12 Carbohydrates By J. F. KENNEDY and D. L. STEVENSON Department of Chemistry University of Birmingham P.0. Box 363 Birmingham B 15 277 1 Introduction This inevitably selective chapter covers the literature since the previous report' in 1984 with some emphasis on work described in 1987.For reasons of space it has had to be restricted to the monosaccharides and to the use of carbohydrates as chiral templates. For a more comprehensive coverage the reader is referred to the Specialist Periodical Report on the Carbohydrates. 2 Monosaccharides G1ycosides.-The stereoselective formation of glycosides continues to be one of the central goals of carbohydrate chemistry. The preparation of C-glycosides has attrac- ted attention. The synthesis of 0-(a-g1yco)-peptides has been achieved2 by treating unsaturated monosaccharides such as (1) with peptides containing serine and threonine in the presence of N-iodosuccinimide to give the 2-iodoglycosides from which the glycopeptides [e.g.(2)] were then obtained by hydrogenolysis with Bu3SnH. The formation of acetal-P-D-glucosides from cytotoxic aldehydes has been examined in the context of cancer ~hemotherapy.~ Compounds such as (3) may act as pro-drugs liberating the aldehyde by acidic or enzymic hydrolysis at the required site. The glucosides were obtained by reaction of trimethylsilyl2,3,4,6-tetra-O-acetyl-p-D-glucopyranoside and an acetal (R'O)2CHR2 in the presence of catalytic amounts of CF3S03SiMe3 followed by deacetylation. The preparation of C-glucopyranosyl derivatives from the readily available 2,3,4,6-tetra-0-benzyl-a-D-glucopyranosyl chloride (4)has been de~cribed.~ Treatment of compound (4)with for example Et02CCH=C(OSiMe3)OEt in the presence of silver triflate gave C-glucopyranosyl derivatives with the a-configuration (5).The synthesis of C-glucosides has also been achieved' using the reaction between O-glycosylimidates [e.g. (6)]and electron- rich heterocycles such as furans and thiophenes to give the P-D-C-glucosides. A novel and stereoselective carbon-carbon bond-forming reaction at the anomeric centre of carbohydrates has been developed by means of a carbenoid displacement reaction with phenylthioglycosides.6 The reaction may proceed via an oxonium ion ' J. Thiem Annu. Rep. Bog. Chem. Secf. B. 1984 81 31 1.H. Kessler M. Kottenhahn and C. Kolar Angew. Chem. 1987 99,919; (Int. Ed. Engl. 1987 26 888). L. F. Tietz R. Fischer H. J. Guder and M. Neumann Liebigs Ann. Chem. 1987 847. P. Allevi M. Anastasia P. Ciuffreda A. Fiecchi and A. Scala J. Chem. SOC.,Chem. Commun. 1987 101. R. R. Schmidt and G. Effenberger Liebigs Ann. Chem. 1987 825. T. Kametani K. Kawamura and T. Honda J. Am. Chem. Soc. 1987 109 3010. 29 1 J. F. Kennedy and D. L. Stevenson CHzOAc AcO &AJ CHzOH HOa0& OI"' Z.PrO.NH C0.Ala.0CH2Ph HO OH OMe AcOEc H (1) (2) (3) CH2OR' vH20R @-l;c13 &J2 R'O RO OR' OR (4) R' = CH,Ph R2 = CI (6) (5) R' = CH2Ph,R2 = CH(CO,Et) intermediate and has the following advantages (i) the preferential participation of a carbenoid with a sulphur atom can restrict the reaction site; (ii) the reaction can be carried out under neutral reaction conditions; and (iii) the introduction of various functionalities can be accomplished by manipulation of the organosulphur groups of the products.This synthetic strategy was successfully applied to the synthesis of the antitumour agent (+)-showdomycin (7). HO OH (7) The conjugate addition of glucosylcopper reagents to enones such as cyclo- hexenone has been applied7 to the stereospecific synthesis of C-glycosides. Some C-glycoside derivatives [ e.g. (9)] of 3-deoxy-~-mannooctulosonic acid (KDO) have been prepared' by reacting the enolate of (8) with a series of electrophiles. The P-configuration predominated in the C-glycosides which were formed.The stereocontrolled synthesis of four C-disaccharides [(lo)-( 1l)] has been rep~rted.