Exploring Electrochemical C(sp3)-H Oxidation for the Late-Stage Methylation of Complex Molecules

Luiz F.T. Novaes, Justin S.K. Ho, Kaining Mao, Kaida Liu, Mayank Tanwar, Matthew Neurock, Elisia Villemure, Jack A. Terrett, Song Lin

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The "magic methyl"effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl"effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

Original languageEnglish (US)
Pages (from-to)1187-1197
Number of pages11
JournalJournal of the American Chemical Society
Volume144
Issue number3
DOIs
StatePublished - Jan 26 2022

Bibliographical note

Funding Information:
This work was supported by the NSF Center for Synthetic Organic Electrochemistry (CHE-2002158; M.N. and S.L.) and Genentech (Innovation Fund; S.L.). This study made use of the Cornell University NMR facility supported by the National Science Foundation (CHE-1531632). S.L. thanks the Camille and Henry Dreyfus Foundation for a Teacher-Scholar Award. J.S.K.H. acknowledges the Department of Defense for an NDSEG fellowship. We thank Samantha MacMillan (Cornell University) for X-ray crystallography data collection and analysis, Prof. Kevin Moeller (Washington University in St. Louis) and Prof. Seiji Suga (Okayama University) for helpful discussions and suggestions about the Shono oxidation, Prof. Phill Milner for use of the FTIR instrument, and the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for computing time.

Publisher Copyright:
© 2022 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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