Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine, nisoxetine, and duloxetine

The asymmetric synthesis of two well-known anti-depressant drugs, fluoxetine and duloxetine has been accomplished in a chemoenzymatic manner. The main highlight of the synthesis is the enantioselective cyanohydrin formation by a plant (R)-HNL (hydroxynitrile lyase). The enantiopure cyanohydrins are then synthetically manipulated into the above two drug molecules and two of their structural analogues, atomoxetine and nisoxetine.

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(R)-2-(tert-Butyldimethylsilyloxy)-2-phenylacetaldehydeC14H22O2Si[α]D28=-19.5 (c 0.6, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: 2R

((S)-1-Phenylallyloxy)(tert-butyl)dimethylsilaneC15H24OSi[α]D28=-31.4 (c 0.9, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(tert-Butyldimethylsilylyloxy)-3-phenylpropan-1-olC15H26O2Si[α]D28=-16.8 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(tert-Butyldimethylsilyloxy)-3-phenylpropyl methanesulfonateC16H28O4SSi[α]D28=-22.5 (c 1.6, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(tert-Butyldimethylsilyloxy)-N-methyl-3-phenylpropan-1-amineC16H29NOSi[α]D28=-19.2 (c 0.6, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(Methylamino)-1-phenylpropan-1-olC10H15NO[α]D28=-36.5 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(R)-3-(4-(Trifluoromethyl)phenoxy)-N-methyl-3-phenylpropan-1-amineC17H18F3NO[α]D28=+3.2 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: R

(R)-3-(o-Tolyloxy)-N-methyl-3-phenylpropan-1-amineC17H21NO[α]D28=-35.0 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: R

(R)-3-(2-Methoxyphenoxy)-N-methyl-3-phenylpropan-1-amineC17H21NO2[α]D28=+36.2 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: R

(S)-2-Hydroxy-2-(thiophen-2-yl)acetonitrileC6H5NOS[α]D28=+42.2 (c 1.6, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-2-(tert-Butyldimethylsilyloxy)-2-(thiophen-2-yl)acetonitrileC12H19NOSSi[α]D28=+55.8 (c 0.8, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-2-(tert-Butyldimethylsilyloxy)-2-(thiophen-2-yl)acetaldehydeC12H20O2SSi[α]D28=+13.5 (c 0.3, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

2-((S)-1-(tert-Butyldimethylsilyloxy)allyl)thiopheneC13H22OSSi[α]D28=+40.6 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(tert-Butyldimethylsilylyloxy)-3-(thiophen-2-yl)propan-1-olC13H24O2SSi[α]D28=+22.4 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(4-Methoxybenzyloxy)-3-(thiophen-2-yl)propyl methanesulfonateC14H26O4S2Si[α]D28=+16.75 (c 1.1, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(4-tert-Butyldimethtylsilyloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amineC14H27NOSSi[α]D28=+28.2 (c 0.8, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(S)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-olC8H13NOS[α]D28=+13.2 (c 1.2, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: S

(R)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amineC18H19NOS[α]D28=+109.5 (c 1.2, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: R