Lipase-catalyzed resolution of chiral 1,3-amino alcohols: application in the asymmetric synthesis of (S)-dapoxetine

The enzymatic resolution of 3-amino-3-phenylpropan-1-ol derivatives has been studied through acylation processes. Candida antarctica lipase A (CAL-A) has been identified as the best biocatalyst for the transesterification reaction of 3-amino-3-phenyl-1-tert-butyldimethylsilyloxy-propan-1-ol using ethyl methoxyacetate as acylating agent and tert-butyl methyl ether as solvent. This enzymatic study has allowed us to obtain a valuable intermediate for the production of (S)-dapoxetine, which has been synthesized in good overall yield and high enantiomeric excess.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(S)-(+)-N,N-Dimethyl-α-[2-(1-naphthalenyloxy)ethyl]benzenemethanamine or (S)-dapoxetineC21H23NOEe = 93% (HPLC, Chiralcel OD)[α]D20=+62.5 (c 0.3, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-N-(O-tert-Butyldimethylsilyl-3-hydroxy-1-phenylpropyl)methoxyacetamideC18H31NO3SiEe = 93% (HPLC, Chiralcel OD)[α]D20=-40.5 (c 0.7, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(+)-3-Amino-O-tert-butyldimethylsilyl-3-phenylpropan-1-olC15H27NOSiEe = 58% (HPLC, Chiralcel OD)[α]D20=+7.1 (c 0.55, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: R

(S)-(−)-3-Amino-3-phenylpropan-1-olC9H13NOEe = 93% (HPLC, Chiralcel OD)[α]D20=-11.2 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(+)-3-(N,N-Dimethylamino)-3-phenylpropan-1-olC11H17NOEe = 93% (HPLC, Chiralcel OD)[α]D20=+38.0 (c 0.6, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S