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Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

Behenna, Douglas C. and Mohr, Justin T. and Sherden, Nathaniel H. and Marinescu, Smaranda C. and Harned, Andrew M. and Tani, Kousuke and Seto, Masaki and Ma, Sandy and Novák, Zoltán and Krout, Michael R. and McFadden, Ryan M. and Roizen, Jennifer L. and Enquist, John A., Jr. and White, David E. and Levine, Samantha R. and Petrova, Krastina V. and Iwashita, Akihiko and Virgil, Scott C. and Stoltz, Brian M. (2011) Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chemistry: a European Journal, 17 (50). pp. 14199-14223. ISSN 0947-6539. PMCID PMC3365686.

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α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Mohr, Justin T.0000-0002-7005-3322
Marinescu, Smaranda C.0000-0003-2106-8971
Krout, Michael R.0000-0002-0539-6986
Roizen, Jennifer L.0000-0002-6053-5512
Virgil, Scott C.0000-0001-8586-5641
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2011 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim. Received: November 24, 2010; Revised: July 29, 2011; Published online: November 14, 2011. This publication is based on work supported by award number KUS-11–006–02, made by the King Abdullah University of Science and Technology (KAUST). We thank the NIH-NIGMS (R01 GM080269–01 and postdoctoral fellowships to AMH and DEW), The Fannie and John Hertz Foundation (predoctoral fellowship to DCB), Eli Lilly (predoctoral fellowships to JTM, RMM, and MRK), Ono Pharmaceutical Co., Ltd. (postdoctoral fellowship to KT), The Hungarian–American Enterprise Scholarship Fund (postdoctoral fellowship to ZN), Takeda Pharmaceutical Co., Ltd. (postdoctoral fellowship to MS), The California Tobacco-Related Disease Research Program of the University of California (predoctoral fellowship to JLR, grant number 14DT-0004), Marcella R. Bonsall and the Dalton Fund (undergraduate fellowships to SRL), the Caltech Amgen Scholars Program (undergraduate fellowship to KVP), The 21st Century COE Program for Frontiers in Fundamental Chemistry from the Ministry of Education, Culture, Sports, Science and Technology, Japan (financial support to AI), the A. P. Sloan Foundation, Research Corporation, the Dreyfus Foundation, Bristol–Myers Squibb, Glaxo-SmithKline, Johnson and Johnson, Amgen, Merck Research Laboratories, Pfizer, Novartis, Roche, Abbott Laboratories, Boehringer–Ingelheim, AstraZeneca, and Caltech for financial support. We acknowledge Dr. Mike Day and Larry Henling for assistance with X-ray crystallography. Ruthenium olefin metathesis catalysts were generously donated by Materia.
Funding AgencyGrant Number
King Abdullah University of Science and Technology (KAUST)KUS-11– 006–02
NIHR01 GM080269–01
NIH Postdoctoral FellowshipsUNSPECIFIED
Fannie and John Hertz FoundationUNSPECIFIED
Ono Pharmaceutical Co., LtdUNSPECIFIED
Hungarian–American Enterprise Scholarship FundUNSPECIFIED
Takeda Pharmaceutical Co., Ltd.UNSPECIFIED
California Tobacco-Related Disease Research Program14DT-0004
Marcella R. BonsallUNSPECIFIED
Caltech Amgen Scholars ProgramUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
Research CorporationUNSPECIFIED
Camille and Henry Dreyfus FoundationUNSPECIFIED
Bristol–Myers SquibbUNSPECIFIED
Johnson and JohnsonUNSPECIFIED
Merck Research LaboratoriesUNSPECIFIED
Abbott LaboratoriesUNSPECIFIED
Ministry of Education, Culture, Sports, Science and Technology (MEXT)UNSPECIFIED
Subject Keywords:alkylation; allylic compounds; asymmetric catalysis; enolates; reaction mechanisms; synthetic methods
Issue or Number:50
PubMed Central ID:PMC3365686
Record Number:CaltechAUTHORS:20120214-111558996
Persistent URL:
Official Citation:Behenna, D. C., Mohr, J. T., Sherden, N. H., Marinescu, S. C., Harned, A. M., Tani, K., Seto, M., Ma, S., Novák, Z., Krout, M. R., McFadden, R. M., Roizen, J. L., Enquist, J. A., White, D. E., Levine, S. R., Petrova, K. V., Iwashita, A., Virgil, S. C. and Stoltz, B. M. (2011), Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chemistry - A European Journal, 17: 14199–14223. doi: 10.1002/chem.201003383
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29280
Deposited By: Jason Perez
Deposited On:14 Feb 2012 21:27
Last Modified:24 Apr 2020 23:38

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