~ The reduction of hemiketals such as (12) with (Pr"),SiH gave pre- dominantly the equatorially substituted C-glycosides. C-Alkylation by displacement ' D. K. Hutchinson and P. L. Fuchs J. Am. Chem. SOC.,1987 109 4930. K. Luthman M. Orbe T. Waglund and A. Claesson J. Org. Chem. 1987 52 3777. S. A. Babirad Y. Wang and Y. Kishi J. Org Chem. 1987 52 1370. 293 Carbohydrates Me 0 Mexoq @COzMe Me Me (10) (8) R = H R,R' = H OH (9) R = CH,OH Ho&;p..oMe "* 'OH HO PhCH2O 'OCH2Ph OH R 'R1 OH OCH2Ph Me0 (11) R R' = H OH (12) of the p-nitrobenzoate (13) gave axially substituted C-glycosides as the major product.Deoxy Branched and Higher Sugars.-There continues to be considerable interest in the synthesis of deoxy-sugars. In a new synthesis" of 2-deoxy-sugars glycosyl bromides [e.g. (14)] underwent reductive dehalogenation with Bu,SnH. This was accompanied by rearrangement of the adjacent acetoxyl group to give (15). OAc -0 A c -Br AcOb -OAc AcOb-AcO OAc AcO lo B. Giese K. S. Groeninger T. Witzel H. G. Korth and R.Sustmann Agnew. Chem. 1987,99,246; (Int. Ed. Engl. 1987 26 233). 294 J. E Kennedy and D. L. Stevenson D-Cordycepose (16) has been prepared with useful levels of diastereoselection by treatment of the glycerol allyl ether (17) with ozone dimethylsulphide and Amberlyst 15." The reaction proceeds via a Wittig rearrangement of the p-D-alkoxyalkyl allyl ether.Some deoxy-KDO derivatives [e.g. (8)] have been prepared in a stereospecific manner starting with the diacetonide of D-mannose.'2 Deprotec- tion of (8) gave an acid (18) that was a potent inhibitor of CMP-KDO synthetase. These derivatives were also useful in the formation of C-glycosides of KDO (see above). CHO I H-C-OH CH20H I Reduction of an a-acetoxyketone [e.g. (19)] with baker's yeast gave predominantly the 2S,4S,5R,6R-carbinol (20). This and some related examples of multiple enzy- matic stereoselectivity permittedt3 the synthesis of chiral synthons such as (21) 4-deoxymannose derivatives and the higher sugar derivative (22) in enantiomerically pure forms.OAc lp ia \ HO 0-/\ }-OH Addition of the 2-and E-alkoxyallylboronates (23) to 0-benzyl-lactaldehyde led,14 with some assymetric induction to various 3,4,5-trioxygenated 1-hexenes (24) of the arubino xylo ribo and lyxo configurations. The synthesis of dideoxy-sugars has been achieved" using triflate rearrangements. Reaction of 2,6-dideoxy- a-D-arabino-hexopyranoside (25) with triflic anhydride [(CF,SO,),O] gave the corresponding triflate which rearranged at room temperature S. L. Schreiber and M. T. Goulet Tetrahedron Left. 1987 28 1043. A. Claesson J. Org. Chem. 1987 52 4414. l3 G. Fronza C. Fuganti P. Grasselli and S. Semi J. Org. Chem. 1987 52 2086.. 14 R. W. Hoffmann R. Metternich and J. W. Lam Liebigs Ann. Chem. 1987 881. R.W. Binkley and M. A. Abdulaziz J. Org. Chem. 1987 52 4713. Carbohy dra tes 295 Me OH (23) OTf OMe OMe (25) (27) to another extremely reactive triflate (26) which on hydrolysis gave the 3- and 4-benzoates of 2,6-dideoxy-a- ~-lyxo- hexopyranoside (27). A new branched-chain monosaccharide 3,6-dideoxy-4C-(1-hydroxyethy1)-D-xylo-hexose (yersiniose) has been isolated16 from the Yersinia enterocolitica 0:4.32 lipopolysaccharide and is the second representative in a new class of monosac-charides. Some axially methyl-branched pyranosiduloses have been ~ynthesized.'