
0$-.-" CU20Ac
OH
i
AcO
OAc
Condensation of methyl 4,6-Q-benzylidene-2,3-Q-butylstannyiene cr-Dglucopyranoside with succinyl chloride furnished the macrocyclic tetralactone (22) and its regioisomer, accompanied by small quantities of a hexa- and an octalactone.%
79
7: Esters
The synthesis of the 3-, 6-, and 6 '-sucrose monoesters of arachidonic acid from sucrose and ethyl arachidonate has been reported." The 2,3,4,6-tetra-Q-acetyl-~-D-glucopyranosyl ester (23) and five other sugar esters of ~-acetyl-thiazolidine-4-carboxylic acid were prepared by DCC coupling,28 Koenigs-Knorr methodology was employed to synthesise three giberellin b-D-glucosyl esters:' and the antineoplastic disaccharide ester (+)-phyllanthostatin 3 was formed by use of the Mitsunobu reaction?' Three carboxylic acid antiinflammatory analgesics (asprin, diclofenac and ketoprofen) were esterified by reaction with acetobromoglucose under phase-transfer conditions. The tetra-Qacetyl-b-D-glucopyranose esters thus obtained had comparable antiinflammatorybut lower ulcerogenic activity than the parent acids?l The Hantzsch ester (24) was prepared to serve as an NADH model in the asymmetric reduction of prochiral ketones?2 A Hantzsch ester with a sugar residue attached to C-4 of the dihydropyridine ring is referred to in Chapter 10.
Reaction of the 6-tosylates of L-glucose, 2-deoxy-D-glucose, 2-amino-2-deoxyD-glucose, and 2-amino-1,5-anhydro-2-deoxy-D-glucitol with the potassium salt of mycolic acid gave monosaccharide esters related to the biologically active glycolipid trehalose 6,6 '-dimy~olate?~ Novel synthetic immunomodulators (25) have been constructed by linking of ~-acetyl-6-Q-(aminoacyl)muramyl dipeptides to the free primary hydroxy group of 6-deoxy-6-mycolylamino-a,a-trehalose a succinic acid bridge. The conjugates (25) displayed biological properties of both moieties.% Activated esters of peptides reacted directly with D-glucose or 2-amin0-2deoxy-D-glucose in the presence of imidazole to give 6-Q-peptidyl derivatives such as compound (26) as well as ~-l-Q-analog~es?~* (26)
6-Q-(Boc-Phe-Leu)-D-Glc
Flavonoid glycosides esterified in the sugar moiety with malonic acid have been observed to lose CO,, furnishing the corresponding acetates, under conditions
80
Carbohydrate Chemistiy
often used to determine their n.m.r. spectra (DMSO-d,, 8O-l0O0C). In the presence of exchangeable deuterium (s D20) trideuteroacetyl derivatives can form by exchange at the malonyl methylene group prior to and during decarboxylation?' Carbohydrates have been used with considerable success as chiral auxiliaries in the asymmetric Paterno-Buchi reaction. Diastereomeric excess of 80% was achieved, for example, in the formation of oxetans (28) from furan and the sugar phenylglyoxalate (27) (Scheme 6).38
Scheme 6
1.2 Isolation from Natural Sources.- The three new tri-Q-acyl-4-D-glucopyranoses (29)-(31) have been isolated from the Mexican desert plant Bahia ~ c h a f i e r i , and 3~ amarelloside, a very bitter constituent of Pobgala amureh, has been identified as the tri-Q-acetyl-tri-Q-benzoyl-tetrasaccharide (32).40 The caffeic esters verbascoside and plantamoside have been found in several Plantago species from widely different locations indicating that they are valuable as taxonomic rnarkers:l and the investigation of a cell culture from Ruta chulepensis yielded rutarensin, a new biscoumarine 8-D-glucoside ester Zed at 0-6 with 3-hydroxy-3-methyl glucaric acid!2
The ionophoretic properties of eight new resin glycoside esters such as merremoside h, (33), isolated from the tuber of the Indonesian medicinal plant Merremia mummosa, and all containing a lactone macrocycle, have been studied by
81
7: Esters
use of erythrocyte membranes and artificial membranes. Opening of the lactone ring destroyed the ion (Na+, K+, Ca2') transporting activities completely!314 From the leaves of Cornus 0ficinaZi.s a novel gallotannin, 1,7-di-Q-galloyl-Dsedoheptulose, has been is0lated.4~ 1,2,3,4,6-Penta- and 1,2,3,4-tetra-Q-galloyl-fl-Dglucose have been shown to be inhibitors of human placenta aldose reductase and of a mitochondria1 oxidoreductase, respe~tively,~~~' and the ability of penta-Q-galloyl-fi-D-glucoseand twenty-four related, more complex, natural, hydrolysable tannins to scavenge radicals (a, superoxide radicals) has been demonstrated.48 "3-Q-Digalloyl-l,2,6-trigalloyl glucose", a tannin isolated several years ago from a fresh water green alga (see Nishizawa a d.,Phvtochem., 1985,24.2411) is a specific, irreversible a-glucosidase inhibitor and has antibiotic activity:' whereas oenothein B, a hydrolysable tannin with a macrocyclic structure, has antiviral properties?' The latter compound is also referred to in Chapter 19. 2 PhosDhates and Related Esters
Reviews have been published on the synthesis of carbohydrate phosphodiesters and trinucleoside mono phosphate^^' and on phosphodiester-bridged saccharide structures comprising both anomerically and non-anomerically linked compounds?2 A number of deoxy-, dideoxy-monofluoro-, and dideoxy-difluoros-Dglucopyranosyl phosphates have been prepared for a comparative study of their acid hydrolysis rates. As in the hydrolysis of alkyl glycosides, deoxy derivatives reacted faster and fluorinated analogues much slower than the parent 1-phosphates, and it was concluded that the transition states for the hydrolysis of glycosides and glycosyl phosphates are essentially identi~al.5~ In an effort to prove that phosphate migration takes place under conditions of acid hydrolysis (4N HCl, 4 h at 100°C) used in the determination of the structure of Lipid A, the 4- and 6-phosphates of 2-amino- and 2-acetamido-2-deoxy-D-glucose as well as the Lipid A model (34) were synthesised. Migration of the phosphate from 0-4 to 0-6 was observed under the above conditions. Deacylation conditions were then found (1N HCl, 1 h at 100°C) which did not cause phosphate migration.54 A rapid, high yield synthesis of 13C-enriched intermediates of the pentosephosphate pathway has been developed based on a combination of chemical and enzymic reactions. [l-13C]Ribose and [l-13C]arbinose 5-phosphqtesYavailable by the classical Kiliani method, were converted to a variety of specifically labelled 5-, 6-, 7-, and 8-carbon sugar phosphates (e.g.,D-erythro-pentulose 5-phosphate, sedoheptulose mono- and di-phosphates) with the help of aldolase, transaldolase, and transketola~e.'~
82
Curbohydrute Chemistry CHzOH
0 0
HO
O(CH-J~OH
0
5, OH
NHC:CH~LH(CH~)IOM~
pot )h,
R
p - - O
1
OH,OEt, S E t , NEt2
R
o*
(34)
(3)
3,6-Cyclic thiophosphates (35) of 1,2-Q-isopropylidene-a-D-glucofuranose have been obtained from the corresponding 3,5,6-bicyclic thiophosphate by treatment with various nucleophiles?6 6-Deoxy-6-sulphono-a-D glucopyranosyl phosphate has been prepared as shown in Chapter 11, Scheme 5; the synthesis of individual enantiomers and racemates of w-inositol mono-, di-, and tri-phosphates is covered in Chapter 18, and the use of glycopyranosyl phosphates as glycosyl donors is referred to in Chapter 3.
Scheme 7
Synthesis of the phosphate-bridged disaccharide (36) was achieved by the method outlined in Scheme 7. Attempts to make compound (36)from the pyridinium salt of a 1-phosphate as the donor and 2-acetamido-1,3,4-tri-Q-acetyl-2deoxy-fl-D-glucopyranoseas the acceptor gave the disaccharide (37) and the disugar diphosphate (38) in~tead.5~
NHAc
NHAc
NHAc
9
(37)
(3
The 2-N-methylaminoethyl group of the phosphonosphingolipid (40) was introduced by selective phosphonylation at the primary hydroxy group of the precursor (39) with an unprotected galactose moiety, by a procedure using DCC and ultrasound, as indicated in Scheme 8.58 Further details regarding the synthesis of e
no
- (CH2)2$H2Me
___, "I-
( 5 '
c,
83
7: Esters
compound (40)are given in Chapters 3 and 24. For the preparation of the 2-Naminoethyl phosphonate (45)from the methyl galactoside (42)the bifunctional reagent bis(benzotriazolyl)-2-bromoethylphosphonate (41)was employed. The transformation of the bromo-intermediate (43)via the iodide (44) to the target (45) is shown in Scheme 9?9 Another benzotriazole-derived reagent, the thiophosphonate (4.6)was very effective in the synthesis of uridine 3 ‘ 3‘-cyclic methyl thiophosphonate (47).60
I
Scheme 9
Phosphitylation of the nucleoside (48) to give the bisamidite (50)without contamination by the monoamidite (49) was possible with tris(diethy1amino)phosphine and tetrazole in the presence of diisopropylamine. The usefulness of bisamidites such as compound (50) in oligodeoxyribonucleotidesynthesis has been demonstrated?’
“ ‘F3 I
OR
OH
(49
I
( 49 ) R =H
O-f-PNEtZ
1,6-Dichloro-l,6-dideoxy-2,4:3,5-bis-~-(piperidinophosphoryl)-D-mannitol (54) and its 1,6-dibromo-bis-Q-(morpholinophosphoryl) analogue (55) were obtained from D-mannitol bisphosphite (51) bis-Q-(halophosphoryl) intermediates (52) and (53), respectively on treatment with halogen and cyclic amine (Scheme (52) X = Y =
CL
=Y=Br Y CH2X
0.
R e a g e n t s : i , CL2or 0r2, i,
,UL,QH
Scheme 1 0
(54) x
= CL, Y
e5) x
=Dr, Y =
=
o+ A
OS””
84
Curbohydrate Chemisrry
3 Subhonates
A protocol has been developed for the one-pot microsynthesis of dianhydrohexitols from monoanhydrohexitolswhich involves primary tosylation followed by basepromoted intramolecular displacement of the tosyloxy group. An example is given in Scheme 11. The products were identified, after acetylation, by g.c.-m.s. As byproducts mono-(and traces of di-) chlorides were detected, formed by substitution of the tosyloxy group by chloride ions liberated during sulphonylation. Dianhydrohexitols uncontaminated by such chloro compounds were obtained after post-tosylation treatment with methoxide.& Treatment of xylitol with two molar equivalents of toluene-p-sulphonyl chloride in pyridine gave the racemic anhydrotosylate (56) in 56% yield. With three
(on19 one cnantiorner Shown)
(59) R'= R2= Ts
(60) R' =Ts , R2= Bz
S c h e m e 11
equivalents of reagent the ditosylates (57) and (58) were produced each in B.30% yield and, in addition, small quantities of the tritosylate (59). This last compound was the only product obtained when five equivalents of tosyl chloride were used. The ditosylate (58), on benzoylation, furnished the triester DL-(60), an important intermediate in the planned synthesis of biotin analogues. Enantiomerically pure the known 2,5triester D-(60) was available in eight steps from D-xylose anhydro-D-xylose derivative (61) (Scheme 12).65 Further papers describing cyclisations under tosylating conditions are referred to in Chapters 5, 11 and 18, and the synthesis of 3,4-di-Q-acetyl-6-~-tosyl-D-glucal from D-glucose is covered in
I ODz ~ e a g mi:, HCL, CcL,Co,h
(6')
; Li, Me2NH-EH3 ; i TsCL, Py
Scheme 12
7: Esters
85
A comparative study of the mono- and di-tosylation of the imidazole-2-tMones (62) and (63) by the standard procedure (toluene-p-sulphonylchloride - pyridine), under phase transfer catalysis, and via organotin intermediates has been published. Both 2-0- and 3-Q-tosylateswere prepared.66
Tosyl groups can be photoremoved in the presence of carboxylic esters and benzylethers by use of tertiary amines as electron donors. Tosyl protection a n thus become valuable in the preparation of selectively substituted products, as exempMed in Scheme 13F7 Photolysis of tosylates in the gas phase is initiated by
electron capture and then proceeds with homolytic C-S cleavage in marked contrast to solution chemistry. A study using negative ion mass spectrometry showed that from the vicinal ditosylate (64) the sulphite ions (65) and (66) are produced which then undergo internal nucleophilic displacement to give the cyclic sulphites (67) and (68) respectively as outlined in Scheme 14.68 Me
(65)
4k
0
)
(66)
(67) S c h e m e 14
Carbon - oxygen bond cleavage in a secondary tosylate during reduction with lithium aluminium hydride due to intramolecular hydride transfer from an alkoxyaluminium hydride intermediate is referred to in Chapters 12 and 13.
Carbohydrate Chrmistry
86 NC
KdOBn
/-0
?L.JOBnQ0*"+
O2 5
TF 0
(70)
Reag&
0
OH
: i, LLCHzCN, L D A j iL, B ~ L ~ N H S O +
OH
u
(69)
(71)
Scheme 15
Scheme 15 shows two reactions undergone by benzyl2,3-anhydro%Q-trifIylD-ribopyranoside (69). With LiCH,CN in the presence of LDA,nucleophilic substitution accompanied by epoxide-openingafforded the 3,4-cyclopropanated analogue of epoxide (69) reacted similarly. Thus, epoxyproduct (70). The triflates with favourable relative configuration offer an entry into annulated sugars. With Bu,NHSO,, compound (69) reacted to give the cyclic sulphate (71).69 4 Other Esters
A symposium paper on new methods of orthoesterification under kinetic control has been published. In particular, the use of ketene dimethylacetal for the preparation of methoxyethylidene derivatives, gg.,compound (72) of Scheme 16, is described. Orthoesters are hydrolysed by very mild acid to give a-hydroxyesters [e.g., compound (73)] or fi-hydroxyesters, as for example in the acid opening of the 4,6-Q-
orthoesters (74) of methyl a- and 8-D-gluco- and -galactopyranosides shown in Scheme 17. In the latter case, mixtures of 4-0- and 6-Q-acyl products (75) and (76), respectively, were formed in ratios varying from 1:2 to 2:l depending on the protecting groups at C-2 and C-3 rather than on the configurations at C-1 and C-4. Exposure of the mixed products (75)/(76) obtained from orthoacetates (74, R=Me) to base caused acetyl migration from 0-4 to 0-6 allowing isolation of 6-acetates in high yields. The 4-benzoates (75, R = C,H,) were stable towards base?1 Me0
OM&
-
CHZOH
dy?) ; -E+
-%O
(74)
R $ - O $1 * 0 ' (75)
+
HO $ ) 4>O
w
kkO.qed%' i, (Me0I3CR2, TSOH, MeCN , LL., TFA , H z O , U ,Py, E t 3 N , H 2 0
S c h e m e 17
CH205
R2
-
-
R ' = h o r @ CHZ+
X = H,OMe, NO2
(76'
Y=H,NOp
R 2 = M e or P h
C0-t
87
7: Esters
Reaction of a number of methyl 2,3-di-Q-benzyl aldohexopyranosides with phenylchlorosulphate - sodium hydride gave, depending on the conditions used, primary phenylsulphates or 4,6-cyclic sulphates?2 The formation of cyclic sulphates from epoxy triflates and of cyclic sulphites from vicinal ditosylates are referred to in Section 3 of this Chapter. The ‘H- and 13C-n.m.r. spectra of methyl 4,6-Q-benzylidene-a-Dglucopyranoside 3-nitrate and of methyl 4,6-Q-benzylidene a- and 8-Dglucopyranoside 2,3-dinitrate have been examined and compared with the spectra of methyl 4,6-Q-benzylidene-a-D-glucopyranoside.”The fact that alkoxy radicals are generated from nitrates on heating with tributyltin hydride in the presence of a radical initiator in benzene has been exploited to regenerate the alcohol (77) from the sugar nitrate (78).’4
(Do ,Ye
(77) R = H (78) R = N O ?
QO
Some cyclic thiocarbonates derived from carbohydrate 1,Zdiols undergo 0 S isomerisation when exposed to methyl iodide and proton sponge. The duco derivative (79), for example, was converted to the rearranged product (80). Others, s., the arabino compound (81), were stable under identical conditions. Attempts to reduce the thiocarbonate (79) by treatment with tributyltin radicals furnished instead the glycal (82)?5 +
(79)
x-0,
(811
Y=S
(SO) X = S , Y = O
The novel carbamate glucuronide (83) has been identified as a metabolite of the tetracyclic compound (84). The key step in its synthesis was the condensation of benzyl 2,3,4-tri-Q-benzyl-D-glucuronatewith the reactive 1,2,4-triazolederivative (S5)?6 (03)
R=
&
0 0-F’
HO
(g4) R = H
OH
0
Curbohydrute Chomistry
88
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a
a
a
8
Halogeno-sugars
1 Fluoro-sugars
A number of reviews on the chemical synthesis of fluorinated carbohydrates have been published,14 as well as others covering the chemoenzymic synthesis of fluorosugars: the preparation and reactions of glycosyl fluorides: and the preparation of '*F-deoxyfluorohexoses? Glycosyl fluorides have been prepared under neutral conditions from the The corresponding free sugars using 1-dimethylamino-1-fluoro-2-methylprop-1-ene. reaction conditions are compatible with the presence of ester, acetal, benzyl and silyl ether protecting groups? An efficient synthesis of the 2,6-dideoxy- 2,2-difluoroL-arabinopyranosyl fluorides (1) by treatment of the fluorinated glycal (2) with XeF2 has been described? The effects on the H-F and C-Fcoupling constants in CH~OAC '
Z
O
i
f
RAcO J-(
BZOQ
p
OMe F
OMe
0 Ac
(2)
(1)
OAc
( 3)
the n.m.r. spectra of a series of C-1 dihalosugars (3) on varying the anomeric configuration and the substitution (R = Br, Cl, F) have been studied." Further examination of the free-radical bromination of peracetylated D-gluco- and Dmanno-pyranosyl halides has given rise to a variety of either 1,l- or 1,5dihalogenated derivatives. The 1,l- bromochloro- derivatives (4) were converted to the chlorofluoro- compounds ( 5 ) or the difluorides
OAc
(4)
(51
(6)." It was incorrectly stated (Vol 21, p.77) that the 8-fluoride (7) affords the
8: Ha logen o -sugars
91
corresponding 1,l-dihalocompoundon photo-bromination whereas in fact the C-5 bromo-glycosyl fluorides (8) are the major products from either the a- or pfluoride. CH2 OAc
(7J
AcO
OAc
OAc (9)
(7)
Methyl 4 -deoxy-4 * -fluoro- and 6 -deoxyd -fluoro-8-D-galactobiosidehave been synthesized12and some related work on derivatives of methyl 8-Dgalactobioside is discussed in Chapter 14. Deoxyfluoro derivatives of the tetrasaccharide Lewis b human blood group determinant modified in the galactose residue have been ~repared.'~ Attempted displacements with Bu,NF in a variety of solvents on benzyl 3-Q-benzyl- 4,6-Q-benzylidene -2-Q-trifluoromethanesulphonyl-aD-mannopyranoside gave only the corresponding 2,3-olefin.l4 The a-fluoro-ketone (9),bearing a chiral sulphoxide group, has been alkylated (LDA, then ally1 bromide) to give adduct (10) and its stereoisomer which were transformed into the 2,3dideoxy-3-fluoro-pentoses (11) and (12) re~pectively.'~
Mea & s.0:
Me
d'
6
a s q "L. - 0F
CH20Bz
CH~OBZ
b
O
H
b
0
i
-
0
(11)
(10)
(9)
(1 2)
2,3,4-Trideoxy-2,3,4-trifluoro-D-glucose and -D-galactose derivatives have been prepared. The known 1,6-anhydrocompound (13), treated with DAST, gave the product (14) with retention of configuration, whereas the alcohols (15) and (16), on treatment with DAST, gave the products (17) and (18) resulting from 0
QOOH
0
HoQo
G J F /-
FQo
RO
BnO F
(1 3)
F
(14) R = D n (15) R = H
F
('6)
F ('7)
F
(1 8)
displacement with inversion of configuration. These trifluorinated compounds were and acetolysed to give 1,6-di-Q-acetyl-2,3,4-trideoxy- 2,3,4-trifluoro-D-galactoglucopyranose respectively.16 3-Deoxy-3-fluoro-derivativesof N-acetylneuraminic acid have been prepared as potential inhibiters of CMP-sialate ~ynthase.'~ Syntheses from D-glucose of methyl 3-Q-benzyl-6-Q-benzoyl- 2,s-dideoxy- 2-fluoro3,5-dideoxy-3-fluoro-D-&D-&-hexofuranoside and 1,2-di-Q-acetyl-6-Q-benzoyl-
1
Carbohydrate Chernistry
92
hexofuranose have been reported." Some 4 ,5 -unsaturated5 -fluoroadenosine nucleosides are described in Chapter 20 as well as some purine nucleosides containing the 2 -deoxy-2 -fluoro-JD-arabinofuransoyl moiety. A number of dideoxymonofluoro- and dideoxydifluoroa-D-glucopyranosyl phosphates have been prepared in order to study their relative rates of acid hydrolysi~.'~The synthesis of a fluorinated 3-deoxy-D-glyceric acid phosphonate is discussed in Chapter 17 and the conversion of a 1,3-anhydro-2deoxy- 2,Zdifluoro-D-hexose derivative into a hydrolytically stable thromboxane A2 mimic is covered in Chapter 24. The rate of reaction of 18F anion with some hexose triflate and cyclic sulphate derivatives showed no apparent difference between Et,N+ and the aminopolyether was synthesized from a kryptofix -2,2,2 as cation.20 2-Deo~y-2-['~F]-D-galactose taloside 2-triflate derivative?l The automated production of 2-deoxy-2-["F]-Dglucose using Bu,N18F as the fluoride source has been achieved using a modified literature procedure,22and another automated process for the production of radiochemicals has been programmed such that 2-deoxy-2-[18F]-D-glucoseis prepared in 55% yield in < 1 hour.23 I
2 Chloro-, Bromo-, and Iodo-sugars to give The photobromination of methyl 4,6-Q-benzylidene-a-D-glucopyranoside methyl 4-Q-benzoyl-6-bromo-6-deoxy-a-D-glucopyranoside has been published as an Org. Synth. procedure.% The bromination of carbohydrate benzyl ethers, a (19), (20), whereas benzyl glycosides using BrCC1, and U.V. light gives a,a-dibromides, afford the corresponding glycosyl bromides.z Glycosyl halides have been prepared from free sugars under neutral conditions using Me2C=C(X)NMe2(X = F, C1, Br, I). The reaction conditions are compatible with the presence of ester, acetal, benzyl and silyl ether protecting groups? CH20Bn
$&q 0
:>I
Dr
(21)
The treatment of pent-4-enyl glycosides with bromine has allowed an exceptionally mild new synthesis of glycosyl bromides, eA, galactoside (21)affords bromide (22). The yields are high and the reactions are generally sufficiently specific for the products to be used in situ for saccharide coupling.26
8: Hnlogm o -sugars
93
2,3-Q-Isopropylidene-L-sorbofuranose has been selectively chlorinated (Ph,P,CC14,Py) to give, after hydrolysis, 6-chloro-6-deoxy-Gsorbose. The above starting material was also treated with MsCl in DMF and then subsequent hydrolysis gave 1,6-dichloro-1,6-dideoxy-Gsorbose?' The conversion of some protected deoxyiodo derivatives of neuraminic acid into 7-, 8-, and 9-deoxy- and 4,7-dideoxy- neuraminic acids is covered in Chapter 12. Another example of an MS - promoted coupling of a glycal with a sugar alcohol has afforded methyl 4-~-(2,6-dideoxy-2-iodod-Gmannopyranosyl)~-L-acos~de,~ and the same procedure has been used to prepare 2 -iodo analogues of flrhodornycin~?~ Some highly selective metal-graphite reductions of deoxyhalosugars have been elucidated. For example, halides (23) (X = I, Br, Cl) (Scheme 1) with K-graphite laminate (C,K) afforded olefin (24), whereas with Zn/Ag-graphite the enal (25) was I
L
/k) Lk7
CI
Reagents
L,
LCL,
C g K , w , Zn/Ag-Gr-apkLk;
(26)
M9- G r q h L t e
Scheme 1
produced. Iodide (23) (X=I) with Mg-graphite gave the product (26) of Wurtz-like ~oupling.~'Liberation of the sensitive aglycone ptaquilosin from its naturally occurring glucoside by zinc reduction of the 6-deoxy-6-iodo-glucosylderivative is mentioned in Chapter 3. The treatment of benzyl 4,6-Q-benzylidene-3-Q-benzyl-20-trifluoromethanesulphonyl-a-D-mannopyranosidewith halide nucleophiles in solvents of varying polarity has given moderate to low yields of products of displacement of triflate along with considerable amounts of the corresponding 2,3olefin resulting from elimination of TfOH.14 The synthesis of some 2-bromo- and 2chloro-2-deoxy-hexopyranosid-3-uloses is discussed in Chapter 15. References 1 2 3
4
P.W. Kent, A.C.S. S ~ DSer., . 1988,374. 1 (Chem. Abstr., 1989,110. 57 921). M. Sharma, R.J. Bernacki, and W. Korytnyk, A.C.S.S V ~ DSer., . 1988,374, 191-206. (Chem. Abstr, 1989,110, 173 563). L.H.B. Baptistella, S. Castillon, A. Dessinges, R. Faghih, G. Luckacs, A. Olesker, and T.T. Thang, F.E.C.S.Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. lProc.l,3rd, 1985 (Publ. 1987) 3, 409 (Chem. Abstr., 1989,110.75 895). W.A. Szarek, A.C.S. .%ID. Ser. 1989, 386 (Trends Synth. Carbohydr. Chem 2) (Chem. Abstr, 1989, 111, 7 689).
Carbohydrate Chemistry
94 5
C.H. Wong, D.G. Dreckhammer, and H.M. Sweers, A.C.S. S v m ~Ser., . 1988,374.29 (Chem. Abstr.,
6 7
J.L. Randall and KC. Nicolaou, A.C.S. Svmu. Ser., 1988,374. 13 (Chem. Abstr., 1989,110. 57 922). S.J. Gatley, J.E. Holden, T.R. De Grado, C.K. Ng, J.R. Halama, and R.A. Koeppe, A.C.S. Svmu. Ser.,
8 9 10 11 12 13 14 15 16
1988,374. 156 (Chem. Abstr., 1989,110.57 924). B. Ernst and T. Winkler, Tetrahedron Lett, 1989,30,3081. C. Bliard, P. Herczegh, A. Olesker, and G. Lukacs, J. Carbohvdr. Chem., 1989,&, 103. J.P. Praly and G. Descotes, C.R. Acad. Sci. Ser. 2, 1988,307. 1637 (Chem. Abst., 1989,111. 58 168). J.-P. Praly, L Brard, G. Descotes, and L.Toupet, Tetrahedron, 1989, 4141. J. Kihlberg, T. Frejd, K Jansson, S. Kitzing, and G. Magnusson, Carbohvdr. Res., 1989,185, 171. R.U. Lemieux, R. Cromer, and U. Spohr, Can. J. Chem., 1988, @, 3083. W. Karpiesiuk, A. Banaszek, and A. Zamojski, Carbohvdr. Res., 1989,186. 156. P.Bravo, E. Piovosi, G. Resnati, and G. Fronza, J. Ore. Chem., 1989, 5171. P. Sarda, F. Cabrera Escribano, R.J. Alves, A. Olesker, and G. Lukacs, J. Carbohvdr. Chem., 1989, &
1989,110.57 923).
a
115. 17 18 19 20 21 22
C.R. Petrie 111, M. Sharma, O.D. Simmons,and W. Korytnyk, Carbohvdr. Res., 1989,186,326. M.W.Chun and M.H. Kim, Yakhak Hoechi, 1988,22,177 (Chem. Abstr., 1989,110.115 198). S.G. Withers, M.D. Percival, and LP. Street, Carbohydr. Res., 1989,187, 43. M.L.Korguth, R.R. De Grado, J.E. Holden and S.J. Gatley, J. Labelled Comud. Radiouharm., 1988, 369 (Chem. Abstr., 1989,110.7 298). T. Haradahira, M. Maeda, Y. Kai, and M. Kojima, J. Labelled ComDd. RadioDharm., 1988, 721 (Chem. Abstr., 1989,110.57 930). J.W. Brodack, C.S. Dence, M.R. Kilbourn, and M.J.Welch, Aupl. Radiat. Isot., 1988, 699 (Chem.
a
a
A&&, 23
1989,110.75 904).
H.C. Padgett, D.G. Schmidt, A. Luzen, G.T. Brida, N. Satyamurthy, and J.R. Barrio, Auul. Radiat. 433 (Chem. Abstr., 1989,111.233 393). S. Hanessian, Ore. Svnth., 1987,g 243 (Chem. Abstr., 1989,111. 58 187). P.M. Collins,P. Premaratne, A. Manro, and A. Hussain, Tetrahedron Lett., 1989, 30,4721. P. Konradsson and B. Fraser-Reid. J. Chem. Soc.. Chem. Commun., 1989, 1124. D. Beaupere, N. Belkhouya, C. Morin, R. Uzan, and G. Demailly, J. Carbohvdr. Chem., 1989, S, 159. B. Abbaci, J.C. Florent, and C.Monneret, J. Chem. SOC.Chem. Commun. 1989,18%. M. Gerken, S. Blank, C. Kolar, and P. Hermentin, J. Carbohvdr. Chem., 1989,8,247. A. Furstner and H. Weidmann, J. Ore. Chem., 1989, g 2307.
Isot.,1989,4024
25 26 27 28 29 30
9
Amino-sugars
1 Natural Products The branched-chain amino-sugar (1) has been identified as a component sugar in glycopeptide antibiotics (see also Chapter 19).*
2 Svnthesis The synthesis and biological effects of immunostimulating analogues of MDP (muramyl dipeptide) have been reviewed, some details of previously patented reaction schemes being included? A review (28 refs) has appeared on the halofunctionalisation of ally1 and homoallyl alcohols for the preparation of aminoalkanediols, and the application of this method for preparation of aminodeoxysugars such as daunosamine and ristosamine? Other syntheses covered in this section are grouped according to the method used for introducing the amino-functionality. The Amadori rearrangement product 1-deoxy-1-[(4-quinazolon-3-yl)amino]-Dfructose was synthesised by condensation of D-glucose with 3-amino-4-quinazolone oxalate salt, in order to observe the effect of the sugar moiety on the central nervous system activity of quinazolones.4
"ooH I
Aminosugar-incorporatingazacrown ethers have been synthesised, as exemplified by compound (2) in Scheme 1.5 Non-glycosyl linked adenosine analogues (3) and (4),and the corresponding hexitol analogues (formed from
96
Carbohydrate Chernistry
:3;; %l9&6
Ad.
OTS
X
(6)
9 (3)X=OH
A d - A W e
L,
A d , Na saLt , u,H30+
, u*.,
(6'
LAH
[ 4 ) %= H
Scheme 2
them by reduction with NaBH4), have been synthesised from the dianhydrosugar tosylate ( 5 ) via epoxide (6) (Scheme 2).6 Mono-(3-arylmethylamiino-3-deoxy)-j?-cyclodextrins have been synthesised from j?-cyclodextrin 2-Q-tosylate by formation and ring-opening of a manno-2,3epoxide, while the corresponding mono-(6-arylmethylamino-6-deoxy)-derivatives were obtained by direct displacement reactions applied to cyclodextrin 6-Q-tosylate. (relative to 4The greater ability of pyridyl-methylamino-j?-cyclodextrins cyclodextrins) to catalyse the hydrolysis of nitrophenyl acetates was demonstrated? A new strategy for the synthesis of L-daunosamine, in which C-6 of Dglucurono-6,3-lactonebecomes C-1 of the target, is shown in Scheme 3. The
(7)
0-t-
wed% i,5 O 2 u 2 ,Py ,
N3 (9) CL,
B u 3 S n H ; a,H: M e O H , w , BnBq A920, v, E t s H , H U , vi, D u i A L H , v y R a n % NL,
vu,MSCL,PY; w, N a N 3 , D M F
Soheme 3
acetonide (7)was first deoxygenated at C-5, methanolysed and benzylated at 0-2 to yield lactone (8). The required amino-function was introduced by mesylate displacement with azide. The 3-azido-2,6-dideoxy-derivative (9), a known precursor of L-daunosamine, was obtained in only 1.9% overall yield, the diisobutylaluminium hydride reduction (step vi) being low yielding8 The lower homologue (10) of N-acetylneuraminic acid, with the same stereochemistry and substitution in the pyranose ring, has been synthesised CHaOBn
9: Amino-sugacy
97
from D-glucal triacetate y& the unsaturated thioglycoside (11) (Scheme 4). The amino-function was introduced by a double inversion sequence at C-4 involving Mitsunobu displacement with benzoate, followed by mesylate displacement with azide? Full details have been published on the [4+2]cyclo-addition of dibenzyl azodicarboxylate to Q-silylated glycals, and the conversion of the adducts to 1,2trans-related 2-amino-2-deoxy-glycosides by reaction with alcohol in the presence of an acid catalyst (cf. V01.22, p.97).lo By using bis(trichloroethy1) azodicarboxylate, this route has now been extended for use with acetylated CH20Ac
@!
AcO
$>
4/N-N
A
L, (JR OCH2CC13
C C l p I * O -co
,N- NHCO2CH2CC1,
p
( z
NH2
C U J CH20.CO
R=
Reagents: L , C D ~ C ! + O C O N = ~ - ~ C O ~ ~ ~ C ii, CRon,Tsou L~; ;hi,Ran9 Ni
Scheme 5
glycals (Scheme S)." The anomalously coupled nucleosides 2,3-dideoxy-3-(7theophylly1)-D-erythro- and -threo-pentopyranose were obtained by coupling theophylline with 2-deoxy-D-ribose (using P20,-Bu,N-H20 in CHCI3)", while the analogous coupling with phthalimide gave 2,3-dideoxy-3-phthalimido-D-arabinohexopyranose and its D-&-hexofuranose isomer.13 1,5,6-Tri-Q-acetyl-2,3-dideoxy3-phthalimido-a-D-arabino-hexofuranose was obtained by reaction of (E)-4,6-di-Qacetyl-2,3-dideoxy-D-erythro-hex-2-enose with the DBU salt of phthalimide, followed by rea~ety1ation.l~Methyl 4-Q-(2,6-dideoxy-2-iodo-a-L-mannopyranosyl)-aGacosaminide (12) and its dehalogenated analogue have been synthesised, the key step being 1,4-addition of hydrazoic acid to the enal formed on hydrolysis of the unsaturated disaccharide (13), which yielded azide (14) and its 3-epimer in a 2:l R O ) " '
L-Lu
>
R O V
0 Ohc
w-vc,
R
O
V
M
e
N H CO C F3 N3 (14) hag,i AcOH, H 2 0 , ~ , N ~ N , wJ k 2 0 ,w, Ph3P, H20, v, ( C F ~ C O ) ~ OVL,, M e O u , M e 3 5 OTf (1 3)
AcO
I
('*)
Scheme 6
ratio (Scheme 6).14 hiridines (15), either as the &isomer or as a mixture of Eand Z-isomers, were obtained from reaction of the bromoenoses (16)with ammonia (Scheme 7). The E-aziridine (16,Y=C02Me) rearranged to the
98
Curbohydruto Chemistry
Y
z- (15) (16) Y = COX'or G N , where X = Me,Ph, O M e ,
U-ents
OT
OEt
L, NH3,MeQw , u , A c B T ; E ~ ~ N,W,NazC03,HzO
Scheme 7
oxazoline (17) with overall retention of stereo-chemistry at the 6,7-positions, and this then was hydrolysed to the 6-amino-6-deoxy-octuronate (18); the corresponding Z-aziridine led to the 7-epimer of uronate (18)." including disaccharides, 8-Glycosides (19) of 2-acetamido-2-deoxy-D-glucose, Staudinger-type reaction (Scheme 8) of the iodo-azide (20), can be obtained CH,OAC
&IuL
AcO(OAc -Jl I N3
A
R J(:
+
(-JR 0 Bn
ReagexLts u, Ph,P,40H,CH2+,
u., NnOMe, MeOH , u , A ~ 0Py ,
Scheme 8
available from addition of iodine azide to D-glucal triacetate (V01.21, p.101). The isomer of (20) epimeric at C-1 and C-2 similarly gave a-glycosides of 2-acetamido-2deoxy-D-mannose,albeit in somewhat lower yield, while iodoazides derived from Dgalactal triacetate failed to react.16 Tsuda and co-workers have coupled their regioselective secondary alcoholketone method (Vo1.15, p.149) with an Qmethyloxime formation and reduction sequence for the synthesis of glycosides of the following amino-sugars in satisfactory and -L-arabinose, 3-amino-3-deoxy-D-allose, yields: 4-amino-4-deoxy-D-galactose -D-glucose, -D-ribose and -D-xylose, 2-amino-2-deoxy-D-mannose (see Scheme 9), and 5-amino-5-deoxy-D-glucose , . e . i ( nojirimycin; c.f.V01.22, p.97 for preliminary 0-7
99
9: A min o-sugars
report). The stereoselectivity of reduction of the 0-methyloxime intermediates by aluminium hydride or by hydrogen over a catalyst was studied.17 Trehalose has been converted into analogues in which one of its glucosyl residues is replaced by a 3-amino-3-deoxy-allosy1, -glucosyl or -mannosy1 residue by enzymatic oxidation to a 3-keto-derivative with the D-glucoside dehydrogenase from Flavobacterium saccharoddurn, followed by reductive amination (NaBH3CN - NH40Ac). The glucosyl residue of sucrose was similarly converted into a 3-amino-3-deoxy-allosyl or -glucosyl residue.18 A key step in the synthesis of the branched chain lactone (21), an intermediate for construction of 1fl-methylcarbapenams,from enone (22), was the electrophilic amination of the 3-deoxy-hexosid-2-ulose (23) (Scheme 10).19 CH2 0 s L
C
H
~
~
S
L
0
~
0 4(----4
Me
4f32kc02D*-++ Bn0-: )--0
06,t
0
4HOCHZ
(22)
1
00 Bkt
CH20 cOBut
L, Me-OH,
P h z W , hv
~
u; O
Me
(21)
(23)
Reagds
rti-
COZH
0
U ~ C L ,UL, I C O D L L ~ w,~
Rn02CN=NCO2&
S c h e m e 10
The Mitsunobu reaction has been employed for the synthesis of the 4isopropylamino-sugar derivative (24) (Scheme 11) and its antipode; the a-L-threo-
Do
0
V
OMe
M
HO
OH
Reagents
6, MeI,Ag,0(36%)
I
e
-
OMe
OMe
U.,05(;;)=0, Phjp, D E A D , u,N2H4
n
$ , H ~ Bt -
p i - N V M c
u-v
(24)
,W,N a B H 3 C N , M e 2 W ,v, 4-BrC&
NCO,
Scheme 1 1
enantiomer shown was identical (by c.d.) to material obtained from the potent antitumor antibiotics esperamicin.20 The Mitsunobu reaction also features in the synthesis of the hydrogen sulphite adduct (25) of nojirimicin from m-inositol 0
BnO
CH2OH
0
CHZOCHZOM~
(26)
(25)
R m g h s L , ( M e 0 ) 3 C H , 7 5 0 H , M e O H , U, L A H ,+MeOo12U,Et2NPrL VL, ( ~ ~ ~ & 6t3N & ,,vu) H, PdCOH)), , VUL, SO, S c h e m e 12 ~
LV,
PhthNY,Ph3P,DEAD,v,
N ~ H ~ ,
Py
Curboil-vdrare Chemistry
100
the optically active seven-membered ring lactone (26) (V01.22, p.165) (Scheme 12). The enantiomer of adduct (25) was synthesised analogously from the enantiomer of lactone (26), and shown to be a potent inhibitor of 8-glucosidase and amannosidaseFl A purported synthesis22 of nojirimycin from 2,3,4,6-tetra-Q-benzylD-glucono-1,5-lactonehas since been refuted.= A number of syntheses of amino-sugars from chiral non-carbohydrate starting materials have been reported. Full details have been published on the synthesis of N-benzoyl-daunosamine (V01.21, p.90) and 3-benzamido-2,3-dideoxy-pentoses (V01.22, p.98) using chiral nitrones derived from 2,3-Q-isopropylidene-Lglyceraldehyde and diethyl Gtartrate, respecti~ely.”~~ Branched-chain aminosugars have been prepared and converted by oxidative cleavage to unbranched (27) was obtained amino-sugars. 2-Amino-2-deoxy-3-~-branched-D-manno-hexose from 2,3-Q-isopropylidene-D-glyceraldehyde (28), epimerised at C-3 to its D-&analogue, and converted by oxidative decarboqlation to compounds such as (29) CO, H
Reagents i, Me2;&iCOZNa;
u , A r C W 2 N H C H ( ~ 2 ~ t ) 2DCC, , Li, D B U
CL
(29)
O
S c h e m e 13
(Scheme 13).% Full details have been published on the synthesis of L-acosamine and L-daunosamine derivatives from ethyl (!3)-3-hydroxybutyrate a common branched-chain intermediate (V01.21, ~ . 8 8 ) 2 ~ The 2-amino-2-deoxy-D-erythrose derivative (30) was synthesised from Lmalic acid (31) the known synthon (32) (Scheme 14). Its D-threose
isomer was obtained by epimerisation (Bu‘OK-BU~OH)of the &-fused intermediate (33). The corresponding 3-amino-3-deoxy-tetroseswere obtained by reversing the oxidation levels at C-1 and C-4.28 2,5,6-Trideoxy-5-amino-D-~-hexosederivative
101
9: Am in o -sugars
(34) and its 3-C-methyl analogue (35) were obtained from the &-fused aldehyde (36) and ketone (37) (Scheme 15), derived from the chiral adducts formed between
t N 3
Me
Me
(34) R = H (37) R = M e
Reagents
L,
vu., N ~ O
(35) R = Me
, V L NaN,, ~
u IB n u . N a H , Lu, A c o H , M ~ O H , LV, T S C LI ,v,~0~ 3 ,MeOH, Me,S MM~~,O H, VU* n2,P ~ C w, , (CF~JCO),O
(+2Z~,
DMF ,
S c h e m e 15
acetaldehyde and cinnamaldehyde or a-methylcinnamaldehyde,respectively, in the presence of baker’s yeast (Vo1.14, p.72; Vo1.15, p.97). The D-&-isomer of compound (34) was similarly synthesised from the trans-fused C-2 epimer of compound (36) (Vo1.15, p.96). The unprotected branched-chain intermediate (38), obtained from ketone (37), was converted to the tosylated (39) which gave the 4azide (40) and the D-arabino-(41) and L-x&-(42) 5-azides from nucleophilic attack of azide at C-5 with inversion, and C-4 with inversion and retention, in a 156520 ratio, respectively (Scheme 16).29
Some amino-sugar syntheses have begun with chiral amino-acids. The four isomeric methyl 2,4,6-trideoxy-4-~-methyl-4-t~fluoroacetamido-L-hexop~anosides have been synthesised from L-threonine. The L-m-isomer (43) was obtained from the known oxazoline derivative (44) by a ten step procedure (Scheme 17). Grignard
c in
’C02Me
“i‘
Ph
Me
Me
L-Lv
B ~ O v
v
+
~ F 3 C O H N 0 0 N e
(46)
(45)
(44) Rqents VU,
OH (431
LAH, uI(COU)2,DM50,Et3N,UL, +‘-MgBr MeONa,MeOH I V I I L , O ~ , Me2S, LX, MQQU , H U L/,
Me
,
, Lv, X,
N a H , BnCL, v, h,o,
H1,QL/C
S c h e m e 17
MeO+!,HCL, VL,(C.~$D)~O,DMAP,
102
Carbohydrate Chemistty
addition (step iii) gave a separable mixture of isomers (45)and (46)in a ratio of 98:2 at -9o”C, but 5545 at 20°C. The minor isomer was converted into the L-arabino-isomer of compound (43). The L-&- and L-&-isomers (47)were separately prepared from the enantiomeric starting material (48)(also available from L-threonine) by a process involving separation of the isomeric adducts (49)
and inversion of configuration at position-5 (final product numbering) (Scheme 18).30 The L-senna1 derivative (50) has been elaborated into the 5-amino-3,5dideoxy-L-arabino-hexose derivatives (51) and (52) (Scheme 19).31A different L-
0
(5’)
(50)
Roclgents i,
q+CDMe,
OWtOLL,
u.)Me+bHE(OAc), ,uIAc20,Py V,
Na0H4
VL)
HgZt, Hz0,
VLL,
w, M e 1
,
0,:ALH
S c h e m e 19
senna1 derivative (53) has been converted by hetero-Diels-Alder methodology into the 6-amino-6-deoxy-L-glycero-D-galacto-heptosederivative (54) (Scheme ZO), an
I
C HO
O Et
B*oo 0
(55)
intermediate previously used in the synthesis of destomic acid; the initial adduct (55) was the major component in an 87:8:4:1 mixture of diastereoi~omers.~~
9: Am in o -sugars
103
Vogel and co-workers have synthesised a variety of aminodeoxy- and deoxysugars from the chiral Diels-Alder adducts of furan with cyanovinyl (1R)- or (15)camphanate. The adduct (56) has been converted to the lactones (57)-(59) by electrophilic functionalisation of the alkene and the masked a-keto-position, and Baeyer-Villiger oxidation, and thence into the hydrochlorides (60)-(62) of Dlivid~samine,~~ all~nojirimycin,~~ and the methyl a-glycoside of 3-amino-3-deoxy-D-
a l t r o ~ e ?respectively ~ (Scheme 21). The nitrogen-functionalityin compounds (60) and (61) was introduced by displacement of halide with azide. While the chlorine in acid (63) was displaced from a lactone intermediate with inversion, the bromine in acid (64) was displaced from the corresponding potassium salt with retention due to participation of the carboxylate group. Racemic methyl a-hikosaminide peracetate (65) has been synthesised DLgalactodialdose derivative (66), by a process involving two hetero-Diels-Alder reactions with diene (67) (Scheme 22).36 A similar approach to racemic N-acetylneuraminic acid has been reviewed.37
Carbohydrate Chemistry
104
a
*CH=O
L
__.
OMe
Dro
+;\sio
R
9
d
(67)
i, E U ( f 4 3
'
Scheme 2 2
2,
DL-( 65)
c
Syntheses of polyoxamic acid from pyroglutamic acid and L-tartaric acid and of a 4-amino-2,3-dihydroxyhexanedioicacid from pyroglutamic acid are covered in Chapter 16. Synthesis of imino-alditols are covered in Chapter 18. 3 Reactions derivative (68) has been The 1-(4-azidobenzamido)-1-deoxy-D-fructose
synthesised from l-azido-l-deoxy-2,3:4,5-di-~-isopropylidene-D-fructopyranose,3s and the e.i.-mass spectra of fifteen N-(1-deoxy-D-fructopyranos-1 -yl)aminoacids have been reported?' The bisulphite adduct (25) of nojirimycin has been converted into the disaccharide mimic (69), which was shown to be an a-glucosidase inhibitor (Scheme CH 2 0 ~
CHZOH
CH~OBZ 5 steps
OH
(25)
bH
ODz
(69)
Syntheses of aminosugar 0-and C-glycosidesare covered in Chapter 3. Three N-acylated 2-amino-2-deoxy-D-glucoses[bearing HO(CH,),CO +, H02C(CH2),C0 -*,or HOCH,CH=CHCO as the acyl group] were synthesised via 23):'
+
105
9: Amino-sugars
per-)-acetylated 2-amino-2-deoxy-b-D-glucose and tested for biological activity as GBH (gamma-hydroxybutyricacid) analogues, but found to be ina~tive.~' 2-&Acylvinyl- and diacylvinyl-amino-2-deoxy-D-glucoses (70), prepared from 2amino-2-deoxy-D-glucoseand readily available materials, have been converted into the bromides (71) or the free sugar (72) by reaction with acetyl bromide or acetyl chloride, respectively (Scheme 24). The bromides (71) were used in Koenigs-borr CH~OAC
R' = H or
0
M~
L.
RZ=COMe,H,C02Et,ortDnMe R3= Me,OMe,OEt, or Ph
R e 9 w L . t ~ i, . AcBr
-+
i L 4
(71) X = c r - B r (72)X= W,/~-OH
;ii, AcCL ;UL, weow, Ay3C03; w,
CLIor er,, C H C L 3
Scheme 24
glycosidations of methanol to give, after &-deprotection, the b-glycosides (73).42 14C-Labelledmethyl 2-acetamido-2-deoxy-3,6-di-Q-pivaloyl-aand 8-Dglucopyranosides have been synthesised from 2-acetamido-2-deoxy-D-[1''C]glucopyranose by glycosidation and partial acylation, and examined as substrates for the esterase from rabbit serum. The 6-ester was rapidly and selectively hydrolysed from the cr-anomer, but hydrolysis was slow and not as selective for the fl-an0mer.4~Several carbohydrate biguanides have been synthesised as potential hypoglycemic agents. The galactos-6-yl derivative (74) was obtained from the corresponding 6-amino-6-deoxy-derivative[by reaction with H,NC( =NH)NHCN]. Glucos-1- and 6-yl biguanido-analogueswere obtained similarly, while the Cglycosidic analogue (75) was obtained from D-arabinose.4 The synthesis and biological activity of Lipid A disaccharide analogues, and of 6-Q-peptidyl-2acetamido-2-deoxy-D-glucosesas glycoconjugates of opioid peptides, are covered in Chapters 3 and 7 respectively. NH CH2 N tiK
NH
FH20H
NH A N H2
Q
N-Ph
OM
Ph
'7)
( 75)
106
Carbohydrate Chernistry
The synthesis and reactions of 1,2-dideoxy-hexopyrano[2,1-~]oxazolines and oxazolinium salts have been reviewed:’ Acid-catalysed cyclisations of H-(glycos-Zyl)-urea and -thiourea derivatives have provided imidazolin-2-oneMand 2-thiazoline4’ derivatives, (76)-(78). Six naturally occurring sialic acids (NeuSAc, Neu5,9-Ac2, NeuSAcgLac, NeuSGc, NeugAcSGc, and the 2-acetoxyacetamido-derivative)have been synthesised in multigram quantities by using immobilised acylneuraminate pyruvate lyase to couple the corresponding mannosamine with pyruvate. Inexpensive routes to substrates avoiding the use of costly mannosamine were reported, and methylated derivatives (NeuSAc7Me and NeuSAcgMe, but not so well NeuSAc8Me) were also synthesised.@ A chemical synthesis of N-acetylmuramic acid from 2-acetamido-2deoxy-D-glucose is covered in Chapter 5. Amino-glycal and -nucleoside derivatives are referred to in Chapters 13 and 20, respectively.
4 Di-amino-Sugars (79) of N-acetylneuraminic acid has been The 4-acetamido-4-deoxy-analogue
““POT CH20H
Co2H
synthesised (see Chapter 16), and shown to be activated by CMP-sialate synthase:’ Full details on the synthesis of the methyl di-N-acetyl-a-glycosidederivative of purpurosamine B (cf. V01.22, p.105) have been p~blished.~’
References 1
2
3
4 5 6 7
N.N. Lomakina, N.L. Tokareva and N.P. Potapova, Antibiol. Khimioter., 1988,3, 726 (Chem. Abstr., 1989,111. 7 716). G.Baschang, Tetrahedron, 1989 45,6331. G.Cardillo, M. Orena and S. Sandri, Pure Appl. Chem, 1988,60, 1679. S.R.Nautial, V.R.Agarwal and D.D. Mukeji, Indian J. Pharm. Sci., 1 9 8 8 , a 26 (Chem. Abstr., 1989, 110,115 225). P. Bako, L. Fenichel, L. Toke and B.E. Davison, J. Chem. SOC.,Perkin Trans. 1, 1989,2514. M. Krecmerova, M. Cerny, M. Budesinsky and A. Holy, Collect. Czech. Chem. Commun., 1 9 8 9 , s 2753. T. Murakami, K Harata and S. Morimoto, Kenkyu Hokoku - Sen’i Kobunshi Zairvo Kenkwsho, 1988, 9 (Chem.,1989,110, 8 512).
9: A m ino-sugars 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
107
M.K. Gujar, S.M. Pawar and P.S. Mainkar, J. Carbohvdr. Chem., 1989, X, 785. S. Valverde and S. Garcia-Ochoa, J. Carbohvdr. Chem., 1989, 8, 553. Y. Leblanc, B.J. Fitzsimmons, J.P. Springer and J. Rokach, J. Am. Chem. SOC.,1989,111, 2995. Y. Leblanc and B.J. Fitzsimmons, Tetrahedron Lett., 1989,%, 2889. L. Andersen, J. Lau and E.B. Pedersen, Chem. Scr., 1988,28, 307 (Chem. Abstr., 1989,110, 154 771). H. Petersen, M.S. Metawia, E.S. Andreassen, J.P. Jacobsen and E.B. Pedersen, Chem. Scr., 1988, 3, 341 (Chem. Abstr., 1989,110,213 237). B. Abbaci, J.C. Florent and C. Monneret, J. Chem. SOC.,Chem. Commun., 1989, 1896. J.M.J. Tronchet and M A M . Massoud, Heterocvcles, 1989,p 419. D. Lafont, P. Guilloux and G. Descotes, Carbohvdr. Res., 1989,193, 61. Y. Tsuda, Y. Okuno, M. Iwahi and K Kanemitsu, Chem. Pharm. Bull., 1989,g, 2673. N. Asano, K Katayama, M. Takeuchi, T. Furumoto, Y.Kameda and K Matsui, J. Antibiot., 1989, g , 585. U.E. Udodong and B. Fraser-Reid, J. Ore. Chem., 1989,54,2103. J. Golik, H. Wong, D.M.Vyas and T.W. Doyle, Tetrahedron Lett., 1989, 3, 2497. N. Chida, Y. Furuno and S. Ogawa, J. Chem. SOC.,Chem. Commun., 1989, 1230. B. Rajanikanth and R. Seshadri, Tetrahedron Lett., 1989,2, 755. G.W.J. Fleet, N.G. Ramsden, N.M. Carpenter, S. Petursson and R.T. Aplin, Tetrahedron Lett., 1%. 405. Y. Kita, F. Itoh, 0. Tamura, Y.Y.Ke, T. Miki and Y. Tamura, Chem. Pharm. Bull., 1989, 1446. Y. Kita, 0. Tamura, F. Itoh, H. Kishino, T. Miki, M. Kohno and Y. Tamura, Chem. Pharm. Bull., 1989,37,2002. M. Shiozaki, N. Ishida and S. Sato, Bull. Chem. SOC.Jpn., 1989, 62, 3950. J.C. Galluchi, D.-C. Ha and D.J. Hart, Tetrahedron, 1989.45- 1283. G. Guanti, L. Banfi and E. Narisano, Tetrahedron Lett., 1989,30,5507. D. Faiardi, G. Fronza, C. Fuganti, G. Pedrocchi-Fantoni and D. Pizzi, J. Carbohvdr. Chem., 1989,8, 469. G. Fronza, C. Fuganti and G. Pedrocchi-Fantoni, J. Carbohvdr. Chem., 1989,g 85. A. Dondoni, G. Fantin and M. Fogagnolo, Tetrahedron Lett., 1989,30- 6063. A. Golebiowski and J. Jurczak, J. Chem. SOC.,Chem. Commun., 1989,263. D. Faltori, E. de Guchteneere and P. Vogel, Tetrahedron Lett., 1989, 7415. Y. Auberson and P. Vogel, Aneew. Chem., Int. Ed. Enel., 1989,28, 1498. C. Nativi, J.-L. Reymond and P. Vogel, Helv. Chim. Acta, 1989, 72, 882. S.J. Danishefsky and C.J. Maring, J. Am. Chem. SOC.,1989,111, 2193. S.J. Danishefsky, M.P. De Ninno, J.E. Audia and G. Schulte, ACS Syrnp. Ser., 1989, 386 (Trends Synth. Carbohydr. Chem.), 160 (Chem. Abstr., 1989,111, 39 770). J.C. Goodwin, Carbohvdr. Res., 1989,195, 150. V. Yaylayan and P. Sporns, Ore. Mass Suectrom., 1988,2, 849 (Chem. Abstr., 1989,111, 134 704). P.B. Anzeveno, L.J. Creemer, J.K. Daniel, C.-H.R. King and P.S. Liu, J. Ore. Chem., 1989,2,2539. F. Dardoize, C. GoasdouC, N. GoasdouB, H.M. Laborit and G. Topall, Tetrahedron, 1989.45, 7783. P. Borrachero Moya and A. Gomez-Sanchez, An. Ouim., Ser. C., 1988,84, 55 (Chem. Abstr., 1989, 110,24 197). S. Tomic, D. Ljevakovic and J. Tomasic, Carbohvdr. Res., 1989, 188,222. A.B. Reitz, R.W. Truman, C.S. Marchione, AD. Jordan Jr., C.R. Bowden and B.E. Maryanoff, Jz Med. Chem., 1989,32- 2110. W.P. StBcbl and H. Weidmann, J. Carbohvdr. Chem., 1989,8, 169. M. Avalos Gonzalez, P.C. Moreno, I.M. Gomez Monterrey, J.L. Jimenez Requejo, J.C. Palacios Albarran, F.R. Vicente and J.F. Mota, Carbohvdr. Res., 1989,187, 1. M. Avalos Gonzalez, P.C. Moreno, I.M. Gomez Monterrey, J.L. Jimenez Requejo and J.C. Palacios Albarran, An. Quim.. Ser. C., 1988, 84, 5 (Chem. Abstr., 1989,110, 24 196). C. Auge, S. David, C. Gautheron, k Malleron and B. Cavaye, New J. Chem., 1988,l2, 733 (Chem. w,1989,111, 23 846). E. Zbiral, E. Schreiner and R. Christian, Carbohvdr. Res., 1989, 194,C15. A. Golebiowski, U.Jacobsson, J. Raczko and J. Jurczak, J. Om. Chem., 1989, 3, 3759.
a
a,
a,
10
Miscellaneous Nitrogen Derivatives
1 Glvcosvlamines The novel pyridone N-glycoside (1) has been isolated from the Algerian newt as a strongly fluorescent pigment.' 2,3,6-Tri-Q-benzoyl-fl-D-galactoand gluco-pyranosylamine hydrogen halide salts have been synthesised by partial benzoylation of the N-[2,2di(ethoxycarbonyl)vinyl]-glycosylamines (2) followed by N-deprotection with chlorine or bromine, and have been converted to the corresponding isothiocyanates (3) on reaction with thiophosgene? The water-soluble spin-labelled glycosylamines (4) were obtained as @-mixtures on reaction of the free sugars with the amines? 4-(~-Galactopyranosylamino)pyrimidines (5) were likewise obtained by direct c~ndensation.~ The N'-8-D-glucosides of the sulphonamide drugs sulfadimidine, sulfamerazine and sulfamethoxazole have been synthesised and shown by h.p.1.c. and m.s. analysis to be the minor urinary metabolites in humans? The 8-Dglucuronide derivative (6)of sulfamethoxazolewas synthesised by reaction of the
X
(4)
x=
corresponding uronosyl bromide with the drug under phase-transfer catalysis.6 The
cr,,9-D-ribosylamino-pyrimido[5,4-ci]pyrimidines (7) have been synthesised by B-
109
10: Miscellarieous Nitrogen Derivatives
heteroarylation of 2,3-Q-isopropylidene-D-ribofuranosylaminep-toluenesulphonic acid salt? The 5-aminoimidazoleribonucleoside (8) rearranged in aqueous buffer at pH 7 to the glycosylamine (9) (Scheme 1): Fructosamine 1,6-diphosphate has been synthesised by transamination of amino-acids, e3. L-alanine, with fructose lY6-diphosphatein the presence of pyridoxal, which acts as the carrier of the aminogroup from amino-acid to ketose. The 1-phosphate group catalysed the reaction.'
The N-ribosylated imide (10) and its dihydro-analogue have been synthesised in good yield by condensation (SnC1,-catalysed) of 1,2,3,5-tetra-Q-acetyl-p-Dribofuranose with the N-silylated carboxyimides, whereas the corresponding phthalimido-analogue was obtained only in low yield." Catalysed fusion condensation of benzothiazole-2-thione with peracetylated aldoses led predominantly or exclusively to the 1,2-trans-N-glycosides. The products were tested as fungicides, but none displayed activity against Fusarium owsuorum The D-pentopyranosyl-pyrazoles(11) were synthesised from the corresponding 2 - o h e derivatives (12) (V01.22, p.108) by reduction of the released ketones.12
m."
Reaction of the N-benzyl-arabinofuranosylamine(13) with vinylmagnesium bromide yielded the alkene (14), which was converted to the C-glycoside (15) by a mercuration-reduction sequence (Scheme 2).13 CH206n
CH20H
BnO NHBn
'
L,
4' MgBr
(15)
(14)
(1 3) fk9Wx.k
I
I
0 Bn , U , Hg(OCOCFA),
, then KCL ; ul,N a B H q , iv, H,
Scheme 2
PcifC
NH2
110
Curbohydrcrtr Chcrnistty
Oligosaccharide N-acryloyl-glycosylamines, required for co-polymerization with acrylamide, have been synthesised in high yield from the corresponding free oligosaccharides ( e s , lactose, lacto-N-tetraose, and lacto-N-fucopentaose I and 11) by amination [(NH,),CO,-H,O] and acylation [CH,=CHCOCl - NaHCO, MeOH].14 Oxidation of the N-vinylglucosylamine derivative (16) yielded the N-acylated and N-formylated derivatives (17) and (18) (Scheme 3); reactions of related
OAc
Reagents,
L,
(16)
N a I O + , KPln04,H20,Me2C0
Scheme 3
derivatives, including examples with the enamine group bonded to C-2, were also ~tudied.'~The sulphuric acid-catalysed reaction of D-glucose with urea in phenolwater solution has been studied as part of an investigation into the chemistry of carbohydrate-based adhesives. a-4-D-Glucopyranosylurea,IV,N -di-j-Dglucopyranosylurea16and the cyclic carbamate (19)" were isolated from the resinous product. N-Glucosyl-biguanidine has been synthesised as a potential hypoglycemic 0
CH20H
CH20H
HobNph Lol{7; O_PNPh
""Ao
HO QNH
('9)
" 4 3
OH
CH20H
(20)
(21)
agent.18 The imidazolin-2-ones(20) and (21) resulted from acid-catalysed cyclisation of the corresponding 2-deoxy-2-(N -phenylureido)-ald~ses.~~ The N-chitobiosylasparaginepeptides (22) have been synthesised as partial structures of a-glycopeptides, a new phase-transfer catalysis procedure being used CH20Ac
CHZOAc
00 0
AcO
NMAc
Reageds . i, N a N 3 , (c8H,,),GMe
--++
GLcNAc-,O-(1+4)-GLcNAc-
-P-!-Asn-
R
NHAc
(231
CL-,CHCL3,H20
Scheme 4
(22) 4 - A h - T h r - A h - S e r c m d Phe-Thr
10: Miscellatit.ous Nitrogen Derivatives
111
in the preparation of the azide (23) (Scheme 4).20 The glycinamide ribonucleotide (24),which is PJ-formylated in the first step of purine biosynthesis, has been synthesized from 2,3,5-tri-Q-benzoyl-B-D-ribosyl azide using conventional protecting group methodology?' Routine syntheses of glycosyl isothiocyanates, involving reaction of the corresponding hexopyranosyl bromides with potassium thiocyanate, and their subsequent conversion to thiourea and thiosemicarbazide derivatives on reaction with amines and hydrazine, respectively, have been reportedF2 Partially protected B-D-galactopyranosylaminederivatives, s.(25) and (26), have been obtained by reaction of the corresponding galactosyl isothiocyanate with a-aminoaceto-phenones and a-aminoacetone, respectively. In acetic anhydride, the thiourea (25) cyclised to compound (27).23
Kunz and co-workers continue to exploit per-Q-pivaloylated hexopyranosylamines as chiral templates for the synthesis of amino-acids and
alkaloids. Optically active (S)-amino-acids (28) were obtained by diastereoselective Ugi reaction employing the D-arabinosylamine (29) (Scheme 5).% The corresponding (R)-amino-acids are available using a D-galactosylamine derivative, which is effectively enantiomeric with compound (29) (V01.22, p.111). Chiral 8amino-acids (30) were constructed by hetero-aldol-type condensation,25and piperidine alkaloids, e&. (+)-confine (31), by tandem Mannich and Michael reactions% applied to the D-galactopyranosylimine derivative (32), respectively
112
Curbohydrate Chernistty
Scheme 6
(Scheme 6). The galactosylamine adducts (33) and (34) were the favoured diastereomers by ratios of between 5:l and 250:l. In the case of compound (32) with R = 3-pyridyl, the opposite diastereoisomer of compound (34, R = 3-pyridyl) predominated, and this was used in the synthesis of (S)-anabasine. The Maillard reaction between reducing sugars and amino-acids or proteins, as it occurs in foods during storage or on thermal treatment, has been reviewed (in German, with 41 refs.), and pathways leading to odour, taste and colour components were presented." From the thermal degradation of fructose-valine products (themselves isolated from Maillard reaction of glucose and valine), 100 compounds have been separated and 70 of them identified by g.c.-m.s. with e.i. and positive ion c.i. detection. Nitrogen heterocyclic compounds made up ca.40% of the reaction product. The mechanism of formation of the various categories of compounds was discussed.= The 3-(2 '-pyrrolyl)-2-cyclopenten-l-one derivative (35) has been isolated from a xylose-lysine Maillard reaction;' and the (1' -pyrrolyl)-norleucine derivative (36) has been shown to be the major product from the glucose-bovine serum albumin Maillard reaction, and synthesized by reaction of glucose with acetyl-lysine.3' In a study of the Maillard reaction of ovalbumin with disaccharides, it was observed that isomaltose and melibiose induced brown coloration and the formation of fluorescent compounds much more strongly than did maltose, cellobiose, and lactose, although all five disaccharides decreased the content of free within one week at 50". It was concluded amino-groups in the protein to ~ 2 0 % that a 4-linked pyranoside unit on the reducing glucose moiety retarded the further degradation to aldehydic compounds of the initial Amadori rearrangement products?l
r-
10: Miscr 1laneous Nirrogeri Derivarivcs
113
2 Azido-, h i - and Diazo-Sugars Several syntheses of azido-sugar derivatives have relied upon sulphonate utilised displacement reactions. A cheap synthesis of 2-azido-2-deoxy-D-mannose the crude mixture containing the 2-hydroxy-compound (37) formed directly from D-glucose [Me2C(OMe),-MeOH-H2S04]. The 2-azide (38) was thus obtained in 10% overall yield from D-glucose by formation and displacement of the 2-Qimidazolesulphonate derivative of compound (37), and was then hydrolysed to the free 2-azido-sugar. Further transformation to the N-acetylneuraminic acid analogue (39) was effected by sialate aldolase catalysed condensation with sodium pyruvate?, For the construction of 2-azido-2-deoxy-~-D-mannopyranosyl-( 1+4)- and -(1+6)-Dglucose, the requisite gluco-disaccharide derivatives with a single free hydroxy-group were constructed, imidazole-sulphonylated,and subjected to displacement with a ~ i d e . 3Displacement ~ reactions of 2-Q-triflate (40) with a variety of nucleophiles as their tetrabutylammonium salts in various solvents have been investigated, the 2azido-Zdeoxy-D-glucoside (41) and its 2-phthalimido-analoguebeing obtained in
I OH
Y
(3 9) (37) X = O H , Y = H
(40) X = OTf Y= H
(3%) X = H , Y = N 3
(41) X
~
5
H
N3
moderate ~ i e l d . 3A~ new route to the 2-azido-2-deoxy-D-galactoside(42) has been reported (Scheme 7),35the product being used in the synthesis of disaccharide fragments of dermatan sulphate (see Chapter 3). A synthesis of the 2-azido-2CH200n I
N3 - 6 s .
L.,
(NH4)2Ce(N03),
,N a N 3 , L, MeONa,
MeOH
,iU, HOAc,H20
Scheme 7
deoxy-D-glucose derivative (43) in B.50% overall yield from the 2-amino-2-deoxyD-glucose tetraacetate (44) has also been reported (Scheme 8)P6
-
CH20Ac
___,
LL
QAc
LV-VL
UL
__f
AcO N H Z HC1
NH Bn
I k q w z k S L , BnBr, Kc,CO,, OM!=, LL, NzO4, CHzCL,, NaOAc
v , Py,Ac20
N3
AcNHiN,Bn
ON/Nw"
, UL, Z n ,HOAc,
AcZO,
w , H2,W C ,TsOU,
(43)
H@
,VC, L S O ~ ~ ~ L ~ L ~ - L ~ ~ , T H F ,
Scheme 8
The D-gluco-diazirine derivative (45)and its D-manno- and D-galactoanalogues have been prepared from the corresponding hexono-1,5-lactone oximes, and shown to be stable at low temperatures (Scheme 9). They are precursors of
( 45)
bDn R e a g e n t s L, M s C L , E t 3 N , u,N H 3 , MeOH , U L , I-,, E t 3 N , Meoti ,
LV,
(46)
Pr'OH
Scheme 9
glycosylidene carbenes, and in a preliminary experiment diazirine (45)was converted into the glycosides (46)?7 derivative (47)has been The 3-deoxy3-diazo-D-arabino-oct-2,4-diulosonate synthesised by condensation of 1-diazo-D-fructosederivative (48)with methyl oxalyl chloride. In contrast to other carbohydrate diazoketones, compound (47) is relatively stable to acids, although it reverts to the precursor (48) on exposure to water.%
(47)
R =
koAc (48)
L*
J.
OAc
CH~OAC
CO, M e
R=H
I 0: Miscelliin e m s Nitrogrri Drrivat ive.s
115
3 Nitro-Sugars Aldehydro-sugar derivatives, e.g. (49), have been chain extended using Seebach's silyl nitronate methodology (Scheme Unhindered nitromethyl-sugar
derivatives such as (50) formed silyl nitronates that could be condensed with pitrobemaldehyde, but silyl nitronates such as (51) from the C-glycoside (52) C H2C H2 NO,
CH20Ac
(51)
Me
x=
(52) X = C H ~ N O Z 0
x0
(501
OAc
(53) X = CHO
failed to react with aldehydes. Ozonolysis converted silyl nitronate (51) into aldehyde (53).40 Chain extension of nitromethyl sugars such as (54) could also be effected as shown in Scheme 11, and one or both of the methylthio-groups in the products could be displaced by nitrogen nucleophiles, e.g. to give compound (55):l
4 Nitriles. Isonitriles, Oximes and Hvdroylamines
Eleven protected sugar derivatives bearing a terminal 1-cyanovinylgroup have been prepared from sugar aldehydes, as shown for the conversion of the 5-aldehvdoriboside (56) into the product (57) (Scheme 12). These compounds were prepared
116
Curb0hydrate Chernistry
pJMe G C HO
NO2
Lfu.
[
>
0
xo(56)
Reag&
L,
M e N 0 2 , MeONa,MeOH,u,A c 2 0 , N a 0 A c I
UL,
CH2 NO2
J
1
w_
TCN J
(57)
K C N , B h 4 N 0 r , H20, P h M e ,
LV,
EtgN
Scheme 12
for use in a structure-activity study of cytotoxic, antiviral and antimicrobial properties. A disaccharide analogue (58) was obtained by condensation of
cyanovinyl-derivative (59) with the hydroxylamine (60) (Scheme 13).42 The extremely hindered analogues (61) and (62) of daunosamine have been synthesized
CF3CONH
Me
(61) R = ti
(62) R = C N
from ketone (63). The &-configurated amino-sugar (64)had to be obtained by reductive decyanation as shown (Scheme 14) because reduction (LiAlHJ of the oxime derivative of ketone (63) unexpectedly gave the arabino-is0mer.4~
10: Misccllmneoics Nitrogoti Derivatives
117
Glycofuranosyl formamide, isonitrile and isocyanate derivatives have been
Reagent6
I, Ph3P : -i,AcOCHO, h.,POCL3,
W,
G = protected- yLycofuranosyL
Pb(OAc),
Scheme 15
prepared from the corresponding glyco-furanosyl azides (Scheme 15).44 The isonitriles (65) were formed as intermediates in the synthesis of 8-linked 2-deoxy-D-
hry CH20Ac
(jR ( j RjR
CH20Bz
=
Lj’
>
f
5
UL
R=e9:oQBn
AcO
NHCHO
NHCHO
(65) ReagdS
OBn
NC
(66)
L , A c C L , H C L , U , R O H , A ~ O T, ~ a, POCL3,Et3N, w , Bu3SnH
S c h e m e 16
arabino-hexose disaccharides (66) (Scheme 16), the isonitrile group being removed by radical reducti0n.4~ The nitrone (67) has been prepared directly from D-glucose oxime and benzaldehyde without protecting groups, and shown to undergo dipolar cycloadditions with dipolarophiles such as acrylonitrile to give isoxazolidine (68) of undetermined stereochemistry.& The novel hydroxylamino sugar (69) has been isolated from a new anthracycline antibiotic, viriplanin A.47 The epimeric 4-hydroxylamino-sugars (70) were obtained by reduction (NaBH,CN) of the corresponding 4-oxime derivative (cf., V01.21, p.108); differences between the e.s.r. spectra of these two spin-labelled derivatives confirmed the sensitivity of e.s.r. to configurational changes.&
Ammonolysis of compounds (70) led to 3+4 benzoyl migration, O+N isomerisation
118
Carbohydrate Cfiemi.rtry
yielding compound (71) in the case of the 3,4-c&-compound, and O+O migration yielding compound (72) in the case of the 3,4-trans-c0mpound.~~
5 Hydrazones. Osazones and Related Heterocvcles The synthesis of per-Q-acetylated aldose ~-methyl-~-(4-arylthazole-2-yl)hydrazones has been described?' 3-Alditolyl-1-methylpyrazolessuch as compound (73) have been obtained by condensation of the methylhydrazones of D-mannose and Dgalactose with nitroalkenes?l 2-Hydrazone 3-oxime derivatives, ea. (74),have been obtained from dehydro-L-ascorbicacid by sequential reaction with arylhydrazine then hydroxylamine. Cyclisation in acetic anhydride under reflux led to triazoles such as compound (79,whereas rearrangement yielded isoxazolidinones,u.(76).52 Direct reaction of dehydro-Lascorbic acid with two equivalents of arylhydrazines gave the 2,3-bis(arylhydrazones), which can exist as two geometrical isomers that were isolated in some cases. Reaction with acetone arylhydrazone, however, gave the 2-aryl-hydrazone deri~ative.5~ q?.azo10[3,4-~]quinoxalines7 ed. (77), have been obtained from dehydro-L-ascorbic and dehydro-D-isoascorbicacids by sequential reaction with 1,2-diamino-4,5-dimethylbenzenethen an arylhydrazine, and dehydrative ring closure (with NaOH).54.55A variety of heterocyclic products have been isolated from the reaction of kojic acid and arylhydrazines in aqueous acetic acid?6
10: Miscellaneous Nitrogcw DerivativcJ
I19
6 Other Heterocvcles
The synthesis and reactions of 1,2-dideoxy-hexopyrano[2,1-~]-oxazolines and oxazolinium salts have been revie~ed.5~ A reinvestigation of the reaction between L-cysteine and penta-0-acetyl-aldehvdo-D-galactose or tetra-Q-acety1-aldehydo-Larabinose revealed that, contrary to earlier reports, the product thiazolidines, a (78), are a mixture of isomers at the newly formed chiral centre.” The nitrile oxide (79) generated from the D-ribose oxime (80) can be trapped with dimethylacetylene dicarboxylate (DMAD) to form the cycloadduct (81) (Scheme 17). In the absence of DMAD the D-ribono-1,Clactone oxime (82)is
r
&O.qe-dS
L,
1
N a O C L ; u, DMAD ; .G, D M A D , E t 3 N
Scheme 17
formed. This can then react with DMAD in the presence of a base to form the ionised spirocyclic adduct (83) that subsequently rearranges to the fused bicyclic system (84).59 Anti-adducts (85)were formed with high n-facial stereoselectivity in the dipolar cycloaddition of mesitylenenitrile oxide to variously 3-substituted hex-5enoses (86), best results being obtained with the 3-Q-benzyl ether (Scheme 18).@
L
___j
(86) X = H , O H , O M e , O B n , Reccgent
L,-@C:N-+O
&G
(*5)
Scheme 18
New types of hydroxyamino- and hydroxyureido-sugars have b6en synthesized as potential antineoplastic agents. Thus, addition of hydroxylamine to the
I20
Carbohydrate Chemistry
bromoenose (87) led to the adduct (88).6l Related syntheses and reactions of aziridines derived from compounds such as (87) are covered in Chapter 9. Hantsch esters, such as (89), having monosaccharide substituents, have been synthesised from sugar aldehydes as chiral NADH and used in the asymmetric reduction of several prochiral ketones with ee’s up to 79% being
?
