Tampellini Nicolò, Mercado Brandon Q, Miller Scott J
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
J Am Chem Soc. 2025 Feb 5;147(5):4624-4630. doi: 10.1021/jacs.4c17080. Epub 2025 Jan 23.
Chiral medium-sized rings, albeit displaying attractive properties for drug development, suffer from numerous synthetic challenges due to difficult cyclization steps that must take place to form these unusually strained, atropisomeric rings from sterically crowded precursors. In fact, catalytic enantioselective cyclization methods for the formation of chiral seven-membered rings are unknown, and the corresponding eight-membered variants are also sparse. In this work, we present a substrate preorganization-based, enantioselective, organocatalytic strategy to construct seven- and eight-membered rings featuring chirality that is intrinsic to the ring in the absence of singular stereogenic atoms or single bond axes of chirality. The reactions proceed under mild conditions and with high levels of stereocontrol. Notably, the same bifunctional iminophosphorane chiral catalyst orchestrates the cyclization of substrates of two different ring sizes, under two different mechanistic paradigms. We envision that the mechanistic and ring size versatility of this method could guide further applications of asymmetric catalysis to other challenging cyclization reactions.
手性中等大小的环尽管在药物开发方面展现出诱人的特性，但由于从空间拥挤的前体形成这些异常张力的阻转异构环时必须进行困难的环化步骤，因而面临众多合成挑战。事实上，用于形成手性七元环的催化对映选择性环化方法尚不存在，相应的八元环变体也很稀少。在这项工作中，我们提出了一种基于底物预组织的对映选择性有机催化策略，用于构建七元和八元环，这些环在手性不依赖于单个手性中心原子或单键手性轴的情况下具有固有的手性。反应在温和条件下进行，且具有高度的立体控制。值得注意的是，相同的双功能亚胺基膦烷手性催化剂在两种不同的机理范式下催化两种不同环大小底物的环化反应。我们设想，该方法的机理和环大小通用性可以指导不对称催化在其他具有挑战性的环化反应中的进一步应用。
