Computational design of S-nitrosothiol Click reactions

To address a long-standing problem of finding efficient reactions for chemical labeling of protein-based S-nitrosothiols (RSNOs), we computationally explored hitherto unknown (3+2) cycloaddition RSNO reactions with alkynes and alkenes. Nonactivated RSNO cycloaddition reactions have high activation enthalpy (>20 kcal/mol at the CBS-QB3 level) and compete with alternative SN bond insertion pathway. However, the (3+2) cycloaddition reaction barriers can be dramatically lowered by coordination of a Lewis acid to the N atom of the SNO group. To exploit this effect, we propose to use reagents with Lewis acid and a strain-activated carbon-carbon multiple bond linked by a rigid scaffold, which can react with RSNOs with small activation enthalpies (approximate to 5 kcal/mol) and high reaction exothermicities (approximate to 40 kcal/mol). The proposed efficient RSNO cycloaddition reactions can be used for future development of practical RSNO labeling reactions. (c) 2013 Wiley Periodicals, Inc.