Merging Late-Stage Diversification with Solid-Phase Peptide Synthesis Enabled by High-Throughput On-Resin Reaction Screening

An integrated workflow is described that combines micromole-scale high-throughput experimentation (HTE) reaction screening and solid-phase peptide synthesis (SPPS) to enable rapid synthetic method development for on-resin peptide diversification. Using this new approach, we have identified several sets of robust Suzuki-Miyaura coupling conditions with complementary scope that collectively display broad coverage with respect to both resin-bound peptide substrates containing aryl halide side chains and (hetero)arylboronic acid coupling partners. We have also demonstrated the utility of this integrated SPPS/chemical diversification method by synthesizing a multidimensional library of diverse peptides in high yields.

Automated summary

An integrated workflow combining high-throughput experimentation and solid-phase peptide synthesis is presented for rapid synthetic method development for peptide diversification. The method allows for the identification of robust coupling conditions and synthesis of diverse peptide libraries in high yields.