Development of a Continuous-Flow System for Asymmetric Hydrogenation Using Self-Supported Chiral Catalysts

Well-designed, self-assembled, metal-organic frameworks were constructed by simple mixing of multitopic MonoPhos-based ligands (3; MonoPhos = chiral, monodentate phosphoramidites based on the 1,1'-bi-2-naphthol platform) and [Rh(cod)(2)]BF4 (cod = cycloocta-1,5-diene). This self-supporting strategy allowed for simple and efficient catalyst immobilization without the use of extra added support, giving well-characterized, insoluble (in toluene) polymeric materials (4). The resulting self-supported catalysts (4) showed outstanding catalytic performance for the asymmetric hydrogenation of a number of alpha-dehydroamino acids (5) and 2-aryl enamides (7) with enantiomeric excess (ee) ranges of 94-98% and 90-98%, respectively. The linker moiety in 4 influenced the reactivity significantly, albeit with slight impact on the enantioselectivity. Acquisition of reaction profiles under steady-state conditions showed 4h and 4i to have the highest reactivity (turnover frequency (TOF) = 95 and 97 h(-1) at 2 atm, respectively), whereas appropriate substrate/catalyst matching was needed for optimum chiral induction. The former was recycled 10 times without loss in ee (95-96%), although a drop in TOF of approximately 20% per cycle was observed. The estimation of effective catalytic sites in self-supported catalyst 4e was also carried out by isolation and hydrogenation of catalyst-substrate complex, showing about 37% of the Rh-1 centers in the self-supported catalyst 4e are accessible to substrate 5c in the catalysis. A continuous flow reaction system using an activated C/4h mixture as stationary-phase catalyst for the asymmetric hydrogenation of 5b was developed and run continuously for a total of 144 h with >99% conversion and 96-97% enantioselectivity. The total Rh leaching in the product solution is 1.7% of that in original catalyst 4h.