Research Projects

Thia-Michael (tM) addition is a conjugate addition reaction where a thiol or thiolate nucleophile adds to an alkene double bond to form a tM adduct. This reaction is widely used in synthesis of natural products, surfactants, pesticides, and pharmaceutical agents. It has applications in surface modifications, dynamic covalent networks, and fluorescence-based probes for bioimaging. The tM reaction is an equilibrium process and is a major factor in dynamic covalent chemistry (DCC). However, the low equilibrium constant (Keq) can hinder efficient labeling of biomolecules under physiological conditions. To improve efficiency, alkenes activated by electron withdrawing groups near the double bond, such as alpha, beta-unsaturated carbonyl compounds, and benzalcyanoacetate (BCA), can be used. Recently, a heterocyclic isoxazolone motif Michael acceptor named "BiOx" was introduced, which significantly enhanced the Keq values of the tM reaction due to aromatic stabilization. However, designing alkenes that can effectively and selectively label thiols of biomolecules under physiological conditions remains a challenge. This project aims to strategically incorporate noncovalent interactions to produce hyperstable tM products for biological labeling.