~ The allyldeoxyglucose (28) can be cyclized to the oxabicyclooctane (29) in a radical chain reaction.'* However the isomer (30) did not cyclize confirming the boat conformation for glucosyl radicals.Dipeptide derivatives of 8-amino-D-glycero-D-talo-octanoate (3 1) have been synthesized" and shown to be effective antibacterial agents against Gram-negative bacteria. The glycopeptides [e.g. (32)] which are KDO analogues interfere with lipopolysaccharide biosynthesis. OAc Me fH2 16 R. P. Gorshkova V. A. Zubkov V. V. Isakova and Y. S. Ovodov Bioorg. Khim. 1987 13 1146. " A. Klemer and W. Klaffke Liebigs Ann. Chern. 1987 759. 18 K. S. Groeninger K. F. Jaeger and B. Giese Liebigs Ann. Chem. 1987 731. 19 A. Claesson A. M. Jansson B. G. Pring and S. M. Hammond. J. Med. Chem. 1987 30,2309. J. F. Kennedy and D. L. Steuenson The extension of the carbohydrate template via the secondary positions C-2 to C-4 and the primary position C-6 ('pyranosidic homologation') continues to attract attention.In one such example Robinson annulation of the hexopyranosidulose (33) with 3-trimethylsilyl-3-buten-2-one gave the tricyclic sugar derivative (34).20 In two papers Fraser-Reid and colleagues describe the preparation of di- [e.g. (36)12' and tri- [(e.g. 37])22 -pyranosides from the readily obtainable dianhydro-sugar (35). These compounds are precursors of the ansamycins such as rifamycin and strep- tovaricin A. PhTO phTo%0 Me '@OMe OMe 0 (33) (34) Halogeno- and Thio-sugars.-The interest in the preparation of fluorinated sugars continues. One recent efficient preparation involved treatment of anhydropen- topyranoside triflates [e.g. (38)] with tetrabutylammonium fluoride in acetonitrile to fluorodeoxy sugars [e.g.(39)] with inversion of configuration. 'H 19F and I3C n.m.r. studies of these compounds provided strong evidence for OH5conformation^.^^ Some other fluorinations that have been reported proceed via a galactal derivative. Thus 2,2-Difluorodaunosamine (40) was prepared24 by treating the galactal (41) with FOCF3 in C13CF in the presence of CaO. In a variation of the procedure "F-labelled 2-fluoro-2-deoxy-~-galactopyranosewas prepared25 by treatment of a galactal with acetyl hypofluorite. The first example of a naturally occurring 5-thiosugar 5-thio-~-mannose has been isolated26 from the marine sponge Clathria pyrurnida. The synthesis of 6-thio-N-*' R. V. Bonnert and P. R. Jenkins J. Chern.SOC.,Chern. Cornrnun. 1987 6. 21 B. Fraser-Reid L. Magdzinski B. F. Moho and D. R. Mootoo J. Org. Chern. 1987 52 4495. 22 B. Fraser-Reid B. F. Moho L. Magdzinski and D. R. Mootoo J. Org. Chern. 1987 52 4505. 23 F. Latif A. Malik and W. Voelter Liebigs Ann. Chern. 1987 617. 24 A. Dessinges F. Cabrera Escribano G. Lukacs A. Olesker and T. T. Thang J. Org. Chern. 1987,52,1633. 25 M. Tada T. Matsuzawa K. Yamaguchi Y. Abe H. Fukuda M. Itoh M. Sugiyama T. Ido and T. Takahashi Carbohydr. Res. 1987 161 314. 26 R. J. Capon and J. K. MacLeod J. Chern. SOC.,Chern. Cornrnun. 1987 1200. 297 Carbohydrates R' "'QOC H2Ph BzO Q 0 CFSCONH F (38) R' = OSO,CF, R2 = H (411 (39) R' = H,R2 = F acetyl-D-neuraminic acid has been achieved.27 Aldol condensation of mannothiazo- line (42) with potassium di-t-butyloxaloacetate gave the two 6-thiosialic acids (43).However the reaction between the thiofuranose (44) and Ni" oxaloacetate gave the 6-thio-N-acetyl-~-neurarninicacid (45). Substitution of oxygen by sulphur in the pyranose ring drastically changed the biological properties. The first synthesis of 2,5-anhydro-5-thio-~-allononitrile (46) has been accomplished.28 During this work a large-scale synthesis of 3,4,5,7-tetra-O-acetyl-2,6-anhydro-~-glycero-~-~a~o-heptanonitrile (47) and an improved synthesis of 2,5-anhydro-3,4,6-tri-O-benzoyl-~-gulononitrile (48) were developed. (7) Ho*co2H A HO' AcO "OAc AcNH OH (42) (43) HO HO' C O Z H G OH AcNH HOCH2 HO OH OBz Amino-sugars.