Enzyme-promoted desymmetrization of bis(2-hydroxymethylphenyl) sulfoxide as a route to tridentate chiral catalysts

The desymmetrization of prochiral bis(2-hydroxymethylphenyl) sulfoxide 3 was efficiently performed via acetylation promoted by commonly available lipases. Two lipases, namely, CAL-B and LPL proved particularly efficient to give 2-acetoxymethylphenyl 2-hydroxymethylphenyl sulfoxide 4 in up to 98% yield and with up to 98% ee. On the basis of an X-ray analysis, the absolute configuration of 4 was determined as (+)-(R). The enantiomerically pure product 4 was then transformed into a series of enantiomerically pure diastereomeric 2-aminomethylphenyl 2-hydroxymethylphenyl sulfoxides 8 in which the amino groups originated from enantiomerically pure amines having additional C-stereogenic centres. Compounds 8 were examined as possible tridentate chiral catalysts in a reference reaction of diethylzinc with benzaldehyde to give the expected product, 1-phenylpropan-1-ol, in moderate yields and with ee’s of up to 50%.

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(R)-2-Acetoxymethylphenyl 2′-hydroxymethylphenyl sulfoxideC16H16O4SEe = 100%[α]D = +60.0 (c 1.0, CHCl3)Source of chirality: enzymatic desymmetrizationAbsolute configuration: (R)

(S)-2-Acetoxymethylphenyl 2′-methanosulfonyloxymethylphenyl sulfoxideC17H18O6S2Ee = 100%[α]D = +12.4 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(RS,SC)-2-Acetoxymethylphenyl 2′-(α-phenylethyl)aminomethylphenyl sulfoxideC24H25NO3SEe = 100%[α]D = −36.2 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC)

(RS,RC)-2-Acetoxymethylphenyl 2′-(α-phenylethyl)aminomethylphenyl sulfoxideC24H25NO3SEe = 100%[α]D = +17.3 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,RC)

(RS,SC)-2-Acetoxymethylphenyl 2′-[1-(α-pyridyl)ethyl]aminomethylphenyl sulfoxideC23H24N2O3SEe = 100%[α]D = −38.1 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC)

(RS,SC1,SC2,SC5)-2-Acetoxymethylphenyl 2′-(cis)-myrtanylaminomethylphenyl sulfoxideC26H33NO3SEe = 100%[α]D = −19.0 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC1,SC2,SC5)

(RS,SC)-2-Acetoxymethylphenyl 2′-[1-(α-naphthyl)ethyl]aminomethylphenyl sulfoxideC28H27NO3SEe = 100%[α]D = −12.0 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC)

(RS,RC)-2-Acetoxymethylphenyl 2′-[1-(α-naphthyl)ethyl]aminomethylphenyl sulfoxideC28H27NO3SEe = 100%[α]D = −4.1 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,RC)

(RS,SC)-2-Hydroxymethylphenyl 2′-(α-phenylethyl)aminomethylphenyl sulfoxideC22H23NO2SEe = 100%[α]D = −15.9 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC)

(RS,RC)-2-Hydroxymethylphenyl 2′-(α-phenylethyl)aminomethylphenyl sulfoxideC22H23NO2SEe = 100%[α]D = −15.6 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,RC)

(RS,SC)-2-Hydroxymethylphenyl 2′-[1-(α-pyridyl)ethyl]aminomethylphenyl sulfoxideC21H22N2O2SEe = 100%[α]D = −17.4 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC)

(RS,SC1,SC2,SC5)-2-Hydroxymethylphenyl 2′-(cis)-myrtanylaminomethylphenyl sulfoxideC24H31NO2SEe = 100%[α]D = −8.8 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC1,SC2,SC5)

(RS,SC)-2-Hydroxymethylphenyl 2′-[1-(α-naphthyl)ethyl]aminomethylphenyl sulfoxideC26H25NO2SEe = 100%[α]D = +13.2 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,SC)

(RS,RC)-2-Hydroxymethylphenyl 2′-[1-(α-naphthyl)ethyl]aminomethylphenyl sulfoxideC26H25NO2SEe = 100%[α]D = −30.7 (c 1.0, CHCl3)Source of chirality: stereospecific synthesisAbsolute configuration: (RS,RC)