X
Ph
~ ~ ~ { 0 4 (90) c X=
OAc CHZOAC.
x=
MerNyc
(92)
4
NO2
Me
(89)
X=
The 3-(D-galacto-pentitol-l-yl)pyrrole(90) was obtained by addition of the zwitterionic reagent (91) to the nitroalkene (92); analogous results were obtained for the D-manno-stereoisomers.61 References 1 2
T. Yoshida, Y.Iwanami and J.T.Bagnara, Eur. J. Biochem., 1988,175,41. J.F. Mota, J.M.G. Fernandez, C.O. Mellet, M A P . Adrian and R.B. Cabarello, Carbohvdr. Re., 1989,
188.35. 3 4
G. Sosnovski and N.U. Maheswara Rao, Carbohvdr. Res., 1989,190, C1. M. Rodriguez, P. Gil, R. Asenjo and M. Melgarejo, Ars Pharm., 1987, 159 (Chem. Abstr.. 1989,
110, 39 274). 5
6 7 8
B. Ahmad and J.W. Powell, J. Drug Metab. Pharmacokinet., 1988,12, 177 (Chem. Abstr., 1989,110. 68 928). B. Ahmad and J.W. Powell, Indian J. Pharm. Sci., 1 9 8 8 , a 291 (Chem. Abstr., 1989,111.39 771). Y.S.Sanghvi, S.B. Larson, S.S. Matsumoto, L.D. Nord, D.F. Smee, R.C. Willis, T.L. Avery, R.K. Robins and G.R. Revankar, J. Med. Chem., 1989,32- 629. M.P. Grosiak, B. Bhat and J.N. Leonard, Proc. Natl. Acad. Sci. USA, 1 9 8 8 , s 7174 CChem. Abstr., 1989,110, 135 631).
9
F.V. Pishchugin and ZSh. Sharshenalieva, Biokhimiva (Moscowb 1988,53-
1509 (Chem. Abstr., 1989,
110, 8 543). 10
KP. Raezke, H. Frister and E. Schlimme, Z. Naturforsch.. C Biosci., 1988,
l 1989, J 11
397 (Chem. Abstr.,
39 291).
F. Benachenhou, G. Gosselin, N. Bounaga and A. Mesli, J. Agric. Food Chem., 1 9 8 8 , s 607 (Chem.
& 1989,110, 135 623). 12 13 14 15
Z Smiatacz and H. Myszka, Carbohvdr. Res, 1989,186.335. M. Carcano, F. Nicotra, L. P a m and G. Russo, J. Chem. SOC.. Chem. Commun., 1989,297. E. Kallin, H. LOM, T. Norberg and M. Elofson, J. Carbohvdr. Chem., 1989,S, 597. R. Babiano, C. Duran, J. Plumet, E. Roman, E. Sanchez, J.A. Serrano and J. Fuentes, J. Chem. Soc., Perkin Trans. 1, 1989, 1923.
16 17
R.F. Helm, J.J. Karchesy and D.F. Barofsky, Carbohvdr. Res., 1989,189. 103. R.F. Helm and J.J. Karchesy, J. Carbohvdr. Chem.. 1989, S, 687.
10: Miscdluneous Nitrogeri Derivutives 18 19
20 21 22 23 24 25 26 27
28 29
121
k B . Reitz, R.W. Truman, C.S. Marchione, AD. Jordan Jr, C.R. Bowden and B.E. Maryanoff, J. M+ Chem., 1989,32- 2110. M.A. Gonzalez, P.C. Moreno, I.M.G. Monterrey, J L J . Requejo, - _ J.C.P. Albarran, F.R Vicente and J.F. Mota, Carbohvdr. Res., 1989,187. 1. H. Kunz, H. Waldmann and J. MOrz., Liebigs Ann. Chem., 1989,45. D.H. Boschelli, D. Powell, V. Sharky and M.L. Semmelhack, Tetrahedron Lett.. 1989.30- 1599. kk Tashpulatov, V A Rakhmatullaev and N. Ismailov, Zh. Ore. Khim., 1988,24- 1893 (Chem. Abstr.. 1989,111.39 684). J. Fuentes-Mota, J.M. Garcia Fernandez, C. Oniz Mellet, M.A. Pradera Adrian and R. Babiano Caballero, Carbohvdr. Res., 1989,193.314. H. Kunz, W. Pfrengle and W. Sager, Tetrahedron Lett., 1989,a 4109. H. Kunz and D. Schanzenbach, Aneew. Chem. Int. Ed. Enel., 1989,28, 1068. H. Kunz and W. Pfrengle, Aneew. Chem. Int. Ed. Enel., 1989, 28, 1067. F. Ledl, GIT-SUDDI.,1988, 26 and 30 (Chem. Abstr., 1989,110.6 419). G. Vernin, J. Metzger, T. Obretenov, K-N. Suon and D. Fraisse, Dev. Food Sci., 1988,& 999 (Chem. Abstr., 1989,110,8 623). S.B. Banks, J.M. Ames and H.E. Nursten, Chem. Ind. (Londonl, 1988,433 (Chem. Abstr., 1989,110. 24 271).
30 31 32 33 34 35 36 37 38 39
40 41 42 43 44 45
46
M. Sengl, F. Ledl and T. Severin, J. Chromatom., 1989,463. 119. Y. Kato, T. Matsuda, N. Kato and R. Nakamura, J. Aeric. Food Chem., 1 9 8 9 , z 1077 (Chem. Abstr., 1989,111. 55 985). C. Auge, S. David and k Malleron, Carbohvdr. Res., 1989,188, 201. S. David, k Malleron and C. DM,Carbohvdr. Res., 1989,188. 193. W. Karpiesiuk, k Banaszek and A. Zamojski, Carbohvdr. Res? 1989,186.156. A. Marra, X Dong, M.Petitou and P. Sinaji, Carbohvdr. Res., 1989,195. 39. F. Dasgupta and P.J. Garegg, J. Chem. SOC.,Chem. Commun., 1989, 1640. K. Briner and k Vasella, Helv. Chim. Acta, 1989.72 1371. B. Meyer, H. Kogelberg, P. K6ll and V. Laumann, Tetrahedron Lett., 1989, 6641. O.R. Martin, F A Khamis, H.A. El-Shenawy and S.P.Rao, Tetrahedron Lett., 1989, 30- 6139. O.R. Martin, F A Khamis and S.P. Rao, Tetrahedron Lett., 1989, 6143. K. Peseke, H.-D. Ambrosi and M. Michalik, Carbohvdr. Res., 1989,194.87. J.M.J. Tronchet and S. Zerelli, J. Carbohvdr. Chem., 1989,&, 217. V. Rocherolle and G. Lukacs, J. Carbohvdr. Chem., 1989,&,645. J. Hiebl, J. Palsterer and E. Zbiral, Nucleosides Nucleotides, 1989, 8. 885. P. Tavecchia, M. Trumtel, A. Veyrieres and P. Sinaj?,Tetrahedron Lett,, 1989, 30- 2533. D.R. Berthakur, D. Prajapati and J.S. Sandhu, Indian J. Chem. Sect. B, 1 9 8 8 , m 724 (Chem. Abstr..
a
a
1989,110, 173 578). 47
48 49 50 51
R. Kind, K Hiitter, A zeeck,K Schmidt-Bhe and E. Egert, J. Antibiot., 1989, 7. J.M.J. Tronchet, N. Bizzozero and M. Geoffroy, Carbohvdr. Res., 1989,191.138. J.M.J. Tronchet, N. Bizzozero and M. Geoffroy, J. Carbohvdr. Chem., 1989, &, 813. H.W. Stock and k Hetzheim, Z. Chem., 1 9 8 8 , s 297 (Chem. Abstr., 1989,110, 173 577). M. Gomez-Guillen, F. Hans-Hans, J.M.L. Simon and M.E. Martin-Zamora, Carbohvdr. Re., 1989, 189.349.
52 53 54 55 56 57 58 59
60
M.k El Sekily and S. Mancy, Pak. J. Sci. Ind. Res., 1988,3l- 616 (Chem. Abstr., 1989,110. 193 282). Y. El Kilany, k Mousaad, H. Abdel Hamid and E.S.H. El Ashry, Gazz Chim. Ital., 1988, @, 617 (Chem. Abstr., 1989,110. 193 281). L Awad, k Mousaad and E.S.H. El Ashry,J. Carbohvdr. Chem., 1989,a 765. k Mousaad, L. Awad, N. El Shimy and E.S.H. El Ashry, J. Carbohvdr. Chem., 1989, &, 773. E.S.H. El Ashry, Y. El Kilany and A. Mousaad, J. Carbohvdr. Chem., 1989,&, 485. W.P. StOckl and H. Weidmann, J. Carbohvdr. Chem., 1989,8, 169. J. Radomski and A. Temeriusz, Carbohvdr. Res.,1989,187.223. M. Yokoyama and N. Yamada, Tetrahedron Lett., 1989, 3675. M. De Amici, C. De Micheli, k Ortisi, G. Gatti, R. Gandolfi and L Toma, J. Org. Chem., 1989,
a
a
793. 61 62 63
64
J.M.J. Tronchet and MAM. Massoud, Mansoura J. Pharm. Sci., 1988,z 99 (Chem. Abstr.,1989,111. 39 6%). S. Zehani, M.F. Llauro and G. Gelbard, Bull. SOC.Chim. Fr., 1989, 104 (Chem. Abstr., 1989,111. 214 820). S. Zehani, J. Lin and G. Gelbard, Tetrahedron, 1989, & 733.
M. Avalos, R. Babiano, I. Bautista, J.I. Fernandez, J.L. Jimenez, J.C. Palacios, J. Plumet and F. Rebolledo, Carbohvdr. Res., 1989,186. c7.
11
Thio- and Seleno-sugars
4-Thio-D-galactofuranose(2) has been synthesised from the methyl a-Dglucopyranoside derivative (1). The sulphur-containing substituent was introduced (Scheme 1) by nucleophilic displacement of the 4-tosyloxy group of the starting compound by thiocyanate ion with inversion of configuration'.
w ,Lu
OH Rvents
L, N CS- , LL, Zn ;HOAc ;'u, Med,MeOH
Po"
CH20 H
(2)
,LV, AczO, H 2 5 0 4
Scheme 1
5-Thio-D-mannose (3), isolated from a marine sponge, is the first 5-thiosugar to be found in Nature. Its synthesis from D-mannose, which is outlined in Scheme 2, involves two stereochemical inversions at C-5.2 Another new thiosugar, (9,a constituent of the methyl 2,6-dideoxy-4-thio-a-D-&~-hexopyranoside calichemycins, a new class of antitumour antibiotics, has been prepared from the
readily available D-digitoxose derivative (4). Application of the tributyltin radicalcatalysed O S J rearrangement of thionocarbonates allowed replacement of 0 - 4 by a sulphur atom with retention of configuration. As indicated in Scheme 3 the OJS rearrangement was not selective and the desired product (5) and its 3-thio isomer (6) were obtained in roughly equal proportion^.^
I I: Thio- und Stdeno-sugurs
123 Me
Me
S cheme 3
The unsaturated 5-thioglucose derivatives (7) and (8) have been prepared and have been shown by 'H-n.m.r. spectroscopy to assume the '€Is and 4H5 conformations, respectively."
Thiourea derivatives (11) are available from 2-amino-2-deoxy-l,3,4,6-tetra-Qacetyl-a-D-glucopyranose(9) or from the corresponding 2-isothiocyanate (10) by treatment with methyl isothiocyanate or a primay amine, respectively (Scheme 4). On exposure to hydrobromic acid they cyclise to give glucopyrano[2,1-d]-2thiazolinium bromides (12):
ReogeFLtS
L, MeNCS
, u, R & H 2 , u ,H D r
Scheme 4
Scheme 5 shows the synthesis of 6-sulphono-a-D-glucopyranose1-phosphate from the appropriately protected a-D-glucose 1-phosphate (13)@ the disulphide (14). The product was isolated as the tris-cyclohexylammonium salt (15): A convenient route to 6-thio derivatives of D-glucal from D-glucose is referred to in Chapter 13.
Carbohydrate Chrmistiy
124 tH2OTf
M+= OH
(14)
OBn
C)-LH,
(1 5)
('3)
R e a g e n t s . i , 8u4NS H ,cur , u,WCPBA I UL,
t i 2 , Pd/L/c; W , o N . 1
. b pH 7
Scheme 5
Derivatives (16) of 6-thio-D-glucosewere formed in 75-80% yield on with the chlorides (17); and treatment of 1,2,3,4-tetra-Q-acetyl-6-thio-p-D-glucose in the course of photoaffinity labelling studies the 1-(azidoary1)thio-D-fructose derivative (18) was synthesised from 2,3 : 43-di-Q isopropylidene-6-Q-triflyl-Dfructopyranose by use of known methodology.8 1-Isoindolyl-(1-thio-p-D-glucoside) derivatives are mentioned in Chapter 3.
(17)
R = CL
OAc
The glucosylthiol (19) underwent 1,3-additionto in situ generated, substituted benzonitrile oxides (20) as outlined in Scheme 6 to give thiohydroximate derivatives (21). The effects of the aromatic ring substituents on the course of this reaction
was examined? Attempts to prepare 2,5-anhydro-L-arabinose derivatives from acyclic 5-Q-tosylates, by heating for example the tosylated dithioacetal (22) under the basic conditions specified in Scheme 7, were only moderately successful. An inseparable mixture was formed which contained the 1-thio-8-L-glycoside(23) as the main product and the target compound (24) as a minor constituent. The two compounds could be separated and isolated as their mesylates (25) and (26). The mechanism by which the 1-thio glycoside (23) is generated has been described before (see Vol. 13, 1979, p. 105)."
11: Thio- and Seleno-sugars
pspp +
125
coyc~(s% OR
HO
L,
(24) R = H -% (26)R = Ms
CH2SPr
C HZOTs (29
f2eo.gem.L.s
RO
OR (23)R=H*
(25) R = M s
Py or ColLcdcne, w ~ t hor WLthOut D M A P , u, M s U - py Scheme 7
The copper(I1) complexes of 1-thio-a- and -8-D-glucopyranoseand 2-amino-2deoxy-1-thio-B-D-glucopyranose and their peracetates have been synthesised by action of copper(I1) acetate on the respective sodium thiolates, followed by acid catalysed acetylation, for an investigation of their anti-inflammatoryactivity." The mesogenic properties of the C, - C,,dialkyl dithioacetals of ten standard pentoses and hexoses have been examined. Most of them form thermotropic liquid crystals with the notable exception of all L-rhamnose derivatives. A model has been proposed to correlate carbohydrate configuration and melting behaviour. Despite the intrinsic chirality of all carbohydrate mesogens no evidence for chiral mesophases was detected.12 In a simulation of the reaction of glucose and cellulose with hydrogen sulphide and polysulphide at ambient temperature in aqueous solution the formation of organic sulphur compounds was observed which yielded thiophene on pyrolysis/evaporation. By such a process carbohydrates in nature might be converted into sulphur compound which, being resistant to microbial attack, would be preserved in ~ediments.'~ The first examples of 1-phosphonoselenatesof a 2-deoxy sugar have been reported. Their synthesis is shown in Scheme 8.14
I/\ AcO
Scheme 8
REFERENCES 1
2 3 4
0. Varela, D. Cicero, and R.M. De Lederkremer, J. Ore. Chem., 1 9 8 9 , a . 1884. H. Yuasa, Y. Izukawa, and H. Hashimoto, J. Carbohvdr. Chem., 1989, S, 753. K van Laak and H.-D. Scharf, Tetrahedron Lett., 1989,30,4505. N.Z Al-Masoudi and N.A.Hussein, J. Iraqi Chem. SOC.,1987,l2, 149.
126 5
6 7 8 9 10 11 12 13 14
Carbohydrutr Chemistry M. Avalos Gonzalez, P.C. Moreno, I.M.Gomez Monterrey, J.L. Jimenez Requejo, and J.C. Palacios 5 (Chem. Abstr., 1 9 8 9 , m , 2 4 1%). Albarran, An. Ouim. Ser. C, 1988, M. Hoch, E.Heinz, and R.R. Schmidt, Carbohvdr. Res, 1989,191. 21. H. Kristen and T. Tach, Z Chem., 1988,28,2% (Chem. Abstr., 1989,110. 173 576). J.C. Goodwin, Carbohvdr. Res., 1989,195, 150. S. Saito, H.Uzawa,and F. Nagatsugi, Chem. Pharm. Bull., 1989, 2519. E.T. Jarvi and B.W. Metcalf, Carbohvdr. Res., 1989,187, 159. L. Garuti, M. Robeni, G. Giovanninetti, R. Gaggi, J. Defaye, and H. Driguez, Pharm. Acta Helv., 1988,63- 202 (Chem. Abstr., 1989,110,50 906). H A van Doren, R. van der Geest, C.A. Keuning, R.M. Kellogg, and M. Wynberg, Lia. Cmt., 1989, 5 265 (Chem. Abstr., 1989,111. 206 076). M.E.C. Moers, J.W. De Leeuw, H.C. Cox, and P.A. Schenck, Org. Geochem, 1 9 8 8 , s 1087 (Chem. Abstr.. 1989,Jl 195 253). M. Michalska, J. Borowiecka, P. Lipka, and T. Rokita-Trygubowin, J. Chem. Soc.. Perkin Trans. 1, 1989, 1619.
12
Deoxy-suga rs
Reviews have been published on the use of carbohydrate free radicals in the synthesis of deoxy-sugars,' and the synthesis of deoxy-sugars generally? 6-Deoxy-D-allose has been found as a terminal pyranosyl unit of a steroidal glycoside from Heleniopsis orientalis.' Two flavonoid C-8-D-oliosides (1) have been isolated from Cassia torosa leaves! 0-and C-Glycosylated benzanthraquinone antibiotics with complex deoxy-sugar oligosaccharide residues are covered in Chapter 19.
x
OH
(1)
X = R - H , X-OH , R = M e
6-Deoxy-L-arabino-hexulose (2) has been obtained in 27% yield by isomerisation of Grhamnose in pyridine under reflux? The known precursor (3) of 2-deoxy-L-&-hexose (cf.V01.21, p.123) has been synthesised from the D-xyluronic C02 H ~
>
H o f 2 L H =ODn cHz
AGO*
HO
4Q0
(4)
h o g 4
L,
o+ Pb(OAc),,py,
CH2 OH
(5)
( 31
U , C H ~ = G H C ~ ~ ~Mger, S L ~ (,~u ~ H3'3+, , W; N Q ' 3 H +
Scheme 1
the chiral synthon ( 5 ) which is equivalent to D-tartaric acid derivative (4), aldehyde (Scheme 1). An equivalent precursor of 2-deoxy-L-&~-hexosewas obtained similarly from the C-3 epimer of compound (4)6 6-Deo~y-D-w-'~C]glucose has been synthesised in five steps and in 11.8% overall radiochemical yield from D-[U-'4C]glucose? A number of analogues of the Lewis b human blood group determinant tetrasaccharide, cr-L-Fuc-(1-.2)-~-D-Gal-(l-.3)-[~-L-Fuc-(l-.4)]~-D-GlcNAc-l-.OM
I28
Carbohydrate Chemistry
in which the galactose residue is replaced by its deoxy- or deoxyhalo-derivatives have been synthesised to determine the role of this residue in bindings A remarkable, and so far unexplained, reversal in the ratio of secondary to primary alcohol product was observed in the one-pot reductive cleavage of 5,6epoxide (6) in 1,2-dimethoxyethaneunder reflux, from 1 5 1 by use of lithium iodide
C"2
f
ReageYLts: i, L, ~ I
to 1 5 using magnesium iodide (Scheme 2). The reaction is presumed to proceed via initial opening of the epoxide with halide ion?
A further evaluation of the mechanism involved in the formation of deoxysugars on photolysis (254 nm) of sugar esters of aliphatic acids in HMPT-H,O ( 9 9 , and the competing formation of the corresponding alcohol derived by de-Qacetylation, has been published." A number of deoxy- and deoxyhalo-analoguesof a-D-glucopyranosyl phosphate have been synthesised, and their acid-catalysed hydrolyses studied. The deoxy-analogues hydrolysed faster, and the deoxyhaloanalogues slower, than the parent phosphate, the relative reactivity paralleling that which has been observed in the hydrolysis of glycosides." Specifically deuterated paratosides (3,6-dideoxy-D-&-hexosides) (7) and (8) have been synthesised as shown in Schemes 3 and 4, respectively, from D-glucose
Me
OTs
D
062
R e a g h S L,LLALD+; L L . , B L ~ O , E ~ ~ N , W , N ~ ~ S , w,Bu3SnH BC~CO~,
Scheme 4
(8)
12: Deuy-sugars
derived starting materials."
129
The 4-deoxy-acetylenic sugar derivative (9) has been C =CH
-----+
0Bn
HO OBn
OBn
('0)
%en.tS
L,
BzCL,py , U,TSCL,PY,UL, LAY, w , (COU),,Me2So,
vu K C N
Et3N , v ,
Me+CrCMg6r,
(9)
MgQr2 > v ~ , A g ~Eo t o~H,,
Scheme 5
obtained from the methyl D-glucoside derivative (10) (Scheme 5),13 and G oleandrose (2,6-dideoxy-3-Q-methyl-Garabino-hexose)(11) from Larabinose sA5
sn s
CHSPh OMe
HO
the
OH
Vkvu
HO
no
HO
CHZOH
OMe Me
02)
dithioacetal (12) (Scheme 6),14 reductive detosylation being employed in both cases to effect deoxygenation. Radical reduction (with Bu3SnH) of thioacylated sugars has featured in several deoxy-sugar syntheses. A new approach to B-linked 2 '-deoxy-disaccharides
is exemplified in Scheme 7,in which the 2 '-acetoy substituent is removed by radical methodology. A related method involving the formation and radical reduction of an 2 '-isonitrile from a 2 '-formamido-disaccharideis covered in full in Chapter 1O.l' 2-Deoxy-C-glycosides have been obtained by reaction of 1,Zanhydro3,4,6-tri-Q-benzyl-fl-D-mannopyranose with organocuprate reagents, and 2deoxygenation of the product radical reduction of the derived phenomhiocarbonyl esters.16 Improved syntheses of the 2-, 3- and 4-deoxy-
130
Carbohydrate Chemistry
derivatives of methyl fl-D-galactopyranosideshave involved radical reductions of otherwise protected Q-(irnidazolethiocarbonyl)-derivatives.176-Deoxy-sucrose was prepared by hydrogenolysis of 6-~-(2-pyridyl)-6-thiosucrose, whereas 4-deoxy- and 3deoxy-sucrose were obtained by radical reductions of thiocarbonyl derivatives.18 Synthesis of, and the conformations adopted by, a variety of methyl fl-D-galabiose analogues (1,4-a-linked disaccharides) modified in the non-reducing termini have been reported. These include the 2 3 4 and 6 '-deoxy-analogues,which were obtained by coupling methyl 2,3,6-tri-Q-benzyl-fl-D-galactopyranoside with glycosyl fluorides deoxygenated at C-3 (known), C-4 (obtained by reduction of a xanthate ester) or C-6 (from D-fucose), or with a D-galactal derivative using iodosuccinimide and deiodination of the prod~ct.'~The synthesis of 3-deoxy-Le~hro-pentono-l,4-lactone,a new chiral building block, from ribitol is covered in Chapter 16. Radical reduction (with Bu,SnH) of halogeno-sugars has featured in several deoxy-sugar syntheses. 4,6-Dideoxy-sucrose was obtained from 2,3,1',3 ',4 ',6 '-hexaO-benzoyl-6-deoxy-6-iodo-sucrose via chlorination (SO,Cl,) and reduction of the resulting 4-chloro-6-iodo-galactosucrosederivative. Its ability to inhibit various Dglucansucrases was compared with those of 3-, 4- and 6-deoxy-sucrose and 4-chloro4-deoxy-D-galactosucrose. It was found that 6-deoxy-sucrose was a strong competitive inhibitor, but the conclusion was drawn that the hydroxy-groups at C-3 and C-4 of sucrose were important for binding?' 7-, 8- and 9-Deoxy- and 4,7dideoxy-N-acetylneuraminicacids have been synthesised by radical reduction of the corresponding fully protected iodo-derivatives?' Their further conversion into deoxy-analogues of 2-deoxy-2,3-didehydro N-acetylneuraminic acid by introduction of a 2,3-double bond, and the topological features of these unsaturated analogues, and their behaviour as sialidase inhibitors, are covered in Chapter 13. The final step in the construction of the 4-epi-L-daunosamine-containing disaccharide (13) was radical deiodination of precursor (14), the synthesis of which is covered in Chapters 3 and 9F2 I-,
I-,
I-
s-
A
c
AcO
o
X
(
o
)M e
NHCOCF3
(13) X = H (14) X = I
yope
CHzCH206z
F
BnO (1 5)
k0TOAC
CH~CH~ODZ
OAc
'6)
The 5-deoxy-fluoro-sugar derivatives (15) and (16) have been synthesised from D-glucose for incorporation into potential chemotherapeutic nucleosides.B Improvements to Ogawa's method for the synthesis of 2-deoxy-fl-glycosides, involving addition of arylsulphenyl esters of the desired aglycon to glycals, with
12: Deoxy-sugars
131
subsequent Raney nickel desulphurisation of the 2 - a ~ o - p r o d u ~are ts~ covered ~ in Chapter 3. The 4-deoxy-analogue (17) of methyl a-D-fructofuranosidewas obtained either via selenide opening of the epoxide (18), selenoxide elimination to give alkene (19), and hydrogenation (Scheme 8), or directly by reduction (LiAlH4) of the unprotected epoxide (20).=
B0ZR
$,,
0
"-,
.\. R0CH2$ *
$ L; : ;
3
yH$":P"
CH2Ot-i
CY20R
CHZOR-
2
PhSe
(18) R = S L S
(191 R =
Lo
S
L
~
(1 7)
(20) R = H Reqent-s
L,
PhSeNa,
LL,
H202,
UL,
C U ~ H ~ C ~ . ~, ~wU, I+,Pd/c ,A
, v,
BUN ,. F
Scheme 8
A convenient synthesis of 5 ' -homoadenosine [&, 9-(5 '-deoxy-fl-D-&hexofuranosyl)adenine] involved hydroboration of 3-Q-benzoyl-5,6-dideoxy-1,2-Qisopropylidene-a-D-&-hex-5-enofuranose, obtained from diacetoneglucose.26 A number of deoxy-sugar syntheses have used non-carbohydrate starting materials. GRhodinose was obtained exclusively as its pyranose derivative (21) from ethyl (S)-lactate (22) using 2-lithiothiazole and 2-
thiazolemethylenetriphenylphosphoraneas masked aldehyde synthons (Scheme 9).27 A separable mixture of the 2,3-dideoxy-D-pento-furanose and -pyranose diacetates (23) and (24), respectively, was obtained from 2,3-di-Q-isopropylidene-DCHO
CH~OAC
C HO
t&
A% :(
(25)
Reagents
L,
-t- oA J-c--A-co(
uJuL
(23)
(241
Ph3PCHZCH0, U, P ~ O ~ , H ~ , H ~ O , H O UL, AA C c, z 0 - P ~
Scheme 10
glyceraldehyde (25) (Scheme 10); they were required for use in the synthesis of
132
Carbohydrate Chemistry
adenosine antagonists.28 The 3-deoxy-D-arabino-hexofuranoside (26) and the 4deoxy-D-m-hexopyranoside(27) have been synthesised from the chiral Diels-Alder the common intermediate adduct (28) of furan with cyanovinyl (1R)-camphanate
(29) (Scheme 1l)?' Derivatives of 4-deoxy-D- and L-erythro-pentopyranoside, D-(30) (Scheme 12), are accessible from dihydropyran (31) via the easily separable diastereomeric phenylselenides (32) and (33):' Full details of the synthesis and
enzymatic hydrolysis of a racemic 2,6-dideoxy-3,4-anhydro-sugar as part of the preparation of boivinosides (cf., Vo1.18, p.128; V01.20, p.134), have been published?l A study on the stereochemistry of epoxidation of &E-isomers of 1,ldimethoxy-hex-3-en-5-01sand -4-en-3-ols, leading to all four possible dimethyl Vo1.18, p.124; Vo1.19, acetals of the 2,6-dideoxy-DL-hexoses, has been reported (d., ~.126),~' and their configurations have been determined by 'H- and '3C-n.m.r. spectro~copy.3~ References 1 2 3 4 5
B. Giese, Pure ARIA.Chem., 1988,a 1655 (Chem. Abstr., 1989,110.213182). V.R.N. Munasinghe, Chem. Sri Lanka, 1988, & 15 (Chem. Abstr., 1989,110.135 580). K Nakano, K Murakami, Y. Takaishi, T. Tomimatsu and T. Nohara, Chem. Pharm. Bull., 1989.37116. S. Kitanaka, K Ogata and M. Takido. Chem. Pharm Bull., 1989,Z 2441. S. Ennifarand, H.S.El Khadem, Carbohvdr. Res., 1989,193,303.
12: Deoxy-sugars 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
22 23 24 25 26 27 28 29 30 31 32 33
133
D.D. Dhavale, E. Tagliavini, C. Trombini and A. Umani-Ronchi, J. Org. Chem., 1989,54- 4100. V. Siglerova and K. Veres, J. Labelled ComDd. RadioDharm, 1989.22, 509 (Chem. Abstr., 1989,111. 214 822). R.U. Lemieux, R. Cromer and V. Spohr, Can. J. Chem., 1988, 3083. C. Bonini, R. Di Fabio, G. Sotgiu and S. Cavagnero, Tetrahvdron, 1989.452895. A. Klausener, G. Beyer, H. Leismann, H.-D. Scharf, E. Mliller, J. Runsink and H. GOmer, Tetrahedron, 1 9 8 9 , g 4989. S.G. Withers, M.D. Percival and I.P. Street, Carbohvdr. Res., 1989,187.43. R.N. Russell and H.-W. Liu, Tetrahedron Lett., 1 9 8 9 , g 5729. S. Czernecki and J.M. Valtry, J. Carbohvdr. Chem., 1989,g 793. R.L. Tolman and L.H. Peterson, Carbohvdr. Res., 1989.189.113. M. Trumtel, P. Tavecchia, A. Veyrieres and P.E. Sinay, Carbohvdr. Res, 1989,191.29. V. Bellosta and S. Czernecki, J. Chem. Soc.. Chem. Commun., 1989, 199. T.S. Lin, P. Kovac and C.P.J. Glaudemans, Carbohvdr. Res., 1989,188. 228. G. Descotes, J. Mentech and N. Roques, Carbohvdr. Res., 1989,188.63. J. Kihlberg, T. Frejd, K. Jansson, S. Kitzing and G. Magnusson, Carbohvdr. Res., 1989,185. 171. k Taniseven and J.F. Robyt, Carbohv1989.186.87. E. Zbiral, H.H. Brandstetter and EP. Schreiner, Monatsh. Chem., 1988,119. 127 (Chem. Abstr., 1989, 110.154 761). B. Abbaci, J.-C. Florent and C. Monneret, J. Chem. Soc.. Chem. Commun., 1989.18%. M.W. Chun and M.H. Kim, Yakhak Hoechi, 1988,32- 177 (Chem. Abstr., 1989,110.115 198). S. Ramesh and R.W. Franck, J. Chem. Soc.. Chem. Commun., 1989,960. O.R. Martin, R.J. Rafka and W.A. Szarek, Carbohvdr. Res., 1989,185.77. E.M. Salcines and S.W. Schneller, Nucleosides Nucleotides, 1989,g 1083. A. Dondini, G. Fantin, M. Fogagnolo and P. Pedrini, Tetrahedron, 1989, 45- 5141. E Dieckmann, K. Friedrich and J. Lehmann, Liebies Ann.Chem., 1989,1247. D. Faltori, E. de Guchteneere and P. Vogel, Tetrahedron Lett., 1989, 7415. 7145. E.A. Mash, J.B. Arterburn and J.A. Fryling, Tetrahedron Lett., 1989, P.L. Barili, G. Berti, G. Catelani, F. Colonna, E. Mastrorilli and M. Paoli, Tetrahedron, 1989, 451553. Yu. E. Raifel'd, B.M. Arshava, LL. Zil'berg and S.M. Markin, Zh.Ore. Khim., 1988, 2258 (Chem. Abstr.. 1989,111.39 690). 1030 (Chem. Abstr., 1989, B.M. Arshava, Y.E. Raifel'd and S.M.Makin, Zh.Ore. Khim., 1988, 110.8 492).
a
a
13
Unsaturated Derivatives
study of the electrochemical reduction of tetra-Q-acety1-a-Dglucopyranosyl bromide in dipolar aprotic solvents with mercury electrodes to afford tri-9-acetyl-D-glucal has been reported.' A method for affording 6-functionalised D-glucal derivatives involves the use of tetra-Q-acetyl-2,6-di-Q-tosyl-D-glucopyranose as illustrated in Scheme 1.2 The specific glycal derivative (1) A
&
CH~SAC
AGO
0.k CH~SAC
Ac 0
AGOO
O
OTs Reagents.
L ,
H e r - H O A c , u, Zn H O A c
CH~OTS
CHzOTS
A
@
AcO
c
0T s
, UL,
KSAc
DMF
Scheme 1
was produced from daunosamine via the substituted compound shown in Scheme 2.3
(2)
as
I
AliTFA
(2)
NHTFA
(1)
ReageGts L, A , x+jLene,sdua yeL
Scheme 2
Treatment of S-phenyl 1-thioglycoside derivatives, or their derived sulphones, with lithium naphthalamide in THF, affords the corresponding glycal derivatives in high yield, 9.Scheme 3 . The elimination can be carried out in the presence of acid- or base-labile protecting groups: in the latter cases deprotection occurs. A free radical induced synthesis was discovered in the same work, and is also illustrated in Scheme 3 . 4 * 5 In related fashion, compound (3) afforded the glycal ( 4 ) on treatment with tributyltin hydride in the presence of a radical initiator."
13: Unsaturated Derivatives
Reagenix
L.,
L L naphthalenide
135
~
u, D u 3 5 n H - A l B N Scheme 3
Ph -
A novel synthesis of a C-3-branched glycal derivative, by application of a cyclopropylmethyl radical ring-opening reaction, is illustrated in Scheme 4 . ’ CH~OAG
U-Y
7
AcO
R q e d s
P(O)(OEt)*, bu3SnH, AlBN
L a EtO,CCC(Z
VL,
LL.,
Bz-Pd./C
, m, Ac20- Py , w , Ac,o-
H’,
v, MQjSLBr
~
Scheme 4
An improved procedure for making Q-benzylated glycal derivatives from acetylated analogues on the molar scale and without isolation of the unsubstituted derivatives and without chromatography has been reported. Tri-Q-benzyl-D-glucal was obtained directly in 70% yield and other pentose and hexose analogues were similarly produced.* Selective acetylation of Dglucal using vinyl acetate as a source and a Candida lipase gave the 6-ester in 90% yield, whereas a Pseudomonas enzyme gave the 3,6-diacetate in 92% yield. Conversely, the latter catalyst afforded the 4,6-diester when used to cleave tri-Q-acety1-Dglucal. Similar studies were carried out in the D-galactal series and also with vinyl benzoate. In this way, selective procedures were developed and, for example, a route to 3-Q-acetyl-6-Qbenzoyl-D-glucal was reported.’
136
Carbohydrate Chemistry
Treatment of the allylic mesylate ( 5 ) with various alkyl or alkynyl Grignard reagents gave mainly the products of direct displacement, whereas methylmagnesium bromide afforded the a,/+ products of S,2' reaction (Scheme 5). Lithium dimethylcuprate, on
R e ~ . c ~ dL ,s M e M g B r ,
LL
R M 9 8 r ( R = A L k y L (except- We) o r aL!--yyL)
Scheme 5
the other hand, reacted in the former way to give the C-3methylglycal. These observations were rationalised in terms of HSAB theory.lo A different type of psubstitution of a glycal derivative is illustrated in Scheme 6. It was found not to be applicable to
=+.
JSnBu3
RoQ1 OR Reagents
L,
=
PeO 0
Me
( 2
/
LV,
C ~ C LV ~ , ,
Scheme
Me
ao,, M a
KOBat ,u,Bu,SnCL, Lu, BULL,
5,
R = SL ButMcZ
6
several other glycals, and the product did not undergo oxy-Cope rearrangement as did the analogue with an unsubstituted dihydropyran ring.l1 Reference is made in Chapters 13 and 2 4 to the synthesis of p-lactams by the addition of trichloroacetyl isocyanate to glycal derivatives followed by periodate cleavage of the sugar rings, and bis(trichloroethy1)azodicarboxylate adds to such compounds to afford a route to 2-amino-2-deoxyglycosides (Chapter 9). A novel cycloaddition reaction is illustrated in Scheme 6A.11* CHzOH
CH20Ac
&
AcO
Reage-ts
'
+
mN:,,,
i ,C a C 0 3 , M e O H ; u, M c O H , D o w e x -
H+
Scheme 6 A
The allylic rearrangement reaction by which tri-Q-acetyl-Dglucal affords 4,6-di-Q-acetyl-2,3-dideoxy-D-er~thro-hex-2-enose has been examined in detail; oxidation of the product, or of the
13: Unsuturated Derivatives
137
6-Q-trityl analogue, gave the corresponding 2,3-unsaturated aldonolactones. A more direct and efficient method for making such unsaturated lactones involves low temperature treatment of glycal esters with small proportions of boron trif1uori.de etherate and 1.2 equivalents of a-chloroperbenzoic acid. A range of glycals were oxidised in this way with high efficiency, but if the reactions were conducted at room temperature or with more than 0.5 equivalents of catalyst, ring cleavage occurred and pentenal derivatives were formed following an allylic acetate rearrangement (Scheme ,).I3 Oxymercuration-demercuration of the D-allal CH20Ac
@
AcO
CH20Ac
CU20Ac
OH
iAcO
0 - 0O y - A y
___f
-2 R e a g c ~ d h L,BFS.Et*O,MCPBA
(-20°C);
0.
AcO
-
CH20Ac
QJAr ?OAc
u., S a m e reufjent5,(20~~)
-
CH2OAc QH0
0
Scheme 7
derivative (6) in the presence of alcohols provides a new way of making unsaturated glycosides (7) together with the aldehydes ( 8 ) .I4
of0 c H2 S C H ,CH=CH* (6) A simple route to 2-hydroxyglycal esters involves treatment of esterified glycosyl bromides with cesium fluoride," and the reaction of such glycal derivatives with boron trifluoride etherate and a-chloroperbenzoic acid affords enones such as compound ( 9 ) . The unusual pyranone (10) was obtained, however,
b-, t,.. CH20Rz
CH20Ac
-
BZO -
*BZ
(9)
N"Ac
(10)
when 2-~-acetylamino-tri-Q-acetyl-D-glucal was subjected to this reagent.I3 of. maltose) are available Compound (11) and analogues (9 from otherwise substituted 3-hydroxypyranoid compounds via the
Carbohydrate Chemistty
138
derived 3-ulose derivatives. Some reactions of the dihydropyran are illustrated in Scheme 8.16 Me
QMe
4
002
0
CH ,002
QYPh
LL
/-J
020
Y
” )
\ic
ODz
(1’)
L , CH2er2, Zn-fru,, DMSO; V L , hY-M e z C O
0
- 0 O B z O+
B Z O0
Bz 0 Reye&:
Q02 BZOCH,
,
u. bMe,cu, ,bi,phL$~$S F n C L Z , w, K c , W ~ W e O Y , D r l S O , v, K2COJ,
Scheme
a
1-Cyano-glycal and 1-cyano-hydroxylglycal derivatives have been produced by elimination reactions applied to the products of photobromination of esterified glycosyl cyanides, the reagents used were, respectively, zinc, pyridine and mercury(I1) cyanide in nitrobenzene in the presence of silver triflate.” 7-, 8- and 9-Deoxy- and 4,7-dideoxy-analogues of the Nacetylneuraminic acid derivative (12) were made as potential sialidase inhibitors; results indicated that the 4-OH and 7-OH and a planar a-surface are important for enzymic recognition and binding.” The related compound (13) has been made by methoxycarbonylation of a 2,3-unsaturated phenylthioglycoside derivative (Chapter 16). OH
!
2
10.
CH20Ac
Other Unsaturated Derivatives
The uses of 2’,3’-cyclicthionocarbonates (with trimethyl phosphite), 2’,3’-cyclic orthoesters (heated with acetic anhydride) and 3’-Q-acetyl-2’-bromo-2-deoxy derivatives (with zinc/copper) as
13: Unsatumted Derivutives
139
means of access to 2’-unsaturated nucleosides have been compared; the last of them was found to be most suitable.” A novel synthesis of enantiomercially pure 2,3-dideoxyhept2-enono-1,4-lactones is illustrated in Scheme 9 , * O and related
0 0
Re-4
‘
‘,
BF3 EtzO
NC
-V
0 NCkC(40Me
~ o Me H ~o
Scheme
9
substances were obtained on acetylation of 2-amino-2-deoxy-Dgluconic acid (Scheme
HO NHAc
NHAc
NHAc
CHzOAc
Reageas
L ,
UL,
AcCL, py , iL, Ac20, N a O A c , A , DBU , w , Uz/Pd-C
N HAc
Scheme 10
Ethyl 4,6-di-Q-acetyl-2,3-dideoxy-a-D-ervthro-hex-2enopyranoside, on treatment with alkali followed by acid, gives the furan (14) in almost quantitative yield,*’ and the analogous glycosyl phenylsulphone affords access to the phenyl C-glycosides (15).23
Intramolecular cyclisations induced by free radicals have afforded stereospecific means of introducing branch-points at C-2 or C-3 of saturated pyranoid compounds via 2,3-unsaturated precursors (Scheme ll).24 Related work showed these principles CH~OAG
ICH2
Reagents
t ,
OLySnH , A I B N
OEt
CHiI
Scheme 11
EtO
Carbohydrate Chemistry
140
could be applied to give analogous products having oxygenated substituents at C-2 of the product‘s pyranoid ring and carbon-bonded substituents at C-2 and C-3 (Scheme 12).25
t EtO CH2I
Reogertts:i,Bu3SnH
(16)X=H--t(17)
X,Y=H
( 1 6 ) x = O A c 4 ( 1 7 ) X = OAc,Y= H i ~BugSnW, , MeOZCCH=Cw2 (16)ar(lB) K = H ( 1 7 ) or
-+
’&, Bu3 S
n
(19)Xe H , Y =
(f6)or(1S) X = H -+ ( 1 7 ) o r ( 1 9 ) X ~ = H , Y =
e
CH,CH2C02Me CHZCki=CtiZ
Scheme 12
An analogous reaction has been applied to a 3-enopyranoside derivative (Scheme 1 3 ) , 2 4 and a member of this class of compound CH20Tr
CHZOTr
QL 0
I C HQOBJ 2 y 0
OEt
OEt
R e a g m t s : i, 0~4,3Sni-i, A l 0 N Scheme 13
bearing a branching group at C-2 has been made by photochemical f c ring-opening of a 2,3-cyclopropa-substance (Scheme 14; . Scheme 4 )
.’
bQwe CHzBr
tH2Br
o
COZEt
i
€320
E t:& :
Reagetvt6: i, h3, F - rnethyiccwbamle,
Mg(CL04Jz
Scheme 14
*-
Whereas p-D-galactopyranosides, e.q. ( 2 0 ) , undergo elimination of acetone to give 4-deoxy-hex-4-enopyranosides ( e 2 . 21) under strongly basic conditions, the a-anomers or compounds with a free hydroxyl group, e.g. ( 2 2 ) , do not react in this way.26 Compound (23) has been made by stereoselective hydrogenation of a
4k?Me OR R= M e
M~OCH~
&ChMe
’MO)& OMe
Me
(20)
(22) R = H
(2’)
(23)
13: Unsaturcrted Derivatives
141
4-enoside in the course of the development of a synthesis of erythronolide B from 1,6-anhydro-p-D-glucopyranose.27 In the area of 5,6-unsaturated furanoid compounds, the alkyne ( 2 4 ) was made from 6-chloro-6-deoxy-1,2:3,5-di-Qisopropylidene D-galactose by treatment with lithiumamide in liquid ammonia,2”and the 5-cyanoalkene ( 2 5 ) from the 6-nitroalkene by the addition of the elements of hydrogen cyanide and the removal of nitrous acid with trieth~lamine.~’Application of the Claisen rearrangement (triethyl orthoacetate) to the enol ( 2 6 ) gave the octuronate epimers ( 2 7 ) in equal proportions, and the (2)-starting material gave similar results. In the case of the analogous 3-hydroxy-D-ribo-alkenes, the &-isomer gave no stereoselectivity, but the 2-compound afforded the D-9110- and Daltro-5-pvinyl octuronates in the ratio 7:1.30 CHZOH
b0
II
I
Qo o+-
O+
(26)
(27)
Methyl 6-bromo-6-deoxy-2,3,4-tri-O-methyl-a-Dglucopyranoside (or the chloro or iodo analogues) underwent loss of hydrogen halide to give the 6-deoxy-5-enoside ( 2 8 ) on treatment with potassium-graphite laminate, whereas reaction with zinc-silver couple-graphite caused attack at the halogen centre and ring opening (Scheme 15).31 A lecture on the use of organometallic methods in carbohydrate synthesis included the description of the use of Tebbe’s reagent to produce --alkenes related to ( 2 8 ) and hence €-linked disaccharides.32 A further report described the conversion of trimethylsilylated aldonolactones into the difluoromethylene --alkenes and hence difluoromethyl C-glycosides (Chapter 3 ) .
I(‘,.,...Me0
@ Me0
OMe
OMe
L ,
Q Me0
OMe OMQ
OMe (2
81
Displacement reactions have been studied in the cases of the 7-ynes ( 2 9 ) , and the Mitsunobu reaction of derived sulphonates was regio- and stereo-selective. The displacement of the tosyloxy
Carbohydrate Chemistry
142
group by benzoate gave mixed products including allenic ben~oates.~ Synthesis ~ of the 4-deoxy compound (30) was accomplished from the corresponding 6-aldehyde (by use of trimethylsilylacetylenemagnesium bromide) in connection with studies on the synthesis of amipurimycin A.34 The extended chain alkyne (31) was made from the 5,6-D-aluco-epoxide by treatment with LiC=C(CH,),OLi which is available by reacting tetrahydrofurfuryl chloride with lithium in liquid
6
&o
0 6n
ODn OMe
03-
001-1
o+(29)
(30)
(31)
Treated with mercury(I1) sulphate in aqueous dioxane followed by acetic anhydride and pyridine, D-lactal gave compound (32) which was chain extended to the two acyclic unsaturated compounds (33) and (34).36 Other literature data suggest these
i:;
CCH0 CH20Ac
RO (32)
CH~OAC
RO
(33)
CH~OAC
-w C 0 2 E t Ro R= A c ~ - ~ - D - G ~ ,
_P
-
L
M
e
(34)
should all be (g)-compounds. Several isomers of (35) were produced on Diels-Alder reaction of cyclopentadiene with penta-Q-acetyl-2,3-dideoxy-l-nitro-D-gluco-, D-galacto- and D-panno-hept-2-enitol. Each was degraded to a nitrobornene-6aldehyde, known isomers of which were obtained from isomers of (35) which had previously been characterised by X-ray diffraction analysis.37
C H20Ac
Other acyclic unsaturated derivatives which have been used in the preparation of C-glycosidic compounds are noted in Chapter 3.
13: Unsaturated Derivatives
143
References 1
F.Maran, E.Vianello, G.Catelani, and F.D'Angeli, Electrochim. Acta, 1989,
34, 587 (Chem. Abstr,, 1989, 111,14 287). 2
D.Milkovic, N.Vukojevic, D.Medakovic, and G.Batta, Carbohvdr. Res., 1989,
193,275.
D.Horton, W.Priebe, and M.Sznaidman, Carbohvdr. Res., 1989, 187, 145. A.Fernandez-Mayoralas,A.Marra, M.Trumpte1, A.Veyrieres, and P.Sinay, Carbohydr. Res., 1989, 188,81. 5 A.Fernandez-Mayoralas,A.Marra, M.Trumpte1, A.Veyrieres, and P.Sinay, Tetrahedron Lett., 1989, 3 0 , 2537. J.J.Patroni, R.V.Stick, D.M.G.Tilbrook, B.W.Skelton, and A.H.White, Aust. 6 J. Chem., 1989, 42, 2127. 7 D.L.J.Cliveand S.Daigneault, J. Chem. SOC., Chem. Commun., 1989, 332. 8 M.Chmielewski, I.Fokt, J.Grodner, G.Grynkiewicz, and W.Szeja, J. Carbohvdr. Chem., 1989, 8 , 735. 9 E.W.Holla, Angew. Chem. Int. Ed. Engl., 1989, 2 , 220. 10 O.Mitsunobu, M.Yoshida, M.Takiya, K.Kubo, S.Maruyama, I.Satoh, and H.Iwami, Chem. Lett,, 1989, 809. 11 L.A.Paquette and J.A.Oplinger, Tetrahedron, 1989, Q , 107. lla A.Choudhury, R.W.Franck, and R.B.Gupta, Tetrahedron Lett., 1989, 30, 4921. 12 T.Matsui, Y.Kawano, and M.Nakayama, Chem. Express, 1988, 3 , 679 (Chem. Abstr., 1989, 111, 58 170). 13 F.W.Lichtenthaler,S.Ronninger, and P.Jarglis, Liebigs Ann. Chem., 1989, 1153. 14 A.Mukhopadhyay, S.N.Suryawanshi,and D.S.Bhakuni, Indian J. Chem., Sect. B, 1988, m, 1009 (Chem, Abstr,, 1989, 110,231 963). 15 S.Jain, S.N.Suryawanshi,S.Misra, and D.S.Bhakuni, Indian J . Chem., Sect, B , 1988, m, 866 (Chem. Abstr., 1989, 110,173 586). 16 F.W.Lichtenthaler,S.Nishiyama, and T.Weimer, Liebirs Ann. Chem., 1989, 1163. 17 L.Somsak, Carbohydr. Res., 1989, 195, C1. 18 E.Zbira1, E.Schreiner, R.Christian, R.G.Kleineidam, and R.Schauer, Liebigs Ann. Chem,, 1989, 159. 19 M.M.Mansuri, J.E.Starrett, J.A.Wos, D.R.Tortolani, P.R.Brodfuehrer, H.G.Howel1, and J.C.Martin, J. Orv. Chem,, 1989, 54, 4780. 20 G.Casiraghi, L.Columbo, G.Rassu, and P.Spanu, Tetrahedron Lett,, 1989, 2 , 5325. 21 D.Horton, J.K.Thomson, O.Varela, A.Nin, and R.M.de Lederkremer, Carbohvdr. Res., 1989, 193,49. 22 J.L.Marco, J. Chem. Res. t S 1 , 1988, 382 (Chem. Abstr,, 1989, 110, 173 582). 23 D.S.Brown,M.Bruno, R.J.Davenport, and S.V.Ley, Gtrahedron, 1989, 45, 4293. 24 Y.Chapleur and N.Moufid, J. Chem. SOC., Chem. Commun., 1989, 39. 25 R.J.Ferrier, P.M.Petersen, and M.A.Taylor, J. Chem. SOC., Chem. Commun,, 1989, 1247. 26 P.L.Barili, G.Berti, G.Catelani, F.Collonna, and F.D'Andrea, Sarbohpdr, b,, 1989, 190, 13. 21 A.F.Sviridov, M.S.Ermolenko, D.V.Yashunskii,V.S.Borodkin, and N.K.Kochetkov, Izv. Akad. Nauk SSSR, Ser. Khim., 1989, 151 (Chem. Abstr., 1989, 111, 195 260). 28 J.S.Yadav,M.C.Chander, and C.S.Rao, Tetrahedron Lett,, 1989, 30, 5455. 29 J.M.J.Tronchet and S.Zerelli, J. Carbohydr. Chem,, 1989, 8 , 217. 30 K.-i.Tadano,K.-i.Shimada, A.Miyake, J.Ishihara, and S.Ogawa, Bull. Chem. SOC. Jpn., 1989, 62, 3978. 31 A.Furstner and H.Weidmann, J. Org. Chem., 1989, &, 2307. 32 G.W.Parshal1, W.A.Nugent, and T.V.Rajan-Babu, Chem. Ser., 1987, &!, 527 (Chem. Abstr., 1989, 110,39 033). 33 J.Glodek, S.Jarosz, and A.Zamojski, F.E.C.S. Int. Conf. Chem. Biotechnol, Biol. Act. Nat. Prod.. (Proc.). 3rd 1985 (Pub. 1987), 2, 346 (Chem. Abstr,, 1989, 110, 115 199). 34 S.Czernecki and J.M.Valery, J. Carbohvdr. Chem., 1989, 8 , 793. 3 4
Carbohydrute Chemistry
144 35 36
37
J.S.Yadav, P.R.Krishna, and M.K.GurJar, Tetrahedron, 1989, 45, 6 2 6 3 . A.G.Tolstikov, O.F.Prokopenko, L.M.Khalilov, V.N.Odinokov, and G.A.Tolstikov, Zh. 0318. Khim,, 1 9 8 8 , 1341 (Chem. Abstr,, 1 9 8 9 , 179). J.A.Serrano and E.Roman, J . O w , Chern,, 1989, 54, 6114.
z,
m, 24
14
Branched-chain Sugars
1 ComDounds with an R-C-0- Branch The diastereomers (1) as well as the compounds epimeric at C-4 have been prepared from levoglucosan as intermediate compounds for the total synthesis of isomers of yersinioses [3,6-dideoxy-4-C-(1-hydroxyethyl)-&-hexoses],’ and the same group has reported such a synthesis? The addition of acetone under basic conditions (K2C03,H,O) to ketone (2) affords a good yield of adduct (3), whereas with other bases or other active methylene compounds only complex mixtures were obtained. When the same conditions (K2C03,H20, acetone) were applied to 1,2:5,6-di-~-isopropylidene-a-D-glucofuran-3-ulose only 15% of the adduct (4) was isolated along with 56% of the product (5) of rearrangement. A mechanism was proposed to explain the formation of (5).3 The synthesis of methyl (2E,3S)-[3-*H1]2-hydroxyisocaproate (+)-methoxy(trifluoromethy1)phenylacetyl ester from Dglucose is described in Chapter 24.
HO Me
0 OPhHO
The lactone (6), prepared by a stereocontrolled aldol condensation followed by resolution of the enantiomers, has been converted into methyl cladinoside (7): Some branched 5-amino-2,5,6-trideoxy-hexose derivatives (eg (8)) have been derivative? Treatment of levoglucosenone prepared from a 1,5-dideoxy-pent-2-ulose with a basic excess of nitromethane has afforded products (9) and (lo), whereas
Carbohydrate Chemistiy
146
when limited quantities of nitromethane were used another product (11) was obtained.6 When 2 -0-tosyl-5 -0-trityluridine was allowed to react with a large excess of methylmagnesium iodide only a small amount of the expected product (12) was isolated as well as products of methyl incorporation in the base moiety.7 6Deoxy-5-C-methyl-DL-&-hexofuranose and 5-C-methyl-DL-~-hexofuranose
derivatives have been prepared by way of enolate alkylation products (13) of lactone (14): The generation of alkoxy radicals from the corresponding nitrate esters of branched alcohol compounds is discussed in Chapter 7. Adducts (15) and (16) were produced when bromide (17) was treated with
tert-butyl isocyanide and allyltributyltin respectively. When the nitrate ester (18)
0
XU#'
O@
CH20Tr X@ O '
ONO,
Ts 0
AcO (15) X
1 s0 OTs
OAc
(19) X = CH2CHZCN CH20Tr (2'>X=
X=
G
O
E
L
(20)
P
(16) x =CH2CH=CH2 (17)
O
EtO
(1 9)
=CN
go
OTs
6r
was allowed to react with Bu,SnH in the presence of acrylonitrile the branched derivative (19) was obtained, and if acrylonitrile was replaced by enone (20) a moderate yield of (21) could be obtained. When the nitrate ester of alcohol (19) was then treated with Bu3SnH the endo-substituted epimer (22) was obtained because of attack of the hydrogen atom. If the reaction was performed in the presence of acrylonitrile the principal product was the bis-alkylated adduct (23)?
($ &(---& CH20Ac
(22) R = CI, Ri= C H ~ C H Z C N
Ts 0
dQ
(23) R =,
OTs
R1= CHzCHaCN
AcO
-
-o
6r
OAc
(24)
( 251
14: Branched-chain Sugars
147
Radical cyclisation of bromoethylglycoside (24) leads to the bicycle (25)" The intramolecular photochemical cyclisation of a carbohydrate ketone onto the benzylic centre of a benzyl ether is covered in Chapter 5. 2 Compounds with an R-C-N Branch
The four isomeric methyl 2,4,6-trideoxy-4-~-methyl-4-trifluoroacetamido-Lhexopyranosides (L-*-, L-arabino, L-xylo,and L-&-) have been synthesised from Lthreonine." The synthesis of some branched-chain derivatives of daunosamine is discussed in Chapter 10. A new naturally occurring branched amino-sugar eremosamine is covered in Chapters 9 and 19.
3 Compounds with an R-C-H. R-C-R or C=R Branch Grandinin (26),a complex novel branched ketose derivative, has been isolated from OH
(26) HHPD =ti0
\ /
\ / O H
corn J.J.
various plant sources.12 The synthesis from D-glucose of olefin (27),a common intermediate for the synthesis of actinobolin, bactobolin, ramulosin and 6-hydroxyramulosin, has been de~cribed.'~ Some C-methyl and C-ethyl derivatives of methyl 8-D-galactobioside have been used in a study of the binding between uropathogenic E. coli bacteria and human P erythrocyte^.'^ Methyl 3-0-benzoyl-2,4,6-trideoxy-2,4di-C-methyl-a-L-talopyranoside and 2,4,6-trideoxy-2,4-di-~-methyl-L-galactitol have been prepared starting from methyl 4,6-dideoxy-4-~-methyl-a-L-talopyranoside,'5 and methyl 4,6-dideoxy-4-C-rnethyl-a-L-mannopyranoside has been converted into methyl 2,4,6-trideoxy-2,4-di-C-methyl-~1-L-gluco-. manno- and &pyrano~ides.'~~'~ 5-C-(2-Hydroxyaryl)-furanoseswith either the D-gluco- (28) or L-ido- (29) configuration can be obtained from 1,2Q-isopropylidene-3-Q-methyl-a-D-x&-
Carbohydrate Chemistry
148
HO CHI3 I .n
H0-l
pento-1,5-dialdofuranose(Scheme l)." This procedure has been extended to other carbohydrate aldehydes.'& A general strategy for the synthesis of erythronolide B from levoglucosan has been outlined, and the synthesis of the branched heptose derivative (30) has been achieved." A branched-chain derivative used in the synthesis of L-daunosamine and L-acosamine is covered in Chapter 9. The stereoselectivity of intermolecular free radical reactions has been reviewed including the use of carbohydrate-based radicals for forming branchedchain sugars.m A number of intramolecular radical cyclisations affording Cbranched compounds have been reported. A 2-deoxy-2-iodo-glycoside on treatment with Bu3SnH affords a C-2 radical which may cyclise onto an appropriate functional
group on the aglycone. For example, iodide (31) gave the bicyclic adduct (32)F1 Radicals derived from haloacetal protecting groups may also cyclise onto an olefin. CH20 R
CH20Tr
(36) R'=H, R =TP
EtO OEt
(35)
(33)
'L
(34) R = T r
(45) R = Bz
(4'6) R = Bz ,Q'=CHzCHzC0,Me
(47)
R = Dz R'= CHZCH=CH;?
Thus iodoacetals (33) and (34)afforded cyclised products (35) and (36), respectively, when treated with Bu,SnH, and glycosides (37) and (38) under the same conditions gave the C-2 alkyl products (39) and (40), whereas the corresponding 3-bromopropyl glycoside afforded the product only of reduction of the aglyconeF2 Similarly the bromoacetal (41), with Bu,SnH, gave the cyclic product (42) as the major stereoisomer at C-4.2, Such cyclisations have also been performed in the presence
14: Branched-chain Sugars
149
of intermolecular radical traps so that the initial radical produced on cyclisation may undergo reaction other than simple reduction. Treatment of bromoethyl glycoside (37) with Bu,SnH in the presence of methyl acrylate or allyltributyltin
afforded the C-2, C-3 doubly branched derivatives (43) and (44) respectively. Similarly, iodoacetal (45) gave the doubly branched compounds (46) and (47),” and bromoacetal (48) gave rise to C-2 branched C-glycosides (49) and (50).
42. >,E,
(49) R = CH2CH2CN (50)R = CH2CH=CH2 CHpOTr (51) R =
6r (49
O
G
L
When enone (20) was used as the radical trap the adduct (51) was produced in good yield.% Radical cyclisations of some o-iodo-aldehyde, nitrile, and a,Bunsaturated ester compounds is discussed in Chapter 24. The stereochemistries of the Claisen rearrangement products of some compounds derived from allylic alcohols (52) have been studied.z These products were converted into derivatives [eg (53)] that were subjected to radical cyclisation
CO NMe2
(54)
procedures as an approach to compounds bearing the diquinane carbon skeleton [eg (54)]. Many modifications of the process were described and the relative radical trapping characteristics of the -CHO, -CONMe, and -CN groups were evaluated” Some radical cyclisations have been effected on carbohydrate derivatives with the aldehyde group as a radical acceptor. Moderate yields were generally obtained.27
Carbohydrate Chemistry
150
A novel procedure has been developed for the electrophilic opening of epoxides. Treatment of methyl 2,3-anhydro-4,6-Q-benzylidene-a-D-allopyranoside with Cp2TiCl and excess of a radical trap such as methyl acrylate gave rise to branched products (55) and (56) as well as some products of elimination of water or methanol from the starting epoxide.28 Radical reduction of the glycosyl bromide (57) is accompanied by rearrangement of the cyclopropylmethylradical intermediate so that olefin (58) is the product ~btained.~’The C-4 radical derived from iodide (59) adds to the a$-unsaturated sulphone (60) affording the undecose derivative (61):’
AcO ‘“2 OH
OH (56)
(55)
0
(57)
0
X
(59)
(60)
Full details on the periodate cleavage of the [2+2] cycloadducts of glycals and trichloroacetyl isocyanate have been p ~ b l i s h e d .Dichloroketene ~~ undergoes [2+ 21 cyclo-additionsto carbohydrate enol ethers affording the expected products. Thus, tri-Q-acetyl-D-glucal gave adduct (62), and the hex-3-ene (63) gave rise to (64).32 C H2 OAC
Q -0lo
0
x
o+(63)
The stereoselectivity of the Claisen rearrangement undergone by some carbohydrate allylic alcohols in the presence of ethyl orthoacetate and ethyl orthopropionate has been studied?3i34A [2,3]-Wittigrearrangement on the carbohydrate template (65) gave olefin (66) (Scheme 2) which opened a new route to the 3-alkylmalic acid (67)?5
14: Branched -chain Sugars
151
COZ H
(651
ReclguS.
L-,L D A , L , C H ~ N Z
Scheme 2
The furyl-tetrahydrofuran (68) and its C-4 epimer were synthesised from 3deoxy-1,2-Q-isopropylidenea-D-erythro-pento-l,5-dialdofuranoseand its C-4 epimer, and these products were proposed as convenient chiral precursors of furanoterpene~.~~ Some 2-amino-2-deoxy-3-C-branched D-manno- and D-&-
CQMe
(69)
hexose derivatives, a (69), have been synthesised from 2,3-Q-isopropylidene-Dgl~ceraldehyde.3~ Some extension of earlier work (Vol. 20, p.148) on the basepromoted condensation of carbohydrate-derived dialdehydes with active methylene compounds has been p~blished.~' A full account has appeared of work described earlier (Vol. 21, p.144) on the synthesis of methyl D- and L-3,6-dideoxy-3-~-methyl-hexofuranosides via a homoaldol reaction. [Two of these formulae, (92) and (94), in Vol. 21 should be tran~posed.1~'In an extension of this work the D-a&- and D-&-furanosides (70) and (71) have been converted via displacement (CsOAc, DMSO)of the derived
triflate esters into the D - m - and D-galacto-hexose derivatives (72) and (73), respectively. The latter compounds are intermediates used for the chiral synthesis of the rifamycin ansa chain!' Aldol condensations with ketone (74) occur exclusively onto the O-face to give either adduct (75) or (76) (Scheme 3) depending on the complexing properties of
Curhohydrutr Chemistry
152
Reaqents
i, K Y ( T Y S ) ~ ,u.,ZnCLZor T L C L;L, ~ RCHO
Scheme 3
the carbohydrate aldehydes RCH0.41 The cross-aldolisation of a chiral enol silyl leading to some octose derivatives ether and 2,3-Q-isopropylidene-D-glyceraldehyde is described in Chapter 2. Treatment of the D-xylose-derived enonate (77)with Me,CuLi.BF, afforded only the reductive elimination product (78), whereas the dimesylate (79)with the same reagent furnished the a-alkylated product (80). Similarly, use of PrCu(CN)Li.BF, and BuCu(CN)Li.BF, with enonate (79)afforded high yields of
(77) R = Ac
(79) R = MS
(82) R1= B u ) R = M s
alkylated products (81)and (82),whereas the L-arabinose-derived enonate (83) with
MeCu(CN)Li.BF, and BuCu(CN)Li.BF, gave alkylation products (84)and (85) re~pectively.~~ When 4,6-Qbenzylidene-3-Q-mesyl-D-allalwas allowed to react with Grignard reagents (RMgBr, R = various alkyl and alkynyl groups) the corresponding 3-C-alkyl or alkynyl-4,6-Q-benzylidene-3-deoxy-D-glucal was the major product except where R = Me when the nucleophile was incorporated at C-1. However, use of MeMgBr/CuBr.SMe, or MezCuLi with the above D-allal derivative afforded 4,6-Q-benzylidene-3-deoxy-3-~-methyl-D-gluca1~3 The gem-dimethyl compounds (86) and (87)were prepared by direct alkylation of the parent ketones (88)and (89), and the derived oximes (90) and (91)
14: Branched-chain Sugars
153
have been subjected to a cyclopalladation sequence (Na,PdCl,-NaOAc then Pb(OAc),-Py-NaBH,) which selectively functionalised the equatorial methyl groups
affording esters (92) and (93) respectively.a The 2-spirocyclopropyl-2-deoxy-Lerythro-pentose (94), a potential suicide inhibitor of 4-galactosidase,has been prepared dichlorocarbene addition to olefin (95):' Treatment of epoxide (96) with E@GCCH20SiMeiBu afforded products with little selectivity between C-2 and C-3 attack by the nucleophile, whereas benzyl ether epoxide (97), under the same conditions, gave the C-2 branched compound (98) in quantitative yield. Similarly, when epoxide (99) was allowed to react with
EbAlGCSiMe, the expected trans-diaxial ring opening product (100) was produced in nearly quantitative yield.46 The palladium-catalysed trimethylenemethane cycloaddition has been applied to the carbohydrate Michael acceptor (101) furnishing the cyclopentane adduct (102). In the presence of excess of reagent, the bis-adduct (103) was formed. This reaction may be extended to carbonyl compounds in general-particularly when an organotin co-catalyst is used. Thus aldehyde (104) gave stereospecificallythe branched adduct (105) (Scheme 4).47 The same cycloaddition reaction applied to a,j-unsaturated sulphones is discussed in Chapter 24.
Carbohydrate Chemistry
154
The coupling of an allylic organotin reagent with a carbohydrate aldehyde affording a branched higher sugar is mentioned in Chapter 17. The formation of 2 ,3 -dideoxy-3 -c-cyan0-2 -substituted thymines is covered in Chapter 20, and the synthesis of blocked sugars bearing a terminal 1-cyanovinyl group is discussed in Chapter 10. The incorporation of an HCHO unit into an a,p-unsaturated lactone by the latter's reaction with hydroxylamine and formaldehyde is outlined in Chapter 16. References 1
V.A. Zubkov, A.F. Sviridov, R.P. Gorshkova, AS.Shashkov and Yu S. Ovodov, Bioore. Khim., 1989, 1989,111, 233 386). V.A. Zubkov, A.F. Sviridov, R.P. Gorshkova, AS. Shashkov and Yu S. Ovodov, Bioorg. Khim., 1989, & 192 (Chem. Abstr., 1989,111. 154 247). A. Calvo-Matea, MJ. Camarasa,A. Diaz-Ortiz, F.G. de las Heras and A. Alemani, J. Carbohvdr.
& 588 (Chem. Abstr., 2 3
Chem..1989,8,395. 4 5
E.R. Koft, P. Doreff and R. Kullnig, J. Ore. Chem., 1989,54- 2936. D. Faiardi, G. F r o m , C. Fuganti, G. Pedrocchi-Fantoni and D. Pizzi, J. Carbohvdr. Chem., 1989,s
6
A.C. Forsyth, R.M. Paton and I. Watt, Tetrahedron Lett., 1989, 30,993. A Grouiller and H. Essadiq, Can. J. Chem., 1989, 67- 708. J. Wagner and P. Vogel, J. Chem. Soc.,Chem. Commun, 1989, 1634. J.C. Lopez, R. Alonso and B. Fraser-Reid, J. Am Chem. SOC, 1989,111,6471. R.J. Femer, P.M. Petersen and M.A. Taylor, J. Chem. SOC.. Chem. Commun., 1989, 1247. G. F r o m , C. Fuganti and G. Pedrocchi-Fantoni, J. Carbohvdr. Chem., 1989,a 85. G. Nonaka, K Ishimaru, R. Azuma, M. Ishimatsu and I. Nishioka, Chem. Pharm. Bull., 1989,37-
469.
7 8 9 10 11 12
2071. 13
M.V. Rao and M. Nagarajan, Indian J. Chem., Sect. B, 1988,27J 222).
718 (Chem. Abstr., 1989,110. 193
14: Branched-chain Sugars 14 15 16 17 18 18a 19 20
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
44 45 46 47
155
J. Kihlberg, S.J. Hultgren, S. Normack and G. Magnusson, J. Am. Chem. SOC.,1989,111.6364. k Y~Romanovich,O.S. Chizhov and A F. Sviridov, Bioore. Khim., 1988, 1103 (Chem. Abstr., 1989,110.154 711). k Y u Romanovitch, O.S. Chizhov and AF. Sviridov, Bioore. Khim., 1988,P J 1109 (Chem. Abstr., 1989,110.154 712). k YuRomanovitch, O.S. Chizhov and kF. Sviridov, Bioorg. Khim, 1988,@, 1113 (Chem. Abstr., 1989,110.154 713). M.Cornia and G. Casiraghi, Tetrahedron, 1989,& 2869. G.Casiraghi, M. Cornia, G.G. Fava, M.F. Belicchi and L. Zetta, Carbohvdr. Res.,1989,186.207. kF. Sviridon, M.S.Ermolenko, D.V. Yashunskii, V.S. Borodkin and N.K Kochetkov, Izv. Mad. Nauk. SSSR,Ser. Khim., 1989,151 (Chem. Abstr., 1989,111.195 260). B. Giese, Aneew. Chem. Int. Ed. Enel., 1989,28,969. k De Mesmaeker, P. Hoffmann, and B. Emst, Tetrahedron Lett., 1989,3357. Y.Chapleur and N. Moufid, J. Chem. SOC.,Chem. Commun., 1989,39. KS.Kim, J.H. Kim,Y.K. Kim,Y.S. Park, C.S. Hahn, Carbohvdr. Res? 1989,194.cl. J.C. Lopez and B. Fraser-Reid, J. Am. Chem. SOC.,1989,111.3450. H. Pak, J.K. Dickson and B. Fraser-Reid, J. Ore. Chem., 1989,B,5357. J.K. Dickson, R. Tsang, J.M. Llera and B. Fraser-Reid, J. Ore. Chem, 1989,a,5350. B.W. Anissa Yeung, R. Alonso, G.D. Vite and B. Fraser-Reid,J. Carbohvdr. Chem., 1989,8,413. T.V.RajanBabu and W.k Nugent, J. Am. Chem. SOC.,1989,111,4525. D.L.J. Clive and S. Daigneault, J. Chem. SOC.,Chem. Commun., 1989,332. G.E. Keck and AM. Tafesh, J. Ore. Chem., 1989,3,5845. M. Chmielewski, Z.Kaluza, W. Abramski, J. Grodner, C. Belzecki and P. Sedmera, Tetrahedron, 1989,& 227. H. Redlich, J.B. Lenfers and J. Kopf, Aneew. Chem. Int. Ed. Enel., 1989,28.777. K-i. Tadano, J. Ishihara, H. Yamada and S. Ogawa, J. Ore. Chem., 1989,2,1223. K-i. Tadano, K-i. Shimada, J. Ishihara and S. Ogawa, Bull. Chem. SOC.JRn., 1989, 3978. K Kakinuma and H.-Y. Li, Tetrahedron Lett., 1989,a 4157. J.L.Marco, Tetrahedron, 1989,45,1475. M. Shiozaki, N. Ishida and S. Sato, Bull. Chem. SOC.JDn., 1989, 3950. F. Santoyo Gonzalez, F. Hernando Mateo and F.J. Lopez Aparicio, Carbohvdr. Res., 1989,194.171. D. Hoppe, G. Tarara and M. Wilckens, Svnthesis, 1989,83. G. Tarara and D. Hoppe, Svnthesis, 1989,89. K-L. Yu and B. Fraser-Reid, J. Chem. SOC.,Chem. Commun., 1989, 1442. T. Ibuka, M.Tanaka, S. Nishii and Y. Yamamoto, J. Am. Chem. SOC.,1989,111.4864. 0. Mitsunobu, M. Yoshida, M. Takiya, K Kubo, S. Maruyama, I. Satoh and H. Iwami, Chem. Lett., 1989,809. V. Rocherolle, J. Cristobal Lopez, A. Olesker and G. Lukacs, J. Carbohvdr. Chem., 1989,8,429. R.C. Petter and D.G. Powers, Tetrahedron Lett., 1989,2,659. L. Magdzinski and B. Fraser-Reid, Can. J. Chem., 1988,@, 2819. B.M. Trost, S . k King and T. Schmidt, J. Am. Chem. SOC.,1989,111.5902.
u,
a,
15
Aldosuloses, Dialdoses, and Diuloses
1 Aldosuloses
Optimum conditions for the electro-oxidation of 1,2:5,6-di-Q-isopropylidene-a-Dglucofuranose to the corresponding 3-dose have been developed'. In a study of the hydration of methyl 4,6-Q-benzylidene-2-bromo-and 2-chloro-2-deoxy-a- and 6-D@-hexopyranosid-3-ulose in acetone solution, only the pD-&-derivatives were observed to hydrate2 and in another investigation the isomeric composition of freshly prepared D-&-hexos-3-ulose in D20 has been examined by 'H-n.m.r. spectroscopf. Full details have been published on the regioselective monooxidation of unprotected glycosides by reaction of Q-stannyl derivatives with bromine4.