-Many unusual amino-sugars are found in antibiotics and this has provided the stimulus for synthetic efforts.A simple method for the preparation of 2-amino-sugars involving the cycloaddition of azodicarboxylate to glycals has been 21 H. Mack and R. Brassmer Tetrahedron Lerr. 1987 28. 191 28 G. D. Kini C. R. Petrie W. J. Hennen N. K. Dalley B. E. Wilson and R. K. Robins Curbohydr. Res. 1987 159 81. 298 J. E Kennedy and D. L. Stevenson de~cribed.'~ Thus the glycal(49) gave in high yield the dihydrooxidiazine (50) which was in turn converted into the 2-aminoglycoside (51). There have been several new routes to the synthesis of 3-amino- and 3-amino-3-C-methyl sugars reported recently. The diastereoselectivity of epoxidation of the (2)-ally1 amides (52) depend3' both on the amide functionality and the reagent.The formation of the threo-epoxide (53) was highly favoured (95:5) with m-chloroperbenzoic acid as oxidant and when (52;R = NHPh) was used as the substrate. High threo selectivity (88 12) was also realized in the Mo(CO),-catalysed epoxidation of (52; R = CC13). However the stereochemistry of epoxidation of the (E)-allylic amide series was much less sensitive to the reagent and amide functionality. This method was applied to the synthesis of N-benzoylristosamine and to precursors of N-benzoyldaunos- amine and N-benzoyl-3-amino-2,3,6-trideoxy-xylo-hexose. M eOC H 2OC €4 'y 0 0i.(OC H2 P h MeOCH20CH2a Me ,C Ph Si0' NHN I Me3CPh2Si0 C02CH2Ph (49) (50) (51) (52; R = CCl, Ph OMe NHPh) (53) A new synthesis of 3-amino-3- C-methyl hexoses involved the stereoselective C-alkylation of the substrates (54) and (55) to give the 3-C-methylated products which were then reduced with sodium borohydride to give the equatorial alcohols.The resultant 3-amino-2,3,6-trideoxy-3-C-methyl-L-lyxo-hexopyranoses were con- verted into antibiotic A355 12B L-vancosamine and D-rubranitrose. The intermedi- ates were also precursors of L-decilonitrose and D-kijano~e.~' 2,3-Dideoxy-3- aminopentoses and 2,3-dideoxy-3- C-methyl-3-aminopentoses have been prepared32 from the azetidinone (56). A highly diastereoselective synthesis of L-N-acety-lacosamine (58) and L-N-benzoylristosamine (59) has been achieved33 by utilizing the conjugate addition of a carbamate group in the Z-a,P-unsaturated esters (57).4-Amino-sugar derivatives have been prepared34 by treating anhydropentopyrano- side triflates [e.g. (60)]with esters of p-aminobenzoic acid. The total syntheses of (+)-nojirimycin and (+)-1-deoxynojirimycin in which the amino is in the 5-position and therefore appears in the pyranose ring have been reported.35 An efficient 29 B. J. Fitzsimmons Y. Leblanc and J. Rokack J. Am. Chem. SOC.,1987 109 285. 30 W. R. Roush J. A. Straub and R. J. Brown J. Org. Chem. 1987 52 5127. 31 A. Klemer and H. Wilbers Liebigs Ann. Chem. 1987 815. 32 F. M. Hauser S. R. Ellenberger and R. P. Rhee J. Org. Chem. 1987 52 5041. 33 M. Hirama T. Shigemoto and S. Ito J. Org. Chem. 1987 52 3342.34 F. Farzana A. Malik and W. Voelter Liebigs Ann. Chem. 1987 717. 35 H. Lida N. Yamazaki and C. Kibayashi J. Org. Chem. 1987 52 3337. Carbohydrates ~2 OMe R'NH OMe R2 (54) R' = CO,CH,Ph; R' = H R' = CO,CMe,; R' = H ?R .:&OH OCONH2 NHAc (57) R = CONH,; SiEt (58) (59) synthesis of 6-amino-6-deoxy-sugars involved the reaction of galactopyranose triflate with the methyl esters of several amino-a~ids.