Introducing covalent warheads on spirocyclic sp2–sp3 fragments by innate C–H functionalization

Abstract

Sp²–sp³ fragments play a vital role in fragment-based drug design (FBDD). Strategies to chemically modify them and efficiently access libraries of these compounds have been goals of the highest priority in the last decades. In this work, a series of sp²–sp³ fragments was synthesized and validated for that purpose, based on their measured physical–chemical properties. Selective C–H cyanation and allylation of these fragments was demonstrated by simple heating in presence of an appropriate hydrogen-atom transfer reagent and a radical acceptor. These conditions enabled a streamlined access to covalent fragments in a single step, by direct introduction of the desired covalent binder. Preliminary results on vinylation, as well as late-stage functionalization of a drug analogue were disclosed.