L
(1)
(2)
Oxidation of alcohol (1) to the corresponding aldehyde (2) without subsequent elimination of acetic acid can be achieved by photolysis of the corresponding pyruvoyl estei. Some aldol condensations between a sugar ketone and some chiral aldehydes are mentioned in Chapter 14.
2 Dialdoses The thiazole adduct (3) obtained from aldehyde (4) and 2-trimethylsilylthiazole,can be converted to the 6-epimer ( 5 ) by an oxidation-reduction sequence (Scheme 1), CHO
m
F=l
15: Aldosuloses, Dialdoses, and Diuloses
157
and hydrolysis of adducts (3) and ( 5 ) illustrates the iterative chain extension of an aldehyde-sugar derivative6. A study of the hydrated dialdoses (6)-(8) has determined that the C-6 aldehydes are very electrophilic and that acetals, thioacetals and m-diamines are easily made. Reduction of (6) with NaBD, afforded the @)-alcohol, whereas (8) gave the corresponding (&)-isomer and (7) CH (0H)2
CH (OH)2
HJ-L HO
OMe
OH
JQ"'
HoQoMe OH
OH
(6)
CH(OH)*
(7)
(0)
gave a 1:l mixture of (_R) and (8) alcohols7. The coupling of a carbohydrate organotin derivative with a sugar aldehyde to produce higher sugars is covered in Chapters 14 and 17, and the synthesis of a higher carbon acetylenic sugar from a dialdose derivative is discussed in Chapter 13. The arylation of a sugar aldehyde to is referred to in Chapter 14. give 5-~-(2-hydroxyaryl)-xylofuranoses 3 Diuloses
A racemic synthesis of the ethylene acetal derivative (9) of cortalcerone has been achieved'.
References 1 2 3 4
5 6
7 8
S. Torii, T. Inokuchi, S. Matsumoto, T. Saeki and T. Oki,Bull. Chem. Soc. Jm., 1989, T. Sakakibara and T. Nakagawa, Carbohvdr. Res., 1989,191.231. P.E. Morris, Jr., ICD. Hope and D.E. Kiely, J. Carbohvdr. Chem., 1989, 8,515.
2108.
Y. Tsuda, M. Hanajima, N. Matsuhira, Y. Okuno and K Kanemitsu, Chem. Pharm. Bull., 1989, 2344. S. Myrvold, L.M. Reimer, D.L. Pompliano and J.W. Frost, J. Am. Chem. Soc., 1989,111. 1861. k Dondoni, G. Fantin, F. Fogagnolo, k Medici and P. Pedrini, J. Ore. Chem., 1989, 702. S. Singh, S. Nambiar, R . k Porter, T.L. Sander, KG. Taylor and R.J. Doyle, J. Ora. Chem., 1989, 2300. B. Szechner, Tetraledron Lett., 1989,3, 3829.
a
16
Sugar Acids and Lactones
1
Aldonic and Aldaric Acids
A review has appeared on carbohydrate-containing amphiphiles with amide
linkages, these compounds being prepared by reaction of aldonolactones of glucose or maltose with alkylamines or by interaction of W(2-aminoethyl) aldonamides with c6-CzO alkanoic acids. 1 An improved procedure has been reported for the conversion of calcium D-gluconate into D-glucono-1,5-1actone under acidic conditions,2 whilst cellobiono- 1,5-1actone can be obtained by electrochemical oxidation of cellobiose or by lactonization of calcium cellobionate over a strong-acid cation exchange resin.3 The oxidation of D-lyXOSe by reaction with various metal ions gives mainly lyxonic acid.* CH20 CH20Dn
c
CHZOCHZOOn
OH
----+ L
Reagents:
b) R h ( D ~ p h o S - 4 ) ( N B D ) ~ F t , H2, CH2C12
Scheme 1
L-Ascorbic acid can be easily converted into (1) (Scheme 1); hydroxyldirected homogeneous hydrogenation of (1) gave (2), which could be deprotected to L-talono-1.4-lactone by catalytic hydrogenolysis.5 A way of effecting exchange of functionality between C-1 and C-5 of aldopentoses relies upon the regioselective oxidation of acyclic 1.5-diols in which one hydroxyl group is sterically hindered: the method is illustrated in Scheme 2 by the conversion of the L-arabinose derivative (3) into the L-lyxono- 1.5-lactone (4), and similar chemistry was used to interconvert L- and D-ribose derivatives.6 .4-lactone (5) was obtained a s the major The 2.3-dideoxy-hept-2-enono-1 product from the BF3-catalysed reaction of isopropylidene-D-glyceraldehyde and 2-trimethylsilyloxyfuran.7A simple and generally applicable one-pot procedure for the preparation of pyranoid 2-enonolactones and enol lactones
16: Sugur Acids and Lactones
159
from glycal and hydroxyglycal esters is illustrated in Scheme 3 by the formation of (6) and (7) in 84% and 91% yield respectively.* CH20H
1
OTBDMS
OTBDMS
u
0
Reaqe'Lts
L ,
NaBHq
, U, RuH2(PPh3),,
0
x.
CHZOH
(41
Ph-MC
0
Scheme 2
I- OH
( 6 ) R = Ac, R'= H
(7) R = B z , R ' = O B z
R b q e n t S ' I, Et,O 0 F 3 , MCPBA Scheme
3
When the racemic unsaturated lactone (8)(Scheme 4) was allowed to react with hydroxylamine and formaldehyde, the Michael adduct (9) was formed at lower temperatures, whilst the nitrone cycloadduct (lo) and its rearrangement product (11) predominated at higher temperatures: methylene groups originating from formaldehyde are indicated in the formulae. The structure of (1 1) was secured by X-ray crystallography.9 CH~OAC
> (9) Weayents
CH20Ac
+
AGO@):
(9)
L , N H ~ ~HCHO H ,
Scheme 4
o
A=OQ
@
(10)
+
Po
AcOCH2
0,N
0
o-----a
(1
'1
The anhydroribonic acid derivative (12) has been prepared from isopropylidene-D-glyceraldehyde. lo Several 8-substituted analogues (13) of 2-deoxyp-KDO have been prepared and shown to be inhibitors of CMP-KDO synthetase. although they did not display antibacterial activity.11 A number of similar 2deoxy compounds are discussed together with their ulosonic analogues in the next section. A full account has been given of the synthesis of D-mannonolactam (14) from L-gulonolactone (see Vol. 22, p. 94).12 A pyroglutamate derivative has been converted as outlined in Scheme 5 into the amino-substituted aldaric lactone (15).13 A paper on the formation of unsaturated lactones of 2-amino-2-deoxy-D-g~uconic acid is discussed in
Carbohydrate Chemistry
160
Chapter 13,and some anhydroaldonic acids which can be regarded as Cglycosides are mentioned in Chapter 3. H~~
*& H;H
OH
HO
O x COz H
(12)
(14)
(13) R = H , F, N H 2
C02Et
0 x 0
Reqents .
HCL,EtOH
L,
Scheme 5
Ulosonic and Ulosaric Acids
2
As part of a major review of enzymic synthesis of carbohydrates, Whitesides and coworkers have discussed the current situation regarding enzymecatalysed syntheses of 3-deoxyulosonic acids.I4 The same group have described the combined enzymatic-chemical route to 3-deoxy-D-arabinoheptulosonic acid-7-phosphate (DAHP,16) outlined in Scheme 6.l5 @3CH20H
+
(3HC>C02Me
@o&co*Mc
L
OH
0
NHAc
NHAc
2
%
@o UL ,LV
'
e
~
5l-I
(mcyor csorney 4
Reagents
rabbLt husclc a-ldbLase
L,
U ,M e 4 N + B H (OAc);
, UL,
6 N HCL
,LV
HO
, Na 990Xy(&
I
06 )
RL3+
Scheme 6
IF"' cLfzMe O
4
R
ReagexLts
U,
u . Ll=Q
I
k;x:, Mg12
CO, Me JCHZ
CH20H
___3 UL
no&oH ;
R = R'= M e or R , R'=:(cH,)~ LL,
NuHS03
, u . HI
Scheme 7
A chemical route to the non-phosphorylated heptulosonic acid is indicated in Scheme 7.16.17 The phosphonate analogues (17) and (18)of DAHP(16) have been synthesized, along with the analogues (19) and (20)
'1
16: Sugar Acids and Lactoties
161
of 2-deoxy-DAHP, and these compounds were evaluated as inhibitors of dehydroquinate synthase from Pisum satiuum; (17) and (20) proved inhibitory, but (18)and (19) did n0t.18919 Knowles and coworkers have independently reported routes to (17) and (18).together with the corresponding carbocyclic analogues.20 and to 2-deoxy-a-DAHP and its carbocyclic analogue;21 these compounds were used in elegant studies of the mechanism of dehydroquinate synthase from E.coli.
(17) n = 1
(19) R = CO,H
(I 8 ) n = 2
(20) R = H , R ' = C 0 2 H
~
R'= H (2')
Methods previously used in the D-arabino-series (Vol. 22, p.17-18) have been applied to the synthesis of derivatives (21) of 3-deoxy-D-mheptulosonic acid.22 Treatment of thioglycoside (22), prepared by acylation of a sulphur-stabilized C- 1 carbanion as described previously for similar systems (Vol. 21. p.131-1321, as indicated in Scheme 8 gave rise to the 4-acetamido-4d e o q derivative (23) related to DAHP; a (2,3]-sigmatropic rearrangement of an ally1 sulphoxide is the key to the synthesis, and similar chemistry applied to acid s y ~ t e r n s . ~ 3 (24) gave 3-deoxy-~-xylo-heptulosonic
/-J% CH20Bn
ACHN
- C02rle
CH20Bn
bOM 0 C02Me
L,LL
AcH N
C02Me
L''Lv
r AcHN
(23)
(22) Reagents
L,
M C P B A . u , E t 3 N , M e O H , u , ~g(OcOCF,),,MeOn
,LV, Ph3SnH
Scheme 8
The synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) and its derivatives continues to attract attention. The Cornforth-type synthesis of KDO from D-arabinose and oxaloacetic acid has been improved by the use of NiC12 to effect rapid decarboxylation, and similarly 3-deoxy-D-glycero-D-galacto-2nonulosonic acid (KDN) could be made in high yield from D-mannose and oxaloacetate.24 Schmidt and coworkers have given a full account of their route to KDO (Vol. 18. p. 152), and also describe various 0-acylated derivatives and
162
Carbohydrate Chenii.wy
the N-methylamide.25 The same group has reported a rather similar synthesis but using the simpler C3-synthon (25); although the yield and martnoselectivity are not as high in the key addition to di-isopropy1idene-aldehydo-Darabinose, the subsequent manipulations to form KDO are considerably easier.26 A synthesis of KDO reported this year is conceptually very similar to a n earlier route (Vol. 21. p.156). involving the interaction of the cyclic sulphate (26) with the lithium derivative of 2-ethoxycarbonyl- 1.3-dithiane to assemble the functionality of A new ‘c6+ C2’synthesis of KDO (27) is outlined in Scheme 9,28and a further report has appeared on the use of asilyloxy-phosphonate anions to effect the appropriate two-carbon extension of
D-mannOSe. derivatives. (see Vol. 22, p. 161).29 A new stereoselective total synthesis of ( + ) - D O (27) proceeds via the adduct (28) from 2-furyllithium and isopropylidene-D-glyceraldehyde(Scheme 10).So A full account has been given of a KDO synthesis by free-radical extension of a mannose derivative at C-6 (see Vol. 22, p. 162),31 and there has been a further report on the preparation of 3deoxy-~-gulo-2-octulosonic acid [the C-7 epimer of (2711 by similar methods to those previously used (see Vol. 22. p. 162).32 The reactions outlined in Scheme 11 have been used for extension of hexose and pentose derivatives a t C-1 to give products which are derivatives of 2-ulosonic acids, but no way could be found to deprotect oxime (29).33 The 7-Q-(a-D-galactopyranosyl) derivative of KDO has been isolated and characterized from the inner core region of the lipopolysaccharide of E.coli EH 100.34 A 3-diazo-oct-2.4-diulosonateis referred to in Chapter 10. Further examples have been given of the use of acylneuraminate pyruvate lyase to catalyse the reaction of pyruvate with D-lyxose. 2-deoxy-~-xylo-hexose, D-glUCOSe, D-xylose, 4-deoxy-D-lyxo-hexose and 2-azido-2-deoxy-~-mannose to give neuraminate analogues (see Vol. 21, p.161).35 The formation of (30) from has been described in more the reaction with 2-azido-2-deoxy-~-mannose
16: Sugar Acids and Lnctones
163
L
Scheme 1 0
4; 4'"""'CH~OAC
+
A c0
C02Et
OAc
detail.36 Various naturally-occurring acylated and 0-methylated derivatives of N-acetylneuraminic acid (NeuNAc) have also been made enzymically.37 A number of derivatives of NeuNAc, suitable for the preparation of NeuNAc (2-8)NeuNAc disaccharides, have been reported: the trimethylsilylethylglycoside (31) is typical.38 Derivatives of 8-epi-NeuNAc were also made by similar chemistry, inverting stereochemistry at C-8 by reaction of a mesylate with CsOAc/ 18-crown-699 Other references to glycosides and oligosaccharides of NeuNAc are given in Chapters 3 and 4. N
J
'OHY
CHzoH OH
(30)
H C02H
A
C
H
OH N
~
~
~
~
~
C
CH20DOM O C H Z C H ~ T M S
060M (31) B O V = - C H Z 0 ( 3 n
O
A~HNF ~ M
~
CH20H C 0 2 H
NH Ac (32)
The 7-. 8-, and 9-deoxy-, and 4,7-didedeoxyderivativesof NeuNAc have been prepared by treatment of the appropriate fully-protected iododerivatives with BugSnH: 40 the side -chain conformations of these analogues were studied by n.m.r.. and their substrate properties towards CMP-sialate synthase were determined. All were good substrates except for the 8-deoxyanalogue, and these findings could be correlated with side-chain shape (see Vol. 21, p.229 for earlier work with side-chain epimers).41 The same series of deoxyanalogues of NeuNAc were also converted into the corresponding
2,3-enes; the topographical features of these were determined, as was their behaviour as sialidase inhibitors in comparison with the 2.3-ene derivative of NeuNAc itself. 42 The 4-acetamido-4-deoxy analogue (32) of NeuNAc has been made by a double-inversion sequence, and this was also found to be activated by CMP-sialate synthase. in accordance with predictions. 43 Some fluoro analogues of NeuNAc are mentioned in Chapter 8. Periodate-borohydride degradation of partially-protected NeuNAc derivatives was used to prepare truncated analogues of NeuNAc such as (33)4* and (34)45(i.e. derivatives of 5-acetamido -3,5-dideoxy-~arabino-2heptulosonic a ~ i d 4 and ~ 5-acetamido-3.5-dideoxy-D-ga~acto-2-octulosonic acid45) suitable for use in the synthesis of modified sialonconjugates. Routes have been developed for the synthesis of the 9-0-. 4-0-. 7-0-, and 7.8-di-0-acetylated derivatives of the 4-methylumbelliferyl-a-glycoside of KDN.46 The synthesis of the a-glycoside itself is mentioned in Chapter 3, and an enzymic synthesis of 9-0-acetyl-NeuNAc is discussed in Chapter 7. The a-NeuNAc-(2+8)-a-NeuNAc(2+3)unit of ganglioside GDlb can form a spirocyclic lactone between the two sialosyl units in the presence of traces of acid, 47 whilst treatment of the ganglioside with DCC in DMSO gives a dilactone. the second lactone involving 0-2 of the galactose residue to which the di-sialosyl unit is a t t a ~ h e d . ~ 8
The intermediate aldehydes produced from the sialosyl units of a glycoprotein by periodate treatment have been reductively aminated with glycine and cyanoborohydride. The resultant glycine-modified sialic acids were isolated by mild acid hydrolysis and ~haracterised.~g Reductive amination has also been used to bond KDO and NeuNAc to 1,6-hexanediamine; the saccharide- 1-(6-aminohexyl)amines obtained were converted to isothiocyanates and coupled to bovine serum albumin for immunological studies.50 Heating of the sodium salt of NeuNAc at 1400 for 3h gave the crystalline anhydroderivative (35)in 53% yield.51 KDN has been shown to exist in its free form in the fertilised eggs of salmon.52 Examination of the cell wall of the green alga TetraseZmis striata has revealed the presence of 3-deoxy-Zyxo-2-heptulosaricacid [previously isolated from another source (Vol 22, p. 165)l. and the 5-0-methyl ether of KDO, the first such methylated derivative found in nature, together with KDO itse lf.53
16: Sugar Acids and Luctones
3
165
Uronic A c i b
Enzymic oxidation of methyl a- or P-D-galactopyranoside to the corresponding aldehydes using galactose oxidase, followed by chemical oxidation with 02/Pt-C gives high yields of methyl a- and p-0galactopyranosiduronic acids.54 The use of 0-levulinoyl esters as protecting groups has been advocated during chromate oxidation to form uronic acid derivatives, since this group is not prone to migration. It was also reported that fully protected 6-O-monomethoxyt1ityl sugars could be converted directly by Jones reagent into uronic acid derivatives.55 A ‘naked-sugar’approach has been used (Scheme 12) to prepare the racemic allofuranuronosyl 6.1-lactone (36)from the Diels-Alder adduct of furan and a-acetoxyacrylonitle.56
R e a g e n t s . i, LDA ; k,T M S C l ; ’ii,M c P B A
S c h e m e 12
The unsaturated ester (37) was converted into the a-aminoacyl glycoside (38)as indicated in Scheme 13.S7 Use of unsaturated esters of type (37) for the formation of higher sugars via hydroxylation is described in Chapter 2.
Scheme 13
An improved route has been developed for the synthesis of the
iminomannuronic acid (39) (see vol. 21. p. 176). in which a protected 6-azido6-deoxy-D-glucofuranose is reduced and cyclized onto C-2 with inversion of configuration (glucose carbons indicated).58 The glucuronic acid derivative (40) was prepared by treating the 6,3lactone with BaO. Ba(OH)2 and benzyl bromide in DMF,whereby both lactone opening and ether formation occurred in situ.59
166
Carbohydrate Chemistry
' C02H
'Hpok2> COzBn
HO '&HT6 4
5
o+(40)
(3 9)
When alkyl hexopyranosiduronates are treated with acetic anhydride, per-acetylated uronolactones are formed, which undergo selective alcoholysis giving uronic esters with a free hydroxy group: the fbD-ghCO-CaSe of Scheme 14 is illustrative.60
I
AcO
OAc
Scheme 14
A new method has been developed for the formation of 1-0-acyl-P-Dglucuronic acids (41). the metabolic conjugates of carboxylic acids, which are highly liable to undergo acyl migration to 0-2and/or hydrolysis at pH>8; the product is generated under very mild conditions as indicated in Scheme 15.61
iL, Ur
0
OH
OKOAU
0 Reo-gdS
L,
RCOZH, PPh3,DEAD;
(4') U,
fdCPPh3)a,
iU, H2, P&/C
S c h e m e 15
Pre-column enzymic conversion to glucuronides was used to determine the enantiomeric purity of some novel chiral phenolic dopamine antagonists, using reversed-phase HPLC .62 Nucleosides of glycuronic acids are covered in Chapter 20. 4
Ascorbic Acids
A report has appeared on the optimization of the conversion of D-glucose into ascorbic acid via di-O-isopropylidene-~-sorbose.63 The antioxidant activity of isoascorbic acid has been reviewed.64 The kinetics and mechanism of oxidation of L-ascorbic acid by ferricyanide in alkaline medium.65 by Cu(II),66and by sodium perborate in perchloric acid67 have been studied. L-Ascorbate was used as reducing agent in work on the
16: Sugar Acids and Lactones
167
kinetics of reduction of potassium dichromate and pyridinium chlorochromate in acidic media.68 and kinetics of electron-transfer from ascorbate to various Ru(II1) species have been shown to exhibit a first-order dependence on both ascorbate and the oxidant, and an inverse first-order dependence on hydrogen ion c~ncentration.~g L-Ascorbic acid is stabilised against autoxidation with the sulphur atom binding superoxide anion by 3-alkyl-2-thiohydantoins, radicals and hydroxy radicals.70 Further studies (see Vol. 22, p. 167) have been reported on the photo oxygenation of L-ascorbic acid derivatives, involving the reactions of 3-0methyl-L-ascorbic acid and the analogues (42).71 R
n
R'
n
Interaction of ascorbic acids with a,P-unsaturated aldehydes has led to adducts of types (43) and (44).72 The diene (45), accessible in four steps from 5,6-O-isopropylidene-~-ascorbic acid, undergoes cycloaddition with various electron-rich dienes. one example being indicated in Scheme 16. The resultant (racemic) spirocyclic lactones have the skeleton and key functionality of the 'top half of chlorothricolide.73
o;f
+y.,70oT
OMOM
-
HO
L-Lv
OH
2--+
CH2NZ
lEo Me
lYeO
(45) OMOM Raagenbs :> , I
Me0
, u ,M e O C H 2 C L , b , D O N ; LV,
M e O C H 2 8 r , v, C
MOM0 O
M
0
e
S c h e m e 16
Treatment of L-ascorbic acid with p-nitrophenyldiazonium tetrafluoroborate gives the diazoderivative (46).74 I t has been shown that the 3,4-enediol form of 2,3-diketogulono-6-lactone is formed in about 10% yield from dehydroascorbic acid under nitrogen in neutral s0lution.~5 8-C-Ascorbyl-(-)-epigalloylcatechin 3-0-gallate (47) has been isolated from commercial oolong tea.76 In a study of the interaction of amines with ascorbigens, compounds (48)gave amides of type (49). which could be acetylated to give ~-xyZo-hex-3-ulosonamides (50) (Scheme 17).77 The ninhydrin-positive substance formed in the initial stages of the browning reaction between dehydroascorbic acid and glycyl leucine has been acid) acetyll leucine.78 Similar identified as N-[(2-nitrilo-2-deoxy-~-ascorbic
168
Carbohydrate Chemistry
CONHR'
S c h e m e 17
compounds can be obtained from other glycyl dipeptides, but non-glycyl dipeptides do not form such products.79 Some other nitrogenous compounds derived from dehydroascorbic acid are mentioned in Chapter 9.
References 1
2 3 4
5 6 7 8 9 10 11 12 13 14 15 16 17
B. Pfannemueller, StarchlStaerke, 1988,%, 476 (Chem.Abstr., 1989,110, 154 690). W. Li, D. Gu, Y. Ding, H. Xu, Z. Cao, and H. Yang, Huaxue Shiji, 1988, lo,246 (Chem. Abstr., 1989,110, 115 233). D. Seethaler and H. Graf, Chem.-Ztg., 1988,112,210 (Chem. Abstr., 1989,110, 8 551). V.I. Krupenskii, Zh. Obshch. Khim., 1988,58, 1658. (Chem. Abstr., 1989, U,231 958). A.J. Poss and M.S. Smyth, Tetrahedron Lett., 1989,2Q, 5201. M. Sabari, Y. Ishii, N. Kaji, T. Aoi, I. Sasaki, S. Yoshikawa, and Y. Ushida, Chem. Lett., 1989, 563. G. Casiraghi, L. Columbo, G. Rassu, and P. Spanu, Tetrahedron Lett., 1 9 8 9 , a , 5325. F.W. Lichtenthaler, S. Ronninger, and P. Jarglis, Liebigs Ann. Chem., 1989, 1153. I. Panfil, C. Belzecki, M. Chmielewski, and K. Suwinska, Tetrahedron, 1989, G,233. R.A. Gakhokidze, N.S. Itriashvili, and M.O. Labartkava, Izv. Akad. Nauk Gruz. SSR, Ser. Khim., 1988,l4, 315 (Chem. Abstr., 1989,111, 115 694). B.G. Pring, A.N. Jansson, K. Person, I. Anderson, I. Gagner-Milchert, K. Gustafsson, and A. Claesson, J. Med. Chem., 1 9 8 9 , 2 , 1069. G.W.J. Fleet, N.G. Ramsden and D.R. Witty, Tetrahedron, 1989, Q, 319. N.Ikota and A. Hanaki, Chem. Pharm. Bull., 1989,2, 1087. E.J. Toone, E.S. Simon, M.D. Bednarski, and G.M. Whitesides, Tetrahedron, 1989, 5365. N.J. Turner and G.M. Whitesides, J. Am. Chem. SOC.,1989,111, 624. V.I. Kornilov, 1.1. Bicherova, S.V. Turik, and Yu.A. Zhdanov, Bioorg. Khim., 1988,l4, 938 (Chem. Abstr., 1989,110, 39 286). 1.1. Bicherova, V.I. Kornilov, S.V. Turik, and Yu.A. Zhdanov, Bioorg. Khim., 1988,&, 560. (Chem. Abstr., 1989,110,213 247).
u,
169
16: Sugar Acids and Lactones
18
19
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
38 39 40 41 42 43 44 45 46 47 48 49 50 51 52
53 54
55 56 57 58 59 60 61
S. Myrvold, L.M. Reimer, D.L. Pompliano, and J.W. Frost, J. Am. Chem. SOC.,1989,
l.U, 1861.
D.L. Pompliano, L.M. Reimer, S. Myrvold, and J.W. Frost, J. Am. Chem. SOC., 1989, 111,1866. S.L. Bender, T. Widlanski, and J.R. Knowles, Biochemistry, 1989,%, 7560. T. Widlanski, S.L. Bender, and J.R. Knowles, Biochemistry, 1989,2, 7572. D. Crich and T.J. Ritchie, Carbohydr. Res., 1989, c3. S. Valverde and S. Garcia-Ochoa, J. Carbohydr. Chem., 1989,& 553. R. Shirai and H. Ogura, Tetrahedron Lett., 1989,2,2263. A. Esswein, R. Betz, and R.R. Schmidt, Helv. Chim. Acta, 1989,=, 213. A. Enhsen and R.R. Schmidt, Liebigs Ann. Chem., 1989.69. P.A.M. van der Klein, G. J. P.H. Boons, G.H. Veeneman, G.A. van der Marel, and J.H. van Boom, Tetrahedron Lett., 1989, 5477. S. Horito, M. Amano, and H. Hashimoto, J. Carbohydr. Chem., 1989,& 681. H. Itoh, Noguchi Kenkyusho Jiho, 1988, 37 (Chem. Abstr., 1989,111, 154 236). S.F. Martin and P.W. Zinke, J. Am. Chem. SOC.,1989, 2311. B.P. Branchaud and M.S. Meier, J. Org. Chem., 1989, s,1320. Yu. M. Mikshiev, B.B. Paidak, V.I. Komilov, and Yu.A. Zhdanov, Zh. Obshch., Khim., 1989,& 945 (Chem. Abstr., 1989,111,233 429). B. Giese, T. Linker, and R. Muhn, Tetrahedron, 1989,Q, 935. 0. Holst, E. Rohrscheidt-Andrzejewski, H-P. Cordes, and H. Brade, Carbohydr.Res., 1989, 212. C. Auge, B. Bouxom, B. Cavaye, and C. Gautheron, Tetrahedron Lett., 1989, 2217. C. Auge, S. David, and A. Malleron, Carbohydr. Res., 1989,188, 201. C . Auge, S. David, C. Gautheron, A. Malleron, and B. Cavaye, New J. Chem., 1988,U, 733 (Chem. Abstr., 1989, JU, 23846). A. Hasegawa, M. Morita, H. Ishida, and M. Kiso, J. Curbohydr. Chem., 1989,&,579. A. Hasegawa, T. Murase, H. Ishida, and M. Kiso, J. Curbohydr. Chem., 1987,8, 589. E. Zbiral, H.H. Brandstetter, and E.P. Schreiber, Monatsh. Chem., 1988, D, 127 (Chern. Absrr., 1989, 154 761). K. Christian, E. Schreiner, E. Zbiral, andG. Schultz, Carbohydr. Res., 1 9 8 9 , m , 4 9 . E. Zbiral, E. Schreiner, R. Christian, R.G. Kleineidam, and R. Schauer, Liebigs Ann. Chem., 1989, 159. E. Zbiral, E. Schreiner, and R. Christian, Carbohydr. Res., 1989,194, c15. A. Hasegawa, Y. Ito, M. Morita, H. Ishida, and M. Kiso, J . Carbohydr. Chem., 1989,s. 125. A. Hasegawa, Y. Ito, M. Morita, H. Ishida, and M. Kiso, J. Carbohydr. Chem., 1989,&, 135. K. Furuhata and H. Ogura, Chem. Pharm. Bull., 1989,2,2037. R. Bassi, L. Riboni, S. Sonnino, and G. Tettamanti, Carbohydr. Res., 1989,193, 141. G. Fronza, G. Kirschner, D. Acquotti, and S . Sonnino, Carbohydr. Res., 1 9 8 9 , m , 5 1 . M.C. Murray, V.P. Bhavanandan, E.A. Davidson, and V. Reinhold, Carbohydr. Res., 1989, m,255. J. Banoule, D.H. Shaw, N.A. Nakhla, and H.J. Hodder, Eur. J . Biochem., 1989, 651. (Chem. Absrr., 1989,110, 173621). K. Sato, K. Sugai, K. Fujikura, N. Yamada, M. Goto, C. Ban, E. Hayasaka, N. Sugiyama, and K. Tomita, Carbohydr. Res., 1989,185, 307. M. Nakamura, K. Furuhata, K. Yamazaki, H. Ogura, H. Kamiya, and H. Ida, Chem. 2204. Pharm. Bull., 1989, B. Becker, K. Hard, M. Melkonian, J.P. Kamerling, and J.F.G. Vliegenthart, Eur. J. Biochem., 1989,182, 153 (Chem. Abstr., 1989,111. 53840). A. Kuroda, S. Matsumura, and S. Yoshikawa, Chem. Express, 1989,4,205 (Chem. Abstr., 1989, U, 23854). R.N. Rej, J.N. Glushka, W. Chew, and A.S. Perlin, Carbohydr. Res., 1989,189, 135. D.J. Ager and M.B. East, J. Chem. Soc., Chem. Commun., 1989, 178. M. Bessodes, D. Komiotis, and K. Antonakis, J. Chem. SOC.,Perkin Trans., I , 1989,41. G.W.J. Fleet, N.G. Ramsden, and D.R. Witty, Tetrahedron, 1989,Q, 327. H.P. Wessel, J. Carbohydr. Chem., 1989,& 443. A. Ya. Chernyak, L.O. Kononov, and K.V. Antonov, Izv. Akad. Nauk SSSR, Ser. Khim, 1988, 1660 (Chem. Abstr., 1989,110, 154763). A. De Mesmaeker, P. Hoffmann, and B. Emst, Tetrahedron Lett., 1989,3,3773.
m,
a,
m,
m,
a,
m,
m,
a,
170 62 63
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79
Carbohydrate Chemistry T.K. Gerdling, B.F.H. Drenth, V.J.M. van de Grampel, N.R. Niemeijer, R.A. de Zeeuw, P.G. Tepper, and A. S . Horn, J . Chromatogr., 1989, &U,125. J.K. Chung, Y.M. Goo, andH.K. Kim, Yakhak Hoe& , 1 9 8 8 , z . 386 (Chem. Abstr., 1989, 154274). Y. Liu, Z. Liu, and Z. Han, Rev. Chem. Interned., 1988, j&, 269 (Chem. Absrr., 1989, 154689). P. Martinez, J. Zuluaga, and C. Sieiro, An. Quim., Ser. A, 1988,84, 310 (Chem. Absrr., 1989, JJJ, 174562). J. Xu,Huaxue Xuebao, 1989, 313 (Chem. Abstr., 1989,111,96475). K.N. Reddy, K.C.Rajanna, P.K. Saiprakash, Orient. J . Chem., 1988,4, 159. (Chem. Absrr., 1989, U, 173648). G.V. Rao and P.K. Saiprakash, Oxid. Commun., 1988, U, 33 (Chem. Absrr., 1989,110, 135 622). M.M. Khan and R.S. Shukla, Inorg. Chim. Acra., 1988,149, 89 (Chem. Abstr., 1989, IlQ,173647). K. Abe, Kochi Joshi Daigaku Kiyo,Shizen Kagakuhen, 1 9 8 7 , 3 , 3 1 (Chem. Abstr., 1989, U, 135 581 ). B-M. Kwon, C.S. Foote, and S.I. Shan, J . Am. Chem. SOC., 1989,111, 1854. K. Eger and R.J. Schmidt, Arch. Pharm. (Weinheim, Ger), 1989,322, 127 (Chem. Abstr., 1989, U,78510). A.J. Poss and M.H. Brodowski, Tetrahedron Leu., 1989, Ur, 2505. M.P. Doyle, C.L. Nesloney, M.S. Shanklin, C.A. Marsh, and K.C. Brown, J . Org. Chem., 1 9 8 9 , 2 , 3785. M. Takagi, A. Kawajiri, K. Nakata, and N. Morita, J . Nutr. Sci. Vitarninol., 1989,%, 61 (Chem. Abstr., 1989, U, 39774). F. Hashimoto, G. Nonaka, and I. Nishioka, Chem. Pharm. Bull., 1 9 8 9 , 2 , 3255. I.L. Plikhtyak, I.V. Yartseva, X.Y. Han, and M.N. Preobrazhenskaya, Bioorg. Khim., 1988,U, 1437 (Chem. Absrr., 1989, 23803). H. Sakurai and K . Ishii, N i b n Daigaku Nojuigakubu Gijutsu Kenkyu Hokuku, 1988, 50 (Chem. Absrr., 1989,IlQ, 76040). H. Sakurai, T. Ito, and K. Ishii, Nihon Daigaku Nojuigakubu Gijutsu Kenkyu Hokoku, 1988, 59 (Chem. Absrr., 1989,110, 76039).
u,
m,
a,
u,
17
Inorganic Derivatives
1 Carbon-bonded Phosphorus Derivatives The D-ribofuranose derivative (1) with a hydroxyphosphinylgroup in the hemiacetal ring has been synthesised (Scheme l),'?'and the same group have described the
x;
kc
TsNHNH
Ts NHC M 42
UI,
p,\
( M 4 2 PQ0 P HO
O x 0
Reage+
H o C H ?bp" ~
L, HP(O@MC)~ ,CF3SO3H,
u,NaBH+,THF, w,
", H202 9
Scheme
NaHZAL(OCH2CH20Me)Z,~v,
O
U
O H (1)
HCLaq,PrOH,
1
preparation of xylopyranose derivatives with ethyl- and phenyl-phosphinyl and phenylphosphinothioyl units in the hemiacetal ring. The methylphosphinyl analogues (2) of D-mannose have been synthesised and three isomers were isolated as their pentaacetate~~. An improved approach to the hydroxyphosphinylD-glucose analogue (3) has been reported5. A novel approach to racemic phenylphosphinyl tetrose derivatives (4) utilised the alkene ( 5 ) as starting material6.
c F o H Hob &
HOCH2
q,
HOCH2
$1
,Ph
H
O H HO
f i o A C
a
,Ph
-
HO
OH (2)
(3)
AcO
OAc
W(4)
(5)
The phosphonate (6) has been synthesised in an attempt to prepare analogue (7) of fl-KDO, but several different attempts to effect the conversion of (6) into (7)
172
Carbohydrute Chemistry
were unsuccessful7. Radicals, eg (8), have been shown to add to Vinyl phosphonates giving rise to isosteric phosphonate analogues, eg (9), of nucleosides'. D-lyxose has been converted into the D-glyceric acid phosphonate isostere ( and the COZH
t
OH
synthesis of some phosphonate analogues of 3-deoxy-D-arabino-heptulosonic acid is covered in Chapter 16. Some diphenylphosphinyl sugar derivatives have been converted into perchlorate complexes of rhodium and used as catalysts for the asymmetric hydrogenation of alkenes affording products with moderate optical yield". 2 Other Carbon-bonded Derivatives A review covering selenium and tellurium derivatives of carbohydrates has been published". The selenium-containingD-fructose derivatives (11) and (12) were obtained from the corresponding 3,4-anhydro compounds, and then were mesylated to give exceptionally stable 8-sulphonyloxyselenidesthat did not undergo elimination even at elevated temperatures. The former was oxidised to the selenoxide which underwent *-elimination affording alkene (13)'*. Treatment of glycal (14) with phenylselenyl triflate and an alcohol (R1OH either a simple alcohol or another saccharide) afforded only a-glycosides (19, which after deselenylation with Bu,SnH C H2 OAc
CH;?OR
A'O
4
0Me Se Ph R = Si ButPh, (11) R'= C H ~ O R R , ~ = O M ~ (12) R ' = OMe
, R'=
CY20R
(13)
Aco ...
(14) R = Du,rTle
R = Ou,Me (IS) X = SePh (16) X = H
gave the a-glycosides (16) of KDO'~. Addition of trimethyl-stannylmethyl lithium to 1,2:5,6-di-~-isopropylidene-a-D-glucofuranos-3-ulose gave the branched chain derivative (17) which on treatment with iodine afforded the stannyl iodide (18)14. The stannylated derivative (19) has been utilised in a TiC1,-catalysed coupling
17: Inorgunic Derivatives
173
k01
$H2Sn Bu,
(17) X = SnMeg
(1%) X = % M e 2 1
(1 9)
reaction with a carbohydrate aldeh~de'~. Reductive oxygenation (NaBH,, 0,, DMF) of organomercurial (20) is known to afford alcohol (21) along with 5% of the by-product (22). If the reaction is performed with only a slow stream of air (rather than a vigorous flow of pure oxygen) the by-product (22) becomes the major product and is isolated in 68% yield. The radical (23) is postulated as an intermediate16. An oxymercurationdemercuration reaction of a D-allal derivative is mentioned in Chapter 13. Addition of dimethylphenylsilylmethyl magnesium chloride to methyl 2,3,4-tri-Qbenzyl-a-D-manno-l,6-dialdo-pyranoside afforded adduct (24) which was oxidised to the L-glycero-D-manno-heptopyranoside (25)17.
3 Oxvgen-bonded Derivatives The dimethylphosphinothioylgroup [-P(S)Me2]has been advocated for the protection of carbohydrate hydroxyl groups. Derivatives are formed from the alcohols by use of Me,P(S)Cl in the presence of DBU and are stable to moderately acidic or basic conditions. Cleavage is effected with BnMe,NOH". Some glucopyranosyl dimethylphosphinothiolate derivates treated with alcohols in the presence of iodine and catalytic trityl perchlorate, have afforded the 8glucopyranosides stereoselectively in good yieldslg. Treatment of 2,4-Q-methyleneD-glucitol with phosphorus trichloride gave 2,4-Q-methylene-D-glucitol-1,3:5,6-bis0-(chlorophosphite)m. The interactions of boric acid or borate with shikimic and quinic acids in aqueous solutions have been studied by "B- and I3C-n.m.r., with various species in
Carbohydrate Chemistry
174
equilibria being identified2'. In an extension of an earlier study the borate complexes in aqueous solution of D-allose, D-talose and D-psicose have been examined by I'B- and 13C-NMR. The spectra were used to determine the site and extent of chelation and showed that the sugars were complexed in the furanose form2. Similarly, "B-NMR spectroscopy has been used to study the complexation of borate ions with xylitol, ribitol and arabinitol in aqueous solution at high pH valuesz. A study by FAB Mass Spectrometry of the reaction of butaneboronic acid with eleven mono-saccharides is mentioned in Chapter 22. Some organotin ethers of carbohydrate derivatives have been synthesised as potential and the selected acylation of some cyclic dibutylstannylene compounds is discussed in Chapter 7. Treatment of cyclopentadienyltitanium trichloride with 1,2:5,6-di-Q-isopropylidene-a-D-glucofuranose affords adduct (26) which may be transformed into the chiral organometallic reagents (27)-(29). These react with aldehydes (RCHO) to give products (30)-(32), respectively, with high stereo~electivity26-~~.
., O l
OH
\/ -.
.
.?] \
/% Adducts of D-glucose and Zn(I1) Cd(II) and Hg(II) ions of the form M(Dglucose)X,.H,O (X = Br or Cl) have been isolated and characterised by FTIR, 'H-NMR spectroscopy and molar conductivity measurements3'. Association constants determined for the interactions of CaC1, and KC1 with ribose, arabinose, lyxose, xylose, glucose, mannose, galactose, talose and allose in dilute water solutions by an electro-chemical method were distinctly smaller than those determined by NMR methods in more concentrated solutions3'. The complexation of Cu(II), Ni(II) and Co(II) ions by D-galactosamine solutions has been studied by potentiometric and spectroscopic methods3,. Complexes of Pb(I1) and a number of carbohydrates have been isolated as solids and investigated by FTIR, 'H- and 13C-NMRmethods, but no specific structures have been concluded33. Cobalt(III) complexes containing glycosylamines formed from ethylenediamine and aldoses (D-mannose, L-rhamnose or D-ribose) have been ~ynthesised~~.
17: Inorganic Derivatives
175
Potentiometric and spectroscopic studies have shown that D-galacturonic acid and D-glucuronic acid are effective ligands for oxovanadium(1V)ions3'. The stoichiometry of the reduction of Fe3+ by D-galacturonic acid has been determined to be 4:l (reduced Fe2+ : oxidised galacturonic acid)36. A full report has appeared on the study with 13C-enrichedD-glucose of the C-2 epimerisation of aldoses promoted by Ni(I1) diamine complexes3'. The alkali-metal cation complexes of a residues cyclic tetrasaccharide made up of peracetylated (1+6)-~-D-glucopyranosyl have been studied by 'H-NMR spectroscopy in (CD,),CO and CD,NO, solutions. The relative ligand affinities were in agreement with the ligand cavity size calculated from molecular models (3.3 A)38. Copper(I1) complexes of 1-thioglucosesare discussed in Chapter 11. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
28 29 30 31 32 33
H. Yamamoto, T. Hanaya, H. Kawamoto and S. Inokawa, Chem. Lett., 1989, 121. T. Hanaya and H. Yamamoto, Bull. Chem. SOC.Jpn., 1989, 62,2320. H. Yamamoto, T. Hanaya, N. Shigetoh, H. Kawamoto and S. Inokawa, Chem. Lett., 1989, 349. H. Yamamoto, T. Hanaya, K Ohmori and H. Kawamoto, Chem. Lett., 1989, 1471. T. Richter, P. Luger, T. Hanaya and H. Yamamoto, Carbohvdr. Res., 1989,193, 9. K h i , A. Iida and M. Yamashita, Svnthesis, 1989, 595. H. Molin, J.-0. Noren and A. Claesson, Carbohvdr. Res., 1989,194, 209. D.H.R. Barton, S.D. Gero, B. Quiclet-Sire and M. Samadi, J. Chem. SOC.,Chem. Commun., 1989, 1OOO. G.M. Blackburn and A Rashid, J. Chem. SOC.,Chem. Commun., 1989,40. M. Yamashita, M. Naoi, H. Imoto and T. Oshikawa, Bull. Chem. SOC.Jpn., 1989,9,942. Z J . Witczak, Chem. Ore. Selenium Tellurium Compd., 1987, 2,765 (Chem. Abstr. 1989,111, 23 7%). O.R. Martin, R.J. R a w and W.A. Szarek, Carbohvdr. Res., 1989,&77. K Ikeda, S. Akamatsu and K Achiwa, Carbohvdr. Res, 1989,189, C1. P.J. Cox, S.M.S.V. Doidge-Harrison, R.A. Howie, LW. Nowell, O.J. Taylor and J.L. Wardell, J. Chem. SOC.Perkin Trans. 1, 1989, 2017. S. Jarosz and B. Fraser-Reid, J. Ore. Chem., 1989, g 4011. L.J. Liotta, R.C. Bernotas, D.B. Wilson and B. Ganem, J. Am. Chem. SOC.,1989,111,783. G.J.P.H. Boons, G.A. van der Marel and J.H. van Boom, Tetrahedron. Lett, 1989, 229. T. Inazu and T. Yamanoi, Noeuchi Kenkvusho Jiho, 1988 (31), 43 (Chem. Abstr., 1989,111,7 685). T. Yamanoi and T. Inazu, Noguchi Kenkvusho Jiho, 1988 (31), 49 (Chem. Abstr, 1989,111.7 684). L.I. Gurarii, LA. Litvinov and E.T. Mukmenev, .Zh. Obshch. Khim., 1988,%, 2743 (Chem. Abstr., 1989,111.39 694). E. Delfourne, J. Veronique, L. Gorrichon, A Munoz and L. hmande, Tetrahedron, 1989, & 2605. S. Chopelle and J.F. Verchere, Carbohvdr. Res., 1989,191.63. C.F. Bell, R.D. Beauchamp and E.L. Short, Carbohvdr. Res., 1989,185.39. 287 (Chem. Abstr., 1989,110. 8 513). k Pate1 and R.C. Poller, Main G r o w Met. Chem., 1987, P.P.L. Jacques and R.C. Poller, J. Oreanomet. Chem., 1989,365.47 (Chem. Abstr. 1989,111,58 179). M. Riediker and R.O. Duthaler, Aneew. Chem. Int. Ed. Enel., 1989, 494. R.O. Duthaler, P. Herold, W. Lottenbach, K Oertle and M. Riediker, Aneew. Chem. Int. Ed. Enel., 1989, 28,495. G. Bold, R.O. Duthaler and M. Riediker, Angew. Chem. Int. Ed. Enel., 1989, 3, 497. M. Riediker, A. Hafner, V. Piantini, G. Rihs and A. Togni, Aneew. Chem. Int. Ed. Enel., 1989, 499. H.-A. Tajmir-Riahi, Carbohvdr. Res., 1989,190, 29. J.P. Morel, C. Lhermet and N. Morel-Desrosiers, J. Chem. SOC.Faradav Trans. 1, 1988, &, 2567 (Chem. Abstr., 1989,110, 24 163). B. Radomska, H. Kozlowski, P. Decock, B. Dubois and G. Micera, J. Inore. Biochem., 1988, 153 (Chem. Abstr., 1989,110.8 538). H.-A. Tajmir-Riahi, Bull. Chem. SOC. Jpn., 1989, 1281.
a
a,
a
a,
I76 34 35 36 37 38
Curhohydrate Chernisrry K. Ishida, S. Nonoyama, T. Hirano, S. Yano, M. Hidai and S. Yoshikawa, J. Am. Chem. SOC., 1989, 111,1599. G. Micera, A. Dessi, H. Kozlowski, B. Radomska, J. Urbanska, P. Decock, B. Dubois and I. Olivier, Carbohvdr. Res., 1989,188.25. S. Deiana, C. Gessa, V. Solinas, P. Piu and R. Seeber, J. Inore. Biochem., 1 9 8 9 , s 107 (Chem. &?&1989,110. 193 287). T.Tanase, F. Shimizu, M. Kuse, S. Yano, M. Hidai and S. Yoshikawa, Inore. Chem., 1988,22, 4085 (Chem. Abstr., 1989, _110, 8 495). G.Bonas and M. Vignon, Red. Trav. Chim. Pam-Bas., 1989,108. 161 (Chem. Abstr., 1989,111,233 401).
18
Alditols and Cyclitols
1 Alditols 1.1 Acyclic Alditols. - Chain-shortening of aldoses to the next lower alditol by decarbonylation has been accomplished by heating in N-methyl-2-pyrrolidinone in the presence of chloro(tripheny1ph0sphine)rhodium (11). 1 Asymmetric aldolysation of glycolaldehyde has been achieved using the asymmetric acetal derivative (1) with triethylamine or calcium hydroxide; the mixture of tetritol stereoisomers ( 2 ) obtained after borohydride reduction showed small stereoselectivities for L over D and erythro over threo isomers.2
v ROCH~CHO (1)
'
+
ROCH~CH(OH)CH(OR)CH~OH
(2)
Mono-2-hydroxyethyl-D-glucitol peracetates have been synthesized as reference compounds for the g.c.-m.s. analysis of hydrolysates 3 of 2-(hydroxyethyll-starch and -cellulose. A crown ether incorporating one residue of D-mannitol has been used as an asymmetric coating for silica chromatography columns which allow baseline resolution of racemic phenylglycine.4 3-~-Hexosyl-D-arabinoses,prepared by Zemplen degradation of (1-4)linked aldonobiononitrile octabenzoates, have been reduced to the corresponding hexosyl-D-arabinitols to facilitate n.m.r. analysis.5
The selective cleavage of carbon-carbon bonds in sugars can be achieved under relatively mild hydrogenolytic conditions using a ruthenium complex catalyst; thus, besides D-mannitol and D-glucitol, D-fructose yielded up to 30% of glycerol.6 2-D N.m.r. techniques have been used to give a full assignment of 'H and I3C signals for mannitol hexaacetate.7 1.2 Anhydro-Alditols. - Unambiguous syntheses of 1,2-anhydro-3,4; 5,6-di-~-isopropylidene-D-glucitol and -D-mannitol from D-glucono1,5-lactone have been described; the claimed stereospecificity of an
178
Carbohydrate Chemistry
earlier synthesis of the latter is questioned.8 Microsynthesis of dianhydro-hexitols from 1,5- and 1,6- anhydro precursors has employed a tosylation procedure.' 2,5-Anhydro-derivatives of DL-ribitol and DL-arabinitol, l o and 2,5 :3,4-dianhydro-1-halo-1-deoxypentitols ,l1 have been prepared froK xylitol using tosyl intermediates, and another study of the cyclization of pentitols under tosylating conditions has been reported.12. The diepoxy branched-chain octitol ( 3 ) has been synthesized from the corresponding diene ( 4 ) by sequential Sharpless epoxidations with L- and then D-tartrate a~xi1iary.l~Likewise, &-butene-l,4diol has been converted to the but-3-en-1,2-diol and hence, by Sharpless oxidation, to the isomeric epoxides (5) and (6) (Scheme 2). 14
CHZOH
-09-
. . :i,H g S 0 + , N ~ S O 4 , H 2 O ; U , N a H , B n B r ; G , TL(OPr')q, Pr;(-) (+) tartrate
tartrute, B U ~ O ~;H iv, asiii, bLLtw'&
Scheme 2
The rearrangement of epoxides formed by base-catalysed reactions of 2,6-dibromo-2,6-dideoxy-D-mannitoland -D-glucitol has been investigated; depending on conditions, dianhydro-sugars containing 3-or 5-membered anhydro-rings were obtained, together with D-glucit01 or D-mannitol.l5 The solvolysis of 1,6-dibrom0-1,6-dideoxygalactitol, a cytostatic agent, has been studied; 3,6-anhydro-1bromo-1-deoxy-DL-galactitol, which is biologically inactive, is readily formed.16 The alkylation of 1,4:3,6-dianhydro-D-mannitolwith ethane-1,2diol derivatives leads to compounds of interest as chiral complexing and phase transfer reagents, including the dimeric compound ( 7 ) The selective esterification of a 1,5-anhydro-D-galactitol is mentioned in Chapter 7, and a biguanido derivative of a 2,5-anhydrohexitol is referred to in Chapter 9.
J7,
18: Aldirols und Cyclirols
179
1.3 Branched-Chain
Alditols. - Reaction of sugar oxiran derivatives with excess of trimethylaluminium yield branched-chain deoxy-alditol derivatives, e.g., ( 8 ) + ( 9 1 , in an unusual ring opening, chain extension process. The conversion of the benzyl glycoside (10) to the alditols (11) was also described."
OH I-.-\
1.4 Amino-Alditols. - Diaminodideoxytetritols have been prepared by standard procedures from butene-diol, mannitol, and tartaronitrile precursors to give stereoisomers of 1,4- or 2,3-diamino compounds which were then complexed with platinum to give analogues of the 20 anti-cancer drug cisplatin. The chiral quaternary salt (12: of 1-amino-1-deoxy-D-glucitol, derived from N-methyl-D-glucamine, has been used in conjunction with N - b e n z y l o x y c a r b o n y l p h e n y l a l a n y l h i s t i d i n e , a chiral active catalyst, to effect enantioselective hydrolysis of enantiomeric esters. 21
Oligosaccharide l-deoxy-l-(4-trifluoroacetamidophenyl)aminoalditols can be oxidized to the corresponding reducing oligosaccharides with hydrogen peroxide, or to the corresponding l-amino-ldeoxy-alditols with ceric ammonium nitrate.22 A 4-step synthesis of 1-deoxynojirimycinfromL-sorbose has been described involving a 6-azido-L-sorbose intermediate which undergoes cyclization concomitantly with reduction to give the required compound. 2 3
Carbohydrate Chemistry
180
Full details of the synthesis of deoxymannojirimycin and D-mannonolactam from L-gulonolactone have been published (see Vo1.22, p.94); the report includes syntheses of the L-enantiomers from D-gulon~lactone.~~ New syntheses of deoxymannojirimycin (13) and the corresponding pipecolic acid ( 1 4 ) have been described (Scheme 31,
a key improvement being efficient intramolecular displacement of the 2-triflate by the 6-amino group in both anomers.25 A combined enzymatic/chemical synthesis of imino-alditols used fructose 1,6-diphosphate aldolase to generate 6-azido-ketohexoses (as outlined in Scheme 4) which could be catalytically reduced to deoxynojirimycin and deoxymannojirimycin. By use of appropriate azido-aldehydes, fagomine(l5) and 1,4-dideoxy-1,4-imino-D-arabinitol (16) were similarly prepared.26 Microbial epimerization of l-deoxynojirimycin to 1-deoxyrnannojirimycin has also been reported.27
&;ti..
CHzOH
CH20R
0
Y-
+ OCH
RO&OH
N3
L
HO
HJ& =
OH R = H2 PO3
ppavnte eraolLt;orne rs)
(--J
CH t OH
CH20H
6
(5epam-k epimers)
Scheme 4 N3/ll,@
OBn
HO
HO
OH
HO 05)
OH
(16)
(17) OBn
(10)
OH
A paper on the use of 1,6-anhydro-hexoses for oligosaccharide synthesis includes a conversion of 1,6-anhydro-2,3-di-g-benzyl-B-Dglucofuranose to the corresponding 5-azido-5-deoxyanalogue ( 1 7 ) by a double inversion sequence, and hence to 1-deoxy-nojirimycin (18).28 A synthesis of 2-acetamido-2-deoxynojirimycin(19) and its 1-deoxy analogue (20) utilizes the Ij-acetyl-D-glucosaminederivative (21) a s outlined in Scheme 5.29 A synthesis of the L-talo isomer ( 2 2 ) of 1-deoxynojirimycin
18: Alditols and Cyclitols
181
utilizes a chain elongation procedure from D-ribose with cyanotrimethylsilane, as indicated in Scheme 6 . 30 CH OTr
R - a !
C, NaOH,0nBr;k , R O Y , T S O H ; ' ~ , H Z O , H O A ~ ; L ~ , T ~ C C; , P ~
V, ~ ~ ~ H ) ~ G ~ ~ , ~ C ~ O , ~ ~ , CViL,RancyNi ( O N ~ ~ U ;vui,TFA,MeOH; . N ~ C O ~ ;
k,Pd.(oOC0,,n2;
I, C F 3 5 0 3 ~
NHAc 09)
Scheme 5
OBn OTWS
0nO -&S:
OMS
CHZOBn
i fTMSCN, OC.3 ;G, Feu2; L, MSCL, Py ; W,L A H ;v,
(22)
CH20Bn NGOAc, E t O H ; v i ,
H,,W/C
Scheme 6
Fleet's group has reported syntheses of the nojirimycin analogues ( 2 3 ) and ( 2 4 ) from 5-azido-5-deoxy-hexono-~-lactoneprecursors using organometallic reagents ,31 and of the 2,6-dideoxy-2,6-imino-heptitols (25) from the heptonolactone (26) derived from diacetone mannose by use of the Kiliani reaction. These imino-heptitol \
,01
CHTOH
epimers show opposite selective inhibitory activity against oc-fucosidase as againstoc-mannosidases; one inhibits the former, whilst the other inhibits the latter. 3 2 2-Amino-2-deoxy-D-mannitolhas been isolated as a minor byproduct from a broth of S . lavendulae which produces moranoline (l-deoxyg- Substituted 4-0-6(-D-glucopyranosy 1-moranoline nojirimycin 1 derivatives have been enzymatically synthesized using soluble starch and a glucosyltransferase with the parent rnoranoline.34 Alter-
.
natively, the parent disaccharide has been alkylated to give a series of N-alkylated derivatives which were assessed as sucrase and maltase inhibitors.35 The 1,6-dideoxy-nojirimycin derivative ( 2 7 ) , obtained by a
182
Carbohydrute Chemistry
reductive-oxygenation modification of a previously reported procedure for making 1-deoxynojirimycin from a 6-bromo-6-deoxy-glucoside derivative (see Vo1.19,p.170,ref.40), has been converted to oligosaccharide derivatives ( 2 8 ) in quest of endo-cellulase inhibitory activity.36
6 -
HO
OBn (27)
mou
(2%) R = H , ~ - D - G L ~ . ~ ,
RO
OH
OH
p - 0-CeUobiosgL
A synthesis of 1-deoxynojirimycin from non-carbohydrate precurinvolves the conversion of (S)-pyroglutamic acid to the lactam ( 2 9 1 , followed by the sequence outlined in Scheme 7 which uses
sors
standard reactions.37 The same starting material was used to prepare the lactam ( 3 0 ) and hence the 1,4-dideoxy-1,4-imino-D-xylitol (31), selective benzylation at 0-2 allowing routine inversion at C-3.38 Other papers describe the synthesis of the isomeric imino-Dlyxitol ( 3 2 ) from D - g l u ~ o s e ,and ~ ~ of the imino-L-xylitol (33) from D-mann~se.~' A paper on the synthesis of swainsonine from mannose mentioned in Chapter 24 includes a practical synthesis of 1,4-dideoxy-1,4-imino-D-mannitol.
.a
Me02c%
Roc
OTr +-+
44
~ c N H OTr
;fi ,+-o
1
(29)
Boc Scheme. 7
OTr OTr BOG
1.5 P o l y h y d r o x y a l k y l - H e t e r o c y c l e s . - Knoevenagel condensation of 41 D-ribose with malononitrile gave the trihydroxypropylfuran (34).
18: Alditols and Cyclitols
183
Condensation of 2-amino-2-deoxy-D-glucose and 1-amino-l-deoxy-Dfructose with nitromethane led to t e t r a h y d r o x y b u t y l p y r r o l e derivat~ ives (35) and ( 3 6 ) r e ~ p e c t i v e l y . ~5'-Phosphates of a variety of D-ribityl-substituted pyrimidines and pteridines have been synthesized.43 2 Cyclitols
Z - g - ( B - L - A r a b i n o p y r a n o s y l ) - m y o - i n o s i t o l has been identified as a main constituent of tea, although it is essentially tasteless.44 Conduritol isomers have been stereospecifically prepared from benzene as shown in Scheme 8 . 4 5 Irradiation of the disilyl ether
oAaoH \
OH
OH
Reogm,lzs: i, p5~clomnasp e t t i d a ; ii,'0,;iii, CS(NH2)2,MeOH; iv, H 2 , P t
OH
&OH
a /
y
(q
b-4
+
&OH
$lM
C ( O H
OH
bH
OH
5H
'r .ih
(il on
Scheme 0
of the peroxide ( 3 7 ) gave the rearranged epoxyketones ( 3 8 ) and (39) which were further rearranged using triethylamine to give the isomers (40) and ( 4 1 ).46 An alternative synthesis of (-1-conduritol used Vogel's "naked sugar" approach as indicated in Scheme 9.47
Scheme 9
Cyclopentane and cyclohexane compounds have been prepared by employing chelation-controlled stereoselective vinylmagnesium bromide additions to aldose sugars, and subsequent construction of the carbocyclic rings by intramolecular nitrone cyclization using Bernet and Vasella's methodology as illustrated for the amino-
184
Carbohydrate Chemistry
cyclitol (421, made from D-mannose, as outlined in Scheme 10.48
0Bn CHO (42) ~ ~ ~ : i , ~ M ~ B r ; b NaH,riL, , B n a~ j o f + ; W , N a 1 0 4 ;v,MeNHOH
S c h e m e 10
The xylose derivative (431, on periodate oxidation, gave an aldose which underwent spontaneous Knoevenagel cyclization to the cyclopentane (441 which could be conventionally converted to 9 - M - L arabinofuranose and 9-P-D-ribofuranosevia the cyclopentene (451 .49
Carbohydrate alkenes derived by Wittig reaction of aldohexoses undergo radical cyclization to cyclopentane analogues, e.g., (46)+ (471(Scheme 11). The stereochemistry of cyclization was found to depend mainly on the substituent at C-2 of the original sugar.50
The unsaturated iodo-sugar (481, obtained from 3,4-di-g-benzyl-Dglucal, underwent reductive cyclization with tributylstannane leading to the cyclopentane isomers (49); the cyclohexane derivative (501 was similarly made. 51
0Bn
Me (49)
18: Alditols and Cyclitols
185
Another reductive coupling technique has been applied to unsaturated carbohydrate aldehydes, giving cyclopentanes with high stereoselectivity following samarium diiodide reduction, as exemplified in Scheme 12.52
OH
'Iii
... u*
+ C02Me
P,
O x 0
&agwLts: t, PhjP=CHCOzEt ;L, P O C ; & , S ~ I , , T H F ,WeOW (-789
Scheme 12
Pseudoheptanose derivatives have been prepared by ring enlargement of an oxabicyloheptane compound using nitromethane on a dialdehyde intermediate as illustrated in Scheme 1 3 ; the derived anhydro compounds resisted anhydro-ring cleavage.53 0 i-iv
~
C H ~ O A ~
(+h acetate s t w -omerr) Reagents:L,NaOMe;L,Na104; iii, M c N O ~ . O M C - ; ' ~ , A C ~ O ;HV,,,
Pd/C;vi, tiB~-,HoAc
S c h e m e 13
Pseudo-3-amino-3-deoxy-DL-hexopyranoses have been synthesized by the nitromethane cyclization procedure from pseudo-M-galactose, the gluco isomer predominating; the ,6-isomer reacted less selectively.54 The same starting material has been used to prepare pseudo derivatives of 4-amino-4-deoxy, 4,7-diamino-4,7-dideoxy, and 4-amino-4,7dideoxy-oc-DL-glucopyranose by standard reactions.55 Selectively substituted symmetrical deoxyinositols (51) and (52) have been made following borohydride reduction of inosose derivat ives 5 6 Pseudo-2- acetamido-2-deoxy-DL-hexopyranoses have been prepared conventionally.57
.
Optically pure isomers of 1 , 4 , 5 , 6 - t e t r a - 2 - b e n z y l - ~ - i n o s i t o l have been obtained after separation of diastereoisomeric 2,3-acetals of =>-inositol witn L- o r D-camphor.58
Curb0hydrute Chemistry
186
The benzenemicrobial oxidation product mentioned above has also been used t o prepare (+)-pinit01 (53) and its enantiomer as outlined in Scheme 14, the diastereoisomeric menthoxyacetic esters being readily separated.59
a;;* pJ:
y
u,w
~
yJlIcr) p
L
.
v,v*
~
" e . y J ~
o**" R w w S
b,
5H (+I (531
B L C L , P ~ , D M A P , UMCPBA , , W, MeOH, H+ ,w, MenMoqacctyL cur&,
Py,DMAP,
OSO4,0&aH,
V,
Vb, €t3NJ,MeOH, H 2 0
Scheme 14
Acetalated F - i n o s i t o l derivatives have been converted by standard reactions into intermediates required for the total synthesis of sugarotoxin and some of its analogues, which are 6-2-acyl derivatives of w-inositol.60 Quebrachitol reacts with DAST to a deoxy-fluoro derivative which, on demethylation, gave the fluoroinositol (54), a cellular replication inhibitor.61 Deoxy-fluoro--inositols have been prepared, and their behaviour as substrates for phosphatidyl-inositol synthetase has been reported.6 2 2 - C fluoromethyl-w-inositol ( 5 5 ) has been prepared conventionally from an exocyclic oxiran precursor. 63 Many papers have appeared on E - i n o s i t o l phosphates and their analogues. Recent developments in their synthesis have been reviewed.64 Syntheses of (-)-w-inositol 1,4,5-triphosphate (56) have
HODH HoQp(0~)~ OP03h
OH
JF (HO OH
OH
HO
"O
OH
%
Ho
OH
OH
(54)
FCH2
OH (55)
OP03H2
(56) X = O (57) x s s
been reported from myo-inositol precursors ,65-67 and also from ( - 1 -quinic acid. 68 Both enantiomers have been synthesized, using D-pinitol and L-quebrachitol respectively to obtain enantiomeric 1,2,5-tri-~-benzoyl-3,4-di-~-benzyl-chiro-inositol intermediates which were inverted to the required myo-inositol derivatives using a triflate ester displacement procedure. 69 Synthesis of racemic myoinositol lY4,5-triphosphatehas been reported, together with the corresponding 5-phosphorothiolate analogue ( 5 7 ) which is phosphatase resistant, using ltnown 2 , 3 , 6 - t r i - ~ - b e n z y l - 4 , 5 - ~ - i s o p r o p y l i d e n e - ~ inositol.70 The inositol derivative (58), previously reported as a product of
18: Alditols and Cyditols
187
benzene oxidation (see Vo1.21,p.179,ref.57), has been used to prepare the 6-deoxy analogues (59)-(61) of F - i n o s i t o l 1,4,5-triphosAnother paper reports conversion of a F - i n o s i t o l derivative to the mono- and di-fluoro-scyllo-inositolanalogues (62) using standard reactions.72 TIPS-Protected derivatives of myoinositol have been used to prepare its 4-mOn0, 5-mOn0, 1,3,4-tris, and 1,3,4,6-tetrakis-phosphate ester d e r i ~ a t i v e s . ~The ~ 2- and 6deoxy-myo-inositol 1-phosphate derivatives (63) and ( 6 4 ) respective l y have been prepared, and then used to show that both the 2 - and the 6-hydroxy group of --inositol 1-phosphate are involved in the mechanism of its hydrolysis by inositol monophosphatase.74
hate.^'
(63) R'=
H, R2= OH
(64) R'=OH, RZ=H
HO
(65) R',R2= H,Bn,AU OR2
5 - i n o s i t o l orthoformate has been used to prepare 4- and 6-substituted derivatives, e.g. (651, and from these 2-mono, 4-mOn0, 1,3-bis, and 1,3,4,5-tetrakis-phosphate esters were prepared.75 (See also Vol. 21, p.183.) Selective phosphorylation of (+)-2,3:5,6-di-Gisopropylidene-ms-inositol has been used to synthesize inositol phospholipid analogues.76 This same precursor has been used to prepare the non-hydrolysable phosphonate analogue (66) of e - i n o s i t o l 1-phosphate via the intermediate inosose (67). 77
Full details of the synthesis of w-inositol phosphate esters from racemic dicyclohexylidene ketal precursors have been published (see Vol.. 21,p.183); phosphorylation has been improved using Bartlett's tetrabenzyl pyrophosphate procedure in this work. 78
188
Carbohydrate Chemistry
Epimeric forms (isomeric at phosphorus) of a mIo-inositol phospholipid incorporating a thiophosphate group have been prepared; the isomeric derivatives (68) and (69) were also synthesized. 79 The regio- and stereo-selective synthesis of inosamines and inosadiamines utilizing Diels-Alder reactions with nitroso compounds has been reviewed.80 Xylose, previously converted to V/-D-arabinofuranose (see V01.21, p.1821, has now been used to prepare (+I-cyclaradine ( 7 0 ) via V - P - D arabinosylamine.81 Intramolecular Diels-Alder reactions of sugarbased decatrienes have been used to prepare the decatetrol derivatives (71) as outlined in Scheme 15.82
r /
OH (70)
I
R
1
Scheme 15
Incorporation of 13C-labelled glucose into hopane triterpenoids revealed that the tetrol sidechain is derived from D-ribose, and that the novel carbocyclic pentofuranose unit ( 7 2 1 , attached to this tetrol, is derived from a hexose linked between C - 1 and C-5.83 N"2
(jH
(72)
The incorporation of an inosamine into the complete synthesis of hygromycin A, the structuredetermination of mannostatins A and 8, and the synthesis of carbocyclic nucleoside antibiotics are mentioned in Chapter 19, and the synthesis of phospholipids incorporating pyranosyl-myo-inositol units is referred to in Chapter 3 . Carbocyclic nucleosides are covered in Chapter 20. Xeferences 1
2 3 4
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18: Aldirols arid Cyclitols
5 6 7
8 9 10 11
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
40 41 42
43 44
189
N.B.D'Accorso and I.M.E.Thie1, J. Carbohydr. Chem., 1989, 5, 743. M.A.Andrews and S.A.Klaeren, J. Am. Chem. S o c . , 1989, l & 4131. , P.Joseph-Nathan, S.Castillo, E.Martinez, R.E.De1 Rio, and C.M.Cerda, Rev. Latinoam. Quim., 1988, 19, 79 (Chem. Abstr., 1989, 110,54603). H-Regeling and G.J.F.Chittenden, Carbohydr. Res., 1989, 190, 313. A.Wisniewski, E.Skorupowa, J.Sokolowski, L.Rozanski, D.Glod, and G.Descotes, J. Carbohydr. Chem., 1989, 8, 73. A.D.Miljkovic and S.S.Velimirovic, J. Serb. Chem. Soc., 1988, 53, 37 Abstr., 1989, 110,95675). A.D.Miljkovic and S.S.Velimirovic, J. Serb. Chem. S o c., 1988, 53, 31 Abstr., 1989, 110, 115222). A-Wisniewski,E.Skorupowa, J.Sokolowski, D.Glod, and G.Descotes, 2. Carbohydr. Chem., 1989, 8, 59. T.Ibuka, M.Tanaka, and Y.Yamamoto, J. Chem. SOC., Chem. Commun., 1989, 967. A.V.Rama Rao, D.S.Bose, M.K.Gurjar, and T.Ravindranathan, Tetrahedron, 1989, 45, 7031. K.Bock, I.Maya Castilla, I.Lundt, and C.Pedersen, Acta Chem. Scand., 1989, 43, 264. K.Horvath, L.Institoris, and E.Gacs-Baitz, Carboh dr. Res., 1989, 194, 305. E .A.El ' perina , R. I.Abylgaziev, M. I.Struchkova, an: E. P. Serebryakovyx. Akad. Nauk SSSR, Ser. Khim., 1988, 627 (Chem. Abstr., 1989, 111,58204). E.A.El'perina, R.I.Abylgaziev, and E.P.Serebryakov, Izv. Akad. Nauk SSSR, Ser. Khim., 1988, 632 (Chem. Abstr., 1989, 111,58205). T.Inghardt and T.Frejd, J. Org. Chem., 1989, 2, 5539. A.H.Haines, C.Morley, and B.A.Murrer, J. Med. Chem., 1989, 32, 742. Y.Ihara, K.Igata, Y.Okubo, and M.Nango, J. Chem. S O C . , Chem. Commun., 1989, 1900. E.Kallin, H.Loenn, and T.Norberg, Glycoconjugate J., 1988, 5, 145 Abstr., 1989, 110,24177). D.Beaup&re, B.Stasik, R.Uzan, and G.Demailly, Carbohydr. Res., 1989, 191,163. G.W.J.Fleet, N.G.Ramsden, and D.R.Witty, Tetrahedron, 1989, 45, 319. G.W.J.Fleet, N.G.Ramsden, and D.R.Witty, Tetrahedron, 1989, 45, 327. C.H.van der Osten, A.J.Sinskey, C.F.Barbas,III, R.L.Pederson, Y.-F.Wang, and C.-H.Wong, J. Am. Chem. SOC., 1989, 111,3924. T.Furumoto, N.Asano, Y.Kameda, and K.Matsui, J. Antibiot., 1989, 42, 1302. R.R.Schmidt, J.Miche1, and E.RUcker, Liebigs Ann. Chem., 1989, 423. E.Kappes and G.Legler, J. Carbohydr. Chem., 1989, 8, 371. H.Hashimoto and M.Hayakawa, Chem. Lett., 1989, 1881. G.W.J.Fleet, S.K.Namgoong, C.Barker, S.Baines, G.S.Jacob, and B.Winchester, Tetrahedron Lett., 1589,-&, 4439. I.Bruce, G.W.J.Fleet, I.Cenci di Bello, and B.Winchester, Tetrahedron Lett., 1989, 30, 7257. Y.Ezure, S.Maruo, K.Miyazaki, T.Seto, N.Yamada, M.Sugiyama, M.Itoh, and T.Nakamura, Agric. Biol. Chem., 1989, 53, 1421. Y.Ezure, S.Maruo, N.Ojima, K.Konno, H.Yamashita, K.Miyazaki, T.Seto, N.Yamada, and M.Sugiyama, Agric. Biol. Chem., 1989, 53, 61. Y.Yoshikuni, Y.Ezure, T.Seto, K.Mori, M.Watanabe, and H.Enomoto, Pharm. Bull., 1989, 37, 106. L.J.Liotta, R.C.Eernotas, D.B.Wilson, and B.Ganem, J. An. Chem. Soc., 1989, 111, 783. N.Ikota, Heterocycles, 19%, 2,1469. N.Ikota, Chem. Pharm. Bull., 1989, 37, 3399. S.Y.Han, P.A.Lidde1, and M.M.Joullie, Synth. Commun., 1988, 18,275. A.Hosaka, S.Ichikawa, H,Shindo, and T.Sato, Bull. Chem. S O C . Jpn., 1989, 62, 797. K.Eger, T.Storz, and S.Spatling, Liebigs Ann. Chem., 1989, 1049. J.-L.Chiara, A.Gomez-Sanchez, F.-J.Hidalgo, and I.Yruela, Carbohydr. Res., 1989, 188,55. P.Nielsen and A.Bacher, Z . Naturforsch., B: Chem Sci., 1988, 43, 1358 K.Sakata, H,Yamauchi, A.Yagi, K.Ina, L.Parkanyi, and J.Clardy, Agric. Biol. Chem., 1989, 53, 2975.
(m.
(e.
(m.
w.
Carbohydrate Chemistty
190 45 46 47 48
49 50 51 52 53 54 55 56 57 58 59 60
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
81 82 83
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(e.
-
(m.
19
Antibiotics
1 Amino-Glycoside Antibiotics Two new streptomycin analogues, ashimycins A and B, have been isolated from the fermentation broth of S. griseus; these are streptomycin derivatives modified in the L-glucosamine unit, ashamycin A (1, part structure) carrying a glycosidically linked branched-chain sugar acid (the stereochemistry has not been established). 1
OH
Me
-
A blocked mutant of istamycin-producing 2. tenjimariensis converts fortimicin B to l-epidactimicin (2)(with C(1)-NH2 inversion and N-4 acylation). 2 The biosynthesis of fortimicin antibiotics has been studied., and common features in their production 3y 2. sannanensis and Micromonospora olivosterospora have been recognized.3 (+)-Validoxylamine A has been prepared by deoxygenation of a validoxylamine B derivative, and validamycins A and E have been synt h e s i ~ e d . ~The imino bond of validoxylamine A derivatives has been cleaved using p-bromosuccinimide to give a mixture of inosamine and inosose derivatives useful for reconstructing modified validoxylamine compounds.5 Syntheses have been reported for (-1-sannamine (2-deoxy-fortamine)6 and its C-6 epimer, (2)-sporamine. 7 The mechanism and stereochemistry of the biosynthesis of 2-deoxystreptamine and neosamine C by 2. ribosidificus have been investigated using labelled 6-2H-D-glucoses.8 The sorbistin analogues ( 3 ) and (4)have been synthesized by coupling azido-precursors to the separate units using modified forms of standard glycosidation procedures. A synthesis of spectinomycin has been reported, together with that of an analogue ( C - 5 ' n-butyl replacing C-methyl) which shows enhanced antimicrobial activity and is the only analogue active 10 against anaerobic bacteria (see also V o l . 17, p. 174, ref. 40).
