Catalyst Controlled Macrocyclization Reactions Chirality Adapted | PNAS

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Importance

Chiral catalysts are generally used to control stereochemistry in organic reactions. Generally, they control the enantioselectivity or the diastereoselectivity. In recent years, applications have expanded to include monitoring site selectivity in reactions involving complex molecules. Even more rarely, they can control chemoselectivity as well as stereochemistry. Here we report that a carefully chosen chiral catalyst can also be decisive for efficient macrocyclization reactions in cases where simple achiral catalysts or stereochemically incompatible catalysts fail. In particular, in these reactions, a chiral catalyst proves to be essential for the control of a reaction in which no new static stereogenic element (that is to say not “dynamic”) is introduced. While fundamentally intriguing, these observations could also influence strategies for the efficient synthesis of macrocyclic compounds in a variety of settings.

Abstract

Macrocycles, formally defined as compounds containing a ring of 12 atoms or more, continue to generate great interest due to their important applications in the physical, pharmacological and environmental sciences. In the syntheses of macrocyclic compounds, the promotion of intramolecular reactions over intermolecular reactions in the ring closing stage is often a major challenge. In addition, syntheses of macrocycles with stereogenic elements present an additional challenge, while access to such macrocycles is of great interest. Here we report the remarkable effect that peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that catalyst chirality is essential to promote favorable and paired transition state relationships that promote macrocyclization of substrates with pre-existing stereogenic elements; oddly enough, the chirality of the catalyst is essential for successful reactions, even if no new static (ie, non-“dynamic”) stereogenic elements are created. Control experiments involving achiral variants of the catalyst or the enantiomeric form of the catalyst fail to provide macrocycles in significant amounts in direct comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies with enzyme catalysts that produce natural macrocycles, presumably through related peripheral interactions defined by the catalyst with their acyclic substrates.

Footnotes

    • Accepted August 28, 2021.
  • This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2020.

  • Author contributions: research designed by JH and SJM; JH and BQM have done research; JH, BQM and SJM analyzed the data; and JH, BQM and SJM wrote the article.

  • Reviewers: PSB, The Scripps Research Institute; and DWCM, Princeton University.

  • The authors declare no competing interests.

  • This article contains additional information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2113122118/-/DCSupplemental.

Data availability

All study data is included in the article and SI Annex.


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