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As other monosaccharide mimics such as the azasugars and the carbasugars (with nitrogen and carbon atom, respectively, instead of oxygen atom in the ring) the thiosugars (with sulfur atom instead of oxygen atom in the ring) have gained importance in glycobiology and as potential drugs. Biological properties of monothiosaccharides are presented and the methods for their synthesis are reviewed and analyzed. Since the report of the synthesis of 5-thio-alpha-D-xylopyranose, the first example of thiosugars ever described, forty years of imaginative chemistry have produced a large number of monothiosaccharides and of analogs of biological interest. The preparative chemists have at their disposal a panoply of methodologies relying on pure chemical or on biochemical means, using carbohydrate or non-carbo hydrate precursors. Because the sulfur moieties can participate more readily than the corresponding oxygen moieties in heterolytical processes, the chemistry of the thiosugars and their analogs is more subtile and sometimes more delicate than that of the corresponding aldoses and alditols.

High yielding resolution of racemic 7-oxabicyclo[2.2.1]hept-5-en-2-one (+/-)-1 ('7-oxanorbornenone') via aminal formation with (R,R)-1,2-diphenylethylenediamine 2 is reported. Ac idle hydrolysis furnishes the enantiomeric ketones (+)-1 and (-)-1 (greater than or equal to 95% ee). The chiral diamine is efficiently recovered. (C) 1999 Elsevier Science Ltd. All rights reserved.

Photoinduced electron transfer from Et(3)N to 7-oxabicyclo[2.2.1]heptan-2-ones can generate the corresponding 3-hydroxycyclohexanone derivatives. The method has been applied to the synthesis of C-alpha-D-galactopyranosides of carbapentopyranoses. Radical alpha-D-galactosidation of (+/-)-(1RS,4RS,5RS, 6RS)-6-endo-methoxy-3-methylidene-5-exo-(phenylseleno)-7-oxabicyclo[2.2. l]hept-2-one ((+)-51) followed by seleno-Pummerer rearrangement and reduction with Bu(3)SnH gave (+)- (1R,2S,3S,4R,6R)-((+)-58) and (+)-(1S,2R,3R,4S,6S)-3-endo-methoxy-5-oxo-6-endo-[(2',3',4',6'-tetra-0-a cetyl-alpha-D-galactopyranosyl)methyl]-7-oxabicyclo[2.2.1]hept-2-endo-yl acetate ((+)-59), which were separated by column chromatography. Irradiation (254 nn) in the presence of Et(3)N gave (+)-(1S,2R,3R,6R)-((+)-60) and (+)-(1R,2S,3S,6S)-2-hydroxy-6-methoxy-4-oxo-3-[(2',3',4',6'-tetra-0-acet yl-alpha-D-galactopyranosyl)methyl]cyclohexyl acetate (+)-61, respectively. NaBH4 reduction and acetylation provided (+)-(1S,2S,3R,4R,5R)-((+)-62) and (+)-(1R,2R,3S,4S,5S)-5-methoxy-2-[(2',3',4',6'-tetra-0-acetyl-alpha-D-ga lactopyranosyl)methyl]cyclohexa-1,3,4-triyl triacetate ((+)-64).

New 3-oxy substituted and 3,6-dioxydisubstituted 7-oxabicyclo[2.2.1]heptan-2-ones have been prepared. The regioselectivity of their Baeyer-Villiger oxidation has been determined and compared with that of other 7-oxabicyclo[2.2.1[heptan-2-one derivatives. If the substituent at C(3-exo) is an O-acyl or another group less electron-releasing, the bridgehead C(1) migration is favoured, leading to 2,8-dioxa-bicyclo[3.2.1]octan-3-ones. When the substituent at C(3) is a MeO or (tBu)Me2SiO group, the Baeyer-Villiger oxidation leads to 3,8-dioxabicyclo[3.2.1]octan-2-ones due to preferred C(3) migration. The latter regioselectivity is higher for 3-endo-MeO than for 3-exo-MeO substituted ketones and it can be enhanced by remote oxy substituents at the C(6-endo) position.