192
Carbohydrate Chemistry
OH
OH
(3)
CL H3N
OH CH*OH
(4)
OH CH20H
A total synthesis reported for the pseudo-tetrasaccharide oc-glucosidase inhibitor acarbose and its hydroxylated analogue adiposin involved converting 1,6-anhydromaltotriose into 3",4"-anhydro analogues which were then condensed with 4,7:5,6-di-c-isopropylidenevalienamine.l1 A synthesis of dihydroacarbose is referred to in Chapter 4. 2 Macrolide Antibiotics
Two new 16-membered macrolide antibiotics, cirramycins F-1 and F-2, have been isolated from mutant strains of 2. cirralus, which produces cirramycins A and B. Compared with cirramycin B, which contains L-cinerulose + D-mycaminose as a substituent disaccharide, cirramycin F-1 has rhodinose and cirramycin F-2 has L-amicetose instead of L-cinerulose in the disaccharide.12 Izenamycins, newly isolated from Micromonospora, contain 4'-deoxy-mycosamine glycosidically linked to a tylonolide 16-membered macrolide ring.13 X-Ray analysis has established the absolute configuration of mycinamicin IV, a 16-membered macrolide containing D-desosamine and D-mycinose separately attached. l4 Mycinamicin VIII, a key intermediate in the biosynthesis of mycinamicins, has been characterized as the desosamine glycoside of the macrolide.15 Vacidin A has also been completely characterized and shown to contain an aromatic and heptaene 38-membered ring with attached mycosamine. A crystal structure of (1413) -14-hydroxy-6-~-methylerythromycin A has been reported.17 16-Deformyl-4'-deoxydesmycosin has been prepared by a method which involved standard 4'-deoxygenation of the mycaminose residue.18 The biosynthesis of cytovaricin, a macrolide antibiotic containing D-cymarose, has been studied, and its 13C n.m.r.spectrum assigned. l9 Analogues o f 8,9-anhydroerythromycin A 6,9-hemiacetal have been prepared in which the &_N-dimethylamine of the desosamine was replaced by other N,_N-dialkylamine units; the _N-ethyl,N-methyl analogue gave the best, desired gastrointestinal motor stimulating
19: Antibiotics
193
activity. 2o
Significant enhancement also occurred on quaternization
of the desosamine dimethylamino group with small, unsaturated alkyl
groups, notably with a propargyl residue.21 4"-Acyl ,-alkyl , and -deoxy-tylosin derivatives have been prepared via a 3",4"-c-dibutylstannyl intermediate, and evaluated as antimicrobial agents . 2 2 3 Anthracycline and Related Polycyclic Antibiotics The synthesis and pharmacology of new antitumour anthracyclines developed between 1983-1986 have been reviewed.23 Viriplanin A, a new member of the nogalomycin group of antibiotics, has been characterized; it contains a novel hydroxyaminosugar, isolated as methyl 2,3,6-trideoxy-3-hydroxyamino-3-~-methyl@-D-ribo-hexopyranoside (51, which on oxidation gave methyl a-Ddecilonitroside ( 6 ) ; viriplanin D, a photo-oxidation product of viriplanin A, has the full structure ( 7 ) ; the authors suggest that
(5) R = N H O H Me
(6) R r N 0 2
R
OMe
OH Me
HO
the L-configuration previously attributed to decilonitrose obtained 24 from anthracycline antibiotics should be corrected to D. Three new platelet aggregation inhibitors (8) have been isolated from 2. matensis culture broth. As 0- and C-glycosylated benzanthraquinones, they are closely related to antibiotics previously reported (see Vol. 16, p.199; Vol. 18, p.120). 25 Anthracycline F 840020 (a 2,6-dideoxy-/3-D-lyxo-hexopyranoside) has been prepared in a multistep procedure from lactose.26
194
Carhohydrate Chernistty
2,6-Dideoxy-a-L-arabino- and -1yxo-hexopyranosyl derivatives of daunomycinone have been synthesized by coupling glycals with daunomycinone and N-iodosuccinimide followed by dehalogenation with tributylstannane; use of the deuterio-stannane reagent gave the 2 ' axially labelled isomers.27 2'-C-Methyl-daunomycins have been prepared by coupling the daunomycinone with the appropriate 2-C-Methyl3-amino-sugar obtained from methyl 4,6-g-benzylidene-2-G-methyl-x-Dribo-hexopyranosid-3-ulose by standard reactions.28 Semi-synthetic 14-chloro analogues of rubomycin and carminomycin have been synthesized, including 2-formyl derivatives of the antibiotics prepared using formic acid with 5-hydroxysuccinimide and dicyclohexylcarbodiimide.29 The biosynthesis of angucycline antibiotics urdamycins A - D has been studied; feeding 3 . fradiae with [1-13C] -glucose showed that the C-glycoside unit and the three sugars (two L-rhodinose and D-olivose) arise from glucose. 30 6-Deoxy-2-~-methyl-a-L-talopyranosyl derivatives o f daunomycinone and adriamycinone, made by standard procedures from a fucose precursor, show improved antitumour activity compared with daunorubicin and doxorubicin re~pectively.~' Corresponding 3-amino-2,3,6-trideoxy-2-fluoro-~-L-talopyranosyl compounds were also made, but these showed no improvement in activity compared with the 3-hydroxy-sugar analogues. 32 Conpounds with high antileukaemic activity have been prepared by coupling 4-demethoxy-9-hydroxymethyl-9-deacetyl-daunorubicinone with 2-deoxy-L-fucose, 2-deoxy-L-rhamnose, and 2,6 dideoxy-2-iodo-a-L-mannose using a Koenigs-Knorr procedure. 33
N-Salicylidene derivatives of pirarubicin , obtained from the antibiotic with aryl aldehydes, showed greater in vitro activity than did the parent compound.34 Semi-synthetic anthracycline antibiotic analogues have been made incorporating an hydroxyethyl spacer between the tetracycline aglycone and the sugar. 3 5 4'-Epi-N-trifluoroacetyl [14-14C] daunorubicin has been converted to 4'-iodo-4'[14- 14C] deoxydoxorubicin hydrochloride.36
195
i 9: Antibiotics
FAB-m.s. on underivatized retamycins (which incorporate a trisaccharide sidechain) have been recorded, allowing sequencing of th4 carbohydrate moiety. 37 The glycosylation of anthracyclinone is a l s o referred to in Chapter 3.
4 Nucleoside Antibiotics 3-Methylpseudouridine ( 9 ) has been isolated from the fermentation broth of Nocardia l a c t a m d ~ r a n s . ~5'-C)-Acyl ~ derivatives of 5f l u ~ r o - u r i d i n eand ~ ~ 3'- and 5'-2-alkyl derivatives of 2'-deoxy-5fl u ~ r o - u r i d i n ehave ~ ~ been synthesized in the search for enhanced antitumour activity, some enhancement being achieved with sone derivatives in each case.
P-D-Rib.f
- (9)
I
j4- D-Rib.f
p-D-RLb.!
('0)
-
(1')
Cadeguomycin ( 1 0 ) and its eand 2'-deoxy-analogues have been synthesi~ed.~'942 Standard coupling procedures have been used to prepare 6-chlorotubercidin (11) and its 3',5'-cyclic phosphate, an analogue of the anticancer 8-chloro-CAMP; the 4-substituted isomer of (11) was also obtained.43 The unsaturated sugar analogues (12) of anti-HIV nucleosides have been prepared,44 and a large scale route to the thymine analogue of (12)(from thymidine) has been described.45 The biosynthesis of ara-A, 2 ' - c h l o r o d e o x y c o f o r m y c i n , 2'-amino-2'-deoxyadenosine, and nucleosidin has been studied using labelled oxygen and hydrogen derivatives; in each case adenosine appeared to be incorporated intact .46 The synthesis and antitumour activity of modified nucleosides i s also referred to in Chapter 20.
Several syntheses of aristeromycin have been reported. The
(-)-
isomer has been made from a cyclopentenone mentioned previously (see
Carbohydrate Chemistry
196
Vol. 21, p. 194),47 and a 21-step procedure from D-glucose has been described.48 ( 5 )-Aristeromycin has been prepared from the cyclopentene-oxiran (13) via the nitromethyl intermediate (14) and the azide (15).49 An alternative approach utilized the (hydroxymethy1)cyclopentene (16) in the 3-step stereoselective synthesis outlined in Scheme 1. 50 CH20H
The racemic cyclopentenone (17), obtained as a byproduct in a synthesis of neplanocin A , has been used t o make (t)-neplanocin F ( 1 8 ~ ~ A ' similar starting material has been used to make 3-deazaneplanocin A (191, which shows antiviral properties and is a powerful inhibitor of S-adenosyl-homocysteine hydrolase.5 2 This enzyme has been used to oxidize neplanocin A to the corresponding 3'-keto analogue; sodium cyanoborohydride reduction of this ketone was neither regio- nor stereo-specific, yielding 5 products by 1,4 as well as 1,2 reduction.53
A biosynthetic study of aristeromycin using labelled precursors has found that the cyclopentane ring is generated by C-C bond formation between C-2 and C-6 of D-glucose; the authors propose oxid54 ation at C-5 or C-4 occurs leading to a cyclopentenone derivative. Other carbocyclic nucleosides which show some antibiotic activity are mentioned in Chapter 20. Protected subunits of tunicamycins have been synthesized. Cyclocondensation of the aldehyde (201, derived from uridine, with the butadiene (21) gave the dihydropyrone derivative ( 2 2 ) after desilylation, and by further manipulation, the tunicamycin subunit (23) (Scheme 2 ) . 5 5 An asymmetric synthesis of thymine polyoxin C (24) has been
19: Antibiotics
197
achieved as outlined in Scheme 3 . 56 &HO
H *,
0
NQoc
X R
Q
Y
!
L.,
x F b
..
HO ,!-=-co2Et
,
+
'7 I5:l,thk s t e e 0 k o m cr
~
BOG
-
H
0
2
N
b
--++ OH OH
L c r C C O z E b , THF, H MPA ., U ,H 2,p d / B e s O + , QuirtdLnc
(24)
Scheme 3
Two new nikkomycins have been isolated from the broth of S.tendae, nikkomycins pseudo-Z and pseudo-J, differing from the Z and J components by having a C-glycosidic link from the allofuranuronic acid and the C - 5 of uracil instead of the usual rJ-glycoside bond.57 Xelatives of rebeccamycin, containing an additional amino-sugar residue attached to the 4-~-methyl-,9-D-glucoseunit, have been isolated from Actinomadura melliaura. Structure (25) summarizes these new compounds, AT 2433-Al , -A2, - B 1 , and -B2. 5 8 * 59
OH
(25) R ~ = R2= H
cL QT
Me
(27) X = C N , Y = O M ~
(29)x=O~,Y="+ [Ref. 60,62 :
(*)I
Various synthetic approaches to bicyclic nucleosides, including octosyl acids and the ezomycins, have been reviewed. 60 The antibiotics neosidomycin (26) and the related SF-2140 (27) have been synthesized by conventional procedures from the corresponding 4-deoxy-hexoseY confirming the m-E-glycoside linkage in these compounds.61
198
Carbohydrate Chemistry
Carbocyclic analogues (28)62’63 and ( 2 9 1 ~ of ~ 9oxetanocin-A ~ ~ and oxetanocin-G, respectively, have been synthesized, and shown to possess high antiviral activity. Use of a chiral titanium catalyst in forming the cyclobutane precursor by a 2+2 cycloaddition process gave a highly enantioselective reaction ( >98% e.e. 1 .63 A 3-0-acrylyl ether of D-allose has been used to prepare a derivative of the sugar moiety of octosyl acids.6 5 5 Glycopeptide Antibiotics
Eromomycin, a new glycopeptide antibiotic produced by actinomycete INA238, which is less toxic and more potent than the related vancomycin, contains a unit of D-glucose and two units of a new aminosugar, eromosamine (3-amino-2,3,6-trideoxy-3-~-methyl-L-arabinohexopyranose), one (2-0-00 linked through glucose as a disaccharAnother new vancomycin relative, antibiotic A 42867, produced by a Nocardia strain, differs from vancomycin in the carbohydrate units, having cx-glucopyranose attached to cx-rhamnopyranose as a disaccharide and vancosamine attached to the peptide core.68 Ramoplanin, (A-16686), obtained from Actinoplanes, has been identified as a glycolipodepsipeptide antibiotic, in which a dimannosyl disaccharide (M-D-manp 1+2cc-D-manp+O-tyrosine) is attached to a 17-membered cyclic polypeptide core.69Two new analogues of teichoplanin have been isolated as minor components of the complex from Actinoplanes teichomyceticus,RS-3 and RS-4, which have 6-methyloctanoic and nonanoic acid residues respectively attached as amide substituents to the two glucosamine units which are separately attached to the cyclic peptide core.70 Antibiotic A82846 B, a close relative of eromomycin mentioned above, has been shown to be identical to chloroorienticin A, and its hydrolysis products are identical to those of chloroorienticin B and C (see V O ~ .22, p. 199).71 Eighty N-alkylated vancomycins have been prepared in which vancosamine and/or N-methylleucine is/are substituted; these compounds exhibited greater antibiotic activity that the parent or J-acylated analogues. 72 A complete 13C n.m.r. assignment of peplomycin has been made. It contains a 3 - ~ - c a r b a m o y l - ~ - D - m a n n o s y l - ( l + 2 ~ - ~ - D - g u 1 o sdisaccharyl ide residue attached to an acyclic peptide chain. 73
19: Antibiotics
199
6 Miscellaneous Antibiotics Mannostatins A an B, newly discovered inhibitors of a-D-mannosidase, have been identified as the amino-methylthio-cyclopentanetriol derivatives ( 3 0 ) and (31) NH2
H O I I I . . O ~
(30) R = SMe
(31) R = ?We Hd
%H
Me
0
A novel member of the efrotomycin family of antibiotics,UK-69753, obtained from a Amycolatopsis orientalis strain, has been identified as the 4"-de-O-methyl analogue of efrotomycin, containing the disaccharide unit ( 3 2 ) attached to factumycin, an acyclic polyene amide. 7 6 Another pair of acyclic polyene antibiotics, glucopiericidinols A1 and A*, which contain a ,3-D-glucopyranosyl unit glycosidically linked, have been isolated from a Streptomyces strain (sp. OM-5689). 7 7 Aleurodiscal, an antifungal sesquiterpenoid from Aleurodiscus mirabilis, contains a glycosidically linked p-D-xylopyranose unit. 78 An alkaloid antibiotic, hatomamicin (YL-0358M-A), obtained from a culture filtrate of Saccharopolyspora, is a glycoside of rhodinose.7 9 Calicheamicins, a novel family of antitumour antibiotics produced by Micromonospora echinospora ssp. calichensis, contain the part structure (33); seven components were identified. 80
OMe
tl0
(33) X = Br or I . R = Me, E t , P r L
RHN OMe
Aculeximycin, a new basic glycosidic antibiotic produced by Streptosporangium albidum, includes five monosaccharide units; a branched trisaccharide chain, aculexitriose (341, is accompanied by separate units of D-mannose and L-vancosamine.81 New inhibitors of
200
Carbohydrate Chemistry
cyclic-nucleotide phosphodiesterase, KS-501 and KS-502, have been isolated from the fungus Sporothrix sp. KAC-1985, and shown to contain p-D-galactofuranose as a phenolic glycoside.82
HO +OH
(34)
OH
A complete synthesis of hygromycin A (35) is outlined in Scheme 4.83
Scheme 4
OAc
Coumamidines X1 and 82, isomeric compounds isolated from an Actinomycete strain, have been characterized as the amino-sugar derivatives of a cinnamamide complex; the same carbohydrate units are present in the related cinodines, which are glycocinnamoylsperm84 idines (see Vol. 12, p. 153, ref. 63, structures (15) and (16)). Further work on the structure of the antibiotic complex sporaviridin has been reported (see Vol. 17, p . 181; Vol. 18, p. 186); six components have been characterized, differing in one unit of the viridapentaose chain (see V o l . 18) or in the aglycone, which is a polyhydroxy C47, 34-ring macrolide. 85 9-P-D-Arabinofuranosyladenine 2',5'-cyclic phosphate shows antiviral activity.86 (See also Chapter 20) -K-Nitroso-ureido derivatives of di- and tri-deoxy sugars have been prepared, all of which showed significant antitumour activity; 87 of those compounds synthesized, (36) was most active. A multistep, stereoselective synthesis of (+)-polyoxamic acid ( 3 7 1 , a constituent of polyoxins, employed an aldehydo-L-threose derivative prepared from L-tartaric acid.88 Another synthesis
19: Aiitihiotics
20 1
starting from L-arabinose is noted in Chapter 24. A synthesis of the enzyme inhibitor 2-deoxy-p-KDO is referred to in Chapter 16. Buchanan's group has reviewed its work on the synthesis of the antiprotozoal antibiotic anisomycin, extended to necine bases of the pyrrolizidine alkaloids; routes from D-ribose and D-erythrose to a key pyrrolidine intermediate using highly stereoselective reactions are included 89 L-Arabinose has been used in a new total synthesis of the antibiotic patulin (23% overall yield). 7-2-p-D-Glycosyl-9a-methoxymitosanes (38) have been prepared using glucose, lactose, glucosamine and galactosamine (Koenigs-Knorr conditions), and t h e i r antibiotic activities have been studied.9 1 A dimeric hydrolysable tannin, oenothein B (391, which shows antiturnour and antiviral activity, has been obtained from the leaves of Oenothera erythrosepala 92 3-2-Digalloyl-1 ,2,6- tr i-2-galloylglucose has been isolated from the freshwater alga spirogyra varians, and shown to be an antibiotic and an cc-glucosidase inhib(See also Chapter 7.)
.
' '
.
f
I
1
OH
HO HO
GsU.
HO (is.,
h0
HO Ofl+OH
(39
The biosynthesis of the aglycone of the disaccharide glycosides benanomicins A and B has been studied.94 References 1
2
J.
S.Tohma, H.Kondo, J-Yokotsuka, J.Iwamoto, G.Hatsuhashi, and T.Ito, Antibiot., 1989, 42, 1205. M.Morioka, K.Hotta, D.Ikeda, H.Naganawa, M.Eamada, and Y.Okami, J . Antibiot., 1989, 32 833.
Carbohydrate Chemistry
202
7 8 9 10 11 12 13
14 15 16 17
18
T.Dairi and M.Hasegawa, J. Antibiot., 1989, 42, 934. Y.Miyamoto and S.Ogawa, J. Chem. SOC. Perkin Trans. 1, 1989, 1013. S.Ogawa, Y.Miyamoto, and A.Nakajima, Chem. Lett., 1989, 725. R.Kuhlmeyer, B.Seitz, T.Weller, H.Fritz, R.Schwesinger, and H.Prinzbach., Chem. Ber., 1989, 122, 1729. B.Seitz, R.Kuhlmeyer, T.Weller, W.Meier, C.Ludin, R.Schwesinger, L.Knothe, and H.Prinzbach, Chem. Ber., 1989, 122, 1745. K.Kakinuma. Y.Ogawa, T.Sasaki, H.Seto, and N.Otake, J. Antibiot., 1989, 42, 926. G.Medgyes, G.Jerkovich, J.Kusmann, and P.Fugedi, Carbohydr. Res., 1989, 186, 225. D.R.White and G.A.Cain, Tetrahedron Lett., 1989, 30, 1469. Y.Shibata and S.Ogawa, Carbohydr. Res., 1989, 189, 309. Y.Sawada, T.Tsuno, T.Miyaki, T.Naito, and T.Oki, J . Antibiot., 1989, 42.242. H.Imai, K.Suzuki, M.Morioka, T.Sasaki, K.Tanaka, S.Kadota, M.Iwanarni, and T.Saito, J. Antibiot., 1989, 42, 1000. K.Kinoshita, S.Satoi, M.Hayashi, and K.Nakatsu, J. Antibiot., 1989, 42,1003. K.Kinoshita, Y.Imura, S.Takenaka, and M-Hayashi, J. Antibiot., 1989, 42, 1869. P.Sowinski, P.Gariboldi, A.Czerwinski, and E.Borowski, J . Antibiot., 1989, 42, 1631. T.Adachi, S.Morimoto, Y.Watanabe, N.Kamiya, and H.Iwasaki, J. Antibiot., 1989, 42, 1012. T.Fujiwara, H.Watanabe, Y.Kogami, Y.Shiritani, and H.Sakakibaka, J, Antibiot., 1989, 42, 903. T.Kihara, M.Ubukata, J.U~awa,and K.Isono, J. Antibiot., 1989, 42, 919. K .Tsuzuki, T .Sunazuki, S .Marui, H.Toyoda, S Omura, X , Inatomi, and Z .Itoh, Chem. Pharm. Bull., 1989, 37, 2687. T.Sunazuka, K.Tsuzuki, S.Marui, H,Toyoda, S.Omura, N.Inatomi, and Z.Itoh, Chem. Pharm. Bull., 1989, 37, 2701. K.Kiyoshima, M.Sakamoto, T.Ishikura, Y-Kukagawa, T.Yoshioka, H.Naganawa, T.Sawa, and T.Takeuchi, Chem. Pharm. Bull., 1989, 37, 861. F.Arcamone and S.Penco, Bioact. Mol., 1988, (Anthracycline AnthracenedioneBased Anticancer Agents), 1 (Chem. Abstr., 1989, 111,214815). R.Kind, K.Hutter, A.Zeeck, K.Schmidt-B&e, and E.Egert, J. Antibiot., 1989, 42, 7. A.Kawashim2, Y.Kishimura, M.Tamai, and K.Hanada, Chem. Pharm. Bull., 1989, 37, 3429. C.Munneret, J.C.Florent, F.Bennani, H.H.Sedlacek, and H.P.Kraemer, Actual. 193234). Chim. Ther., 1988, 15, 253 (Chem. Abstr., 1989, D.Horton, W.Priebe, and M.Sznaidman, Carbohydr. Res., 1989, 187, 149. V.Rocherolle, A.Olesker, and G.Lukacs, J. Antibiot., 1989, 42, 1393. E.N.Olsuf'eva, L.G.Aleksandrova, B.V.Rozynov, N.P.Potapova, L.M.Rubasheva, and L.S.Povarov, Antibiot. Khimioter., 1988, 33, 729 (Chem. Abstr., 1989, 111, 58210). J.Rohr, J.M.Beale, and H.G.Floss, J. Antibiot., 1989, 42, 1151. Y.Takagi, N.Kobayashi, T.Tsuchiya, S.Umezawa, T.Takeuchi, K.Komuro, and C.Nosaka, J. Antibiot., 1989, 42, 1318. Y.Takagi, H.-I.fark, T.Tsuchiya, S.Umezawa, T.Takeuchi, K.Komuro, and C.Nosaka, J. Antibiot., 1989, 42, 1315, J.C.Florent, A.Genot, and C.Monneret, J. Antibiot., 1989, 42, 1823. K.Ajito, D.Ikeda, K.Komuro, C.Nosaka, N.Wako, S.Kondo, and T.Takeuchi, J. Antibiot., 1989, 42, 1133. J.V.Jizba, P.Sedmera, V.Prikrylova, J.Vokoun, K.Mikulik, and Z.Vanek, Collect. Czech. Chem. Commun., 1989, 2, 1104. E.Fontana, A.Suarato, M.Caruso, and G.P.Vicario, J . Labelled Compd. Radiopharm., 1988, 2, 1129 (Chem. Abstr., 1989, 111,39744). F.De Angelis, R.Nicoletti, L.W.Bieber, and B.Botta, Biomed. Environ. Mass Spectrom., 1988 (Publ. 1989), 2, 553 (Chem. Abstr., 1989, 111, 195271). J.B.K.Nielsen and B.H.Arison, J. Antibiot., 1989, 42, 1248. S.Ozaki, T.Akiyama, Y.Ike, H.Mori, and A.Hoshi, Chem. Pharm. Bull., 1989, 37, 3405.
-
-
~
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
.
a
u,
19: Antibiotics 40
41 42 43
44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
60 61 62 63 64 65 66 67
68 69 70 71 72
203
J-Yamashita, S.Takeda, H.Hatsumoto, N.Unemi, and M.Yasumoto, J. Med. Chem., 1989, 32, 136. K.Ramasamy, R.V.Joshi, X.K.Robins, and G.R.Revankar, J. Chem. SOC. Perkin Trans. 1, 1989, 2375. K-Ramasamy, R.K.Robins, and G.R.Revankar, J. Chem. SOC., Chem. Commun., 1989, 560. J.D.Anderson, R.J.Bontems, S.Seary, H.B.Cottam, S.B.Larson, S.S.Katsumoto, D.F.Smee, and R.K.Robins, Nucleosides Nucleotides, 1989, 8, 1201. S.H.Krawczyk and L.B.Townsend, Nucleosides Nucleotides, 1989, 8, 97. M.M.Mansuri, J.E.Starrett,Jr., I.Ghazzouli, M.J.M.Hitchcock, R.Z.Sterzycki, V.Brankovan, T.-S.Lin, E.?I.August, U.H.Prusoff, J.-P.Sommadossi, and J.C.Martin, J. Ned. Chem., 1989, 32, 461. F..J.Suhadolnlk, J.C-Hanvey, S.Pornbanlualap, J.M.Wu,K.N.Tiwari, A.K.Hebbler, and D.C.Baker, Nucleosides Nucleotides, 1989, 8, 983. M.S.Wolfe, D.R.Borcherding, and R.T.Borchardt, Tetrahedron Lett., 1989, g, 1453. M.Yoshikawa, Y.Okaichi, B.C.Cha, and I.Kitagawa, Chem. Pharm.Bull., 1989, 37, 2555. D.R.Deardorff, M.J.Shulman, and J.E.Sheppeck 11, Tetrahedron Lett., 1989, 30, 6625. A.Hutchinson, M-Grim, and J.Chen, J. Heterocycl. Chem., 1989, 26, 451. M.Bodenteich and V.E.Marquez, Tetrahedron Lett., 1989, 30, 4909. C.K.H.Tseng, V.E.Marquez, R.W.Fuller, B.M.Goldstein, D.R.Haines,H.McPherson, J.L.Parsons, W.M.Shannon, G.Arnett, M.Hollingshead, and J.S.Driscol1, J. Med. Chem., 1989, 32, 1442. S.D.Paisley, M.S.Wolfe, and R.T.Borchardt, J. Med. Chem., 1989, 32, 1415. R.J.Parry, V.Bornemann, and R.Subramanian, J. Am. Chem. SOC., 1989, 111,5819. S.J.Danishefsky, S.L.DeNimmo, S.Chen, L.Boisvert, and M.Barbachyn, J. Am. Chem. SOC., 1989, 111, 5810. P.Garner and J.M.Park, Tetrahedron Lett., 1989, 30, 5065. H.Heitsch, W.A.Kgnig, H.Decker, C.Bormann, H.-P.Fiedler, and H. Zghner, J. Antibiot., 1989, 42, 711. J.A.Matson, C. Claridge, J.A.Bush, J.Titus, W.T.Bradner, and T.W.Doyle, J. Antibiot., 1989, 42, 1547. J.Golik, T.W.Doyle, B-Krishnan, G.Dubay, and J.A.Matson, J. Antibiot., 1989, 42, 1784. S.Hanessian, J.Kloss, and T.Sugawara, ACS Symp. Ser., 1989, 386 (Trends Synth. Carbohydr. Chem.) 64 (Chem. Abstr., 1989, 111, 23873). J.G.Buchanan, J.Stoddart, and R.H.Wightman, J. Chem. SOC., Chem. Commun., 1989, 823. M.Honjo, T.Maruyama, Y.Sato, and T.Horii, Chem. Pharm. Bull., 1989, 37, 1413. Y.Ichikawa, A.Narita, A.Shiozawa, Y.Hayashi, and K.Narasaka, J. Chem. SOC., Chem. Commun., 1989, 1919. W.A.Slusarchyk, M.G.Young, G.S.Bisacchi, D.R.Hockstein, and R.Zahler, Tetrahedron Lett., 1989, 30, 6453. Y.Araki, T.Endo, Y.Arai, M.Tanji, and Y.Ishido, Tetrahedron Lett., 1989, 30, 2829. G.F.Gause, M.G.Brazhnikova, N.N.Lomakina, L.E.Gol'berg, A.V.Laiko, G.B.Fedorova, and T.F.Berdnikova, Antibiot. Khimioter., 1989, 34, 348 Abstr., 1989, 111,20621). G.F.Gause, M.G.Brazhnikova, N,N.Lomakina, T.F.Berdnikova, G.B.Fedorova, N.L.Tokareva, V.N.Borisoya, and G.Y.Batta, J. Antibiot., 1989, 42, 1790. E.Riva, L.Gastaldo, M.G.Beretta, P.Ferrari, L.F.Zerilli, G-Cassani, E.Selva, B.P.Goldstein,M.Berti, F.Parenti, and M.Denaro, J. Antibiot., 1989, 42, 497. R.Ciabatti, J.K.Kettenring, G.Winters, G.Tuan, L-Zerilli, and B.Cavalleri,, J. Antibiot., 1989, 42, 254. A.Borghi, P-Antonini, M.Zano1, P.Ferrari, L.F.Zerilli, and G.C.Lancini, J. Antibiot., 1989, 42, 361. R.Nagarajan, D.M.Berry, and A.A.Schabe1, J. Antibiot., 1989, 42, 1438. R.Nagarajan, A.A.Schabe1, J.L.Occolowitz, F.T.Counter, J.L.Ott, and A.M.Felty-Duckworth, J. Antibiot., 1989, 42, 63.
(m.
204 73 74 75 76 77 78 79 80 81 82 83
84 85 86 87 88 89
90 91 92 93
94
Carbohydrate Chemistry H.Naganawa, Y.Kadokura, Y.Muraoka, T.Nakatani, and T.Takita, J. Antibiot., 1989, 42, 633. H.Morishima, K.Kojiri, T.Yamamoto, T.Aoyagi, H.Nakamura, and Y.Iitaka, J. Antibiot., 1989, 42, 1008. T.Aoyagi, T.Yamamoto, K.Kojiri, H.Morishima, M.Nagai, M.Hamada, T.Takeuchi, and H.Umezawa, J. Antibiot., 1989, 42, 883. M.R.Jefson, J.Bordner, C.P.Reese, and E.B.Whipple, J. Antibiot., 1989, 42, 1610. S.Funayama, M.Ishibashi, Y.Anraku, M.Miyauchi, H.Mori, K.Komiyama, and S.Omura, J. Antibiot., 1989, 42, 1734. U.Laver, T.Anke, W.S.Sheldrick, A.Scherer, and W.Steglich, J. Antibiot., 1989, 42, 875. H.Imai, S.Fujita, K.Sumki, M.Morioka, T.Tokunaga, M.Shimizu, S.Kadota, T.Furuya, and T.Saito, 3 . Antibiot., 1989, 42, 1043. M.D.Lee, J.K.Manning, D.R.Williams, N.A.Kuck, R.T.Testa, and D.B.Borders, J. Antibiot., 1989, 42, 1070. H.Murata, K.-I.Harada, M.Suzuki, T.Ikemoto, T.Shibuya, T.Haneishi, and A.Torikata, J. Antibiot., 1989, 42, 701. S.Nakanishi, K.Ando, I.Kawamoto, and H.Kase, J. Antibiot., 1989, 42, 1049. N.Chida, M.Ohtsuka, K-Nakazawa, and S.Ogawa, J. Chem. SOC., Chem.Commun., 1989, 436. R.H.Chen, D.N.Whittern, A.M.Buko, and J.B.McAlpine, J. Antibiot., 1989, 42, 533. K.-I.Harada, I.Kimura, T.Sakazaki, H.Murata, and M-Suzuki, J. Antibiot., 1989, 42, 1057. L.Zhang, F.Wang, C.Wang, G.Lin, and L.Ma, Yiyao Gongye, 1988, 19, 154 (M. Abstr., 1989, 110,57981). P.Roger, C.Monneret, J.-P.Fournier, P.Choay, R.Gagnet, C.Gosse, Y.Letourneux, G.Atassi, and A.Gouvette, J. Med. Chem., 1989, 32, 16. 1.Savage and E.J.Thomas, J. Chem. SOC., Chem. Commun., 1989, 717. J.G.Buchanan, A.R.Edgar, B.D.Hewitt, V.B.Jigajinni, G.Singh, and R.H.Wightman, ACS Symp. Ser., 1989, 386 (Trends Synth. Carbohydr. Chem.),l07. J.A.Seijas, M.P.Vasquez Tato, R.Estevez, L.Castedo, and R.Riguera, Heterocycles, 1989, 2, 181. K.Furuhata, K.Komiyama, K.Takeda, H.Takayanagi, K.Torii, K.Mishima, H.Ogura, and T.Hata, Chem. Pharm. Bull., 19e9, 37, 2651. T.Hatano, T.Yasuhara, M.Matsuda, K.Yazaki, T.Yoshida, and T.Okuda, Pharm. Bull., 1989, 37, 2269. R.J.P.Cannel1, P.FarEr, and J.M.Walker, Biochem. J., 1988, 255, 937 Abstr., 1989, 110,20373 ). S.Gomi, M.Sezaki, M.Hamada, S.Kondo, and T.Takeuchi, J. Antibiot., 1989, 42, 1145.
m.
(w.
20
Nucleosides
A new cytokinin, the 2'-deoxy-derivative (1) of zeatin riboside, has been
isolated from the culture filtrate of Pseudomonas amygdati; it was also synthesised conventionally, together with its a-anomer. 1 3-Methyluridine2 and 5'-deoxyxanthosine3 have been isolated from normal human urine. The 4-pyridone nucleoside (2) has also been isolated from the same source: the analogous 2-pyridone, which had been previously synthesized (Vol. 19, p.194). was also found, and was prepared by oxidation of nicotinamide mononucleotide with ferricyanide followed by treatment with phosphatase.4 3-Hydroxyuridine. isolated from the rain forest tree BaiZZoneZZa toxisperma, has potent plant growth regulatory properties.5 Me d C H Z O H
OH
1
0
(1)
Svnthesis
A two-part review has been published, in Russian, on the use of
monosaccharides in nucleoside synthesis.6 The use of the sodium-salt glycosylation procedure for synthesis of p-Dribofuranosyl. -arabinofuranosyl and 2-deoxy -P-D-ribofuranosyl systems has also been reviewed,' and this technique has been applied to the preparation of pyrazolo[3,4-b]pyridine nucleosides (3)(together with Z'-deoxy- and arabinoanalogues),8~9and pyrrolo[3,2-c]pyridines such as 3-deazatubercidin (41,l o p 1 The protected imidazole where again 2'-deoxy systems were also prepared. nucleoside (5)was made in a similar manner, and reaction with hydrazine then led to the imidazo[4,5-d]pyridazinone(6)(2-aza-3-deazainosine). l2 Conventional condensation procedures have been used to prepare 2pyridone nucleosides of type (7). l 3 6-aza- and 2-thio-6-azauracil derivatives of type@),14 1-P-D-ribofuranosyl derivatives of nitrobenzimidazoles, 5 chloroindazoles, 16 and 6- and 7-p-chlorophenyllumazines. 17 and 2-
206
Curhohydrate Chemistty
CHO
I
p -D -RLb ,F
I
p - D - ~ i b -(oA,]~ _~
-
I
D - R Lb-f (OBZ)~
p -0-RLb-f
P-0-RLb- f (4)
(3)
p
I
(5)
(6)
I
P-D-RLb f (7) R = NH20rOEt
I
(8) X = 0,s (9) (10) (1 '1 methylthiopteridine-i@-ribosides, from which 8-~-D-ribofuranosylleucopterin (9)was available.'8 Conditions have been found for the formation of the I@isomer (10)as major product of the ribosylation of the pyrazino[2,3-c]l.2,6-
thiadiazine dioxide. 19 The pyrroloquinoline (1 11, and the P-D-glucopyranosyl analogue, have been prepared by M n 0 2 oxidation of the 2,3-dihydro derivatives,20 whilst the pyridine derivative (12) has been reported as formed by reaction of 2-aminopyridine with the 1'-0-tosyl sugar derivative, 4-aminopyridine also giving the analogous product.21 The pyrido[2,3-d] pyrimidine nucleoside ( 13). and related pyrrolo[2,3-d]pyrimidinesystems have been prepared by ribosylation of 1 -benzyl-6-chlorouracil and annulation of the second ring using Pd(I1) dehydrocyclization.22 M.J.Robins has reviewed his group's work on methods for obtaining high yields of the A@-regioisomersin the formation of guanine nucleosides (see Vol. 21, p.201). and for kinetic formation of the fl-isomers (see also Vol. 22. p. 206).23 R.K. Robins and coworkers have also described the highly regioselective formation of (14) by Vorbruggen-type coupling, and its use for making guanosine and inosine analogues.2* The N7-ribosylated derivatives ( 1 5) of N3-methyl guanosine were prepared by fusion or chloromercuri methods, o&No2
0
0
X
20: Nucleosides
207
and the @-isomer (made from an imidazole nucleoside) underwent thermal rearrangement to ( 15L25 The N,N,3-trialkyl adenosine derivatives ( 16, R=Me,Et) were prepared by SnC14-catalysed glycosylation; the @-ethyl compound underwent hydrolysis to the imidazole (17).26 Enzymic methods of nucleoside synthesis continue to attract attention, and the synthesis of radiolabelled ribo- and deoqribonucleosides by transglycosylation catalysed by crude E.colt homogenates has been reviewed.27 A promising method for the enzymic synthesis of nucleosides is illustrated by the example of virazole synthesis in Scheme 1: the use of I”-methyl guanosine
,B - D -Rib-f R e c ~ g e n t s: I, P u r i n c n ~ 4 e o s i d ephosphorylo-se
Scheme I
makes the reaction essentially irreversible, and this method removes the need for the use of more than one enzyme or for the isolation of the intermediate ribose- 1-phosphate. 3-Deazaadenosine could be prepared similarly in good yield.28 8-Azaguanosine, 14C-labelled in the sugar, was prepared in a two-step enzymic method from (U-l4C]-inosine,29 and ribo-, 2-deoqribo- and arabinofuranosyl nucleosides of the purines azathioprine and thiamiprene have been prepared enzymically by glycosyl-transfer procedures from uracil or thymine n u c l e o ~ i d e s . ~ ~ 6-Amino-5-azacytidine (18)has been prepared by a process of building up the heterocyclic ring on a protected ribosyl isocyanate,3l and some 2-substituted 5-amino-ribofuranosyl imidazoles have been synthesized by Shaw’s methods from the ribofuranosylamine.32 Both chemical and microbiological methods have been used for the
Carbohydrate Chemistry
208
synthesis of 1-(p-D-arabinofuranosyl)thymine,33 and the pyrazolopyrimidine ( 19) has been synthesized by oxidation-reduction of a 3'.5'-TIPDS-derivative.34 Solid-liquid phase transfer glycosylation has been used for preparation of l-(~-~-arabinofuranosyl)pyrrolo[3,2-clpyridines (and some related 2'-deoxyand 2',3'-dideoxy systems: see also Vol. 21. p.206).35 9-(P-D-Xylofuranosy1)adeninehas been prepared by regiospecific opening of the 2',3'-ribo-epoxide with KCNO in acetonitrile containing BF3 and a crown ether.36 and also by an oxidation-reduction sequence at C-3' of a suitablyprotected adenosine derivative.3' Triflate displacement at C-2' of a suitable derivative of xylofuranosyladenine was used in a new high yielding synthesis of 9-(P-D-lyxofuranosyl)adenine.38 The P-D-glucopyranosyl conjugates (20) of some common barbiturates have been synthesized conventionally,39 and N1-a-.hn-p-. M-P-.and N1,I@bis-D-glucopyranosides of allopurinol (21) have been reported.40 A number of P-D-glycopyranosyl pyrrolo(2.3-d]pyrimidines such as (22) have been prepared a by annulating the pyrrole ring onto a (glycopyranosylamino)py~imidine;~1,*2 sequence of nitrosation-reduction-diazotizationof these intermediates gave rise to P-D-glycopyranosyl u~-triazolo[4.5-d]pyrimidines.41 A further report has appeared dealing with 'glycosyl-0-N analogues of nucleosides (see Vol. 22. p. 207).43 2
Anhvdro- and Cvclonucleosides
2,5'-Anhydro-2-thiouridine (23) has been prepared by Mitsunobu reaction as indicated in Scheme 2. I t had been hoped that, after selective acylation at0-3', nucleophilic displacements might be possible at C-2'. but the rearranged 2,2'-cyclonucleoside (24) resulted during reaction with triflyl chloride: similar findings have been observed earlier for the oxygen-bridged analogues (V01.2 1, ~.203).~~ 0
p-D- Rib-f 1
0Ac (24)
i, Ph,P,
DEAD ; u, 6u2Sn0,M e O H ,iu, Ac$,
LV,
TFCL,Py,Et+J,DMAP
Scheme 2
Treatment of the 3'-phenylselenoyl -2'- ene (25) (see Sect. 6) with dimethylamine gave the 2,2'-anhydrouridine derivative (26); by analogy with reactions of (25) with primary amines (Sect. 5). a 2'.3'-aziridinium
20: Nucleosides
209
intermediate is most likely involved.45 Some 6,2'-anhydrouridines of type (27) have been prepared from their parent barbiturates and 1-0-acetyl -2.3.5-tri-0benzoyl P-D-ribof~ranose,~6 and 2'-deoxy-8,2'-methanoguanosine (28) has been synthesized by the same method as was used (V01.20, p.206) for the adenosine andogue.47 M M T r O $H2
NMe2
(26)
OH
(27)
Various 2,3'-anhydro-2'-deoxypyrimidine nucleosides (29) have been prepared by cyclization of the 5'-O-protected deoxynucleosides with DAST or related r e a g e n t ~ ; ~ some *~~ further ~ references to the synthesis and use of 2,3'-anhydrothymidine derivatives are mentioned in Sections 4 and 5. The 2,3'-iminopyranosyl nucleoside (30)was produced by base-catalysed ring expansion of the furanosyl anal0gue.5~and a similar process occurred when 5'-alkylamino compounds (31). made from uridine in three steps, were treated with alkali to give the piperidine nucleosides of type (32).51 A number of 2,5'-anhydro- derivatives of AZT and similar compounds with other substituents at C-5 have been prepared by base-catalysed cyclization of 5'-0-tosylates.52 When the 5'-O-tosyl derivative of 2',3'-O-isopropylidene adenosine was treated with MezCuLi. the product was unexpectedly the
(29)
R
= H or Me R'=% or MMTr
(31) R = Me, B n
(30)
X = O o r N H
R
NC
0
X0 (33)
O x 0
(34)
(32)
210
Carbohydrutr Chemistry
imidazole cyclonucleoside (33). Also, when isopropylidene nebularine was treated with acetyl chloride in pyridine, the cyclic product (34, R=Ac), confirmed by X-ray, was obtained as the only isolable product: use of TsCl led to the formation of (34, R=Ts). together with the 8-epimer and the expected 5'-O-tosyl derivative.53 The 6,5'-methano-linked uridine (35)has been prepared as indicated in Scheme 3.54 The strained, doubly-bridged compound (36) (Scheme 4) underwent ready hydrolysis under acidic or basic conditions to give the 2',5'-imino system (37). which under further basic conditions gave the Michael adduct (38).55
yyMe- p... -
CHO
L -LV
v-VUI.
6
J
ReageriLs VL,
b, OL D x A 0, TMS
Ac,o , E t 3 ~, VLL,
3
OH
J i N
OMo ,&) AcCL,EtNPr:,
S n C L + , wlr NUOH
U, B u q N F ,
W,
H1, W / C ,V, H304,
OH (35)
aq
Scheme 3
Deoqmucleosides
Solid-liquid phase-transfer glycosylation has been used to prepare 2'deoxyribonucleosides of pyrrolo[2,3-blpyridines and indoles.56 further pyrrolo[2,3-d]pyrimidines.57and nitrobenzimidazoles.58 with a further report appearing on this route to 2-deoxyribonucleosides of pyrazolo[3,4-d] pyrimidines (see V01.22, p. 209).59 A study has been made of the regio- and stereoselectivity of the reaction between 2-deoxy- 3,5-di-O-to~uoyl-a-D-erythropentofuranosyl chloride and the ambident bases 2-pyridone. 4-pyridone, and 2pyrimidinone: kinetically-controlled reactions gave mainly 0-glycosides, which could be isomerized in acid to the N-linked products.60 The same pentosyl chloride was used to prepare 2-deoxyribofuranosides of some triazol0[4,5-d] pyrimidines (39)via the sodium salts: the process was P-selective. but also gave N1-and N2-regioisomers.61 TWO procedures have been reported to effect condensation between adenine and furanosyl chlorides so as to give
20: Nuclrosides
21 I
stereoselectively the P-isomer of 2'-deoxyadenosine, but only in moderate yields.62.- In the pyrimidine series, condensation of silylated uracils and 6azauracils with 2-deoxy-3,5-di-O-toluoyl-a-D-enrthro pentofuranosyl chloride gave high proportions and high yields of the P-isomer when carried out in chloroform in the presence of CuI,G4 whilst the reaction of (40) with bis(trimethylsily1)thymine and TMSOTf was also highly P-selective; the bulky 3'-O-blocking group could be removed by base treatment.65 Transglycosylation of 2'-deoxy-2'-3H-uridine with 5-halouracils, catalysed by pyrimidine nucleoside phosphorylase, was used to prepare the labelled 2'deoxy-5-halouridines.66 and 15N-enriched 2-aminopurine-2'deoxyribonucleoside has been prepared enzymically from the labelled base.67 The imidazole deoxynucleoside (41) was prepared by biotransformation from the base and 2'-deoxyuridine. along with about half as much of the I@regioisomer; chemical synthesis gave a mixture of regio- and stereoisomers.68
'is...
CH20Dn HO
I
OH
(39)
Swern oxidation and subsequent reduction was used in an improved route to [5'-2H]-labelled thymidine.69 A study of the reaction of 1,3,4-tri-0-benzoy1-2-deo~-~-D-ribopyranose with bis(trimethylsily1)thymine has confirmed that the stereo- and regioselectivity are catalyst-dependent.70 An oxidation-reduction sequence was used to invert stereochemistry at C-3' in a preparation of some 2'-deoxy-P-D-threo-pentofuranosyl pyrrolopyrimidines (42, R=OH).71 A hydride shift process (Scheme 5) was used to make 3'-deoxy-P-~-fhreo-pentofuranosyl nucleosides of type (43),72 whilst a similar process is involved in the formation of (43,B=Ad) by treatment of 2',3'-di-O-tosyladenosine with LiEt3BH; the same product (43,B=Ad) was also obtained, in higher yields, by the same reduction of the analogous D-arabinoand D-k~xesysterns.~~
Reagents : i, N ~ o N N~ ,~
B H ~
Scheme 5
212
Curhohydrate Chemistry
The synthesis of 2',3'-dideoxynucleosidescontinues to attract attention. The synthon (44) has been used to give P-selective condensation with silylated bases: reductive desulphurization then gave 2'.3'-dideoxy systems.73 Deoxygenation procedures have been used to prepare 2',3'-dideoxy- and 2'.3'dideoxydidehydro nucleosides of 2-substituted adenines,74.75 pyrrolo[2,3-d] pyrimidines (42, R=H),56*71and further pyrazolo[3.4-d]pyrimidines.59 Enzymic
bOAC pJ.&UpJ
CH2 0 SL$
CHZOMS
0 Ms
S Ph Recrg&3
(44)
:
L,
NaOc(,H20
CH OH
(45)
; u , base, 9 M S O
transglycosylation with the broad-specificity transglycosidase from Lactobacillus heluiticus has been used to make diverse purine and pyrimidine 2',3'-dideoxynucleosides.76 The potent anti-HIV agent 2',3'-didehydro-2'.3'-dideoxythymidine (d4T. 45) has been prepared in a high-yielding way as indicated in Scheme 6,77 whilst the 5'-0-tritylderivative of (45) has been made by treatment of the 2.3'-anhydronucleoside (29, R=Me, R=Tr, X=O) with CsF in DMSO.78 A range of 2'.3'-didehydrodideoxy nucleosides, and the corresponding saturated hydrogenation products, have been made by BusSnH reduction of 2',3'-bisxanthates or cyclic thionocarbonates.79 and 2',3'didehydrodideoxyuridine is accessible via Corey-Winter reaction on a 5'-0protected uridine thionocarbonate.*O A reference to such derivatives of the pyrrolopyrimidine nucleoside antibiotics is discussed in Chapter 19, and various truncated analogues of type (46) have been reported.81 A new convenient synthesis of 5'-deoxy-~-~-ribo-hexofuranosyladenine('homoadenosine',47) involves the preparation of an appropriate deoxyhexose derivative from D-glucose. and conventional nucleoside synthesis.82 Some 2'.6'-dideoxyhexose nucleosides of thymine have been prepared by hydride reduction of chloroderivatives .83 Methods have been reported to differentiate between isomeric 2'. 3'-, and 5'-deoxynucleosides using E.I. and (2.1.-linked scanning mass spectrometry.84 4
Haloaenonucleosides
A rapid synthesis of 2'-deoxy-2'-fluoroadenosineinvolves the use of DAST on a suitably protected ara-A derivative.85 A number of purine nucleosides moiety (48) have been containing the 2'-deoxy-2'-fluoro-~-~-arabinofuranosyl
prepared from glycosyl bromide and purine bases: the guanosine analogue (48,
213
20: Nucleosides
B=Gua) shows promising antileukaemic activity.86 The 2',2'-difluoro- analogues of 2'-deoxyadenosine and -guanosine have been made by methods similar to those used previously for pyrimidine analogues (Vol. 22, p. 2lO),87 and, by introducing a conventional deoxygenation, this chemistry could be adapted for the synthesis of 2'.3'-dideoxy-2',2'-difluorocytosine.88Treatment of a
O B U W U U CH 2CH2OH
CH$H
CHzOH
CH20H
OH
F
OH
OH
(47)
F
(40)
F
F (51)
OH
(52)
R
(50)
(49)
0CHzOH
CH2 OH
F
F OH
OH
(53) R=OH
(54) R = H
(55)
3-ketosugar with DAST was used during a synthesis of 2',3'-dideoxy-3',3'difluorocytosine and -uridine (49. B=U or ( 3 . 8 8 Other workers have reported the corresponding thymidine analogue (49, B=T), and its conversion by methoxide to the unsaturated fluoronucleoside (50). This paper also reports a variety of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides,with the uridine derivative (51)displaying good anti-HN activity.89 The Leiden group have also reviewed earlier methods for the introduction of fluorine into nucleosides,g0 and given further examples of the use of DAST to produce 3'-deoxy-3'fluoronucleosides (52) from xylo-compounds.90~91 Other workers have also reported the synthesis of the guanosine analogue (52, B=Gua), by a similar halogenation with inversion using DAST,g2 whilst a number of compounds of type (52) have been made by conventional nucleoside synthesis from a 3-deoxy3-fluoro-ribose derivative.93.94 The D - x y b analogue (53)has also been synthesized by base-sugar coupling, and a deoxygenation step gave the 2'-deoxy compound (54).95 3'-Deoxy-3'-fluorothymidine (55, B=T)has also been made by a DAST reactiong6 and both it and the uridine analogue (55, B=U) can be prepared by fluoride-ion opening of a cyclonucleoside of type (29).96*97 When a series of 8-substituted adenosines was treated with thionyl chloride in HMPA, the corresponding 5'-chloro- 5'-deoxy compounds were obtained in moderate to good yields.98 When 2'-deoxyuridine was treated with benzoyl chloride in DMF. 5'-chloro-2'. 5'-dideoxyuridine was formed slowly, whereas the same reagents in the presence of MCPBA gave rapid chlorination of the heterocycle to give 5-chloro-2'-deoxyuridine.Several other similar cases were also reported.99 The unsaturated compound (56).and its (2)-isomer,
214
Carbohydrate Chemistry
have been synthesized and shown to be powerful inhibitors of Sadenosylhomocysteine hydrolase. 100 p-D-Glucopyranosyltheophyllinehas been converted into its 6'-deoxy-6'fluoro- analogue, and fluorine was also introduced using DAST into the same starting material at C-3' and C-4'. with inversion of configuration, to give p-Dalb- and -D-gUlUCtO- products, respectively. 101
5
Nucleosides with Nitrogen-substituted SUEt3l-S
A new route to the antineoplastic nucleosides 2'-azido- and 2'-amino-2'-deoxyP-D-arabinofuranosykytosine(57) involves the reaction of the uridine derivative (58)as indicated in Scheme 7; the N-benzoyl group prevents intramolecular 0
vt
CH20H 4 - 5 steps
OH
(57) x = N, or
N H ~
Scheme 7
participation of 0-2 during the Mitsunobu reaction. 102 A similar displacement was used to prepare the analogues in the 2-alkylpurine series: in this case the inversion at C-2' was carried out on a protected imidazole nucleoside, and the pyrimidine was annulated at a late stage.103 A paper describing the synthesis of 2'-azido-2'-deoxy-~-~-xylofuranosyluracil (Vol. 2 1, Chapter 20, ref.68) has been reprinted with two previously-omitted pages now present. lo4 A range of monoand diaminoderivatives of 2I-deoxyadenosine. cordycepin (3'-deoxyadenosine), and their P-D-threO-andOgUeS have been prepared, using standard hydroxyl + a i d e conversions with inversion of configuration. 105 An efficient synthesis of 3'-amino-3'-deoxyadenosine (59) proceeds from the ribo-epoxide as indicated in Scheme 8.106 A route to 3'-acetamido-3'deoxy-P-warabinofuranosyladenineinvolves opening of the D-lyxo-epoxide at
oAd DA' oA*
CH20H
b,L
Ph BZ+.O~H, ph
l.4
,w
9h BLA.!~L 0 CH2 Ph
CHZ O H
v-VLL.
___f
0
OH
DnN
0
NHz
OH
20: Nucleosides
215
C-3'by potassium I~ocyanate.~6 The diaminopurine analogue (60)of AZT, which displays good anti-HNactivity, has been made as indicated in Scheme 9 using a 1.2-hydride shift.107 The same sort of approach has been used by other workers to prepare the corresponding adenosine analogue (61). and this paper also gives a full account of the use of such chemistry to make 2'-azido-2',3'dideoxyadenosine (see Vol. 21, p.208).'o8 Diamino analogue (60)has also been prepared from a 2'-deoxyguanosine precursor, where inversion of configuration at C-3'was accomplished by intramolecular participation of a 5'-O-benzoyl group (Scheme 10).109 This approach can similarly be used to make (61).110
-
OMS
ru3/
OH
OH
2'
N3
(60) R = N Y 2
A new direct route to AZT (62) via the anhydroderivative (63) is shown in Scheme 11,111 and other workers have used compounds of type (63)/(29) to and related systems. 112.113 prepare AZT,3'-amino-3'-deoxythymidine, Dehydration of N-formyl derivatives of 3'-amino-3'-deoxythymidinehas been 0
S c h e m e 11
Carbohydrate Chemistry
216
used to make the 3-isocyanocompound.113~1~4 An alternative approach to 3'-amino-3'-deoxythymidine is indicated in Scheme 12;115 this work has also been carried out in the enantiomeric series starting from L-arabinal'lG and extended to the synthesis of 3'-aminohexofuranosyl nucleosides. 117
3'-azido/amino-3'-deoxy-(64) and 5'-azido/amino-5'-deoxyanalogues (65) of 5-methoxymethyl-2'-deoxyuridine have been prepared by sulphonate displacement: their conformations were studied, and the 5'-aminocompound was found to have a considerable proportion of the syn-rotamer.118 Two papers on the phosphonate analogue of AZT monophosphate are mentioned in Section 11. Treatment of the selenoylalkene (25) with various primary amines has led to a range of 2',3'-epiminocompounds (66);45this result may be compared with the analogous sulphonyl case reported last year Wol. 22. p. 210-21 1). The 5'-alkylaminoadenosine (67) has been synthesised from adenosine, and found to be a potent irreversible inhibitor of S-adenosyl-L-methionine decarboxylase. 119 A range of N-acyl derivatives (68).and corresponding N-sulphonyl compounds, have been prepared as viral thymidine kinase inhibitors. 120 6
Thio- and Seleno-nucleosides
In contrast to the case of uridine derivatives noted above.80 attempts to carry out a Corey-Winter fragmentation of N4.5'- protected cytidine 2',3'thionocarbonates caused isomerisation to 2'-deoxy-2'-thiocytidine-2',3'carbonates (69).121 The 3'-thiomethyl-. methylsulphinyl-. and methylsulphonyl derivatives of 3'-deoxythymidine have been prepared by treatment of the 5I-O-trityl derivative of (63) with methanethiolate ion, followed by oxidation at sulphur and deprotection as appropriate. 122 5'-Deoxy-5'-(cyclopropylmethylthio)adenosine (70) has been prepared from 5'-chloroadenosine,123 and there has been a further report on the (7 1). formed with the 5'-fluoro-5'synthesis of 5'-(fluoromethy1thio)adenosine methylthio compound discussed last year (see V01.22, p. 212) from reaction of the 5'-methylsulphinyl derivative with DAST. Thioether (71) is a potent inhibitor of methylthioadenosine phosphorylase. 124 An oxidation-reduction
20: Nucleosides
c" '
217
PHCOR'
N / ~ O
ROCH,
OKS
G;: d
CH2S CHZF
OH OH
OH OH
pJq $J /&T .
C HZSePh
. p
CH2 Se Ph
053
(72) (71) (731 * (69) sequence has been used to convert 5'-deoxy-5'-methylthioadenosineinto its (70)
3'-epimer, a natural product (V01.21, p.209).125 The 3'-phenylselenoyl-2',3'-ene (25)has been prepared by ring-opening of a 2',3'-Zyxo-epoxide with PhSeLi, followed by elimination and oxidation at ~ e l e n i u m . ~The 5 applications of (25)in synthesis are mentioned in Sections (72) and (73) have been 2. 5,and 7. The 5'-deoxy-5'-phenylselenonucleosides obtained by ring-opening of an oxetan and an oxolane, respectively.126 7
Nucleosides with Branched-chain Sugars
An interesting ring expansion has been observed when tribenzoyl-oxetanocin
(74) is treated with Lewis acids, giving (75).127 A similar process also occurred when the N-benzoyl-0,O-diacetyl analogue of (74) was treated with stannic chloride and bis(trimethylsilyl)uracil,giving a mixture of the 0,Odiacetyl analogue of (75)and the equivalent compound in which transglycosidation had occurred to give the uracil nucleoside. 128 In an account of a review lecture, Ueda has covered the work of his group on 2'-C-methyl and -methylidene derivatives of cytosine and thymidine (see V01.22, p.213, and earlier volumes).129 The same group has also reported the synthesis of 2'.3'-dideoxy -3'-methylidene thymidine (76) and the isomeric 2'.3'-didehydro-2',3'-dideoxy-3'-methylthymidine (77). both of which were obtained by deoxygenation of the allylic alcohol system in 3'-deoxy-3'methylidene-S-methyluridine. 130 When MeMgI reacted with a protected 3'ketonucleoside. subsequent deprotection gave (3'-C-methyl-P-~-qZo furanosy1)adenine (78)as the major product, along with lesser amounts of the epimer, 3'-C-methyladenosine. The orientation of the methyl group affected the sugar conformation (n.m.r.1: (78) had a predominant 3T2 shape, whilst the
218
Curbohydrutc Chemistry
k:y
CHZOH
Me
i<
OH
(79)
(79)
epimer adopted a 2T3 arrangement.131 The Madrid group has given further details of their work on the synthesis of 3'-cyano-3'-deoxyt.hymidine and related compounds (Vol. 22. p. 214), with extensions to similar analogues containing the other nucleoside bases, 132 and another synthesis of 3'-cyano-3'-deoxythymidineitself has been reported, in which bis-TMS-thymine was coupled with a preformed C-cyan0 sugar unit: the product was again found to be inactive against HIV.in contrast to the initial reports.133 Products of type (79, X = -NHMe, morpholino-. -CH2N02) have been obtained by Michael additions to a 3'-cyano-5'-protected -2',3'-ene: the D - X ~ Z O isomers shown predominated, except in the case of addition of ammonia, where the cis-(D-ribo)-product was the major. 134 Deoxyadenosine has been converted into 3'-cyano- 2',3'-dideoxyadenosine and its 3'-epimer, and these were converted via DIBAL reduction into the branched-chain aldehyde (80)and its epimer, 135 whilst two groups have synthesized C-ally1 compounds of type (81, B = U,T,C) by coupling of C-3' free radicals with alkyltributyl stannane;136e137the free radicals could also be added to methyl acrylate and acrylonitrile to give the expected a-adducts.137 An interesting 'homo-Ferrier' reaction has been used to prepare the cyclopropacytosine analogue (82), as outlined in Scheme 13.138 When the selenoyl alkene (25) was treated with the potassium salt of nitromethane. the cyclopropyl system (83)was formed, whilst reaction of (25) with the anion of ethyl acetoacetate gave the product (84).45
20: Nucleosides
8
219
Nucleosides of Unsaturated S u ~ a r sKetosugars. . and Yronic Acids
An improved procedure for the preparation of 3'-keto-5'-O-tritylthymidine (85)
has been reported, using PDC oxidation in the presence of molecular sieves.l39
v
D
MMTYOCH~
COzMe
(Q
AcO
0
X
( 0 6 ) X = N H COCF3
(87)
x = OAc
Derivatives of 2-amino-2-deoxy-D-glucopyranuronic acid nucleosides (86) have been prepared by conventional coupling procedures,l40 and uronic ester nucleosides of type (87)give the 4',5'-ene on treatment with DBU.141
9
C-Nucleosides
The asymmetric synthesis of C-nucleosides by Diels-Alder reaction between furan and di(l-menthyl)(acetoxymethylene)malonatehas been briefly reviewed.142 In rather similar work, Vogel has used his 'naked sugar' approach to prepare thiazofurin (88)from the homochiral adduct of furan and cyanovinyl (S)-camphanate, as indicated briefly in Scheme 14,143 and similar chemistry
I
O x " ReagenQ:
L, 0 3 , MeOH , CH&%
;b , N a W e ; 'd, CH2N2
.
I J5-0-RLb-k
(88)
S c h e m e 14
was also used by the same group to prepare 2,5-anhydro-4-deoxy-~-ribohexonic acid, and hence the C-nucleoside analogue (89)of cordycepin. 144 A number of papers have discussed the use of derivatives of 2,5anhydroallonic acid to prepare C-nucleosides. Condensation of the ethyl dithioate with 2-hydrazinopyrazine gave the 1,2,4-triazolo[4,3-a]pyrazine (90). whilst a similar reaction with 2-hydrazinopyrimidine gave the 1,2,4triazolo[ 1,5-aIpyrimidine (911, the product of Dimroth rearrangement. 145 Reaction of a protected S-benzylthioimidate with 5-benzyloxy-4hydrazinopyrimidine gave a mixture of two protected systems, both of which gave the same rearranged triazolo[1,5-c]pyrimidine (92) on base-catalysed deprotection. 146 Use of various 3-hydrazinopyridazines gave triazol0(4,3-bj
Carbohydrate Chemistry
220
pyridazines (93) with a n amino group at position 6.7, or 8.147 The pyrimidine 'homo-C-nucleoside' (94) has been made by a Wittig reaction followed by Michael-type cyclization, and this could be converted into the 1,2,3-triazolo[1,5-cIpyrimidine systems (95).148 Pyrazolo[3,4-c]pyridine Cnucleosides have been prepared via the [3+2] cycloaddition shown in Scheme 15,149 and the lumazine C-nucleoside (96)has been prepared from an intermediate reported last year (VoI.22, p.216)150 BnOCH2
DnN2 +
BnO
00"
c
S c h e m e 15
The 2'-deoxy-derivatives of formycin B and oxoformycin have been prepared by fairly standard methods, 151 and the 2',3'-didehydro-2',3'-dideoxyand 2'.3'-deoxyderivatives of 9-deazaadenosine have been prepared from 9-deazaadenosine itself via the reaction with 2-acetoxyisobutyryl bromide. 152 9-Deazainosine has been labelled with deuterium and tritium using reduction of
(97)
20: Nucleosides
22 1
a C-5'- aldehyde. 153 In the area of pyridine C-nucleosides. a full account has been given of the synthesis of 3-chloro-4-(~-D-ribofuranosyl)pyridine and 3-(P-D-ribofuranosyl) pyridone (V01.21, ~ . 2 1 1 ) , 1 and 5 ~ both a- and p- isomers of 2-carbamoyl-5-~ribofuranosyl pyridine have been prepared by a similar approach. 155 Some 'pseudo-C-nucleosides' such as (97)have been prepared from diisopropylidene glucose.156 Tri-O-acetyl-2,6-anhydro-~-galactonic acid (98)is available from D-galacturonic acid in three steps, and has been used to prepare some 0-L-lytopyranosyl C-nucleosides such as (99).157 10
Carbocvclic Nucleoside AnaloaueS
where R is electron-withdrawing, undergo Racemic bicycles of type (100). reductive cleavage with sodium borohydride to give (101);where R = CONHMe. reduction and heterocycle formation gave rise to 2',3'-dideoxy-@-methyl uridine.15* In an extension of earlier work (see V01.21, p.213-4) on the synthesis of carbocyclic C-nucleosides, Diels-Alder adducts (102) could be transformed into synthons (103)(Scheme 16) by hydroxylation and reductive retroaldol cleavage. By use of a chiral auxiliary. R = I-menthyl. good asymmetric inductions could be obtained in favour of the 'natural' absolute configuration. 159 Similar work has also been reported using the (racemic) Diels-Alder adduct of cyclopentadiene and (104).160
LJ
0
222
Carhohydrute Chemistry
The carbocyclic analogue of 3-deazaadenosine is a promising antiviral agent, and a number of 5'-substituted analogues of it have been prepared.161 Carbocyclic uronamides of type (105) have also been reported: these incorporate features which give hypotensive effects in adenosine analogues. 162 The neplanocin analogue (106) (see V01.21, p.194) is a powerful inhibitor of S-adenosyl homocysteine hydrolase: it has been shown that it is oxidized by the enzyme to the 3'-ketone, which can also be made chemically using MnO2, and that this ketone binds tightly to the NADH form of the enzyme.163 Some other references to neplanocin and aristeromycin analogues are given in Chapter 19. along with papers on carbocyclic analogues of oxetanocin. Michael addition of @-benzoyladenine to nitroalkene (107). and reductive denitration, were key steps in a synthesis of cyclaridine (108).164 The thymine analogue of (108)has been prepared by building up the pyrimidine ring around the amino group of an aminocyclopentane,165and some 2-arylaminoderivatives of ( 108) were similarly synthesized. 166 Griengl and coworkers have used the same synthon as in previous work (V01.22, p.217; V01.21, p.213-4) to prepare carbaanalogues of BVDU and 5-iodo-2'-deoxyuridine in optically-pure forms,167 and the 2',3'-dideoxycarbanucleoside (109) has been reported.168 The CHF analogues (110) and (111) of AZT have been prepared from the previously-known strained tricyclic ketones shown in Scheme 17.169 with DAST led not only to Treatment of carbocyclic 5'-O-trityl-3'-epi-thymidine the expected carba-3'-deoxy-3'-fluorothymidine. but also to the 4'-fluoro-3'deoxy isomer and the 3',4'-alkene.l70
The same type of chemistry as was used for the synthesis of (108)has also been applied to the synthesis of the carbocyclic analogue of (p-Dglucopyranosyl)adenine. 171 11
Nucleoside PhosDhates and Phosphonates
A review on gene synthesis includes a discussion of methods for the preparation of oligonucleotides.172 Bis(allyloxy)(diisopropylamino)phosphine has been developed as a new reagent for phosphorylation; intermediates such
20: Nucleosides
223
as (112). obtained after oxidation of the initial phosphite. can be deprotected at the phosphate by use of Pd(PPhg)4.173 Pfleiderer's group have described preparative-scale syntheses of protected di-2'-deoxynucleotide phosphotriesters and thiophosphotriesters via the phosphoramidite approach,174 and the 2-(4-pyridyl)ethyl protecting group has been used for phosphite/phosphate protection during such syntheses. 175 A 2-5Aanalogue which is deoxygenated at C-3'in both end units has been synthesised (see also V01.2 1. p.2 151,176 and 2'-5'-linked oligoadenylates with a nucleotide branch at the 3'-position have also been reported. 177 Four different strategies for synthesis of related branched-chain ('lariat') structures have been reviewed. 178 Di-deoxynucleoside methylphosphonates, with the Rp isomer predominating, can be obtained by sequential reaction of a 3'-hydroxyl group and a 5'-hydroxyl group with MePC12, followed by oxidation with t-butylhydroperoxide,179 and a somewhat similar sequence was used to prepare dithymidine phosphomorpholidate. 180 The (Rp, Rp) and (Sp, Sp) -isomers of TpTpT diphosphorothioate have been prepared. l8 Di(deoxynuc1eoside) phosphorodithioates have been synthesized using deoqmucleoside thiophosphoramidites as intermediates,l82 or from deoxynucleoside 3'hydrogenphosphonodithioates (113). either directly183 or using di(deoxynuc1eoside)hydrogen phosphonothioates (1 14) as intermediates. 183. The cytidine diphosphate of D-quinovose has been prepared by coupling the sugar 1-phosphate and CMP.l85
In an investigation of a possible way of delivering nucleoside drugs across cell membranes, the glucosyl phospholipid (115) of thymidine was prepared. This was found to interact with large unilamellar vesicles so as to place the nucleotide derivative inside the vesicles, suggesting transport across the lipid bilayer. 186 Similar mannose phosphate derivatives of A2T. ddT and FDU were
224
Carbohydrate Chemistiy
also synthesized as membrane-soluble prodrugs towards cells with mannosyl receptors,187 and other workers have linked mannose with 5-iodo-2'deoxyuridine and 2-5Avia a diphosphate. with a similar aim in mind. 188 The a.P-imido analogue (116) of thymidine diphosphate has been of some 2',3'-dideoxynucleosides prepared 189 and 5'-O-(a-thio)triphosphates have been synthesized. lgo A cyclic dimer of FDU monophosphate has been shown to have in vim antitumour activity as does FDU itself, and with less toxicity. 191 The interaction of cyanogen bromide and imidazole gives rise to IVcyanoimidazole and diimidazole imine. both of which can be used to make 2l.3'cyclic AMP from 3'-AMP.192 There have been further reports on the cyclodextrin-catalyzed cleavage of 2',3'-cyclic nucleoside phosphates (see v01.22, p.218); use of a-cyclodextrin cleaves 2l.3'-cUMP to the 3'-phosphate in 94% yield,l93 whilst a fuller account has been given of the hydrolysis of 2l.3'CAMP and -GMP to the 2'-phosphates by p- A d y-cyclodextrins.194 and the same selectivity can be achieved using 6-O-a-D-glucopyranosyl-Pcyclodextrin. 195 The rate and selectivity of the P-cyclodextrin-induced cleavage of 2',3'-cAMP are considerably increased by the presence of alkalimetal cations. 196 A method has been developed for the direct synthesis of 3',5'-cyclic phosphates from unprotected nucleosides, lg7 and the 2',5'-cyclic phosphate of ara-A has been prepared. l98 The 3'.5'-cyclic phosphoramidate (117). of Rp chirality, undergoes acid hydrolysis (with P-N cleavage) more rapidly than does the analogue without the axial methyl group, whilst there is no such effect for the Sp isomer, results which can be rationalised on stereoelectronic grounds. 199 A comparable study was carried out on both P-chiral isomers of the corresponding compound with an equatorial methyl group.200 An n.m.r. study of the demethyl analogue of (117). its Sp isomer, and N-methylated derivatives, (see v01.22, p.2 17) has been reported.201 An efficient route to 3',5'-cyclic phosphoramidates of 5-substituted-2'-deoxyuridinesinvolves the formation and oxidation of the cyclic phosphoramidites.2°2 In the area of phosphonates, analogues of type (118)have been prepared by coupling of silylated bases with a 1-0-acetyl derivative of the phosphonosugar;203 in the case of (118. B = Gua), the base unit (14) was used to ensure good A@-selectivityin the coupling.24 A similar method was used to prepare the higher homologues (119).and here the hexose unit required for coupling was elaborated from diisopropylidene glucose ,204 The Gif group have applied some of their free-radical methods to the synthesis of the isosteric phosphonate of UMP (119, B = U),205 and to the phosphonate analogue (120) of AZT monophosphate; as applied to the latter target, the process is indicated
20: Nucleosidc>s
225
in Scheme 18.206 Other workers have also made (120). using as the key step the opening of a 3'.5'-oxetan (Scheme 191.207 Isosteric phosphonate analogues ii-w
bTB DP5
~
3'
of 2',3'-dideoxynucleosidemonophosphates have been prepared by Wittig extension of the 5'-aldehydes.208 The phosphonate (121). devised as a potential precursor to a transition-state analogue of purine nucleoside phosphorylase. has been prepared from fructose in a multistep process.209 12
Ethers. esters and acetals of nucleosidetj
In a study on oligoribonucleotide synthesis by the phosphoramidite approach, the chemical properties of various 2'-O-protecting groups (e.g. THP. TBDMS) have been investigated.210 Other workers have similarly evaluated the stability and resistance to migration of the 2'-O-TBDMS group during ribonucleotide formation, and found it to be satisfactory for most methods.211 The p-cyanophenylethylsulphonyl(CPES)and carbomethoxyethylsulphonyl (CMES) groups have been developed for 2'-OH protection during ribonucleotide formation. The former is more stable than the previously-used p-nitrophenylethylsulphonyl group, but can be removed with fluoride ion, whilst the CMES group seems more labile, and thus less generally useful.212 Studies on the methylation of 1-P-D-ribofuranosyl derivatives of 2pyridone, 4-pyridone and 3-methyluracil using trimethylsulphonium hydroxide suggested that the reactivity of the 2'-OH is enhanced by hydrogen bonding to O-2.213 Syntheses of 3'-O-propargyl thymidine (an AZT analogue)214 and 3'-0benzyltrifluridine215 have been reported.
