Cobalt-Catalyzed Enantio- and Regioselective C(sp3)−H Alkenylation of Thioamides

Lucia Staronova; Ken Yamazaki; Xing Xu; Heyao Shi; F. Matthias Bickelhaupt; Trevor A. Hamlin; Darren J. Dixon

doi:10.1002/anie.202316021

Cobalt-Catalyzed Enantio- and Regioselective C(sp³)−H Alkenylation of Thioamides

Lucia Staronova
, Ken Yamazaki
, Xing Xu
, Heyao Shi
, F. Matthias Bickelhaupt
, Trevor A. Hamlin^*
, Darren J. Dixon^*

^*Corresponding author for this work

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

Abstract

An enantioselective cobalt-catalyzed C(sp³)−H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

Original language	English
Article number	e202316021
Pages (from-to)	1-9
Number of pages	9
Journal	Angewandte Chemie - International Edition
Volume	63
Issue number	13
Early online date	24 Dec 2023
DOIs	https://doi.org/10.1002/anie.202316021
Publication status	Published - 22 Mar 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Funding

L.S. and H.S. are grateful to the EPSRC Centre for Doctoral Training in the Synthesis for Biology and Medicine for the studentship, generously supported by AstraZeneca, Diamond, Light Source, Defense 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. and F.M.B. thank 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.

Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Honjo International Scholarship Foundation
SURF Cooperative
Engineering and Physical Sciences Research Council
Defence Science and Technology Laboratory
AstraZeneca

Keywords

Cobalt Catalysis
C−H Alkenylation
Density Functional Calculations
Enantioselective
Thioamide

Access to Document

10.1002/anie.202316021

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Cite this

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title = "Cobalt-Catalyzed Enantio- and Regioselective C(sp3)−H Alkenylation of Thioamides",

abstract = "An enantioselective cobalt-catalyzed C(sp3)−H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 \%) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.",

keywords = "Cobalt Catalysis, C−H Alkenylation, Density Functional Calculations, Enantioselective, Thioamide",

author = "Lucia Staronova and Ken Yamazaki and Xing Xu and Heyao Shi and Bickelhaupt, \{F. Matthias\} and Hamlin, \{Trevor A.\} and Dixon, \{Darren J.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

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T1 - Cobalt-Catalyzed Enantio- and Regioselective C(sp3)−H Alkenylation of Thioamides

AU - Staronova, Lucia

AU - Yamazaki, Ken

AU - Xu, Xing

AU - Shi, Heyao

AU - Bickelhaupt, F. Matthias

AU - Hamlin, Trevor A.

AU - Dixon, Darren J.

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N2 - An enantioselective cobalt-catalyzed C(sp3)−H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

AB - An enantioselective cobalt-catalyzed C(sp3)−H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

KW - Cobalt Catalysis

KW - C−H Alkenylation

KW - Density Functional Calculations

KW - Enantioselective

KW - Thioamide

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