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Catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines using asymmetric protonation : a method development and mechanistic study

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Ashford_2020_CEJ_Catalytic_CC.pdf (1.534Mb)
Date
21/09/2020
Author
Ashford, Matthew
Xu, Chao
Molloy, John J.
Carpenter-Warren, Cameron Lewis
Slawin, Alexandra Martha Zoya
Leach, Andrew G.
Watson, Allan J. B.
Funder
The Leverhulme Trust
Grant ID
RPG-2015-308
Keywords
Asymmetric
Brønsted acid
Catalysis
Fluorine
Heterocycles
QD Chemistry
DAS
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Abstract
A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza‐Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C−F stereocentre in high enantioselectivity, and is also amenable to stereogenic C−CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate‐determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran‐type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.
Citation
Ashford , M , Xu , C , Molloy , J J , Carpenter-Warren , C L , Slawin , A M Z , Leach , A G & Watson , A J B 2020 , ' Catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines using asymmetric protonation : a method development and mechanistic study ' , Chemistry - A European Journal , vol. 26 , no. 53 , pp. 12249-12255 . https://doi.org/10.1002/chem.202002543
Publication
Chemistry - A European Journal
Status
Peer reviewed
DOI
https://doi.org/10.1002/chem.202002543
ISSN
0947-6539
Type
Journal article
Rights
Copyright © 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Description
Funding: Leverhulme Trust (Grant Number(s): RPG-2015-308), University of St Andrews, University of Manchester.
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  • University of St Andrews Research
URL
https://doi.org/10.26434/chemrxiv.11920947.v1
URI
http://hdl.handle.net/10023/20485

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