226
Carbohydrate Chemistry
Reaction of deoxyadenosine and deoxythymidine with 1 dialkyldichlorosilanes gives 3',5'-O-dialky,silanediyl derivatives of which the dit-butyl species (122. B = Ad or T)are the most useful (see also Vol. 19, ~ . 2 0 7 ) . ~ 1Similar 6 derivatives (123) can be obtained for ribonucleosides.217 Acidic hydrolysis of (122. B = T) gives mainly the 3'-O-hydroxysilyl ether.218 whilst base treatment gives a mixture of 3'-and 5'-O-isomers, these being stable to further hydrolysis under mild acidic or basic conditions.219 Complete removal of the di-t-butylsilanediyl group is best done with tributylamine hydrofluoride in THF.220 The sugar conformations of compounds (122) have been studied.221 lV6,lV6-Dimethyladenosinehas been converted into a series of mono-,diand triesters with fatty acids, using conventional protection-deprotection procedures. The 2'-monoesters could not be isolated due to facile ester migration, but 3'- and 5'-monoesters with C1o-C13 acids were obtained and were potent antitumour agents.222 Various 5'-O-acyl derivatives of 5-iodo-2'deoxyuridine223 and 5-fluorouridine have been prepared: the 5'-O-heptanoyl ~4 derivative of 5-fluorouridine showed good antiturnour a ~ t i v i t y . ~Enzymic synthesis of 5'-O-acyl derivatives of some 2'-deoxy-5-substituted uridines can be carried out efficiently by use of the acid anhydride and Pseudomonas fluorescens lipase (PFL) in a n organic s0lvent.2~5 Alternatively, the 3l.5I-di-0acyl derivatives can be selectively hydrolysed to the 5'-O-acyl deoqnucleosides using PFL in DMF; hydrolysis by subtilisin gives the 3'-O-acyl derivatives instead, but in only moderate yield.226 Cytosine nucleosides can be selectively acylated on nitrogen, avoiding 0-acylation, by the use of acetic or benzoic anhydride in DMF at room temperature.227
oxo
(122) X = H (123) X = O H
CHEWz
(126)
Further analogues of UDPG (see V01.22, p.221, and earlier) of type (124). and also simpler N-alkyl sulphamoyl derivatives, have been reported.228 A set of selectively-protected nucleosides such as (125) have been prepared for use in phosphotriester syntheses of oligonucleotides,229 and the
20: Nucleosides
227
acetal (126) has been coupled to 6-aminohexyl sepharose 4B, for use in affinity chromatography.230 13
Miscellaneous nucleoside analogues
A number of unusual and interesting furanose analogues have been reported. 'Iso-ddA'(127) has been prepared as indicated in Scheme 20, and shown to have anti-HIV acti~-ity.~31 The anti-tumour pyrrolidine analogues (128) and
(129) have been made from 4-hydro~y-proline.~3~ and the racemic dioxolane ( 130) shows anti-HIV properties.233 The carbocyclic analogue (13 1). prepared
as its racemate by reaction of the anion of 2-amino-6-benzyloxypurine with an epoxide, has antiviral activity similar to acyclovir.234 Related carbocyclic analogues of oxetanocin are mentioned in Chapter 19.
(127) Reage&
L,
1 ° / 4 H O A ~ , M e O H ,u,TsCL
,h,Adenine, K
p 3 , 18-crown-6,
Lv,
H30+,v, HZ, PtOz
Scheme 2 0
v OH
on (1331
The epoxide (132). and its 6',7'-epimer, have been prepared as potential precursors of nucleosides of higher-carbon sugars.235 Pentofuranosyl nucleosides have been chain-extended at C-5' by Wittig reactions236 and reactions of 5'-halides with stabilized carbanions.237 The epoxide (133).a possible trap for monophosphate binding sites of enzymes utilising nucleotides, has been produced using Wittig ~hemistry.23~ Abnormal nucleoside/nucleotide-like compounds of type (134),239 (135),240 and (136)241 have been prepared. 14
Reactions
A review has been published on the acidic hydrolysis of nucleosides and
nucleotides, particularly with regard to the influence of sugar and base substitutions on the stability of the N-glycosidic bond.243 First-order rate
228
Carbohydrate Chemistry
H2
0
p c OH
('35)
1.5:"
AcOCH~
constants have been determined for the acidic hydrolysis and for acidic and acid-buffer catalysed deamination of cytidine and a number of methylated deri~atives.2~3 A study of the influence of metal ions on the acidic hydrolysis of 2'-deoxyguanosine and 2I-deoxyadenosine has shown that certain metals can be used to protect 2'-deoxyguanosine selectively against acidic depurination, with the metals binding to hn of the deoxyguanosine.244 The mechanism for acidcatalysed hydrolysis of benzimidazole nucleosides has been shown to involve cleavage of an N3-protonated substrate to give the free base and a carbocation.245 The N-glycosidic bond in @-methylxanthosine (137)has been shown to undergo acidic cleavage 103 times faster than that of xanth0sine,~46 and a review of the minor components of t-RNA discusses the rates of hydrolysis of the unusually labile glycosidic bonds in these nucleosides.247 The enzymic and chemical stabilities of 2',3'-dideoq~-2'.3'-didehydropyrimidine nucleosides have been assessed. While showing enzymic stability, they are less stable chemically, to either acid or base, than araC; for example, the cytosine analogue degrades rapidly (tl/2 20 min) at pH3.248 A study has been reported of the kinetics and mechanism of phosphate migration, phosphate hydrolysis, and purine hydrolysis for adenosine 2'- and 3'-phosphates in aqueous solution at different pH v a l u e ~ . ~ ~ g The aminoimidazole nucleoside derivative (138) has been shown to undergo rearrangement in aqueous buffer at pH7 to give the glycosylamines (139), with the p-anomer predominating: this observation may well be relevant to the previously-noted lability of the corresponding nucleoside and nucleotide.250 A study has been made of the reactions of hydroxyl radicals and the sulphate anion radical with uridine, 2'-deoxyuridine, and related nucleosides under anoxic conditions. With HO' the e.s.r. spectra observed were mainly those of species formed by addition to the double bonds. With SO4-e, radicals were derived from the bases of the deoqnucleosides, whereas the
20: Nucleosidrs
229
ribonucleosides gave radicals derived from the sugar. Radicals formed at C-3' underwent ring opening by cleavage of the C(4')-0 ring b0nd.25~The reactions of hydroxyl radicals with purine nucleosides and deoxynucleosides have also been investigated. In all cases, H-abstraction from C-5' was observed, and for dAIvIP and dGMP, also from C-4'.251 On y- irradiation of adenine and guanine nucleotides in dilute aqueous solution, the degree of cleavage of the N-glycosidic bond is greater for ribonucleotides than for 2'-deoxy systems, or where the 2'-OH is protected as a cyclic acetal. The experimental data support the formation of ortho- and metaphosphate ions during irradiation.253 In further studies of the cleavage of oligonucleotides by bleomycin- metal systems, the balance between the oxygen-dependent pathway for breakdown of the C-4I-radical and the 02-independent pathway has been ihvestigated with various deoxy-tetranucleotides. In certain cases an unusual selective hydroxylation at C-4' of a terminal cytidine unit was observed.254 15
SDectroscoDic and Conformational Studies
The anomeric configurations of D-ribo-, D-arabino-. 2'-deoxyribo-. and 2',3'dideoxyribonucleosides have been determined unambiguously by NOEDS methods. The 1'-H signals were saturated and the n.0.e. factors for 4I-H. 3'-H and 2'-H were measured.255 Conformational analyses have been carried out on 2',3'-0alkylideneuridines by n.m.r. meth0ds,~56and on 8-substituted-2',3'-O-isopropylideneadenosine 5'-carboxylic acids, using n.m.r. and c.d. measurements, to carboxyl group interaction was demonstrated.257 where stabilisation by an References 1 2 3 4 5 6 7 8
9 10 11
12
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35 36 37 38 39 40 41 42 43 44 45 46 47 48
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23 1
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49
so 51 52 53 54 55 56 57
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85
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a,
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88 89 90 91 92 93 94
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m,
u,
95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
a,
u,
m,
m,
a,
a,
a,
a,
233
20: Nucleosides 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
K. Kato, T. Minami, T. Takita, S. Nishiyama, T. Ohgiya, and S. Yamamura, J . Chem. Soc., Chem. Commun., 1989, 1037. K. Kato, T. Minami, T. Takita, S. Nishiyama, S. Yamamura, and N. Naganawa, Tetrahedron Lett., 1989,3,2269. T . Ueda, A. Matsuda, Y. Yoshimura, and K. Takenuki, Nucleosides Nucleorides, 1989,s. 743. A. Matsuda, H. Okajima, and T. Ueda, Heterocycles, 1989,2, 25. L.H. Koole, H.M. Buck, J.-M.Vial, and J. Chattopadhyaya, Acta Chem. Scand., 1989, 665. M.-J. Camarasa, A. Diaz-Ortiz, A. Calvo-Mateo, F.G. De Las Heras, J. Balzarini, and E. De Clercq, J. Med. Chem., 1989,2, 1732. C.W. Greengrass, D.W.T. Hoople, S.D.A. Street, F. Hamilton, M.S. Marriott, J. Bordner, A.G. Dalgleish, H. Mitsuya, and S. Broder, J. Med. Chem., 1989,2, 618. J.-C. Wu and J. Chattopadhyaya, Tetrahedron, 1989, &5, 855. D. Yu and M. DAlarcao, J. Org. Chem., 1989, s,3240. C.K. Chu, B. Doboszewski, W. Schmidt, and G.V. Ullas, J. Org. Chem., 1989, s,2767. J. Fiandor, D.M. Huryn, B. Sluboski, L.J. Todaro, and S. Tam, Nucleosides Nucleotides, 1989,&, 1107. M. Okabe and R.-C. Sun, Tetrahedron Lett., 1989,2,2203. M.L. Froelich, D.J. Swartling, R.E. Lind, A.W. Mott, and D.E. Bergstrom, Nucleosides Nucleotides, 1989,8, 1529. V.A. Timoshchuk and L.N. Kulinkovich, Zh. Obshch. Khim., 1988, 1144 (Chem. Abstr., 1989, IlQ,24 206). V.A. Timoshchuk and L.N. Kulinkovich, Zh. Obshch. Khim., 1988,3, 1651, (Chem. Abstr., 1989, 231 994). N. Katagiri, H. Akatsuka, and C. Kaneko, Nucleic Acids Symp. Ser., 1988,20,29 (Chem. Abstr., 1989, M, 57 992). R.M. Bimwala and P. Vogel, Helv. Chim. Acta, 1989,22, 1825. F. Gasparini and P. Vogel, Helv. Chim. Acta, 1989.2, 271. H.S. El Khadem, J. Kawai, and D.L. Swartz, Carbohydr. Res., 1989, B, 149. F. Dennin, 0. Rousseaux, D. Blondeau, and H. Sliwa, J. Heterocycl. Chem., 1989,26,991 Y. Kang, S.B. Larson, R.K. Robins, and G.R. Revankar, J. Med. Chem., 1989.22, 1547. F.J. Lopez Herrera, M.S. Pino Gonzalez, and R. Pabon Aquas, J . Chem. Soc. Perkin Trans. I, 1989, 1401. D.R. Sauer and S.W. Schneller, Nucleosides Nucleotides, 1989,8, 1079. I. Maeba, R. Kitaori, and C. Ito, J . Org. Chem., 1989,s, 3927. V.C. Solan and A. Rosowsky, Nucleosides Nucleotides, 1989,8, 1369. S . Tam, M. Holman, R.S. Klein, M. Mitsuya, and S . Broder, Nucleosides Nucleotides, 1989,8, 1109. A.K. Singh and R.S. Klein, J. Labelled Compd. Radiopharm., 1988,a, 1219. (Chem. Abstr., 1989,110, 193 300). M. Belmans, I. Vrijens, E.L. Esmans, R.A. Dommisse, J.A. Lepoivre, F.C. Alderweireldt, L.B. Townsend, L.L. Womng, J. Balzarini, and E. De Clercq, Nucleosides Nucleotides, 1989, &, 307. F.C. Alderweireldt, I. Vrijens, E.L. Esmans, L.L. Womng, L.B. Townsend, J. Balzarini, and E. De Clercq, Nucleosides Nucleotides, 1989,8, 89 1. A.P. Rauter, J.A. Figueireda, and I.M. Ismael, Carbohydr. Res., 1989,188, 19. U. Klein and W. Steglich, Liebigs Ann. Chem. 1989,247. N. Katagiri, M. Muto, and C. Kaneko, Tetrahedron Lett., 1989,3, 1645. N. Katagiri, M. Hirose, M. Sato, and C. Kaneko, Chem. Pharm. Bull., 1989,2,933. M. Sato, K. Takayama, and C. Kaneko, Chem. Pharm. Bull., 1989, 2615. A. Secrist, R.M. Brash, R.J. Gray, R.N. Comber, and J.A. Montgomery, Nucleosides Nucleotides, 1989,8, 1153. J. Chen, M. Grim, C. Rock, and K . Chan, Tetrahedron Lett., 1989,2, 5543. D. Paisley, M. Hasobe, and R.T. Borchardt, Nucleosides Nucleotides, 1989,8, 689. M. Yoshikawa, T. Nakae, B.C. Cha, Y. Yokokawa, and I. Kitagawa, Chem. Phurm. Bull., 1989, 545. T.S. Lin, X.H. Zhang, Z.H. Wang, and W.H. Prusoff, Synth. Comrnun., 1988, U, 925 (Chem. Abstr., 1989,110, 39 294). M. Koga and S.W. Schneller, Nucleosides Nucleotides, 1989,8, 1085.
a,
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Curhohydrate Chemistly
J. Balzarini, H. Baumgartner, M. Bodenteich, E. De Clercq, and H. Griengl, J. Med. Chem., 1 9 8 9 , 2 , 1861. 168 J.W. Leahy and S.W. Schneller, Nucleosides Nucleotides, 1989,& 1081. 169 C.A. Fletcher, H. Hilpert, P.L. Myers, S.M. Roberts, and R. Storer, J. Chem. Soc., Chem. Commun., 1989, 1707. 170 J. BCres, Gy. Slgi, E. Baitz-Glcs, I. Tomoskozi, L. Gruber, and L. Otvos, Tetrahedron, 1989, 6271. 171 I. Kitagawa, B.C. Cha, T. Nakae, Y. Okaichi, Y. Takinami, and M. Yoshikawa, Chem. Pharm. Bull., 1989, z,542. 172 J.W. Engels and E. Uhlmann, Angew. Chem. Int. Ed. Engl., 1989, 716. 173 W. Bannwarth and E. Kung, Tetrahedron Lett., 1989,2Q, 4219. 174 A.H. Beiter and W. Pfleiderer, Synthesis, 1989,497. 175 S. Hmamoto, Y. Shishido, M. Furuta, H. Takaka, M. Kawashima, and M. Takaki, Nucleosides Nucleotides, 1989, 3 17. 176 R. Charubala, W. Pfleiderer, D. Alster, D. Brozda, and P.F. Torrence, Nucleosides Nucleotides, 1989,& 273. 177 Y.Hayakawa, M. Hirose, and R. Noyori, Nucleosides Nucleotides, 1989,8, 867. 178 N. Balgobin, X.-X.Zhou, J.-M. Vial, A. Nyilas, A. Foldesi, and J. Chattopadhyaya, Nucleosides Nucleotides, 1989,&,793. 5587. 179 T. Liischner and J. Engels, Tetrahedron Lett., 1989, 180 H. Ozaki, K. Yamana, and T. Shimidzu, Tetrahedron Lett., 1 9 8 9 , U 5899. 181 Z.J. Lesnikowski and M.M. Jaworska, Tetrahedron Lett., 1989,3,3821. 182 B.K. Dahl, K. BjergArde, V.B. Sommer, and 0. Dahl, Acra Chem. Scand., 1989,43, 896. 183 W.K.-D. Brill, E.K. Yau, and M.H. Caruthers, Tetrahedron Lett., 1989,N, 6621. 184 G.M. Porritt and C.B. Reese, Tetrahedron Lett., 1989, 2Q,4713. 35. 185 L.-d. Liu and H.-w. Lui, Tetrahedron Lett., 1989, 186 J.-M. Neumann, M. HervC, J-C. Debouzy, F.I. Guerra, C. Gouyette, B. Dupraz, and T. Huynh-Dinh, J. Am. Chem. Soc., 1989, U,4270. 187 C. Gouyette, J.M. Neumann, R. Fauve, and T. Huynh-Dinh, Tetrahedron Lett., 1989,30, 6019. 188 K. Lesiak, E. De Clercq, and P.F. Torrence, Nucleosides Nucleotides, 1989,8, 1387. 189 L.C. Davies, Nucleosides Nucleotides, 1989,& 1053. 190 M. Auer, C. Krieger, M. Gautel, S. Labeit, G. Sczakiel, S. Weiss, and R.S. Goody, Nucleosides Nucleotides, 1989, &, 849. 191 G. Hamoir,E. Sonveaux, M. Iigo, and E. De Clercq, Nucleosides Nucleotides, 1989,8,285. 192 J.P. Ferris, C.-H. Huang, and W.J. Hagan, Jr., Nucleosides Nucleotides, 1989,&,407. 193 M. Komiyama, Makromol. Chem. Rapid Commun., 1988,2,453. (Chem.Abstr., 1989, LuT,8574). 194 M. Komiyama and Y. Takeshige, J. Org. Chem., 1989,24,4936. 195 M. Komiyama, Makromol. Chem., Rapid Commun., 1988,9, 825 (Chem. Abstr., 1989, m , 3 9 311). 196 M. Komiyama, Y.Takeshige, and S. Sawada, Chem. Lett., 1989, 1785. 197 H.-G. Genieser, E. Butt, U. Bottin, W. Dostmann, and B. Jastorff, Synthesis, 1989, 53. 198 L. Zhang, F. Wang, C. Wang, G. Lin, and L. Ma, Yiyao Gongye, 1988,& 154 (Chem. Abstr., 1989,110, 57 981). 199 S. Bottka, L. Radics, and J. Tomasz, Nucleosides Nucleotides, 1989,& 1217. 200 L. Radics, S. Bottka, and J. Tomasz, Nucleosides Nucleotides, 1989,8, 1305. 201 J. Tomasz, S. Bottka, and L. Radics, Nucleosides Nucleotides, 1989,8, 1297. 202 W.G. Bentrude, M.R. Khan,, M.R. Saadein, and A.E. Sopchik, Nucleosides Nucleotides, 1989,8, 1359. 203 N. Raju, D.F. Smee, R.K. Robins, and M.M. Vaghefi, J. Med. Chem., 1989,32, 1307. 204 S.N. Mikhailov, N.S. Padyukova, M. Ya. Karpeiskii, L.I. Kolobushkina, and L.N. Beigelman, Collect. Czech. Chem. Commun., 1 9 8 9 , 3 , 1055. 205 D.H.R. Barton, S.D. Gero, B. Quiclet-Sire, and M. Samadi, J. Chem. SOC.,Chem. Commun., 1989, 1OOO. 206 D.H.R. Barton, S.D. GCro, B. Quiclet-Sire, and M. Samadi, Tetrahedron Lett., 1 9 8 9 , 3 , 4969. 207 H. Tanaka, M. Fukui, K. Haraguchi, M. Masaki, and T. Miyasaka, Tetrahedron Left., 1989, 3, 2567. 208 R.M.Riggs, R.N. Comber, J.A. Montgomery, J.A. Secrist 111, J.M. Leeds, S. Chaffee, and M.S. Hershfield, Nucleosides Nucleotides, 1989,& 1119.
167
s,
a,
a,
a,
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235
R.D. Elliott, S. Niwas, J.A. Montgomery, and J.A. Secrist 111, Nucleosides Nucleotides, 1989, &, 1103. R. Kierzek, M. Rozek, and W.T. Markiewicz, Bull. Pol. Acad. Sci..,Chem., 1988, 507 (Chem. Abstr., 1989, U,),57 990). J. Milecki, P. Dembek, and W.Z. Antkowiak, Nucleosides Nucleotides, 1989,&,463. M. Pfister and W. Pfleiderer, Nucleosides Nucleotides, 1989,&,1001. K. Yamauchi, T. Hosokawa, and M. Kinoshita, J . Chem. SOC.Perkin Trans. 1 , 1989, 13. A. Rosowsky, R.M. Ruprecht, and V.C. Solan, Nucleosides Nucleotides, 1989,&,491. J. Yamashita, H. Matsumoto, K. Kobayashi, K. Noguchi, M. Yasumoto, and T. Ueda, Chem. Phann. Bull., 1989,31, 2287. K. Furusawa, T. Katsura, T. Sakai, and K. Tsuda, Kenkyu Hokoku - Sen'i Kobunshi Zairyo Kenkyusho ,1988,97 (Chem. Abstr., 1 9 8 9 , m , 8 567). K. Furusawa, T. Katsura, T. Sakai, and K. Tsuda, Kenkyu Hokoku-Sen'i Kobunshi Zairyo Kenkyusho, 1988, 115 (Chem. Abstr., 1989,110, 8 568). K. Furusawa, T. Sakai, and K. Tsuda, Kenkyu Hokoku-Sen'i Kobunshi Zairyo Kenkyusho, 1988, 121 (Chem. Abstr., 1989, 8 569). K. Furusawa, T. Katsura, J. Tadokoro, T. Sakai, and K. Tsuda, Kenkyu Hokoku-Sen'i Kobunshi Zairyo Kenkyushu, 1988, 109 (Chem. Abstr., 1989, UQ,24 219). K. Furusawa, Chem. Lett., 1989, 509. T. Katsura, K. Furusawa, T. Sakai, and K. Tsuda, Kenkyu Hokoku-Sen'i Kobunshi Zairyo Kenkyusho, 1988, 125 (Chem. Abstr., 1989, JJQ, 8 570). T. Takamura, T. Kato, E. Arakawa, S . Ogawa, Y. Suzumura, and T. Kato, Chem. Pharm. Bull., 1989, 2828. M.M. Narurkar and A.K. Mitra, Pharm. Res., 1988,5,734. (Chem. Abstr., 1989,110, 173 677). S. Ozaki, T. Akiyama, Y. Ike, H. Mori, and A. Hoshi, Chem. Pharm. Bull., 1 9 8 9 , 3 , 3405. A. Uemura, K. Nozaki, J. Yamashita, and M. Yasumoto, Tetrahedron Lett., 1989,3,3817. A. Uemura, K. Nozaki, J. Yamashita, and M. Yasumoto, Tetrahedron Lett., 1 9 8 9 , 3 , 3819. V. Bhat, B.G. Ugarkar, V.A. Sayeed, K. Grimm, N. Kosora, P.A. Domenico, and E. Stocker, Nucleosides Nucleotides, 1989,8, 179. J. Fiandor, M.T. Garcia-Lopez, F.G. De Las Heras, P.P. Mendez-Castrillon, C.GilFernandez, S . Perez, P. Vilas, C. Perez, and A. Garcia Gancedo, Nucleosides Nucleotides, 1989, &, 257. J.M. Brown, C. Christodoulou, S.S. Jones, A.S. Modak, C.B. Reese, S . Sibanda, and A. Ubasawa, J . Chem. SOC.Perkin Trans. I, 1989, 1735. A.I. Zinchenko, V.N. Barai, V.I. Lyakhovets, T.I. Kulak, E.I. Kvasyuk, and I.A. Mikhailopulo, Bioorg. Khim., 1988, U, 1401 (Chem. Abstr., 1989,111, 7 724). D.M. Huryn, B.C. Sluboski, S.Y. Tam, L.J. Todaro, and M. Weigele, Tetrahedron Lett., 1989,33, 6259. K.E. Ng and L.E. Orgel, J . Med. Chem., 1 9 8 9 , 2 , 1754. D.W. Norbreck, S . Spanton, S. Broder, and H. Mitsuya, Tetrahedron Lett., 1989,2,6263. G.A. Jacobs, J.A. Tino, and R. Zahler, Tetrahedron Lett., 1989, 6955. D. Komiotis, M. Bessodes, and K. Antonakis, Carbohydr. Res., 1989, .El, 153. K.S. Kim, S.J. Kim, J.H. Kim, and C.S. Hahn, Bull. Korean Chem. SOC.,1989, lQ,116 (Chem. Abstr., 1 9 8 9 , U , 7 8 534). J. Fiandor, M.T. Garcia-Lopez, and F.G. De Las Heras, Nucleosides Nucleotides, 1989,8, 1325. H.J. Thomas, J.M. Riordan, R.D. Elliott, and J.A. Montgomery, Nucleosides Nucleotides, 1989,&, 947. M. Bobek, S.-H. An, D. Skrincosky, E. De Clercq, and R.J. Bernacki, J . Med. Chem., 1 9 8 9 , 2 , 799. V.V. Kolomeitseva, G.V. Denisov, D.S. Terekhov, L.A. Uvarova, E.A. Pyaivinen, and N.S. Sidorova, Zh. Obshch. Khim., 1988,58,2387 (Chem. Abstr., 1989,111. 78 531). S.M. Bennett, K.K. Ogilvie, and J.P. Roduit, Nucleosides Nucleotides, 1989, 8, 49. E. Zielonacka-Lis, Nucleosides Nucleotides, 1989,& 383. J. Kusmierek, R. Kappi, K. Neuvonen, D. Shugar, and H. Lonnberg, Acta Chem. Scand., 1989, 196. J. Arpalahti, R. Kappi, J. Hovinen, H. Lijnnberg, and J. Chattopadhyaya, Terruhedron, 1989, Q, 3945. M. Oivanen, H. Lonnberg, 2. Kazimierczuk, and D. Shugar, Nucleosides Nucleotides, 1989, 8, 133.
s,
m,
u,
a
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236
Carbohydrate Chem isrly
246 247 248
T. Itaya and T. Harada, Chem. Pharm. Bull., 1 9 8 9 , 2 , 1235. T. Itaya, Yakugahu Zasshi, 1 9 8 8 , m , 697 (Chem. Abstr., 1989, N 7 5 896). T. Kawaguchi, S. Fukushima, M. Ohmura, M. Mishima, and M. Nakano, Chem. Pharm. Bull., 1989, 2, 1944. M. Oivanen and H. Lonnberg, J. Org. Chem., 1989, s,2556. M.P. Grosiak, B. Bhat, and J.N. Leonard, Proc. Natl. Acad. Sci. U.S.A., 1988, &, 7174 (Chem. Abstr., 1989,1112, 135 631). K. Hildenbrand, G. Behrens, D. Schulte-Frohlinde, and J.N. Herak, J. Chem. Soc., Perkin Trans. 2, 1989,283. W. Hiraoka, M. Kuwabara, and F. Sato, lnt. J. Radiat. Biol., 1989, 51 (Chem. Abstr., 1989, 110, 149 966). E.P. Petryaev, S.V. Moshchinskaya, V.A.Timoshahuk, and 0.1. Shadyro, Zh. Org. Khim, 1988,& 982 (Chem.Abstr., 1989, 95 690). H. Sugiyama, T. Tashiro, Y.Dannoue, T. Miwa, T. Matsuura, and I. Saito, Tetrahedron Lett., 1989,X. 7213. H. Rosemeyer, G. Toth, and F. Seela, Nucleosides Nucleotides, 1989,8, 587. J. Kimura, K. Taira, S . Goto, and Y.Sensui, Nippon Kagaku Kaishi, 1988,1122 (Chem. Abstr., 1989, UQ,39 299). V.A. Timoshchuk, T.M. Ennolenko, and A.A.Akhrem, Zh. Org. Khim., 1 9 8 8 , 2 , 1214 (Chem Abstr., 1 9 8 9 , m , 2 4 223).
249 250 25 1 252 253 254 255 256 257
s,
m,
21
N.M.R. Spectroscopy and Conformational Features
1 Theoretical and General Considerations Reviews have appeared on the use of high resolution n.m.r. spectroscopy in the structural determination of complex carbohydrates' and of some 3-0-, 4-0-, and 3,4di-0-glycopyranosyl-substitutedmethyl D-glycopyranosides. The latter publication includes complete assignments of 'H- and 13C-n.m.r. resonances as well as conformational studies using HSEA effect theory? The application of various n.m.r. techniques (multi-relayed correlation, 'H-'H-correlated, triple quantum field 'H-'H-correlated and 'H-'H homonuclear Hartmann Hahn spectroscopy) to carbohydrate analysis has been reviewed in Japanese: and in a further Japanese review the interactions of metal ions with uronic acids and amino sugars as observed by the lanthanide-probe n.m.r. method are di~cussed.~ A symposium report deals with the use of n.m.r. spectroscopy for piecing together fragments of oligosaccharides, inter alia, isolated from liverworts (Hepaticae)? As part of a paper on the analysis of components of complex sugar mixtures by two-dimensional mass- and n.m.r.-spectroscopy, the 2D J-coupled COSY spectra of six sugars (arabinose, xylose, sorbose, cellobiose, lactose and melibiose) in D,O have been presented! A modified version of the 2D semi-selective INEPT technique for the determination of three-bonded heteronuclear coupling constants (3&-ca.c)has been developed, its potency being demonstrated by application to compounds (1) and (2) as examples of rigid and flexible carbohydrate derivatives, respectively.' For the magnitude of 3$Hc.0-C and the corresponding dihedral angle a Karplus-like relationship has been proposed? 7
0
238
Ccrrbohydratt. Che?niitry
The kinetics of anomerisation of D-talose have been investigated by 'H-n.m.r. spectroscopy, and by 13C-n.m.r. spectroscopy using I3C-labelled substrate. Six tautomeric forms (a- and ppyranose, a- and p-furanose, aldehydo and hydrated aldehydo) were observed in D,O? A 13C-n.m.r. spin - lattice relaxation study of the effect of solvent on the rotational dynamics of methyl a- and 8-glucopyranosides has been published. For both anomers the rate of overall motion increases on going from D20, MeOH or DMF to pyridine to DMSO, this trend reflecting, apparently, the increasing viscosities and increasing molecular weights of solvated entities.lo 2 Acyclic Systems
In a first application of pattern recognition to n.m.r. spectroscopy by a neural network, the 'H-n.m.r. spectra of six alditols have been assigned." Analysis of the preferred conformations of partially acetylated alditols in CDC1, showed that they are mainly determined by intramolecular hydrogen-bondingbetween the free hydroxy group^.'^ 3 Furanose Svstems
In a simulation study of the pseudorotation of methyl 2-deoxy-pD-e+hropentofuranoside, use was made of several model compounds of increasing complexity (cyclopentane, tetrahydrofuran, 3-hydroxy-, and 2,3-dihydroxytetrahydrofuran) to examine in detail the conformation of the furanose ring.I3 An interesting new analysis of the anomeric effect in furanoses indicated that in these systems the axial orientation of electronegative groups at the anomeric centre is particularly favoured which implies an sp2 hybridised ring-oxygen with nonequivalent lone pairs.14 The 13C-n.m.r. spectra of various glycosides of a- and 4-L-arabinofuranose [e.g.monosaccharides (3) and glucosylated derivatives such as disaccharide (4)] have been assigned, and chemical shill patterns characteristic of certain types of
glycosides have been established." The l3C-n.m.r. spectra of a large number of branched a-D-allofuranose acetals (5) and a-D-ribofuranose acetals (6) have been
21: N.M.R. Spectroscopy und Conforniutional Features
239
described with special attention to the effect of substitution on the ring carbon atom chemical shifts.16 'H-n.m.r. and CD data have been reported for seventeen 8-substituted adenosine 5 '-carboxylic acid derivatives (7). The magnitudes of the spin - spin coupling constants for the protons of the ribose moieties were consistent with preference for the proposed 3E conformations, and the orientations of the RO ' CH2
?H,OR~
G-_oia OH
(5)
O+R1
R1
heterocycles relative to the furanose rings appeared to depend on the size of the substituent R2at C-8." A number of antiviral nucleosides such as 3 '-azido3 '-deoxythymidine and the 2 ',3'-dideoxy analogues of adenosine, cytidine and inosine have been examined by 13C-n.m.r.spectroscopy. Assignments were made on the basis of twenty 2D INADEQUATE experiments to determine carbon - carbon connectivities."
It has been established by 'H-n.rn.r. spectroscopy that D-threo-3,4-hexodiulose exists in solution (D,O) as a 2:l mixture of the bicyclic a,a- and &/?-forms(8) and (9), respectively, both with endo-endo geometry, whereas in the solid state it is present as the endo-exo-,!?,fl-conformer(10) (see also Chapter 22).19
240
Carbohydrate Chemistry
4 Pyranose Svstems
A quantitative investigation of the 'H-n.m.r. line shifts induced by Eu(fod), in the spectra of the methyl 4,6-Q-benzylidene-2- or 3-deoxy-D-hexopyranosides(11)-( 15) has been undertaken. In addition, the ',C-n.m.r. spectra of these compounds have been completely assigned by use of selective 'H-spin decoupling and off-resonance experiments.m A comparative evaluation of the 13C-n.m.r. data of ten 1-C-aryl-Dglucopyranoses including four pairs of anomers showed that, with the exception of C-4, the carbon atoms of the j?-pyranose rings resonate at lower fields than do the corresponding carbon atoms of the a-anomersFl The configurations at the acetal centres of hexopyranoside 4,6-Q-pyruvate acetals [compounds (20)-(25) in
I
R2
1
R'
(11) R'= O H, R2=R3=
H
('5)
(12) R"=OTs, R 2 = R 3 = H (13) R'= H , R2= O H ,R3= H
(14) R' = R2= H , R3 = OH
Chapter 61 have been assigned on the basis of the finding that the 13C-n.m.r. signals of axially disposed methyl groups appear at higher fields than do those of equatorial ones.= The 'H- and ',C-n.m.r. spectra of the pseudo-2-acetamido-2-deoxy-DLhexopyranoses with a- and 1-gluco-,-manno- and -galacto-configurationshave been compared with those of the corresponding true sugar analogues. No major conformational differences were observed between the pyranose- and pseudopyranose-rings, but a somewhat different rotamer distribution about the exocyclic C-5 - C-6 bond (carbohydrate numbering) seemed indicated by the chemical shifts of H-6 and H-6 ' and the .15,6 values.u The solution conformation (in DMSO-d,) of has been studied by 'H-n.m.r. spectroscopy;% the methyl 6-deoxy-a-D-idopyranoside solid state conformation of this compound is referred to in Chapter 22. The conformations of the 7-, 8- and 9-deoxy- and the 4,7-dideoxy-analogues of Bacetylneuraminic acid have been investigated by 'H-n.m.r. spectroscopy and hard sphere calculations, with emphasis on the shapes adopted by the side-chains, as these play a major role in enzyme-binding.
21: N.M.R. Spectroscopy arid Conformational Features
24 1
The differences in (A&/AT), the temperature-dependence of the n.m.r. chemical shift, of the amide protons in anomeric pairs of alkyl2-acetamido-2-deoxyD-glucopyranosides have been measured in a number of solvents together with the rates of exchange of the amide protons with solvent protons.26 5 Di- and Oligo-Saccharidesand Related Compounds
Structural parameters for the modelling of complete 13C-n.m.r. spectra of disaccharides have been derived from forty experimental spectra by use of molecular mechanics techniques. The average difference between simulated and experimentally determined chemical shift values was k0.45 ppm.” The I3C chemical shifts of glycosides with chiral cyclohexane-type aglycons and of disaccharides with pyranosyl aglycons are affected by the anomeric configuration of the glycosylating sugar residue, by the relative absolute configurations of glycon and aglycon and by stereochemical factors such as, for example, the orientation of the proton@) on the carbon atoms adjacent to the glycosylated centre of the aglycon. Simple rules have been formulated for predicting the magnitude of these glycosylation effects, which can be used for determining unknown structural features in glycosides and disaccharides, in particular the absolute configuration of one of the constituent sugars.28 Complete ‘H- and 13C-n.m.r. spectral assignments, by application of combined 1D- and 2D-correlation experiments, have been reported for two sulphated oligosaccharide alditols derived from hen o v o r n ~ c i nfor ~ ~eight oligosaccharides of the lacto-E-tetraose- and the neotetraose-series,%for some xylose-containing oligosaccharides derived from the carbohydrate chains of N-glycoproteins?’ and for the new, hexuronic acid-containing disaccharide (16), isolated after mild hydrolysis from the red alga Rhodella reticulata?2 Improved 2D n.m.r. methods (RECSY,COSY-LR)allowed the accurate measurement of the chemical shifts of most protons of A-pentasaccharide (17) and of some other tri-, tetra- and penta-saccharides containing the sequence fl-D-Galp (1+4)-D-Glc7without the need for a variety of solvents, derivatisation, or end group reduction. The results provided extended data sets for a chemical shift libra~y.3~ Q-D-Glc,UA-( 1+3)&Gal (16)
a-D-GalpNAc-(1+3)-fl-D-Galp-(1-.4)-D-Glc 3 3 t t (17) 1 1 WGFUCQ ~ - L F u c Q
242
Carbohydrate Chemistly
Complete 'H-n.m.r. spectral data have also been recorded for lactosyl ceramide, globotriasyl-z-, and isoglobotriasyl-E-ceramides,special attention being and E-ceramide given to glycosylation- induced shifts and to shielding by the residues. Some reassignments in related structures have been suggested?,
z-
a-D-Galp-(l+4)-fi-D-GalpOR
(18) R=Me (19) R=Et
A conformational analysis of furanoid - pyranoid non-reducing disaccharides, based on crystallographic data, has been published,35and the conformation of trehalose incorporated in a micelle has been studied by 'H-n.m.r. spectroscopy?6 Conformational analysis by use of various 'H- and 13C-n.m,r. techniques in combination with theoretical calculations has been achieved for the two galactobiosides (18) and (19),37for the eight-membered 3,2 '-Q-isopropylidene acetals (20) and (21) of methyl pcellobioside and benzyl 8-D-lactoside, respectively, CHZOH
CH20H
and that of !-methyl maltoside,38 for the disaccharide moiety of avermectin B,, for the G, ganglioside (22) in DMSO-d, which contains two oleandrose and its component disaccharide in D,0,40 for several branched trisaccharide methyl glycosides with a 2,3- or 3,4-disubstituted D-galactose residue, le_,g, compounds (23) and (24),41,42and for four branched, (1+6)-linked trisaccharides. In the last case chiral deuteration at C-6 allowed the signals for H-6R and H-6s to be di~tinguished.~~
a-NeuSAc-(2+3)-B-D-Galp( l-.1)-Cer
(22)
a-D-Glcp-(l+n)-8-D-Galp-OMe 3
(23) n=2
t
(24) n=4
1 a-D-Mane The stereochemistry of the glycosidic linkages of Corynetoxin 17a (25), an antibiotic in the tunicamycin group, have been unambiguously determined with the help of 1D and 2D n.m.r. methods,@and in a powerful illustration of the potency of n.m.r. spectral analysis the structure of a new bisdesmosidic triterpene saponin
21: N.M.R. Spectroscopy and Conformational Features
243
containing ten sugar residues has been solved almost entirely by n.m.r. techniques, especially by use of selective excitation by Gauss-shaped pulses in combination with coherence transfer experiment^:^
h*qwN20 0
HOCH,
RHN
/--Jyo
HO
NHAc
R = M~C~I,CH(M~)(CH,),,CH(OH)CH~”
(25)
Some antihistaminic and analgesic agents have become amenable to chiral analysis by ‘H-nmr spectroscopy after formation of cyclodextrin inclusion complexes. In many cases equivalent protons of enantiomeric pairs showed different chemical shifts after inclusion.& Negative NOE’s have been observed between H-3 and the anomeric proton of the 3-@sugar moieties in a number of soponins such as compound (26):’
oc-L-Rhap-(1+2)-[4-OAc-p
-D-Glc.p]-O
Me
Me
OH
(26)
6 N.m.r. of Nuclei other than ‘H and I3C A multi-nuclear n.m.r. study (lH, 13C, 51V)of the interaction of vanadate with monosaccharides has been published. Aldoses give rise to mono-, bi- and/or tridentate vanadate complexes depending on the number of consecutive &-disposed hydroxy groups available in their various tautomeric forms.48 The ‘H, 31P relayed spin-echo difference spectra of maltose 1-phosphate and D-glucose 1-phosphate have been reported. Use of this technique allowed
observation of the total sub-spectrum of the phosphorylated glucose residue of the di~accharide?~
244
Carbohydrate Chemistry
REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
40 41 42 43
44
C.A. Bush, Bull. Maen. Reson., 1988, 73. H. BaUmaM, Chem. Commun. Univ. Stockholm, 1988, g 47 (Chem. Abstr., 1989,110. 173 565). H. Ohrui, NipDon Noeei Kaeaku Kaishi, 1988,621251 (Chem. Abstr., 1989,110,95 646). K. Izumi, Kapaku Koevo, 19838-!, 918 (Chem. Abstr., 1989,110, 87 263). D.S. Rycroft, Nat. Prod. Chem., 1988, 43 (Chem. Abstr., 1989,111.39 682). B.E. Wilson, W. Lindberg, and B.R. Kowalski, J. Am. Chem. Soc., 1989,111.3797. M. Hricovini, I. Tvaroska, D. Uhrin, and G.Y. Batta, J. Carbohvdr. Chem., 1989, S, 389. I. Tvaroska, M. HricoVini, and E. Petrakova, Carbohvdr. Res, 1989,189. 359. J.R. Snyder, E.R. Johnston, and AS. Serianni, J. Am. Chem. Soc., 1989,111.2681. P. Dais and AS. Perlin, Carbohvdr. Res., 1989,194.288. J.V. Thomsen and B. Meyer, J. Maen. Reson., 1989,s 212 (Chem. Abstr., 1989,111.233 420). SJ.Angyal and R. Le Fur,J. Ow. Chem., 1989.54- 1!927. P. Herzyk and A. Rabczenko, J. Chem. SOC.,Perkin Trans. 2,1989,209. A. Cosse-Barbi, D.G. Watson, and J.E. Dubois, Tetrahedron Lett., 1 9 8 9 , s 163. K. Mizutani, R. Kasai, M. Nakamura, 0. Tamaka, and H. Matsuura, Carbohvdr. Re., 1989,185,27. M.I. Struchkova, S. Mikhailov, LN. Beigelman, and S.V. Yarotskii, Antibiot. Khimioter., 1988,33570 (Chem. Abstr., 1989,110. 173 570). V.A. Timoshchuk, T.M. Ermolenko, and A.A. Akhrem, Zh. Ore. Khim., 1988,241703 (Chem. Abstr.. 1989,110. 154 777). G.W. Buchanan and K Bourque, Maen. Reson. Chem., 1989,27- 200 (Chem. Abstr., 1989,111. 214 858). S.J. An&, D.C. Craig, and J. Kuszmann, Carbohvdr. Res., 1989,194. 21. E. Lee, P. McArdle, P. Browne, and N. Gavin, Carbohvdr. Res., 1989,191.351. S. Chen, D. Qiu, Z. Lm,Y Wang, and M. Cai, BoDuxue Zazhi. 1988, & 373 (Chem. Abstr., 1989,111. 39 ns). k Liptak and L. Szabb, J. Carbohvdr. Chem., 1989,S, 629. K. Bock, S. Ogawa, and M. Orihara, Carbohvdr. Res., 1989,191.357. R.M. Giuliano, R.F. Bryan, P. Hartley, S. Peckler, and M.K. Woode, Carbohvdr. Res.,1989,191. 1. R. Christian, E. Schreiner, E. Zbiral, and G. Schultz, Carbohvdr. Res., 1989,194.49. L A Buffington, D.W. Blackburn, C.L. Hamilton, T.C. Jarvis, J.J. Knowles, P.A. Lodwick, L.M. McAllister, D.J. Neidhart, and J.L. Serumgard, J. Am. Chem. Soc., 1989,111, 2451. G.W. Small and M.K. McIntyre, Anal. Chem., 1989,6l- 666 (Chem. Abstr., 1989,110. 135 603). AS. Shashkov, G.M. Lipkind, Yu A. Knirel, and N.K. Kochetkov, Maen. Reson. Chem., 1988, & 735 (Chem. Abstr., 1989,110. 154 729). G. Strecker, J.M. Wieruszeski, C. Martel, and J. Montreuil, Carbohvdr. Res., 1989,185. 1. G. Strecker, J.M. Wieruszeski, J.C. Michalski, and J. Montreuil, Glvcoconiufzate J.. 1989,G 67 (Chem. Abstr., 1989,111,233 423). J.B. Bouwstra, J. Kerekgarto, J.P. Kamerling, and J.F.G. Vliegenthart, Carbohvdr. Res.. 1989,186. 39. M. Jaseja, AS. Perlin, 0. Dubinsky, D. Christiaen, S. Arad, and R. Glaser, Carbohvdr. Res., 1989, &l 313. N. Platzer, D. Davoust, M. Lhermitte, C. Bauvy, D.M. Meyer, and C. Derappe, Carbohvdr. Res., 1989, 191.191. J. Dabrowski, K. Trauner, and K. Koike, Chem. Phvs. Lipids, 1988,49- 31 (Chem. Abstr., 1989,110, 115 218). J.E. Dubois, A Cosse-Barbi, and D.G. Watson, Tetrahedron Lett., 1 9 8 9 , s 167. P. Ram, L. Mazzola, and J.H. Prestegard, J. Am. Chem. SOC., 1989,111, 3176. D.E. Portlock, G.S. Lubey, and B. Borah, J. Ore. Chem., 1 9 8 9 , a 2327. M. Bernabe, A. Fernandez-Mayoralas, J. Jimenez-Barbero, M. Martin-Lomas, and A. Rivera, J. Chem. SOC..Perkin Trans. 5 1989, 1867. A. Neszmelyi, D. Machykta, A. Kmety, P. Sandor, and G. Lukacs, J. Antiobiot., 1989,421494. L Poppe, J. Dabrowski, C.W. Von der Lieth, M. Numata, and T. Ogawa, Eur. J. Biochem., 1989,180, 337 (Chem. Abstr., 1989,110. 135 593). G.M. Lipkind, AS.Shashkov, O.A. Nechaev, V.I. Torgov, V.N. Shibaev, and N.K. Kochetkov, Carbohvdr. Res., 1989,195. 11. G.M. Lipkind, AS.Shashkov, O.A. Nechaev, V.I. Torgov, V.N. Shibaev, and N.K. Kochetkov, Carbohvdr. Re., 1989,195.27. Y. Nishida, H. Hori, H. Ohrui, H. Meguro, K. Reimer, V. Sinnwell, and H. Paulsen, Tennen Yuki. Koeobutsa Toronkai Koen Yoshishu, 1988 -03 316 (Chem. Abstr., 1989,111.23 826). D.J. Craik, J.J. Gosper, and C.C.J. Culvenor, Aust. J. Chem., 1989, -24 541.
a
21: N.M.R. Spectroscopy und Conformational Feutures 45 46 47
48 49
245
G. Reznicek, J. Jurenitsch, G. Michl, and E. Haslinger, Tetrahedron Lett., 1989.30- 4097. AF. Casy and AD.Mercer, Maen. Reson. Chem., 1988,26- 765 (Chem. Abstr., 1989,111.39 721). H.K Wang, K He, L. Ji, Y. Tezuka, T. Kikuchi, and I. Kitagawa, Chem. Pharm. Bull., 1989,37- 2041. C.F. Geraldes and M.M. Castro, J. Inorg. Chem., 1 9 8 9 , s 79 (Chem. Abstr., 1989,110. 154 6%). P. De Waard and J.F.G. Vliegenthan, J. Maen. Reson., 1 9 8 9 , a 173 (Chem. Abstr., 1989,110. 154 736).
22
Other Physical Methods
1 1.r. Spectroscopy F.t.i.r. spectra of both anomers of a variety of peracetylated 2,4-dinitrophenyl Dgluco- and galacto-pyranosides' and peracetylated aryl 1-thioglycosides2 have been recorded. The anomers give characteristic absorptions. F.t.i.r. spectra of adducts formed between D-glucose and zinc(II), cadmium(II) and mercury(II) halides in the solid (KBr pellets) and in 'solution' (film cast) have been discussed in detail? 2 Mass Spectrometry Reviews have appeared on stereochemical and other applications of m.s. techniques in carbohydrates and other oxygen heterocycles (365 refs)4, and on the application of c.i.-m.s. for determining carbohydrate structure and reactivity? The fast atom bombardment (FAB)-m.s.-m.s. fragmentation patterns of heptaacetate daughter ions formed from disaccharide octaacetate primary ions have been used to identify the interglycosidic linkages and sugar constituents of disaccharides and their methyl glycosides.6 FAB-m.s. spectra of the a- and 8anomers of 1-C-D-glucopyranosylbenzene have been studied; the fragmentation patterns were established by FAB-collisional activation - MIKES methods, but no differences were observed between the a n ~ m e r s .The ~ intensity of the [M+H,NCH,C02Et]+ ion in the FAB-m.s. of permethylated monosaccharides in the presence of glycine ethyl ester hydrochloride was shown to be dependent upon the sugar configuration8 Acyl-linked glucuronides have been characterised by e.i.m.s. and both positive and negative ion FAB-m.s9 Hydrolysable tannins based on galloylated glucose gave [M-HI- and diagnostic fragment ions upon negative ion FAB-m.s. from an HMPA-glycerol matrix." While the positive and negative ion FAB-mass spectra could not be used to differentiate methyl a-D-galactopyranoside 2-, 3-, 4- and 6-(sodium sulphate), the metastable ion and collisional activation spectra of the [M+Na]+ and [M-Na]- ions could be used for this purpose." FABm.s. has been used to determine the structures of butaneboronate esters formed with monosaccharides,lh galactosides and glucosides.12b
22: Other Physical Methods
247
The mechanism of the cationisation of sucrose by sodium during laser desorption m.s. has been studied using a split probe on which the sucrose and sodium chloride were spatially separated.13 ERIAD-m.s. has been used to identlfy the products of periodate oxidation of sucrose.14 The four cyclic and one acyclic isomers of each of the four pertrimethylsilylated ketohexoses (sorbose, fructose, tagatose, and psicose) were separated and identified by capillary g.c.-e.i.-m.s.15 The e.i.-m.s. fragmentation patterns of pertrimethylsilylated aldononitriles have also been detailed.16 Further applications of coupled h.p.1.c.-m.s. systems have been detailed; a review on biomedical applications included a section on the analysis of carbohydrate^.'^ Capillary h.p.1.c. with gradient elution on a 0.22mm i.d. column using a 1 p1.min-1 liquid flow (which is equivalent to a 1 ml.min-1 gas flow), has been coupled to an e.i.- m.s. system with an improved ion source interface, and applied to glucose, sucrose, w-inositol, and the cyanogenic glucoside dhurrin. The glucose spectrum compared with those obtained by e.i., field ionization, field desorption and c.i. techniques.'* Thermospray h.p.1.c.-m.s. and -m.s.-m.s. have been used for the identification and determination of desulphoglucosinolates derived from plant material." The post-column addition of a reverse gradient to a salt gradient eluant avoided interface clogging and permitted the use of up to 0.8 M ammonium acetate buffer needed for the ion-exchange h.p.1.c.-thermospray m.s. analysis of an inositol phosphate mixture."') A preparative reversed-phase h.p.1.c. system, which employed detection by thermospray-m.s. on a split effluent flow in which 75-93% of the eluant is collected, has been used for the isolation from a crude reaction mixture containing three isomeric di-Q-cyclohexylidene-1,2,3,4,5,6[2&]-~-inositolsof the 1,2:4,5-i~omer.~'The trimethylsilyl ether and ester derivative of inositol triphosphate, which is not suitable for g.c. analysis, can be employed in capillary CO, supercritical-fluid chromatography-m.s.; chemical ionization (iso-C4Hl0)gave an MHf base peak, but e.i. - like spectra could also be obtainedF2 A capillary h.p.1.c. - coaxial continuous flow FAB-m.s.-m.s. system in which capillaries independently deliver eluant and FAB matrix to the ion source, has been used to obtain an MH+ ion peak on 230 pmol of the aminoglycoside antibiotic dihydrostreptomycin.23 H.p.1.c.-thermospray m.s. has been used for the analysis of nucleosides derived from DNA chemically modified by the action of the anticancer drugs mitomycin C and porfir~mycin?~
3 X-rav and Neutron Diffraction Crvstallograuhv
O-H****O-H * H-0. ***H-O)in which the Flip-flop hydrogen bonding k,, directionality is inverted dynamically even in the crystalline state, has been detected
248
Carbohydrate Chemistry
by neutron diffraction in crystaline pcyclodextrin undecahydrate by comparison of data at 120 and 293KZ Specific x-ray crystal structures have been reported as follows: Free Sugars and Simple Derivatives Thereof.- The inclusion complex of (R)phenylethylaminewith 2,3,4,6-tetra-Q-a~etyl-D-glucose.~~ Glvcosides and Derivatives Thereof.- 2,6-Dimethoxy-p-hydroquinone 1-0-4-Dgluc~pyranoside:~methyl 6-deoxys-D-idopyrano~ide,~ heptyl 1-thio-a-Dglucopyran~side:~sucrose.NaBr.2H20 (a redetermination)?' (su~rose)~(NaI),.3H~O?' methyl 2-Q-(a-D-mannopyranosyl)-a-Dmannopyranoside?2 methyl 4,6-Q-ethylidene-2,3-di-Q-nitro-aand 4-Dgl~copyranoside?~ 3-Q-benzoyl-4,5-Q-isopropylidene-and 2,3:4,5-di-Qisopropylidene-derivativesof methyl ~-D-gluco~eptanoside~~ flavanoid C-4-Doliosides (1) and (2)p5 and the C-glucoside aloin B (3).%
( 2 ) X =OH,R=We OAG
(4)
Anhydro-sugars.- Methyl 2,3-anhydr0-4-deoxy-pD-&-hexopyranoside~~and the anhydro-sugar-like material (4) and its stereoisomer epimeric at the asterisked carbon atoms?' Nitrogen- and Suluhur-containing Compounds.- The dioxopiperazine derivative (5) (from base treatment of methyl 2-amin0-2-deoxy-D-gluconate)?~ the
ox:l:
R\'"
bMe
2,4,6- MejC&
H
R = " I o H OH
H
$N
p-Br-C6Hq t-0 0
CH20H
(5)
H,N
CO
-eO)l, (6)
o+
x-N-h-C6ti+-0r(p)
-
0
(7) X = H (8)
x = OH
dehydroisoxazole derivative (6),402,6-anhydro-1-deoxy-1-nitro-D-glvcero-D-&- and D-glvcero-L-manno-heptitol and their 3,4,5,7-tetra-Q-acetates, 2,6-anhydro-l-deoxy1-nitro-L-manno- and D-galacto-hexitol,and 3,4,5-tri-Q-acetyl-2,6-anhydro-l-deoxy1-nitro-Gmanno- and D-&-hexitol?' 6-benzylamino-6-deoxy-l,23,4-di-Qisopropylidene-L-~vcero-a-D-~alacto-heptopyranurono~t~e~2 the branched-chain
22: Other Physical Methods
249
amino- and hydroxylamino-sugar derivatives, (7) and (8), respectively,” 6-thio-B-D-
fructopyranose,44and the thiosugar derivative (9) (an enzymic hydroxylation product from the antibiotic alb~mycin)!~
Yo;[ C02 M e
(’1)
Branched-chain Sugars.- Methyl 6-deoxy-3-C-rnethyla-L-mannopyrano~ide,~ the tricyclic lactone the 3-carboxymethyl-3-deoxy-sugar(11),48 the adduct (12) from levoglucosenone and nitr~methane?~ and the cyclobutanone derivative (13)”
(13)
(’4)
(15)
C02Me
(16)
Diuloses, Sugar Acids. and their Derivatives.- The cyclic fl,j?-isomericform (14)of D-threo-3,4-hexodiulose~’methyl 3,5-Q-benzylidene-1,2-Q-isopropylidene-B-L threo-D-gluco-octofuranuronate?2the acetal glucuronide derivative (15p3 the acyclic glucronate derivative (16p4 calcium galactarate?’ magnesium galactarate,” and 6-bromo-6-deoxy-L-ascorbic acid?7 Inorg;anic Derivatives.- The 5-deoxy-5-phosphinyl-D-glucosederivative ( 17):’ the branched-chain tin-containing sugar (119,’~(methyl 5-deoxy-@-D-ribofuranos-5yl)(pyridine) cobaloxime,60and the bis(glucos-3-Q-y1ated)titanate (19).6l
Alditols, Qclitols and Derivatives Thereof.- 4-(D-arabino-Tetritol-l-y1)-4imidazolin-2-ylideneammonium (4R,5R)-4-(D-arabino-l,2,3,4tetraacetoxybutyl)-1,2-dimethyl-5-nitro-l-cyclohexene,63 the D-gluco-pentitol-1-ylated anthraquinone derivative (20),641-(3,5-dimethy1-3-nitro-l-pyrazolin-4-yl)-penta-Q-
250
Carbohydrate Chemistiy
acetyl-D-~alacto-pentit01,6~ 1,2:3,4:5,6-tris-Q-[(diethylamido)thionophosphate] galactitol,& toxocarol (21)F7 and the 2-deoxy-~-inositolcamphanate derivative (22).@
Nucleosides and their Analogues and Derivatives.- 3-Methyladenosine ptoluenesulphonic acid salt:' 4-amino-6-chloro-l-/?-D-ribofuranosyl-pyrrolo[2,3-~]pyrimidine?' 8-amino-3-~-D-ribofuranosyl-l,2,4-triazolo[4,3-~]pyridazine~1 5(trifluoromethyl)-2 '-deoxyuridiney2973 5-methyl-2 '-deoxycytidine 5 '-phosphate?4 1(2-deoxy -/?-D-ribofuranosyl)-5-[(1S)-2,2-dibromocyclopropyl]uracil~5 2, ' 3,'5 ' -tri-Qacetyl-4-( 1,2,4-triazol-l-yl)~ridine~~ 2 ',3'-Q-isopropylidene-g~anosine,~~ 6,5 '-cyclo5 '-deoxy-4-thiouridine, 6,5 '-cyclo-5 '-deoxy-2 ',3'-Q-isopropylideneuridine,and 6,6 cyclo-5 ',6' -dideoxy-D-&-hexofuranosyluracil?8 the 8,s' -Q-cyclonebularine derivatives (23)?9 the urethane bridged cyclonucleoside (24),80 ethyl hydrogen I-
3 € 2 ) , 5 ' -anhydro-:! ' ,3 ' -Q-isopropylideneadenosine-8-phosphonate hemi(ethy1 acetate) solvate?' 6,l '-anhydro-6-hydroxy-l-(2-/l-D-psicofuranosyl)cytosine (25)82 and the analogous 8,l'-anhydro-8-hydroxy-9-(2-/?-D-psicofuranosyl) 3 amino-2 ',3 '-dideoxythymidinehydrochloride,84 3 '-azid0-2 ',3 '-dideoxy-l-/?-Derythro- and threo-pentofuranosyluracil,= 2,4,6-trichloro- and 4-amino-6-chloro-8(2,3-Q-isopropylidene-/l-D-ribofuranosylamino)pyrimido[5,4~]pyrimidine,% 3 deo~ythymidine,8~ 2 ',3 *-dideoxyadenosine,%1-(6-deoxy-/l-D-allo-and 6-deoxy-a-LI -
I-
talof~ranosyl)-cytosine,~~ 2 ',3 '-dideoxyformycin
2 ',3'-dideoxy-2 ',3'-
22: Other Physical Methods
25 1 0
(29
(26)
didehydrocytidine?' 1-(2-C-methyl-fl-D-ribofurano~yl)uracil,~ the 3-C-ally1 nucleoside (26),93 and l-(6-amino-9EJ-purin-9-yl)-l-deoxy-~-ethyl-pDribof~ranuronamide?~
Differences were observed in the e.s.r. spectra of the epimeric methyl 2,3,6-tri-Qbenzoyl-4-deoxy-4-hydroxylamino-a-D-glucoand -galacto-pyranosidesg' A one step synthesis of water-soluble spin-labelled glycosylamine derivatives involved condensation of amino-substituted &oxides with free sugars (see Chapter 10); e.s.r. spectra were recorded.%
5 Polarimetrv. Circular Dichroism and Related Studies A method to determine the absolute and relative stereochemistry of 1,2,3-triols of general formula RCHOH.CHOH.CH,OH has been reported. Derivatisation with 9anthroyl chloride gives the primary anthroate ester, then treatment with pmethoxycinnamoyl chloride gives the dicinnamate. The c.d. spectra of such derivatives are diagnostic.97 O.r.d., c.d. and U.V. data for nine acylated glucose, 1thioglucose, and 2-amino-2-deoxy-D-glucose derivatives have been reported, and spectral variations correlated with structureg' The chiroptical properties of thiazolidines derived from aldoses have been reported.* References 1 2 3 4 5
6
Y . Liu and Y. Ding, Fenxi Huaxue, 1 9 8 8 , s 498 (Chem. Abstr., 1989,110,115 210). Y. Ding and Y.Liu, Guanmuxue Yu Guanmu Fenzi, 1988, S, 14 (Chem. Abstr., 1989,110.154 721). H.-A. Tajmir-Riahi, Carbohvdr. Res. 1989,190,29. J.R.J. Pare, K. Jankowski, and J.W.ApSimon, Adv. Heterocvcl. Chem., 1 9 8 7 , s 335 (Chem. Abstr., 1989,110, 115 195). V.I. Kadentsev, LA. Trushkina, O.S. Chizhov, and A.G. Kaimarazov, Bioorg. Khim., 1 9 8 8 , s 1317 (Chem. Abstr., 1989,110, 213 179). B. Domon, D.R. Mueller, and W.J. Richter, Ore. Mass SDectrom,, 1989,24- 357 (Chem. Abstr., 1989, 111,233 405).
252 7 8 9 10 11 1% 12b 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
30 31 32 33 34 35 36 37 38 39
40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
Carbohydrate Chemistry W. Liang, D. Qui and M. Cai, Gaodene Xuexiao Huaxue Xuebao, 1988,e 630 (Chem. Abstr., 1989, 110.30 880). M. Sawada, L.Ouyang, Y. Takai, H. Yamada, and T. Hanafusa, Chem. Lett., 1989,1743. R.B. van Breemen, M. Stogniew, and C. Fenselau, Biomed. Environ. Mass SDectrom., 1 9 8 8 , z 97 (Chem. Abstr., 1989,111.39 763). R. Isobe, T. Tanaka, G. Nonaka, and I. Nishioka, Chem. Pharm. Bull, 1989,37- 1748. W. Henna, C. Versluis, W. Kulik, R.R. Contreras, and J.P. Kamerling, Biomed. Environ. Mass Spectrom., 1 9 8 8 , n 257 (Chem. Abstr., 1989,110. 193 231). L.Yan and Y. Fang, Huaxue Xuebao, 1 9 8 8 , s 1001 (Chem. Abstr., 1989,110. 154 707). Y.W. Fang, L. Yan, and XY. Liang, Yaoxue Xuebao, 1988,23- 895 (Chem. Abstr., 1989,111.39 719). M.P. Chiarelli and M.L. Gross, Int. J. Mass SDectrom. Ion Processes, 1 9 8 7 , z 37 &hem. Abstr., 1989,110.75 900). A.A. Derzhavets, O.A. Mirgorodskaya, L.V.Poletaeva, and P.N. Potapov, Khim. Prir. Soedin., 1988, 687 (Chem. Abstr., 1989,111.39 724). A. Garcia-Raso, M. Fernandez-Diaz,M.I. Paez, J. Sanz, and I. Martinez-Castro,J. Chromatoer., 1989, 471. 205. EM. Rubino, J. Chromatoer., 1989,473. 125. KB. Tomer and C.E. Parker, J. Chromatom., 1989,492. 189. G. Stenhagen and H. Alborn, J. Chromatom., 1989,474,285.
C.E.M. Heermans, R AM. van der Hoeven, W.M.A Niessen, J. Vuik, R.H. de Vos, and J. van der Greef, J. Chromatom., 1989,472.219. F. Hsu and W.R. Sherman, J. Chromatoer., 1989,479,437. F. Hsu, S. Ghosh, and W.R. Sherman, J. Chromatom., 1989,478.429. J.D. Pinkston, D.J. Bowling, and T.E. Delaney, J. Chromatoer., 1989,474.97. M.A. Moseley, L.J. Deterding, K.B. Tomer, and J.W. Jorgenson, J. Chromatom., 1989,480.197. S.M. Musser, S.-S. Pan, and P.S. Callery, J. Chromatom., 1989, 474, 197. 153 (Chem. Abstr., J.E.H. Koehler, W. Saenger, and W.F. Van Gunsteren, Eur. BioDhvs. J., 1988, 1989,110.20 102). 80 (Chem. Abstr., 1989,111.233 388). E. Francotte and G Rihs, Chirality, 1989, H. Otsuka, M. Takeuchi, S. Inoshiri, T. Sato, and K. Yamasaki, Phvtochemistrv, 1989, 28- 883. RM. Giuliano, R.F. Bryan, P. Hartley, S. Peckler and M.K. Woode, Carbohvdr. Res., 1989,191. 1. H.A. van Doren, R. van der Geest, F.van Bolhuis. R.M. Kellogg, and H. Wynberg, Carbohvdr. Res., 1989,194. 79. C.A. Accorsi, F. Bellucci, V. Bertolasi, V. Ferretti, and G. Gilli, Carbohvdr. Res. 1989,191,105. C.A. Accorsi, V. Bertolasi, V. Ferretti, and D. Gilli, Carbohvdr. Res., 1989,191,91. T. Srikrishnan, M.S. Chowdhary, and KL. Matta, Carbohvdr. Res., 1989,186.167. Yu.T. Struchkov, V.F. Sopin, G.N. Marchenko, R.G. Zhbankov, N.V. Ivanova, T.E. Kolosova, and LK. Prikhodchenko, Kristallomafiva, 1989.34- 632 (Chem. Abstr., 1989,111,124 255). S.J. Foster, VJ. James, and J.D. Stevens, Acta Crvstallom., Sect. C, 1989, & 1329. S. Kitanaka, K. Ogata, and M. Takido, Chem. Pharm. Bull., 1 9 8 9 , z 2441. H.W. Rauwald, K Lohse, and J.W. Bats, Aneew. Chem. Int. Ed. En&, 1989, 28- 1528. J.W. Krajewski, Z Urbanczyk-Lipowska,P.Gluzinski, and ABanaszek, Carbohvdr. Res., 1989,194.31. N. Hirayama and K Shirahata, Acta Crvstalloer., 1989, c45.151. k Perael, M. Hollosi, J. Csaszar, V. Fulop, A. Kalman, and G.D. Fasman, Carbohvdr. Res., 1989, 187. 187. M. De Amici, C. De Micheli, A. Ortisi, G. Gatti, R. Gandolfi, and L. Toma, J. Orp. Chem., 1989,54, 793. J. Kopf, C. Topf, and P. KO11 Carbohvdr. Res., 1989,186. 1. E. Miler-Srenger, Carbohvdr. Res., 1989,195. 1. 7. R. Kind, K Hatter, A zeeck,K Schmidt-Btise, and E. Egert, J. Antibiot., 1989, RJ . Woods, KA. Watson, K. Trouton, S. Fortier, and W.A. Szarek, Carbohvdr. Res., 1989,193.1. Y. Nawata, Y. IshitaN, I. Matsuura, H. Oishi and K. Ando, Acta Crvstalloer..Sect. C, 1989, & 1112. R.M. Giuliano, S. Kasperowicz, W.J. Boyko, and A.L. Rheingold, Carbohvdr. Res., 1989,185.61. I. Panfil, C. B e h k i , M. Chmielewski, and K Suwinska, Tetrahedron, 1989,45- 233. M. Shiozaki, N. Ishida, and S. Sato, Bull. Chem. SOC. h n . , 1989,62- 3950. A.C. Forsyth, R.M. Paton, and I. Watt, Tetrahedron Lett., 1 9 8 9 , a 993. H. Redlich, J.B. Lenfers, and J. Kopf, Aneew. Chem. Int. Ed. Enel., 1989.28- 777. S.J. Angyal, D.C. Craig, and J. Kusmann, Carbohvdr. Res, 1989,194.21. J.C. Barnes, J.S. Brimacombe, and G. McDonald, J. Chem. SOC. Perkin Trans.. 1,1989,1483. J. Antel, G.M. Sheldrick, B kiting, and L-F.Tietze, Acta Cmtallom., 1989, c45.60. 0. Kanie, T. Takeda, Y. Ogihara, and K Hatano, Carbohvdr. Res., 1989,193.271. B. Sheldrick, W. Mackie, and D. Akrigg, Acta Crvstalloer.. Sect. C, 1 9 8 9 , s 191. B. Sheldrick and W. Mackie, Acta Cmtallom.. Sect. C, 1 9 8 9 , s 1072.
