Relative Rates of Michael Reactions of 2‘-(Phenethyl)thiol with Vinyl Sulfones, Vinyl Sulfonate Esters, and Vinyl Sulfonamides Relevant to Vinyl Sulfonyl Cysteine Protease Inhibitors

Abstract

[reaction: see text] The relative rates of Michael additions of 2'-(phenethyl)thiol to representative vinyl sulfonyl Michael acceptors were measured. The dependence of the reactivity of the Michael acceptor on the nature of the sulfonyl R substituent was determined in order to evaluate the effect of these substituents on the inactivation kinetics of comparably substituted vinyl sulfonyl cysteine protease inhibitors. The rates of these Michael additions vary over 3 orders of magnitude, with phenyl vinyl sulfonate esters (R = OPh) being ca. 3000-fold more reactive than N-benzyl vinyl sulfonamides (R = NHBn).