Indolizidine-type glycosidase inhibitor

Addition of pyruvate to Cbz-protected D-mannosamine 194 under NeuA catalysis has furnished an JV-acyl derivative of neuraminic acid 5 from which internal reductive amination yielded an azasugar which could be further elaborated to 195, an analog of the bicyclic, indolizidine type glycosidase inhibitor castanospermine [91]. 

Starting from the AT-Cbz-protected aldolase product 6, aza sugar 7 has been obtained stereoselectively by internal reductive amination as an analog of the bicyclic, indolizidine-type glycosidase inhibitor castanospermine [66]. Also, it had been recognized that the C12-C20 sequence of the macrolide antibiotic amphotericin B resembles the P-pyranose tautomer of 3 [76]. Thus, the branched-chain manno-configurated substrate 10 [77] was successfully chain-extended under NeuA catalysis to )deld the potential amphotericin B synthon 11 (Fig. 8) in good yield. 

Guanidinium and isothiourea derivatives such as 46 and 47 were also reported that exhibited potent and selective (3-glycosidase inhibitory activity, in contradiction with the previous castanospermine analogues depicted above. Noteworthy, sulfamide-type indolizidines such as 48, in which the thiourea moiety has been replaced by a sulfamide group, were also described and found to be modest a-mannosidase inhibitors... 

All these advances allowed the preparation of a collection of polyhydroxy-lated piperidine, pyrrolidine, pyrrolizidines, indolizidine, and quinolizidine type iminocyclitols (e.g.. Scheme 16.9) which were widely investigated against a panel of commercial glycosidases as well as inhibitors of intestinal rat disaccharidases [16, 19, 21]. 

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