Asymmetric synthesis of the active form of loxoprofen and its analogue

The asymmetric synthesis of the active form of the antiinflammatory drug loxoprofen has been reported in this article. Enzymatic kinetic resolution/racemization of a substituted homo-benzylic primary alcohol with lipase-PS, asymmetric alkylation of cyclic ketones using either Enders’ or Meyers’ strategy followed by a stereoselective biocatalytic reduction of carbonyl group are the key reactions employed successfully to achieve the target molecule and one of its analogue.

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Acetic acid (S)-2-[4-(4-methoxy-benzyloxymethyl)-phenyl]propyl esterC20H24O4Ee = 98%[α]D29=+6.1 (c 0.33, MeOH)Source of chirality: Enzymatic transesterificationAbsolute configuration: (2S)

(R)-2-[4-(4-Methoxy-benzyloxymethyl)-phenyl]-propan-1-olC18H22O3Ee = 94%[α]D29=+2.7 (c 1.0, MeOH)Source of chirality: Enzymatic transesterificationAbsolute configuration: (2R)

tert-Butyl-{(S)-2-[4-(4-methoxy-benzyloxymethyl)-phenyl]-propoxy}-diphenyl-silaneC34H40O3SiEe = 98%[α]D29=-28.2 (c 1.0, MeOH)Source of chirality: Enzymatic transesterificationAbsolute configuration: (2S)

{4-[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-methyl-ethyl]-phenyl}-methanolC26H32O2SiEe = 98%[α]D29=-5.2 (c 0.3, MeOH)Source of chirality: Enzymatic transesterificationAbsolute configuration: (2S)

[(S)-2-(4-Bromomethyl-phenyl)-propoxy]-tert-butyl-diphenyl-silaneC26H31BrOSiEe = 98%[α]D29=-11.2 (c 0.5, MeOH)Source of chirality: Enzymatic transesterificationAbsolute configuration: (2S)

(R)-2-{4-[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-methyl-ethyl]-benzyl}-cyclopentanoneC31H38O2Si[α]D29=+12.3 (c 0.5, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (R,S)

(R)-2-{4-[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-methyl-ethyl]-benzyl}-cyclohexanoneC32H40O2Si[α]D29=+15.2 (c 0.5, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (R,S)

(R)-2-[4-((S)-2-Hydroxy-1-methyl-ethyl)-benzyl]-cyclopentanoneC15H20O2[α]D29=+31.2 (c 0.5, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (R,S)

(S)-2-[4-((R)-2-Oxo-cyclopentylmethyl)-phenyl]-propionic acidC15H18O3[α]D29=-28.2 (c 0.5, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (R,S)

(S)-2-[4-((1R,2S)-2-Hydroxy-cyclopentylmethyl)-phenyl]-propionic acidC15H20O3[α]D29=+76.1 (c 0.5, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S,R,S)

(S)-2-[4-((1R,2S)-2-Hydroxy-cyclohexylmethyl)-phenyl]-propionic acidC16H22O3[α]D29=+48.7 (c 0.5, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S,R,S)