美国芝加哥大学Dong Guangbin团队报道了环丁酮与1,5-烯炔之间铑催化的异对映和对映选择性发散环化反应——复合物富C(sp3)支架的偿还构建。相关研究成果发表在2022年11月18日出版的《美国化学会杂志》。

鉴于药物发现对“escape from flatland”概念的新需求，能够有效构建具有多立体中心的复杂三维结构的合成方法变得越来越有价值。

该文中，研究人员描述了Rh（I）催化的环丁烷和1,5-炔基之间的分子内环化，以构建复杂的富含C（sp3）的支架。用不同的催化剂实现了不同的反应，并获得了优异的非对映选择性和对映选择性。使用（R）-H8-binap作为配体有利于形成具有多个四元立体中心的双双环支架，而（R）-segphos配体更倾向于生成四氢氮杂皮诺酮产物。由于酮部分的多功能反应性，这些富含C（sp3）的支架可以进一步功能化。

实验和计算机制研究支持一种反应途径，包括烯基环金属化、1,2-羰基加成，然后消除β-碳；不同的反应性由决定Rh烷基迁移剂插入步骤的产物决定。

附：英文原文

Title: Rhodium-Catalyzed Diastereo- and Enantioselective Divergent Annulations between Cyclobutanones and 1,5-Enynes: Repaid Construction of Complex C(sp3)-Rich Scaffolds

Author: Si-Hua Hou, Xuan Yu, Rui Zhang, Cole Wagner, Guangbin Dong

Issue&Volume: November 18, 2022

Abstract: Given the emerging demand to “escape from flatland” for drug discovery, synthetic methods that can efficiently construct complex three-dimensional structures with multi-stereocenters become increasingly valuable. Here, we describe the development of Rh(I)-catalyzed intramolecular annulations between cyclobutanones and 1,5-enyne groups to construct complex C(sp3)-rich scaffolds. Divergent reactivities are realized with different catalysts, and excellent diastereo- and enantioselectivity have been achieved. The use of (R)-H8-binap as the ligand favors forming the bis-bicyclic scaffolds with multiple quaternary stereocenters, while the (R)-segphos ligand prefers to generate the tetrahydro-azapinone products. Owing to the versatile reactivity of ketone moieties, these C(sp3)-rich scaffolds can be further functionalized. Experimental and computational mechanistic studies support a reaction pathway involving enyne-cyclometallation, 1,2-carbonyl addition, and then β-carbon elimination; the divergent reactivities are dictated by a product-determining Rh-alkyl migrator insertion step.

DOI: 10.1021/jacs.2c09814

Source: https://pubs.acs.org/doi/10.1021/jacs.2c09814