The development of new cyclization strategies for rapid assembly of complex molecules from simple precursors will be described. Intramolecular alkynyl Prins reactions provide a starting point for both halo-Nazarov cyclization cascades and a novel double annulation process that builds fused heterobicyclic systems. The Prins reaction constitutes an efficient coupling cascade, beginning with the condensation of two simple precursors, and then undergoing an annulation process. In the case of the halo-Nazarov cyclization protocol, the cascade continues with ionization and electrocyclization. These sequences are one-pot stereospecific cationic cascades that can build up to three stereogenic centers from achiral precursors. We also demonstrate a sterochemical relay that occurs with memory of chirality, in which enantioenriched halocyclopentene derivatives can be prepared from the coupling/ cyclization of nonracemic chiral secondary alkynyl alcohols and simple aldehydes. In the case of the double annulation, a series of oxacyclo[3,2-c]azepine and azocine ring systems can be prepared from alkynyl alcohols and hemiaminal derivatives. Finally, an cascade combining alkynyl aza-Prins cyclization with oxidative initiation of the halo-Nazarov cyclization is described.

New cyclization strategies enabled by the alkynyl Prins reaction

ACS Spring 2022

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