An Efficient and Practical Synthesis of (+)-11-Bromovincamine by Rigioselective Bromination of Tetra hydro-β -carbolines

Abstract

Bromination of the HC1 salt of 1-methoxycarbony1-1-methyl-1, 2, 3, 4-tetrahydro-p-carboline ( 4 ) in methanol gave a 21: 79 mixture of 7-bromo-(8 a) and 6-bromo-(8 b) tetrahydro-pcarbolines. On the other hand, reaction of 2-formylated derivarive (4 b) with bromine in chloroform gave an 84: 16 mixture of 7-bromo-(8 ab) and 6-bromo-(8 bb) tetrahydro-p-carbolines. (8 a) was easily isolated by treatment of the mixture with HC1/Me0H.5-Bromo-2ethylpentanal ( 6 ) was prepared by the radical addition of hydrogen bromide to 2-(1-ethy1-3buteny1)-1, 3-dioxolane (9 a) followed by hydrolysis. Condensation of (8 a) and ( 6 ) in the p resense of sodium benzoate yielded 16-bromovincadifformine (7 c), which could be resolved to () ap. d (+)-enantiomers via diastereomeric salts of (R, R)-tartaric acid, respectively. Heating of the (+)-enantiomer in N, N-dimethylacetamide caused the racemization effectively. Compound ()-(7 c) was treated with 30%hydrogen peroxide to give 3-hydroxyaspidospermidine 9-oxide (11). The 9-oxide was reduced with Raney Ni and rearranged at pH 2.5 to afford a ca.3: 7 mixture of (+)-11-bromovincamine ( 3 ) and its epimer (13). The mixture was completely epimerized to ( 3 ) in Me0Nai Me0H.