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

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The first controlled and stereoselective [10+2] cycloaddition has been developed. The reaction generates a tricyclic ring system with four contiguous stereocenters via an aminocatalytic cascade in high diastereo- and enantioselectivity for a variety of different homologated indene carbaldehydes and a,b-unsaturated aldehydes. It also exhibits exceptional formal periselectivity among five different potential reaction paths. The reaction takes advantage of in situ generation of a highly reactive isobenzofulvene intermediate via an aromative aminocatalytic strategy. Mechanistic investigations show that the reaction displays a significant nonlinear effect, consistent with a dual-activation model. Kinetic studies suggest a stepwise mechanism which is further supported by the identification and isolation of diastereomeric pre-cyclization intermediates. These intermediates have been shown, in the presence of the aminocatalyst, to re-enter the catalytic cycle affording the observed optically active [10+2] cycloadduct with the same level of stereoinduction as obtained by the synthetic procedure. 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.
Original languageEnglish
JournalJournal of the American Chemical Society
Pages (from-to)1-16
Number of pages16
ISSN0002-7863
Publication statusIn preparation - 14 Jan 2020

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