Direct conversion of amino acids to oxetanol bioisosteres via photoredox catalysis Journal Article
| Authors: | Delos Reyes, A. M. V.; Nieves Escobar, C. S.; Muñoz, A.; Huffman, M. I.; Tan, D. S. |
| Article Title: | 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. © 2023 The Royal Society of Chemistry. |
| Keywords: | catalysis; amino acids; ketones; carboxylic acids; hydrogen bonds; reaction intermediates; amino-acids; pharmacological properties; direct conversion; chlorine compounds; structural feature; condition; chromium compounds; bioisosteres; biological targets; bonding capacity; cr-free; photoredox catalysis |
| Journal Title: | Chemical Science |
| Volume: | 14 |
| Issue: | 38 |
| ISSN: | 2041-6520 |
| Publisher: | Royal Society of Chemistry |
| Date Published: | 2023-10-14 |
| Start Page: | 10524 |
| End Page: | 10531 |
| Language: | English |
| DOI: | 10.1039/d3sc00936j |
| PROVIDER: | scopus |
| PMCID: | PMC10548506 |
| PUBMED: | 37799988 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Derek S. Tan -- Source: Scopus |
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