Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides

Guanglong Su; Michele Formica; Ken Yamazaki; Trevor A. Hamlin; Darren J. Dixon

doi:10.1021/jacs.3c03182

Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides

Guanglong Su
, Michele Formica
, Ken Yamazaki
, Trevor A. Hamlin^*
, Darren J. Dixon^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

Original language	English
Pages (from-to)	12771-12782
Number of pages	12
Journal	Journal of the American Chemical Society
Volume	145
Issue number	23
Early online date	30 May 2023
DOIs	https://doi.org/10.1021/jacs.3c03182
Publication status	Published - 14 Jun 2023

Bibliographical note

Funding Information:
M.F. is grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for studentships, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. K.Y. thanks the Honjo International Scholarship Foundation for a postgraduate scholarship. T.A.H. thanks The Netherlands Organization for Scientific Research (NWO) for financial support. All DFT calculations were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Funding

M.F. is grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for studentships, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. K.Y. thanks the Honjo International Scholarship Foundation for a postgraduate scholarship. T.A.H. thanks The Netherlands Organization for Scientific Research (NWO) for financial support. All DFT calculations were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

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title = "Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides",

abstract = "A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99\%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.",

author = "Guanglong Su and Michele Formica and Ken Yamazaki and Hamlin, \{Trevor A.\} and Dixon, \{Darren J.\}",

note = "Funding Information: M.F. is grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for studentships, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. K.Y. thanks the Honjo International Scholarship Foundation for a postgraduate scholarship. T.A.H. thanks The Netherlands Organization for Scientific Research (NWO) for financial support. All DFT calculations were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

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AU - Dixon, Darren J.

N1 - Funding Information: M.F. is grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for studentships, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. K.Y. thanks the Honjo International Scholarship Foundation for a postgraduate scholarship. T.A.H. thanks The Netherlands Organization for Scientific Research (NWO) for financial support. All DFT calculations were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/6/14

Y1 - 2023/6/14

N2 - A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

AB - A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

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Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides

Abstract

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