The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.
Bibliographical noteFunding Information:
Financial support for this work was provided by National Science Foundation Center for Synthetic Organic Electrochemistry (CHE-2002158) and the National Institutes of Health (grant number GM-118176). M.S. was supported by a Postdoctoral Fellowship for Research Abroad (JSPS), R.N. was supported by an Experientia Foundation Fellowship, M.M. was supported by a Banting Postdoctoral Fellowship (NSERC), P.H. was supported by a George E. Hewitt Foundation Fellowship for Medical Research, and C.A.M was supported by the National Institute of General Medical Sciences of the National Institutes of Health (K99GM140249)