Synthesis of Bicyclic Hemiacetals Catalyzed by Unnatural Densely Substituted γ-Dipeptides

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.Financial support for this work was provided by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICINNFEDER, Grants PID2019-104772GB-I00 and RED2018-102387-T) and the Gobierno Vasco/Eusko Jaurlaritza (GV/EJ, Grant IT-1553-22). M.d.G.R. thanks the DIPC and UPV/EHU for her postdoctoral contract. M.A. thanks the Gobierno Vasco/Eusko Jaurlaritza for her Ph.D. grant. J.Z. thanks the China Scholarship Council for his Ph.D. grant (CSC 201908390051). The authors also thank the SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of analytical and computational resources