Rh-Catalyzed Asymmetric Hydrogenation of 3-Amino-4-alkyl/aryl Disubstituted Maleimides

Abstract

A highly efficient Rh-catalyzed asymmetric hydrogenation of rigid cyclic 3-amino-4-alkyl/aryl disubstituted maleimides has been developed for the first time by using 5,5′-bridged axially chiral biaryl diphosphine ligands (BridgePhos), whose dihedral angle can be controlled by modifying the length of the 5,5′-bridging chain. Both 4-aryl and alkyl-substituted substrates exhibit outstanding catalytic behavior using the BridgePhos-Rh catalyst with the most suitable dihedral angle, enabling the construction of chiral disubstituted succinimides with excellent yields (up to 99%) and stereoselectivities (up to 99% ee and >20:1 dr). Mechanistic studies based on the control experiments and DFT calculations indicated that the two added hydrogen atoms of the products originate from two different H₂ molecules and the hydrogenation proceeds via a H₂ σ-bond metathesis pathway for the alkane release in the hydrogenation cycle. This protocol can be performed on a gram-scale with a low catalyst loading (S/C = 5000) and allows stereodivergent access to all four stereoisomers. The resulting hydrogenation products offer several potential transformations, including the first asymmetric catalytic synthesis of moxifloxacin hydrochloride, a novel fluoroquinolone antibiotic developed by Bayer Pharmaceuticals, with high efficiency.