A ring-closing metathesis based synthesis of bicyclic nucleosides locked in S-type conformations by hydroxyl functionalised 3′,4′- trans linkages

Abstract

A [4.3.0]bicyclic nucleoside that contains an unsaturated hydroxylated 3′,4′- trans linkage has been efficiently synthesised. Thus, from diacetone- d-glucose as the starting material, stereoselective Grignard reactions for the introduction of allyl groups, a nucleobase coupling and, subsequently, a ring-closing metathesis (RCM)-reaction were applied as the key reactions. The cyclohexene moiety introduced in this nucleoside reveals a large potential for further derivatisation, and as the first example, a stereoselective dihydroxylation followed by deprotection afforded a multihydroxylated bicyclic nucleoside. The configuration and conformational behaviour was determined by NMR spectroscopy and ab initio calculations, and both this bicyclic nucleoside and its unsaturated analogue were found to be strongly restricted in S-type conformations.