Direct conversion of N-Aryl alpha-amino acids to 3-oxetanol bioisosteres via Cr/photoredox catalysis Avelyn Mae Delos Reyes 2 , 1 Alberto Muñoz, 2 and Derek S. Tan 1,2,3 1 Weill Cornell Graduate School of Medical Sciences, USA, 2 Sloan Kettering Institute, USA, 3 Memorial Sloan Kettering Cancer Center, USA Carboxylic acids are an important structural feature in many drugs, but are associated with a number of unfavorable pharmacological properties. 1-7 To address this problem, carboxylic acids can be replaced with bioisosteric mimics that interact similarly with biological targets but have improved properties. 8 Recently, 3-oxetanols have been identified as useful carboxylic acid bioisosteres that maintain similar hydrogen- bonding capacity while decreasing acidity and increasing lipophilicity. 9 However, the installation of 3-oxetanols generally requires multistep de novo synthesis, presenting an obstacle to full investigation of these promising bioisosteres. 9-12 We report a new approach involving the direct conversion of carboxylic acids to 3-oxetanols using a dual Cr/photoredox catalytic system. The transformation is effective for a variety of N -aryl α-amino acid substrates. Mechanistic studies suggest that the reaction proceeds via addition of an alkyl Cr-reagent formed in situ to 3-oxetanone. References 1. Mao, F.; Ni, W.; Xu, X.; Wang, H.; Wang, J.; Ji, M.; Li, J. Molecules 2016 , 21 , 1–18. 2. Ghuman, J.; Zunszain, P. A.; Petitpas, I.; Bhattacharya, A. A.; Otagiri, M.; Curry, S. J. Mol. Biol. 2005 , 353 , 38–52. 3. Skonberg, C.; Olsen, J.; Madsen, K. G.; Hansen, S. H.; Grillo, M. P. 2008 , 4 , 425–438. 4. Kalgutkar, A.; Daniels, J. RSC Drug Discovery Series 2010 , 1 , 99–167. 5. Ballatore, C.; Huryn, D. M.; Smith III, A. B. Chem. Med. Chem. 2013 , 8 , 385–395. 6. Charifson, P. S.; Walters, W. P. J. Med. Chem. 2014 , 57 , 9701–9717. 7. Varma, M. V.; Feng, B.; Obach, R. S.; Troutman, M. D.; Chupka, J.; Miller, H. R.; El-Kattan, A. J. Med. Chem. 2009 , 52 , 4844–4852. 8. Brown, N. In Bioisosteres in Medicinal Chemistry , 2012, pp 1–14. 9. Lassalas, P.; Oukoloff, K.; Makani, V.; James, M.; Tran, V.; Yao, Y.; Huang, L.; Vijayendran, K.; Monti, L.; Trojanowski, J. Q.; Lee, V. M. Y.; Kozlowski, M. C.; Smith, A. B.; Brunden, K. R.; Ballatore, C. Med. Chem. Lett. 2017 , 8 , 864–868. 10. Bach, T.; J dicke, K.; Kather, K.; Fr hlich, R. J. Am. Chem. Soc. 1997 , 119 , 2437–2445. 11. Witty, D. R.; Fleet, G. W. J.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Tetrahedron Lett. 1990 , 31 , 4787–4790. 12. Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F. Chem. Rev. 2016 , 116 , 12150–12233.
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