Enantiospecific Synthesis of 1-Azafagomine

Abstract

For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.

A Free-Energy Relationship between the Rate of Acidic Hydrolysis of Glycosides and the pKa of Isofagomines

“…We recently observed [3] that the basicity of galactoazafagomine (2) is slightly higher than that of the gluco isomer 1 [4] (Scheme 1). While this difference in basicity might appear insignificant, the only structural difference between the two hydrazines is whether the 4-hydroxyl group is equatorial or axial, and no difference in base strength was anticipated.…”

Self-disproportionation of enantiomers (SDE) of chiral sulfur-containing compounds via achiral chromatography

“…6 With (aminopropyl)silica gel as the stationary phase the same chromatographic behaviour was observed for 1,1'-binaphthol, 1-anthryl-2,2,2-trifluoroethanol, N-benzoylalanine methyl ester, a benzodiazepine, and chloromezanone. 7 It should be noted that this phenomenon is observed with HPLC, 2,4-11 medium-pressure liquid chromatography (MPLC), 12 and flash 13 and regular [14][15][16] chromatography. Before 2006 different definitions of this phenomenon were proposed in the literature: among them were "self-amplification of optical activity", 2 "enantiomer differentiation",…”

“…"separation of excess enantiomer", 6,8 "enantiomeric enrichment", [8][9][10][11][12][13][15][16] and "optical purification".…”

Synthesis and evaluation of α-, β-glucosidase inhibition of 1-N-carboxamide-1-azafagomines and 5-epi-1-azafagomines

“…2 It was a surprising finding that the a-glucosidase inhibitory activity of the laevo-and the dextrorotatory enantiomers of 1-azafagomine N-phenyl carboxamide (1) were of the same order of magnitude; 4 In contrast Bols found the opposite trend with the two enantiomers of 1-azafagomine. 5 In this paper two new 1-N-carboxamide-1-azafagomines, and two 1-N-carboxamide-5-epi-1-azafagomines bearing different carboxamide moieties were synthetized, and its activity measured against a-and b-glucosidase. These compounds belong to N-sp 2 -iminosugars classes known to be conformationally locked compounds displaying excellent selectivities.…”