One-pot synthesis of CRBN PROTACs via photoinduced C(sp2)–C(sp3) cross coupling and amide formation for PROTAC library synthesis

Abstract

In this study, a one-pot synthesis via photoinduced C(sp2)–C(sp3) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol was studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, a bromodomain inhibitor, to generate BET (bromodomain and extra terminal domain) targeting protein degraders. The generated PROTACs were profiled in-vitro and tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of the one-pot transformation were carefully optimized for CRBN binder functionalization and multiple heterobifunctional linker moieties were designed and synthesized. Separate scopes detailing the C(sp2)–C(sp3) coupling and one-pot PROTAC synthesis are described in this report as well as a library minituarization study showing the high-throughput compatibility. Overall, the developed protocol provides rapid access to PROTACs in a single process thereby allowing efficient generation of CRBN-based PROTAC libraries.