Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States.
Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
J Am Chem Soc. 2023 Feb 8;145(5):3092-3100. doi: 10.1021/jacs.2c12163. Epub 2023 Jan 25.
The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for parasubstituted arene rings, appearing in a number of lead pharmaceutical candidates. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often nonmodular sequences. While challenging, direct functionalization of the strong bridge BCP C-H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here, we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C-H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one-step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogues, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.
用饱和碳环结构替代芳环在药物发现中引起了极大的兴趣，因为取代后可能改善药代动力学性质。特别是，1,3-二官能化双环[1.1.1]戊烷（BCP）已被广泛用作取代芳环的生物等排体，出现在许多先导药物候选物中。然而，尽管 2-取代的 BCP 作为邻位或间位取代的芳环替代品具有药物价值，但这些支架的通用和快速合成仍然难以实现。目前，2-取代的 BCP 的方法依赖于在 BCP 核心构建之前安装桥取代基，导致步骤数冗长且通常非模块化序列。虽然具有挑战性，但直接官能化强桥 BCP C-H 键将提供一种更精简的途径来获得多种 2-取代的 BCP。在这里，我们报告了一种通过 BCP 核心的自由基 C-H 抽提进行桥官能化的通用合成关键策略。通过温和地生成强氢原子抽提剂，我们可以一锅快速合成新型 2-取代的 BCP 合成关键中间体。然后，这些合成关键中间体作为复杂 2-取代的 BCP 的常见前体，允许通过两种新的金属光氧化还原协议一步获得以前无法获得的 2 位上的许多亲电体和亲核片段。总的来说，该平台能够快速合成四个药物类似物，它们的性能与含芳基的类似物相似或有所改善，这表明这些 2-取代的 BCP 在药物开发中的潜力。
