8 イミンへの高選択的不斉付加反応を基盤とするイソキノリンアルカロイドの不斉合成(口頭発表の部)

抄録

Tetrahydroisoquinoline alkaloid is a class of biologically potent compounds. The existence of 1,2,3,4-tetrahydroisoquinoline (4: TIQ) and 1-methyl-TIQ (6: 1MeTIQ) in the human brain is now in no doubt. The complete prevention of MPTP (1) induced parkinsonism by pretreatment with 6 and inhibition of monoamine oxidase have renewed interest related to the pathogenesis of Parkinson's disease and have been suggested as a leading compound for development of medicine. 1-Phenyl-TIQ (5: 1PhTIQ), originally developed as a general anesthetic agent, also shows phencyclidine-like stereotyped behavior and ataxia. Since the enantiomers were observed to vary in affinity, the synthesis of chiral 1-substituted TIQ is the current focus in medicinal organic chemistry. We report here a novel asymmetric synthetic methodology involving an asymmetric addition of organolithium to an imine and subsequent cyclization by Moffat oxidation as the key steps. In the chiral ligand mediated asymmetric addition of organolithium to imine, a naphthalene unit was developed as a N-substituent of imine to realize high abilities in activation of imine, enantioselectivity, and oxidative dearylation. In the presence of 13, the reaction of methyllithium with the imine (24) bearing N-naphthyl group gave the corresponding amine (25) in up to 97%ee and 99% yield. Conversion of the resulted chiral amine to 1-substituted TIQ was readily achieved through cyclization by Moffat oxidation as a key step. Addition of methyllithium to imine (29) in the presence of 13 gave 30 in 93%ee and 99% yield. Subsequent hydroboration and oxidative work up gave 31 in 76% yield, and following Moffat oxidation afforded TIQ (32) in 75% yield. Dearylation was done by ammonium cerium(IV) nitrate oxidation to give 33 in 94% yield, and finally deacetylation with KOH-hydrazine gave salsolidine (3) in 69% yield. Combination of enantioselective alkylation of imine with the cyclization reaction realized the asymmetric synthesis of potentially biologically active 1-substituted TIQ (3, 6, 7).