A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines: Via intramolecular aza-Michael reaction to α,β-unsaturated esters

Guanglong Su, Connor J. Thomson, Ken Yamazaki, Daniel Rozsar, Kirsten E. Christensen, Trevor A. Hamlin, Darren J. Dixon*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

Original languageEnglish
Pages (from-to)6064-6072
Number of pages9
JournalChemical Science
Volume12
Issue number17
Early online date18 Mar 2021
DOIs
Publication statusPublished - 7 May 2021

Bibliographical note

Funding Information:
C. J. T. thanks Bayer AG for generous nancial support. K. Y. thanks the Honjo International Scholarship Foundation for funding. D. R. thanks 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, Pzer, Syngenta, Takeda, UCB and Vertex. T. A. H. thanks The Netherlands Organization for Scientic Research (NWO) for nancial support. All DFT calculations were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

Publisher Copyright:
© 2021 The Royal Society of Chemistry.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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