LiCl-driven direct synthesis of mono-protected esters from long-chain dicarboxylic fatty acids

Abstract

A one-step mono-esterification method for long-chain dicarboxylic fatty acids [HO₂C(CH₂)_nCO₂H; n ≥ 14] was developed using TFAA (trifluoroacetic anhydride) and LiCl as esterification reagents. This approach was particularly effective for synthesizing mono tert-butyl esters, which are key intermediates in the production of segments of semaglutide and tirzepatide—two blockbuster drugs with their 2024 sales valued in billions of dollars. The addition of LiCl critically enhanced the monoester selectivity over diester formation. Mechanistic studies suggest that this selectivity originates from a shielding effect, where LiCl interacts with one terminal carboxylic acid group.