Carbohydrate Chemistry provides review coverage of all publications relevant to the chemistry of monosaccharides and oligosaccharides in a given year. The amount of research in this field appearing in the organic chemical literature is increasing because of the enhanced importance of the subject, especially in areas of medicinal chemistry and biology. In no part of the field is this more apparent than in the synthesis of oligosaccharides required by scientists working in glycobiology. Clycomedicinal chemistry and its reliance on carbohydrate synthesis is now very well established, for example, by the preparation of specific carbohydrate- based antigens, especially cancer-specific oligosaccharides and glycoconjugates. Coverage of topics such as nucleosides, amino-sugars, alditols and cyclitols also covers much research of relevance to biological and medicinal chemistry. Each volume of the series brings together references to all published work in given areas of the subject and serves as a comprehensive database for the active research chemist Specialist Periodical Reports provide systematic and detailed review coverage in major areas of chemical research. Compiled by teams of leading authorities in the relevant subject areas, the series creates a unique service for the active research chemist, with regular, in-depth accounts of progress in particular fields of chemistry. Subject coverage within different volumes of a given title is similar and publication is on an annual or biennial basis.

Carbohydrate Chemistry Volume 33

Monosaccharides, Disaccharides, and Specific Oligosaccharides

By R. J. Ferrier

The Royal Society of Chemistry

Copyright © 2002 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-233-3

Contents

Chapter 1 Introduction and General Aspects, 1,
Chapter 2 Free Sugars, 3,
Chapter 3 Glycosides and Disaccharides, 16,
Chapter 4 Oligosaccharides, 62,
Chapter 5 Ethers and Anhydro-sugars, 93,
Chapter 6 Esters, 99,
Chapter 7 Esters, 104,
Chapter 8 Halogeno-sugars, 121,
Chapter 9 Amino-sugars, 126,
Chapter 10 Miscellaneous Nitrogen-containing Derivatives, 144,
Chapter 11 Thio-, Seleno- and Telluro-sugars, 165,
Chapter 12 Deoxy-sugars, 176,
Chapter 13 Unsaturated Derivatives, 180,
Chapter 14 Branched-chain Sugars, 191,
Chapter 15 Aldosuloses and Other Dicarbonyl Compounds, 205,
Chapter 16 Sugar Acids and Lactones, 207,
Chapter 17 Inorganic Derivatives, 219,
Chapter 18 Alditols and Cyclitols, 223,
Chapter 19 Antibiotics, 257,
Chapter 20 Nucleosides, 275,
Chapter 21 NMR Spectroscopy and Conformational Features, 334,
Chapter 22 Other Physical Methods, 348,
Chapter 23 Separatory and Analytical Methods, 365,
Chapter 24 Synthesis of Enantiomerically Pure Non-carbohydrate Compounds, 375,
Author Index, 411,

CHAPTER 1

Introduction and General Aspects

Review material published this year includes an essay ‘the unexpected and the unpredictable in organic synthesis’ which is a valuable account by Mukaiyama of the extraordinary history of his research, sections on stereoselective routes to sugars and glycosides being of special relevance.

As the subject continues to be driven increasingly by biological challenges a larger proportion of the text/review literature reflects this trend. The third of a series of major texts on Bioorganic Chemistry entitled ‘Carbohydrates’ follows two on nucleic acids (1996) and proteins (1997). Thirteen chapters by distinguished authors are introducted by Professor Ray Lemieux whose death in 2000 marked the end of the most notable of modern carbohydrate chemical careers. The topics covered in the book lay appropriately heavy emphasis on glycobiological aspects of the subject.

