Issue 38, 2023

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.

Graphical abstract: Direct conversion of amino acids to oxetanol bioisosteres via photoredox catalysis

Supplementary files

Article information

Article type
Edge Article
Submitted
17 feb 2023
Accepted
26 aug 2023
First published
15 sep 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 10524-10531

Direct conversion of amino acids to oxetanol bioisosteres via photoredox catalysis

A. M. V. Delos Reyes, C. S. Nieves Escobar, A. Muñoz, M. I. Huffman and D. S. Tan, Chem. Sci., 2023, 14, 10524 DOI: 10.1039/D3SC00936J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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