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 migratory insertion step.

中文翻译：

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铑催化环丁酮和 1,5-烯炔之间的非对映和对映选择性发散环化：快速构建复杂的富含 C(sp3) 的支架

鉴于药物发现“逃离平地”的新兴需求，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。在这里，我们描述了环丁酮和 1,5-烯炔基团之间 Rh(I) 催化的分子内环化的发展，以构建复杂的富含 C(sp ³ ) 的支架。使用不同的催化剂实现了不同的反应性，并实现了优异的非对映选择性和对映选择性。使用( R )-H ₈ -binap作为配体有利于形成具有多个四级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酮产物。由于酮部分的多功能反应性，这些富含C(sp ³ )的支架可以进一步功能化。实验和计算机理研究支持涉及烯炔环金属化、1,2-羰基加成、然后β-碳消除的反应途径；不同的反应性由决定产物的Rh-烷基迁移插入步骤决定。