Two volumes of Advances in Carbohydrate Chemistry and Biochemistry appeared in 1999, one taking the form of useful Tables of Contents, and Subject and Author indices for volumes 1–53, the first of which appeared in 1945. The other contains obituary notices on Lord Todd, Professor Melvin Calvin and Dr Margaret A. Clarke, the first two winning Nobel Prizes for their work which illuminated issues associated with the roles played by the carbohydrates in natural processes, and the third making major contributions to sugar chemistry within the industrial/commercial scene. The volume also contains reviews on A-thiocarbonyl derivatives of sugars – isothiocyanates, thioamides, thioureas and thiocarbamates (J.M. García Fernández and C. Ortiz Mellet), the synthesis of chiral polyamides from carbohydrate-derived monomers (O. Varela and H.A. Orgueira) and hydrazine derivatives of carbohydrates (H. El Khadem and A.J. Fatiadi).

An extensive range of other reviews has been published, many being referred to at the beginning of relevant chapters. Of general significance are assessments of recent developments in polymer-supported syntheses of oligosaccharides, of recent advances in solid- and solution-phase methods relevant to the generation of carbohydrate and glycoconjugate libraries and of the use of carbohydrates as molecular scaffolds for library synthesis, of the preparation of biologically active carbocyclic oligosaccharides and their structure-activity relationships as glycosidase inhibitors, and of the synthesis of ‘glycopolymers’ made from sugars with natural and unnatural linkages and from copolymers comprising carbohydrates in part.

Further reviews of relevance in glycobiology have dealt with the synthesis and function of glycoconjugates, with recent developments in this field and with the use of carbohydrate mimetics in the study of carbohydrate-mediated biomolecular recognition. Bertozzi has reported on her new approaches to the preparation of stable C-glycosidic glycopeptide mimetics.

Of general relevance in glycobiology is a review of the impact of evolutionary considerations in respect of oligosaccharide diversity and biological function. A paper on single yeast cell studies of the enzymic hydrolysis of a tetramethylrhodamine-labelled triglucoside could revolutionize in vitro whole cell analysis of oligosaccharide processing, and the finding that low molecular weight dextrans enter the nucleus and are better inhibitors of breast cancer cell growth than are larger oligomers is of obvious potential value.

CHAPTER 2

Free Sugars

1 Theoretical Aspects

AMI and ab initio calculations performed on D-glucopyranose and its monoalkoxy anions indicated that the C-1- and C-4-hydroxyl groups are the most acidic for the α- and β-anomers, respectively. In all cases, the primary hydroxyl group was the least acidic.

In a molecular dynamics study on the hydration properties of an 85 w/w aq. solution of glucose, the radial distribution function, H-bond residence times, hydration number, and the mean life time and size of glucose and water clusters have been computed, and in a theoretical investigation of the mutarotation of glucose assisted by up to five H2O molecules the participation of water dimers and trimers, which provide a strain-free hydrogen bond network for ready H-transfer, has been considered.

2 Synthesis

A paper entitled ‘The unexpected and unpredictable in organic synthesis’ covering Mukaiyama’s work in the aldol condensation field contained a section on the synthesis of carbohydrates from D-glyceraldehyde and L-erythrose.

2.1 Tetroses and Pentoses. – All D-tetroses and D-pentoses have been synthesized from 2,3-O-isopropylidene-D-glyceraldehyde by consecutive one-carbon chain-elongation using the Li salt of ethyl ethylthiomethyl sulfoxide. The additions proceeded with high anti-diastereoselectivity and the formations of the major products, D-erythrose and D-ribose, are outlined in Scheme l.

D-Xylose has been converted into D-lyxose via mesylate 1, which on treatment with one molar equivalent of NaOH in aqueous DMF gave 2, possibly by way of the l,2-β-D-lyvo-epoxide. Conversion of D-xylose into L-xylose involved resolution of the racemic xylitol derivative 3 by lipase-catalysed hydrolysis to give a mixture of the D-alcohol and unreacted L-acetate. The latter was hydrolysed chemically, then oxidized (Pfitzer Moffat) and deacetalized. L-Xylose was the starting compound for the synthesis of L-ribo-nucleosides, the required inversion of configuration at the 3-position being achieved by oxidation-reduction (CrO3/pyridine-LAH). In the synthesis of [3,4,5′,5″-2H]-ribonucleosides from diacetone-D-glucose, the deuterium atoms were introduced consecutively by reduction of a keto group with NaBD, hydrogen-deuterium exchange α to an aldehyde using D2O and reduction of an ester group with LiAlD4, as shown in Scheme 2.

