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.