Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement
Graphical Abstract
The notion of late-stage, site-selective chemistry to modify chemical structures is of growing interest and utility. Here, we perform a single-atom ring contraction in macrocyclic backbones using the Cornforth rearrangement. This chemistry could be used to rapidly access unique chemical space which would be difficult to achieve using a standard building block approach.
Abstract
Site-selective transformations of densely functionalized scaffolds have been a topic of intense interest in chemical synthesis. Herein we have repurposed the rarely used Cornforth rearrangement as a tool to effect a single-atom ring contraction in cyclic peptide backbones. Investigations into the kinetics of the rearrangement were carried out to understand the impact of electronic factors, ring size, and linker type on the reaction efficiency. Conformational analysis was undertaken and showed how subtle differences in the peptide backbone result in substrate-dependent reaction profiles. This methodology can now be used to perform conformation-activity studies. The chemistry also offers an opportunity to install building blocks that are not compatible with traditional C-to-N iterative synthesis of macrocycle precursors.
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
