Organic Chemistry

Organometallic AlaM Reagents for Umpolung Peptide Diversification

Maciej Walczak University of Colorado at Boulder


Selective modification of peptides and proteins is emerging as a promising strategy to develop novel mechanistic probes and prepare compounds with translational potential. While many methods to perform direct bioconjugation rely on reactions with dehydroalanine, an alternative strategy capitalizing on polarity reversal at the β carbon in amino acids can open access to a new type of diversification reactions characterized by absolute control of regio- and stereoselectivity. Here, we report that alanine carbastannatranes AlaSn can serve as a universal synthon in various C-C and C-heteroatom bond-forming reactions demonstrated in over 50 diverse examples. These reagents are compatible with peptide and protein manipulation techniques and undergo chemoselective conjugation in minutes when promoted by Pd(0). Despite their increased nucleophilicity and propensity to transfer the alkyl group, AlaSn operate 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 (7-13 membered macrocycles). Taken together, metalated alanine AlaSn demonstrate unparalleled scope and represent a new type of umpolung reagents suitable for structure-activity relationship studies and peptide diversification.


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Supplementary material

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SI Combined