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Chirality-Matched Catalyst-Controlled Macrocyclization Reactions

preprint
submitted on 07.05.2021, 15:39 and posted on 10.05.2021, 12:01 by Jaeyeon Hwang, Brandon Q. Mercado, Scott Miller

Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue

to attract great interest due to their important applications in physical, pharmacological and

environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over

intermolecular reactions in the ring-closing step, is often a key challenge. Furthermore, syntheses

of macrocycles with stereogenic elements confer an additional challenge, while access to such

macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts

can have in promoting efficient macrocyclization reactions. We show that the chirality of the

catalyst is essential for promoting favorable, matched transition state relationships that favor

macrocyclization of substrates with pre-existing stereogenic elements; curiously, the chirality of

the catalyst is essential for successful reactions, even though no new stereogenic elements are

created. Control experiments involving either achiral variants of the catalyst, or the enantiomeric

form of the catalyst, fail to deliver the macrocycles in significant quantity in head-to-head

comparisons. The generality of the phenomenon, demonstrated here with a number of substrates,

stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles,

presumably through related, catalyst-defined outer-sphere interactions with their acyclic substrates.

Funding

NIH grant R35 GM132092 to S.J.M.

History

Email Address of Submitting Author

scott.miller@yale.edu

Institution

Yale University

Country

USA

ORCID For Submitting Author

0000-0001-7817-1318

Declaration of Conflict of Interest

No conflict of interest.