The stereoisomers of 1,2,3,4-tetrahydroisoquinoline amino alcohol analogues and derivatives thereof were separated in normal-phase mode on chiral stationary phases based on preprepared silica coated with cellulose tris-(3,5-dimethylphenyl carbamate), cellulose tris-(3-chloro-4-methylphenyl carbamate), cellulose tris-(4-methylbenzoate) or cellulose tris-(4-chloro-3-methylphenyl carbamate). On all the investigated chiral columns, the retention and the enantioseparation were influenced by the nature and the concentrations of the mobile phase components and additives, and also the temperature. Experiments were performed in the temperature range 10-50°C. Thermodynamic parameters were calculated from plots of lnα vs 1/T. On these polysaccharide-based chiral columns, both enthalpy-driven separations and entropy-controlled enantioseparations were observed. The latter was advantageous with regard to the shorter retention and greater selectivity at high temperature. The sequence of elution of the stereoisomers was determined in all cases.

Homocalycotomine enantiomers (R)-4 and (S)-4 were prepared by the Candida antarctica lipase B (CAL-B)-catalysed asymmetric O-acylation of N-Boc-protected 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethanol (±)-1. The preliminary small-scale experiments were performed either in a continuous-flow system or as batch reactions, while the preparative-scale resolution was carried out in two steps with vinyl acetate as the acyl donor in the presence of Et3N and Na2SO4 in toluene at 3°C, as a batch reaction. Treatment of the resulting amino alcohol (S)-1 and amino ester (R)-3 (ee ⩾94%) with 18% HCl, and then with 5M NaOH, furnished the desired (R)-4 and (S)-4 without a decrease in the enantiomeric excess (ee ⩾94%).

Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmetric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol [(±)-3)]. The optimum conditions for the enzymatic resolution were determined under continuous-flow conditions, while the preparative-scale resolution of (±)-3 was performed as a batch reaction with high enantioselectivity (E>200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high enantiomeric excess (ee=99%), were transformed into the desired calycotomine (S)-5 and (R)-5 (ee=99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetrahydroisoquinoline amino alcohol homologues (±)-1 to (±)-3 containing a remote stereogenic centre.

Both enantiomers of the antitumour-active alkaloid crispine A (ee=95%) were synthesised through the Burkholderia cepacia lipase-catalysed acylation of the primary hydroxy group of N-Boc-protected 1-(3-hydroxypropyl)-6,7-bis(methyloxy)-1,2,3,4-tetrahydroisoquinoline (±)-3 and the enantioselective hydrolysis of the corresponding O-decanoate (±)-4 [R=(CH2)8Me] with a remote, four-atom distant stereogenic centre. High enantioselectivities were observed for the (S)-selective O-acylation with vinyl decanoate in the presence of Et3N and Na2SO4 in t-BuOMe at 45°C (E=68), and for the (S)-selective hydrolysis with H2O in t-BuOMe at 45°C (E=52). The enzymatic resolutions, performed in two steps, afforded the key alcohol and ester enantiomers with high enantiomeric excesses (ee⩾94%). Ring-closure reactions of alcohol enantiomers (+)-3 and (−)-3 with thionyl chloride afforded the desired crispine A enantiomers (+)-1 and (−)-1 (ee⩾95%).

Enantiomerically enriched hydroxy-substituted b-amino esters have been synthesized through CAL-B-catalyzed enantioselective hydrolysis in organic media. Moderate to good enantiomeric excess values (ee ≥ 52%) were obtained when the CAL-B-catalyzed reactions were performed in t-BuOMe, at 60 ºC with 0.5 equiv. of added H2O as nucleophile.