22: Other Physical Methods 57 58 59 60 61 62 63
64 6s 66 67 68 69 70 71 72 73 74 75 76 77 78 79
80 81 82 83 84 85 86
87 88 89 90
91 92 93 94
95 %
97 98 99
253
Z Ruzic-Toros, B. Kojic-Prodic, D. Horvatic, AS. Suskovic, Acta Crvstallom, Sect. C, 1989,
269. T. Richter, P. Luger, T. Hanaya, and H. Yamamoto, Carbohvdr. Res., 1989,193.9. P.J. Cox, S.M.S.V. Doidge-Harrison,R.A. Howie, LW. Nowell, OJ. Taylor, and J.L Wardell, J, Chem. Sot.. Perkin Trans..l,1989,2017. W. Clegg, R.J. Anderson, and B.T. Golding, Acta Clvstallom.. Sect. C, 1989,s383. M. Riediker, A. Hafher, V. Piantini, G. Rihs, and ATogni, Aneew.Chem.Int.Ed.Enel.,1989,28- 499. A.L. Castro, R. Vega, J. Fernandez-Bolanos, and M.A. Barragan, Carbohvdr. Re., 1989,187.139. J. Loub, J. Podlahova, J. Kopf, and L. Walz, Acta Crvstallom.. Sect. C, 1989,& 1082. 0.Johnson,D.W. Jones, R.G. Hazell, and B. Sheldrick, Acta Crvstalloer., 1989,-123. C.F. Conde and A. Conde, Acta Crystalloer.,Sect. C, 1989,& 1563. LA. Litvinov, LI. Gurarii, and E.T. Mukmenev, Izv. Asad. Nauk SSSR.Ser. Khim., 1988,1408 (Chem. Abstr., 1989,110.24188). Z Zhang and M. Zhang, Jieeou Huaxue, 1987,& 128 (Chem. Abstr., 1988,m 167 846). R. Baker, J.J. Kulagowski, D.C. Billington, P.D. Leeson, LC. Lemon, and N. Liverton, J. Chem. Sot, Chem Commun., 1989,1383. T. Fujii, T. Sat0 and T. Date, Chem. Pharm. Bull., 1989, 1208. J.D. Anderson, RJ. Bontems, S. Geary, H.B. Cottam, S.B. Larson, S.S. Matsumoto, D.F. Smee, and R.K. Robins, Nucleosides Nucieotides, 1989,s1201. S.B. Larson, Y. Kang, G.R. Revankar, and R.K. Robins, Acta Crvstalloer., Sect. C, 1989,fi 1093. T. Sato, Anal. Sci, 1989, 117 (Chem. Abstr., 1989,111.58 243). T.N. Low, P. Tollin, and R.A. Howie, Acta Crvstallom., 1989,-99. H.N. Lalitha, S. Ramahmar, and M.A. Viswamitra, Acta Crvstalloer.. Sect. C,1989,& 1653. S.A. Moore, B.D. Santarsiero, T. Lin, M.N.G. James, M. Tandon, L.I.Wiebe, and EE Knaus,-A Crvstalloer.. Sect. C, 1989,s647. C. Smykalla, J.M.M. Smits, G. Beurskens, P.T. Beurskens, E.A.V. Rijk,and G.I. Tesser, J. Crvstalloer. Spectrosc. Res, 1988,ltJ, 457 ($hem. Abstr., 1989,110.31691). S.S.Mande, T.P. Seshadri, and M.A. Viswamitra, Acta Crvstalloer., 1989,c45.92. Y. Yamagata, K. Tomita, H. Usui, T. Samo, and T. Ueda, Chem. Pharm. Bull, 1989, 1971. H. Hayakawa, H. Ashizawa, H. Tanaka, T. Miyasaka, and K. Yamaguchi, &cleosides Nucleotides, 1989,& 1287. K Minamoto, N. Shiomi, K. Knodo, S. Eguchi, M. Honda, C. Katayama, A. Katayama and J. Tanaka, 571. Bull. Chem. Soc. JDn., 1989, Y. Yamagata, K. Tomita, T. Maruyama, and M. Honjo, Nucleosides Nucleotides, 1989,&213. G.V. Gurskaya, G.M. Dzhavadova, S.G. Zavgorodnii, V.L. Florent’ev, and B.P. Gottikh, Bioorg, Khim.. 1987,G 1382 CChem. Abstr., 1989,109,23295). G.V. Gurskaya, G.M. Dzhavadova, AN. Sobolev, N. Yu. Chernikova, S.G. Zavgorodii, V.L Florent’ev, and B.P. Gottikh, Bioorg. Khim., 1987,a 1388 CChem. Abstr., 1988,109,23 2%). G.V. Gurskaya, E.N. Tsapkina, S.V. Lindeman, Yu. T. Struchkov, and A.A. Kramkii, Dokl. Akad. Nauk. SSSR, 1988,303.1378CChem. Abstr., 1989,111,58241). J.N. Low and P. Tollin, Acta Crvstalloer.. Sect. C, 1989,s 664. S.B. Larson,Y.S.Sanghui, G.R. Revankar, and R.K. Robins, Acta Crvstalloer.. Sect. C, 1989,G 1194. M. Auer, C. Krieger, M. Gautel, S. Labeit, G. Sczakiel, S. Weiss, and R.S. Goody, Nucleosides Nucleotides, 1989,g 849. C.K. Chu, V.S. Bhadti, B. Doboszewski, ZP. Gu, Y. Kosugi, K.C. Pullaiah, and P. Van Roqr, J. Or& chem,1989,% 2217. G.M. Dzhavadova, G.V. Gurskaya, E.SL Gorelik, and S.N. Mikhailov, Kristalloerafiva, 1988, 1408 (Chem. Abstr. 1989,111.7728). S. Neidle, L. Urpi, P. Serahowski, and D. Whitby, Biochem. BioDhys. Res. Commun., 1989,161.910 (Chem. Abstr., 1989,111, 70 328). G.I. Birnbaum, J. Giziewicz, T.-S. Lin, and W.H. Prusoff, Nucleosides Nucleotides, 1989,& 1259. E.N. Tsapkina, G.M. Dzhavadova, G.V. Gurskaya, LN. Beigelman, S.N. Mikhailov, and S.V. Lindeman, Kristalloerafiva, 1988, 1415 (Chem. Abstr., 1989,111.7229). CK. Chu, B. Doboszewski, W. Schmidt, and G.V. Ullas, J. Ore. Chem., 1989,s2767. W.H. Moss, H.W. Hamilton, D.F. Onwine, M.D. Taylor, and AT. McPhail, Nucleosides. Nucleotides, 1989,5449. J.M.J. Tronchet, N. Bizzozero, and M. Geoffroy, Carbohvdr. Res., 1989,191,138. G. Sosnovski and N.U. Maheswara Rao, Carbohvdr. Res., 1989,190.C1. W.T. Wiesler, and K. Nakanishi, J.Am. Chem. Soc, 1989,111.3446. K. Satsumabayashi and Y.Nishida NiDDOn Shika Daieaku Kivo. IDDan Kvoiku-kei, 1987,& 89 (Chem. Abstr., 1989,110.154753). Z Gyorgydeak, A. Levai, and G. Snatzke, F.E.C.S. Int. Conf. Circ. Dichroism, proc.] 1985 (Pub. 1987). 352 (Chem. Abstr, 1989,110.76016).
a
23
Separatory and Analytical Methods
1 Chromatomaphic Methods Gas-Liquid Chromatomaphv.- Unless otherwise stated, all analyses were performed on capillary g.c. columns. The separation on several columns of the isomeric forms of several aldohexoses' and the four ketohexoses (fructose, psicose, sorbose and tagatose)2 as their pertrimethylsilyl ether derivatives has been reported, and a mathematic approach used in an attempt to relate retention times to structures. Monosaccharides can be identified by Curie-point pyrolysis (358") and g.c. analysis (packed column) of the volatile products since fragments characteristic of the sugar class (= hexose, pentose, deoxy-sugar, uronic acid, alditol and amino-sugar) were obtained? Sugars and polyols in biological fluids have been determined quantitatively by g.c. of their pertrimethylsilyl ether derivatives: D-Arabinitol is a Candida metabolite, and can be used as a diagnostic marker of infection. Levels of D- and Garabinitol, with ribitol as internal standard, have been determined by dual column g.c. of their heptafluorobutyrate derivatives, the mixture of alditol derivatives being collected from the first column by cold trapping and separated on the second bonded chiral phase column? Mannitol, galactitol, glucitol and m-inositol have been determined in biological samples by g.c.-m.s. as their tris(buty1boronate) derivatives in runs of 4 minute duration. The application of flame ionisation, flame photometric and c.i.-m.s. detection, and the use of packed columns were also investigated: A series of aldoses has been reductively aminated (NaBH3CN) with octadecylamine to give hydrophobic conjugates as model compounds in the g.c.-m.s. analysis (as the N-acetylated 0-trimethylsilyl ether derivatives) of reductively aminated oligosaccharides from the StreDtococcus pneumoniae capsular polysaccharide? Isosorbide dinitrate and its metabolites have been assayed in plasma by g.c. with electron-capture detection? Methods have been developed to reveal the presence and the position of phosphate ester moieties on sugars. Phosphorylated sugar constituents, KDO, heptoses and glucosamine, in bacterial polysaccharides were detected by comparison
255
23: Separarory arid Analytical Methods
of the results obtained by methanolysis - pertrifluoroacetylation - g.c. analysis before and after reaction with conc. hydrogen fluoride (48% w/w in H,O) at room temperature. This treatment dephosphorylates without cleaving glycosidic linkages. Without this treatment, the phosphorylated residues are not detected? A methylation analysis procedure for synthetic disaccharides composed of reducing sugars linked non-glycosidicaly by phosphate ester groups, as in compound (1),has been devised. A five step reduction sequence (i, NaBD,; ii, CH2N2-EQO;iii, NaOH-MeI-DMSO; iv, LiAIH,; v, Ac,O-py) provides partially methylated alditol acetate derivatives for g.c.-m.s. analysis." O-a-D-Galactopyranosyl-saccharinic acids such as compounds (2) and (3) have been identified by g.c.-m.s. of their pertrimethylsilyl ether derivatives." CH2*\._
0
0
CO H
CH2OH
m~P+Q-o
H0-+Ye
140/H ,
HO QOH
OH
fH2
0H
oc-0 -C-al-p
-0
V O H
C" 2
I-
OH
The relative merits of a variety of derivatisation procedures in the g.c. analysis of monosaccharides have been examined in detail. While pertrimethylsilylated Q-methyloxime derivatives were concluded to be the best for the separation of simple mixtures, two new procedures were developed to enable the separation of more complex mixtures. Sequential Q-benzyloximationpertrifluoroacetylation permitted the best resolution to date of the %-C6 aldoses and the corresponding alditols, but complications interfered with the quantitative analysis of ketoses. Pertrimethylsilylated 0-benzyloximes were particularly useful for C, sugars, ketohexoses and mixtures of sugars, alditols, and lactones.12 A procedure for g.c. analysis of aldoses as their peracetylated Q-pentafluorobenzyloxime derivatives (Vol. 23, p.245) has been modified to permit amino-sugars (GlcNAc and GalNAc) to be determined as well. The method, using a shorter column (6 m cf. 15 m) and helium carrier gas of increased purity, was applied to the analysis of sugars in known g1y~oproteins.l~ A procedure has been defined for the rapid quantitative analysis of free sugars (tetroses to disaccharides) and related compounds (43 in total) in plants at the 1% level. After extraction with cold ethanol, the sugars are converted to peracetylated aldononitriles, ketoximes, alditols and non-reducing sugars for g.c. ana1y~is.l~ The analysis of aldoses by g.c. and g.c.-m.s. as their pertrimethylsilylated aldono-nitriles has been reported, using a new derivatisation procedure [i, H2NOS03H-Et3N;ii, N,Q-bis(trimethylsily1)-trifluoroacetamide]which is claimed to give a single product peak for each ~accharide.'~
256
Carbohydrate Chemistry
Thin-Laver Chromatoeraphy.- A review of the current status of planar chromatographic techniques, essentially t.l.c., in biomedicine has included sections on carbohydrates, gangliosides and cerebrosides.l6 High performance t.1.c. of monoto oligo-saccharide mixtures on silica using the forced-flow technique has been reported.17 a- and 4-C-glycosides with aromatic substituents,18and the dansylhydrazone derivatives of unsaturated disaccharides produced enzymically from chondroitin sulphates,lg have been separated on silica plates. High-pressure Liquid Chromatography- Reviews on the biomedical applications of h.p.l.c.-m.s.,m and immobilised enzyme reactors in h.p.1.c. detector systems?l have included carbohydrate applications. A new detector with considerable promise for use with underivatised carbohydrates eluted from microbore h.p.1.c. columns (1.0 mm id), a refractive index gradient detector, has been demonstrated with the separation of fructose and sucrose on a normal phase column. The apparatus is relatively simple and relies upon angular deflection of a 780 nm laser beam onto a position-sensitive detector. Good linearity and reproducibility were attained, and detection limits (a 1 ng) were three orders of magnitude lower than with commercial refractive index detectorsF2 The use of an evaporative light scattering detector in sugar analysis has been described, in which a silica-based diol phase was preferred to aminopropylsilica because it permitted gradient elution with good sensitivity of detection (30-50 ng).= a- and 8-Qclodextrin silica-bonded phase columns are an interesting new development. When used in the separation of 50 mono- to tetra-saccharides, deoxysugars, and alditols with water-organic solvent eluant combinations, they proved more efficient and selective than bonded-phase alkylamine and ion-exchange columns. Retention was related to molecular size and number of available hydroxygroups in the solute.% Additionally, anomeric pairs of 16 free sugars and of 18 glycosides were separated on such columns.25 New developments in the separation of mono- and di-saccharides on anionexchange columns using alkaline eluants and pulsed amperometric detection have been reported.% The major monosaccharides (Glc, Gal, Man, Ara and Xyl) in soil hydrolysates have been determined by h.p.1.c. on a polystyrene-based Pb2+-form cation-exchange column. Minor sugars (Rha and Fuc) co-eluted with major c0mponents.2~ Enantiomers of diginose (2,6-dideoxy-3-Q-methyl-&-hexose) and cymarose, oleandrose and digitoxose (all 2,6-dideoxyhexoses) have been resolved by h.p.1.c. as their methyl glycoside Q-3,5-dinitrophenylcarbamate derivatives on chiral amine-
23: Separarory und Analytical Merhods
257
bonded silica columns.28929 Enantiomers of digitoxose?’ rhamnose and lyxose were similarly separated as carbamate derivatives of their acet0nides.2~ H.p.1.c. on a pellicular anion-exchange resin (Dionex HPIC-AS6, a 10 fim substrate coated with a monolayer of anion-exchange latex) with a strongly alkaline eluant and pulsed amperometric detection, has given extraordinarily good separations of homologous series of (1+2)-, (1+3)-, (1+4)- and (1+6)-linked a- or 8D-gluco-oligosaccharidesup to DP2 50?l and of cyclodextrins, branched cyclodextrins and cyclo-sophoraoses with DP’s in the 6-25 range?2 The drug carrier ‘2-hydroxypropyl-~-cycyclodextrin’ of DS 0.4, which is a mixture of variously ablated derivatives, has been determined in plasma by reversed-phase extraction followed by h.p.1.c. on a size exclusion column (diol bonded-silica) with indirect colorimetric detection using the ability of the derivatives to bind phen~lphthalein?~ The specific detections of the galactose-containingoligosaccharides stachyose, raffinose and melibiose, along with galactose, in the aqueous h.p.1.c. eluant from a cation exchange resin, have been achieved with a post-column enzyme reactor with co-immobilised galactose oxidase/peroxidase coupled to a fluorimetric detection system for the H,O, generated.34 Homologous series of a-( 1+6)-D-gluco-oligosaccharides(DP 1-13 and 6-20), chito-oligosaccharides(DP 1-5), and oligosaccharides released from ovomucoid by hydrazinolysis, have been reductively aminated (NaBH3CN) with 2-aminopyridine and fractionated by size on a Na+-form cation exchange resin eluted with aqueous acetonitrile containing NaOAc or Et3N*HOAc to suppress protonation of the derivative^.^^ Lactosamine and 34 mixed-type and oligo-mannoside-type oligosaccharidesfrom glycoproteins and glycopeptides have been converted to &(4methylcoumarin-7-y1)glycaminesby reductive amination and separated by h.p.1.c. on reversed-phase and size exclusion column^?^ Oligosaccharides released from Klebsiella Dneumoniae OIKl lipopolysaccharide on mild hydrolysis have been separated on a silica-based anion exchange c0lumn.3~ Modified procedures have been detailed for the direct cleavage of perbenzoylated (especially per-bromobenzoylated) oligosaccharides convenient for microscale analysis of the derived monomers by h.p.1.c. separation and u.v., c.d. and m.s. characterisation. Reaction with bromoacetyl bromide and water (which generates HBr-BrCH,CO,H) yielded glycosyl bromides and bromoacetates of the liberated alcohols without benzoyl migration. The glycosyl bromides were converted to methyl glycosides, the bromoacetate groups removed with thiourea, and the liberated hydroxy-groups cinnamoylated to yield the desired monomers?’ A systematic study on the elution profiles of structurally related isomeric benzyl and nitrophenyl glycosides of mono- to tetra-saccharides on a Waters Carbohydrate Analysis column has been reported?’
258
Carbohydrate Chemistry
The h.p.1.c. analysis of naturally occurring monoterpene, cyanogenic, and coumarin glycosides and saponins on a recently developed hydroxyapatite column revealed a correlation of elution behaviour with that obtained on silica gel t.lca Reversed-phase analyses of maysin [6-Q-(2-Q-a-L-rhamnosyl-6-deoxy-L-~-hexos-4ulosyl)luteolin], the flavonoid glycoside in corn silks that is toxic to corn earworm:’ monolignols and their glucosides:2 and secondary cardiac glycosides in Digitalis puqurea leaves43 have been reported. Narrow-bore h.p.l.c.(0.22 mm id, 3 or 5 pm silica particles)-e.i.-m.s. with gradient elution has been applied to glucose, sucrose, w-inositol, and the cyanogenic glucoside dhurrh4 Reversed-phase h.p.1.c.-thermospray m.s. and m.s.m.s. has been used to identify and determine desulphogluco-sinolates derived from plant rnateria1.4~ The phenolic constituents, including galloylglucoses and acyl-glucoses, in rhubarb (Rhei Rhizoma) have been determined by reversed-phase h.p.l.c.,& and the stevia food sweeteners, diterpene oligosaccharide glycoside/glycosyl esters such as stevioside, by h.p.1.c. on a primary amine bonded silica c0lumn.4~ Galactosamine, glucosamine and 26 amino-acids have been analysed by h.p.1.c. as their N-phenylthiocarbamate derivatives.48 Unsaturated disaccharides generated by enzymic cleavage of heparin sulphates have been separated on a polystyrenebased cation exchange resin:’ while unsaturated disaccharides with 0-3 sulphate moieties similarly released from chondroitin sulphate, have been separated on a primary amine gel, with post-column reaction with 2-cyanoacetamide and fluorimetric detection?’ The reversed-phase analysis of l-S-(fl-Dglucopyranosy1)amobarbital diastereomers in urine has also been reported?’ Low molecular weight organic solutes in marine algae, including altritol, mannitol and volemitol, have been assayed on silica modified with amine in the eluant?’ Inositol phosphate mixtures have been separated and analysed on an ionexchange h.p.1.c.-thermospray m.s. system that permitted post-column addition of a reverse gradient so that a high salt gradient eluant could be used?3 The trimethylsilyl ether/ester derivative of an inositol triphosphate has been analysed by capillary SFC (supercritical CO, - fluid chromatography)-c.i.-m.s.’4 Preparative reversed-phase h.p.1.c. of three di-Q-cy~lohexylidene-l,2,3,4,5,6-[~H&~m o inositol isomers was conducted on a system that employs detection by thermospray-m.s. on a split effluent flow such that 75-93% of the eluant is collected?’ A ‘solid injection technique’ for applying relatively insoluble samples to preparative h.p.1.c. columns, which involved packing a powdered sample mixed with silica into a pre-column, has been demonstrated using the purification of N-butyl-1-deoxynojirimycin as an example.56
23: Separurory and Analyticul Methods
259
A variety of h.p.1.c. methods have been used to analyse sugar acids and their conjugates. A versatile, rapid ion-pair reversed-phase method using cethexonium bromide, has been described for the separation of alcohols, phenols, steroids and carboxylic acids and their glucuronic acid conjugates in biological systems, and used to monitor in vivo glucuronidation of clofibric acid.57 The mixed saponins in GvpsoDhila extracts have been quantified by conversion to the single acid-stable gypsogenin 3-0-glucuronide by acid hydrolysis and ion-pair reversed-phase h . p . l . ~ . ~ ~ The triterpene glucuronic acid disaccharide glycyrrhizin and its aglycon have been determined in plasma on a reversed-phase c0lumn,5~phenols and their glucuronic acid and sulphate conjugates on a strong anion-exchange column,6oand carbohydrate substrates and metabolites (Glc, GalA, gluconic acid and galactonic acid), along with other compounds in mammalian cell cultures, on a strongly-acidic cation-exchange resin in the H+-form.61 The h.p.1.c. analysis of KDN (3-deoxy-Dglycero-D-galacto-2-nonulopyranosonic acid) and N-acetyl-D-neuraminic acid on a strongly-basic anion-exchange resin has been applied to their determination in fertilized eggs of Chum salmon.62 Sialo-oligosaccharidesreleased from gangliosides have been chromatographed on tryptamine- or serotonin-bonded silica, while &acetyl- and N-glycolyl-neuraminic acids have been separated on a novel silica-bound wheat germ agglutinin stationary p h a ~ e . 6 ~ Ascorbic and dehydroascorbic acids in plasma and cerebrospinal fluids,64 and common water-soluble antioxidants including ascorbic acid in biological samples,65 have been determined by reversed-phase h.p.1.c. with electrochemical detection. In a study of chromium toxiciy, ascorbic acid and chromium(VI) in biological samples have been simultaneously analysed on an anion-exchange column.66 The principal anionic components in wine and soft drinks, including ascorbate, have been determined using ion-interaction reversed-phase chromatography, using C, or C, allrylamines with salicylic acid as ion-interaction reagents." The aminoglycoside sisomicin and its 1-ðyl derivative, netilmicin, have been determined in blood and dried blood by precolumn derivatization with uphthalaldehyde and p-mercaptopropanoic acid and reversed-phases analysis.68*69 Dihydrostreptomycin has been used in the exemplification of capillary h.p.1.c.-coaxial continuous flow FAB-m.s.-m.s. in which capillaries independently deliver eluant and FAB matrix to the m.s. source?' A number of papers on the reversed-phase h.p.1.c. analysis of nucleosides and related compounds have appeared. The analysis of both the major and modified ribonucleosides present in nucleic acids and biological fluids using photodiode array detection has been critically reviewed. Retention times under standardised chromatographic conditions and u.v.-data, along with the preparation of samples from various RNA's, are dealt with in detail?l Useful increases in the retention of
Curbohydrute Chemistry
260
nucleotides was achieved by addition of metal ions ( K', M$+, Mn2+, Ni2+, Zn2+) to the eluant, while nucleoside retention was unaffected?2 The advantages of microcolumn h.p.1.c. using 50 and 250 pm id fused silica columns with 70-100 x Id theoretical plates and miniaturized U.V. detection have been exemplified by the simultaneous analysis of nucleosides, bases, and n~cleotides?~Other applications have been to the determination in biological samples of the ratio of deoxyguanosine to deoxythymidine in complex mixtures of ribo- and deoxyribo-nucleoside~?~ cytosine arabinoside and uracil arabinoside?' 2 ',3 '-dideoxycytidine:6 adenosine and its cyclic 3 ',5 '-monophosphate," 5-bromo-2 '-deoxyuridine and its free base?' 5-brom0-5-deoxyuridine?~and trace levels of AZT (3 '-azido-2 ',3 dideoxythymidine) using on-line preconcentration on a Ag(1)-thiol stationary phase.s0 Modified nucleosides formed from the action of the anticancer drugs mitomycin C and porfiromycin on DNA have been analysed by h.p.1.c.-thermospray I-
mssl
The h.p.1.c. separation of 2 and 3 '-0-acyl derivatives of uridine and their 5 '-Q-monomethoxytrityl derivatives has been used in a study of acyl migrations2 Ion-pair reversed-phase h.p.1.c. separations of purine nucleosides, bases and nucleotides in cells, employing various ion-pairing and of pseudouridine and creatinine in urine for monitoring patients with cancer,% have been reported. A vinyl alcohol copolymer column (Asahipak GS-320H), which works by both adsorption and gel permeation mechanisms, proved best for the h.p.1.c. analysis of adenine compounds including nucleosides and nucleotides following derivatisation with chloroacetaldehyde. Detection limits of 0.17-0.5 pmoVlO p1 injection were attained using fluorescence detections' 2 ',3'-Dideoxycytidine and AZT have been analysed in plasma by preconcentration on a glycine-phenylalanine-phenylalanine silica column then chromatography on two pcyclodextrin-bonded silica columns in series.= The immunosuppresive imidazole-nucleoside mizoribine in human serum has been chromatographed on primary amine bonded silica?' and 3H-labelled cytosine arabinoside and eight metabolites in cell extracts have been analysed on a silica-based ion-exchange column with U.V. and scintillation counter detection.= I-
Column ChromatoPraphy.- An anion-exchange resin chromatographic procedure for the analysis of sugars in polysaccharide hydrolysates has been described. Using a boric acid-containing eluant (pH 8.4-8.8) and post-column colorimetric derivatisation the analysis was complete inside 4 h. The main advantages over previous systems were that no regeneration of the column was required between analyses, and no special pretreatment of the hydrolysate was required.89 The sorption and diffusion characteristics of glucose, maltose and maltotriose in silica gels, required for the design of large scale gel permeation chromatographic separations, have been
23: Separarory and Analytical Methods
26 1
evaluated using chromatographic responses.g0 The Stokes radii of hyaluronate oligosaccharides have been calculated from the chromatographic behaviour of evennumbered di- to hexadeca-saccharides on size-exclusion meia (Sephadex G-25, -50 and -75)?' Partition ChromatoPrauhy.- A dual-flow countercurrent extraction procedure for the continuous separation of glucosides has been applied to phenyl fl-Dglucopyranoside and esculin9 Further applications of centrifugal partition chromatography to the separation of labile oligomeric hydrolysable tann ,i.nfsc( Vol. 20, p.254) have been reported.= 2 Other Analytical Methods Amino-sugars, alditols and acidic sugars have been detected by electrocatalytic oxidation on a copper-containing electrode produced by deposition of a CuClcontaining crystalline species on to glassy carbon. This electrode is readily adapted for use in flow-injection analysis and h.p.l.c., giving detection limits in the nano- to pico-gram range." A maltose-specific amperometric enzyme electrode based on an oligosaccharide dehydrogenase-modifiedcarbon paste electrode containing gbenzoquinone, has been de~cribed.9~ Reducing carbohydrates produced fluorescence when heated with eight 1,2diarylethylenediaminesin meso- or DL-form. The most favourable reagent, mesol72-bis(4-rnethoxyphenyl)-ethylenediaminepermitted sensitive fluorimetic detection of reducing sugars including 2-deoxy-sugars, amino-sugars, and sialic acids at concentrations as low as 0.2-0.9 nmol.ml-'.% A new colormetric method has been proposed for estimating 2-deoxy-3-Cmethyl branched-chain sugars, such as (4) (Scheme 1). Thus treatment with periodate affords acetylacetaldehyde (5) which is condensed with 2-thiobarbituric acid to give the chromophore (6) with an absorption maximum at 372
Sugar solutions have been desalted by electrodialysis using an ion-exchange membrane ?'
262
Carbohydrate Chemistry
References 1 2
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 38 39 40 41 42 43 44 45
46 47 48 49 50
51 52 53
I. Martinez-Castro, M.I. Paez, J. Sanz, and k Garcia-Raso, J. Chromatom., 1989, 462.49. A. Garcia-Raso, M. Fernandez-Diaz, M.I. Paez, J.Sanz, and I. Martinez-Castro, J. Chromatom., 1989, 471.205. N. Mitsuo, N. Nakayama, H. Matsumoto, and T. Satoh, Chem. Pharm. Bull., 1989,37- 1624. J. Kusmien, J.J. De George, D. Sweeney, C. May, and S.I. Rapoport, J. Chromatom., 1 9 8 9 , 5 3 9 . B. Wong and M. Castellanos, J. Chromatom., 1989,495.21. D.M. Eades, J.R. Williamson, and W.R. Sherman, J. Chromatops., 1989,490.1. J.E.G. van Dam, A.A.M. Maas, J.P. Kamerling, and J.F.G. Vliegenthart, Carbohvdr. Re., 1989,187. 25. G. Michel, L. Fay, and M. Prost, J. Chromatom, 1989,493. 188. A. Sonesson, K. Bryn, E. Jantzen, and L. Lamon, J. Chromatom.. 1989,487.1. 0. Holst, H. Mall,H. Brade, and J. Thiem, Carbohvdr. Res., 1989,188.219. K. Niemeu, Carbohvdr. Res., 1989,194,37. M.A. Andrews, Carbohvdr. Res., 1989,194. 1. P.A. Bondi, F. Manca, A. Negri, G. Tedeschi, and C. Seahi, J. Chromatom., 1989,467.315. F.R. Seymour, S.L.Unruh, and D.A. Nehlich, Carbohvdr. Res., 1989,191.175. EM. Rubino, J. Chromatom., 1989,473.125. A.M. Siouffi, E. Mincsovics, and E. 'I)ihak, J. Chromatom., 1989,492,471. J. Vajda and J. Pick, J. Planar Chromatom. - Mod. TLC, 1988,1,347. D. Qui and M. Cai, Huazue Tonebao, 1988,43 (Chem. Abstr., 1989,109.243 286). K Shinomiya, Y. Hoshi, and T. Imanari, J. Chromatom., 1989,462,471. K.B. Tomer and C.E. Parker, J. Chromatom., 1989,492. 189. K. Shimada, T.Oe, and T. Nambara, J. Chromatom., 1989,492, 345. D.O. Hancock and R.E. Synovec, J. Chromatom., 1989,464.83. M. Lafosse, B. Herbreteau, M. Drew, and L. Morin-Allory, J. Chromatom., 1989,472.209. D.W. Armstrong and H.L.Jin, J. Chromatom., 1989,462.219. D.W. Armstrong and H.L.Jin, Chiralitv, 1989, 27 (Chem. Abstr., 1989,111.233 385). C. Jansen, Labor Praxis, 1989, fi 56 (Chem. Abstr., 1989,111.49 655). D.A. Angers, P. Nadeau, and G.R. Mehuys, J. Chromatom, 1988,454,444. S. Tsukamoto, K. Hayashi, K. Kaneko, and H. Mitsuhashi, J. Chem. Soc.. Perkin Trans. I, 1988,787. S. Tsukamoto, K. Kaneko, and K. Hayashi, Chem. Pharm. Bull., 1989,37- 637. S. Tsukamoto, K Hayashi, and K Kaneko, J. Chem. Soc.,Perkin Trans I, 1988 2621. K. Koizumi, Y. Kubota, T. Tanlmoto, and Y. Okada, J. Chromatom., 1989,464,365. K. Koizumi, Y.Kubota, T. Taninoto, and Y. Okada, J. Chromatom., 1988,454, 303. S. Cs. Szathmary, J. Chromatom., 1989,487,W. N. Kiba, K. Shitara,and M. Furusawa, J. Chromatom., 1 9 8 9 , 9 1 8 3 . Y. Set0 and T.Shinohara, J. Chromatom., 1989,464.323. S.D.Shiyan, V.V. Nasonov, V.A. Markin, and I. Belanchikov, Bioorg. Khim., 1988,U- 1197 Abstr.. 1989,110,36 414). 0. Kol, J. Montreuil, B. Fournet, R. Zalisz, and P. Smets, J. Chromatom., 1989,474.452. M. Ojika, H.V. Meyers, M. Chang, and K. Nakanishi, J.Am.Chem.Soc., 1989,8944. R.L. Thomas, S.A. Abbas, C.F. Piskon, and K.L. Matta. Carbohvdr. Res., 1989,189, 13. T. Okuyama, M. Takata, K. Takahashi, T. Ishikawa, K Miyasaka, and N. Kaneyama, J. Chromatom., 1989.466.390. M.E. Snook, N.W. Widstrom and R.C. Gueldner, J. Chromatoer., 1989,477.439. N.G. Lewis,EJ. Inciong, K.P. Dhara, and E. Yamamoto, J. Chromatom., 1989,479,345. Y. Fujii, Y. Ikeda,and M. Yamazaki, J. Chromatom., 1989,479,319. G. Stenhagen and H. Alborn, J. Chromatom, 1989,474,285. C.E.M. Heermans, R A M . van der Hoeven, W.M.A. Niessen, J. Vuik, R.H. de Vos, and J. van der Greef, J. Chromatom., 1989,472, 219. Y.Kashiwada, G Nonaka, and I. Nishioka, Chem. Pharm. Bull., 1989,22,999. Y. Kitada, M. Sasaki, Y. Yamazoe, and H. Nakazawa, J. Chromatom., 1989,474,447. R. Gupta and N. Jentoft, J. Chromatom., 1989, 474.411. K. Murata, Y. Yokoyama, and K. Yoshida, J. Chromatom., 1 9 8 9 , m 27. H. Yoyoda, S. Yamanashi, Y. Hakamada, K. Shinomiya, and T. Imanari, Chem. Pharm. Bull., 1989, 1627. P.J. Soine and W.H. Soine, J. Chromatom., 1987,422,309. N.W. Kerby, R.H. Reed,and P. Rowell, 2. Chromatom., 1989,479.353. F.-F. Hsu and W.R. Sherman, J. Chromatom., 1989,479,437.
23: Separatoty and Anulytical Methods 54 55 56 57 58 59 60 61 62 63 64
65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
81 82 83 84
8s 86 87 88 89 90 91 92
93 94 95 96 97 98
263
J.D. Pinkston, D.J. Bowling, and T.E. Delaney, J. Chromatom., 1989, 474. 97. F. Hsu, S. Ghosh, and W.R. Sherman, J. Chromatom., 1989,478, 429. L. Miller, H. Bush, and E.M. Demco, J. Chromatom, 1989,484.259. H. Liu, P. Leroy, A. Nicolas, J. Magdalou, and G. Siest, J. Chromatoer., 1987,493. 137. M. Henry, D. Panthe-Dayde, and M. Rochd, J. Chromatoer., 1989,477.413. XY. Zhang, R.J. Wu, J. Chen, and D.K. An, J. Chromatom., 1989,495.343. F.R. Brown and W.M. Draper, J. Chromaton., 1989,479,441. F. Weigang, M. Reiter, A. Jungbauer, and H. Katinger, J. Chromatoer., 1989,497, 59. M. Nakamura, K Furuhata, K Yamazaki, H. Ogura, H. Kamiya, and H. Ida, Chem. Pharm. Bull., 1989, 2204. Z El Rassi, C. Horvath, R. K Yu,and T. Ariga, J. Chromatoar., 1989,488. 229. E. Nagy and I. Degrell, J. Chromatom, 1989,497, 276. C.G. Honegger, H. Langemann, W. Krenger, and k Kempf, J. Chromatoar., 1989,487.463. Y. Suzuki and K Fukuda, J. Chromatom., 1989,489,283. M.C. Gennaro and P.L. Bertolo, J. Chromatom., 1989,472,433. R. Tawa, S. Hirose, and T. Fujimoto, J. Chromatom., 1989,490. 125. 174. T. Fujimoto, R. Tawa, and S. Hirose,Chem. Pharm. Bull., 1989, M.A. Moseley, L.J. Deterding, KB. Tomer, and J.W. Jorgenson, J. Chromatoar., 1989,480,197. C.W. Gehrke and KC.Kuo,J. Chromatoer., 1989,471.3. R.S. Ramsey, V.W. Chan, B.M. Dittmar, and KH. Row, J. Chromatogr., 1989,468. 167. J.F. Banks, Jr. and M.V. Novotny, J. Chromatoer., 1989,475, 13. M. Mesbah and W.B. Whitman, J. Chromatom., 1989,479,297. k Riccardi, T. Servidei, A. Lasorella, and R. Riccardi, J. Chromatoer., 1989,497, 302. M. Magnani, L. Rossi, M.Bianchi, L. Cucchiarini and V. Stocchi, J. Chromatom., 1989,491,215. B. Guattani, J. Chromatom, 1989,489,394. D.A. Ganes and J.G. Wagner, J. Chromatom., 1988,432,233. P.G. Montaldo and M. Dhcalci, J. Chromatom., 1989,491. 129. H. Irth,R. Tocklu, K Welten, G.J. de Jong, U.A. Th. Brinkman, and R.W. Frei, J. Chromatom., 1989,491,321. S.M. Musser, S.-S.Pan, and P.S. Callery, J. Chromatoer, 1989,474. 197. L. Xia, Y. Xu, F. Tao, and Y. Chen, Fenxi Huaxue, 1 9 8 8 , s 293 (Chem. Abstr? 1989,110.24 217). R.T. Toguzov, Y.V. Tikhonov, A.M. Pimenov, V. Yu. Prokudin, W.Dubiel, M. Ziegler, and G. Gerber, J. Chromatom.. 1988, 434,447. F. Palmisano, T. Rotunno, A. Guemeri, and P.G. Zambonin, J. Chromatom., 1989,493.35. S. Sonori, Y. Tanaka, S. Hisamatsu, and T. Kobayashi, J. Chromatom., 1989,47$, 311. L.E. Mathes, G. Muschik, L. Demby, P. Polas, D.W. Mellini, H.J. Issaq, and R. Sam, J. Chromatom, 1988,432.346. H. Hosotsubo, S. Takahara, and N. Taenaka, J. Chromatom., 1988,432.340. L.-M. Wang, C.N. Woodward, J.C. White, and RL. Capizzi, J. Chromatoer., 1989, 491,331. P.L. van Biljon and S.P. Olivier, J. Chromatom, 1989,473, 305. C.B. Ching, K Hidajat, and M.N. Rathor, J. Chromatoar., 1989,463.261. E. Shimada and G. Matsumura, J. Chromatom., 1989,472, 145. H. Nishizawa, Y. Watanabe, S. Okimura, and Y. Abe, Anal. Sci., 1989,s 345 (Chem Abstr., 1989, 111.195 265). T. Yoshida, T. Hatano, and T. Okuda, J. Chromatom., 1989,467. 139. S.V. Prabhu and R.P. Baldwin, Anal. Chem., 1 9 8 9 , a 2258 (Chem. Abstr., 1989,111,146 064). T. Ikeda, T. Shibata, and M. Senda, J. Electroanal. Chem. Interfacial Electrochem., 1989,261.351. Y. Umegae, H. Nohta, and Y. Ohkura, Anal. Chim. Acta, 1989,217.263 (Chem. Abstr., 1989,111, 208 457). S.F.Lo, Y. Yu, D.H Long, and H.W. Liu, Carbohvdr. Res.,1989,189,368. Y. Shigemasa, K Tanaka, N. Wakasaki, R. Nakashima, H. Sashiwa, and H. Saimoto, Chem. b r a s , 1988,a 695 (Chem. Abstr., 1989 110.193 197).
a
24
Synt hesis of Enant iomericaI Iy Pure Non-carbohydrate Compounds
A review on the synthesis of optically-active pheromones includes a section on the use of carbohydrates as chiral starting materials. 1 1
Carbocvclic Compoun&
The glucose-derived alkene (1)has been converted into the prostaglandinrelated hydroxycyclopentenone (2). using a n aldol condensation, as indicated in Scheme 1.2 Reductive cyclization using SmI2 was employed in a route to the chiral cyclopentane (3)from the L-arabinose derivative (4) (Scheme 2); the functionality and chirality of (3)corresponds with that of the C-ring of the trichothecene-type sesquiterpene anguidine.3 0
OMe
K
A review has appeared from Fraser-Reid's group describing some of their work on the annulation of carbocyclic rings onto carbohydrate template^.^ This group has reported the free-radical cyclization of unsaturated ester (5) (Scheme 3) into carbocycle (6), which was converted in seven steps into the intermediate (7) in Collum's synthesis of phyllanthocin.5 The same team have given a full account of their routes to pyranoside diquinanes by serial radical cyclization (see Vol. 21, p. 148-9),6 and some more sophisticated examples, designed to
24: Synthesis of Enantiomerically Pure Non-curbohjidrate Compounds
265
yield diquinanes with additional functionality present in natural products, have also been described: the transformation shown in Scheme 4 is typical.7
The intramolecular Diels-Alder cyclizations shown in Scheme 5 gave just one cycloadduct in each case even though the starting dienes. made from 2,3,4-tri0-benzyl-D-xylose, were E/Zmixtures; the yield was not good in the case of the
Scheme 5
oxime, however.8 Similar cyclizations of glucose-derived 1.7.9-trienes gave the 6,6-ring system (8)(sugar carbons numbered),g and a n intermolecular DielsAlder reaction between a diene derived from triacetyl-D-glucal (carbons numbered) and a quinone generated in situ gave cycloadduct (9) stereo- and regiospecifically. 10 Trost's trimethylenemethane-palladium complex has been shown to undergo [3+21 cycloadditions to a$-unsaturated sulphones; cyclopentane derivative (10) was obtained from the glucose-derived trans-a,p-
266
Carbohydrate Chemistry
unsaturated sulphone as the major diastereomer (7.5:1).Ozonolysis and elimination of phenylsulphinic acid gave the corresponding chiral cyclopentenone. 1 1 a-D-Isosaccharinolactone (11) can be converted (J.Org. Chern, 1987, 52. 1057) into aldehyde (12) (Scheme 6). This can undergo stereoselective intramolecular cyclization to tetralin (13) in the presence of SnC14, giving a route to a precursor (14) of 4-deoxy-y-rhodomycinone (15).12 In somewhat similar work, the synthon (16),derived from D-glucose (carbons numbered), was transformed (Scheme 7) by Marschalk reaction with leucoquinizarin into
u; OMe
I
OMe
0
\ OMe Scheme
Tr?
""OH
I
6 0
OH
0
OH
(14) R
= Me
(15) R =
H
(13)
oTr
anthraquinone (17), which could be converted, again with stereocontrol in the cyclization, into 4-deoq-y-rhodomycinone (15)!3 In a total synthesis of (+)olivin (18).the side-chain chirality could be constructed from D-galactose (sugar carbons numbered), although a n alternative approach in which the sidechain was built up by stereoselective reactions of a threonine derivative proved more efficient. 14 HO
H H
Methyl 3.4-O-isopropylidene-~-threonate, available from L-ascorbic acid in three steps, can be converted into L-threose derivative (19). and the dihydrofuran (20).This latter compound underwent photocycloaddition to
24: Synthesis of Enaritiomericrrlly Pure Non-carbohydrurc Cornpounds
267
cyclopentenone to give (211, as the first key step in the synthesis of (-)echinosporin (22);the carbons of L-ascorbate are numbered in the formulae.15 A route to a cyclopropyl aminoacid is discussed in Section 4. 2
Y- and &Lactones
The new chiral building block (23) has been obtained by lipase-catalysed hydrolysis of the corresponding meso-diacetate, which was itself prepared from ribitol; monoester (23) was converted in three steps into the lactone (24), which has been reported to have hunger-modulating properties. 16 Full details have been given of the synthesis of the marine metabolite, leptosphaerin (see Vol. 20, p.26O-1),l7 and also of the synthesis of the antitumour pyrone (+)-altholactone and its enantiomer (see Vol. 21, p.259).18 The lactone (25) is a degradation product of the macrolide nyastatin A, and to confirm its absolute configuration, it has been synthesized from D-glucal (sugar carbons numbered); the key reaction involved the formation of the acuprate (26) and its reaction with an epoxide.19 The chiron (27), suitable for synthesis of the &lactone moiety of the mevinic acids, has been prepared from levoglucosan.20 The P,y-unsaturated lactone (28) is a potential precursor for polyhydroxylated a-aminoacids; it has been made from di-0-acetyl-D-xylal, the key step being the [3,3]-sigmatropic rearrangement of the allylic trichloroacetimidate (29).2
Do
(231
0
OBz
(27)
3
(29
UMe
NHCOCCL3 0
3
cL3cYo NH
(29)
Macrolides. Macrocvclic Lactams, and their Constituent Segments
A full account has been given of Danishefsky's carbohydrate-based synthesis of avermectin A1, (see Vol. 21, p.262-3).22
In the erythromycin area, Kochetkov's group has described in full their route to erythronolides A and B by linking C(1) - C(6) and C(9) - C(13) units derived from laevoglucosan (see Vol. 21, p.261),23 and Yonemitsu's group has given a full account, with some improvement^,^^ of their synthesis of (9S)-9dihydroerythronolide A Wol. 21 p.261; Vol. 19, ~ . 2 6 3 - 4 ) . ~Other 5 Japanese
Carbohydrate Chemistvy
268
workers have described fully their alternative route to erythronolide A from sugar precursors (see Vol. 20. p.263).26 A segment of the marine toxin debromoaplysiatoxin has been prepared from D-glucose as outlined in Scheme 8;27carbons 1 and 2 (glucose numbers) and 0 - 2 of intermediate (30)were then incorporated into the complete macrodiolide of 3-deoxydebromoaplysiatoxin by combination with two other tartrate-derived fragments.28 TsO-FH~
OBn
Scheme 8
The 18-ring macrolide concanamycin contains a stereochemically-complex side-chain unit. Much of this chirality is incorporated in the synthon (31) prepared from D-glucose (Scheme 9). the sugar carbons being indicated. A 2,6dideoxy-D-glucose unit, also present in the antibiotic, was attached to 0-2 of (31) with moderate P-selectivity.29
Ph I
Me
Chirality from D-mannose was used to establish most of the chiral centres in a synthesis of the lichen metabolite (+)-aspicillin (32; sugar carbons numbered).30 The known lactone (331, accessible in two steps from Dgalactono-y-lactone, was used to prepare the fragment (34)containing the chirality of C(21)- C(27) of the antineoplastic bryostatins.31 OH
CH2
(33) (32)
'Mc
(34)
24: Synthesis of Enantiomerically Pure Non-carbohydrate Cornpourids
269
The powerful immunosuppressant FK-506 has attracted much synthetic activity, and the viability of carbohydrate-based approaches to segments of this molecule has been demonstrated by several groups. In one approach to a C(10) C(19) fragment, the D-galactose derivative (35)was converted as indicated briefly in Scheme 10 to diene (36)(galactose carbons indicated): hydroxyldirected homogeneous hydrogenation of this gave, with high stereoselectivity, reduction product (37).extendable to the chiron (38).32In another approach, which also recognizes the hidden symmetry of this segment, L-arabinitol was CH2OH
9Bn
%O
“
e
o
~
O
H-++o
HO
c
OH
o
z
OMe ;Me
/Ie
5
H
4
Me
-+-+
OMe
a , m ’>: ; nB
HoJoA‘
w-VL
~
Me
0 Dn
c+&21
(3Y 9M )?.-
OS‘L
-
6Me
New
CH2CI
Me
i
0
AcO
CH20~
f
e~ e o 2 c ~ C H 2 C H 2 0 6 z
C HzCL
CH2OH CI 0 {OH
~
-
~
0
Me,
OMe 6Mc fie
R e Y m s u, ACOC(Me)2coc~,U, N a O M e
co* Me , U,BnBr,NAN , W , HCEC OEt , 0 F 3 , v, HU,PIPOH
,VL,
LDA,MeI
Scheme 11
converted into diepoxide (39) (Scheme 11). which was further manipulated as indicated to give a C(10) - C(18) unit.33 In another approach, L-arabinose was
Curbohydrute Chemi s q
270
converted in seven steps (60% overall with no chromatography) into the allylic alcohol (40). and hence into lactone (41) (sugar carbons indicated) in a number of steps, the first being an Ireland-Claisen rearrangement with the usual chirality transfer. Intermediate (41) was then built up into a C(10) - C(24) unit of FK-506.34 Other workers have converted the known alkene (42) into the uronic ester (43). representing C(10) - C(15) of FK-506, and then extended this unit to prepare a C(10) - C(23) structure.35 In an approach to the C(1) C(15) 'left-hand' segment of FK-506. lactone (44) was prepared from methyl aD-glucopyranoside, and then elaborated into (451, the key step being the reaction of (44) with the lithium enolate of ethyl a-tetrahydropyranyloxyacetate.36 A report of a review lecture describes progress by Fraser-Reid's group on the synthesis of the ansa-chain of streptovaricin A using the concept of pyranosidic homologation,37 and the same team has successfully converted the known tripyranoside (46) into the advanced precursor (47) of streptovaricin A.38
4
Other Oqgen Heterocycles
The synthesis of muscarine analogues from hexitols has been reviewed.39 A major landmark in synthetic organic chemistry is the completion of Kishi's synthesis of palytoxin carboxylic acid and amide by linking together eight chiral building blocks and subsequent removal of the 42 protecting Full reports have been given of the synthesis of building blocks of the polyether antibiotic salinomycin (see Vol. 21, p.263)41.42 and the linking of these units to complete the synthesis of salinomycin itself.43 constituting the ABC ring framework of The tricyclic structure (48), brevetoxin B has been prepared in chiral form from tri-O-acetyl-D-gl~ca1,~~ and the IJK substructure (49) of the same major target has been synthesized from penta-O-acetyl-~-mannopyranose.~5 In both sequences, the first step involved formation of a C-glycoside by reaction with allyl-trimethylsilane; sugar carbons are numbered.
27 1
24: Synthesis of Enantiomerically Pure Non-carbohydrate Compounds
A homochiral unit corresponding with the H-ring of the halichondrin class of antitumour polyethers has been synthesized from the 3-deoxy-3-C-methyl-~glucose derivative (50) as indicated in Scheme 12.46
The total synthesis of pseudomonic acids has been reviewed,47 and Keck has streamlined his earlier synthesis (Vol. 18, p.247; Vol. 19, p.257) of pseudomonic acid C by direct linkage of an L-lyxose derivative with a chiral side-chain, using free-radical methods.48 Alkene (51) can be prepared by reaction of allyl-trimethylsilane with diacetyl-D-xylal, the stereoselectivity in this reaction being opposite to that observed with triacetyl-D-glucd (Vol. 16, p.40); further manipulation of (51) led to the conformationally-restricted analogue (52) of leukotriene D4.49
The unsaturated nitrocompound (53)could be converted in two steps into (-)-cryptosporin (541, the enantiomer of the natural product.50 Other workers have prepared the same compound by use of the Bradsher cycloaddition shown in Scheme 13,51 and a number of similar cycloadditions to glycals have also
gMe mBe ' L LANiO OMe CHO
NO2
OH
+
OH
NO2
Recrgads. L, Meou,Cn~~,; i;, H C L , ~
Scheme 13
L,LL
~
OH
++ (54)
272
Carbohydrure Chemistry
been rep0rted.5~The enone (55).derived from L-rhamnal (Scheme 14). could be converted to granaticin (56)via reaction with a phthalide.53 0 W
~eagents: L, C H ~ = C ~ ~ : + of3 , j ii, M ~ D - ;iii,M ~ C LE, ~ ;~ N
iv, SiOz ; v, Me2ALNMe2 ’, vi,
PCC
( 5 6)
Scheme 14
A route has been described for the preparation of anhydrous (R)-epichlorohydrin (57) from D-mannitol; this epoxide could be converted (Scheme 15) into the lactone (58)by initial attack at the epoxide, and hence into (-)(1S,2R)-1-amino-2-(hydroxymethyl)cyclopropanecarboxylic acid (59) through Hoffmann reaction. 54 HOCH, D-Mannitol
-+-+
&C”CL
L
Qo
---f
NH2 ‘’C02H
C02Me
(58)
( 5 p
(59)
Reagents : i, c H ~ ( C O ~ M ~Na,M@-OH )~,
S c h e m e 15
5
Nitrogen HeterocvcleS
Full details55 and further examples55956 have been reported of the [2+21cycloadditions of glycal derivatives and isocyanates to give p-lactams. In such reactions, the major direction of attack on the glycal is trans to the oxygen substituent at C-3. Use of the D-allal derivative and trichloroacetyl isocyanate gave adduct (60).convertible to the P-lactam synthon (61),56 the enantiomer of which is accessible from ~ - g a l a c t a l . sVarious ~ chiral isoxazolidin-5-ones such as (62) are accessible by Michael addition of N-alkylhydroxylamines to a$unsaturated glycono- 1.5-lactones.S7 The chiral pyrrolidine (63)has been prepared from 1,2:5,6-di-O-isopropyl-
24: Synthesis of Enanriomerically Pure Non-carbohydrate Compounds
273
idene-D-mannitol by free-radical deoxygenation at the central carbons, and cyclization of the 1.6-di-0-benzyl derivative.58 In a new and interesting approach to functionalized pyrrolidines. the epoxide (64). accessible from was converted into the D-mannitol via 2,3-O-isopropylidene-D-glyceraldehyde, aminoacid (65) as indicated in Scheme 16. Similarly, starting from mannosederived 1,2-anhydro-5-azido-5-deoxypentitols, 1.4-dideoxy- 1.4-iminopentitols could be produced, but in certain cases the bicyclic intermediates underwent ring opening to piperidine derivatives instead .59 Alkene tosylate (66),derived from 2,3-O-isopropylidene-D-erythrose. has been used in a new chiral synthesis of the mannosidase inhibitor swainsonine (67), as indicated in Scheme 17.60
Ts
'
m
/
C
\
xo
0
,
Et
HO
L
(66)
(671 S c h e m e 17
The same group has reported routes to 8-epi-. 8a-epi-, and 8.8a-di-epistereomers of swainsonine (see 67), using 2,3-O-isopropylidene-~-erythrose as precursor, and epoxide intermediates.61 In somewhat similar work by others, the D-mannose-derived azidoepoxide (68) was converted into swainsonine (67). its ring-contracted analogue (69). and the 7-epimer of ( 6 9 ) . G 2 D-Arabinose has been converted via intermediates (70) and (71) into the chiral quinuclidine diol (72),63 whilst D-glUCOSe, via (73) and (74), gave the meso-isomer (75);64 sugar carbons are numbered, but in each case the HO. , , / 5 C H 2 0 H
OH
CH20H N3 CH2
(691
CH20CI
CO25n (74)
A
214
Carbohydrate Chemistry
symmetry of the target is such that alternative initial cyclizations of the azidoethyl chains onto C-5also led to the same products (72) and (73.63.64 The side-chain chirality of (-)-biopterin (76) has been assembled from 2,30-cyclohexylidene-D-ribose as indicated in Scheme 18.65 H
OH
C H20H L,&
~
M 0 u M e
u,w
6H
:N?N&Mej+
L
?5
Reagents
L,
y
\
p
e
-
H2NAN
"ij"
N
6H N'
OH
(76)
M e M g I , k , N a Z 0 4 , b,M f H 2 0 , t k,PhNHNtiZ
S c h e m e 18
6
Acvclic ComDounds
Earlier work on the synthesis of chiral a-hydroxyaldehydes (see Vol. 21, p. 174 and Vol. 20, p.270) from D-mannitol-derived diepoxides has been extended to the synthesis of methyl (R)- and (S)-9-hydroxyeicosatetraenoates(methyl 9Rand 9S-HETE),66+67and to coriolic acid [ 13(S)-hydroxy-92,11E-octadecadienoic made from a bis-aziridine (Vol. 20, acid] and its 13(S)-N-tosylamino-analogue. p.27 1).68 D-Sphingosine (77) and some related compounds have been prepared from 2-amino-2-deoxy-D-g~ucose (sugar carbons numbered) in a multistep process involving inversion of configuration of the sugar at C-3.69 A full account has been given of the synthesis of the marine sulpholipid D-erythro- 1-deoxydihydroceramide-1 -sulphonic acid from D-gdaCtOSe (see Vol. 22, p. 267), together with the synthesis of a phosphonocerebroside.70
I
(7 7)
A number of papers have described routes from carbohydrates to hydroxylated aminoacids. The a i d e (78). derived from L-arabinose, was converted, via the 4.5-aziridine. into polyoxamic acid (79). a constituent of the polyoxin class of antibiotics7 The aminosugar derivative (SO),an intermediate in Horton's daunosamine synthesis, can be transformed (Scheme 19) into (81).and hence into the lactone (821,which is a protected form of the hydroxylated j3-aminoacid found in the antiulcerogenic compound AI-77-B; the regiochemistry in the reductive opening of the acetal is unexpected.72 D-Glucose has been converted
24: Synthesis of Enantiomerically Pure Non-curhohydraie Compounds
phT& CF3CONH
R ~ c L ~ & ' i, Et3SLCI,
275
Cki20Bn I,,& ,
B.O+
OMe (80) T&L+ ; u., BzCL
5steps 3
B
z
O
e
o
CF3CONH (81)
(82)
Scheme 19
in a multistep process into MeBmt (83).a constituent of cyclosporin (sugar carbons indicatedl.73 and glucose was also used in a synthesis of statine (84) and some anal0gues.~4The related lactone (85).corresponding to a hydroxyethylene dipeptide isostere, has been prepared from triacetyl glucal.75 The lactone (28).a potential precursor for hydroxylated a-aminoacids, was mentioned earlier.21 A route has beendetailed for the preparation of (I?)-0-isopropylideneglyceraldehyde from D-glucono-1,5-1act0ne.~6A good route has been worked out for the conversion of (S)-0-isopropylidene-glycerol (from D-mannitol) into (S)-(+)-glycerolmonotosylate (86).and the [R)-isomer is also accessible starting from L-ascorbic acid.77 An alternative preparation of (86)proceeds from Dribonolactone via the 2,3-O-benzylidene -5-O-tosyl derivative .78 The stereospecifically deuteriated derivative (87)of 1,6-anhydro-P-~galactopyranose can be made by the known photobromination-reductive dehalogenation of its triester derivatives; degradation of (87) has provided a route to (lS)-(l-2H)-sn-glycerol(88).and, by a longer sequence involving inversion at C-1, the (1R)-diastereomer can also be 0btained.~9 Some chiral polyhydroxyalkynes have been prepared by treating 2-alkoxy- 1chlorosugar derivatives with strong bases (LiNH2/NH3 or LDA); the conversion of (89),derived from D-XylOSe, into alkyne (90)is typical.80 Periodate cleavage followed by Wadsworth-Emmons reaction, of 3,4-O-isopropylidene-~-mannitol, gave diene diester (91).*1 6
Me
NHMe
M e b A . AOH 5 G CO*H 2
CH20T5
(e41 C H2CL
lo@ ?O ;H
o+
to
CH20H
OH
CH20H
OH
(93)
(37)
SCH
H2NG;02H toH Me2CHCH2
(86)
-
("5)
ii
Hoi:x
0
COzMe
-t
O-----/$0
($8) (89)
(901
CO2Me (91)
276
Carbohydrate Chemistry 7
Carbohvdrates as Chiral Auxiliaries
The stereostructure of (-)-bostricin has been revised following the asymmetric synthesis of its enantiomer (92) using Stoodley's glycosyloxydiene approach (Scheme 20).82 The chiral alkoxydienes (93, R=H, Me) have also been shown to undergo highly diastereoselective Diels-Alder reactions with naphthoquinone (Scheme 21); the hydrolysis products (94) were estimated as being 97.5% enantiomerically pure.83 Vinyl glycosides can be used in the Bradsher cycloaddition to give chiral tetralins with high enantiomeric excess (e.e.) (Scheme 22).s2
___$
0
0 (*a-0-A.)
OH
( 92)
I p - D - Gtc-p Scheme 20
A group of papers have described elegant work with chiral units derived from the titanium(IV) species (95), where R* is the 1,2:5,6-di-O-isopropylidene-a-D-glucofuraosyl unit. The ally1 titanate (96) reacts with aldehydes to give adducts (97) of >85% e.e.,84 whilst the chiral enolate (98) gives P-hydroxyesters (99) with >90%e.e. in high yields.85 The nitrogen-substituted enolate [loo) reacted with aldehydes to give, after hydrolysis and conversion to N-BOC derivatives, a-amino-P-hydroxy acids with high e.e. and high diastereomeric excess in favour of the syn-adducts (101).86 Kunz's group have extended their work on the use of galactosylamine
24: Synthesis of Enantiornerically Pure Nan-carbohydrate Compounds
R%--?;-OR*
277
*
RO - T ~ -OR*
derivatives (1021 as chiral auxiliaries (see Vol. 21, p.101) to the reactions of Scheme 23. In most cases studied, the major diastereomers formed in high excess were those indicated, leading, in the case of R= n-Pr, to a synthesis of (+I-coniine (103),87 but in the case of R= 3-pyridyl. the major diastereomer had opposite chirality (96:4 ratio), leading to a synthesis of (S)-anabasine (104);87,88 transition-state models were proposed to account for the difference.87 Reaction of imines of type (102) with the TMS-ketene acetal derived from methyl isobutyrate, followed by hydrolysis, gave P-aminoacids (105)with high e.e.89 The stereoselective Ugi synthesis of a-aminoacids using D-galactosylamine auxiliaries (Vol. 22, p. 110-1 11) has been employed using the D-arabinopyranosylamine derivative (106); since the D-arabinose derivative is enantiomeric with a D-galactose system, except for loss of C-6, the aaminoacids are now produced with (S)-chirality.90 PvO C H ~ O P V
When phenylglyoxylate esters derived from various carbohydrate alcohols
are employed in the Patemo-Buchi reaction with furan, the products (107) can show up to 80%diastereomeric excess.91 The nitrone (108) underwent facially-selective addition to the appropriate alkene to give adduct (109);
278
Curb0hydrate Chemistry
hydrolytic removal of the auxiliary and further manipulation was used to make the aminoacid (+)-negamycin and its C-3 epimer.92
A [2.3]Wittig rearrangement carried out on a carbohydrate template has been used in a route to 3-alkyl malic acids, as indicated in Scheme 24. The product of opposite chirality at C-3 could be obtained from the cis-alkene, and transition-state models were proposed to rationalize the results.93 Somewhat similar intermediates were used in a synthesis of the stereospecificallyrequired as a standard in a study of enzyme deuteriated ester (110). stereospecificity; in this case C-3 of D-glucose became C-1 of the carboxylic acid by oxidative cleavage.94
R e a 9 ~ ~ 1: -i, b3
LDA ;i,C H ~ N ~
Scheme 24
References 1 2
3 4 5
6 7 8 9 10 11 12 13 14 15 16
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24: Synthesis of En an riom erica Ily Pure Non -carbol?ydrute Compounds
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a,
a,
a,
m,
s,
x,
280
60 61 62 63
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79
80 81 82 83 84 85
86 87 88 89 90 91 92 93 94
Carbohydrate Chemistry
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a,
a,
a,
a,
Author Index
In t h i s i n d e x t h e number g i v e n i n p a r e n t h e s i s i s t h e C h a p t e r number o f t h e c i t a t i o n and t h i s i s f o l l o w e d b y t h e r e f e r e n c e number or numbers of t h e r e l e v a n t c i t a t i o n s w i t h i n t h a t Chapter
Abbaci, B. (3) 117; (8) 28; (9) 14; (12) 22 Abbas, S.A. (4) 31, 34; (23) 39 Abdel Hamid, H. (10) 53 Abdel-Malik, M.M. (7) 72 Abdel-Megid, A.E.-S. (20) 1.15 Abe, K. (16) 70 Abe, S. (2) 6 Abe, Y. (2) 21; (23) 92 Abramski, W. (14) 31; (24) 55 Abylgaziev, R.I. (18) 17, 18 Accorsi, C.A. (22) 30, 31 Acemoglu, M. (24) 11 Achiwa, K. (3) 20, 25, 86; (17) 13 Ackermann, J.E. (3) 52, 53 Acquotti, D. (4) 70; (16) 48 Adachi, H. (7) 47 Adachi, T. (19) 17 Adinolfi, M. (4) 71 Adrian, M.A.P. (7) 4; (10) 2 Aduma, P.J. (20) 118 Agarwal, V.R. (9) 4 Ager, D.J. (16) 56 Agyei-Aye, K. (20) 48 Ahluwalia, J.C. (2) 4 1 Ahmad, B. (10) 5, 6 Ajisaka, K. (4) 13 Ajito, K. (19) 34 Akamatsu, S. (3) 20; 17) 13 Akatsuka, H. (20) 142 Akedo, H. (7) 43 Akhrem, A.A. (20) 257 (21) 17
Akhvlediani, R.N. (20) 20 Akiyama, T. (19) 39; (20) 224
Akrigg, D. (22) 55 Akulov, G.P. (2) 42 Akutsu, N. (24) 94 Albarran, J.C.P. (10) 19 Alborn, H. (22) 18; (23) 44
Alderweireldt, F.C. (20) 154, 155
Aleksandrova, L.G. (19) 29
Alekseev, Yu.E. (5) 25 Alekseeva, I.V. ( 2 0 ) 14 Alekseeva, V.G. (5) 25 Alemani, A. (14) 3 Alevi, P . (3) 175 Alfoeldi, J. (3) 94 Ali, S.M. (24) 10 Alieva, M.I. (2) 40 Al-Janabi, S.A.S. (20) 21 Allevi, P. (3) 174 Al-Masoudi, N.A. (20) 17 Al-Masoudi, N.Z. (11) 4 Alonso, R. (5) 30; (14) 9, 27; (18) 5 1 Al-Sakkal, N.M. (20) 21 Alster, D. (20) 176
Alvarez de Cienfuegos, G. (20) 42
Alvarez Guardia, L. (3) 196
Alvarez Macho, M.P. (2) 58
Alves, R.J. (8) 16 Amano, M. (16) 28 Ambrosi, H.-D. (10) 41 Ames, J.M. (10) 29 An, D.K. (23) 59 An, S.-H. (20) 239 Anand, K.K. (20) 40
Anastasia, M. (3) 174 Andari, C. (7) 4 1 Anderle, D. (7) 5 Andersen, L. (9) 12 Anderson, J.D. (19) 43; (22) 70
Anderson, R.J. (22) 60 Andersson, F. (3) 150 Andersson, I. (16) 11 Ando, K. (19) 82; (22) 45 Andreassen, E.S. (9) 13 Andrews, C.W. (3) 135, 137; (6) 8
Andrews, M.A. (2) 66; (18) 1, 6; (23) 12
Angers, D.A. (23) 27 Angyal, S.J. (21) 12, 19; (22) 5 1
Anissa Yeung, B.W. (14) 27
Anke, T. (19) 78 Anraku, Y. (19) 77 Antel, J. (22) 53 Antkowiak, W.Z. (20) 211 Antonakis, K. (16) 57; (20) 101, 235
Antonini, P. (19) 70 Antonov, K.V. (16) 60 Anzeveno, P.B. (3) 73; (9) 40
Aoi, T. (16) 6 Aoyagi, T. (19) 74, 75 Aoyama, Y. (2) 67, 68 Aplin, R.T. (9) 23 ApSimon, J.W. (22) 4 Aqeel, A. (2) 26 Arad, S. (21) 32 Arai, M. (24) 26 Arai, Y. (5) 40; (19) 65 Arakawa, E. (20) 222 Araki, Y. (3) 188; (5) 40; (19) 65
282 Arbuzov, B.A. (7) 63 Arcamone, F. (19) 23 Arens, H. (7) 42 Ariga, H. (4) 61 Ariga, T. (23) 63 Arison, B.H. (19) 38 Arizuka, M. (3) 44; (7) 58; (24) 70 Armistead, D.M. (24) 22 Armstrong, D.W. (23) 24, 25 Armstrong, R.W. (3) 173; (24) 40 A r n e t t , G. (19) 52 Arora, K.K. (7) 55 A r p a l a h t i , J. (20) 244 Arshava, B.M. (12) 32, 33 Arterburn, J.B. (12) 30 Asano, N. (9) 18; (18) 27 Asen, S. (7) 37 Asenjo, R . (10) 4 Ashizawa, H. (20) 53; (22) 79 Atal, C.K. (20) 40 Atassi, G. (19) 87 Auberson, Y. (1) 7; (2) 29; (9) 34 Audia, J.E. (9) 37 Auer, M. (20) 85, 190; (22) 87 Auge, C. (4) 18; (6) 2; (9) 48; (10) 32; (16) 35-37 August, E.M. (19) 45; (20) 52, 77 Avalos, M. (10) 64 Avalos Gonzalez, M. (9) 46, 47; (10) 19; (11) 5 Avery, T.L. (10) 7 Awad, L. (10) 54, 55 Azuma, I. (3) 71; (4) 19; (7) 33, 34 Azuma, K. (20) 50, 51, 55 Azuma, R. (14) 12
Baas, J.M.A. (5) 35 Babiano, R. (10) 15, 64 Babiano C a b a l l e r o , R . (10) 23 Bacher, A. (18) 43 Backinovsky, L.V. (3) 132, 133; (4) 8, 9, 33 Badger, R.A. (24) 17 Baek, N.I. (4) 45 Baer, H.H. (1) 5; (5) 37 Bagnara, J.T. (10) 1 Baines, S. (18) 3 1 Bairamova, N.E. (3) 104 Baitz-Gdcs, E. (20) 170 Bajza, I. (24) 8 Baker, D.C. (18) 62; (19)
Carbohydrate Chemistry 46; (20) 48 Baker, R. (18) 74, 75, 78; (22) 68 Bako, P. (5) 21; (9) 5 Baldwin, R.P. (23) 94 Balgobin, N. (20) 178 B a l l a b i o , K.C. (7) 13 B a l l e s t e r o s , A. (7) 19 Ballou, C.E. (18) 69 B a l z a r i n i , J. (20) 89, 91, 105, 107, 132, 154, 155, 167 Ban, C. (16) 5 1 Banaszek, A. (8) 14; (10) 34; (22) 37 Banfi, L. (9) 28 Bani, S. (3) 33 Banks, J.F., jun. (23) 73 Banks, S.B. (10) 29 Bannwarth, W. (20) 173 Banoub, J. (3) 126 Banoule, J. (16) 50 Banthorpe, D.V. (3) 52, 53 B a p t i s t e l l a , L.H.B. (7) 13; (8) 3 Barai, V.N. (20) 33, 230 Barbachyn, M. (19) 55 Barbas, C.F., I11 (18) 26 Barbe, B. (24) 66, 67 B a r i l i , P.L. (5) 28; (12) 31; (13) 26 Barker, C. (18) 3 1 Barnes, J.C. (2) 32; (22) 52 Barofsky, D.F. (10) 16 Barone, G. (2) 38; (4) 71 Barragan, M.A. (22) 62 B a r r e t t , A.G.M. (3) 4, 10 B a r r i o , J . R . (8) 23 Barton, D.H.R. (17) 8; (20) 205, 206 Baschang, G. (9) 2 Bassi, R. (16) 47 Basson, M.M. (7) 26 B a t s , J . W . (22) 36 Batta, G. (13) 2 ; (24) 8 B a t t a , G.Y. (19) 67; (21) 7 Baumann, H. (3) 74, 92; (4) 27; (21) 2 Baumes, R.L. (3) 111 Baumgartner, H. (20) 167 B a u t i s t a , I. (10) 64 Bauvy, C. (21) 33 Bayonove, C.L. (3) 111 Beach, J . W . (20) 73 Beagley, B. (24) 82 Beale, J.M. (19) 30 B e a t t i e , T.R. (18) 63 Beau, J.-M. (4) 21; (24) 19, 40
Beauchamp, R.D. (17) 23 Beaucourt, J.P. (2) 24 Beaupdre, D. (8) 2 7 ; (18) 23 Beavis, A. ( 2 ) 64 Becker, B. (16) 53 Becker, R. (5) 29; (24) 59 Bednarski, M.D. (2) 11, 16; (4) 2; (16) 14 Behrens, G. (20) 251 Beigelman, L.N. (20) 6, 204; (21) 16; (22) 92 Beiter, A.H. (20) 174 Bekker, A.R. (7) 56 Belanchikov, I. (23) 36 B e l i c c h i , M.F. (14) 18 Belkhouya, N. (8) 27 Bell, C.F. (17) 23 Beller, M. (3) 26 B e l l o s t a , V. (3) 168; (12) 16 B e l l u c c i , F. (22) 30 Belmans, M. (20) 154 B e l ' s k i l , V.K. (7) 56 Belzecki, C. (5) 17; (14) 31; (16) 9; (22) 47; (24) 55, 57 Benachenhou, F. (10) 11 Bender, S.L. (16) 20, 21 Bennani, F. (19) 26 Bennett, R.B., I11 (24) 60
Bennett, S.M. (20) 241 Bentrude, W.G. (20) 202 Beraud, P. (7) 8 Berdnikova, T.F. (19) 66 Berenbaum, M.C. (5) 14 Bgres, J. (20) 170 B e r e t t a , M.G. (19) 68 Bergstrom, D.E. (20) 139 Bernabe', M. (7) 19; (21) 38 Bernacki, R . J . (8) 2; (20) 123, 239 Bernikova, T.F. (19) 67 Bernotas, R.C. (17) 16; (18) 36 Berry, D.M. (19) 7 1 Berscheid, H.G. (7) 12 Berthakur, D.R. (10) 46 B e r t i , G. (5) 28; (12) 31; (13) 26 B e r t i , M. (19) 68 B e r t o l a s i , V. (22) 30, 3 1 B e r t o l o , P.L. (23) 67 Bessodes, M. (16) 57; (20) 235 B e t a n e l i , V.I. (3) 96; (6) 12 Betz, R. (16) 25 Beurskens, G. (22) 76
283
Author Index Bey, P. (20) 100 Beyer, G. (12) 10 Bezuidenhoudt, B.C.B. (3) 4, 10 (20) 79; (22) 88 Bhakuni, D.S. (13) 14, 15; (24) 10 Bhat, B. (10) 8; (20) 250 Bhat, V. (20) 227 Bhavanandan, V . P . (16) 49 Bianchi, M. (23) 76 Bibilashvilli, R . S . (20) 94 Bicherova, 1.1. (16) 16, 17 Bieber, L.W. (19) 37 Bienayme, H. (3) 19 Billinge, J . R . (18) 46 Billington, D.C. (18) 64, 74, 75, 78; (22) 68 Bimwala, M. (1) 7 Bimwala, R.M. (20) 143 Bindig, U. (20) 57, 60, 61 Binkley, R.W. (3) 116; (7) 67, 68 Birberg, W. (3) 150; (4) 81 Bird, C.W. (5) 16; (24) 83 Birnbaum, G . I . (22) 9 1 Bisacchi, G . S . (19) 64 Bishop, D.F. (3) 18 Bizzozero, N. (10) 48, 49; (22) 95 Bjerggrde, K. (20) 182 Bjoerkling, F. (7) 15 Blackburn, D.W. (21) 26 Blackburn, G.M. (17) 9 Blair, N.P. (3) 32 Blank, S. (3) 48; (8) 29 Bliard, C. (8) 9 Blizzard, T.A. (3) 55, 112 Blondeau, D. (20) 146 Blumenberg, K. (5) 15 Bobek, M. (20) 239 Bock, K. (3) 7; (18) 15, 57; (21) 23 Bodenteich, M. (19) 51; (20) 167 Boechardt, R.T. (19) 47 Boettger, D. (7) 12 Bognar, R. (18) 82; (24) 8, 9 Boisvert, L. (19) 55 Bokut, S.B. (20) 33 Bold, G. (17) 28; (24) 86 Bolitt, V. (3) 172 Bommer, R. (4) 39 Bonas, G. (17) 38
Bhadti, V.S.
Bondi, P.A. (23) 13 Bonini, C. (5) 26; (12) 9 Bonnet, R . (5) 14 Bontems, R . J . (19) 43; (22) 70 (2) 30; (4) 20, 24; (16) 27; (17) 17 Boquel, P. (3) 139; (6) 7 Borah, B. (21) 37 Borchardt, R.T. (19) 53; (20) 163 Borcherding, D.R. (19) 47 Borders, D.B. (19) 80 Bordner, J. (19) 76; (20) 133 Borghi, A. (19) 70 Borisova, V.N. (19) 67 Bormann, C. (19) 57 Bornemann, V. (19) 54 Borodkin, V.S. (13) 27; (14) 19; (24) 23 Borowiecka, J . (11) 14 Borowski, E. (19) 16 Borrachero Moya, P. (9) 42 Boryski, J. (20) 25 Boschelli, D.H. (10) 21 Boschetti, A. (3) 197 Bose, D.S. (18) 14 BOSSO, C . (4) 51 Botta, B. (19) 37 Bottin, U. (20) 197 Bottka, S. (20) 199-201 Bouchra, M. (7) 70 Boullanger, P. (3) 126; (5) 31, 41 Bounaga, N. (10) 11 Bourgeois, W. (20) 35, 56, 58 Bourhim, A. (7) 8 Bourque, K. (21) 18 Boursier, M. (3) 3 Bouwstra, J . B . (4) 48; (21) 3 1 Bouxom, B. (16) 35 Bovin, N.V. (3) 104 Bowden, C.R. (9) 44; (10) 18 Bowen, J.P. (3) 135 Bowlin, T.L. (20) 88, 100 Bowling, D . J . (22) 22; (23) 54 Boyko, W.J. (22) 46 Brade, H. (4) 12; (16) 34; (23) 10 Brade, W. (24) 50 Bradner, W.T. (19) 58 Brady, J . W . (2) 4 Brakta, M. (3) 183 Branchaud, B.P. (16) 3 1 Brandstetter, H.H. (12)
Boons, G . J . P . H .
