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Global Diastereoconvergence in the Ireland–Claisen Rearrangement of Isomeric Enolates: Synthesis of Tetrasubstituted α-Amino Acids

Fulton, Tyler J. and Cusumano, Alexander Q. and Alexy, Eric J. and Du, Yun E. and Zhang, Haiming and Houk, K. N. and Stoltz, Brian M. (2020) Global Diastereoconvergence in the Ireland–Claisen Rearrangement of Isomeric Enolates: Synthesis of Tetrasubstituted α-Amino Acids. Journal of the American Chemical Society, 142 (52). pp. 21938-21947. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20201104-135041447

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Abstract

A dual experimental/theoretical investigation of the Ireland–Claisen rearrangement of tetrasubstituted α-phthalimido ester enolates to afford α-tetrasubstituted, β-trisubstituted α-amino acids (generally >20:1 dr) is described. For trans allylic olefins, the Z- and E-enol ethers proceed through chair and boat transition states, respectively. For cis allylic olefins, the trend is reversed. As a result, the diastereochemical outcome of the reaction is preserved regardless of the geometry of the enolate or the accompanying allylic olefin. We term this unique convergence of all possible olefin isomers global diastereoconvergence. This reaction manifold circumvents limitations in present-day technologies for the stereoselective enolization of α,α-disubstituted allyl esters. Density functional theory paired with state-of-the-art local coupled-cluster theory (DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.0c11480DOIArticle
https://doi.org/10.26434/chemrxiv.13175012.v1DOIDiscussion Paper
ORCID:
AuthorORCID
Fulton, Tyler J.0000-0002-9343-2456
Cusumano, Alexander Q.0000-0002-2914-2008
Alexy, Eric J.0000-0002-2971-9698
Zhang, Haiming0000-0002-2139-2598
Houk, K. N.0000-0002-8387-5261
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2020 American Chemical Society. Received: November 1, 2020; Published: December 15, 2020. We thank the NIH-NIGMS (R01GM080269), NSF Grant CHE-1764328, the Gordon and Betty Moore Foundation, and Caltech for financial support. We thank the Caltech High Performance Computing Center for support. E.J.A. thanks the National Science Foundation for a predoctoral fellowship. We thank Dr. David VanderVelde (Caltech) for NMR expertise. Dr. Scott Virgil (Caltech Center for Catalysis and Chemical Synthesis) is thanked for instrumentation and SFC assistance. Dr. Michael Takase (Caltech) and Lawrence Henling (Caltech) are acknowledged for X-ray analysis. We acknowledge the X-ray Crystallography Facility in the Beckman Institute at Caltech and a Dow Next Generation Instrumentation Grant. Alexandra Beard (Caltech) is acknowledged for initial studies on phthalimide removal strategies. This manuscript is dedicated to our friend and colleague Professor Michael Krout (Bucknell University). Author Contributions: T.J.F. and A.Q.C. contributed equally. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIHR01GM080269
NSFCHE-1764328
Gordon and Betty Moore FoundationUNSPECIFIED
CaltechUNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Dow Next Generation Educator FundUNSPECIFIED
Subject Keywords:diastereoconvergence; Ireland–Claisen; Tetrasubstituted amino acid
Issue or Number:52
Record Number:CaltechAUTHORS:20201104-135041447
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201104-135041447
Official Citation:Global Diastereoconvergence in the Ireland–Claisen Rearrangement of Isomeric Enolates: Synthesis of Tetrasubstituted α-Amino Acids. Tyler J. Fulton, Alexander Q. Cusumano, Eric J. Alexy, Yun E. Du, Haiming Zhang, K. N. Houk, and Brian M. Stoltz. Journal of the American Chemical Society 2020 142 (52), 21938-21947; DOI: 10.1021/jacs.0c11480
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106432
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Nov 2020 00:23
Last Modified:05 Jan 2021 23:26

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