First asymmetric synthesis of (un)substituted bridged tetrahydro-2-benzazepines

A new and flexible route for the asymmetric synthesis of a variety of alkylated bridged tetrahydro-2-benzazepines has been developed. The key steps are the highly diastereoselective Michael addition of metalated SAMP-hydrazones to α,β-unsaturated esters combined with cyclomethylenation/Mitsunobu coupling reactions to secure the formation of the seven-membered azaheterocycle and of the bridged unit, respectively.

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(R)-3-(3,4-Dimethoxyphenyl)-5-[(S)-2-(methoxymethyl)pyrrolidin-1-ylimino]pentanoic ethyl esterC21H32N2O5De >96%[α]D25=-57.7 (c 0.87, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3R,2S)

(3S,4S)-3-(3,4-Dimethoxyphenyl)-5-[(S)-2-(methoxymethyl)pyrrolidin-1-ylimino]-4-methylpentanoic ethyl esterC22H34N2O5De >96%[α]D25=-68.4 (c 1.18, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3S,4S,2S)

(3S,4S)-3-(3,4-Dimethoxyphenyl)-4-{[(S)-2-(methoxymethyl)pyrrolidin-1-yl-imino]methyl}hexanoic ethyl esterC23H36N2O5De >96%[α]D25=-86.4 (c 0.86, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3S,4S,2S)

(3S,4S)-3-Benzo[1,3]dioxol-5-yl-4-{[(S)-2-(methoxymethyl)pyrrolidin-1-ylimino]methyl}hexanoic ethyl esterC22H32N2O5De >96%[α]D25=-90.4 (c 4.58, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3S,4S,2S)

(3S,4S)-3-Benzo[1,3]dioxol-5-yl-4-{[(S)-2-(methoxymethyl)pyrrolidin-1-ylimino]methyl}nonanoic ethyl esterC25H38N2O5De >96%[α]D25=-86.6 (c 1.58, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3S,4S,2S)

Acetic acid 2-[(R)-7,8-dimethoxy-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]ethyl esterC22H34N2O5De >96%[α]D25=-82.6 (c 1.58, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R,2S)

Acetic acid 2-{(4S,5S)-7,8-dimethoxy-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-4-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}ethyl esterC23H36N2O5De >96%[α]D25=-86.0 (c 1.40, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S,5S,2S)

Acetic acid 2-{(4S,5S)-4-ethyl-7,8-dimethoxy-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}ethyl esterC24H38N2O5De >96%[α]D25=-55.8 (c 1.46, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S,5S,2S)

Acetic acid 2-{(8S,9S)-8-ethyl-6-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta[f]inden-9-yl}ethyl esterC23H34N2O5De >96%[α]D25=-54.0 (c 0.69, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (8S,9S,2S)

Acetic acid 2-{(8S,9S)-6-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-8-pentyl-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta[f]inden-9-yl}ethyl esterC26H40N2O5De >96%[α]D25=-53.4 (c 0.52, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (8S,9S,2S)

2-[(R)-7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]ethanolC14H21NO3Ee >96%[α]D25=-15.5 (c 1.51, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R)

2-[(4S,5S)-7,8-Dimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]ethanolC15H23NO3Ee >96%[α]D25=-14.7 (c 1.09, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S,5S)

2-[(4S,5S)-7,8-Dimethoxy-4-ethyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]ethanolC16H25NO3Ee >96%[α]D25=-13.5 (c 1.33, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S,5S)

2-[(8S,9S)-8-Ethyl-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta[f]inden-9-yl]ethanolC15H21NO3Ee >96%[α]D25=-10.6 (c 0.80, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (8S,9S)

2-[(8S,9S)-8-Pentyl-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta[f]inden-9-yl]ethanolC23H38N2O3Ee >96%[α]D25=-6.9 (c 1.63, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (8S,9S)

(1S,11S)-4,5-Dimethoxy-11-methyl-9-azatricyclo[7.2.2.02,7]trideca-2,4,6-trieneC15H21NO2Ee >96%[α]D25=-2.3 (c 0.92, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (1S,11S)

(1S,11S)-4,5-Dimethoxy-11-ethyl-9-azatricyclo[7.2.2.02,7]trideca-2,4,6-trieneC16H23NO2Ee >96%[α]D25=-1.6 (c 1.36, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (1S,11S)

(1S,11S)-4,5-Methylenedioxy-11-ethyl-9-azatricyclo[7.2.2.02,7]trideca-2,4,6-trieneC15H19NO2Ee >96%[α]D25=-1.6 (c 0.83, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (1S,11S)

(1S,11S)-4,5-Methylenedioxy-11-pentyl-9-azatricyclo[7.2.2.02,7]trideca-2,4,6-trieneC18H25NO2Ee >96%[α]D25=+2.2 (c 0.63, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (1S,11S)