~~ 4,8-Anhydro-N-acetylneuraminic acid (61) has been isolated3' from the edible bird's nest following mild acid hydrolysis which supports an earlier finding that in the glycoprotein at least a proportion of N-acetylneuraminic acid (NANA) is acetylated at HO-4. Attempts have been made3* to correlate the side-chain conforma- tion of NANA and its epimers at C-7 and C-8 with activation by NANA-CMP- synthetase.The synthesis of the side-chain epimers of 2-deoxy-2,3-dianhydro-NANA has been Both the conformation and stereochemistry of the side chains influenced the action of sialidase from Vibrio cholerae. Anhydro-sugars.-Since anhydro-sugars have considerable synthetic utility this sec- tion reports some preparations and properties of these compounds. An efficient synthesis of anhydroalditols has been reported4' involving the silylation of glycosides followed by reductive cleavage with triethylsilane in the presence of trimethylsilyltri- flate. The method was also an efficient means to prepare ally1 C-glycosides by simply replacing Et3SiH with Et,SiCH,CH=CH,. Mono- (62) and di-oxetanes (63) of coy HOCH2 36 A.Malik Z. Ahmed N. M. Kazmi and A. Q. Khan. 2. Naturjorsch. Teil B 1987 42 514. 37 V. Pozsgav H. Jennings and D. L. Kasper Eur. J. Biochem. 1987 162 445. 38 R. Christian G. Schulz H. H. Btandstetter and E. Zbiral Carbohydr. Rex 1987 162 1. 39 E. Zbiral H. H. Brandstetter R. Christian and R. Schauer Liebigs Ann. Chem. 1987 781. 40 J. A. Bennek and G. R. Gray J. Org. Chem. 1987 52 892. 300 J. F. Kennedy and D. L. Stevenson 2,5-anhydroalditols have been prepared4' from the appropriate 2,5-anhydroalditols by the selective mono- and ditosylation of the primary hydroxyl groups and sub- sequent treatment with base. Nucleophilic ring-opening of some of these oxetanes gave new derivatives of 2,5-anhydrohexitols with the L-ido and D-gluco configur-ation.Treatment of tosylated anhydrosugars with trimethylsilylazide in the presence of BF3Et20 gave the azidodeoxy-sugars without disp€acement of the toluene-p-~ulphonate.~~ The anionic ring-opening and polymerization of 1,6 :2,3-dianhydro-4-0-allyl-D-mannopyranose has been reported43 to give a polymer with intact ally1 groups. The polymerization of anhydro-sugars has been reviewed.44 Ethers Isotopic Labelling and Epimerization.-Some 3-0-alkyl-~-glucose and D-allose derivatives have been found to be cytotoxic agents against cultured leukemia L-5178Y cells.45 The butylation of pyranoses by phase-transfer and the preparation of 2- 0-allyl-D-glucose derivatives4' has been reported. Chiral deuteriation of 1,5-anhydropentofuranosederivatives at C-5 has been simply achieved48 by photobromination followed by metal deuteride reduction.Aldoses and ketoses have been labelled with carbon-13 at a number of sites by using '3C-pyruvate and the enzymes from the glycolytic pathway.49 The aldolase-catalysed reaction between a labelled aldopentose 5-phosphate and dihydroxyacetone has been used5' to prepare ''C-~~t~lo~e mono- and diphosphates. The epimerization of aldoses at C-2 by combinations of divalent metal ions and diamines have been examined in a number of st~dies.~'-~~ 3 Chiral Synthons This area of carbohydrate chemistry involves the synthesis of chiral non-carbohydrate structures from carbohydrate starting materials. Cyclitols are chiral polyhydroxy- cyclohexane derivatives which have many applications in organic synthesis.Three cyclitols [(64)-(Mi)] have been synthesized from D-glucurono-6,3-lactone by a synthetic strategy which involved an efficient conversion of the D-gluco configuration into the L-ido configuration and reductive cyclization of dials to cy~litols.