Asymmetric synthesis of ring-fused tetrahydroquinolines using organocatalytic enantioselective conjugate addition and cross-dehydrogenative coupling

Enantioenriched ring-fused tetrahydroquinolines were synthesized by a facile and straightforward process involving the organocatalytic enantioselective conjugate addition reaction of malonates with o-N-tetrahydroisoquinolinyl-substituted cinnamaldehyde, followed by intramolecular cross-dehydrogenative coupling. Diphenylprolinol TMS ether was used as an organocatalyst in the asymmetric catalytic conjugate addition reaction and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was used as an oxidant in the cross-dehydrogenative coupling (CDC) reaction. The desired ring-fused tetrahydroquinolines were obtained in moderate yields and with high enantioselectivities (up to 97% ee).

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Dimethyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ethyl)malonateC23H25NO5ee = 95%[α]D28=-7.1 (c 0.88, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Diethyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ethyl)malonateC25H29NO5ee = 96%[α]D28=-0.7 (c 0.51, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Diisopropyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ethyl)malonateC27H33NO5ee = 97%[α]D28=-7.3 (c 0.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Dibenzyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ethyl)malonateC35H33NO5ee = 91%[α]D26=+3.8 (c 0.69, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(13R)-Dimethyl-13-(formylmethyl)-6,7-dihydro-11bH-isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylateC23H23NO5ee = 95%[α]D27=-72.7 (c 0.10, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(13R)-Diethyl-13-(formylmethyl)-6,7-dihydro-11bH-isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylateC25H27NO5ee = 96%[α]D28=+22.7 (c 0.14, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(13R)-Diisopropyl-13-(formylmethyl)-6,7-dihydro-11bH-isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylateC27H31NO5ee = 97%[α]D27=-36.9 (c 0.15, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(13R)-Dibenzyl-13-(formylmethyl)-6,7-dihydro-11bH-isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylateC35H31NO5ee = 91%[α]D28=-26.4 (c 0.16, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)