21; (16) 40
Brankovan, V. (19) 45; (20) 52, 77, 96
Brard, L . (8) 11 Brash, R.M. (20) 161 Bravo, P. (8) 15 Brazhnikova, M.G. (19) 66, 67
Bredenkamp, M.W. (7) 26 Brida, G.T. (8) 23 Brill, W.K.-D. (20) 183 Brimacombe, J.S. (2) 32, 33; (22) 52
Briner, K. (3) 2; (10) 37 Brinkman, U.A.Th. (23) 80 Brodack, J . W . (8) 22 Broder, S. (20) 133, 152, 233
Brodfuehrer, P.R. (13) 19 Brodowski, M.H. (16) 73 Brossmer, R. (5) 13 Brown, D . J . (24) 63, 64 Brown, D.S. (3) 182; (13) 23
Brown, F.R. (23) 60 Brown, J.M. (20) 229 Brown, K.C. (16) 74 Browne, P. (21) 20 Brozda, D. (20) 176 Bruce, I. (18) 32 Brunner, E. (5) 29; (24) 59
Bruno, M. (3) 182; (13) 23
Bruzik, K.S. (18) 58 Bryan, R.F. (21) 24; (22) 28
Bryn, K. (23) 9 Buchanan, G.W. (21) 18 Buchanan, J . G . (19) 61, 89
Buchholzer, F.J. (1) 8; (4) 5
Buck, H.M. (20) 131 Budesinsky, M. (9) 6 Buenger, G.S. (20) 75 Bueno Iborra, N. (7) 23 Buffington, L.A. (21) 26 Bukharov, A.V. ( 4 ) 9 Buko, A.M. (19) 84 Buleon, A. (2) 8 Bundle, D.R. (4) 56, 57, 69
Burchenal, J . H . (20) 86 Buroker, R. (20) 96 Bush, C.A. (21) 1 Bush, H. (23) 56 Bush, J . A . (19) 58 Butt, E. (20) 197 Cabarello, R.B. (7) 4;
284 (10) 2
Cabaret, D . (3) 102 Cabrera Escribano, F. (8) 16
Cadas, 0. (5) 3 1 Cai, M. (3) 160, 163; (7) 9; (21) 21; (22) 7; (23) 18 Cain, G.A. (19) 10 Calinaud, P. (7) 70 Callery, P.S. (22) 24; (23) 81 Calvo-Mateo, A. (14) 3; (20) 132 Camarasa, M.-J. (14) 3; (20) 132 Cambon, A. (4) 5 1 Camici, M. (20) 29 Campbell, M.M. (24) 21 Campos Valdes, M.T. (5) 12 Cannell, R.J.P. (7) 49; (19) 93 Cao, 2. (16) 2 Capizzi, R.L. (23) 88 Carcano, M. (3) 169, 177; (10) 13 Cardillo, G. (9) 3 Carless, H.A.J. (18) 45, 46 Carlton, L. (3) 67 Caron, I. (7) 17 Carpenter, N.M. (9) 23; (24) 62 Carpino, P. (3) 62 Carrea, G. (7) 16 Carreaux, F. (24) 7 1 Carson, D.A. (20) 76 Caruso, M. (19) 36 Caruthers, M.H. (20) 183 Casara, P. (20) 119 Casiraghi, G. (2) 25; (3) 159, 180; (13) 20; (14) 18; (16) 7 Cassani, G. (19) 68 Castedo, L. (19) 90 Castellanos, M. (23) 5 Castillo, S. (18) 7 Castillon, S. (8) 3 Castro, A.L. (22) 62 Castro, M.M. (21) 48 Castronuovo, G . (2) 38 Casy, A.F. (21) 46 Catelani, G. (5) 28; (12) 31; (13) 1, 26 Cavagnero, S. (5) 26; (12) 9 Cavalleri, B. (19) 69 Cavaye, B. (9) 48; (16) 35, 37 Cenci di Bello, I. (18) 32; (24) 62
Carbohydrate Chemistty
Cerda, C.M. (18) 7 Cerny, I. (3) 54 Cerny, M. (3) 149; (9) 6 Cha, B.C. (19) 48; (20) 164, 171 Cha, J . K . (24) 60, 6 1 Chaffee, S. (20) 208 Chakraborty, T.K. (5) 22 Chan, K. (20) 162 Chan, V.W. (23) 72 Chander, M.C. (13) 28 Chandler, M.C. (24) 80 Chandrasekar, S. (24) 73 Chang, M. (23) 38 Chapleur, Y. (3) 139; (6) 7; (13) 24; (14) 22 Charron, M. (24) 3 1 Charubala, R. (20) 176 Chatterjee, U. (2) 60 Chattopadhyaya, J. (20) 45, 131, 134, 178, 244 Chauvet, C.J. (1) 3 Cheeseman, K.H. (2) 64 Cheetham, P.S.J. (3) 72 Chekunova, E.V. (20) 33 Chen, C.-S. (18) 66 Chen, J. (19) 50; (20) 162; (23) 59 Chen, L.-C. (20) 44 Chen, R.H. (19) 84 Chen, S. (4) 72; (19) 55; (21) 21 Chen, Y. (23) 82 Chen, Z. (3) 29; (7) 28 Cheng, Y, (3) 1 Cheon, S.H. (24) 40 Chernikova, N.Yu. (22) 83 Chernyak, A.Ya. (3) 115, 119; (16) 60 Chernyak, N.V. (3) 119 Chew, W. (16) 55 Chiara, J.-L. (18) 42 Chiarelli, M.P. (22) 13 Chida, N. (2) 27; (9) 21; (19) 83 Ching, C.B. (23) 90 Chittenden, G.J.F. (5) 24; (6) 3, 5; (18) 8; (24) 76 Chizhov, O.S. (14) 15, 16, 17; (22) 5 Chmielewski, M. (5) 17; (13) 8; (14) 31; (16) 9; (22) 47; (24) 55-57 Choay, P. (19) 87 Choi, J.-R. (24) 60 Chong, W.K.M. (24) 14 Chopelle, S. (17) 22 Chou, T.-C. (20) 86 Choudhury, A . (3) 40; (13) 11; (24) 52 Chowdhary, M.S. (22) 32
Christ, W.J. (24) 40 Christiaen, D. (21) 32 Christian, R. (9) 49; (13) 18; (16) 41-43; (21) 25 Christodoulou, C. (20) 229 Chu, C.K. (20) 73, 79, 86, 136; (22) 88, 93 Chubb, S. (20) 87 Chun, M.W. (8) 18; (12) 23 Chung, J . K . (16) 63 Ciabatti, R. (19) 69 Cicero, D. (11) 1 Cihak, A. (20) 31 Cirelli, A . F . (5) 2; (7) 13 Ciuffreda, P. (3) 91, 174, 175 Claesson, A. (16) 11; (17) 7 Clardy, J. (3) 69; (18) 44 Claridge, C. (19) 58 Clark, A . J . (3) 83, 84 Classon, B. (4) 46 Clegg, W. (22) 60 Clive, D . L . J . (13) 7; (14) 29 Collins, J . G . (7) 55 Collins, P.M. (8) 25 Collonna, F. (13) 26 Colombo, D. (3) 175 Colonna, F. (5) 28; (12) 31 Columbo, L. (13) 20; (16) 7 Comber, R.N. (20) 161, 208 Conde, A. (22) 65 Conde, C.F. (22) 65 Conner, A.H. (2) 17 Contescu, A. (2) 44 Contour, M.-0. (3) 146 Contreras, R.R. (22) 11 Cooke, A.M. (18) 70 Cordes, H.-P. (16) 34 Cordonnier, R.E. (3) 111 Corey, E.J. (3) 62 Cornett, C. (3) 187 Cornia, M. (2) 25; (3) 159, 180; (14) 18 Corsaro, M.M. (4) 71 Coss6-Barbi, A. (21) 14, 35 Coteron, J.-M. (3) 89 Cottam, H.B. (19) 43; (22) 70 Cottaz, S. (4) 65, 75 Countelles, J.L.M. (24) 5 Counter, F.T. (19) 72
285
Author Index
Cox, H.C. (11) 13 Cox, P.J. (17) 14; (22) 59
Craig, D.C. (21) 19; (22) 51
Craik, D.J. (21) 44 Creemer, L.J. (3) 73; (9) 40
Cregge, R.J. ( 3 ) 181; (24) 49
Crgtien, F. ( 3 ) 139; (6) 7
Crich, D. ( 3 ) 9 , 21; (16) 22
Cristalli, G. (20) 10, 11 Cristobal Lopez, J. (14) 9 , 24, 44
Cromer, R. ( 8 ) 13; (12) 8 Cruzado, C. (7) 19 Csangdi, J. ( 5 ) 39; (7) 65
Csaszar, J. (22) 39 Cucciarini, L. (23) 76 Culvenor, C.C.J. (21) 44 Czernecki, S. ( 3 ) 167, 168; ( 7 ) 8, 68; (12) 13, 16; (13) 34
Czerwinski, A. (19) 1 6 Dabrowski, J. (21) 34, 40 D'Accorso, N.B. ( 2 ) 20; (18) 5
Daeuble, J.F. ( 3 ) 145 Dahl, B.K. (20) 182 Dahl, 0. (20) 182 Daigneault, S. (13) 7 ; (14) 29
Dairi, T. (19) 3 Dais, P. ( 3 ) 142; (21) 10 D'Alarcao, M. (20) 135 Dalgleish, A.G. (20) 133 Dalley, N.K. (20) 107 Daly, S.M. ( 3 ) 173 D'Andrea, F. (13) 26 D'Angeli, F. (13) 1 Daniel, J.K. (3) 73; ( 9 ) 40
Danieli, B. ( 7 ) 16 Danishefsky, S.J. (3) 88, 110; ( 5 ) 23; (9) 36, 37; (19) 55; (24) 22, 32 Dannoue, Y. (20) 254 Danzin, C. ( 3 ) 6 ; (20) 119 Dao, L.H. ( 2 ) 65 Daoud, L. ( 3 ) 121 Dardoize, F. (9) 41 Dasgupta, F. ( 3 ) 143; ( 7 ) 3; (10) 36 Date, T. (22) 69
Date, V. (24) 37 Davenport, R.J. ( 3 ) 182; (13) 23
Daves, G.D. (3) 190, 194 David, C. (24) 20 David, S. (3) 108; ( 6 ) 2; ( 9 ) 48; (10) 32, 33; (16) 36, 37 Davidson, E.A. (16) 49 Davies, L.C. (20) 189 Davis, N.J. (20) 4 Davison, B.E. ( 5 ) 21; ( 9 ) 5 Davoust, D. (21) 33 De Amici, M. (10) 60; (22) 40 De Angelis, F. (19) 37 Deardorff, D.R. (19) 49 Debouzy, J.-C. (20) 186 Decker, H. (19) 57 De Clerq, E. (20) 89, 91, 105, 107, 132, 154, 155, 167, 188, 191, 239 Decock, P. (17) 32, 35 Defaye, J. (3) 15, 146; (11) 11 De George, J.J. (23) 4 De Gracia, M. ( 3 ) 171 De Grado, R.R. (8) 20 De Grado, T.R. (8) 7 Degrell, I. (23) 64 de Guchteneere, E. ( 1 ) 7 ; (9) 33; (12) 29 Dehmel, K. (3) 49 Deiana, S. (17) 36 de Jong, G.J. (23) 80 Delaney, T.E. (22) 22; (23) 54 De las Heras, F.G. ( 3 ) 8; (14) 3; (20) 132, 228, 237
Delbressine, L.P.C. (7) 76
Del Corso, A. (20) 29 De Lederkremer, R.M. (3) 98; ( 5 ) 2; ( 7 ) 13; (11) 1; (13) 21 De Leeuw, J.W. (11) 13 Delfourne, E. (17) 21 Del Rio, R.E. (18) 7 Del Vecchio, P. ( 2 ) 38 Demailly, G. (8) 27; (18) 23 Dembek, P. (20) 211 Demby, L. (23) 8 6 De Mesmaeker, A. (3) 157, 158; (14) 21; (16) 6 1 De Micheli, C. (10) 60; (22) 40 Denaro, M. (19) 68 Dence, C.S. ( 8 ) 22 de N i j s , M.P. ( 7 ) 18
DeNimo, S.L. (19) 55 De Ninno, M.P. ( 9 ) 37 Denisov, G.V. (20) 240 Dennin, F. (20) 146 Denzel, K. (7) 21 Depew, W.T. (3) 99, 100 Depezay, J.-C. (24) 66-68, 71
Derappe, C. (21) 33 Derome, A.E. ( 3 ) 129 Derrico, E.M. (23) 56 Derzhavets, A.A. (22) 14 Deschamps, J. (2) 24 Descotes, G. (3) 3, 1 4 , 126; (5) 27, 31, 41; ( 7 ) 1 7 , 64; (8) 10, 11; ( 9 ) 16; (12) 18; (18) 9 , 12 Desnick, R.J. ( 3 ) 18 deSolms, S.J. (18) 75, 78 Dessi, A. (17) 35 Dessinges, A . (8) 3 Deterding, L.J. (22) 23; (23) 70 Devi, S. (3) 33 de Vos, R.H. (22) 19; (23) 45 de Vries, N.D. ( 7 ) 17 de Vroom, E. ( 7 ) 60 De Waard, P. (21) 49 Deya, E. (4) 25 de Zeeuw, R:A. (16) 62 Dhara, K.P. (23) 42 Dhavale, D.D. (12) 6 Diaz-Ortiz, A. (14) 3; (20) 132 Dickson, J.K. (14) 25, 26; (24) 6 , 7 Dieckmann, E. (12) 28 Di Fabio, R. (12) 9 Di Falsio, R. ( 5 ) 26 D'Incalci, M. (23) 79 Ding, Y. (16) 2; (22) 1, 2 Dini, C. ( 3 ) 108; (lo) 33 Dinya, 2. (18) 82; (24) 9 Dittmar, B.M. (23) 72 Doboszewski, B. (20) 79, 136; (22) 88, 93 Doi, Y. (2) 43
Doidge-Harrison, S.M.S.V. (17) 14; (22) 59
Domenico, P.A. (20) 227 Dominguez Aciego, R.M. ( 3 ) 192
Dommisse, R.A. (20) 154 Domon, B. (22) 6 Dondoni, A . ( 2 ) 1 5 , 48; ( 9 ) 31; (12) 27; (15) 6 Dong, L. (3) 160 Dong, X. ( 3 ) 108; (10) 35
Carbohydrate Chemistry
286
Doreff, P. (14) 4 Dostmann, W. (20) 197 Doyle, M.P. (16) 74 Doyle, R . J . (3) 145; (15) 7
Doyle, T.W. (9) 20; (19) 58, 59
Draper, W.M. (23) 60 Drasar, P. (3) 54 Dreckhammer, D.G. (8) 5 Dreef, C.E. (3) 40; (4) 16; (7) 59
Drenth, B.F.H. (16) 62 Dreux, M. (23) 23 Driguez, H. (4) 65, 75; (11) 11
Driller, H. (20) 59 Driscoll, J.S. (19) 52 Drueckhammer, D.G. (1) 3 Du, J. (1) 9
Dubay, G. (19) 59 Dubiel, W. (23) 83 Dubinsky, 0. (21) 32 Dubois, B. (17) 32, 35 Dubois, J.E. (21) 14, 35 Dubois, M.-A. (7) 40 Dudycz, L.W. (20) 80, 121 Dufat-Trinh Van, H. (3) 50
Duggan, M.E. (24) 44, 45 Dumas, J. (24) 66 Dumont, W. (24) 8 1 Duncan, I.B. (20) 120 Dunlap, S.E. (24) 54 Dupraz, B. (20) 186 Dupuis, J. (3) 156 Duran, C. (10) 15 Dureault, A. (24) 68, 71 Durner, G. (24) 30 Durrwachter, J.R. (1) 3 Duthaler, R.O. (17) 26-28;
(24) 84-86
Dzhavadova, G.M. (22) 82, 83, 89, 92
Dzurova, M. (3) 120 Eades, D.M. (23) 6 East, M.B. (16) 56 Eckes, P. (24) 30 Edamatsu, R. (7) 48 Edgar, A.R. (19) 89 Edwards, M.L. (20) 100 Efimiseva, E.V. (20) 70 Eger, K. (16) 72; (18) 41; (20) 46
Egert, E. (10) 47; (19) 24; (22) 43
Eguchi, S. (20) 50, 51, 55; (22) 80
Ekiel, I. (20) 118 El Ashry, E.S.H. (10)
53-56
Elguero, J. (20) 19 Elia, V. (2) 38 Elie, C . J . J . (3) 40 El Khadem, H.S. (2) 47; (12) 5; (20) 145 El Kilany, Y. (10) 53, 56 Elliott, R.D. (20) 209, 238
Elofsson, M. (10) 14 El'perina, E.A. (18) 17, 18
El Rassi, Z. (23) 63 El Sekily, M.A. (10) 52 El-Shenawy, H.A. (3) 165;
93
Fasman, G.D. (22) 39 Fauq, A.H. (18) 6 1 Fauve, R. (20) 187 Fava, G.G. (14) 18 Fay, L. (23) 8 Fedorova, G.B. (19) 66, 67
Fel'dman, D.P. (6) 1 Fellows, L.E. (24) 62 Felty-Duckworth, A.M. (19) 72
Fenichel, L. (5) 21; (9)
(10) 39
El Shimy, N. Elsley, D.A. Endo, K. (3) Endo, T. (5) Engels, J.W.
Faraj, A . (20) 113 Farkas, J. (3) 130 Farmer, P. (7) 49; (19)
(10) (18) 36 40; (20)
55 48 (19) 65 172,
179
England, T.M. (20) 39 Enholm, E.J. (18) 52; (24) 3
5
Fenselau, C. (22) 9 Fernandez, J.I. (10) 64 Fernandez, J.M.G. (7) 4; (10) 2, 23
Fernandez-Bolanos, J. (7) 66; (22) 62
Fernandez-Bolanos Guzman, J. (7) 66
Enhsen, A . (16) 26 Ennifar, S. (2) 47 Ennifarand, S. (12) 5 Enomoto, H. (18) 35 Erbing, B. (3) 92; (4) 27 Erhard, A. (3) 6 Erlansson, K. (4) 77 Ermolenko, M.S. (13) 27;
Fernandez-Bolanos Vazquez, J. (7) 23 Fernandez-Diaz, M. (22)
( 1 4 ) 19; (24) 23 Ermolenko, T.M. (20) 257; (21) 17 Ernst, B. (3) 157, 158; (8) 8; (14) 21; (16) 6 1 Esmans, E.L. (20) 154, 155 Essadiq, H. (14) 7 Esswein, A. (16) 25 Esterbauer, H. (2) 64 Estevez, R. (19) 90 Ettmayer, P. (2) 19; (18) 2 Evidente, A. (20) 1 Evtushenko, E.V. (5) 4 Ewing, D. (20) 68 Ezure, Y. (18) 33-35
Fernando dos Santos, J.
Faghih, R. (8) 3 Faiardi, D. (9) 29; (14) 5
Falck, J.R. (3) 172; (18) 68
Faltori, D. (9) 33; (12) 29
Fang, Y. (22) 12 Fantin. G. (2) 15. 48; (9) 31; (12) 27; (15) 6
15; (23) 2
Fernandez-Mayoralas, A . (13) 4, 5; (21) 38
Fernandez-Santana, V. (3) 16 (7) 13
Fernholz, E. (24) 30 Ferrari, P. (19) 68, 70 Ferrari Belicchi, M. (3) 180
Ferretti, V. (22) 30, 3 1 Ferrier, R . J . (13) 25; (14) 10 Ferris, J.P. (20) 192 Fiandor, J . (20) 137, 228, 237
Fiebig, M. (7) 40 Fiecchi, A. (3) 174 Fiedler, H.-P. (19) 57 Figueireda, J.A. (20) 156 Filip, J. (20) 27 Finan, P.A. (5) 42 Fischer, H. (7) 42 Fischer, R. (3) 26 Fisher, M.H. (3) 112 Fitzsimmons, B.J. (9) 10, 11
Fleet, G.W.J. (9) 23; (16) 12, 58; (18) 24, 25, 31, 32; (24) 62-64 Fletcher, C.A. (20) 169 Florent, J.-C. (3) 117; (8) 28; (9) 14; (12)
Author Index 22; (19) 26, 33; (20) 113; (24) 12 Florent'ev, V.L. (22) 82, 83 Floss, H.G. (19) 30 Floyd, A.J. (24) 21 Foldesi, A. (20) 178 Fogagnolo, F. (2) 48; (15) 6 Fogagnolo, M. (2) 15; (9) 31; (12) 27 Fokt, I. (13) 8 Folkers, G. ( 2 0 ) 46 Fontana, E. (19) 36 Foote, C.S. (16) 71 Fordham, W.D. (3) 52, 53 Forstner, M. (7) 14 Forsyth, A.C. (14) 6; (22) 49 Fortier, S. (22) 44 Fortt, S.M. (3) 9 Foster, S.J. (22) 34 Fournet, B. (23) 37 Fournier, J.-P. (19) 87 Fox, J.J. (20) 86 Fraisse, D. (10) 28 Franchetti, P. (20) 10, 11 Franck, R.W. (3) 12, 40; (12) 24; (13) 11; (24) 51, 52 Francotte, E. (22) 26 Frangulyan, G.A. (7) 27 Franzkowiak, M. (7) 52 Frappier, F. (20) 113 Fraser-Reid, B. (3) 14, 93, 135, 137, 138; (4) 11, 60; (5) 30; (6) 8; (7) 74; (8) 26; (9) 19; (14) 9, 24-27, 41, 46; (17) 15; (18) 51; (24) 4-7, 37, 38 Freeman, F. (3) 193 Frei, R.W. (23) 80 Frejd, T. (3) 97; (5) 6; (8) 12; (12) 19; (18) 19 Freskos, J.N. (20) 64 Freytag, K. (7) 14 Frick, W. ( 3 ) 164 Friedrich, K. (12) 28 Friedrich-Bochnitschek, s. (3) 59 Friesen, R.W. (3) 110 Frister, H. (10) 10 Fritz, H. (19) 6 Froelich, M.L. (20) 139 Fronza, G. (4) 70; (8) 15; (9) 29, 30; (14) 5, 11; (16) 48 Frost, J.W. (15) 5; (16) 18, 19
287 Fryling, J.A. (12) 30 Fudem-Goldin, B. (2) 22 Fudong, W. (5) 17 Fuegedi, P. (3) 150 Fuentes, J. (10) 15 Fuentes Mota, J. (7) 66; (10) 23 Fuganti, C. (9) 29, 30; (14) 5, 11 Fugedi, P. ( 4 ) 81; (19) 9 Fujii, T. (20) 26; (22) 69 Fujii, Y. (23) 43 Fujikura, K. (16) 51 Fujimoto, H. (4) 13 Fujimoto, K. (24) 15 Fujimoto, T. (23) 68, 69 Fujimoto, Y. (24) 94 Fujioka, H. (24) 40 Fujita, K. (3) 191; (4) 76 Fujita, S. (19) 79 Fujita, Y. (7) 48 Fujiwara, N . (20) 50, 51 Fujiwara, T. (19) 18 Fukuda, H. (2) 21 Fukuda, K. (23) 66 Fukui, M. (20) 207 Fukunaga, T. (18) 50 Fukushima, S. (20) 248 Fuller, R.W. (19) 52 Fulop, V. (22) 39 Funayama, S. (19) 77 Funke, C.W. (7) 76 Furstner, A. (8) 30; (13) 31 Furuhata, K. (3) 22, 64; (16) 46, 52; (19) 91; (23) 62 Furumoto, T. (9) 18; (18) 27 Furuno, Y. (9) 21 Furusawa, K. (20) 216-221 Furusawa, M. (23) 34 Furushima, R. (7) 47 Furuta, M. (20) 175 Furuya, T. (19) 79 Fuse, M. (2) 28 Gacs-Baitz, E. (18) 16 Gadelle, A. (3) 15 Gaffney, S.H. (2) 36 Gaggi, R . (11) 11 Gagner-Milchert, I. (16) 11 Gagnet, R. (19) 87 Gakhokidze, R.A. (16) 10 Galluchi, J.C. (9) 27 Galoyan, A.A. (3) 57, 144 Gandolfi, R. (10) 60; (22) 40
Ganem, B. (5) 9; (17) 16; (18) 36 Ganes, D.A. (23) 78 Gao, J. (3) 29 Gao, Y. (3) 160 Garaeva, L.D. (20) 34 Garcia Calvo-Flores, F. (3) 196 Garcia-Fernandez, G. (5) 12 Garcia Fernandez, J.M. (10) 23 Garcia Gancedo, A. (20) 228 Garcia-Lopez, M.T. (3) 8; (20) 228, 237 Garcia-Ochoa, S. (9) 9; (16) 23 Garcia-Raso, A. (22) 15; (23) 1, 2 Garegg, P.J. (3) 143, 150; (4) 46, 81; (10) 36 Gargadennec, A. (7) 41 Gargiulo, D. (3) 55 Gariboldi, P. (19) 16 Garner, P. (19) 56 Garuti, L. (11) 11 Gasiecki, A.F. (3) 4 Gasparini, F. (20) 144 Gasparri Fava, G. (3) 180 Gastaldo, L. (19) 68 Gatley, S.J. (8) 7, 20 Gatti, G. (10) 60; (22) 40 Gause, G.F. (19) 66, 67 Gautel, M. (20) 190; (22) 87 Gautheron, C. (4) 18; (9) 48; (16) 35, 37 Gavagnin, M. (20) 125 Gavin, N. (21) 20 Geary, S. (19) 43; (22) 70 Gehrke, C.W. (23) 71 Gelas, J. (7) 70 Gelbard, G. (7) 32; (10) 62, 63 Genesier, H.-G. (20) 197 Gennaro, M.C. (23) 67 Genot, A. (19) 33; (24) 12 Geoffroy, M. (10) 48, 49; (22) 95 Geraldes, C.F. (21) 48 Gerber, G. (23) 83 Gerdling, T.K. (16) 62 Gerhart, F. (3) 6 Gerken, M. (3) 48, 49; (7) 12; (8) 29 Ggro, S.D. (17) 8; (20) 205, 206
288
Carbohydrate Chemisty
Gessa, C. (17) 36 Gesson, J.-P. (24) 18, 20, 72
Ghazzouli, I. (19) 45; (20) 52, 77, 96
Ghosh, P.K. (3) 13 Ghosh, S. (22) 21; (23) 55
Giese, B. (3) 153, 154, 156; (12) 1; (14) 20; (16) 33 Gigg, R. (18) 70 Gil, P. (10) 4 Gil-Fernandez, C. (20) 228 Gillhouley, J.G. (18) 48 Gilli, D. (22) 31 Gilli, G. (22) 30 Gilmanova, G.Kh. (7) 63 Giovanninetti, G. (11) 11 Giuliano, R.M. (21) 24; (22) 28, 46 Giziewicz, J. (22) 91 Glaser, R. (21) 32 Glaudemans, C.P.J. (3) 85, 87, 95; (4) 10; (7) 7; (12) 17 Glod, D. (7) 64; (18) 9, 12 Glodek, J. (13) 33 Glushka, J . N . (16) 55 Gluzinski, P. (22) 37 Goasdou6, C. (9) 41 Goasdou6, N. (9) 41 Godtfredsen, S.E. (7) 15 Gorner, H. (12) 10 Golankiewicz, B. (20) 25 Gol'berg, L.E. (19) 66 Goldberg, R.N. (2) 41 Golding, B.T. (22) 60 Goldstein, B.M. (19) 52 Goldstein, B.P. (19) 68 Golebiowski, A. (9) 32, 50 Golik, J. (9) 20; (19) 59 Gomes, L.J.F. (4) 41 Gomez-Guillen, M. (10) 51 Gomez Herrera, C. (7) 23
Gomez Monterrey, I.M. (9) 46, 47; (11) 5
Gomez-Sanchez, A. (9) 42; (18) 42
Gomi, S. (19) 94 Gondo, S. (2) 50 Gonzalez, M.A. (10) 19 Goo, Y.M. (16) 63 Goodman, M. (24) 77 Goodman, M.F. (20) 67 Goodwin, J.C. (9) 38; (11) 8
Goody, R.S. (22) 87
Gorelik, E.Sh. (22) 89 Gorrichon, L. (17) 21 Gorshkova, R.P. (14) 1, 2 Gosper, J.J. (21) 44 Gosse, C. (19) 87 Gosselin, G. (10) 11; (20) 92, 95
Goto, M. (16) 51 Goto, S. (20) 256 Goto, T. (3) 122 Gottikh, B.P. (22) 82, 83 Gould, G.L. (18) 1 Gouvette, A. (19) 87 Gouyette, C. (20) 186, 187
Goya, P. (20) 19 Graf , H. (16) 3 Gras, J.-L. (6) 9 Gray, R.J. (20) 161 Greengrass, C.W. (20) 133 Greiner, J. (3) 80 Griengl, H. (20) 167 Grierson, D.S. (20) 113 Grifantini, M. (20) 10, 11
Grigera, J . R . (2) 5 Grim, M. (19) 50; (20) 162
Grim, K. (20) 227 Grochowski, E. (20) 43 Grodner, J. (13) 8; (14) 31; (24) 55
Gronberg, G. (4) 77 Grosiak, M.P. (10) 8; (20) 250
Gross, B. (18) 4 Gross, G.G. (7) 21 Gross, M.L. (22) 13 Grossman, C.S. (20) 87 Grouiller, A. (14) 7 Gruber, L. (20) 170 Grynkiewicz, G. (13) 8 Gu, D. (16) 2 Gu, T. (3) 148 Gu, Z.P. (20) 79; (22) 88 Guanti, G. (9) 28 Guattani, B. (23) 77 Gueldner, R.C. (23) 41 Guenther, T.M. (3) 32 Guerra, F.I. (20) 186 Guerrieri, A. (23) 84 Guilloux, P. (3) 14; (9) 16
Gumbiowski, R. (20) 56 Gunata, Y.Z. (3) 111 Gunnarsson, A. (3) 105 Guo, Q. (4) 51 Gupta, R. (23) 48 Gupta, R.B. (3) 40; (13) 11; (24) 51, 52
(20) 85, 190;
Gupta, R.C. (3) 37 Gupta, S.V. (20) 118
Gurarii, L.I. (7) 62, 63; (22) 66
Gurjar, M.K.
(3) 13; (9) 8; (13) 35; (18) 14 Gurskaya, G.V. (22) 82-84, 89, 92 Gustafsson, K. (16) 11 Guuarii, L.I. (17) 20 Gyorgydeak, Z. (22) 99
Ha, D.-C. (9) 27 Habuka, K. (18) 49 Hacking, A.J. (3) 72 Hafner, A. (17) 29; (22) 61
Hagan, W.J., jun. (20) 192
Hagiwara, H. (2) 61 Hahn, C.S. (14) 23; (20) 236
Haines, A.H. (18) 20 Haines, D.R. (19) 52 Hakamada, Y. (23) 50 Halama, J.R. (8) 7 Halazy, S. (3) 6 Halcomb, R.L. (3) 88; (5) 23
Hale, K.J. (24) 35 Hall, M.J. (20) 120 Hall, W.W. (20) 30 Ham, W.-H. (24) 40 Hamada, M. (19) 2, 75, 94 Hamada, T. (24) 24 Hamamoto, S. (20) 175 Hamatake, M. (7) 46 Hamilton, C.L. (21) 26 Hamilton, F. (20) 133 Hamilton, H.W. (22) 94 Hamoir, G. (20) 191 Han, B.H. (1) 10 Han, C. (1) 9 Han, S.Y. (18) 39 Han, X.Y. (16) 77 Han, Z. (16) 64 Hanada, K. (19) 25 Hanada, S. (5) 43; (24) 79
Hanafusa, T. (22) 8 Hanajima, M. (15) 4 Hanaki, A. (16) 13 Hanaya, T. (17) 1-5; (22) 58
Hancock, D.O. (23) 22 Handa, S. (24) 37 Hanessian, S. (8) 24; (19) 60
Haniff, M . I . (2) 65 Hanna, N.B. (20) 13, 31 Hans-Hans, F. (10) 51 Hansske, F. ( 2 0 ) 23 Hanvey, J.C. (19) 46
Author Index Hara, A . ( 7 ) 46 Harada, K.-I. ( 1 9 ) 8 1 , 85 Harada, T. ( 2 0 ) 26, 246 Haradahira, T. ( 8 ) 21 Haraguchi, K. ( 2 0 ) 126, 207
Harangi, J . ( 6 ) 13 Harata, K. ( 9 ) 7 Harborne, J . B . ( 3 ) 56 Hard, K. ( 1 6 ) 53 Harris, D . J . ( 2 4 ) 14 Hart, D . J . ( 9 ) 27 Hartley, P. ( 2 1 ) 24; ( 2 2 ) 28
Hasegawa, A. ( 3 ) 7 1 , 123, 124, 127, 152; ( 4 ) 1 4 , 1 9 , 36, 54, 5 5 ; ( 7 ) 2 , 33, 34; ( 1 6 ) 3 8 , 39, 44, 45 Hasegawa, M. ( 1 9 ) 3 Hashimoto, F. ( 1 6 ) 76 Hashimoto, H. ( 1 1 ) 2 ; ( 1 6 ) 2 8 ; ( 1 8 ) 30 Hashimoto, S . ( 3 ) 82 Hashizume, K. ( 1 8 ) 60 Haslam, E. ( 2 ) 36 Haslinger, E. ( 2 1 ) 45 Hasobe, M. ( 2 0 ) 163 Hata, T. ( 3 ) 6 4 ; ( 1 9 ) 91 Hatano, K. ( 2 2 ) 54 Hatano, T. ( 7 ) 48, 5 0 ; ( 1 9 ) 9 2 ; ( 2 3 ) 93 Havel, M. ( 3 ) 54 Hawkins, L.D. ( 2 4 ) 40 Hay, G.W. ( 3 ) 9 9 , 100 Hayakawa, H. ( 2 0 ) 53; ( 2 2 ) 79 Hayakawa, J. ( 3 ) 179 Hayakawa, M. ( 1 8 ) 30 Hayakawa, Y. ( 2 0 ) 177 Hayasaka, E. ( 1 6 ) 51 Hayashi, K. ( 2 3 ) 28-30 Hayashi, M. ( 1 9 ) 14, 15 Hayashi, Y. (19) 63 Hayashida, M. ( 4 ) 7, 4 0 ; ( 5 ) 34 Hazell, R.G. ( 2 2 ) 64 He, K. ( 2 1 ) 47 Hebbler, A.K. ( 1 9 ) 4 6 ; ( 2 0 ) 48 Hedbys, L. (3) 105 Heerma, W. ( 2 2 ) 11 Heermans, C.E.M. ( 2 2 ) 1 9 ; ( 2 3 ) 45 Hehemann, D.G. ( 7 ) 68 Heinrichova, K. ( 3 ) 120 Heinz, E. ( 1 1 ) 6 Heinz, H. ( 2 4 ) 13 Heitmann, A.C. ( 4 ) 32 Heitsch, H. ( 1 9 ) 57 Heitz, A . ( 3 ) 111 Helland, A.C. ( 4 ) 46
289 Helm, R.F. ( 2 ) 1 7 ; ( 1 0 ) 1 6 , 17
Helpap, B. ( 4 ) 35 Heneishi, T. ( 1 9 ) 81 Hennen, W.J. ( 1 ) 3 ; ( 2 0 ) 28
Henry, M. ( 2 3 ) 58 Herak, J . N . ( 2 0 ) 251 Herbreteau, B. ( 2 3 ) 23 Herczegh, P. ( 8 ) 9 ; ( 1 8 ) 82; (24) 8 , 9
Herdewijn, P. ( 2 0 ) 38, 89-91, 105, 107, 109, 110 Hermans, J.P.G. ( 4 ) 1 6 , 42 Hermentin, P. ( 3 ) 48, 49; ( 7 ) 1 2 ; ( 8 ) 29 Hernando Mateo, F. ( 5 ) 37; ( 1 4 ) 38 Herold, P. ( 1 7 ) 27; ( 2 4 ) 85 Hershfield, M.S. ( 2 0 ) 208 Hertel, L.W. ( 2 0 ) 87 Her&, M. ( 2 0 ) 186 Herzyk, P. ( 2 1 ) 13 Hetzheim, A. ( 1 0 ) 50 Heubl, G. ( 7 ) 40 Hewedi, F. ( 2 0 ) 32 Hewitt, B.D. ( 1 9 ) 89 Hidai, M. ( 2 ) 4 5 ; ( 1 7 ) 34, 37 Hidajat, K. ( 2 3 ) 90 Hidalgo, F.-J. ( 1 8 ) 42 Hiebl, J. ( 1 0 ) 44 Hikino, H. ( 3 ) 36 Hikota, M. ( 2 4 ) 24, 25 Hildenbrand, K. ( 2 0 ) 251 Hill, R.E. ( 2 ) 62 Hilpert, H. ( 2 0 ) 169 Hindsgaul, 0. ( 4 ) 1 5 , 62 Hingorani, L.L. ( 7 ) 31 Hino, T. ( 3 ) 42 Hiramatsu, M. ( 7 ) 48 Hirano, T. ( 1 7 ) 34 Hiraoka, W. ( 2 0 ) 252 Hiragama, N. ( 2 2 ) 38 Hirose, M. ( 2 0 ) 159, 177 Hirose, S. ( 2 3 ) 6 8 , 69 Hiroto, T. ( 2 0 ) 50 Hirsch, J. ( 3 ) 134 Hisamatsu, S. ( 2 3 ) 85 Hitchcock, M.J.M. ( 1 9 ) 45; ( 2 0 ) 7 7 , 96 Hlavati, J. ( 3 ) 94 Hoch, M. ( 3 ) 101; ( 1 1 ) 6 Hockstein, D.R. ( 1 9 ) 64 Hodder, H.J. ( 1 6 ) 50 Hoffman, P. ( 3 ) 157, 158 Hoffmann, P. ( 1 4 ) 21; ( 1 6 ) 61 Holden, J.E. ( 8 ) 7 , 20
Holla, E.W.
( 7 ) 20; ( 1 3 )
9
Hollingshead, M, ( 1 9 ) 52 Hollosi, M. ( 2 2 ) 39 Holman, M. (20) 152 Holst, 0. ( 1 6 ) 34; ( 2 3 ) 10
Holy, A . ( 9 ) 6 ; ( 2 0 ) 68 Holzapfel, C.W. ( 7 ) 26 Honda, A. ( 1 8 ) 3 Honda, M. ( 2 2 ) 80 Honda, T. ( 3 ) 82 Honegger, C.G. ( 2 3 ) 65 Honig, H. ( 1 8 ) 56 Honjo, M. ( 1 9 ) 6 2 ; ( 2 0 ) 103; ( 2 2 ) 81
Honma, Y. ( 2 0 ) 22 Hoogerhout, P. ( 4 ) 1 6 , 42 Hoople, D.W.T. ( 2 0 ) 133 Hope, K.D. ( 1 5 ) 3 Hoppe, D. ( 1 4 ) 39, 40 Hori, H. ( 5 ) 1 8 ; ( 2 1 ) 43 Horii, T. ( 1 9 ) 62 Horikoshi, I. ( 7 ) 47 Horita, K. ( 2 4 ) 41-43 Horito, S . ( 1 6 ) 28 Horn, A.S. ( 1 6 ) 62 Horowitz, R.M. ( 7 ) 37 Horton, D. ( 3 ) 171; ( 1 3 ) 3 , 21; ( 1 9 ) 27
Horvat, J. ( 7 ) 3 5 , 36 Horvat, S. (7) 35, 36 Horvath, C. ( 2 3 ) 63 Horvath, K. ( 1 8 ) 16 Horvatic, D. ( 2 2 ) 57 Hosaka, A. ( 1 8 ) 40 Hoshi, A. ( 1 9 ) 39; ( 2 0 ) 224
Hoshi, Y. ( 2 3 ) 19 Hoshino, Y. ( 2 0 ) 55 Hosokawa, T. ( 2 0 ) 213 Hosotsubo, H. ( 2 3 ) 87 Hotta, K. ( 1 9 ) 2 Hovinen, J. ( 2 0 ) 244 Howell, A . R . ( 3 ) 4 , 10 Howell, H.G. ( 1 3 ) 19 Howie, R.A. ( 1 7 ) 1 4 ; ( 2 2 ) 59, 73
Hozumi, M. ( 2 0 ) 22 Hricovini, M. ( 2 1 ) 7 , 8 Hronowski, I.J.J. ( 3 ) 9 9 , 100
Hsu, F. ( 2 2 ) 20, 21; ( 2 3 ) 53, 55
Hu, Y. ( 4 ) 51 Huang, C.-H. ( 2 0 ) 192 Huang, J.-T. ( 2 0 ) 86 Hudlicky, T. ( 2 ) 18 Hiitter, K. (10)47; ( 1 9 ) 24; ( 2 2 ) 43
Huff, J . R . ( 1 8 ) 75, 78 Hug, P. ( 3 ) 157, 158
Cnrbohydrate Chemistry
290 Hughes, R.G., jun. (20) 123
Hultgren, S.J. ( 5 ) 7; (14) 14
Humble, R.W. (20) 32, 68 Hungate, R. (24) 22 Huryn, D.M. (20) 137, 231 Husain, M. (24) 10 Hussain, A . (8) 25 Hussein, N . A . (11) 4 Hutchinson, A. (19) 50 Huynh-Dinh, T. (20) 186, 187
Hwang, C.K. (24) 44, 45 Hwang, T.-H. (3) 66
Inokawa, S. (17) 1, 3 Inokuchi, T. (15) 1 Inoshiri, S. (22) 27 Inoue, S. (18) 60 Institoris, L. (18) 16 Ipata, P.L. (20) 29 Ireland, R.E. (24) 36 Irie, S. (2) 14 Irth, H. (23) 80 Isaka, A . (18) 55 Isbell, H.S. (2) 47 Ishibashi, M. (19) 77 Ishida, H. (3) 71, 124; (4) 14, 54, 55; (7) 33, 34; (16) 38, 39, 44, 45
Ishida, K. (17) 34 Ishida, N. (9) 26; (14) Iacobellis, N.S. (20) 1 Ibuka, T. (14) 42; (18) 13
37; (22) 48
Ishido, Y. (3) 188; ( 5 ) 40; (19) 65
Ichikawa, S. (18) 40 Ichikawa, Y. (3) 191;
Ishihara, J. (13) 30;
(19) 63 Ida, H. (16) 52; (23) 62 Igarashi, S. (4) 25 Igata, K. (18) 21 Igolen, J. (3) 17 Ihara, Y. (18) 21 Ihida, H. (4) 19 Iida, A. (17) 6 Iida, H. (24) 92 Iigo, M. (20) 191 Iijima, H. (4) 30, 50 Iijima, T. (3) 195 Iitaka, Y. (19) 74 Ikai, K . (17) 6 Ike, Y. (19) 39; (20) 224 Ikeda, D. (19) 2, 34 Ikeda, K. (3) 20; (17) 13 Ikeda, T. (23) 95 Ikeda, Y. (23) 43 Ikegami, S. (3) 82 Ikemoto, T. (19) 8 1 Ikota, N. (16) 13; (18) 37, 38 Imai, H. (19) 13, 79 Imai, Y. (3) 71; (4) 19; (7) 34 Imamura, Y. (3) 140 Imanari, T. (23) 19, 50 Imbach, J.-L. (20) 92, 95 Imberty, A. (2) 8 Imoto, H. (17) 10 Imoto, T. (4) 76 Imura, Y. (19) 15 Ina, K . (2) 61; (3) 69; (18) 44 Inatomi, N. (19) 20, 21 Inazu, T. (3) 125; (17) 18, 19 Inciong, E.J. (23) 42 Inghardt, T. (18) 19
Ishii, K. (16) 78, 79 Ishii, Y. (16) 6 Ishikawa, I. (20) 22 Ishikawa, T. (23) 40 Ishikura, T. (19) 22 Ishimaru, K. (14) 12 Ishimatsu, M. (14) 12 Ishimura, M. (2) 35 Ishitani, Y. (22) 45 Ismael, I.M. (20) 156 Ismailov, N. (10) 22 Isobe, R . (22) 10 Isono, K. (19) 19 Issaq, H.J. (23) 86 Itaya, T. (20) 26, 246,
(14) 33, 34
247 (20) 150 (3) 45 (16) 79; (19) 1 (3) 152; (4) 38, 44, 52, 53, 67, 68, 74; (16) 44, 45 Itoh, F. (9) 24, 25 Itoh, H. (16) 29 Itoh, K. (20) 62, 63 Itoh, M. (2) 21; (18) 33 Itoh, T. (3) 86; (20) 22 Itoh, Z. (19) 20, 21 Itriashvili, N.S. (16) 10 Ivanova, N.V. (22) 33 Iwahi, M. (9) 17 Iwami, H. (13) 10; (14) 43 Iwamoto, J. (19) 1 Iwanami, M. (19) 13 Iwanami, Y. (10) 1 Iwasaki, H. (19) 17 Izukawa, Y. (11) 2 Izumi, K. (21) 4
Ito, C. Ito, F. Ito, T. Ito, Y.
Jacob, G . S . (18) 31 Jacobs, G . A . (20) 234 Jacobs, P.L. (7) 76 Jacobsen, J.P. (9) 13 Jacobsson, U. (9) 50 Jacques, P.P.L. (17) 25 Jacquesy, J.-C. (24) 18, 20, 72
Jain, S.M. (3) 33; (13) 15; (20) 40
James, M.N.G. (22) 75 James, V.J. (22) 34 Janado, M. (2) 43 Jankowski, K. (22) 4 Jansen, C. (23) 26 Janssen, G . (20) 105 Jansson, A.N. (16) 11 Jansson, K. (3) 97; (5) 6; (8) 12; (12) 19
Jansson, P.-E. (3) 92; ( 4 ) 27 Jantzen, E. (23) 9 Jarglis, P. (13) 13; (16) 8
Jarosz, S. (3) 93; (13) 33; (17) 15
Jaroszewski, J.W. (3) 187 Jarvi, E.T. (5) 38; (11) 10; (20) 88, 100
Jarvis, T.C. (21) 26 Jaseja, M. (21) 32 Jastorff, B. (20) 197 Jaworska, M.M. (20) 181 Jefson, M.R. (19) 76 Jeganathan, S. (2) 31 Jentoft, N. (23) 48 Jergorov, A. (3) 149 Jerkovich, G. (19) 9 Jeroncic, 1.0. ( 5 ) 2 Jeroncic, L.O. (7) 13 Jezek, J. (3) 130 Ji, L. (21) 47 Jiang, C. (18) 62 Jigajinni, V.B. (19) 89 Jimenez-Barbero, J. (2) 9; (3) 89; (21) 38 Jimenez Requejo, J.L. (9) 46, 47; (10) 19; (11) 5
Jiminez, J.L. (10) 64 Jin, H.L. (23) 24, 25; (24) 40
Jizba, J.V. (19) 35 Johansson, E. (3) 105 Johnson, D.C. (2) 52 Johnson, 0. (22) 64 Johnston, E.R. (21) 9 Joly, J.-P. (18) 4 Jona, H. (3) 162 Jones, D.W. (22) 64 Jones, M. (18) 76 Jones, S.S. (20) 229 Jordan, A.D., jun. (9)
29 1
Author Index 44; (10) 18
Jorgenson, J.W. (22) 23; (23) 70
Jork, H. (3) 5 1 Joseph-Nathan, P. (18) 7 Joshi, R.V. (19) 41; (20) 13
Joullie, M.M. (18) 39 Jiirgens, T. (20) 35 Jutten, P. (7) 38; (24) 91
Jun-Dong, Z. (20) 37 Jung, K.-H. (3) 101 Jungbauer, A. (23) 6 1 Junginger, G . (20) 46 Jurczak, J. (9) 32, 50 Jurenitsch, J. (21) 45
(9) 17; (15) 4
Kaneyama, N. (23) 40 Kang, S.H. (24) 40 Kang, Y. (20) 147; (22) 71
Kanie, 0. (4) 29; (22) 54 Kantoci, D. (3) 129; (7) 35
Kappes, E. (18) 29 Karakasa, T. (7) 73 Karaksonyi, S. (3) 94 Karchesy, J.J. (10) 16, 17
Karl, R. (20) 114 Karmanova, I . B . (3) 119 Karny, J.F. (20) 123 Karpeiskii, M.Ya. (20) 204
Karpiesiuk, W. (8) 14; Kadentsev, V . I . (22) 5 Kadokura, Y. (19) 73 Kadota, S. (19) 13, 79; (20) 50
Kappi, R. (20) 243, 244 Kagatani, S. (20) 26 Kahne, D. (3) 1 Kai, Y. (8) 21 Kaimarazov, A.G. (22) 5 Kaiser, K. (20) 57, 59 Kaji, N. (16) 6; (20) 5, 24
Kakinuma, K. (14) 35; (19) 8; (24) 93, 94
Kakoi, H. (18) 60 Kale, A. (2) 57 Kalicheva, I . S . (3) 57, 144
Kallin, E. (10) 14; (18) 22
Kalman, A . (22) 39 Kaluza, Z. (5) 17; (14) 31; (24) 55, 56
Kameda, Y. (9) 18; (18) 27
Kamerling, J.P. (4) 17, 48; (16) 53; (21) 31; (22) 11; (23) 7 Kameyama, A. (3) 124; (4) 36, 54, 55 Kamikawa, T. (3) 44; (7) 58 Kaminskii, Yu.L. (2) 42; (20) 66 Kamiya, H. (16) 52; (23) 62 Kamiya, N. (19) 17 Kan, Y. (3) 76 Kanazaki, T. (24) 74 Kaneko, C. (20) 142, 158- 160 Kaneko, K. (23) 28-30 Kanemitsu, K. (3) 136;
(10) 34
(3) 123, 124; (4) 36; (7) 2 Kasahara, K. (24) 92 Kasai, R. (21) 15 Kase, H. (19) 82 Kase, M. (3) 136 Kashiwada, Y. (3) 66; (23) 46 Kasperowicz, S. (22) 46 Kaspersen, F.M. (7) 76 Katagiri, N . (20) 142, 158, 159 Katayama, C. (22) 80 Katayama, K. (9) 18 Kates, M. (3) 44; (7) 58; (24) 70 Katinger, H. (23) 6 1 Kato, K. (20) 127, 128 Kato, N. (10) 3 1 Kato, T. (20) 222, 222 Kato, Y. (10) 3 1 Katsuki, M. (3) 28, 161, 162 Katsura, T. (20) 216, 217, 219, 221 Kawaguchi, T. (20) 248 Kawahara, N. (20) 22 Kawai, H. (2) 21 Kawai, J. (20) 145 Kawajiri, A. (16) 75 Kawakami, H. (20) 62, 63 Kawamoto, H. (17) 1, 3, 4 Kawamoto, I. (19) 82 Kawana, M. (20) 72, 108 Kawanishi, H. (7) 43, 44 Kawano, Y. (13) 12 Kawase, T. (3) 136 Kawashima, A. (19) 25 Kawashima, M. (20) 175 Kayumov, V.G. (2) 42 Kazimierczuk. Z. (20) . . 15.. 16, 61, 245
Kartha, K.P.R.
Ke, Y.Y. (9) 24 Keck, G . E . (14) 30; (24) 48
Keglevic, D. (3) 129 Kellogg, R.M. (3) 147; (11) 12; (22) 29
Kempf , A. (23) 65 Kenne, L. (3) 92; (4) 27 Kent, P.W. (8) 1 Kerby, N.W. (23) 52 Kerekgyarto, J. (4) 48; (21) 31
Kerremans, L. (20) 90 Kessel, D. (20) 8 1 Kettenring, J.K. (19) 69 Kezar, H . S . (24) 17 Khalilov, L.M. (13) 36 Khamis, F.A. (3) 165, 166; (10) 39, 40
Khan, M.M. (16) 69 Khan, M.R. (20) 202 Khan, S.H. (4) 34 Khar'kovskii, V.M. (5) 25 Khilya, V . P . (3) 58 Khwaja, T.A. (20) 67 Kiba, N. (23) 34 Kibayashi, C. (24) 92 Kieboom, A.P.G. (5) 32, 35
Kiely, D.E. (15) 3 Kierzek, R . (20) 210 Kigoshi, H. (3) 140 Kihara, T. (19) 19 Kihlberg, J. (3) 97; (5) 6, 7; (8) 12; (12) 19; (14) 14 Kiho, T. (18) 3 Kikuchi, H. (24) 65 Kikuchi, T. (21) 47 Kilbourn, M.R. (8) 22 Kim, G.M. (1) 10 Kim, H.K. (16) 63 Kim, J.H. (14) 23; (20) 236 Kim, J.N. (20) 99 Kim, K.S. (14) 23; (20) 236 Kim, M.H. (8) 18; (12) 23 Kim, M . J . (1) 4 Kim, S. (24) 46 Kim, S.J. (20) 236 Kim, Y.G. (24) 61 Kim, Y.K. (14) 23 Kimura, H. (18) 49, 8 1 Kimura, I. (19) 85 Kimura, J. (20) 256 Kinamoto, K. (20) 55 Kind, R. (10) 47; (19) 24; (22) 43 Kinder, J.P. (3) 53 King, C.-H.R. (3) 73; (9) 40
Cnrbo hydrate Chemistry
292 King, S.A. ( 1 4 ) 47 Kinoshita, K. ( 1 9 ) 1 4 , 15 Kinoshita, M. ( 2 0 ) 213; ( 2 4 ) 26, 29
Kinzy, W. ( 4 ) 47 Kiriasis, L. ( 2 0 ) 18 Kirk, 0 . ( 7 ) 15 Kirschner, G. ( 4 ) 7 0 ; ( 1 6 ) 48
Kishi, Y. ( 2 4 ) 40 Kishimura, Y. ( 1 9 ) 25 Kishino, H. ( 9 ) 25 Kiso, M. ( 3 ) 7 1 , 123, 124, 127, 152; ( 4 ) 1 4 , 1 9 , 36, 54, 55; ( 7 ) 2 , 33, 34; ( 1 6 ) 38, 3 9 , 44, 45 Kita, K. ( 7 ) 47 Kita, Y. ( 9 ) 24, 25 Kitada, Y. ( 2 3 ) 47 Kitagawa, I. ( 4 ) 4 5 ; ( 7 ) 43, 44; ( 1 9 ) 48; ( 2 0 ) 164, 171; ( 2 1 ) 47 Kitamura, S. (2) 7 Kitanaka, S. ( 1 2 ) 4 ; ( 2 2 ) 35 Kitaori, K. ( 3 ) 195 Kitaori, R. ( 2 0 ) 150 Kito, T. ( 3 ) 127 Kitzing, S . ( 3 ) 9 7 ; ( 5 ) 6 ; ( 8 ) 1 2 ; ( 1 2 ) 19 Kiyoshima, K. ( 1 9 ) 22 Klaeren, S . A . ( 1 8 ) 1 , 6 Klaffke, W. ( 3 ) 114 Klaska, K.-H. ( 3 ) 90 Klausener, A. ( 1 2 ) 10 Kleeberg, M. ( 3 ) 90 Klein, J. ( 5 ) 15 Klein, R . S . ( 2 0 ) 152, 153 Klein, U. ( 3 ) 186; ( 2 0 ) 157 Kleineidam, R.G. (3) 23; ( 1 3 ) 1 8 ; ( 1 6 ) 42 Klimov, E.M. ( 3 ) 7 7 , 79 Kloosterman, M. ( 7 ) 1 7 , 18 Kloss, J. ( 1 9 ) 60 Kmety, A . ( 2 1 ) 39 Knaus, E.E. ( 2 2 ) 75 Knirel, Yu.A. ( 2 1 ) 28 Knodo, K. ( 2 2 ) 80 Knoedler, U. ( 3 ) 49 Knollmiiller, M. ( 2 ) 1 9 ; (18) 2 Knothe, L. ( 1 9 ) 7 Knowles, J.J. ( 2 1 ) 26 Knowles, J . R . ( 1 6 ) 20, 21 Kobayashi, H. ( 2 ) 7 Kobayashi, K. ( 2 0 ) 215 Kobayashi, M. ( 4 ) 44 Kobayashi, N . ( 3 ) 188; ( 1 9 ) 31
Kobayashi, S. ( 3 ) 5 Kobayashi, T. ( 2 3 ) 85 Kobylinskaya, V . I . ( 2 0 ) 14
Koch, M. ( 3 ) 50 Kochetkov, N . K . ( 3 ) 7 7 , 7 9 , 9 6 , 115, 119, 132, 133; ( 4 ) 8 , 9 , 33; ( 6 ) 12; ( 7 ) 56; (13) 27; ( 1 4 ) 1 9 ; ( 2 1 ) 28, 41, 42; ( 2 4 ) 23 Kodato, S. ( 3 ) 42 Koehler, J.E.H. ( 2 2 ) 25 Koll, P. ( 1 0 ) 38; ( 2 2 ) 41 Konig, W.A. ( 1 9 ) 57 Koeppe, R . A . ( 8 ) 7 Koft, E.R. ( 1 4 ) 4 Koga, M. ( 2 0 ) 166 Koga, T. ( 4 ) 76 Kogami, Y. (19) 18 Kogelberg, H. ( 1 0 ) 38 Kohno, M. ( 9 ) 25 Koholic, D.J. ( 3 ) 116; ( 7 ) 67 Koike, K. ( 3 ) 4 1 ; ( 2 1 ) 34 Koizumi, K. ( 2 3 ) 31, 32 Kojic-Prodic, B. ( 2 2 ) 57 Kojima, M. ( 8 ) 21 Kojiri, K. ( 1 9 ) 7 4 , 75 Kojiro, S. (3) 136 Kol, 0. ( 2 3 ) 37 Kolar, C. ( 3 ) 48, 49; ( 7 ) 1 2 ; ( 8 ) 29
Kolobushkina, L. I . (20) 204
Kolomeitseva, V .V 240
. (20)
Kolosova, T.E. ( 2 2 ) 33 Komiotis, D. ( 1 6 ) 5 7 ; ( 2 0 ) 235
Komiya, K. ( 1 9 ) 77 Komiyama, K. ( 3 ) 6 4 ; ( 1 9 ) 91
Komiyama, M. ( 2 0 ) 193-196 Komkov, A . V . ( 7 ) 27 Komuro, K. ( 1 9 ) 31, 32, 34
Kondo, H. ( 1 9 ) 1 Kondo, S . ( 1 9 ) 34, 94 Kondo, Y. ( 7 ) 11 Konishi, K. (7) 47 Konno, K. ( 1 8 ) 34 Kononov, L.O. ( 1 6 ) 60 Konradsson, P. ( 4 ) 1 1 , 60; ( 6 ) 8 ; ( 8 ) 26
Koole, L.H. ( 2 0 ) 131 Kopf, J. ( 1 4 ) 32; ( 2 2 ) 41, 50, 63
Kopper, S. ( 4 ) 23 Korguth, M.L. ( 8 ) 20 Kornilov, V . I . ( 1 6 ) 1 6 , 1 7 , 32
Korol, E.L. ( 5 ) 25 Koroteev, M.P. ( 7 ) 56 Korytnyk, W. ( 8 ) 2 , 17 Kosai, S . ( 3 ) 44; ( 7 ) 5 8 ; ( 2 4 ) 70
Koscielniak, T. ( 2 4 ) 6 6 , 67
Koshimizu, K. ( 2 0 ) 5 Kosma, P. ( 3 ) 121; ( 4 ) 12 Kosora, N . ( 2 0 ) 227 Kossmehl, G. ( 7 ) 22 Kosugi, Y. ( 2 0 ) 7 3 , 7 9 ; ( 2 2 ) 88
Koten, A . ( 7 ) 76 Koto, S. ( 3 ) 136 Kovac', P. ( 3 ) 87; ( 7 ) 7 ; ( 1 2 ) 17
Kovalev, V . N . ( 3 ) 58 Kowalski, B.R. ( 2 1 ) 6 Koyama, W. ( 7 ) 44 Kozikowski, A . P . ( 1 8 ) 61 Kozlowski, H. ( 1 7 ) 32, 35 Kozyreva, 0.1. ( 2 0 ) 66 Kraaijeveld, N . A . ( 4 ) 59 Kraemer, H.P. ( 1 9 ) 26 Kraeva, S.E. ( 5 ) 4 Kraevskii, A . A . ( 2 2 ) 84 Kragmann, C. ( 4 ) 43 Krajewski, J.W. ( 2 2 ) 37 Kramer, D.L. (20) 123, 124
Krasavina, L.S. ( 2 0 ) 20 Krausz, P. ( 7 ) 8 Krawczyk, S.H. ( 1 9 ) 44 Krebs, A. ( 3 ) 99, 100 Krecmerova, M. ( 9 ) 6 Krenger, W. ( 2 3 ) 65 Krenitsky, T.A. ( 2 0 ) 30 Kresze, G. ( 1 8 ) 80 Krief, A . ( 2 4 ) 81 Krieger, C. ( 2 0 ) 190; ( 2 2 ) 87
Krishna, P.R. ( 1 3 ) 35 Krishnan, B. ( 1 9 ) 59 Kristen, H. ( 1 1 ) 7 Krohn, K. ( 2 4 ) 13 Kroin, J.S. ( 2 0 ) 87 Kroon, J. ( 2 ) 3 Krupenskii, V . I . ( 2 ) 4 0 ; (16) 4
Kryazhevskikh, I . A . ( 3 ) 9 6 ; ( 6 ) 12 Krylova, V . N . ( 1 8 ) 67 Kubo, K. ( 1 3 ) 10; ( 1 4 ) 43 Kubota, H. ( 3 ) 191; ( 2 0 ) 65
Kubota, K. ( 2 ) 21 Kubota, Y. ( 2 3 ) 31, 32 Kucar, S . ( 7 ) 5 Kuck, N . A . ( 1 9 ) 80 Kuening, C . A . ( 1 1 ) 12 Kuge, !f. ( 2 ) 7
293
Author Index
Kuhlmeyer, R. (19) 6, 7 Kuhn, C.-S. (3) 95 Kukagawa, Y. (19) 22 Kulagowski, J.J. (18) 74, 75, 77, 78; (22) 68
Kulak, T.I. (20) 33, 97, 230
Kulik, W. (22) 11 Kulinkovich, L.N. (20) 140, 141
Kulkarni, V.R. (3) 78, 113; (7) 10
Kullnig, R. (14) 4 Kumar, A . (20) 40 Kung, E. (20) 173 Kunz, H. (3) 59; (4) 4; (10) 20, 24-26; (24) 87-90 Kuo, C.K. (3) 63 Kuo, K.C. (23) 71 Kuroda, A . (16) 54 Kuse, M. (2) 45; (17) 37 Kusmierek, J. (20) 243 Kusmierz, J. (23) 4 Kuszmann, J. (19) 9; (21) 19; (22) 51; (24) 39 Kuwabara, M. (20) 252 Kuzuhara, H. (3) 131; (4) 7, 40; (5) 34; (20) 108 Kvasyuk, E.I. (20) 33, 36, 94, 97, 230 Kwok, D.-I. (3) 190 Kwon, B.-M. (16) 71
Labartkava, M.O. (16) 10 Labeit, S. (20) 190; (22) 87
Labler, L. (4) 58 Laborit, H.M. (9) 41 Lacher, B. (1) 3 Lafont, D. (3) 14, 126; (5) 31; (9) 16
Lafosse, M. (23) 23 Laiko, A . V . (19) 66 Lakhmiri, R. (5) 8 Lalitha, H.N. (22) 74 Lamande, L. (17) 2 1 Lambert, R.W. (20) 120 Lancini, G.C. (19) 70 Langemann, H. (23) 65 Lanzetta, R. (4) 7 1 Larew, L.A. (2) 52 Larreta-Garde, V. (2) 34 Larsen, D.S. (3) 37, 38; (24) 82
Larson, S.B. (10) 7; (19) 43; (20) 8, 9, 13, 147; (22) 70, 71, 86 Larsson, L. (23) 9 Larsson, P.-0. (3) 105 Lasorella, A . (23) 75
Lau, J. (9) 12; (20) 116, 117
Laumann, V. (10) 38 Laver, U. (19) 78 Lay, H. (2) 23 Leahy, J.W. (20) 168 Le Berre, F. (24) 68 Le Blanc, M. (3) 80 Leblanc, Y. (9) 10, 11 Leclerq, F. (20) 101 Lecomte, Ph. (24) 81 Ledl, F. (10) 27, 30 Ledvina, M. (3) 130 Lee, A.C. (3) 10 Lee, E. (21) 20 Lee, M.D. (19) 80 Lee, S.H. (7) 45 Leeds, J . M . (20) 208 Leeson, P.D. (18) 74; (22) 68
Leftheris, K. (24) 77 Le Fur, R. (21) 12 Le Gallic, J. (3) 19 Legler, G. (18) 29 Lehmann, J. (2) 23; (3) 27, 95; (4) 10; (12) 28
Leismann, H. (12) 10 Leiting, B. (22) 53 Le Lem, G. (5) 4 1 Le Merrier, Y. (24) 66-68 Lemieux, R.U. (3) 18; (8) 13; (12) 8 Lemen, P. (20) 114 Lenfers, J.B. (14) 32; (22) 50 Lenieux, C. (7) 36 Lennon, I.C. (18) 74; (22) 68 Leonard, J.N. (10) 8; (20) 250 Lepoivre, J.A. (20) 154 Le Prian, C. (18) 47 Leroy, P. (23) 57 Lertratanangkoon, K. (20) 4 Lesiak, K. (20) 188 Lesnikowski, 2. J. (20) 181 Lesur, B.M. (24) 14 Letourneux, Y. (19) 87 Levai, A. (22) 99 Levine, H. (2) 37 Levinskii, A.B. (3) 115 Lewis, A . (5) 16; (24) 83 Lewis, N.G. (23) 42 Lewis, T. (24) 21 Ley, S.V. (3) 182; (5) 5; (13) 23; (18) 59, 71 Lhermet, C. (17) 31 Lhermitte, M. (21) 33 Lhoste. P. (3) 183: (5) 8 Li, H.-Y. ( 1 4 j 3 5 ; ’ ( 2 4 j
93
Li, J. (3) 29 Li, W. (16) 2 Li, X. (7) 28 Liang, W. (22) 7 Liang, X.Y. (22) 12 Libby, P.R. (20) 124 Lichtenthaler, F.W. (13) 13, 16; (16) 8
Lidak, M.Yu. (6) 1 Lidaks, M. (20) 98 Liddel, P.A. (18) 39 Liepins, E. (20) 98 Li-He, Z. (20) 37 Lilley, T.H. (2) 36 Lin, G. (18) 79; (19) 86; (20) 198
Lin, J. (7) 32; (10) 63 Lin, T. (22) 75 Lin, T.-S. (12) 17; (19) 45; (20) 52, 77, 165; (22) 9 1 Lin, Y.S. (3) 80 Lin, Z. (7) 9; (21) 21 Lind, R.E. (20) 139 Lindberg, W. (21) 6 Lindeman, S.V. (22) 84, 92 Lindh, F. (4) 77 Lindh, I. (7) 51 Lindroos-Heinanen, R (2) 59 Linker, T. (16) 33 Liotta, L.J. (5) 9; (17) 16; (18) 36 Lipka, P. (11) 14 Lipkind, G.M. (21) 28, 41, 42 Lipniunas, L. (4) 77 Lippmaa, E. (3) 134 LiptAk, A . (4) 48; (6) 11; (21) 22 Little, M. (3) 146 Litvinov, I . A . (7) 62; (17) 20; (22) 66 Liu, H.-W. (12) 12; (23) 57, 97 Liu, L. (7) 57 Liu, L.-d. (20) 185 Liu, P.S. (3) 73; (9) 40 Liu, Y. (16) 64; (22) 1, 2 Liu, Y.-C. (18) 66 Liu, Z. (16) 64 Liverton, N. (18) 74; (22) 68 Ljevakovic, D. (9) 43 Llauro, M.F. (10) 62 Llera, J.M. (14) 26; (24) 6 Lo, S.F. (23) 97 Lodwick, P.A, ( 2 1 ) 26
.
294
Cnrbohydrate Chemistry
Lonn, H. (4) 49; (10) 14; (18) 22
Lonnberg, H. (20) 16, 243-245,
249
Loeschner, T. (20) 179 Logers, M. (3) 26 Lohse, K. (22) 36 Lomakina, N.N. (9) 1; (19) 66, 67 Long, D.H. (23) 97 Lopez, J.A. (5) 36 Lopez, J.C. (14) 9, 24, 44 Lopez Aparicio, F.J. (3) 196; (14) 38 Lopez Herrera, F.J. (3) 192; (20) 148 Lottenbach, W. (17) 27; (24) 85 Loub, J. (22) 63 Low, J.N. (22) 85 Low, T.N. (22) 73 Lubey, G.S. (21) 37 Lubineau, A. (3) 19, 39 Ludin, C. (19) 7 Luger, P. (17) 5; (22) 58 Lui, H.-w. (20) 185 Lukacs, G. (8) 3, 9, 16; (10) 43; (14) 44; (19) 28; (21) 39 Luna, H. (2) 18 Lundgren, T. (4) 77 Lundt, I. (18) 15 Luning, B. (3) 60 Luzen, A. (8) 23 Lyakhovets, V . I . (20) 230
Ma, L. (19) 86; (20) 198 Maas, A.A.M. (4) 17; (23) 7
McAllister, L.M. (21) 26 McAlpine, J.B. (19) 84 McArdle, P. (21) 20 McCarthy, J.R. (20) 100 McCleary, B.V. (3) 30 McClure, T.D. (20) 2, 3, 84
McDonald, G. (2) 32, 33; (22) 52
Machykta, D. (21) 39 Maciejewski, S. (24) 57 McIntyre, M.K. (21) 27 Mackenzie, G. (20) 32, 68 Mackie, W. (22) 55, 56 MacLeod, J.K. (7) 55 McPhail, A.T. (22) 94 McPherson, H. (19) 52 McWhorter, W.W., jun. (24) 40 Madej, D. (20) 23 Maeba, I. (3) 195; (20)
150
Maeda, M. (8) 21 Maeta, H. (3) 75, 107 Magdalou, J. (23) 57 Magdzinski, L. (14) 46 Magnani, M. (23) 76 Magnusson, G. (3) 97; (5) 6, 7; (8) 12; (12) 19; (14) 14
Magomedova, N.S. (7) 56 Mahapatra, A. (2) 56, 60 Maheswara Rao, N.U. (10) 3; (22) 96
Mahon, M.F. (24) 21 Maier, F.K. (24) 78 Maillard, M. (20) 113 Mainkar, P.S. (9) 8 Mak, M. (6) 13 Makarova, Z.G. (3) 77 Malinowski, N. (18) 62 Mall, H. (23) 10 Mallams, A.K. (3) 151 Malleron, A. (3) 108; (6) 2; (9) 48; (10) 32, 33; (16) 36, 37 Malysheva, N.N. (3) 77, 79 Manca, F. (23) 13 Mancy, S. (10) 52 Mande, S.S. (22) 77 Manfredi, A. (3) 80 Mangoni, L. (4) 71 Manitto, P. (3) 175 Manning, J.K. (19) 80 Manro, A. (8) 25 Mansuri, M.M. (13) 19; (19) 45; (20) 77, 96, 122 Manyan, S.S. (3) 144 Maracek, J.F. (18) 72 Maran, F. (13) 1 Marchal, P. (20) 119 Marchenko, G.N. (22) 33 Marchione, C.S. (9) 44; (10) 18 Marco, J.L. (13) 22; (14) 36 Marennikova, S.S. (20) 33 Maring, C.J. (9) 36 Marino, C. (3) 98 Marino, G. (3) 112 Marino-Albernas, J.R. (3) 16 Markiewicz, W.T. (20) 210 Markin, S.M. (12) 32 Markin, V.A. (23) 36 Markovskii, L.N. (20) 49, 97 Marquez, V.E. (19) 51, 52 Marra, A. (3) 24, 108; (7) 1; (10) 35; (13) 4, 5
Marriott, M.S. (20) 133 Marsaioli, A.J. (7) 13 Marsh, C.A. (16) 74 Martel, C. (21) 29 Martin, G. (3) 171 Martin, J.A. (20) 120 Martin, J.C. (13) 19; (19) 45; (20) 77, 96, 122
Martin, O.R. (3) 165, 166; (10) 39, 40; (12) 25; (17) 12
Martin, S.F. (16) 30 Martinelli, M.J. (24) 40 Martinez, A . (20) 19 Martinez, E. (18) 7 Martinez, P. (16) 65 Martinez-Castro, I. (22) 15; (23) 1, 2
Martin-Gil, F.J. (2) 39 Martin-Gil, J. (2) 39 Martin-Lomas, M. (3) 70, 89; (5) 11, 20; (7) 19; (21) 38
Martin-Zamora, M.E. (10) 51
Marui, S. (19) 20, 21 Maruo, S. (18) 33, 34 Maruyama, S. (13) 10; (14) 43
Maruyama, T. (19) 62; (20) 103; (22) 81
Maryanoff, B.E. (9) 44; (10) 18
Marzi, M. (24) 58 Masada, M. (3) 45 Masaki, M. (20) 207 Mash, E.A. (12) 30 Masnovi, J. (7) 68 Massoud, M.A.M. (9) 15; (10) 61
Mastrocilli, E. (5) 28; (12) 31
Masuzawa, T. (3) 86 Mateo, F.H. (5) 37 Mathes, L.E. (23) 86 Mathlouthi, M. (2) 34 Matson, J.A. (19) 58, 59 Matsuda, A. (20) 47, 54, 102, 129, 130
Matsuda, M. (7) 50; (19) 92
Matsuda, T. (10) 3 1 Matsuhashi, G. (19) 1 Matsuhira, N. (15) 4 Matsui, K. (9) 18; (18) 27
Matsui, T. (13) 12 Matsumoto, H. (19) 40; (20) 215; (23) 3
Matsumoto, S. (15) 1 Matsumoto, S.S. (10) 7;
A uth or Index
295
(19) 43; (22) 70 Matsumoto, T. (3) 28, 75, 107, 161, 162 Matsumura, G. (23) 91 Matsumura, S. (16) 54 Matsushita, H. (20) 62, 63 Matsuura, H. (21) 15 Matsuura, I. (22) 45 Matsuura, T. (20) 254 Matsuzawa, T. (2) 21 Matta, K.L. (4) 31, 34; (22) 32; (23) 39 Matthews, C.J. (24) 63, 64 Matthews, D.P. (20) 100 Matulic-Adamic, J. (20) 86 Matulova, M. (7) 5 Mawer, I.M. (18) 75, 78 May, C. (23) 4 Maya Castilla, I. (18) 15 Mayerl, F. (3) 68 Mazzola, L. (21) 36 Medakovic, D. (13) 2 Medgyes, G. (19) 9 Medhi, S. (20) 100 Medici, A. (2) 15, 48; (15) 6 Meguro, H. (3) 141; (5) 18, 43; (21) 43; (24) 79 Mehuys, G.R. (23) 27 Meier, M.S. (16) 31 Meijer, E.M. (7) 17, 18 Melgarejo, M. (10) 4; (20) 41, 42 Melguizo, M. (20) 42 Melik-Ohanjanian, R.G. (20) 22 Melkonian, M. (16) 53 Mellet, C.O. (7) 4; (10) 2 Mellini, D.W. (23) 86 Mendez-Castrillon, P.P. (20) 228 Mentech, J. (5) 27; (7) 17; (12) 18 Merat, S. (20) 39 Mercer, A.D. (21) 46 Mereyala, H.B. (3) 78, 113; (7) 10 Merten, H. (5) 13 Mesbah, M. (23) 74 Mesli, A. (10) 11 Metawia, M.S. (9) 13 Metcalf, B.W. (5) 38; (11) 10 Metzger, J. (10) 28 Meyer, B. (10) 38; (21) 11
Meyer, D.M.
