Rhodium-Catalyzed Diastereo- and Enantioselective Divergent Annulations between Cyclobutanones and 1,5-Enynes: Rapid Construction of Complex C(sp 3 )-Rich Scaffolds.
Si-Hua HouXuan YuRui ZhangCole WagnerGuangbin DongPublished in: Journal of the American Chemical Society (2022)
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(sp 3 )-rich scaffolds. Divergent reactivities are realized with different catalysts, and excellent diastereo- and enantioselectivity have been achieved. The use of ( R )-H 8 -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(sp 3 )-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.