Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Paul A. Jackson, John C. Widen, Daniel A. Harki^* and Kay M. Brummond^*

Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States

Journal of Medicinal Chemistry

Publication Date (Web): December 20, 2016

DOI: 10.1021/acs.jmedchem.6b00788

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.