Highly diastereoselective approach to novel phenylindolizidinols via benzothieno analogues of tylophorine based on reductive desulfurization of benzo[b]thiophene

Chiral tetra- and hexahydro[1]benzothieno[2,3-f]indolizines 3–5, 9, and 11 were synthesized easily from benzo[b]thiophene-2-carboxaldehyde (1) and (S)-glutamic acid (2) in good overall yields and both high enantio- and diastereomeric purities. Applying a diastereoselective reductive desulfurization of benzo[b]thiophene followed by lactam reduction, epimeric alcohols 4a and 4b were readily converted into (7R or S,8aS)-phenylindolizidinols 6a,c. During these studies, the reduction of benzothienoindolizines 3–5, 9, 11, and 12, was investigated and the results obtained are also discussed.

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(S)-N-(1-(Benzo[b]thien-2-ylmethyl)glutamic acidC14H15NO4S[α]D20=-31.8 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (S)

(S)-1-(Benzo[b]thien-2-ylmethyl)-5-oxopyrrolidine-2-carboxylic acidC14H13NO3S[α]D20=+53.8 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (S)

(11aS)-1,11a-Dihydro[1]benzothieno[2,3-f]indolizine-3,11(2H,5H)-dioneC14H11NO2S[α]D20=-64.5 (c 1.0, CH3COCH3)Source of chirality: (S)-glutamic acidAbsolute configuration: (11aS)

(11R,11aS)-11-Hydroxy-1,5,11,11a-tetrahydro[1]benzothieno[2,3-f]indolizin-3(2H)-oneC14H13NO2S[α]D20=+56.8 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (11R,11aS)

(11S,11aS)-11-Hydroxy-1,5,11,11a-tetrahydro[1]benzothieno[2,3-f]indolizin-3(2H)-oneC14H13NO2S[α]D20=-9.4 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (11S,11aS)

(7R,8S,8aS)-8-Hydroxy-7-phenylhexahydroindolizin-3(5H)-oneC14H17NO2[α]D20=-142.2 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (7R,8S,8aS)

(7R,8R,8aS)-8-Hydroxy-7-phenylhexahydroindolizin-3(5H)-oneC14H17NO2[α]D20=-73.2 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (7R,8R,8aS)

(7R,8S,8aS)-7-Phenyloctahydroindolizin-8-olC14H19NO[α]D20=+0.9 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (7R,8S,8aS)

(7R,8R,8aS)-7-Phenyloctahydroindolizin-8-olC14H19NO[α]D20=+7.5 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (7R,8R,8aS)

(11R,11aS)-3-Oxo-1,2,3,5,11,11a-hexahydro[1]benzothieno[2,3-f]indolizin-11-yl acetateC16H15NO3S[α]D20=+24.0 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (11R,11aS)

(11R,11aS)-1,2,3,5,11,11a-Hexahydro[1]benzothieno[2,3-f]indolizin-11-olC14H15NOS[α]D20=+140.4 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (11R,11aS)

(11aS)-1,5,11,11a-Tetrahydro[1]benzothieno[2,3-f]indolizin-3(2H)-oneC14H13NOS[α]D20=+73.5 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (11aS)

(11aS)-1,2,3,5,11,11a-Hexahydro[1]benzothieno[2,3-f]indolizineC14H15NS[α]D20=+118.4 (c 1.0, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (11aS)