A New Synthetic Approach to the Carbocyclic Core of Cyclopentane-Type Glycosidase Inhibitors: Asymmetric Synthesis of Aminocyclopentitols via Free Radical Cycloisomerization of Enantiomerically Pure Alkyne- Tethered Oxime Ethers Derived from Carbohydrates

Abstract

The synthesis of compounds 6-8, derived from 2,3:5,6-bis-O-isopropylidene-d-mannofuranose (3), and the preparation of products 16 and 17, obtained from 2,3-O-isopropylidene-d-ribose (13) is reported. The first free radical cyclization of enantiomerically pure alkyne-tethered oxime ethers derived from carbohydrates (6, 8, 16, and 17) is described. These radical precursors have been submitted to cyclization with tributyl or triphenyltin hydride plus triethylborane to yield, after ring closure, the aminocyclopentitols 9−12 and 18−20, respectively. These carbocycles have been obtained as mixtures of Z and E vinyltin isomers, but with excellent diastereoselection at the new stereocenter formed during the ring closure. After protodestannylation, only one diastereoisomer was detected and isolated. The absolute configuration at the new stereocenter formed during the carbocyclization has been established by detailed 1H NMR analysis. The specific transformation of compound 19 (or 20) into aminocyclitol 24 is described. Compound 24 is an analogue of the aminocyclopentitol moiety of trehazolin (1a), a known and powerful glycosidase inhibitor of trehalase. From these results, we can conclude that a new method for the asymmetric synthesis of aminocyclitols of biological interest is now available.