The synthesis of racemic, fluorinated xylulose derivatives based on a Wittig approach and two syntheses of labelled 1-deoxy-D-xylulose are covered in Chapters 8 and 15, respectively, and the preparation of 3-deoxy-3-C-methylene-pentofuranosides (as precursors of novel nucleoside analogues) from commercial 3-methyL-2-butenal is referred to in Chapter 14.

2.2 Hexoses. – In a new protocol for the synthesis of hexopyranoses from furfuraldehyde, resolution was achieved at an early stage by asymmetric dihydroxylation (e.g. 4 -> 5, Scheme 3). Careful choice of conditions for the reduction at the 4-position and for the second dihydroxylation gave preferential access to either enantiomer of manno-, gulo- and talo-pyranose, as the 6-silylated 1-esters, such as benzoate 6 in the example chosen.

Construction of 6,6,6-trideoxy-trifluoro-hexopyranose ring systems by inverse-demand Diels Alder reaction is covered in Chapter 8. The syntheses of 4-deoxyfructose 6-phosphate and of a branched hexulose phosphate from achiral starting materials by routes involving biocatalytic reactions are referred to in Chapters 12 and 14, respectively, and the synthesis of L-ascorbic acid from chlorobenzene via L-gulono-1,4-lactone is dealt with in Chapter 16.

Stereospecific cis-hydrogenation of the known, diacetone-D-glucose-derived enol acetate 7 over a Rh/Al catalyst offers easy access to D-gulose derivative 8. The preparation of imidazolo-sugars from 8 is referred to in Chapter 18. L-Glucose has been obtained from D-gulono-1,4-lactone via 2,3,4,5,6-penta –O-benzyl-L-glucitol (9), which was oxidized with CrO3/pyridine complex to give 2,3,4,5,6-penta-O-benzyl-aldehydo-L-glucose in 59% yield. Immobilized glucose isomerase, which accepts D-allo- and D-tallo-configured substrates, has been applied to the synthesis of 5-functionalized 2-ketoses from the corresponding hexofuranose derivatives, for example 10 ->11. The 2-ketoses thus obtained were converted into powerful glycosidase inhibitors (see Chapter 18). Treatment of 1,2-O-isopropylidene-D-fructopyranose with chloral/DCC caused the concomitant formation of a trichloroethylidene acetal and introduction of a carbamoyl function at C-5. Configurational inversion occurred at the central hydroxyl group of the cis-trans-triol (see Vol. 32, Chapter 6, ref. 8; Vol. 30, p. 99, refs. 17-19) furnishing D-tagatose via intermediate 12.

Intramolecular Tishchenko oxidoreduction of a protected hexos-5-ulose intermediate to give an aldonic acid ester (14 ->15, Scheme 4) was the key-step in the conversion of tetra-O-benzyl-D-glucitol (13) to L-idose in 65% overall yield. A D-galactitol derivative was similarly converted to L-altrose.

The synthesis of the previously unknown L-ribo-hexos-5-ulose from an L-arabino-configured precursor, involving a stereocontrolled oxidation-reduction as the key-step, is covered in Chapter 15, and the isomerization of D-glucose- to D-allose-derivatives by use of Mitsunobu reactions is referred to in Chapter 7.

Chain-extensions of pentodialdo-1,4-furanoses with C Grignard reagents (ROCH2MgCl, R = Me, All, Bn or Tbdps) gave the expected stereoisomeric hexoses (e.g.16 ->17), accompanied in some cases by C-4-inverted products (in the illustrated example 18). The selectivity at both C-4 and C-5 varied with the protecting group of the reagent.

2.3 Chain-extended Sugars. – A review (27 pp., 79 refs.) on the synthetic applications of indium-mediated reactions in aqueous media contained several examples of carbohydrate homologation at the ‘reducing’ as well as at the ‘non-reducing’ end.

