A-Glycosidase inhibitors

Three classes of oral therapeutic agent are available for treating patients with diabetes mellitiis (NIDDM) the arylsulfonylureas (known simply as sulfonylureas), biguanides, and a-glycosidase inhibitors. Since 1977, only the sulfonylureas have been approved for use in the United States, although the other classes are used elsewhere. 

A. Varrot, M. Schiilein, M. Pipelier, A. Vasella, and G. J. Davies, Lateral protonation of a glycosidase inhibitor. Structure of the Bacillus agaradhaerens Cel5A in complex with cellobiose-derived imidazole at 0.97 A resolution,./. Am. Chem. Soc., 121 (1999) 2621—2622. 

Results of a similar study on the enantiospecific synthesis of a glycosidase inhibitor, using chiral (3-benzyloxy acrylamide, show that even electron-rich alkenes can serve as dipolarophiles. A large influence of the polarity of the solvent is observed the greater the polarity the greater is the diastereoselectivity. Thus, DMF and acetonitrile are found to be the best solvents. On the basis of these observations, the desired enantiomerically pure glycosidase inhibitor, (3R. 4R)-4-(hydroxymethyljpyrrolidin-3-ol, could be prepared in two steps in 87% overall yield.436... 

Three a-glycosidase inhibitors of 2,5,6-trideoxystreptamine (compounds 427-429) have been prepared by glycosylation of the quinic acid derived ditosyloxycyclo-hexanol derivative 430, with the corresponding glycal derivatives (e.g., 431 and 432)... 

Acarviosin 441, an a-glycosidase inhibitor, is a maltose-type pseudodisaccharide that can be prepared from methanolysis of acarbose 442 [255]. It has been shown to have five times more inhibitory activity than its precursor acarbose, for which the first total synthesis has been described by Ogawa s group in 1989 [256]. 

The oxazoline AT-oxides have been converted into cyano alcohols or hydroxy esters which were known precursors to carbanucleosides such as carbovir, aris-teromycin, and valienamine which is a glycosidase inhibitor. 

Polyhydroxylated piperidines from natural sources, which have structures and shapes resembling monosaccharides have been found as a -glycosidase inhibitors. They competitively inhibit glycosidases whose substrates they most closely resemble. 1-Deoxynojirimycin (moranoline) (98 1), was isolated from Mori Cortex (root bark of the mulberry tree, Morus bombycis (Moraceae)), leaves of Jacobinia suberecta (Acanthaceae)... 

The activation of nitrones using (la) enables their reactions with carbon nucleophiles such as silyl enolates, allylsilanes, and allylstannanes [143]. Lombardo and Trombini successfully utilized the (la)-catalyzed reaction of homochiral nitrone (90) with 2-trimethylsiloxyfuran for an efficient asymmetric synthesis of a protected 1,2,7,8-indolizidinetetrol, whose deprotected form is attractive as a glycosidase inhibitor [144] (Scheme 9.59). They have recently found that an allylzinc reagent smoothly adds to nitrones in the presence of (la) [145]. 

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