Carbene-Catalyzed Enantioselective Sulfonylation of Enone Aryl Aldehydes: A New Mode of Breslow Intermediate Oxidation

A carbene-catalyzed sulfonylation reaction between enone aryl aldehydes and sulfonyl chlorides is disclosed. The reaction effectively installs sulfone moieties in a highly enantioselective manner to afford sulfone-containing bicyclic lactones. The sulfonyl chloride behaves both as an oxidant and a nucleophilic substrate (via its reduced form) in this N-heterocyclic carbene (NHC)-catalyzed process. The NHC catalyst provides both activation and stereoselectivity control on a very remote site of enone aryl aldehyde substrates. Water plays an important role in modulating catalyst deactivation and reactivation routes that involve reactions between NHC and sulfonyl chloride. Experimental studies and DFT calculations suggest that an unprecedented intermediate and a new oxidation mode of the NHC-derived Breslow intermediate are involved in the new asymmetric sulfonylation reaction. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University National Research Foundation (NRF) Submitted/Accepted version We acknowledge funding supports from the National Natural Science Foundation of China (22061007 and 22071036); Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules, Department of Education, Guizhou Province [Qianjiaohe KY number (2020)004]; The 10 Talent Plan (Shicengci) of Guizhou Province ([2016] 5649); Science and Technology Department of Guizhou Province ([2018]2802, [2019]1020); Program of Introducing Talents of Discipline to Universities of China (111 Program, D20023) at Guizhou University; Singapore National Research Foundation under its NRF Investigatorship (NRF-NRFI2016- 06) and Competitive Research Program (NRF-CRP22-2019- 0002); Ministry of Education, Singapore, under its MOE AcRF Tier 1 Award (RG7/20, RG5/19), MOE AcRF Tier 2 (MOE2019-T2-2-117), and MOE AcRF Tier 3 Award (MOE2018-T3-1-003); a Nanyang Research Award Grant; and a Chair Professorship Grant, Nanyang Technological University. X.Z. acknowledges the support from the IHPC, A*STAR, and thanks the Deputy Chief Executive Research Office (DCERO), A*STAR, for a Career Development Fund (CDF Project Number C210812008) for this work