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

Douglas C. Behenna; Justin T. Mohr; Nathaniel H. Sherden; Smaranda C. Marinescu; Andrew M. Harned; Kousuke Tani; Masaki Seto; Sandy Ma; Zoltán Novák; Michael R. Krout; Ryan M. McFadden; Jennifer L. Roizen; John A. Enquist; David E. White; Samantha R. Levine; Krastina V. Petrova; Akihiko Iwashita; Scott C. Virgil; Brian M. Stoltz

doi:10.1002/chem.201003383

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

Douglas C. Behenna, Justin T. Mohr, Nathaniel H. Sherden, Smaranda C. Marinescu, Andrew M. Harned, Kousuke Tani, Masaki Seto, Sandy Ma, Zoltán Novák, Michael R. Krout, Ryan M. McFadden, Jennifer L. Roizen, John A. Enquist, David E. White, Samantha R. Levine, Krastina V. Petrova, Akihiko Iwashita, Scott C. Virgil, Brian M. Stoltz

Research output: Contribution to journal › Article › peer-review

160 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	14199-14223
Number of pages	25
Journal	Chemistry - A European Journal
Volume	17
Issue number	50
DOIs	https://doi.org/10.1002/chem.201003383
State	Published - Nov 14 2011
Externally published	Yes

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledged KAUST grant number(s): KUS-11-006-02
Acknowledgements: 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, GlaxoSmithKline, 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.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.

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10.1002/chem.201003383

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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., & Stoltz, B. M. (2011). Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chemistry - A European Journal, 17(50), 14199-14223. https://doi.org/10.1002/chem.201003383

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

abstract = "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.",

author = "Behenna, {Douglas C.} and Mohr, {Justin T.} and Sherden, {Nathaniel H.} and Marinescu, {Smaranda C.} and Harned, {Andrew M.} and Kousuke Tani and Masaki Seto and Sandy Ma and Zolt{\'a}n Nov{\'a}k and Krout, {Michael R.} and McFadden, {Ryan M.} and Roizen, {Jennifer L.} and Enquist, {John A.} and White, {David E.} and Levine, {Samantha R.} and Petrova, {Krastina V.} and Akihiko Iwashita and Virgil, {Scott C.} and Stoltz, {Brian M.}",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledged KAUST grant number(s): KUS-11-006-02 Acknowledgements: 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, GlaxoSmithKline, 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. This publication acknowledges KAUST support, but has no KAUST affiliated authors.",

year = "2011",

month = nov,

day = "14",

doi = "10.1002/chem.201003383",

language = "English (US)",

volume = "17",

pages = "14199--14223",

journal = "Chemistry - A European Journal",

issn = "0947-6539",

publisher = "Wiley-VCH Verlag",

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Behenna, DC, Mohr, JT, Sherden, NH, Marinescu, SC, Harned, AM, Tani, K, Seto, M, Ma, S, Novák, Z, Krout, MR, McFadden, RM, Roizen, JL, Enquist, JA, White, DE, Levine, SR, Petrova, KV, Iwashita, A, Virgil, SC & Stoltz, BM 2011, 'Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies', Chemistry - A European Journal, vol. 17, no. 50, pp. 14199-14223. https://doi.org/10.1002/chem.201003383

TY - JOUR

T1 - Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

AU - Behenna, Douglas C.

AU - Mohr, Justin T.

AU - Sherden, Nathaniel H.

AU - Marinescu, Smaranda C.

AU - Harned, Andrew M.

AU - Tani, Kousuke

AU - Seto, Masaki

AU - Ma, Sandy

AU - Novák, Zoltán

AU - Krout, Michael R.

AU - McFadden, Ryan M.

AU - Roizen, Jennifer L.

AU - Enquist, John A.

AU - White, David E.

AU - Levine, Samantha R.

AU - Petrova, Krastina V.

AU - Iwashita, Akihiko

AU - Virgil, Scott C.

AU - Stoltz, Brian M.

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledged KAUST grant number(s): KUS-11-006-02 Acknowledgements: 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, GlaxoSmithKline, 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. This publication acknowledges KAUST support, but has no KAUST affiliated authors.

PY - 2011/11/14

Y1 - 2011/11/14

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10754/598161

UR - http://doi.wiley.com/10.1002/chem.201003383

UR - http://www.scopus.com/inward/record.url?scp=82255189929&partnerID=8YFLogxK

U2 - 10.1002/chem.201003383

DO - 10.1002/chem.201003383

M3 - Article

C2 - 22083969

SN - 0947-6539

VL - 17

SP - 14199

EP - 14223

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 50

ER -

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

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