A new asymmetric synthesis of 2,6-cis-diarylated piperidines

A new synthetic approach to a variety of enantioenriched 2,6-cis-diarylated piperidines has been developed. This new methodology hinges upon the diastereoselective reduction of enantioenriched endocyclic enecarbamates obtained through a two step sequence involving a Suzuki–Miyaura cross coupling reaction between an aminovinyl phosphate and a variety of (hetero)aromatic boronic acids.

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(6S)-6-(3-Methoxyphenyl)piperidin-2-oneC12H15NO2Ee >96%[α]D20 = −52.2 (c 0.58, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (6S)

(6S)-2-Oxo-6-phenylpiperidine-1-carboxylic acid tert-butyl esterC16H21NO3Ee >96%[α]D20 = −19.6 (c 0.24, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (6S)

(2S)-2-(3-Methoxyphenyl)-6-oxopiperidine-1-carboxylic acid tert-butyl esterC17H23NO4Ee >96%[α]D20 = −20.8 (c 1.44, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2S)-6-(3-Chlorophenyl)-2-phenyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterC22H24ClNO2Ee >96%[α]D20 = −88.7 (c 0.78, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2S)-6-(2-Methoxyphenyl)-2-phenyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterC23H27NO3Ee >96%[α]D20 = −122.9 (c 0.76, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2S)-6-Furan-2-yl-2-phenyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterC20H23NO3Ee >96%[α]D20 = −96.3 (c 0.83, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2S)-2-(3-Methoxyphenyl)-6-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterC26H33NO6Ee >96%[α]D20 = −90.5 (c 1.89, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2R,6S)-2-(3-Chlorophenyl)-6-phenylpiperidine-1-carboxylic acid tert-butyl esterC22H26ClNO2De >96%[α]D20 = −51.6 (c 0.41, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R,6S)

(2R,6S)-2-(2-Methoxyphenyl)-6-phenylpiperidine-1-carboxylic acid tert-butyl esterC23H29NO3De >96%[α]D20 = −16.4 (c 0.46, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R,6S)

(2R,6S)-2-Furan-2-yl-6-phenylpiperidine-1-carboxylic acid tert-butyl esterC20H25NO3De = 84%[α]D20 = −20.5 (c 0.16, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R,6S)

(2S,6R)-2-(3-Methoxyphenyl)-6-(3,4,5-trimethoxyphenyl)piperidine-1-carboxylic acid tert-butyl esterC26H35NO6De >96%[α]D20 = −38.4 (c 0.34, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,6R)

(2R,6S)-2-(3-Chlorophenyl)-6-phenylpiperidineC17H18ClNDe >96%[α]D25 = +14.9 (c 0.95, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (2R,6S)

(2R,6S)-2-(2-Methoxyphenyl)-6-phenylpiperidineC18H21NODe >96%[α]D20 = −17.0 (c 1.18, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (2R,6S)

(2S,6R)-2-(3-Methoxyphenyl)-6-(3,4,5-trimethoxyphenyl)piperidineC21H27NO4De >96%[α]D20 = −53.0 (c 0.10, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (2S,6R)