The introduction of two hydroxy groups with differential protection at the endo positions of C(5) and C(6) of the ''naked sugars of the first generation'' has been achieved by seleno-Pummerer rearrangement of 5-endo-hydroxy-6-exa-phenylseleno-7-oxabicyclo[2.2.1]heptan-2-one derivatives followed by deselenation with Bu(3)SnH.

Using readily available chiral auxiliaries such as (+)- and (?)-camphanic acid, (R,R)- and (S,S)-tartaric acid derivatives (e.g. RADO(R)-COCl, SADO(R)-COCl) efficient diastereoselective syntheses of rare sugars and glycomimetics have been developed. They engage the 'naked sugar' (enantiomerically pure 7-oxanorbornene) methodologies in which the chiral auxiliaries are recovered at an early stage of the multistep syntheses. A new reaction cascade starting with the hetero-Diels-Alder addition of sulfur dioxide to 1-(1-phenylethoxy)-1,3-dienes derived from inexpensive (+)- and (?)-1-phenylethanol allows the one-pot, four-component synthesis of polyfunctional sulfones, sulfonamides and sulfonic esters containing up to three stereogenic centers. The method ensures a high molecular and stereochemical diversity. The reaction cascade can also produce polyketide and polypropionate fragments in one-pot operations. The latter contain up to three contiguous stereogenic centers and do not have to be modified (deprotection, activation) before using them as nucleophilic partners in diastereoselective cross-aldol reactions, thus permitting the quick access to complicated polypropionate antibiotics such as Baconipyrones, Ryfamicyn S and Apoptolidines.

(+/-)-Cyclophellitol has been prepared in a highly stereoselective fashion from the Diels-Alder adduct of furan to 1-cyanovinyl acetate.

The lithium enolate 16 derived in 5 steps from the Diels-Alder adduct of furan to 1-cyanovinyl (1S)-camphanate [(+)-12: a "naked sugar" of the first generation] was reacted with (+)(1R,4S,5S,6S)-6-endo-chroro-3-methylidene-5-exo-phenylseleno-7-oxabic yclo[2.2.1]. heptan-2-one [(+)-8] to give a unique product of Michael addition after acidic quenching. This adduct (-)-18 was transformed into branched long-chain carbohydrate derivatives such as benzyl 5-deoxy-5-[(5"-O-acetyl-3"-deoxy-2"-O-methoxymethyl-D-manno-furanurono-6 , 1-lactone-3''-yl)methyl]- (tert-butyl)dimethylsilyl-2,3-di-O-methoxymethyl-alpha and beta-L-gulo-furanosideuronate [(-)-27]. Hydrogenolysis, followed by a Curtius rearrangement permitted to construct the corresponding branched 5-amino-5,6-dideoxydodecose derivative (-)-30 which was converted into 5-O-acetyl-3- [ 5'-N-(benzyloxy)carbonyl-2',3'-di-O-methoxymethyl-alpha and beta-D-manno-furanose]-2-O-methoxymethyl-D-manno-furanurono-6, 1-lactone [(-)-31] and then into methyl 3-deoxy-3-(1',2',6'-trideoxy-2',6'-imino-D-galactitol-1'-yl)-alpha-D-man no-pyranoside [(-)-1]. Its H-1 NMR spectrum measured at variable temperature demonstrated that (-)-1 exist as a double equilibrium involving two pairs of rotamers about the sigma C(1')-C(2') and sigma C(1')-C(3) bond [CH2 bridge linking beta-C(I) of the I,5-dideoxy-1,5-imino-D-lyxitol unit at C(3) of methyl alpha-D-manno-pyranoside]. Rotamers B' in which C(3) is gauche with respect to C(3') is preferred to conformers C' in which C(3) is anti with respect to C(3'). An equilibrium constant K (B' = C') congruent to 0.35 (25 degrees C) was evaluated. Rotamers B [C(2) gauche with respect to C(2')] and C [C(2) anti with respect to C(2')] are equally populated. Disaccharide mimetic (-)-1 is a moderate inhibitor of alpha-L-fucosidases from bovine liver (K-i = 100 mu M) and human placenta.

