Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective β-Lactone Formation by N-Heterocyclic Carbene Catalysis Public Deposited

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  • This study describes the combined experimental and computational elucidation of the mechanism and origins of stereoselectivities in the NHC-catalyzed dynamic kinetic resolution (DKR) of α-substituted-β-ketoesters. Density functional theory computations reveal that the NHC-catalyzed DKR proceeds by two mechanisms, depending on the stereochemistry around the forming bond: 1) a concerted, asynchronous formal (2+2) aldol-lactonization process, or 2) a stepwise spiro-lactonization mechanism where the alkoxide is trapped by the NHC-catalyst. These mechanisms contrast significantly from mechanisms found and postulated in other related transformations. Conjugative stabilization of the electrophile and non-classical hydrogen bonds are key in controlling the stereoselectivity. This reaction constitutes an interesting class of DKRs in which the catalyst is responsible for the kinetic resolution to selectively and irreversibly capture an enantiomer of a substrate undergoing rapid racemization with the help of an exogenous base.
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  • Johnston, R. C., Cohen, D. T., Eichman, C. C., Scheidt, K. A., & Cheong, P. H. Y. (2014). Catalytic kinetic resolution of a dynamic racemate: highly stereoselective β-lactone formation by N-heterocyclic carbene catalysis. Chemical Science, 5(5), 1974-1982. doi:10.1039/C4SC00317A
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  • 5
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  • 5
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  • DTC, CCE, and KAS acknowledge financial support generously provided by the NIH (NIGMS RO1-GM073072). RCJ and PHYC acknowledge financial support generously provided by Oregon State University and computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF CHE-1102637). D.T.C. thanks the ACS Division of Organic Chemistry for a 2011-12 Graduate Fellowship, sponsored by Organic Syntheses/Organic Reactions. RCJ thanks Oregon State University for the Tartar Research Fellowship.
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