Journal
ACS CATALYSIS
Volume 10, Issue 18, Pages 10784-10793Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.0c03378
Keywords
aminocatalysis; higher-order cycloadditions; DFT; nonlinear effect; Curtin-Hammett principle; isobenzofulvenes
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Funding
- Villum Investigator grant [25867]
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A stereoselective [10 + 2] cycloaddition for the reaction of homologated indenecarbaldehydes with alpha,beta-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.
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