An asymmetric hetero-Diels Alder reaction has been used to make optically active 5-C-aryl pentopyranoses, as outlined in Scheme 5.

A new, one-pot procedure involving a cascade of four enzymatic steps (phosphorylation, oxidation, aldol condensation with butanal and dephosphorylation), leading from glycerol to trideoxy-D-xylo-hept-2-ulose, is covered in Chapter 12

2.3.1 Chain-extension at the ‘Non-reducing End’. – Further use has been made of protected dialdoses for this purpose: t-Butyl 7-deoxyocturonic esters 20 have been synthesized in from aldehyde 19 by exposure to MeCO2But-LDA. Conversion of 20 and related compounds into castanospermine analogues is referred to in Chapter 18. On exposure of aldehyde 21 to LDA at – 30 °C, a complex mixture was obtained which contained, in addition to the reduction product 22, the chain-extended compounds 23 and 24, formed by deacetonation of some of the sample and subsequent aldol condensation between the acetone thus liberated and the starting aldehyde. Reaction of aldehyde 25 with but-3-enylmagnesium bromide, followed by iodolactonization, gave a 4:1 mixture of the bis-THF compound 26 and its 2′,5′-syn-isomer.

The phosphonate isostere 29 of methyl-α-D-mannoside 6-phosphate resulted from the reaction of aldehyde 27 with the carbanion of tetraethyl methylene-bisphosphonate to furnish the 6,7-unsaturated intermediate 28, followed by concomitant reduction of the double bond and debenzylation on exposure to H2-Pd/C. Allyl phosphonate 31 was prepared from dialdose derivative 30 on exposure to diethyl 1-bromo-2-propenylphosphonate in the presence of Zn/Ag on graphite. Extending the chain of the known aldehyde 32 by treatment with (EtO)2POCH2CN/NaH gave the unsaturated tetradeoxy-nonurononitrile 33, which underwent in situ a highly stereoselective intramolecular Michael addition to afford the annulated furanose 34.

The 7-deoxy-β-D-gluco-heptos-6-ulose deivative 35, available by reaction of 1,2-O-isopropylidene-5-O-Tbdms-D-mannono-3,6-lactone with methyl lithium, gave (6S)-6-C-methyl-D-mannose (36) on reduction with NaBH4, followed by desilylation and acetal hydrolysis. When the reaction sequence was reversed, i.e. with desilylation prior to reduction, the (6R)-isomer 37 was obtained as the main product.

Metathetic dimerization of ω-unsaturated hexofuranoses over Grubbs’ catalyst furnished unsaturated products, in several cases with ≥ 95% Z- selectivity (e.g. 38 -> 39). Dihydroxylation (0sO4, NMO) of the new double bond gave decadialdoses, such as 40.

For the synthesis of compound 43, incorrectly termed a ‘coumarin C-glycoside’, a one-pot Knoevenagel condensation of the known β-keto sugar ester 41 with salicylaldehyde was used, followed by reduction of the C-5 carbonyl group to furnish intermediate alcohol 42. Rearrangement to the chain-extended target-pyranose, isolated as the peracetate 43, took place on deprotection. A number of chromenes with C-2 linked to L-arabinose, e.g. 45, resulted from the condensation of protected E-7-nitrohept-6-enes with substituted salicylaldehydes in the presence of basic alumina and subsequent replacement of the nitro groups of the initial products, e.g.44, by cyanide (Scheme 6). In this particular case, only the (6S)-isomer 45 was formed, due to stereoelectronic factors.

New examples of the ‘nitrile oxide/isoxazoline route’ (see Vol. 31, p.7, ref. 21) and of the ‘phosphonate route’ (see Vol. 32, Chapter 2, refs. 28, 29) to higher sugars have been published. The former approach led to C11-mono -saccharides by cycloaddition of di-O-isopropylidene-D- or -L-arabinononitrile oxide and the 3-O-benzyl analogue of the glucose-derived alkene 38 or an analogous, mannose-derived alkene. The initial addition products were functionalized isoxazolines, such as 46. In the latter approach C13- and C15- monosaccharides were produced from C-aldehydes and C- or C-phosphonates, respectively (e.g.47 + 48 ->49). Reaction of phosphonate 48 with Tbdps-protected glycolaldehyde gave a silyloxy-enone which cyclized on desilylation, then aromatized affording 2-furyl sugar 50.

