Development and Investigation of an Organocatalytic Enantioselective [10 + 2] Cycloaddition

A stereoselective [10 + 2] cycloaddition
for the reaction of homologated
indenecarbaldehydes with α,β-unsaturated aldehydes, providing
tetrahydrocyclopenta­[a]­indenes, has been developed
and investigated mechanistically. The reaction proceeds via an aminocatalytic double Michael addition in high formal peri-,
diastereo-, and enatioselectivity (up to 99% enantiomeric excess).
Mechanistic investigations conclude that the reaction takes advantage
of the in situ generation of a highly reactive amino
isobenzofulvene intermediate via an aromative aminocatalytic
strategy. A significant nonlinear effect is observed, consistent with
a dual-activation model. Kinetic studies suggest a stepwise mechanism
which is further supported by the identification and isolation of
diastereomeric precyclization intermediates. These intermediates showed
that in the presence of the aminocatalyst, they re-enter the catalytic
cycle and afford the [10 + 2] cycloadduct with the same stereoselectivity
observed in the prototypical reaction. Density functional theory calculations
identified a Curtin–Hammett scenario where the stereoisomer
of the [10 + 2] cycloadduct is determined by downstream species. These
mechanistic investigations provide an understanding of the reaction
pathway and stereoselectivity and continue to increase the knowledge
of higher-order cycloadditions.