~~ Cyclitols which are currently enjoying much interest are the so-called pseudo- sugars which resemble sugars but lack the ring oxygen. 41 P. Koell and M. Oelting Liebigs Ann. Chem. 1987 205. 42 G. Janairo W. Kowollik and W. Voelter Liebigs Ann. Chem. 1987 165. 43 A. A. Gorkovenko E. L. Berman and V. A. Ponomarenko Vysokomol. Soedin. Ser. B. 1987 29 134. 44 N. K. Kochetkov Terrahedron 1987 43 2389. 45 T. Ikekawa.K. Irinoda K. Saze T. Katori H. Matsuda M. Ohkawa and M. Kosik Chem. Pharm. Bull. 1987 35 2894. 46 R. Nouguier and C. Medani Tetrahedron Letr. 1987 28 319. 47 M. K. Gurjar and S. M. Pawar Carbohydr. Res. 1987 159 325. 48 H. Ohrui T. Misawa H. Hori Y. Nishida and H. Meguro Agric. Bid. Chem. 1987 51 81. 49 W. J. Goux US. Patent 4,656,133. so K. K. Arora J. K. MacLeod and J. F. Williams J. Labelled Comp. Radiopharm. 1987 24 205. " T. Tanase F. Shimizu M. Kuse S. Yano S. Yoshikawa and M. Hidai J. Chem. SOC. Chem. Commun. 1987 659. 52 R. E. London J. Chem. SOC. Chem. Commun. 1987 661. 53 B. Klaic Z. Raza M. Sankovic and V. Surjic Helu. Chim. Acra 1987 70 59. 54 Y. Watanabe M. Mitani and S. Ozaki Chem. Lett. 1987 123. Carbohydrates 301 PhCH2O OH PhCH20 OH PhCHzO ROQH RoQ OH Ro@H OCHzPh OCH2Ph OCHzPh (64) (65) (66) R = CH2Ph Several such pseudo-pyranoses [e.g.(70)] have been prepared5' by treatment of D-glucose diethylthioacetal with lithium dimethylmethyl phosphonate to produce (67). Conversion of (67) into (68) followed by Swern oxidation produced a ketone (69) which on stereospecific hydrogenation yielded (70). 0'BDPSi OX0 OCH2Ph PhC HzO' C H( 0H)C H2POJMe OCHzPh% OCHzPh P03Me2PhCH20' PhCH20 OH (67) (68) 7H2OR' CHZOH R200 0 "-OH HO OH OR2 (69) R' = SiMe,CMe, RZ= CH2Ph Other pseudo-monosaccharides which have been prepared include (71)56 and (72).57Some pseudo-disaccharides containing an ether linkage between a cyclitol and a sugar component have been synthe~ized.~' The condensation reaction of a cyclitol derivative carrying a free hydroxyl group with a sugar triflate occurred in the presence of sodium hydride.Both primary and secondary triflate groups were substituted to yield (1 + 6) and (1 + 4) linked pseudo-disaccharide analogues of isomaltose maltose and cellobiose. New water-soluble trans-butadienyl ethers [e.g. (73)] have been prepared from D-gl~cose.~~ Cycloaddition reactions with a variety of dienophiles in an aqueous medium showed both rate and stereoselectivity enhancements when compared to the reactions of similar peracetylated dienes in organic solvents. The sugar moiety may subsequently be removed enzymatically to give highly functionalized chiral cyclohexanes.( 1 S,2S)-2-(Hydroxymethyl)-2-methylcyclohexanolwas prepared this way. 55 H. Paulsen and W. von Deyn Liebigs Ann. Chem. 1987 125. 56 H. Paulsen and W. von Deyn Liebigs Ann. Chem. 1987 133. 57 K. Tadano H. Maeda M. Hoshino Y. Iimura and T. Suami J. Org. Chem. 1987 52 1946. 58 H. Paulsen and W. von Deyn Liebigs Ann. Chem. 1987 141. 59 A. Lubineau and Y. Queneau J. Org. Chem. 1987 52 1001. J. E Kennedy and D. L. Stevenson AcO OAc (71) R = CH,Ph (72) CH20H OH (73) (74) Enantiomerically pure L-and D-muscarine halides (74) have been prepared6' on the one hand from (R)-2,3-0-isopropylidineglyceraldehyde, and on the other from D-glucose. Diastereoselective Diels- Alder reactions have been carried out on carbohydrates.Addition of cyclopentadiene to the protected glucofuranose (75) gave the norbor- nenecarboxylate (76) and its (1'S,2'S)diastereoisomer in the ratio 93 :7.61 D-Mannitol has found particular application as a chiral synthon. Thus the chiral butenolide (77) which is readily available from D-mannitol has been used a 'replicating lactone template' affording structural sub-units such as (78) in natural Me3SiOCH2 I HO HOCHz 1 I 02CCH=CHI 0 +Me Me OH OH Ph 2( Me3C)SiO Ro+Co,H Me (77) (78) 60 J. Mulzer A. Angermann W. Muench G. Schlichthoerl and A. Hentzschel Liebigs Ann. Chem. 1987,7. 