title: Enzymatic Strategy for the Resolution of New 1-Hydroxymethyl Tetrahydro-β-carboline Derivatives in Batch and Continuous-Flow Systems.
abstract: 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 %).
authors.affiliation: University of Szeged Institute of Pharmaceutical Chemistry Eötvös u. 6 6720 Szeged Hungary.
authors.forename: Rita
authors.initials: R
authors.lastname: Megyesi
authors.affiliation: University of Szeged Institute of Pharmaceutical Chemistry Eötvös u. 6 6720 Szeged Hungary.
authors.forename: Enikő
authors.initials: E
authors.lastname: Forró
authors.affiliation: University of Szeged Institute of Pharmaceutical Chemistry Eötvös u. 66720 Szeged Hungary; MTA-SZTE Stereochemistry Research Group Hungarian Academy of Sciences Eötvös u. 66720 Szeged Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
keywords: Candida antarctica lipase B; acylation; continuous-flow system; enzyme catalysis; tetrahydro-β-carboline