The optically pure Diels-Alder adduct of furan to 1-cyanovinyl (1R)-camphanate was converted to methyl(methyl 5-bromo-5-deoxy-2,3-O-isopropylidene-beta-L-allo-hexo-furanosid)uronate. Ester reduction, followed by HBr elimination afforded (+)-methyl 5,6-anhydro-2,3-O-isopropylidene-D-beta-talo-hexofuranoside. Applying the method of Adley and Owen, (+)-methyl 5,6-dideoxy-5,6-epithio-2,3-O-isopropylidene-L-beta-allo-hexofuranoside was obtained and acetolysed to give, after deprotection, (-)-5-deoxy-5-thio-L-allose.

The efficient resolution of racemic N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (+/-)-2 via aminal formation with (R,R)-1,2-diphenylethylenediamine 4 is reported. Acidic hydrolysis furnishes the enantiomeric ketones (+)-2 and (-)-2 that were transformed into 7-azabicyclo[2.2.1]heptan-2-one (-)-3 and (+)-3. The process constitutes a formal synthesis of (+)- and (-)-epibatidine. (C) 2003 Elsevier Ltd. All rights reserved.

Addition of radicals to silyl ketene acetal followed by cyclization of the radical adducts were used to introduce C-moieties in the 6-endo position of 7-oxabicyclo[2.2.1]hept-5-en-2-one.

Starting from (+/-)-7-oxanorbornenone ((+/-)-14), (+/-)-(1RS, 2RS, 3SR, 6SR)-6-azidocyclohex-4-en-1,2,3-triol ((+/-)-24) and (+/-)- 1RS, 2RS, 3SR, 6RS)-6-azidocyclohex-4-en-1,2,3-triol ((+/-)-26) were obtained. Epoxidation of the latter cyclohexene derivative gave two epoxides (+/-)-30 and (+/-)-31 that were converted into (+/-)-conduramine F-1 epoxides (+/-)-10 and (epoxides (+/-)-30 and (+/-)-31 that were converted into (+/-)-conduramine F-1 epoxides (+/-)-10 and (+/-)-11 and N-substituted derivatives (+/-)-12 and (+/-)-13. Compound (+/-)-(1RS, 2SR, 3RS, 4SR, 5RS, 6SR)-5-({[4-(trifluoromethyl) phenyl] methyl} amino)-7-oxabicyclo[4.1.0]heptane-2,3,4- triol ((+/-)-12c) is a good, non-competitive inhibitor of beta-xylosidase from Aspergillus niger (K-i=2.2 mu M), and (+/-)( 1RS, 2RS, 3SR, 4RS, 5SR, 6SR)-5-{[(biphenyl-4-yl) methyl] amino}-7-oxabicyclo[4.1.0] heptane-2,3,4-triol ((+/-)-13d) is a good inhibitor of alpha-glucosidase from brewer's yeast (Ki 2.8 mu M, non-competitive). (c) 2007 Elsevier Ltd. All rights reserved.

Epoxidation of (1RS,2SR,3SR,4RS,6RS,7RS,8RS, 12RS, 13RS)-6,13-bis(benzyloxy)-15,16-dioxapentacyclo[10. 2.1.1(4.7).0(2,11).0(3.8)]hexadec-10-en-8-yl-methanol (12) led to the stereoselective formation of (1RS,2RS,3RS,5RS,6SR, 7RS,8RS, 10RS,11SR, 12SR,16SR)-3,10-bis(benzyloxy)-13,17,18-trioxahexacyclo[10.2.2. 1(2,5).1(8,11).0(1,6).0(7,12)]octadecan-16-ol (13). Epoxidation of the acetate (19) derived from 12 gave an epoxide (20) that generated (1RS,2SR,3RS,4RS, 6RS,7SR,8RS,9SR,11RS,12RS,13RS)-13-benzyloxy-9-hydroxy-15,16,17-trioxahe xacyclo[10.2.1.1(4,7). 1(6,8).0(2,11).0(3,8)]heptadecane-11-methyl acetate (21) under acidic conditions. These reactions imply the formation of 2-alkyl-6-endobenzyloxy-7-oxabicyclo [2.2.1]hept-2-yl cation intermediates (e.g. 14) that are quenched intramolecularly by the hydroxymethyl group to give the corresponding 2-oxabicyclo[2.2.2]octane systems (12-->13). In the case of the acetoxymethyl containing intermediate, the latter cyclization is retarted and a facile 1,3-migration of the endo-benzyloxy group occurs leading to the corresponding 4,7-dioxatricyclo[3.2.1.0(3,6)]octane derivative (20-->21).