(21) 33
Meyers, H.V. (23) 38 Mezzina, E. (24) 2 Mhaskar, D.N. (20) 67 Micas-Languin, D. (24) 66 Micera, G. (17) 32, 35 Michaelides, M.R. (24) 14 Michalik, M. (10) 4 1 Michalska, M. (11) 14 Michalski, J.C. (21) 30 Michel, G. (23) 8 Michel, J. (5) 33; (18) 28 Michl, G. (21) 45 Miethchen, R. (6) 10 Mignani, S. (24) 11 Mikamo, M. (7) 6 Mikhailopulo, I.A. (20) 33, 36, 49, 78, 94, 97, 112, 230 Mikhailov, S.N. (20) 6, 70, 83, 204; (21) 16; (22) 89, 92 Miki, T. (9) 24, 25 Mikshiev, Yu.M. (16) 32 Mikulik, K. (19) 35 Milecki, J. (20) 211 Miler-Srenger, E. (22) 42 Miljkovic, A.D. (18) 10, 11
Miljkovi;, D. (5) 39; (6) 13; (7) 65; (13) 2 Miller, L. (23) 56 Mills, G.C. (20) 4 Min, J.M. (18) 63 Minagawa, M. (5) 10 Minami, T. (20) 127, 128 Minamoto, K. (20) 50, 51; (22) 80 Mincsovics, E. (23) 16 Mineishi, S. (20) 87 Mioskowski, C. (3) 172 Mirgorodskaya, O.A. (22) 14 Mishima, K. (3) 64; (19) 91 Mishima, M. (20) 248 Misiti, D. (24) 58 Misra, S. (13) 15 Mitani, M. (18) 73 Mitra, A.K. (20) 223 Mitsuhashi, H. (23) 28 Mitsunobu, 0. (13) 10; (14) 43 Mitsuo, N . (23) 3 Mitsuya, H. (20) 133, 233 Mitsuya, M. (20) 152 Miwa, T. (20) 254 Miyake, A. (13) 30 Miyaki, T. (19) 12 Miyamoto, Y. (19) 4, 5 Miyasaka, K. (23) 40 Miyasaka, T. (20) 47, 53,
126, 207; (22) 79 Miyauchi, M. (19) 77 Miyazaki, K. (18) 33, 34 Miyoshi, E. (3) 35 Mizawa, M. (24) 29 Mizuno, M. (24) 40 Mizuno, Y. (20) 22 Mizuta, A. (7) 33 Mizutani, K. (21) 15 Modak, A.S. (20) 229 Moers, M.E.C. (11) 13 Morz, J. (10) 20 Mokubo, E. (3) 188 Molin, H. (17) 7 Molina, J.M. (5) 36 Molino, R. (24) 31 Mondon, M. (24) 18, 72 Monneret, C. (3) 50, 117, 118; (8) 28; (9) 14; (12) 22; (19) 26, 33, 87; (20) 113; (24) 12 Montaldo, P.G. (23) 79 Monterrey, I.M.G. (10) 19 Montgomery, J.A. (20) 161, 208, 209, 238 Montgomery, W.D. (24) 60 Monti, D. (3) 175 Montreuil, J. (21) 29, 30; (23) 37 Moore, S.A. (22) 75 Mootoo, D.R. (3) 14, 137; (4) 60; (6) 8; (24) 37, 38 Morel, J.P. (17) 3 1 Morel-Desrosiers, N. (17) 31 Moreno, P.C. (9) 46, 47; (10) 19; (11) 5 Mori, A. (7) 48 Mori, H. (19) 39, 77; (20) 224 Mori, K. (18) 35; (24) 1, 65 Mori, M. (4) 52, 53, 67, 68; (6) 4 Morimoto, S. (9) 7; (19) 17 Morin, C. (8) 27 Morin-Allory, L. (23) 23 Morioka, M. (19) 2, 13, 79 Morishima, H. (19) 74, 75 Morishima, N. (3) 136 Morissette, D.G. (4) 69 Morita, M. (16) 38, 44, 45 Morita, N. (16) 75 Morita, T. (18) 73 Morizawa, Y. ( 2 0 ) 93 Morley, C. (18) 20 Morris, P.E., jun. (15) 3 Mosbach, K. (3) 105
296
Moseley, M.A. ( 2 2 ) 23; ( 2 3 ) 70
Moshchinskaya, S.V. ( 2 0 ) 253
Moss, W.H. ( 2 2 ) 94 Mota, J.F. ( 7 ) 4 ; ( 9 ) 4 6 ; ( 1 0 ) 2 , 19
Motawia, M.S. ( 2 0 ) 115 Motherwell, M.B. ( 3 ) 178 Mott, A.W. ( 2 0 ) 139 Motte-Florac, M.E. ( 7 ) 41 Moufid, N. ( 1 3 ) 24; ( 1 4 ) 22
Moussad, A. ( 1 0 ) 53-56 Moyer, J.D. ( 1 8 ) 62 Mrozik, H. ( 3 ) 112 Mueller, C.E. ( 2 0 ) 46 Mueller, D.R. ( 2 2 ) 6 Miiller, E. ( 1 2 ) 10 Muhn, R. ( 1 6 ) 33 Mukaiyama, T. (1) 2 ; ( 3 ) 5
Mukerji, D.D. ( 9 ) 4 Mukherjee, A. ( 5 ) 3 Mukhopadhyay, A. ( 1 3 ) 1 4 ; ( 2 4 ) 10
Mukmenev, E.T. ( 7 ) 6 2 , 6 3 ; ( 1 7 ) 20; ( 2 2 ) 66 Mulzer, J. ( 5 ) 2 9 ; ( 2 4 ) 59 Munasinghe, V.R.N. ( 1 2 ) 2 Munoz, A. ( 1 7 ) 21 Murakami, K. ( 3 ) 8 1 ; ( 1 2 ) 3 Murakami, T. ( 9 ) 7 Muramatsu, H. ( 3 ) 195 Muraoka, Y. ( 1 9 ) 73 Murase, S. ( 3 ) 127 Murase, T. ( 3 ) 123, 124; ( 4 ) 1 4 ; ( 1 6 ) 39 Murata, H. ( 1 9 ) 8 1 , 85 Murata, K. ( 2 3 ) 49 Murray, M.C. ( 1 6 ) 49 Murrer, B.A. ( 1 8 ) 20 Muschik, G. ( 2 3 ) 86 Musser, S.M. ( 2 2 ) 24; ( 2 3 ) 81 Muth, H.-P. ( 2 0 ) 56 Muto, M. ( 2 0 ) 158 Myers, P.L. ( 2 0 ) 169 Myrvold, S. ( 1 5 ) 5 ; ( 1 6 ) 1 8 , 19 Myszka, H. (10) 12
Nadeau, P. ( 2 3 ) 27 Naf, R. ( 3 ) 68 Nagai, K. ( 1 8 ) 3 Nagai, M. ( 1 9 ) 75 Naganawa, H. ( 1 9 ) 2 , 22, 73
Naganawa, N. ( 2 0 ) 128
Carhohydrutt. Chemistry
Nagarajan, M. ( 1 4 ) 13 Nagarajan, R. ( 1 9 ) 7 1 , 72 Nagasawa, J. ( 3 ) 188 Nagata, R. ( 2 ) 50 Nagato, S. ( 2 4 ) 42, 43 Nagatsugi, F. ( 1 1 ) 9 Nagy, E. ( 2 3 ) 64 Nair, V. ( 2 0 ) 75 Naito, T. ( 1 9 ) 12 Nakae, T. ( 2 0 ) 164, 171 Nakagawa, M. ( 7 ) 46 Nakagawa, T. ( 1 5 ) 2 Nakahara, Y. ( 4 ) 7 9 , 80 Nakajima, A. ( 1 9 ) 5 Nakamoto, S. ( 3 ) 86 Nakamura, H. ( 1 9 ) 74 Nakamura, M. ( 3 ) 2 2 ; ( 1 6 )
Nativi, C. ( 9 ) 35 Nautial, S.R. ( 9 ) 4 Nawata, Y. ( 2 2 ) 45 Nechaev, O.A. ( 4 ) 22;
52; ( 2 1 ) 1 5 ; ( 2 3 ) 62
Neuvonen, K. ( 2 0 ) 243 Nevala, H. ( 2 ) 53, 55 Ng, C.K. ( 8 ) 7 Ng, K.E. ( 2 0 ) 232 Nicolaou, K.C. ( 8 ) 6 ;
Nakamura, R. ( 1 0 ) 31 Nakamura, T. ( 3 ) 136; ( 1 8 ) 33
Nakanishi, K. ( 3 ) 5 5 ; ( 2 2 ) 9 7 ; ( 2 3 ) 38
Nakanishi, S . ( 1 9 ) 82 Nakano, H. ( 7 ) 61 Nakano, K. ( 1 2 ) 3 ; ( 2 0 ) 3 Nakano, M. ( 2 0 ) 248 Nakashima, R. ( 2 3 ) 98 Nakata, K. ( 1 6 ) 75 Nakata, M. ( 2 4 ) 26, 40 Nakatani, J. ( 2 ) 51 Nakatani, T. ( 1 9 ) 73 Nakatsu, K. ( 1 9 ) 14 Nakatsubo, F. ( 3 ) 81 Nakayama, M. ( 3 ) 4 2 ; ( 1 3 ) 12
Nakayama, N. ( 2 3 ) 3 Nakayama, T. ( 7 ) 46; ( 2 0 ) 93
Nakazawa, H. ( 2 3 ) 47 Nakazawa, K. ( 1 9 ) 83 Nakhla, N.A. ( 1 6 ) 50 Namba, Y. ( 3 ) 45 Nambara, T. ( 2 3 ) 21 Nambiar, S. ( 3 ) 145; ( 1 5 ) 7
Namgoong, S.K. ( 1 8 ) 31 Nand, R.C. ( 2 ) 57 Nango, M. ( 1 8 ) 21 Naoi, M. ( 1 7 ) 10 Naoi, Y. ( 2 0 ) 6 2 , 63 Narasaka, K. ( 3 ) 191; ( 1 9 ) 6 3 ; ( 2 0 ) 65
Narisada, M. ( 2 4 ) 69 Narisano, E. ( 9 ) 28 Narita, A. ( 1 9 ) 63 Narkin, S.M. ( 1 2 ) 33 Narurkar, M.M. ( 2 0 ) 223 Nash, R.J. ( 2 4 ) 62 Nashed, E.M. ( 3 ) 85 Nasini, E. ( 2 0 ) 10 Nasonov, V.V. ( 2 3 ) 36
( 2 1 ) 41, 42
Negri, A. ( 2 3 ) 13 Nehlich, D.A. ( 2 3 ) 14 Neidhart, D.J. ( 2 1 ) 26 Neidle, S. ( 2 2 ) 90 Nejedly, Z. ( 2 0 ) 27 Nepogod'ev, S.A. ( 4 ) 33 Nesloney, C.L. ( 1 6 ) 74 Neszmelyi, A. ( 7 ) 4 0 ; ( 2 1 ) 39
Neumann, D. ( 2 4 ) 30 Neumann, J.-M. ( 2 0 ) 186, 187
( 2 4 ) 44, 45
Nicolas, A. ( 2 3 ) 57 Nicoletti, R. ( 1 9 ) 37 Nicotra, F. ( 2 ) 25; ( 3 ) 169, 177, 197; ( 7 ) 20; ( 1 0 ) 13 Nielsen, J.B.K. ( 1 9 ) 38 Nielsen, P. ( 1 8 ) 43 Niemeijer, N.R. ( 1 6 ) 62 Niemela, K. ( 2 3 ) 11 Niessen, W.M.A. ( 2 2 ) 1 9 ; ( 2 3 ) 45 Nieto Sampedro, M. ( 3 ) 192 Nifant'ev, N.E. ( 3 ) 132, 133; ( 7 ) 56 Nilsson, B. ( 4 ) 77 Nilsson, K.G.I. ( 3 ) 106; (4) 3 Nilsson, M. ( 4 ) 78 Nilsson, S. ( 4 ) 49 Nin, A. ( 1 3 ) 21 Nishi, T. ( 2 4 ) 24, 25, 74 Nishida, A. ( 5 ) 19 Nishida, Y. ( 3 ) 141; ( 5 ) 1 8 , 43; ( 2 1 ) 43; ( 2 2 ) 98; ( 2 4 ) 79 Nishii, S. ( 1 4 ) 42 Nishijima, Y. ( 7 ) 61 Nishikawa, M. ( 2 0 ) 72 Nishimura, S.-I. ( 3 ) 131 Nishino, T. ( 7 ) 44 Nishioka, I. ( 3 ) 66; ( 7 ) 45; ( 1 4 ) 1 2 ; ( 1 6 ) 7 6 ; ( 2 2 ) 1 0 ; ( 2 3 ) 46 Nishiyama, S. ( 1 3 ) 1 6 ; ( 2 0 ) 127, 128; ( 2 4 ) 27, 28 Nishizawa, H. ( 2 3 ) 92 Nishizawa, M. ( 3 ) 76
Author /ndrx
Niwa, H. ( 3 ) 140 Niwas, S. ( 2 0 ) 209 Nix, M. ( 3 ) 156 Nizhnik, A.N. ( 5 ) 14 Noble, N.J. ( 1 8 ) 70 Noble, 0. ( 2 ) 9 Nocentini, G. ( 2 0 ) 11 Noe, C.R. ( 2 ) 1 9 ; ( 1 8 ) 2 Noguchi, K. ( 2 0 ) 215 Nogueras, M. ( 2 0 ) 41, 42 Nohara, T. ( 1 2 ) 3 Nohta, H. ( 2 3 ) 96 Nomura, K. ( 2 4 ) 53 Nonaka, G. ( 3 ) 66; ( 7 ) 45; ( 1 4 ) 1 2 ; (16) 7 6 ; ( 2 2 ) 1 0 ; ( 2 3 ) 46
Nonoyama, S. ( 1 7 ) 34 Noort, D. ( 4 ) 42 Norberg, T. ( 3 ) 6 0 ; ( 4 ) 3 7 , 49, 7 8 ; (10) 1 4 ; ( 1 8 ) 22
Norbreck, D.W. ( 2 0 ) 233 Nord, L.D. ( 1 0 ) 7 Noren, J.-0. ( 1 7 ) 7 Normack, S. ( 5 ) 7 ; ( 1 4 ) 14
Nosaka, C. ( 1 9 ) 3 1 , 32, 34
Nougier, R. ( 6 ) 9 Novotny, M.V. ( 2 3 ) 73 Novotny, P. ( 3 ) 54 Nowak, B. ( 2 0 ) 87 Nowell, I.W. ( 1 7 ) 1 4 ; ( 2 2 ) 59
Noyori, R. ( 2 0 ) 177 Nozaki, K. ( 2 0 ) 225, 226 Nugent, W.A. ( 3 ) 176; ( 1 3 ) 32; ( 1 4 ) 28
Nukada, T. ( 4 ) 74 Numata, M. ( 4 ) 38; ( 2 1 ) 40
Nunomura, S. ( 4 ) 52, 53 Nursten, H.E. ( 1 0 ) 29 Nyilas, A. ( 2 0 ) 178 Oak, O.Z. ( 1 8 ) 4 5 , 46 Oba, H. ( 2 ) 28 Obretenov, T. (10) 28 Occolowitz, J.L. ( 1 9 ) 72 Odinokov, V.N. ( 1 3 ) 36 Oe, T. ( 2 3 ) 21 Oertle, K. ( 1 7 ) 27; ( 2 4 ) 85
Otvos, L. ( 2 0 ) 170 Ogata, K. ( 1 2 ) 4 ; ( 2 2 ) 35 Ogawa, S. ( 2 ) 2 7 ; ( 9 ) 21; ( 1 3 ) 30; ( 1 4 ) 3 3 , 3 4 ;
(18) 49, 53-55, 57, 8 1 ; (19) 4 , 5 , 11, 83; ( 2 0 ) 222; ( 2 1 ) 23
Ogawa, T. ( 4 ) 30, 3 8 , 44,
297 50, 52, 53, 66-68, 7 4 , 7 9 , 8 0 ; ( 2 1 ) 40 Ogawa, Y. ( 4 ) 1 9 ; ( 7 ) 34; (19) 8 Ogihara, Y. ( 4 ) 29; ( 2 2 ) 54 Ogilvie, K.K. ( 2 0 ) 241 Ogilvie, R.J. ( 2 4 ) 21 Ogino, Y. ( 2 ) 51 Ognyanik, S.S. ( 2 0 ) 14 Ogura, H. ( 3 ) 22, 6 4 ; ( 1 6 ) 24, 46, 52; ( 1 9 ) 9 1 ; ( 2 0 ) 22; ( 2 3 ) 62 Oguri, K. ( 3 ) 63 Ohashi, K. ( 3 ) 4 4 ; ( 4 ) 45; ( 7 ) 43, 4 4 , 5 8 ; ( 2 4 ) 70 Ohgiya, T. ( 2 0 ) 127 Ohigashi, H. ( 2 0 ) 5 Ohkura, Y. ( 2 3 ) 96 Ohmori, K. ( 1 7 ) 4 Ohmura, M. ( 2 0 ) 248 Ohrui, H. ( 3 ) 141; ( 5 ) 1 8 , 4 3 ; (21) 3 , 4 3 ; ( 2 4 ) 79 Ohsawa, N. ( 2 4 ) 26 Ohta, K. ( 2 4 ) 29 Ohtsuka, M. ( 1 9 ) 83 Oikarinen, E. ( 2 ) 53, 54 Oikawa, A. ( 2 ) 21 Oikawa, Y. ( 2 4 ) 24, 25, 41-43 Oishi, H. ( 2 2 ) 45 Oishi, S . ( 5 ) 19 Oivanen, M. ( 2 0 ) 245, 249 Ojika, M. ( 2 3 ) 38 Ojima, N. ( 1 8 ) 34 Oka, A. (7) 61 Okabe, M. ( 2 0 ) 138 Okada, K. ( 1 8 ) 60 Okada, Y. ( 2 3 ) 31, 32 Okaichi, Y. ( 1 9 ) 4 8 ; ( 2 0 ) 171 Okajima, H. ( 2 0 ) 130 Okami, Y. ( 1 9 ) 2 Okamoto, K. ( 3 ) 122 Okauchi, T. ( 3 ) 191; ( 2 0 ) 65 Okazaki, K. ( 2 4 ) 53 Oki, T. ( 1 5 ) 1 ; ( 1 9 ) 12 Okimura, S . ( 2 3 ) 92 Oku, N. ( 3 ) 45 Okubo, Y. ( 1 8 ) 21 Okuda, T. ( 7 ) 48, 50; ( 1 9 ) 9 2 ; ( 2 3 ) 93 Okuno, Y. ( 9 ) 1 7 ; ( 1 5 ) 4 Okuyama, T. ( 2 3 ) 40 Olafsdottir, E.S. ( 3 ) 187 Olea, D.P. ( 5 ) 36 Olesker, A. ( 8 ) 3 , 9 , 1 6 ; ( 1 4 ) 4 4 ; ( 1 9 ) 28 Olivier, I. ( 1 7 ) 35
Olivier, S.P. ( 2 3 ) 89 Olsuf'eva, E.N. ( 1 9 ) 29 Omura, S. ( 1 9 ) 20, 21, 77 Oplinger, J . A . (13) 11 Orban, J. ( 2 0 ) 69 Orena, M. ( 9 ) 3 Orgel, L.E. ( 2 0 ) 232 Orihara, M. ( 1 8 ) 5 3 , 5 4 , 57; ( 2 1 ) 23
Orr, G. ( 2 ) 22 Ortisi, A. (10) 6 0 ; ( 2 2 ) 40
Ortiz Mellet, C. (10) 23 Ortwine, D.F. ( 2 2 ) 94 Oscarson, S. ( 7 ) 71 Oshikawa, T. ( 1 7 ) 10 Oshima, T. ( 2 4 ) 94 Ostrowski, T. ( 2 0 ) 25 Otake, N. ( 1 9 ) 8 Otero, C. ( 7 ) 19 Otsuka, H. ( 2 2 ) 27 Ott, A.Ya. ( 3 ) 9 6 ; ( 6 ) 12 Ott, J.L. ( 1 9 ) 72 Outten, R.A. ( 3 ) 194 Ouyang, L. ( 2 2 ) 8 Overhand, M. ( 4 ) 2 0 , 24 Overton, B.W. ( 2 0 ) 39 Ovodov, Yu.S. ( 5 ) 4 ; ( 1 4 ) 1, 2
Oya, H. ( 7 ) 47 Ozaki, H. ( 7 ) 6 1 ; ( 2 0 ) 180
Ozaki, S . ( 1 8 ) 7 3 ; (19) 39; ( 2 0 ) 224
Ozaki, T. ( 2 ) 7 Ozawa, K. ( 2 4 ) 94 Ozawa, S . ( 2 ) 51 Paal, M. ( 3 ) 49; ( 7 ) 12 Pabon Aquas, R. ( 2 0 ) 148 Pacak, J. ( 3 ) 54 Pace, S. ( 3 ) 80 Padgett, H.C. ( 8 ) 23 Padyukova, N.Sh. ( 2 0 ) 8 3 , 204
Paez, M.I. ( 2 2 ) 1 5 ; ( 2 3 ) 1, 2
Paidak, B.B. ( 1 6 ) 32 Paisley, D. ( 2 0 ) 163 Paisley, S.D. (19) 53 Pak, H. ( 1 4 ) 25; ( 2 4 ) 7 Palacios, J.C. ( 1 0 ) 64 Palacios Albarran, J.C. ( 9 ) 46, 47; ( 1 1 ) 5
Palcic, M.M. ( 4 ) 62 Pallenberg, A.J. ( 2 4 ) 17 Palmisano, F. ( 2 3 ) 84 Palsterer, J. ( 1 0 ) 44 Pan, S.-S. ( 2 2 ) 24; ( 2 3 ) 81
Panek, J.S. ( 3 ) 155, 170
298
Panfil, I. (16) 9; (22) 47; (24) 57
Pankiewicz, K.W. (20) 44 Panov, K.I. (20) 83 Panthe-Dayde, D. (23) 58 Panza, L. (3) 169, 177, 197; (10) 13
Panzica, R.P. (20) 12 Paoli, M. (5) 28; (12) 3 1 Paquette, L.A. (13) 11 Pare, J.R.J. (22) 4 Parenti, F. (19) 68 Parilli, M. (4) 71 Park, H.-I. (19) 32 Park, J.M. (19) 56 Park, Y.S. (14) 23 Parkanyi, L. (3) 69; (18) 44
Parker, C.E. (22) 17; (23) 20
Parra, M. (18) 7 1 Parry, R.J. (19) 54 Parshall, G.W. (3) 176; (13) 32
Parsons, J.L. (19) 52 Pasau, P. (24) 8 1 Paschke, E. ( 7 ) 14 Pashinnik, V.E. (20) 49, 97
Pastor, R. (4) 5 1 Patel, A. (7) 24, 25; (17) 24
Paton, R.M. (14) 6; (22) 49
Patroni, J.J. (7) 75; (13) 6
Paulsen, H. (4) 32, 35, 43; (21) 43
Pauwels, R. (20) 89, 105 Pavia, A.A. (3) 46 Pawar, S.M. (9) 8 Payne, S. (18) 70 Peckler, S. (21) 24; (22) 28
Pedersen, C. (3) 15; (18) 15
Pedersen, E.B.
(9) 12, 13; (20) 115-117 Pederson, R.L. (18) 26 Pedrini, P. (2) 15, 48; (12) 27; (15) 6 Pedrocchi-Fantoni, G. (9) 29, 30; (14) 5, 11 Pelzer, R. (7) 38; (24) 91 Penades, S. (5) 11, 20 Penco, S. (19) 23 Penedes, S. (3) 70, 89 Percival, M.D. (7) 53; (8) 19; (12) 11 Perczel, A. (22) 39 Pgrez, A.-L. (7) 39
Curhohydrate Chemistiy
Perez. C. (20) 228 Perez, C.S. (5) 12 Perez, M. (4) 21 Perez, S. (2) 9; (20) 228 Perez-Martinez, C.S. (3) 16
Perlin, A.S. (3) 142; (7) 72; (16) 55; (21) 10, 32 Perlman, M.E. (20) 104 Perold, G.W. (3) 67 Persson, K. (16) 11 Peseke, K. (10) 4 1 Peters, D. (6) 10 Peters, T. (4) 56, 57 Petersen, H. (9) 13 Petersen, P.M. (13) 25; (14) 10 Peterson, L.H. ( 5 ) 1; (12) 14 Petitou, M. (3) 108; (10) 35 Petrakova, E. (3) 134; (21) 8 Petrie, C.R., I11 (8) 17 Petryaev, E.P. (20) 253 Petter, R.C. (14) 45 Petursson, S. (9) 23 Pfandler, H.R. (24) 78 Pfannemueller, B. (16) 1 Pfeffer, C. (2) 9 Pfister, M. (20) 212 Pfleiderer, W. (20) 16-18, 174, 176, 212 Pfrengle, W. (10) 24, 26; (24) 87, 88, 90 Phadtare, S. (20) 8 1 Phinney, B.O. (3) 61; (7) 29 Piantini, V. (17) 29; (22) 6 1 Pick, J. (23) 17 Pikrylova, V. (19) 35 Pilotti, A . (4) 8 1 Pimenov, A.M. (23) 83 Pinkston, J.D. (22) 22; (23) 54 Pino Gonzalez, M.S. (3) 192; (20) 148 Pinto, B.M. (4) 69 Piovosi, E. (8) 15 Pippig, C. (2) 49 Pirrung, M.C. (24) 54 Pishchugin, F.V. (10) 9 Piskala, A . (20) 31 Piskorz, C.F. (23) 39 Piu, P. (17) 36 Pivovarenko, V.G. (3) 58 Pizzi, D. (9) 29; (14) 5 Platzer, N. (21) 33 Plikhtyak, I.L. (16) 77 Plostinaru, S. (2) 44
Plumet, J. (10) 15, 64 Plunkett, W. (20) 87 Plyamovatyi, A.Kh. (7) 62 Pochet, S. (3) 17 Podlahova, J. (22) 63 Pohjola, S. (2) 55 Polas, P. (23) 86 Polenov, V.A. (5) 25 Poletaeva, L.V. (22) 14 Poller, R.C. (7) 24, 25; (17) 24, 25
Pompliano, D.L. (15) 5; (16) 18, 19
Poopeiko, N.E. (20) 94 Poots, I. (3) 53 Poppe, L. (21) 40 Popsavin, M. (6) 13 Popsavin, V. (5) 39; (6) 13; (7) 65
Pora, H. (4) 18 Pornbanlualap, S. (19) 46 Porritt, G.M. (20) 184 Porter, C.W. (20) 123, 124
Porter, R.A. (15) 7 Portlock, D.E. (21) 37 Poss, A.J. (16) 5, 73 Potapov, G.P. (2) 40 Potapov, P.N. (22) 14 Potapova, N.P. (9) 1; (19) 29
Potter, B.V.L. (18) 70 Povarov, L.S. (19) 29 Powell, D. (10) 21 Powell, J.W. (10) 5, 6 Powers, D.G. (14) 45 Pozddev, O.K. (7) 63 Prabhu, S.V. (23) 94 Pradera Adrian, M.A. (10) 23
Prajapati, D. (10) 46 Prakash, N.J. (20) 100 Praly, J.-P. (8) 10, 11 Prandi, J. (24) 19 Premaratne, P. (8) 25 Preobrazhenskaya, M.N. (16) 77; (20) 34
Prestegard, J.H. (21) 36 Prestwich, G.D. (18) 72 Preuss, R. (3) 184, 185 Price, J.D. (2) 18 Priebe, W. (13) 3; (19) 27
Prikhodchenko, L.K. (22) 33
Prikota, T.I. (20) 94 Pring, B.G. (16) 11 Prinzbach, H. (19) 6, 7 Pritchard, R.G. (24) 82 Prokof'ev, E.P. (7) 27 Prokopenko, O.F. (13) 36 Prokudin, V.Yu. (23) 83
Author Index
Prost, M. (23) 8 Prusoff, W.H. (19) 45; (20) 52, 77, 165; (22) 91 Pucci, B. (3) 46 Puech, F. (20) 92, 95 Pugashova, N.M. (7) 56 Pullaiah, K.C. (20) 79; (22) 88 Pupeiko, E.I. (20) 97 Purnima, B. (20) 40 Pyaivinen, E.A. (20) 240
Qadir, M.H. (6) 6 Qiu, D. (21) 21 Qiu, D.-X. (3) 163 Queneau, Y. (3) 39 Qui, D. (22) 7; (23) 18 Qui, D.-X. (7) 9 Quiclet-Sire, B. (17) 8 ; (20) 205, 206
Quijano, M.L. (20) 41, 42 Quinkert, G. (24) 30 Raab, E. (7) 12 Rabczenko. A. (21) 13 Raczko, J. ( 9 ) 50 Radics, L, (20) 199-201 Radomska, B. (17) 32, 35 Radomski, J. (10) 58 Raezke, K.P. (10) 10 Rafka, R.J. (12) 25; (17) 12
Raghavachari, R. (20) 73 Ragonnet, B. (3) 4 6 Raifel'd, Yu.E. (12) 32, 33
RajanBabu, T.V. (3) 176; (13) 32; (14) 28; (18) 50 Rajanikanth, B. (9) 22 Rajanna, K.C. (16) 67 Raju, N . (20) 203 Rakhmatullaev,V.A. (10) 22 Ram, P. (21) 36 Ramakumar, S. (22) 74 Rama Rao, A.V. (18) 14; (24) 73 Ramasamy, K. (19) 41, 42 Ramesh, K. (20) 12 Ramesh, S. (3) 12; (12) 24 Ramiliarison, C. (3) 118 Ramos-Sanchez, M.C. (2) 39 Ramsden, N.G. (9) 23; (16) 12, 58; (18) 24, 25 Ramsey, R.S. (23) 72
299
Rana, K.K. (18) 76 Randall, J.L. (8) 6 Rao, C.S. (13) 28; (24) 80
Rao, G.V. (16) 68 Rao, M.V. (14) 13 Rao, S.P. (3) 165, 166; (10) 39, 40
Rao, T. (20) 111 Rapoport, S.I. (23) 4 Rashid, A. (17) 9 Rassu, G. (2) 25; (3) 159, 180; (13) 20; (16) 7 Ratcliffe, A.J. (3) 137, 138; (6) 8 Ratcliffe, R.M. (4) 62 Rathbone, E.B. (7) 24 Rathor, M.N. (23) 90 Rauter, A.P. (20) 156 Rauwald, H.W. (22) 36 Ravi, D. (3) 113 Ravindranathan, T. (18) 14 Ray, A.K. (4) 26, 28 Rebolledo, F. (10) 64 Reddy, G.S. (18) 50 Reddy, G.V. (3) 78; (5) 22 Reddy, K.N. (16) 67 Redgrave, A.J. (18) 7 1 Redlich, H. (14) 32; (22) 50 Redslob, J. (3) 3 1 Reed, R.H. (23) 52 Reese, C.B. (20) 111, 184, 229 Reese, C.P. (19) 76 Refn, S. (3) 7 Regeling, H. (5) 24; (18) 8 Reid, B.R. (20) 69 Reidy, J.P. (5) 42 Reimer, K.B. (4) 69; (21) 43 Reimer, L.M. (15) 5; (16) 18, 19 Reimer, M.L.J. (20) 84 Reinhold, V. (16) 49 Reiter, M. (23) 61 Reitz, A.B. (9) 44; (10) 18 Reizes, 0. (18) 62 Rej, R.N. (16) 55 Requejo, J.L.J. (10) 19 Resnati, G. (8) 15 Reuter, G. (5) 10 Reutter, W. (2) 23 Revankar, G.R. (10) 7; (19) 41, 42; (20) 7-9, 13, 147; (22) 71, 86 Rey, A.W. (24) 31
Rey, F.J. (2) 39 Reymond, J.-L. (9) 35 Reznicek, G. (21) 45 Rheingold, A.L. (22) 46 Riboni, L. (16) 47 Riccardi, A. (23) 75 Riccardi, R. (23) 75 Richter, T. (17) 5; (22) 58
Richter, W.J. (22) 6 Riediker, M. (17) 26-29; (22) 61; (24) 84-86
Riego Martin, M.B. (7) 23 Riess, J.G. (3) 80 Riggs, R.M. (20) 208 Riguera, R. (19) 90 Rihs, G. (17) 29; (22) 26, 61
Rijk, E.A.V. (22) 76 Riordan, J.M. (20) 238 Ritchie, T.J. (3) 9 , 21; (16) 22
Riva, E. (19) 68 Riva, S. (7) 16, 20 Rivera, A. (21) 38 Rivero, R.A. (7) 30 Robarge, K.D. (3) 193 Roberti, M. (11) 11 Roberts, S.M. (20) 169 Robins, M.J. (20) 23, 106, 107
Robins, R.K. (10) 7; (19) 41-43; (20) 7-9, 13, 24, 147, 203; (22) 70, 71, 86 Robles Diaz, R. (3) 196 Robowsky, A. (20) 74 Robyt, J.F. (12) 20 Rochd, M. (23) 58 Rocherolle, V. (10) 43; (14) 44; (19) 28 Rock, C. (20) 162 Rodriguez, M. (10) 4
Rodriguez-Mendez, M.L. (2) 39
Roduit, J.P. (20) 241 Roelen, H.C.P.F. (7) 60 Roemer, A. (7) 42 Roesch, P. (20) 85 Roger, P. (19) 87 Rohmer, M. (18) 83 Rohr, J. (19) 30 Rohrscheidt-Andrzejewski, E. (16) 34 Rokach, J. (9) 10
Rokita-Trygubowicz, T. (11) 14
Roman, E. (10) 15; (13) 37
Romanovich, A.Yu. (14) 15-17
Romero-Avila, C. (5) 36
Carbohydrate Chemistry
300 Romo de Vivar, A. (7) 39 Ronchetti, F. (3) 9 1 Ronninger, S. (13) 13; (16) 8
Roques, N. (12) 18 Rosemeyer, H. (20) 59, 71, 255
Rosowsky, A. (20) 151, 214
Ross, B.C. (3) 178 Rossi, L. (23) 76 Rossman, R.R. (3) 151 Rotunno, T. (23) 84 Roush, W.R. (1) 6; (24) 14
Rousseau, B. (2) 24 Rousseaux, 0. (20) 146 Row, K.H. (23) 72 Rowell, P. (23) 52 Roy, N . (4) 26, 28; (5) 3 Roy, R. (24) 31 Rozanski, L. (7) 64; (18) 9
Rozek, M. (20) 210 Rozynov, B.V. (19) 29 Rubasheva, L.M. (19) 29 Rubino, F.M. (22) 16; (23) 15
Riicker, E. (5) 33; (18) 28
Rulin, F. (2) 18 Runova, O.B. (18) 65, 67 Runsink, J. (12) 10 Ruprecht, R.M. (20) 74, 214
Rusnak, J.M. (18) 61 Russell, M.A. (3) 4, 10 Russell, R.N. (12) 12 RUSSO, G. (3) 169, 177, 197; (10) 13
Rutan, J.F. (4) 3 1 Ruzic-Toros, Z. (22) 57 Rycroft, D.S. (21) 5 Ryu, E.K. (20) 99 Saadein, M.R. (20) 202 Sabari, M. (16) 6 Sabol, J.S. (3) 181; (24) 49
Sadamitsu, M. (5) 10 Saeki, T. (15) 1 Saenger, W. (22) 25 Sager, W. (10) 24; (24) 90
Sggi, Gy. (20) 170 Sahm, H. (18) 83 Saimoto, H. (2) 13; (23) 98
Saiprakash, P.K. (16) 67, 68
Saito, I. (20) 254
Saito, S. (11) 9 Saito, T. (4) 61; (19) 13, 79; (20) 26
Sakagami, M. (4) 45 Sakai, K. (24) 16 Sakai, T. (20) 216-219, 221
Sakairi, N. (4) 7, 40; (5) 34
Sakaki, M. (20) 5 Sakakibaka, H. (19) 18 Sakakibara, T. (3) 45; (15) 2
Sakamoto, M. (19) 22 Sakamoto, T. (4) 6 1 Sakata, K. (2) 61; (3) 69; (18) 44
Sakazaki, T. (19) 85 Sakurai, D. (3) 71 Sakurai, H. (16) 78, 79 Sakurai, T. (4) 19 Salamonczyk, G.M. (18) 58 Salcines, E.M. (12) 26; (20) 82
Salomon, R.G. (24) 46 Salunkhe, M.M. (3) 23 Samadi, M. (17) 8; (20) 205, 206
Samano, M.C. (20) 106 Samarskova, N.N. (5) 25 Sammakia, T. (24) 33 Samo, T. (22) 78 Sams, R. (23) 86 Sanchez, A. (20) 41, 42 Sanchez, E. (10) 15 Sander, T.L. (15) 7 Sandhu, J.S. (10) 46 Sandor, P. (21) 39 Sandri, S. (9) 3 San Felix, A. (3) 8 Sangen, 0. (7) 6 1 Sanghvi, Y.S. (10) 7; (20) 8, 9; (22) 86
Saniere, M. (24) 66, 67 Santasiero, B.D. (22) 75 Santoyo Gonzalez, F. (14) 38
Sanz, J. (22) 15; (23) 1, 2
Sarda, P. (8) 16 Sarfati, S.R. (3) 17 Sarkar, A.K. (4) 26, 28 Sasaki, I. (16) 6 Sasaki, M. (23) 47 Sasaki, T. (19) 8, 13 Sashiwa, H. (23) 98 Sathyanarayana, B.K. (2) 10
Satici, H. (24) 3 Sato, F. (20) 252 Sato, K. (2) 26; (16) 51 Sato, M. (2) 51; (20)
159, 160
Sato, S. (4) 74; (9) 26; (14) 37; (22) 48
Sato, T. (18) 40; (22) 27, 69, 72
Sato, Y. (19) 62; (20) 103
Satoh, I. (13) 10; (14) 43
Satoh, T. (23) 3 Satoi, S. (19) 14 Satsumabayashi, K. (7) 73; (22) 98
Satyamurthy, N. (8) 23 Sauer, D.R. (20) 149 Savage, I. (19) 88 Savochkina, L.P. (20) 94 Savoia, D. (24) 2 Sawa, T. (19) 22 Sawada, A. (3) 140 Sawada, H. (7) 46 Sawada, M. (22) 8 Sawada, S. (20) 196 Sawada, Y. (19) 12 Saxena, A.K. (20) 40 Sayeed, V.A. (20) 227 Sayer, B.G. (2) 62 Scala, A . (3) 174 Schabel, A.A. (19) 71, 72 Schallenberger, R.S. (2) 1
Schanzenbach, D. (10) 25; (24) 89
Scharf, H.-D. (7) 38; (11) 3; (12) 10; (24)
91
Schauer, R. (3) 23; (13) 18; (16) 42
Schenck, P.A. (11) 13 Scherer, A . (19) 78 Scheuring, M. (4) 10 Schiehser, G.A. (24) 17 Schiller, P.W. (7) 36 Schindler, D. (3) 18 Schlewer, G. (18) 65 Schlimme, E. (10) 10 Schloz, U. (20) 46 Schmidt, D.G. (8) 23 Schmidt, R.J. (16) 72 Schmidt, R.R. (3) 43, 101, 128, 164, 184, 185; (4) 39, 47; ( 5 ) 33; (11) 6; (16) 25, 26; (18) 28 Schmidt, T. (14) 47 Schmidt, W. (20) 136; (22) 93 Schmidt-Base, K. (10) 47; (19) 24; (22) 43 Schneider, G. (3) 61; (7) 29 Schneller, S.W. (12) 26;
301
A u thor Index (20) 82, 149, 166, 168 Schoemaker, H.E. (7) 17, 18 Schram, K.H. (20) 2, 3, 84 Schraml, J. (3) 134 Schreiber, E.P. (16) 40 Schreiber, K. (3) 61; (7) 29 Schreiber, S.L. (24) 33 Schreiner, E. (3) 23; (9) 49; (13) 18; (16) 41-43; (21) 25 Schreiner, E.P. (12) 21 Schullerus, P.G. (2) 44 Schulte, G. (9) 37 Schulte-Frohlinde, D. (20) 251 Schultz, G. (16) 41; (21) 25 Schultz, M. (3) 36 Schulz, G. (3) 23, 121; (4) 12 Schumacher, J. (3) 51 Schwabe, K. (3) 31 Schwesinger, R. (19) 6, 7 Sczakiel, G . (20) 85, 190; (22) 87 Secchi, C. (23) 13 Secrist, J.A., 111 (20) 161, 208, 209 Secundo, F. (7) 16, 20 Sedlacek, H.H. (19) 26 Sedmera, P. (14) 31; (19) 35; (24) 55 Seeber, R. (17) 36 Seela, F. (20) 35, 56-61, 71, 255 Seethaler, D. (16) 3 Seguin, E. (3) 50 Seijas, J . A . (19) 90; (24) 63, 64 Seitz, B. (19) 6, 7 Selnick, H.G. (24) 22 Selph, J.L. (20) 30 Selva, E. (19) 68 Sembdner, G. (3) 61; (7) 29 Semmelhack, M.L. (10) 21 Senda, M. (23) 95 Sengl, M. (10) 30 Sen Gupta, K.K. ( 2 ) 56, 60 Sen Gupta, S. (2) 56 Sensui, Y. (20) 256 Seoane, P. (24) 11 Serafinowski, P. (22) 90 Serebryakov, E.P. (18) 17, 18 Serianni, A.S. (21) 9 Serrano, J . A . (10) 15; (13) 37
Serratrice, G. (4) 51 Serumgard, J.L. (21) 26 Servidei, T. (23) 75 Seshadri, R. (9) 22 Seshadri, T.P. (22) 77 Seto, H. (19) 8 Seto, T. (18) 33-35 Seto, Y. (23) 35 Seufer-Wasserthal, P. (18) 56 Severin, T. (10) 30 Seya, K. (3) 36 Seymour, F.R. (23) 14 Sezaki, M. (19) 94 Shadyro, 0.1. (20) 253 Shakir, K.I. (20) 21 Shalamai, A.S. (20) 14 Shan, S.I. (16) 71 Shanklin, M.S. (16) 74 Shannon, W.M. (19) 52 Sharky, V. (10) 21 Sharma, M. (8) 2, 17 Sharshenalieva, Z.Sh. (10) 9 Shashkov, A.S. (14) 1, 2; (21) 28, 41, 42 Shaw, D.H. (16) 50 Shaw, G. (20) 32, 68 Sheldrick, B. (22) 55, 56, 64 Sheldrick, G.M. (22) 53 Sheldrick, W.S. (19) 78 Shelkani, M.S. (7) 69 Shen, Z.-Y. (20) 52 Sheppeck, J . E . , I1 (19) 49 Sherman, W.R. (22) 20, 21; (23) 6, 53, 55 Shibaev, V.N. (4) 22; (21) 41 Shibagaki, M. (20) 63 Shibata, K. (7) 73 Shibata, T. (23) 95 Shibata, Y. (19) 11 Shibuya, H. (4) 45; (7) 43, 44 Shibuya, T. (19) 81 Shigemasa, Y. (2) 13; (23) 98 Shigemori, H. (3) 35 Shigetoh, N. (17) 3 Shimada, E. (23) 91 Shimada, K. (23) 21 Shimada, K.-i. (13) 30; (14) 34 Shimahara, K. (3) 131 Shimamskaya, M.V. (6) 1 Shimidzu, T. (7) 61; (20) 180 Shimizu, C. (3) 25 Shimizu, F. (2) 45; (17) 37
Shimizu, M. (19) 79 Shimizu, T. ( 3 ) 86 Shimomiya, K. (23) 19 Shimoura, N. (3) 136 Shimpuku, T. (3) 5 Shindo, H. (18) 40 Shing, T.K.M. (18) 48 Shinkai, K. (7) 43 Shinohara, T. (23) 35 Shinohara, Y. (6) 4 Shinomiya, K. (23) 50 Shiomi, N. (22) 80 Shiozaki, M. (9) 26; (14) 37; (22) 48; (24) 75 Shiozawa, A. (19) 63 Shirahata, K. (22) 38 Shirai, R. (16) 24 Shiritani, Y. (19) 18 Shishido, Y. (20) 175 Shitara, K. (23) 34 Shiyan, S.D. (23) 36 Shizuri, Y. (3) 35 Short, E.L. (17) 23 Shugar, D. (20) 15, 243, 245 Shukla, R.S. (16) 69 Shulman, M.J. (19) 49 Shvets, V.I. (18) 65, 67 Sibanda, S. (20) 229 Sichauer, R. (5) 10 Sidorova, N.S. (20) 240 Sieiro, C. (16) 65 Siemsen, L. (5) 37 Siest, G . (23) 57 Siglerova, V. (12) 7 Simmons, O.D. (8) 17 Simon, E.J. (2) 11 Simon, E.S. (4) 2; (16) 14
Simon, J.M.L. (10) 51 Sinay, P. (3) 11, 24, 103, 108, 109; (7) 1; (10) 35, 45; (12) 15; (13) 4, 5 Singh, A.K. (20) 153 Singh, G. (19) 89 Singh, G.B. (3) 33 Singh, N.P. (3) 43 Singh, P. (7) 3, 31 Singh, S. (3) 33; (15) 7 Sinnwell, V. (21) 43 Sinou, D. (3) 183; (5) 8 Sinskey, A . J . (18) 26 Siouffi, A.M. (23) 16 Sisto, A. (20) 1 Sivets, G.G. (20) 36 Skala, L. (2) 12 Skelton, B.W. (7) 75; (13) 6 Skorupowa, E. (7) 64; (18) 9, 12 Skrincosky, D. (20) 239
302 Skurai, T. (7) 34 Slade, L. (2) 37 Slaghek, T.M. (4) 17 Slawin, A.M.Z. (3) 37 Sliwa, H. (20) 146 Slubowski, B. (20) 137, 231
Slusarchyk, W.A. (19) 64 Small, G.W. (21) 27 Smee, D.F. (10) 7; (19) 43; (20) 203; (22) 70
Smets, P. (23) 37 Smiatacz, Z. (10) 12 Smith, A.B., I11 (7) 30; (24) 15, 35
Smith, D.F. (4) 73 Smith, G.L. (1) 3 Smits, J.M.M. (22) 76 Smykalla, C. (22) 76 Smyth, M.S. (16) 5 Snatzke, G. (22) 99 Snetkova, E.V. (2) 42 Snook, M.E. (23) 4 1 Snyder, J.K. (4) 72 Snyder, J.R. (21) 9 Sobolev, A.N. (22) 83 Sodano, G. (20) 125 Sodroski, J.G. (20) 74 Soine, P.J. (20) 39; (23) 51
Soine, W.H. (20) 39; (23) 51
Sokolowski, J. (7) 64; (18) 9, 12
Solan, V.C. (20) 74, 151, 214
Solinas, V. (17) 36 Sommadossi, J.-P, (19) 45; (20) 77, 96
Sommer, V.B. (20) 182 Somsak, L. (2) 63; (13) 17
Sonesson, A. (23) 9 Sonnino, S. (4) 70; (16) 47, 48
Sonori, S. (23) 85 Sonveaux, E. (20) 191 Sopchik, A.E. (20) 202 Sopin, V.F. (22) 33 Sosnova, L.P. (20) 66 Sosnovski, G. (10) 3; (22) 96
Sotgiu, G. (5) 26; (12) 9 Sowers, L.C. (20) 67 Sowinski, P. (19) 16 Spatling, S. (18) 41 Spanton, S. (20) 233 Spanu, P. (13) 20; (16) 7 Sparks, M.A. (3) 155, 170 Spenser, I.D. (2) 62 Speranza, G. (3) 175 Spiess, A.J. (20) 123,
Carbohydrate Chemistry 124
Spiess, B. (18) 65 Spohr, U. (3) 18; (8) 13 Spohr, V. (12) 8 Sporns, P. (9) 39 Springer, J.P. (9) 10 Srikrishnan, T. (22) 32 Srinivas Rao, C. (24) 73 Srivastava, H. (7) 3 Srivastava, V. (4) 15 Starrett, J.E., jun. (13) 19; (19) 45; (20) 77
Stasik, B. (18) 23 Steglich, W. (3) 186; (19) 78; (20) 157
Steker, H. (20) 59 Stenhagen, G. (22) 18; (23) 44
Stepanov, A.E. (18) 65, 67
Stepowska, H. (20) 43 Sternfeld, F. (5) 5; (18) 59, 71
Sterzycki, K. (20) 96 Sterzycki, R.S. (20) 77 Sterzycki, R.Z. (19) 45 Stevens, E.S. (2) 10 Stevens, J.D. (22) 34 Stick, R.V. (7) 75; (13) 6
Stocchi, V. (23) 76 Stock, H.W. (10) 50 Stocker, E. (20) 227 Stoddart, J. (19) 6 1 Stockl, W.P. (9) 45; (10) 57
Stogniew, M. (22) 9 Stoodley, R.J. (3) 37, 38; (24) 82
Storer, R. (20) 169 Storz, T. (18) 4 1 Straathof, A.J.J. (5) 32, 35
Strating, H. (3) 84 Strecker, G. (21) 29, 30 Street, I . P . (7) 53; (8) 19; (12) 11
Street, S.D.A. (20) 133 Struchkov, Yu.T. (22) 33, 84
Struchkova, M.I. (18) 17; (21) 16
Stuart, A.L. (20) 118 Stuetz, A.E. (18) 56; (24) 40
Su, T.L. (20) 44 Suarato, A. (19) 36 Subramanian, R. (19) 54 Sudareva, T.P. (5) 25 Sufrin, J.R. (20) 123, 124
Sugahara, S. (2) 68
Sugai, K. (16) 5 1 Sugawara, T. (19) 60; (24) 69
Sugimoto, M. (4) 38 Sugiyama, H. (2) 21; (20) 254
Sugiyama, M. (18) 33, 34 Sugiyama, N. (16) 5 1 Suhadolnik, R.J. (19) 46 Sulikowski, G.A. (24) 15 Sun, C. (3) 29; (7) 28 Sun, R.-C. (20) 138 Sunazuka, T. (19) 21 Sunazuki, T. (19) 20 Sunkara, P.S. (20) 88, 100
Suon, K.-N. (10) 28 Surico, G. (20) 1 Suryawanishi, S.N. (13) 14, 15; (24) 10
Suskovic, A.S. (22) 57 Sutter, B. (18) 83 Suvorov, N . N . (20) 20 Suwama, M. (2) 27 Suwinska, K. (16) 9; (22) 47
Suzuki, K. (3) 28, 75, 107, 162; (19) 13, 79
Suzuki, M. (2) 27; (3) 161; (19) 81, 85
Suzuki, T. (3) 107; (24) 27, 28
Suzuki, Y. (23) 66 Suzumura, Y. (20) 222 Svensson, S. (3) 105 Sviridov, A.F. (13) 27; (14) 1, 2, 15-17, 19; (24) 23 Sviryaeva, T.V. (20) 94 Swartling, D.J. (20) 139 Swartz, D.L. (20) 145 Sweeney, D. (23) 4 Sweers, H.M. (1) 3; (8) 5 Synovec, R.E. (23) 22 Szabb, L. (6) 11; (21) 22 Szab6, P. (7) 54 Szarek, W.A. (3) 99, 100; (8) 4; (12) 25; (17) 12; (22) 44 Szathmary, S.Cs. (23) 33 Szechner, B. (15) 8 Szeja, W. (13) 8 Szilagyi, L. (18) 82; (24) 8, 9 Sznaidman, M. (5) 2; (7) 13; (13) 3; (19) 27 Szonyi, M. (7) 71 Szweda, R. (3) 18
Tada, M. (2) 21 Tadano, K.-i. (13) 30;
Author Index (14) 33, 34; (18) 49, 81 Tadokoro, J . (20) 219 Taenaka, N. (23) 87 Tafesh, A.M. (14) 30; (24) 48 Tagliavini, E. (12) 6 ; (24) 2 Tahara, T. ( 4 ) 76 Tai, D.F. (24) 14 Taira, K. (20) 256 Tajmir-Riahi, H.-A. (17) 30, 33; (22) 3 Takagi, M. (16) 75 Takagi, Y. (19) 31, 32 Takahara, S. (23) 87 Takahashi, K . (23) 40 Takahashi, Y . ( 4 ) 66 Takai, Y. (22) 8 Takaishi, Y. (12) 3 Takaka, H. (20) 175 Takaki, M. (20) 175 Takamiya, S. ( 7 ) 47 Takamura, T. (20) 222 Takano, T. ( 3 ) 81 Takashima, T. ( 3 ) 5 Takata, M. (23) 40 Takayama, K. (20) 160 Takayanagi, H. ( 3 ) 64; (19) 91 Takeda, K. ( 3 ) 64; ( 7 ) 33; (19) 91 Takeda, S. (19) 40 Takeda, T. ( 4 ) 29; (22) 54 Takemura, M. ( 2 ) 28 Takenaka, K . ( 3 ) 136 Takenaka, S. (19) 15 Takenuki, K. (20) 129 Takeshige, Y. (20) 194, 196 Takeuchi, M. ( 9 ) 18; (22) 27 Takeuchi, T. ( 3 ) 195; (19) 22, 31, 32, 34, 75, 94 Taki, T. (18) 55 Takido, M. (12) 4; (22) 35 Takiguchi, Y. ( 3 ) 131 Takinami, Y. (20) 171 Takita, T. (19) 73; (20) 127, 128 Takiya, M. (13) 10; (14) 43 Talamas, F.X. (24) 40 Tam, S. (20) 137, 152 Tam, S.Y. (20) 231 Tamai, M. (19) 25 Tamaka, 0. (21) 15 Tamaka, Y. ( 2 ) 68 Tamura, 0. ( 9 ) 24, 25
303 Tamura, Y. ( 9 ) 24, 25 Tanaka, H. (20) 53, 126, 207; (22) 79 Tanaka, J. (22) 80 Tanaka, K. (2) 43; (19) 13 Tanaka, M. (14) 42; (18) 13 Tanaka, T. ( 7 ) 45; (22) 10 Tanaka, Y. ( 2 ) 67; (23) 85 Tanase, T. ( 2 ) 45, 46; (17) 37 Tandon, M. (22) 75 Taniguchi, M. (24) 40 Tanimoto, T. (23) 31, 32 Tanino, H. (18) 60 Tanji, M. (19) 65 Tao, F. (23) 82 Tarara, G. (14) 39, 40 Tarnavskii, S.S. (20) 14 Tarrago, M.T. ( 4 ) 73 Tarriseven, A . (12) 20 Tashiro, T. (20) 254 Tashpulatov, A.A. (10) 22 Tateno, Y. ( 2 ) 28 Tatsuta, K . ( 3 ) 179; ( 2 4 ) 29 Tatsuzawa, Y. ( 3 ) 179 Tavecchia, P. (3) 11, 103; (10) 45; (12) 15 Tawa, R. (23) 68, 69 Taylor, K.G. ( 3 ) 145; (15) 7 Taylor, M.A. (13) 25; (14) 10 Taylor, M.D. (22) 94 Taylor, O . J . (17) 14; (22) 59 Tedeschi, G. (23) 13 Teeaar, R. ( 3 ) 134 Tegge, W. (18) 69 Tejbrant, J. ( 3 ) 60 Tejima, S. ( 6 ) 4 Temeriusz, A. (10) 58 Tepper, P.G. (16) 62 Terekhov, D.S. (20) 240 Termin, A. ( 3 ) 128 Tesch, T. (11) 7 Tesser, G . I . (22) 76 Testa, R.T. (19) 80 Tettamanti, G . (16) 47 Tewari, Y.E. ( 2 ) 41 Tezuka, Y. (21) 47 Thang, T.T. ( 8 ) 3 Thiel, I.M.E. ( 2 ) 20; (18) 5 Thiem, J. ( 3 ) 65, 90, 114; ( 4 ) 6; ( 7 ) 52; (23) 10 Thomas, A.F. ( 3 ) 68
Thomas, D. ( 2 ) 34 Thomas, E.J. (19) 88 Thomas, G . J . (20) 120 Thomas, H . J . (20) 238 Thomas, R.L. ( 4 ) 31; (23) 39
Thomsen, J . V . (21) 11 Thomson, J.K. (13) 21 Tietze, L.-F. ( 3 ) 26; (22) 53 Tikhonov, Y.V. (23) 8 3 Tilbrook, D.M.G. ( 7 ) 75; (13) 6 Tillequin, F. ( 3 ) 50 Timoshchuk, V.A. (20) 140, 141, 253, 257; (21) 17 Tino, J . A . (20) 234; (24) 40 Titus, J . (19) 58 Tiwari, K.N. (19) 46 Tkachenko, O.V. (20) 33 Tocklu, R. (23) 80 Todaro, L.J. (20) 137, 231 Tomoszkozi, I. (20) 170 Togni, A . (17) 29; (22) 61 Toguzov, R.T. (23) 8 3 Tohma, S. (19) 1 Tokareva, N.L. ( 9 ) 1; (19) 67 Toke, L. ( 5 ) 21; ( 9 ) 5 Tokunaga, T. (19) 79 Tollin, P. (22) 73, 85 Tolman, R.L. ( 5 ) 1; (12) 14 Tolstikov, A.G. (13) 36 Tolstikov, G.A. (13) 36 Toma, L. ( 3 ) 91; (10) 60; (22) 40 Tomasic, J. ( 9 ) 43 Tomasz, J. (20) 199-201 Tomer, K.B. (22) 1 7 , 23; (23) 20, 70 Tomic, S. ( 9 ) 43 Tomimatsu, T. (12) 3 Tomita, K. (16) 51; (22) 78 Tomita, Y. (22) 81 Tomooka, K. (24) 26 Tone, H. (24) 24, 25 Toone, E.J. ( 2 ) 11; ( 4 ) 2; (16) 14 Topall, G. ( 9 ) 41 Topf, C. (22) 41 Torgov, V . I . (4) 22; (21) 41, 42 Torii, K. ( 3 ) 64; (19) 91 Torii, S. (15) 1 Torikata, A. (19) 81 Torrence, P.F. (20) 176,
304 188
Tortolani, D.R. ( 1 3 ) 19 Toshima, H. ( 2 4 ) 27, 28 Toshima, K. ( 2 4 ) 29 Tosto, M.T. ( 2 ) 38 Toth, G. ( 2 0 ) 255 Toupet, L. ( 8 ) 11 Tourigny, G. ( 2 0 ) 118 Tovstenko, V.I. ( 2 0 ) 49,
Carbohydrace Chemistry
Turchin, K.F. ( 2 0 ) 20 Turchina, R.P. ( 2 0 ) 20 Turik, S.V. ( 1 6 ) 1 6 , 17 Turner, N.J. ( 1 6 ) 15 Tvaroska, I. ( 7 ) 5 ; ( 2 1 ) 7, 8
Tyihak, E. ( 2 3 ) 16 Tyrrell, D.L.J. ( 2 0 ) 23
97
Townsend, L.B. ( 1 9 ) 4 4 ; ( 2 0 ) 154, 155 Toyoda, H. ( 1 9 ) 20, 21 Tozer, M.J. ( 3 ) 178 Tozzi, M.G. ( 2 0 ) 29 Tran, V. ( 2 ) 8 Tranchepain, I. ( 2 4 ) 68 Trauner, K. ( 2 1 ) 34 Trinks, U.P. ( 2 4 ) 54 Triska, J. ( 3 ) 149 Trivedi, G.K. ( 7 ) 31 Trivellas, A. ( 1 8 ) 5 2 ; (24) 3 Trnka, T. ( 3 ) 149 Trombini, C. ( 1 2 ) 6 ; ( 2 4 ) 2 Tronchet, J.M.J. ( 1 ) 8 ; ( 4 ) 5 ; ( 9 ) 1 5 ; ( 1 0 ) 42, 48, 49, 6 1 ; ( 1 3 ) 29; ( 2 2 ) 95 Trost, B.M. ( 1 4 ) 4 7 ; ( 2 4 ) 11 Trouton, K. ( 2 2 ) 44 Truay, J.F. ( 2 0 ) 30 Truman, R.W. ( 9 ) 4 4 ; ( 1 0 ) 18 Trumtel, M. ( 3 ) 1 1 , 103, 109; ( 1 0 ) 45; ( 1 2 ) 1 5 ; (13) 4, 5 Trushkina, I.A. ( 2 2 ) 5 Tsai, M.-D. ( 1 8 ) 79 Tsai, T.Y.R. ( 3 ) 55 Tsang, J.K. ( 2 4 ) 6 Tsang, R. ( 1 4 ) 26; ( 2 4 ) 4 Tsapkina, E.N. ( 2 2 ) 8 4 , 92 Tschiersch, B. ( 3 ) 31 Tschopp, T.B. ( 4 ) 58 Tseng, C.K.H. ( 1 9 ) 52 Tsuchiya, T. ( 1 8 ) 3 ; ( 1 9 ) 31, 32 Tsuda, K. ( 2 0 ) 216-219, 221 Tsuda, Y. ( 9 ) 1 7 ; ( 1 5 ) 4 Tsukamoto, S . ( 2 3 ) 28, 29, 30 Tsuno, T. ( 1 9 ) 12 Tsuzuki, K. ( 1 9 ) 20, 21 Tsvetkov, Yu.E. ( 4 ) 8 , 9 Tu, Ch. ( 7 ) 57 Tuan, G. ( 1 9 ) 69 Tucker, H.K. ( 4 ) 73
Ubasawa, A. ( 2 0 ) 229 Ubukata, M. ( 1 9 ) 19 Ubukata, Y. ( 2 ) 67 Uchida, K. ( 2 0 ) 93 Udodong, U.E. ( 6 ) 8 ; ( 9 ) 19
Ueda, K . ( 2 4 ) 40 Ueda, T. ( 2 ) 1 3 ; ( 2 0 ) 47, 54, 102, 129, 130, 215; ( 2 2 ) 78 Uedeira, H. ( 2 ) 35 Uehling, D.E. ( 2 4 ) 33 Uemura, A. ( 2 0 ) 225, 226 Uenishi, J. ( 2 4 ) 40 Ugarkar, B.G. ( 2 0 ) 227 Ugi, I. ( 2 0 ) 114 Uhlmann, E. ( 2 0 ) 172 Uhrin, D. ( 2 1 ) 7 Ukai, S . ( 1 8 ) 3 Ulbrich, B. ( 7 ) 42 Ullas, G.V. ( 2 0 ) 7 3 , 136; ( 2 2 ) 93 Umani-Ronchi, A . ( 1 2 ) 6 ; (24) 2 Umegae, Y. ( 2 3 ) 96 Umezama, H. ( 1 9 ) 75 Urnezawa, S . ( 1 9 ) 31, 32 Unemi, N. ( 1 9 ) 40 Unger, F.M. ( 3 ) 121; ( 4 ) 12 Unruh, S.L. ( 2 3 ) 14 Unverzagt, C. ( 4 ) 4 Urashima, T. ( 4 ) 61 Urbanczyk-Lipowska, Z. ( 2 2 ) 37 Urbanska, J. ( 1 7 ) 35 Urpi, L. ( 2 2 ) 90 Ushida, Y. ( 1 6 ) 6 Usui, H. ( 2 2 ) 78 Uvarova, L.A. ( 2 0 ) 240 Uzan, R. ( 8 ) 27; ( 1 8 ) 23 Uzawa, H. ( 3 ) 141; ( 5 ) 43; ( 1 1 ) 9 ; ( 2 4 ) 79 Uzawa, J. ( 1 9 ) 19
Vaaks, E. ( 2 0 ) 49, 7 8 , 112
Vacca, J.P. ( 1 8 ) 7 5 , 78 Vaccaro. H.A. ( 7 ) 30 Vaghefi; M.M. ( 2 0 ) 24, 203
Vajda, J. ( 2 3 ) 17 Vakojevic, N. ( 6 ) 13 ValGry, J.M. ( 7 ) 6 8 ; ( 1 2 ) 1 3 ; ( 1 3 ) 34
Valverde, S. ( 9 ) 9 ; ( 1 6 ) 23
Van Aerschot, A . (20) 89-91, 105, 109, 110
Van Bekkum, H. ( 5 ) 32 van Biljon, P.L. ( 2 3 ) 89 van Boeckel, C.A.A. ( 4 ) 5 9 ; ( 7 ) 76
van Bolhuis, F. ( 2 2 ) 29 van Boom, J.H. ( 2 ) 30; ( 3 ) 40; ( 4 ) 1 6 , 20, 24, 41, 42; ( 7 ) 59, 6 0 ; ( 1 6 ) 27; ( 1 7 ) 17 van Breemen, R.B. ( 2 2 ) 9 van Dam, J.E.G. ( 2 3 ) 7 van de Graaf, B. ( 5 ) 35
van de Grampel, V.J.M. ( 1 6 ) 62
van der Geest, R. ( 3 ) 147; ( 1 1 ) 1 2 ; ( 2 2 ) 29
van der Greef, J. ( 2 2 ) 1 9 ; ( 2 3 ) 45
van der Hoeven, R.A.M. ( 2 2 ) 1 9 ; ( 2 3 ) 45
van der Klein, P.A.M. ( 2 ) 30; ( 7 ) 59; ( 1 6 ) 27
van der Marel, G.A. ( 2 ) 30; ( 3 ) 40; ( 4 ) 1 6 , 20, 24, 42; ( 7 ) 5 9 , 60; ( 1 6 ) 27; ( 1 7 ) 17 van der Osten, C.H. ( 1 8 ) 26 van Doren, H.A. ( 3 ) 147; ( 1 1 ) 12; ( 2 2 ) 29 van Eijck, B.P. ( 2 ) 3 Vanek, Z. ( 1 9 ) 35 Van Engen, D. ( 3 ) 1 van Estrik, A. ( 5 ) 35 Van Gunsteren, W.F. ( 2 2 ) 25 van Halbeek, H. ( 4 ) 73 van Laak, K. ( 1 1 ) 3 Van Roey, P. ( 2 0 ) 7 9 ; ( 2 2 ) 88 van Vliet, M.J. ( 4 ) 17 Varela, 0 . ( 3 ) 98; ( 1 1 ) 1 ; ( 1 3 ) 21 Varescon, C. ( 3 ) 80 Varga, L. ( 7 ) 35 Vasella, A . ( 3 ) 2 ; ( 1 0 ) 37; ( 2 4 ) 50 Vasil'ev, S.A. ( 3 ) 58 Vasquez Tato, M.P. ( 1 9 ) 9 0 ; ( 2 4 ) 6 3 , 64 Vayrieres, A. ( 3 ) 103 Veeneman, G.H. ( 4 ) 41; ( 1 6 ) 27 Veesler, S . ( 5 ) 27
305
Author index Vega, R. (22) 62 VeIimiroviE, S. (5) 39; (7) 65; (18) 10, 11 Vellone, R. (20) 1 Venot, A.P. (4) 62 Verchere, J.F. (17) 22 Verduyn, R. (3) 40 Veres, K. (12) 7 Verez Bencomo, V. (3) 16; (5) 12 Vernin, G. (10) 28 Veronique, J. (17) 21 Versluis, C. (22) 11 Veyrikres, A. (3) 11, 109; (10) 45; (12) 15; (13) 4, 5 Vial, J.-M. (20) 131, 178 Vianello, E. (13) 1 Vicario, G.P. (19) 36 Vicent, C. (5) 11 Vicente, F . R . (9) 46; (10) 19 Vidal, A. (18) 71 Vieira, E. (1) 7; (18) 47 Vigdorchik, M.M. (20) 20 Vignon, M. (17) 38 Vilas, P. (20) 228 Villalobos, A. (24) 32 Ville, G. (3) 167 Vilpo, J. (20) 16 Vincent, C. (3) 70, 89; (5) 20 Vinegar, R. (20) 30 Virtanen, P . O . I . (2) 53-55, 59 Viswamitra, M.A. (22) 74, 77 Vite, G.D. (5) 30; (7) 74; (14) 27; (18) 5 1 Vittori, S . (20) 10, 11 Vliegenthart, J . F . G . (4) 17, 48; (16) 53; (21) 31, 49; (23) 7 Vlitos, M. (3) 72 Voelter, W. (7) 69 Vogel, J. (2) 49 Vogel, P. (1) 7; (2) 29, 31; (9) 33-35; (12) 29; (14) 8; (18) 47; (20) 143, 144 Voitenko, A.D. (6) 1 Vokoun, J. (19) 35 Volkheimer, J. (7) 22 Von der Lieth, C.W. (21) 40 Votruba, I. (20) 68 Voulalas, P. (2) 22 Voznyi, Ya.V. (3) 57, 144 Vrijens, I. (20) 154, 155 Vuik, J. (22) 19; (23) 45 Vukojevic, N. (13) 2 Vyas, D.M. (9) 20
Wagner, H. (7) 40 Wagner, J. (1) 7; (14) 8; (20) 119; (23) 78 Wakasaki, N. (23) 98 Wako, N. (19) 34 Wakselman, M. (3) 102 Walding, M. (4) 37 Waldmann, H. (3) 59; (10) 20 Waldstalten, P. (3) 121 Walker, J.M. (7) 49; (19) 93 Walker, S. (3) 1 Walz, L . (22) 63 Wang, C. (19) 86; (20) 198 Wang, F. (19) 86; (20) 198 Wang, H.K. (21) 47 Wang, L.-M. (23) 88 Wang, R. (7) 28 Wang, Y. (3) 29; (21) 21 Wang, Y.-F. (1) 3; (18) 26 Wang, Z. (24) 34 Wang, Z.H. (20) 165 Ward, J . G . (18) 76 Ward, T.R. (2) 36 Wardell, J.L. (17) 14; (22) 59 Wasson, D.B. (20) 76 Watanabe, H. (19) 18 Watanabe, K. (20) 47 Watanabe, K.A. (20) 44, 86, 104 Watanabe, M. (18) 35 Watanabe, T. (3) 44; (7) 58; (24) 70 Watanabe, Y. (18) 73; (19) 17; (23) 92 Watson, D.G. (21) 14, 35 Watson, K.A. (22) 44 Watt, I. (14) 6; (22) 49 Webber, J.M. (6) 6 Weidmann, H. (8) 30; (9) 45; (10) 57; (13) 3 1 Weigang, F. (23) 6 1 Weigele, M. (20) 231 Weijnen, J . G . J . (7) 17, 18 Weimer, T. (13) 16 Weisemann, S. (7) 21 Weiss, S. (20) 190; (22) 87 Weitz, D . J . (2) 16 Welch, M.J. (8) 22 Weller, T. (19) 6, 7 Welply, J . K . (4) 1 Welten, K. (23) 80 Wengel, J. (20) 115-117 Wessel, H.P. (4) 58; (16) 59
Westphal, G. (2) 49 Whipple, E.B. (19) 76 Whitby, D. (22) 90 White, A.H. (7) 75; (13) 6 White, D.R. (19) 10 White, J . B . (24) 40 White, J . C . (23) 88 White, J.D. (24) 17 Whitesides, G.M. (1) 4; (2) 11; (4) 2; (16) 14, 15 Whitman, W.B. (23) 74 Whittern, D.N. (19) 84 Widlanski, T. (16) 20, 21 Widstrom, N.W. (23) 4 1 Wiebe, L.I. (22) 75 Wienen, W.S. (2) 1 Wieruszeski, J.M. (21) 29, 30 Wiesler, W.T. (22) 97 Wiesner, K. (3) 55 Wiesner, M. (3) 65 Wightman, R.H. (19) 61, 89 Wilckens, M. (14) 39 Williams, C.A. (3) 56 Williams, D . J . (3) 37 Williams, D.R. (19) 80 Williams, J.F. (7) 55 Williamson, J . R . (23) 6 Willis, R.C. (10) 7; (20) 8 Wilson, B.E. (21) 6 Wilson, D.B. (17) 16; (18) 36 Wilson, H.A. (20) 32 Wimmer, E. (5) 4 1 Winchester, B. (18) 31, 32; (24) 62 Wincott, F.E. (24) 22 Winkler, T. (3) 157, 158; (8) 8 Winters, G. (19) 69 Wiorkiewicz-Kuczera, J. (2) 2 Wipf, P. (24) 36 Wisniewski, A. (7) 64; (18) 9, 12 Witczak, Z . J . (1) 1; (17) 11
Withers, S.G. (7) 53; (8) 19; (12) 11 Witty, D.R. (16) 12, 58; (18) 24, 25 Wohlrab, W. (3) 3 1 Wolfe, M.S. (19) 47, 53 Wong, B. (23) 5 Wong, C.-H. (1) 3; (8) 5; (18) 26; (20) 28 Wong, E. (3) 146 Wong, H. (9) 20
306 Wong-Kai-In, P. ( 2 0 ) 120 Woo, P.W.K. ( 3 ) 189 Wood, S.G. ( 2 0 ) 107 Woode, M.K. ( 2 1 ) 24; ( 2 2 ) 28
Woods, R.J. ( 2 2 ) 44 Woodward, C.N. ( 2 3 ) 88 Wos, J . A . ( 1 3 ) 1 9 ; ( 2 0 ) 122
Wotring, L.L. ( 2 0 ) 154, 155
WU, J.-C. ( 2 0 ) 45, 134 Wu, J.M. ( 1 9 ) 46 Wu, R . J . ( 2 3 ) 59 Wu, Z. ( 6 ) 8 Wylde, R. ( 3 ) 111 Wynberg, H. ( 3 ) 147; ( 2 2 ) 29
Wynberg, M. ( 1 1 ) 12 Xi, C. ( 2 0 ) 37 Xia, L. ( 2 3 ) 82 Xie, X. ( 3 ) 29 Xie, Z.-F. ( 2 4 ) 16 Xu, G. ( 3 ) 148 Xu, H. ( 1 6 ) 2 Xu, J. ( 1 6 ) 66 Xu, Y. ( 2 3 ) 82 Xu, Z.F. ( 2 ) 34 Yadakiri, P. ( 1 8 ) 68 Yadav, J.S. ( 1 3 ) 2 8 , 35; ( 2 4 ) 7 3 , 80 Yagi, A. ( 2 ) 6 1 ; ( 3 ) 69; ( 1 8 ) 44 Yajima, M. ( 4 ) 40 Yakovleva, L.A. ( 2 0 ) 66 Yamada, H. ( 3 ) 7 6 ; ( 1 4 ) 33; ( 2 2 ) 8 Yamada, K. ( 3 ) 140 Yamada, N. ( 1 0 ) 5 9 ; ( 1 6 ) 51; ( 1 8 ) 33, 34 Yamagata, Y. ( 2 2 ) 7 8 , 81 Yamagiwa, T. ( 2 4 ) 70 Yamagiwa, Y. ( 3 ) 4 4 ; ( 7 ) 58 Yamaguchi, K. ( 2 0 ) 5 3 ; ( 2 2 ) 79 Yamaguchi, M. ( 2 ) 7 Yamamoto, E. ( 2 3 ) 42 Yamamoto, H. ( 1 7 ) 1-5; ( 2 2 ) 58 Yamamoto, N. ( 7 ) 33 Yamamoto, T. ( 7 ) 44; ( 1 9 ) 7 4 , 75 Yamamoto, Y. ( 1 4 ) 42; ( 1 8 ) 13 Yamamura, S . ( 3 ) 35; ( 2 0 ) 127, 128; ( 2 4 ) 27, 28 Yamana, K. ( 7 ) 61; ( 2 0 )
Carbohydrate Chemistry 180
Yamanashi, S. ( 2 3 ) 50 Yamanoi, T. ( 1 7 ) 1 8 , 19 Yamasaki, K. ( 2 2 ) 27 Yamasaki, N. ( 2 0 ) 72 Yamashita, H. ( 1 8 ) 34 Yamashita, J. ( 1 9 ) 4 0 ; ( 2 0 ) 215, 225, 226
Yamashita, M. ( 1 7 ) 6 , 10 Yamauchi, H. ( 3 ) 69; ( 1 8 ) 44
Yamauchi, K. ( 2 0 ) 213 Yamazaki, F. ( 4 ) 44, 74 Yamazaki, K. ( 1 6 ) 52; ( 2 3 ) 62
Yamazaki, M. ( 2 3 ) 43 Yamazoe, Y. ( 2 3 ) 47 Yamoni, T. ( 3 ) 125 Yan, L. ( 2 2 ) 1 2 Yan, S . ( 2 0 ) 48 Yanagihara, Y. ( 3 ) 86 Yanagisawa, H. ( 2 4 ) 74 Yanahira, S. ( 4 ) 25 Yanaka, K. ( 2 3 ) 98 Yang, H. ( 1 6 ) 2 ; ( 2 0 ) 52 Yang, L.J.S. ( 1 ) 3 Yang, S.S. ( 1 8 ) 63 Yano, S . ( 2 ) 45, 46; ( 1 7 ) 34, 37
Yano, Y. ( 2 ) 43 Yarotskii, S.V. ( 2 1 ) 16 Yartseva, I . V . ( 1 6 ) 7 7 ; ( 2 0 ) 34
Yasaka, T. ( 2 0 ) 3 Yashunskii, D.V. ( 1 3 ) 2 7 ; ( 1 4 ) 19
Yashunsky, D.V. ( 2 4 ) 23 Yasuda, A . ( 2 0 ) 93 Yasuhara, T. ( 7 ) 4 8 , 50; ( 1 9 ) 92
Yasumoto, M. ( 1 9 ) 4 0 ; ( 2 0 ) 215, 225, 226
Yasuoka, J. ( 2 0 ) 102 Yau, E.K. ( 2 0 ) 183 Yaylayan, V. ( 9 ) 39 Yazaki, K. ( 7 ) 50; ( 1 9 ) 92
Yeung, B . A . ( 2 4 ) 5 Yli-Pyky, A . ( 2 ) 54 Yokokawa, Y. ( 2 0 ) 164 Yokotsuka, J. ( 1 9 ) 1 Yokoyama, M. ( 1 0 ) 59 Yokoyama, Y. ( 2 3 ) 49 Yonaga, M. ( 2 4 ) 40 Yonemitsu, 0 . ( 5 ) 1 9 ; ( 2 4 ) 24, 25, 41-43
Yoshida, K. ( 2 3 ) 49 Yoshida, M. ( 1 3 ) 1 0 ; ( 1 4 ) 43
Yoshida, S. ( 2 4 ) 27 Yoshida, T. ( 7 ) 48, 50; (10) 1 ; ( 1 9 ) 9 2 ; ( 2 3 )
93
Yoshii, E. ( 2 4 ) 53 Yoshikawa, M. ( 4 ) 45; ( 1 9 ) 48; ( 2 0 ) 164, 171
Yoshikawa, S . ( 2 ) 45; ( 1 6 ) 6 , 54; ( 1 7 ) 34, 37 , H. ( 2 0 ) 6 2 , 63 Yoshikuni Y. ( 1 8 ) 35 Yoshimura H. ( 3 ) 63 Yoshimura J. ( 2 ) 26 Yoshimura Y. ( 2 0 ) 54, 129 Yoshino, T. ( 5 ) 10 Yoshioka, T. ( 1 9 ) 22 Young, M.G. ( 1 9 ) 64 Young, R.A. ( 2 ) 17 Young, R.C. ( 1 8 ) 76 Yoyoda, H. ( 2 3 ) 50 Yruela, I. ( 1 8 ) 42 Yu, D. ( 2 0 ) 145 Yu, K.-L. ( 6 ) 8 ; ( 1 4 ) 41 Yu, R.K. ( 2 3 ) 63 Yu, Y. ( 2 3 ) 97 Yuasa, H. ( 1 1 ) 2
Yoshikosh
Zahner, H. ( 1 9 ) 57 Zahler, R . ( 1 9 ) 6 4 ; ( 2 0 ) 234
Zaitseva, G.V. ( 2 0 ) 49, 7 8 , 97, 112
Zajicek, J. ( 3 ) 130; ( 2 0 ) 31
Zalisz, R. ( 2 3 ) 37 Zambonin, P.G. ( 2 3 ) 84 Zamojski, A. ( 8 ) 1 4 ; ( 1 0 ) 34; ( 1 3 ) 33
Zanol, M. ( 1 9 ) 70 Zaoral, M. ( 3 ) 130 Zarif, L. ( 3 ) 80 Zarina, D. ( 2 0 ) 98 Zavgorodnii, S.G. ( 2 2 ) 8 2 , 83
Zbiral, E. ( 3 ) 2 3 ; ( 9 ) 49; ( 1 0 ) 44; ( 1 2 ) 21; ( 1 3 ) 1 8 ; ( 1 6 ) 40-43; ( 2 1 ) 25 Zeeck, A. ( 1 0 ) 4 7 ; ( 1 9 ) 24; ( 2 2 ) 43 Zehani, S. ( 7 ) 3 2 ; ( 1 0 ) 6 2 , 63 Zehavi, V. ( 4 ) 23
Zemek, J. ( 7 ) 5 Zemlicka, J. ( 2 0 ) 81 Zemlyanukhina, T.V. ( 3 ) 104
Zen, S. ( 3 ) 136 Zenz, E. ( 1 8 ) 56 Zerelli, S . ( 1 0 ) 42; ( 1 3 ) 29
Zerilli, L. (19) 68-70
307
Author Index Z e t t a , L. ( 3 ) 180; (14) 18 Zhang, D. ( 3 ) 148 Zhang, L. (19) 86; (20) 198 Zhang, M. (22) 67 Zhang, X.H. (20) 165 Zhang, X.Y. (23) 59 Zhang, Y. ( 7 ) 28 Zhang, Z. (22) 67 Zhbankov, R.G. (22) 33 Zhdanov, Yu.A. (16) 1 6 ,
17, 32 Zhou, X.-X. (20) 178 Zhpanov, Yu.A. (5) 25 Zhulin, V.M. ( 3 ) 77 Z i e g l e r , M. (23) 83 Z i e g l e r , T. ( 3 ) 87; ( 7 ) 7 Zielonacka-Lis, E. (20) 242
Z i l ' b e r g , L.L. (12) 32 Zinchenko, A . I . (20) 33, 230 Zinke, P.W. (16) 30
Z i s e r , L. (2) 23; (3) 27 Zorkler, G . ( 3 ) 34 Z o t t o l a , M.A. ( 5 ) 30 Zou, R. (20) 23 zou, w. ( 7 ) 57 Z s e l y , M. (18) 82; (24) 8, 9 Zubkov, V.A. (14) 1, 2 Z u c c h e l l i , L. ( 3 ) 197; (7) 20 Zuluaga, J . (16) 65 Zuzuhaka, H. (20) 72
