Computational Exploration of the Mechanism of Critical Steps in the Biomimetic Synthesis of Preuisolactone A, and Discovery of New Ambimodal (5 + 2)/(4 + 2) Cycloadditions

• Published in: Journal of the American Chemical Society Vol. 143; no. 17; pp. 6601 - 6608
• Main Authors: Zhang, Hong, Novak, Alexander J. E, Jamieson, Cooper S, Xue, Xiao-Song, Chen, Shuming, Trauner, Dirk, Houk, K. N
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.05.2021
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.1c01856

Computational studies with ωB97X-D density functional theory of the mechanisms of the steps in Trauner’s biomimetic synthesis of preuisolactone A have elaborated and refined mechanisms of several unique processes. An ambimodal transition state has been identified for the cycloaddition between an o-quinone and a hydroxy-o-quinone; this leads to both (5 + 2) (with H shift) and (4 + 2) cycloaddition products, which can in principle interconvert via α-ketol rearrangements. The origins of periselectivity of this ambimodal cycloaddition have been investigated computationally with molecular dynamics simulations and tested further by an experimental study. In the presence of bicarbonate ions, the deprotonated hydroxy-o-quinone leads to only the (5 + 2) cycloaddition adduct. A new mechanism for a benzilic acid rearrangement resulting in ring contraction is proposed.