Enantioselective Type II Cycloaddition of Alkynes via C–C Activation of Cyclobutanones: Rapid and Asymmetric Construction of [3.3.1] Bridged Bicycles

• Published in: Journal of the American Chemical Society Vol. 142; no. 30; pp. 13180 - 13189
• Main Authors: Hou, Si-Hua, Yu, Xuan, Zhang, Rui, Deng, Lin, Zhang, Mengxi, Prichina, Adriana Y, Dong, Guangbin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.07.2020; Amer Chemical Soc
• Subjects: Alkynes - chemistry; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Chemistry; Chemistry, Multidisciplinary; Cycloaddition Reaction; Cyclobutanes - chemical synthesis; Cyclobutanes - chemistry; Molecular Conformation; Physical Sciences; Science & Technology; Stereoisomerism; CATALYSIS; INSERTION; DIELS-ALDER REACTIONS; NATURAL-PRODUCTS; OLEFINS; BOND ACTIVATION; RING-SYSTEMS; MOLECULES; ATOM
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.0c05647

Synthesis of bridged scaffolds via Type II cyclization constitutes substantial challenges due to the intrinsic ring strain accumulated in reaction transition states. Catalytic enantioselective Type II-cyclization methods are even rarer. Here, we describe a detailed study of developing a Rh­(I)-catalyzed enantioselective intramolecular Type II cyclization of alkynes via C–C activation of cyclobutanones. This method offers a rapid approach to access a wide range of functionalized [3.3.1]-bridged bicycles along with an exocyclic olefin and an all-carbon quaternary stereocenter. Excellent enantioselectivity has been achieved using a combination of cationic rhodium­(I) and DTBM-segphos. Attributed to the redox neutral and strong acid/base-free reaction conditions, high chemoselectivity has also been observed. For the oxygen-tethered substrates, the reaction can proceed at room temperature. In addition, partial kinetic resolution has been achieved for substrates with existing stereocenters, forging interesting chiral tricyclic scaffolds. The methylalkyne-derived substrates gave unexpected dimeric structures in good yield with excellent enantioselectivity and complete diastereoselectivity. Furthermore, the bridged bicyclic products can be diversely functionalized through simple transformations. Finally, mechanistic studies reveal a surprising reaction pathway that involves forming a metal-stabilized anti-Bredt olefin intermediate.