Since aminocatalysis was established as a potent tool for asymmetric synthesis, the principle of vinylogy has allowed for expanding the pool of substrates and transformations which can be accommodated. Aminocatalytic activation of unsaturated carbaldehydes leads to the formation of conjugated species which may undergo cycloaddition chemistry, and in recent years enantioselective processes beyond traditional Diels-Alder chemistry have been developed. Higher-order cycloadditions are those which involve more than six π-electrons; they depend on reactive cycloaddends, but catalytic generation may allow for their highly controlled usage. The merger of aminocatalysis and higher-order cycloadditions permits for the stereoselective synthesis of complex, multicyclic molecular frameworks, and among these, scaffolds belonging to the cyclazine family were deemed an exciting synthetic challenge. Through the development of enantioselective aminocatalytic [12+2] and [8+2] cycloadditions, cycl[3.2.2]azines (pyrrolo[2,1,5-<i>cd</i>]indolizines) and their benzofused counterparts have been obtained with up to four contiguous stereocenters. Key to the construction of these tricyclic cores containing a central ring-junction nitrogen atom was the design of cycloaddends as well as catalytic system. While the Nobel prize in chemistry of 2021 acknowledges organocatalysis as a mature scientific field, the progress of organocatalytic higher-order cycloadditions within the last five years inspires continued efforts to bring this exciting chemistry down new avenues.

Aminocatalytic higher-order cycloadditions: Toward the cycl[3.2.2]azine core

ACS Spring 2022

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