Many alkaloids containing a tetrahydro-β-carboline skeleton have well-known therapeutic effects, leading to increased interest in the synthesis of these natural products. Enantiomers of N-Boc-protected 1-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline [(±)-7], 1-hydroxymethyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline [(±)-8], and 1-hydroxymethyl-6-fluoro-1,2,3,4-tetrahydro-β-carboline [(±)-9] were prepared through enzymecatalyzed asymmetric acylation of their primary hydroxyl group. The preliminary experiments were performed in a continuous-flow system, while the preparative-scale resolutions were done as batch reactions. Excellent enantioselectivities (E>200) were obtained with Candida antarctica lipase B (CAL-B) and acetic anhydride in toluene at 60 °C. The recovered alcohols and the produced esters were obtained with high enantiomeric excess values (ee≥96 %). The O-acylated enantiomers [(S)-10-(S)-12)] were transformed into the corresponding amino alcohols [(S)-7-(S)-9)] with methanolysis. Microwave-assisted Boc removals were also performed and resulted in the corresponding compounds (R)-4-(R)-6 and (S)-4-(S)-6 without a drop in the enantiomeric excess values (ee≥96 %).
Keywords: Candida antarctica lipase B; acylation; continuous-flow system; enzyme catalysis; tetrahydro-β-carboline.