Alama Layth, Frank Nils, Brücher Lennart, Nienhaus Johanna, List Benjamin
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
ACS Catal. 2025 May 2;15(10):8297-8302. doi: 10.1021/acscatal.5c02225. eCollection 2025 May 16.
The bioisosteric replacement of 2D aromatic scaffolds with sp-rich surrogates has become an important design element in modern medicinal chemistry. Within the sp-rich world, the azabicyclo[2.1.1]hexane (aza-BCH) scaffold stands out as a pyrrolidine replacement and a useful building block. However, despite recent advancements in the field, a modular enantioselective synthesis of aza-BCHs remains challenging. In this study, we introduce an asymmetric organocatalytic approach relying on a confined imidodiphosphorimidate (IDPi) Brønsted acid that catalyzes the formal cycloaddition reaction of bicyclo[1.1.0]butanes (BCBs) with -aryl imines under mild conditions, generating chiral aza-BCHs with high enantioselectivity (up to 99:1 er). Notably, the reaction proceeds effectively with a range of BCBs featuring ester, ketone, and amide functionalities. Experimental studies suggest that the reaction proceeds via a stepwise mechanism.
用富含sp的替代物对二维芳香骨架进行生物电子等排体替代已成为现代药物化学中的一个重要设计元素。在富含sp的领域中，氮杂双环[2.1.1]己烷（aza-BCH）骨架作为吡咯烷替代物和有用的结构单元脱颖而出。然而，尽管该领域最近取得了进展，但aza-BCHs的模块化对映选择性合成仍然具有挑战性。在本研究中，我们引入了一种不对称有机催化方法，该方法依赖于一种受限的亚氨基二磷酸亚胺酯（IDPi）布朗斯特酸，它在温和条件下催化双环[1.1.0]丁烷（BCB）与芳基亚胺的形式环加成反应，以高对映选择性（高达99:1的对映体过量）生成手性aza-BCHs。值得注意的是，该反应对一系列具有酯、酮和酰胺官能团的BCB都能有效进行。实验研究表明，该反应通过逐步机理进行。
