Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles

We recently reported a chiral phosphoric acid (CPA) catalyzed enantioselective photomediated ring contraction of piperidines and other saturated heterocycles. By extruding a single heteroatom from a ring, this transformation builds desirable C(sp3)–C(sp3) bonds in the ring contracted products; however, the origins of enantioselectivity remain poorly understood. In this work, enantioselectivity of the ring contraction has been explored across an expanded structurally diverse substrate scope, revealing a wide range of enantioselectivities (0–99%) using two distinct CPA catalysts. Mechanistic investigations support rate-determining excitation that generates short-lived achiral intermediates that are intercepted by the CPA in an enantiodetermining ring closure. The effects of competitive uncatalyzed reactivity and light-driven reversibility of the enantiodetermining ring closure on enantioselectivity have been elucidated. Statistical models were built by regressing the range of enantioselectivities from the substrate scope against key structural features of the products for both CPA catalysts. The resultant models suggested distinct factors that influence the enantioselectivity response for each catalyst and enabled rational modification of a pharmaceutically relevant target molecule to improve enantioselectivity. Finally, density functional theory (DFT)-based transition state analysis identified distinct noncovalent interactions with each catalyst that correlated with the unique selectivity-relevant features uncovered through statistical modeling. Our findings not only offer comprehensive insight into the origins of enantioselectivity in this system but should also aid future development of related photomediated CPA-catalyzed reactions.

我们此前报道了一例手性磷酸（chiral phosphoric acid, CPA）催化的、光介导的哌啶类及其他饱和杂环化合物的对映选择性环收缩反应。该转化通过从环骨架中脱除单个杂原子，在环收缩产物中构建了极具应用价值的C(sp³)–C(sp³)键；然而，该反应的对映选择性起源至今仍不甚明晰。本研究针对扩大的结构多样性底物范围，系统探究了该环收缩反应的对映选择性，结果显示使用两种不同的CPA催化剂时，产物对映选择性跨度为0%至99%。机理研究表明，反应的决速步骤为激发过程，该过程会生成寿命较短的非手性中间体，随后由CPA在对映决定型环闭合步骤中捕获该中间体。本研究还阐明了竞争性非催化反应路径，以及对映决定型环闭合步骤的光驱动可逆性，二者对对映选择性的影响。研究人员通过将底物范围对应的对映选择性范围，与两种CPA催化剂对应产物的关键结构特征进行回归分析，构建了统计模型。所得模型揭示了影响两种催化剂各自对映选择性响应的不同因素，并据此实现了对一个具有药学相关价值的目标分子的合理修饰，提升了其反应的对映选择性。最后，基于密度泛函理论（density functional theory, DFT）的过渡态分析，鉴定出了与每种催化剂结合的独特非共价相互作用，该相互作用与统计建模揭示的、与选择性相关的独特特征相契合。本研究结果不仅为该体系中对映选择性的起源提供了全面的机制认知，也将为未来相关光介导CPA催化反应的开发提供重要指导。