Catalytic Regio- and Enantioselective Hydroformylation of Trisubstituted Alkenes to Construct α-Quaternary Lactams
Dequan Zhang1, Jianqiang Zheng1, Cai You2
1Department of Chemistry and Shenzhen Grubbs Institute, Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen 518055, China.
Abstract:
Developing novel stereoselective methods for α-quaternary lactams is of significant importance for advancing structure-activity studies, discovering new antibiotics, and synthesizing diverse functional compounds for synthetic and materials research. Herein, we have successfully developed a Rh-catalyzed asymmetric hydroformylation (AHF) of trisubstituted olefins, overcoming both the inherent inertness of trisubstituted olefins in such reactions and Keulemans' rule, efficiently generating diverse β- and γ-lactams bearing an α-quaternary stereocenter with exceptional regio- and enantioselectivities (up to >20:1 rr, 99% ee). This mild and operationally simple reaction proceeds in an atom-economic manner with a broad substrate scope, along with excellent functional-group tolerance, scalability, and product diversification. Computational studies suggest that the enantio- and/or regioselectivity may originate from the Rh-C bonding along with the noncovalent interactions between the Boc group on the substrate and Ph groups on the ligand.
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