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Published August 12, 2020 | Supplemental Material + Accepted Version
Journal Article Open

Reaction Mechanism, Origins of Enantioselectivity, and Reactivity Trends in Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp³)–C(sp³) Cross-Coupling


We utilize quantum mechanics to evaluate a variety of plausible mechanistic pathways for the entirety of the catalytic cycle for asymmetric decarboxylative allylic alkylation of allyl β-ketoesters. We present a mechanistic picture that unites all current experimental observations, including enantioinduction, reaction rate, catalyst resting state, enolate crossover experiments, water tolerance, and the effects of solvation on inner- and outer-sphere mechanisms. Experiments designed to evaluate the fidelity and predictive power of the computational models reveal the methods employed herein to be highly effective in elucidating the reactivity of the catalytic system. On the basis of these findings, we highlight a computational framework from which chemically accurate results are obtained and address the current limitations of the decarboxylative asymmetric allylic alkylation reaction.

Additional Information

© 2020 American Chemical Society. Received: June 9, 2020; Published: July 8, 2020. We thank the NIH (R01 GM080269) and Caltech for financial support. We further thank Dr. Michael Bartberger (1200 Pharma) for insightful discussion. W.A.G. received support from ONR (ONR N00014-18-1-2155). The Caltech High Performance Computing (HPC) center is acknowledged for support of computational resources. The authors declare no competing financial interest.

Attached Files

Accepted Version - nihms-1656743.pdf

Supplemental Material - ja0c06243_si_001.pdf

Supplemental Material - ja0c06243_si_002.xlsx


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