61 H. Kunz N. Muller and D. Schanzenbach Angew. Chem. 1987,99 269; (In?.Ed. Engl. 1987 26,267). Carbohydrates 303 product synthesis.62 cis-Caronaldehyde an intermediate in the production of the pyrethroid insecticides has been prepared63 by a route involving the periodate cleavage of 1,2:5,6-di-0-isopropylidene-~-mannitolto (R)-0-isopropylidenegly-ceraldehyde followed by a Horner-Emmons reaction with (EtO),P(O)CHMeCO,Et.Some new chiral macrocylic ethers [e.g. (79)] have been prepared64 via the condensa- tion of 2,3,4,5-tetra-O-benzyl-D-rnannitol with tetraethyleneglycol ditoluene-p- sulphonate in the presence of sodium hydride. The synthesis of diepoxides and diaziridines of D-mannitol as precursors of enantiomerically pure a-hydroxy and a-amino-aldehydes and acids has been reported.65 A short practical synthesis of the (2S,5S)-bis-hydroxymethyL(3R4R)-bis-hydroxypyrrolidine (80) from D-man- nitol has also been achieved.66 D-and L-Arabinose have also been used as the chiral starting points for some syntheses of y-la~tones,~~*~* whilst levoglucosan (81) formed the starting material for a synthesis of the diolide (82).69 Some building blocks for the total synthesis of the antibiotics amphotericin B and amphoteronolide B have been synthesized using (+)-and (-)-xylose as the starting material.70 Me 62 S.Hanessian and P. J. Murray J. Org. Chem. 1987 52 1170. 63 S. Takano A. Kurotaki M. Takahashi and K. Ogasawara J. Cbem. Soc. Perkin Trans. 1 1987 91. 64 M. Alonso-Lopez M. Martin-Lomas S. Penades C. Bosso and S. Ulrich J. Carbohydr. Chem. 1986 5 705. 65 Y. Le Merrer A. Dureault C. Greck D. Micas-Languir C.Gravier and J. C. Depezay Heterocycles 1987 25 541. 66 T. K. M. Shing J. Chem. SOC.,Chem. Commun. 1987 262. 67 A. B. Reitz A. D. Jordan jun. and B. E. Maryanoff J. Org. Chem. 1987 52 4800. 68 Y. Nishida M. Konno M. H. Hori H. Ohrui and H. Meguro Agric. Biof. Cbem. 1987 51 635. 69 T. Wakamatsu S. Yamada H. Nakamura and Y. Ban Heterocycles 1987 25 43. 70 K. C. Nicolaou R. A. Daines J. Uenishi W. S. Li D. P. Papahatjir and T. K. Chakraborty J. Am. Chem. Soc. 1987 109 2205. J. F. Kennedy and D. L. Stevenson Several amino-acid derivatives have been obtained in an enantiomerically pure form starting from carbohydrate precursors. Thus the 4,5,6-trihydroxylated nor-leucines [(83)-(85)] have been prepared” from vitamin C and isovitamin C deriva-tives.The Schiff bases from the protected D-galactodialdehyde (86) and the amino- OH NH2 OH NH2 HO &C02H acid methyl esters of valine leucine and isoleucine were diastereoselectively alky- lated uia their lithium derivatives. Hydrolysis gave the optically active a-alkylated methyl (S)-valinates leucinates and i~oleucinates.~~ Finally C-glycosides are useful chiral synthons a point which is illustrated in the total synthesis of the antibiotic pseudomonic acid (87).73 ” J. A. J. M. Vekemans R. G. M. de Bruyn R. C. H. M. Caris A. J. P. M. Kokx J. J. H. G. Konings E. F. Godefroi. and G. J. F. Chittenden J. Om. Chem. 1987 52 1093. ’’ U. Schoellkopf R. Toelle E. Egert and M. Nieger Liebigs Ann. Chem. 1987 399. 73 J. C. Barrish H.L. Lee E. G. Baggiolini and M. R. Uskokovic J. Org. Chem. 1987 52 1372.