Enzymatic Strategy for the Resolution of New 1-Hydroxymethyl Tetrahydro-ß-carboline Derivatives in Batch and Continuous-Flow Systems.

Many alkaloids containing a tetrahydro-ß-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-ß-carboline [(±)-7], 1-hydroxymethyl-6-methoxy-1,2,3,4-tetrahydro-ß-carboline [(±)-8], and 1-hydroxymethyl-6-fluoro-1,2,3,4-tetrahydro-ß-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 %).

Enantioseparation of ß-carboline derivatives on polysaccharide- and strong cation exchanger-based chiral stationary phases. A comparative study.

In this study we attempted to describe in a comparative manner the enantioselectivity performance of six different polysaccharide- and two strong cation exchanger-type chiral stationary phases (CSPs) for the resolution of free and N-protected ß-carboline derivatives. On commercially available cellulose- or amylose-based CSPs, the enantioseparations were carried out in normal-phase mode by variation of the nature and the concentration of the alcohol modifier in n-hexane as mobile phase. With the application of strong cation exchanger-type CSPs, the enantioseparations were optimized by the variation of methanol-acetonitrile bulk solvent compositions in the presence of various amounts of acid and base additives acting as counter-ions. Detailed thermodynamic investigations revealed that in all cases the enantioseparations observed were enthalpically driven, i.e. the retention and selectivity decreased with increasing temperature. Elution sequences were determined routinely; no general rule was found on polysaccharide-based CSPs, while on the two enantiomeric strong cation exchanger-type CSPs the predicted reversal of the elution sequence could be confirmed on switching from one enantiomeric CSP to the other form.