The first highly enantioselective iridium-catalyzed hydrogenation of cyclic enamines has been developed. This new reaction provided an efficient method for the synthesis of optically active cyclic tertiary amines including natural product crispine A.
An efficient asymmetric hydrogenation of 1alkyl 3,4-dihydroisoquinolines catalyzed by chiral spiro iridium phosphoramidite complexes has been developed, providing very useful chiral 1-alkyl tetrahydroisoquinolines with high yields (88−96%) and good to excellent enantioselectivities (85−99% ee). This reaction also affords a convenient synthetic route to tetracyclic alkaloid (S)-xylopinine.
A new efficient and highly enantioselective direct asymmetric hydrogenation of α-keto acids employing the Ir/SpiroPAP catalyst under mild reaction conditions has been developed. This method might be feasible for the preparation of a series of chiral α-hydroxy acids on a large scale.
Two efficient processes for the synthesis of rivastigmine, one of the most potent drugs for the treatment of mild-to-moderate dementia of the type presenting in Alzheimer's disease, has been developed. Of particular note is the processes used for the asymmetric hydrogenation by applying the highly efficient chiral spiro catalyst, Ir-SpiroPAP. The first route was easy to scale up in industry and provided the commercial intermediate (S)-3-(1-dimethylaminoethyl)phenol, 6, which is suitable for the manufacture of rivastigmine in active pharmaceutical ingredient (API) demand. The second route was convenient for operation and purification and completed the synthesis of rivastigmine (1) in four steps and 84% overall yield.
Chiral iridium complexes based on spiro phosphoramidite ligands are demonstrated to be highly efficient catalysts for the asymmetric hydrogenation of unfunctionalized enamines with an exocyclic double bond. In combination with excess iodine or potassium iodide and under hydrogen pressure, the complex Ir/A C H T U N G T R E N N U N G (S a ,R,R)-3a provides chiral N-alkyl-A C H T U N G T R E N N U N G tetrahydroisoquinolines in high yields with up to 98% ee. The L/Ir ratio of 2:1 is crucial for obtaining a high reaction rate and enantioselectivity. A deuterium labeling experiment showed that an inverse isotope effect exists in this reaction. A possible catalytic cycle including an iridiumA C H T U N G T R E N N U N G (III) species bearing two monophosphoramidite ligands is also proposed.
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