Synthesis of 2,3-dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses and their use in the preparation of conformationally locked bicyclic nucleosides.

Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons-Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2',3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-2',3'-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an (o)E/(o)T1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.

C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB-L-isoDMDP compared to miglitol and miglustat.

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 µM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.

Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone.

The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by-side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase.

6-De-oxy-6-fluoro-d-galactose.

The crystal structure unequivocally confirms the relative stereochemistry of the title compound, C(6)H(11)FO(5). The absolute stereochemistry was determined by the use of d-galactose as the starting material. The compound exists as a three-dimensional O-H⋯O hydrogen-bonded network with each mol-ecule acting as a donor and acceptor for four hydrogen bonds.

1-De-oxy-1-fluoro-l-galactitol.

The crystal structure unequivocally confirms the relative stereochemistry of the title compound, C(6)H(13)FO(5) [6-de-oxy-6-fluoro-d-galactitol or (2S,3R,4R,5S)-6-fluoro-hexane-1,2,3,4,5-penta-ol]. The absolute stereochemistry was determined from the use of d-galactose as the starting material. In the crystal, the molecules are linked by O-H⋯O and O-H⋯F hydrogen bonds, forming a three-dimensional network with each mol-ecule acting as a donor and acceptor for five hydrogen bonds.

Enantioselective synthesis of tetrafluorinated ribose and fructose.

A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in the pyranose form, is described.

(1S)-1,2-O-Benzyl-idene-α-d-glucurono-6,3-lactone.

X-ray crystallographic analysis has established that the major product from the protection of d-glucoronolactone with benzaldehyde is (1S)-1,2-O-benzyl-idene-α-d-glucurono-6,3-lactone, C(13)H(12)O(6), rather than the R epimer. The crystal structure exists as O-H⋯O hydrogen-bonded chains of mol-ecules lying parallel to the a axis. The absolute configuration was determined by the use of d-glucuronolactone as the starting material.

Stereoselective cyclopropanation in the synthesis of 3'-deoxy-3'-C-hydroxymethyl-2',3'-methylene-uridine.

The synthesis of the novel 2',3'-cyclopropane nucleoside 3'-deoxy-3'-C-hydroxymethyl-2',3'-methylene-uridine is described. Stereoselective construction of the cyclopropane ring was achieved via Simmons-Smith cyclopropanation of a benzyl protected silyl enol ether, which was itself derived from 1,2-O-isopropylidene-α-D-xylofuranose.

Inhibition of nonmammalian glycosidases by azetidine iminosugars derived from stable 3,5-di-O-triflates of pentoses.

Efficient ring closure of stable crystalline 3,5-di-O-triflates of pentofuranosides with amines to form azetidines allowed preliminary evaluation of four-ring iminosugars as glycosidase inhibitors; significant and specific inhibition of nonmammalian α-glucosidases is shown by L-xylo- and L-arabino-iminosugar azetidines.