Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Justin M. Lopchuk, Kasper Fjelbye, Yu Kawamata, Lara R. Malins, Chung Mao Pan, Ryan Gianatassio, Jie Wang, Liher Prieto, James Bradow, Thomas A. Brandt, Michael R. Collins, Jeff Elleraas, Jason Ewanicki, William Farrell, Olugbeminiyi O. Fadeyi, Gary M. Gallego, James J. Mousseau, Robert Oliver, Neal W. Sach, Jason K. SmithJillian E. Spangler, Huichin Zhu, Jinjiang Zhu, Phil S. Baran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

187 Citations (Scopus)

Abstract

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

Original languageEnglish
Pages (from-to)3209-3226
Number of pages18
JournalJournal of the American Chemical Society
Volume139
Issue number8
DOIs
Publication statusPublished - 1 Mar 2017
Externally publishedYes

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