Ene reaction and Prins cyclization. Synthesis of 2H-chromenes and octahydro-2H-tetrahydropyrans via tandem process promoted by iron(III) salts Humberto A. Rodríguez 1 , Daniel A. Cruz 1 , Juan I. Padrón 1 , and Israel Fernández 2 1 Instituto de Productos Naturales y Agrobiología, Spain 2 Departamento de Química Orgánica I and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad Complutense de Madrid, Spain The 2H -tetrahydropyran ( 2H -THP) moiety is frequently present in a diverse array of natural products, encompassing marine toxins, pheromones, and acetogenins, which have exhibited diverse biological activities. 1 Herein, we describe a pioneering approach for the synthesis of tetrasubstituted 2H -THP and octahydro- 2H - chromenes derivatives. This strategy involves a tandem process comprising of an ene reaction succeeded by a Prins cyclization, where iron(III) salts act as catalysts.
Figure 1. Proposed mechanism of the tandem process: ene reaction - Prins cyclization. The ene reaction is a versatile methodology for the fabrication of homoallylic alcohols, which involves the activation of the allylic C-H bond and a consequent allylic transposition of the C-C double bond. The E - and Z - homoallylic alcohols procured from this reaction can serve as substrates for a well-established Prins cyclization reaction. This reaction implies an oxocarbenium intermediate, which is pivotal for the formation of 2H -THP. 2 The reaction is characterized by high regioselectivity and delivers the corresponding tetrahydropyran derivatives with remarkable yield. The reaction can be co-catalyzed by utilizing stoichiometric quantities of TMSX, and the catalyst can be conveniently regenerated, making this an efficient and practical protocol for the synthesis of 2H -THPs and octahydro- 2H -Chromenes. Acknowledgments : This research was supported by the Ministerio de Ciencia e Innovación (MCIN), la Agencia Estatal de Investigación (AEI), and Fondo Europeo de Desarrollo Regional (FEDER). Grant PID2021-126747NB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe.”. H.A.R. thanks the Spanish MCIU for an FPU fellowship. References 1. Inoue, M. Chem. Rev. 2005 , 105 , 4379. 2. Pérez, S. J.; Purino, M.; Miranda, P. O.; Martín, V. S.; Fernández, I.; Padrón, J. I. Chem. - A Eur. J. 2015 , 21 , 1521.
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