Diastereoselective Norrish-Yang photocyclization of 2-(hydroxyimino)aldehydes Antonio Di Sabato 1 , Francesca D’Acunzo 2 , Dario Filippini 1 , Fabrizio Vetica 1 , Antonio Brasiello 3 , Davide Corinti 4 , Enrico Bodo 1 , Cinzia Michenzi 1 , Edoardo Panzetta 1 , Patrizia Gentili 1 1 La Sapienza University of Rome, Italy, 2 Institute of Biological Systems (ISB), Rome, Italy, 3 Department of Chemical Engineering Materials Environment, Rome, Italy, 4 Dipartimento di Chimica e Tecnologie del Farmaco, Rome, Italy The field of organic photochemistry, usually considered born in 1912 with the pioneeristic work of G. Ciamician, 1 remained mostly unexplored throughout the XX century. In recent years, a renewed interest has been growing in the field, mainly due to the availability of more efficient light sources such as LEDs and CFLs. 2 An important photochemical reaction of ketones and aldehydes is the Norrish-Yang cyclization, which leads to the formation of valuable hydroxylated 4-membered rings, a scaffold present in many natural and bioactive molecules. 3 The only requirement for this reactions to happen is the presence of γ-hydrogen in the substrate, thus avoiding the use of costly and polluting catalysts or photosensitizers, in full respect of Green Chemistry principles. Herein we present the highly efficient diastereoselective synthesis of 2-hydroxy-cyclobutanone oximes (CBOs) via the Norrish-Yang photocyclization of 2-(hydroxyimino)aldehydes (HIAs). This synthetic methodology is applicable to variously substituted HIAs, with little to none competing fragmentation pathways, full conversions of the starting material, high yields (up to 95 %), high diastereoselectivity (up to > 20:1 dr) and affording the resulting CBOs in high levels of purity by simple evaporation of the reaction solvent. The study of the reaction coordinate through DFT calculations further contributed to have deeper insights on the chemoselectivity and stereochemical outcome of the reaction. 4 References 1. G. Ciamician, Science, 1912, 36 , 385; (b) T. P. Yoon, M. A. Ischay, J. Du, Nat. Chem., 2010, 2 , 527. 2. M. Ruggeri, A. W. Dombrowski, S. W. Djuric, I. R. Baxendale, ChemPhotoChem, 2019, 3 , 1212; 3. K. A. Konieczny, A. Szczurek, J. Bąkowicz, R. Siedlecka, A. Ciesielski, M. K. Cyrański, I. Turowska-Tyrk, Cryst. Growth Des. 2020, 20 , 5061; 4. H. Liu, H. Gao, S. Wang, S. Yao, F. Wu, Y. Zhao, K. S. Chan, Z. Shen, Chem. Eur. J. 2020, 26 , 12418; 5. J. Paternoga, J. Kühlborn, N. O. Rossdam, T. Opatz, J. Org. Chem. 2021, 86 , 3232. 6. B. Tang, R. Paton Org. Lett. 2019 , 21, 1243; 7. Y. Chen, J. Zhou, S. Li, J. Xu, Nat. Prod. Rep., 2019, 36 , 263.A. Di Sabato, F. D’Acunzo, D. Filippini, F. Vetica, A. Brasiello, D. Corinti, E. Bodo, C. Michenzi, E. Panzetta, P. entili,J.Org. Chem.under revision.
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