Stereoselective Synthesis of 1-Substi- tuted 1,2,3,4-Tetrahydro-b-carbolines by Asymmetric Electrophilic a-Amido- alkylation Reactions

Abstract

An efficient procedure for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-9-methyl-β-carbolines based on asymmetric electrophilic α-amidoalkylation reactions is described. Stereoselective addition of variousorganometallic reagents to a chiral N-acyl-β-carbolinium ion gave the corresponding 1-substituted 1,2-dihydro-β-carbolines in high yields and very good to excellent diastereomeric ratios. Catalytic hydrogenation followed by the removal of the chiral auxiliary via reductive cleavage of the amide bond proceeded with complete conservation of the absolute configuration at the newly created stereocenter leading to 1-substituted 1,2,3,4-tetrahydro-9-methyl-β-carboline derivatives in high yields. Their absolute stereochemistry was proven by X-Ray analysis. The 1-phenyl-substituted 1,2,3,4-tetrahydro-β-carbolines were evaluated for their affinity to the PCP binding site of the NMDA receptor.