Development and Investigation of an Organocatalytic Enantioselective [10 + 2] Cycloaddition
David McLeod, Joseph A. Izzo, Danny K. B. Jørgensen, Rune F. Lauridsen, Karl Anker Jørgensen
Abstract
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.