78(P-71) Asymmetric Synthesis of Isoquinoline Alkaloids by Using New Intramolecular Allylic Amination as the Key Step : Synthesis of (R)-Carnegine
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Many alkaloids possessing 1-substituted tetrahydroisoquinoline skeleton show unique pharmacological activity. Thus, construction of this class of compounds in optically active forms has drawn much attention of synthetic organic chemists. Although many efficient methodologies have been reported, most of them use stoichiometric asymmetric reaction for introducing the chirality at C1. A few highly enantioselective syntheses using catalytic asymmetric reactions have also been reported but, in these syntheses, the chirality introduction and the hetero-cyclization have been carried out in separate steps. We expected that the more efficient synthesis would be realized, if chirality introduction and the hetero-cyclization can be carried out in a single step. Intramolecular allylic amination was considered to be a highly potent method from this point of view. Furthermore, the resulting chiral tetrahydroisoquinoline bears 1-vinyl group that is amenable to further functionalization. We have already demonstrated that chiral 2-(phosphinophenyl)pyridine ligands bearing 7-substituted dihydropyrindine unit are efficient chiral auxiliaries for palladium-catalyzed allylic alkylation of both acyclic and cyclic alkenyl substrates. Thus, we examined palladium-catalyzed asymmetric intramolecular allylic amination of 1 using 2-(phosphinophenyl)pyridine as the chiral auxiliary. The key intermediate allylic acetate 1a and pivalate 1b was prepared from commercial 3,4-dimethoxy-β-phenethyl amine in a conventional manner. The allylic pivalate 1b was found to undergo the desired intramolecular allylic amination using Pd(0) complex of 2-(phosphinophenyl)pyridine 2 as the catalyst in the presence of potassium carbonate to give the desired 1-vinyltetrahydroisoquinoline 6 of 88% ee. The compound 6 was converted into (R)-carnegine in six steps. Thus, we were able to demonstrate the newly developed asymmetric intramolecular allylic amination using Pd(0) complex of 2-(phosphinophenyl)pyridine 2 as the catalyst was a useful tool for asymmetric synthesis of isoquinoline alkaloids.
