Stereoselective α-amidoalkylation of phenylglycinol-derived lactams. Synthesis of enantiopure 5,6-disubstituted 2-piperidones

The stereochemical outcome of α-amidoalkylation reactions of chiral nonracemic bicyclic lactams 2b and 2c with indole, allyltrimethylsilane, TMSCN and Grignard reagents to gain access to enantiopure 5,6-disubstituted 2-piperidones is discussed.

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(5R,6R)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-(3-indolyl)-2-piperidoneC23H26N2O2[α]D22=-34.8 (c 1.03, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6R)

(5R,6S)-6-Cyano-5-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-piperidoneC16H20N2O2[α]D22=-16.0 (c 0.18, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6S)

(5R,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-methyl-2-piperidoneC16H23NO2[α]D22=-2.9 (c 0.48, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6S)

(5R,6S)-5,5-Diethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-piperidoneC17H25NO2[α]D22=-48.9 (c 0.27, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6S)

(5R,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-propyl-2-piperidoneC18H27NO2[α]D22=-34.8 (c 1.03, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6S)

(5R,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-vinyl-2-piperidoneC17H23NO2[α]D22=-142.2 (c 0.18, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6S)

(5S,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-(3-indolyl)-2-piperidoneC23H26N2O2[α]D22=-5.4 (c 0.11, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5S,6S)

(5S,6R)-6-Allyl-5-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-piperidoneC18H25NO2[α]D22=-19.6 (c 10.9, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5S,6R)

(5S,6R)-5-Ethyl-6-phenyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-piperidoneC21H26NO2[α]D22=-126.1 (c 0.23, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5S,6R)

(5R,6S)-5,6-Diethyl-2-piperidoneC9H17NO[α]D22=+5.0 (c 0.08, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6S)

(5R,6R)-5-Ethyl-6-phenyl-2-piperidoneC13H17NO[α]D22=-10.4 (c 0.27, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6R)

(5R,6R)-6-Allyl-5-ethyl-2-piperidoneC10H17NO[α]D22=+48.4 (c 1.19, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5R,6R)

(5S,6R)-5-Ethyl-6-phenyl-2-piperidoneC13H17NO[α]D22=-75.6 (c 0.53, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (5S,6R)