Yasushi Shibata

Synthesis and biological activities of methyl oligobiosaminide and some deoxy isomers thereof

Methyl oligobiosaminide (1) the core structure of oligostatin C, and five analogues, the 6-hydroxy-(2), 2-deoxy- (3), 2-deoxy-6-hydroxy- (4), 3-deoxy- (5), and 3-deoxy-6-hydroxy derivatives (6), were synthesized by coupling the protected pseudo-sugar epoxide 46 with suitable methyl 4-amino-4-deoxy-alpha-D-hexopyranoside derivatives. Compounds 3 and 6 showed notable inhibitory activity against alpha-D-glucosidase and alpha-D-mannosidase, respectively, whereas compound 1 had almost no activity.

Chemical modification of the sugar part of methyl acarviosin: synthesis and inhibitory activities of nine analogues

Nine analogues of methyl acarviosin (1), the core structure of acarbose and its homologues, the 6-hydroxy-(2), 6-azido-(3), 6-amino- (4), 6-acetamido-(5), 6-methoxy-(6), 6-hydroxy-2-O-methyl-(8), and 6-hydroxy-3-O-methyl derivatives (9), including the 5-methoxycarbonyl analogue (7) and 3,6-anhydro derivative (10) of 2, were synthesized by chemical modification of the sugar part of 2 derived by condensation of methyl 3,4-anhydro-alpha-D-galactopyranoside (17) and 4,7:5,6-di-O-isopropylidenevalienamine (26) or by direct coupling between 26 and the 6-substituted methyl 3,4-anhydro-alpha-D-galactopyranoside derivatives. Compounds 2 and 8 show notable inhibitory activity against yeast alpha-D-glucosidase almost comparable to that of 1. Introduction of a polar substituent at C-6 of 1 decreases the inhibitory activity. Interestingly, inversion of the conformation of the sugar part of 1 by introduction of the 3,6-anhydro bridge elicits almost no effect on the inhibitory activity.

Synthesis of pseudo-trehaloses: [(1,2,43,5)-2,3,4-trihydroxy-5-hydroxymethyl-1-cyclohexyl] d-glucopyranosides

Abstract All the theoretically possible, foru diastereoisomeric pairs, α,α (2A and 2B), α,β (3A and 3B), β,α (4A and 4B), and β,β (5A and 5B), of pseudo-trehalose, composed of d -glucopyranose and pseudo- d - or l -glucopyranose, have been synthesised by coupling of the appropriately protected pseudo-α- (6) and -β- dl -glucopyranoses (9) with d -glucopyranose derivatives (10 and 11) in the presence of trimethylsilyl trifluoromethanesulfonate. Elucidation of the structures and absolute configurations of the pseudo-disaccharides was based on the 1H-n.m.r. spectra of their octa-acetates and the optical rotations. None of the pseudo-trehaloses inhibited trehalase.

Synthesis of dl-penta-N,O-acetylvaliolamine and related branched-chain aminocyclitols

Abstract Valiolamine ( 1 ), a branched-chain aminocyclitol α- d -glucosidase inhibitor, has been synthesised as the racemic penta- N,O -acetyl derivative ( 10 ) from dl -(1,3/2,4)-1,2,3-triacetoxy-4-bromo-6-methylenecyclohexane ( 2 ). Epoxidation of 2 with m -chloroperbenzoic acid, followed by hydrolysis and acetylation, gave exclusively dl -(1,2,4/3,5)-2,3,4-triacetoxy-1- C -acetoxymethyl-5-bromocyclohexanol ( 4 ), from which 10 was obtained by azidolysis in N,N -dimethylformamide, and successive catalytic hydrogenation and acetylation. In contrast, azidolysis in aqueous 2-methoxyethanol gave dl -(1,2,4/3,5)-2,3,4-triacetoxy-1- C -acetoxymethyl-5-azidocyclohexanol, which was converted into the 5-epimer of 10 . Hydroxylation of 2 with osmium tetraoxide and hydrogen peroxide, followed by acetylation, gave the 1-epimer ( 6 ) of 4 . The 1,5-diepimer of 10 was prepared from 6 by the same sequence.

Synthesis of biologically active pseudo-trehalosamine: [(1S)-(1,2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethyl-1-cyclohexyl] 2-amino-2-deoxy-α-d-glucopyranoside

Le compose aglycone tetra-O-benzyl-2,3,4,7 pseudo-α-D.L glucopyranose est obtenu a partir du di-O-isopropylidene-2,3:4,7 pseudo α-D-L glucopyranose. Il reagit ensuite avec le bromure de [dinitro-2,4 anilino]-2 glucopyranosyle protege pour donner la pseudo-trehalosamine du titre

Synthesis of a carba-sugar analog of trehalosamine, [(1S)-(1,2,43,5)-2-amino-3,4-dihydroxy-5-hydroxymethyl-1-cyclohexyl] α-d-glucopyranoside, and a revised synthesis of its β anomer

The synthesis of α-D-glucosides was performed by condensation of the newly prepared 3,4,7-tri-O-benzyl-2-deoxy-2-p-toluenesulfonamido-5a-carba-α-DL-glucopyranose with 1,6-di-O-acetyl-2,3,4-tri-O-benzyl-β-D-glucopyranose 2 in the presence of trimethylsilyl trifluoromethanesulfonate

Synthesis of some derivatives of pseudo-α-galactopyranose [(1,2/3,4,5)-5-hydroxymethyl-1,2,3,4-cyclohexanetetrol]

Abstract Isopropylidenation of dl -(1,2/3,4,5)-5-hydroxymethyl-1,2,3,4-cyclohexanetetrol ( 1 ) with 2,2-dimethoxypropane in N,N -dimethylformamide in the presence of toluene- p -sulfonic acid gave the 1,2:3,4-, 1,2:4,7-, and 2,3:4,7-di- O -isopropylidene derivatives. Several C-7 substituted derivatives of 1 of biological interest have been prepared by nucleophilic displacement reactions of the tosylate derived from the most readily available 1,2:3,4-di- O -isopropylidene derivative 3 . Condensation of 3 with 2,3,4,6-tetra- O -acetyl-α- d -glucopyranosyl bromide gave diastereoisomeric products, which were converted into 7- O -(β- d -glucopyranosyl)-pseudo-α- d - ( 26a ) and - d -galactopyranose ( 26B ), the structures of which were confirmed by degradation of the octa-acetate of 26A , yielding the known pseudo-α- d -galactopyranose penta-acetate.

Synthesis of potent α-glucosidase inhibitors: methyl acarviosin analogue composed of 1,6-anhydro-β-D-glucopyranose residue

Compound 3a has been shown to possess stronger inhibitory activity against α-glucosidase than methyl acarviosin 1.

Total synthesis of acarbose and adiposin-2

The first complete synthesis of acarbose (1a), the pseudotetrasaccharidic α-amylase inhibitor, is reported: coupling of the protected (+)-valienamine (16) and the epoxide (9) derived from 1″,6″-anhydromaltotriose (3), followed by deprotection; likewise, adiposin-2 (2a), the 6′-hydroxy analogue of (1a), has also been synthesised.