Total synthesis of crispine A enantiomers through a Burkholderia cepacia lipase-catalysed kinetic resolution

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%).

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(1R)-N-(tert-Butoxycarbonyl)-(3-hydroxypropyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineC19H29NO5Ee = 95% by HPLC on a Chiralpak IA column[α]D25=-60 (c 0.5, CHCl3)Source of chirality: Burkholderia cepacia lipase PS-catalysed enantioselective acylationAbsolute configuration: (1R)

(1R)-N-(tert-Butoxycarbonyl)-(3-decanoiloxypropyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineC29H47NO6Ee = 96% by HPLC on a Chiralpak IA column[α]D25=-58 (c 0.305, CHCl3)Source of chirality: Burkholderia cepacia lipase PS-catalysed enantioselective hydrolysisAbsolute configuration: (1R)

(1R)-8,9-Dimethoxy-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolineC14H19NO2Ee = 95% by HPLC on a Chiralcel OD-H column[α]D25=+82 (c 0.255, MeOH)[α]D25=+60 (c 0.255, CHCl3)Source of chirality: Pseudomonas cepacia lipase PS-catalysed enantioselective acylation or hydrolysisAbsolute configuration: (1R)