Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: synthesis of calycotomine enantiomers

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.

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(1R)-tert-Butyl-(1-hydroxymethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylateC17H25NO5ee = 99% by HPLC on a Chiralpak IA column[α]D25=+82 (c 0.255, CHCl3)Source of chirality: CAL-B-catalysed enantioselective acylationAbsolute configuration: (1R)

(1S)-tert-Butyl-(1-acetoxymethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylateC19H27NO6ee = 99% by HPLC on a Chiralcel OD-H column[α]D25=-103 (c 0.24, CHCl3)Source of chirality: CAL-B-catalysed enantioselective acylationAbsolute configuration: (1S)

(1R)-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanolC12H17NO3ee = 99% by HPLC on a Chiralpak IA column[α]D25=+16 (c 0.165, CHCl3)Source of chirality: CAL-B-catalysed enantioselective acylationAbsolute configuration: (1R)