Wu Licheng, McIntyre Baylee N, Wu Supeng, Jiao Ziqi, Fox Carter B, Schley Nathan D, Schuppe Alexander W
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
J Am Chem Soc. 2025 Apr 2;147(13):11080-11088. doi: 10.1021/jacs.4c16769. Epub 2025 Mar 19.
Quaternary stereocenters play a crucial role in shaping both the molecular topology of small molecules and the outcome of stereoselective transformations. While considerable progress has been achieved in constructing highly substituted carbon centers with varied substitution patterns, the stereoselective synthesis of quaternary carbon centers remains a significant challenge. Here we report a protocol for the precise manipulation of quaternary stereocenters through epimerization. The critical design element of our ketone α-epimerization process was developing a photoactive imine, which circumvents the numerous deleterious pathways of carbonyl photochemistry. Excitation of this imine with visible light in the presence of a photocatalyst enables reversible C-C bond cleavage and reformation to vary the stereochemistry of the quaternary center. This approach allows us to override intrinsic stereochemical outcomes of C-C bond construction, therefore providing novel tactics for retrosynthetic planning. The broad utility of this protocol was demonstrated by the topological alteration of various classes of carbocyclic scaffolds bearing diverse functional groups.
季碳立体中心在塑造小分子的分子拓扑结构以及立体选择性转化的结果方面起着至关重要的作用。虽然在构建具有不同取代模式的高度取代碳中心方面已经取得了相当大的进展，但季碳中心的立体选择性合成仍然是一个重大挑战。在此，我们报告了一种通过差向异构化精确操纵季碳立体中心的方法。我们的酮α-差向异构化过程的关键设计要素是开发一种光活性亚胺，它规避了羰基光化学的众多有害途径。在光催化剂存在下用可见光激发这种亚胺能够实现可逆的C-C键断裂和重新形成，从而改变季碳中心的立体化学。这种方法使我们能够超越C-C键构建的固有立体化学结果，因此为逆合成规划提供了新策略。通过对带有各种官能团的各类碳环支架进行拓扑改变，证明了该方法的广泛实用性。
