Synthesis of chiral alkenyl cyclopropane amino acids for incorporation into stapled peptides

Synthesis of chiral alkenyl cyclopropane amino acids for incorporation into stapled peptides

The Journal of Organic Chemistry

10.1021/acs.joc.9b02659

closed

https://doi.org/10.1021/acs.joc.9b02659

Tsz Ying Yuen, Christopher J. Brown, Yaw Sing Tan, Charles W. Johannes

11 December 2019

Yuen, T. Y.; Brown, C. J.; Tan, Y. S.; Johannes, C. W., Synthesis of chiral alkenyl cyclopropane amino acids for incorporation into stapled peptides. The Journal of Organic Chemistry 2020, 85 (3), 1556-1566.

α,α′-Disubstituted amino acids serve as important non-proteinogenic amino acids in the construction of stabilized helical peptides. To expand the repertoire of α,α′-disubstituted amino acids, chiral alkenyl-containing cyclopropane amino acids were synthesized via a two-step olefination and cyclopropanation procedure. Herein, we report the first example of the use of alkenyl cyclopropane building blocks to constrain MDM2-targeting helical peptides. The increased potency and efficacy associated with C-terminal cyclopropane substitution is postulated to be driven by a combined effect of net hydrophobicity and enhanced protein association rates.

PublisherCopyrights

This work was supported by the Industry Alignment Fund - Pre-Positioning Programme (IAF-PP) of Agency for Science, Technology and Research (A*STAR) (H1701a0010) and the JCO Visiting Investigatorship Programme of Agency for Science, Technology and Research (A*STAR) (JCO 1235d00048).

This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.joc.9b02659.

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