2.3.2 Chain-extension at C-1 of Ald-2-uloses – Extended-chain uloses have been prepared by highly selective boron aldol additions. On treatment with dicyclohexylboron chloride, L-erythrulose derivative 51, for example, formed a Z-enolate, which reacted with benzaldehyde to furnish the synlsyn-product 53, whereas under similar conditions the dibenzoate 52 formed an E-enolate and hence the synlanti adduct 54.

2.3.3 Chain-extension at the ‘Reducing End’ – The molybdic acid-mediated skeletal rearrangement of 2-C-hydroxymethyl-D-allose to D-altro-heptulose (sedoheptulose), which results in a 2:12 equilibrium mixture, has been exploited in a facile synthesis of the latter compound from D-allose (see Vol. 32, Chapter 2, ref. 41).

Several papers have been published on reactions of phosphoranes with protected aldehydo sugars, osuloses and sugar lactones. On condensation of 2,3:4,5-di-O-isopropylidene-D-xylose with benzoylmethylenetriphenylphos -phorane, enone derivative 55 was formed. Conversion to ketoxime 56 and oxidative cyclization with I2/KI/Na2CO3 furnished, after deprotection, 3-phenyl-5-(tetrahydroxybutyl)isoxazole 57. 2,3:4,6-Di-O-isopropylidene-β-D –arabino-hexos-2-ulopyranose (58) reacted with (cyanomethylene)triphenyl-phosphorane to give, after catalytic hydrogenation of the double bond, 4-octulosononitrile 59. Reaction of osulose 58 with phosphorane 61, synthesized from 2-ethyl-1,3-propanediol in four steps, including enzyme-catalysed, desymmetrizing acetylation, furnished 60, after saturation of the double bond. This was further processed to give spiroketal 62.

Compound 63 and similar exo-glycals were prepared by conventional Wittig alkylidenation of protected hexono-1,5-lactones. They were either hydrogenated, or dihydroxylated then deoxygenated, to furnish β-C-glycosides, such as 64 and 65, respectively, after acetylation. An efficient approach to the construction of the spiroketal moiety 67 of papulacandins was based on the condensation of the D-arabinono-1,4-lactone derivative 66 with 2-lithiated 3-phenylsulfonyl-4,5-dihydrofuran, as shown in Scheme 7.

Acetylenic C-glycosides, for example compound 68, have been obtained by reaction of a sugar lactone with a carbohydrate-derived lithium acetylide (see Vol. 31, p. 48, ref. 303). They were deoxygenated at C-1′ and further transformed to C-linked disaccharides, such as 69. An iterative process has been developed on the basis of these reactions to furnish C-linked-β-(1 -> 6) -D-galactooligosaccharides 70. The synthesis of aza-sugar-containing, C-linked disaccharides from acetylenic C-glycosides is covered in Chapter 18, and related C-linked disaccharides are discussed in Chapter 3.

3 Natural Products

1-Deoxy-1-(4-hydroxyphenyl)-L-sorbose and -L-tagatose (71) and (72) were isolated from the roots of the Nepalese medicinal plant Dactylorhizia hatagires and named Dactylose A and B, repectively, and sarioside (73), found in the shrub Picramnia antidesma, has been shown by X-ray crystallography to be a sugar derivative with the carbon-chain extended from the ‘non-reducing end’.

4 Other Aspects

The thermodynamic parameters of the interaction of HC1 with D-arabinose in water have been determined from electromotive force measurements between 278.15 and 318.15K.

(Continues…)Excerpted from Carbohydrate Chemistry Volume 33 by R. J. Ferrier. Copyright © 2002 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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