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A palladium-catalysed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocentres

Streuff, Jan and White, David E. and Virgil, Scott C. and Stoltz, Brian M. (2010) A palladium-catalysed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocentres. Nature Chemistry, 2 (3). pp. 192-196. ISSN 1755-4330. PMCID PMC2917108.

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The catalytic enantioselective synthesis of densely functionalized organic molecules that contain all-carbon quaternary stereocentres is a challenge to modern chemical methodology. The catalytically controlled, asymmetric α-alkylation of ketones represents another difficult task and is of major interest to our and other research groups. We report here a palladium-catalysed enantioselective process that addresses both problems simultaneously and allows the installation of vicinal all-carbon quaternary and tertiary stereocentres at the α-carbon of a ketone in a single step. This multiple bond-forming process is carried out on readily available β-ketoester starting materials and proceeds by conjugate addition of a palladium enolate, generated in situ, to activated Michael acceptors. As a result, the CO_2 moiety of the substrate is displaced by a C–C fragment in an asymmetric cut-and-paste reaction with high yield, diastereomeric ratio and enantiomeric excess.

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Virgil, Scott C.0000-0001-8586-5641
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2010 Nature Publishing Group. Received 7 September 2009; accepted 4 December 2009; published online 31 January 2010. The authors thank the National Institute of Health’s National Institute of General Medical Sciences (R01 GM 080269-01 and a postdoctoral fellowship to D.E.W.), the German Academic Exchange Service (DAAD, postdoctoral fellowship to J.S.), Abbott Laboratories, Amgen, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, the Gordon and Betty Moore Foundation and Caltech for financial support. We thank S. Reisman for discussions. L. Henling and M. Day carried out the X-ray crystallographic analysis. The Bruker KAPPA APEXII X-ray diffractometer was purchased with a National Science Foundation Chemistry Research Instrumentation and Facilities: Departmental Multi-User Instrumentation award to the California Institute of Technology (CHE-0639094). J.S. planned and carried out the experimental work and wrote the manuscript. D.E.W. and S.C.V. took part in the initial reaction development and screening experiments. B.M.S. initiated and directed the project. All authors commented on the manuscript. The authors declare no competing financial interests. Supplementary information and chemical compound information accompany this paper at naturechemistry. Reprints and permission information is available online at http://npg.nature. com/reprintsandpermissions/. Correspondence and requests for materials should be addressed to B.M.S.
Funding AgencyGrant Number
Deutscher Akademischer Austauschdienst (DAAD)UNSPECIFIED
Abbott LaboratoriesUNSPECIFIED
Boehringer IngelheimUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Subject Keywords:Organic chemistry; Synthesis
Issue or Number:3
PubMed Central ID:PMC2917108
Record Number:CaltechAUTHORS:20100305-152223080
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17682
Deposited By: Jason Perez
Deposited On:11 Mar 2010 22:55
Last Modified:10 Jun 2020 23:05

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