Applications of 5-exo-trig Thiyl Radical Cyclizations for the Synthesis of Thiosugars

Abstract

The application of thiyl-radical-mediated 5-exo-trig cyclization reactions for the preparation of a series of C-linked 4-thiofuranoside sugars has been investigated. The cyclization reactions were found to proceed in high yield with complete regioselectivity and moderate to excellent diastereoselectivity for a number of benzyl-protected precursors. The diastereoselectivity of the radical cyclization was determined by a number of factors, primarily the stereochemistry at the C-2 position and the nature of the substituents attached to the olefin. The cyclization reactions proceed via transition-state intermediates that favor formation of the 1,2-trans products. For D-sugars, a chairlike transition state is proposed. For L-sugars, both chair- and boatlike transition states could be considered. Inversion of the stereochemistry at C-4 also induced a significant effect on the diastereoselectivity of the radical process. The synthetic route is general for both D- and L-sugars and offers a highly novel and efficient strategy for accessing C-linked 4-thiofuranosides. A fluorescently labeled thiosugar was prepared as a putative glycosidase inhibitor.