Organometallic AlaM reagents for umpolung peptide diversification

Summary Selective modifications of peptides and proteins have emerged as a promising strategy to develop novel mechanistic probes and prepare compounds with translational potentials. Here, we report alanine carbastannatranes AlaSn as a universal synthon in various C-C and C-heteroatom bond-forming reactions. These reagents are compatible with peptide manipulation techniques and can undergo chemoselective conjugation in minutes when promoted by Pd(0). Despite their increased nucleophilicity and propensity to transfer the alkyl group, C(sp3)-C(sp2) coupling with AlaSn can be accomplished at room temperature under buffered conditions (pH 6.5–8.5). We also show that AlaSn can be easily transformed into several canonical L- and D-amino acids in arylation, acylation, and etherification reactions. Furthermore, AlaSn can partake in macrocyclizations, exemplified by the synthesis of medium-size cyclic peptides with various topologies. Taken together, metalated alanine AlaSn demonstrates unparalleled scope and represents a new type of umpolung reagent suitable for structure-activity relationship studies and peptide diversification.