Homologation of Carboxylic Acids Using a Radical-Polar Conjunctive Reagent

Abstract

Homologations of organic molecules that add a carbon atom to the substrate are useful in drug discovery to access compounds with improved properties that otherwise present a synthetic challenge. Carboxylic acids are present in many bioactive molecules and are widely available building blocks for chemical synthesis, yet their direct homologation is unknown. This valuable transformation currently necessitates implementation of multistep processes that require the use of carboxylic acid derivatives rather than the native substrates, and commonly involves highly reactive and toxic reagents. Herein, we report the first one-step homologation directly from native carboxylic acids using a novel, bench-stable (1-phosphoryl)vinyl sulfonate reagent under mild conditions. This strategy was applied to a wide range of aliphatic carboxylic acid building blocks and biologically relevant complex molecules to access an array of ester, amide, and carboxylic acid homologues in a single step. The (1-phosphoryl)vinyl sulfonate reagent participates in complementary homologation protocols featuring either radical-chain transfer or organic photoredox catalysis and introduces a new synthon, the distonic acylium radical, for molecular diversification. We anticipate this strategy, which addresses a long-standing challenge in organic synthesis, will expedite drug discovery by enabling the rapid synthesis of diversified homologues.