Abstract
Density functional theory calculations suggest that asymmetric boronate addition to o-quinone methides proceeds via a Lewis acid catalyzed process through a closed six-membered transition structure. The BINOL-derived catalyst undergoes an exchange process with the original ethoxide boronate ligands. This activation mode successfully accounts for the sense and level of enantioselectivity observed experimentally. A qualitative model which accurately predicts the observed enantioselectivity has been developed and is consistent with results from our study of ketone propargylation demonstrating the reaction model's generality. The effects of replacing the BINOL framework with H8-BINOL have been rationalized.
Highlights
Density functional theory calculations suggest that asymmetric boronate addition to o-quinone methides proceeds via a Lewis acid catalyzed process through a closed sixmembered transition structure
Investigation of uncatalyzed boronate addition to o-Quinone methides (oQMs) indicated that the reaction proceeds via a cyclic, six-membered ring sofa-like transition structure (TS) when both arylboronate and alkenylboronate nucleophiles were employed, TS-1 and TS-3, respectively (Figures 1 and 2)
When the protons of the nucleophile and oQM at the reacting centers are syn (TS-4) the TS is destabilized by 2.9 kcal mol−1 relative to TS-3, which benefits from the more sterically favorable anti arrangement
Summary
O-Quinone methides (oQMs) have been proposed as key reactive intermediates in the total synthesis of many natural products including carpanone,[1] tectol,[2] and rubioncolin A.3 Notable reactions involving oQMs include hetero-Diels−Alder reactions[4,5] and nucleophilic addition at the exocyclic carbon in 1,4-conjugate addition reactions.[6]. A full understanding of selectivity-controlling factors enables rational design of further experimental work, helping develop this and related transformations Exploration of this reaction would give us an insight into the generality of the reaction model we have developed for ketone propargylation.[13]. We report the results of DFT calculations that provide a mechanistic insight into this important transformation The results of these calculations indicate that the reaction proceeds via a six-membered ring sofa-like transition structure (TS) corresponding to a Lewis acid type activation mode in which the chiral diol completely displaces the original boronate ligands. This pathway accurately reproduces the experimentally observed enantioselectivity. A qualitative model has been developed which accurately predicts the observed enantioselectivity and agrees with results from our study of ketone propargylation demonstrating the generality of this reaction model
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