Eenheid Algemene Chemie (ALGC), Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050Brussels, Belgium.
J Org Chem. 2023 Feb 17;88(4):2046-2056. doi: 10.1021/acs.joc.2c02318. Epub 2023 Feb 3.
Anti-Felkin-Anh diastereoselectivity can be achieved for nucleophilic additions to α-chiral ketones upon stretching the ketone with a mechanical pulling force. Herein, a mechanochemical Felkin-Anh model is proposed for predicting the outcome of a nucleophilic addition to an α-chiral ketone. Essentially, the fully stretched chiral ketone has one substituent shielding each side of the carbonyl, in contrast to the Felkin-Anh model, in which free rotation around a bond is required to achieve the two rotamers of the ketone. Depending on the pulling scenario, either Felkin-Anh or anti-Felkin-Anh diastereoselectivity is obtained. The model is entirely based on the distance between the pulling points, which is maximized in the anti-periplanar arrangement. The major diastereomer is associated with the approach with the least steric interactions. The intuitive model is validated by means of mechanochemical density functional theory calculations. Importantly, the ketone is fully stretched in the sub 1 nN force regime, thus minimizing the risk of undesired homolytic bond rupture. Moreover, the mechanical force is not used for lowering the reaction barriers associated with the nucleophilic addition; instead, it is solely applied for locking the conformation of a molecule and provoking otherwise inaccessible reaction pathways on the force-modified potential energy surface.
在手性酮的羰基处施加机械拉力，可以实现亲核加成的反 Felkin-Anh 非对映选择性。在此，提出了一个机械化学的 Felkin-Anh 模型，用于预测手性α-酮的亲核加成反应的结果。本质上，完全拉伸的手性酮的一个取代基屏蔽羰基的每一侧，与 Felkin-Anh 模型相反，在 Felkin-Anh 模型中，需要围绕键自由旋转才能实现酮的两种构象。根据拉伸情况，可以得到 Felkin-Anh 或反 Felkin-Anh 非对映选择性。该模型完全基于拉力点之间的距离，在反共面排列中距离最大。主要的非对映异构体与最小空间位阻相互作用的接近相关。通过机械化学密度泛函理论计算验证了直观模型。重要的是，在低于 1 nN 的力的作用下，酮完全被拉伸，从而最大限度地降低了不期望的均裂键断裂的风险。此外，机械力不是用于降低与亲核加成相关的反应势垒；相反，它仅用于锁定分子的构象，并在力修饰的势能表面上引发原本无法到达的反应途径。
