Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides

Daniel Rozsar, Michele Formica, Ken Yamazaki, Trevor A. Hamlin*, Darren J. Dixon

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and electrophiles under mild reaction conditions, enabled by a novel squaramide-based bifunctional iminophosphorane catalyst. Low catalyst loadings (2.0 mol %) were achieved on a decagram scale, demonstrating the scalability of the reaction. Computational analysis revealed the origin of the high enantiofacial selectivity via analysis of relevant transition structures and provided substantial support for specific noncovalent activation of the carbonyl group of the α,β-unsaturated amide by the catalyst.

Original languageEnglish
Pages (from-to)1006-1015
Number of pages10
JournalJournal of the American Chemical Society
Volume144
Issue number2
Early online date6 Jan 2022
DOIs
Publication statusPublished - 19 Jan 2022

Bibliographical note

Funding Information:
D.R. and M.F. are 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. Yaseen A. Almehmadi (for the synthesis of substrates 1f and 1q ) and F. Wieland Goetzke (for determining the ee of 4c by supercritical fluid chromatography) are gratefully acknowledged. Roman Kučera, J. Andrew P. Maitland, and Daniel Matheau-Raven are thanked for useful discussions and proofreading.

Funding Information:
D.R. and M.F. are 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. Yaseen A. Almehmadi (for the synthesis of substrates 1f and 1q) and F. Wieland Goetzke (for determining the ee of 4c by supercritical fluid chromatography) are gratefully acknowledged. Roman Kuc?era, J. Andrew P. Maitland, and Daniel Matheau-Raven are thanked for useful discussions and proofreading.

Publisher Copyright:
© 2022 American Chemical Society

Funding

D.R. and M.F. are 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. Yaseen A. Almehmadi (for the synthesis of substrates 1f and 1q ) and F. Wieland Goetzke (for determining the ee of 4c by supercritical fluid chromatography) are gratefully acknowledged. Roman Kučera, J. Andrew P. Maitland, and Daniel Matheau-Raven are thanked for useful discussions and proofreading. D.R. and M.F. are 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. Yaseen A. Almehmadi (for the synthesis of substrates 1f and 1q) and F. Wieland Goetzke (for determining the ee of 4c by supercritical fluid chromatography) are gratefully acknowledged. Roman Kuc?era, J. Andrew P. Maitland, and Daniel Matheau-Raven are thanked for useful discussions and proofreading.

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