Integrating Umpolung and CO2 Shuttling Strategies for the Synthesis of 12C- and 13C-α-Ketoacids from Aldehydes

Abstract

The direct carboxylation of aldehydes with CO₂ is rare due to the polarity mismatch between these two electrophilic substrates. To address this challenge, we propose a sequential approach for synthesizing α-ketoacids from commercially available aldehydes by integrating umpolung and CO₂ shuttling strategies. This transition metal-free shuttle carboxylation method enables the transfer of CO₂ from triphenylacetic acid potassium salt to thioacetal, eliminating the need for handling pressurized CO₂ gas or using specialized equipment, while also enhancing the reaction’s functional group tolerance. Furthermore, the use of stoichiometric or slightly excess amounts of triphenylacetic acid potassium salt as a formal CO₂ donor makes it suitable for complete ¹³C labeling of α-ketoacids.