Direct conversion of amino acids to oxetanol bioisosteres via photoredox catalysis

Abstract

Carboxylic acids are an important structural feature in many drugs, but are associated with a number of unfavorable pharmacological properties. To address this problem, carboxylic acids can be replaced with bioisosteric mimics that interact similarly with biological targets but avoid these liabilities. Recently, 3-oxetanols have been identified as useful carboxylic acid bioisosteres that maintain similar hydrogen-bonding capacity while decreasing acidity and increasing lipophilicity. However, the installation of 3-oxetanols generally requires multistep de novo synthesis, presenting an obstacle to investigation of these promising bioisosteres. Herein, we report a new synthetic approach involving direct conversion of carboxylic acids to 3-oxetanols using a photoredox-catalyzed decarboxylative addition to 3-oxetanone. Two versions of the transformation have been developed, in the presence or absence of CrCl₃ and TMSCl cocatalysts. The reactions are effective for a variety of N-aryl α-amino acids and have excellent functional group tolerance. The Cr-free conditions generally provide higher yields and avoid the use of chromium reagents. Further, the Cr-free conditions were extended to a series of N,N-dialkyl α-amino acid substrates. Mechanistic studies suggest that the Cr-mediated reaction proceeds predominantly via in situ formation of an alkyl-Cr intermediate while the Cr-free reaction proceeds largely via radical addition to a Brønsted acid-activated ketone. Chain propagation processes provide quantum yields of 5 and 10, respectively.