(-)-7-Oxabicyclo[2.2.1]hept-5-en-2-one has been converted to (-)-6-exo-[(tert-butyl)dimethylsilyloxy]-7-endo-benzyloxy-8-oxabicyclo[3 .2.1]oct-3-en-2-one and methyl 3,5-di-O-acetyl-2,6-anhydro-4-O-benzoyl-D- glycero-D-galacto-heptouronate that were condensed with Me2AlSPh into a single aldol which was transformed into a beta-D-ManAp-CH(OAc)(1-->3)-alpha-L-GulAp-CH(SEt)(2) derivative. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.

Zaragozic acids (or squalestatins) are very potent inhibitors of squalene synthase. They or simpler analogs have potential as drugs for lowering the endogenous level of cholesterol in human serum. These compounds are Ras farnesyltransferase inhibitors and might become antitumor drugs. They are also antifungal agents. This account presents synthetic studies subsequent to those reviewed by Nadin and Nicolaou [1]. A wealth of new chemistry has been developed for the generation of highly oxygenated 2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic triacids and analogs, so demonstrating the fascination of synthetic chemists for zaragozic acids.

Protonation of norbom-5-en-2-one gives 6-oxo-2-norbomyl cation (2) as most stable C7H9O+ cation. Quantum calculations at B3LYP/6-31G(d) level (gas phase, 1 atm, 25 degrees C) predict a C-s-structure for 2 that can be represented as an intramolecular pi-complex (Dewar pi-complex model) of an acetylium ion with an alkene (cyclopent-3-enyl moiety). Isomeric 5-oxo-2-norbornyl (1) cation is calculated to be 16.7 kcal/mol less stable than 2. Part of the relatively high stability of 2 arises from the electron-releasing carbonyl group through n(C=O) sigma 2p(C+) hyperconjugation. This effect is also present in more stable 6-oxo-3-oxa (14) and 6-oxo-3-aza-2-norbornyl cation (19) as these ions are calculated to be 7.4 and 3.3 kcal/ mol, respectively, more stable than their 5-oxo isomers. (c) 2007 Elsevier B.V. All rights reserved.

Nowadays any natural and non-natural monosaccharide can be prepared pure in both enantiomeric forms starting from inexpensive starting materials. Depending on the target, pure chemical procedures relying upon asymmetric catalysis using either metallic or pure organic catalysts can be applied successfully, alone or in combination with chemoenzymatic methods.

Protected forms of exo-5-amino-exo-6-hydroxy-7-oxabicyclo [2.2.1]heptan-2-one and of exo-5-amino-endo-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-one can be obtained readily and with high stereoselectivity from exo-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl acetate (+/-)-(7). The processes involve acid promoted rearrangements of N-carbonyl aziridines 10 [(1RS,2SR,4RS,5RS, 6SR)-6-cyano-8-oxa-3-azatricyclo[3.2.10(2,4)]oct-6-yl acetate derivatives] derived from (+/-)-7.

Intercellular communication is governed by interactions between surface oligosaccharides and glycoproteins. The biosynthesis of these molecules involves glycosidations catalyzed by glycosyltransferases and hydrolysis of O-glycosyl linkages catalyzed by glycosidases. Monosaccharide and disaccharide mimics such as carbasugars, iminosugars and C-linked disaccharides can be glycosidase or glycosyltransferase inhibitors. They are leads as new drugs to treat infective diseases and cancer. The preparation of a conduramine, a pentahydroxyindolizidine, and two C-linked disaccharides are outlined.

The electron-releasing ability of certain carbonyls is exploited in the chemistry of the ''naked sugars'' which allows the stereoselective synthesis of rare sugars, C-nucleosides, C-glycosides and a variety of disaccharide mimetics.