Organocatalytic Michael addition of aldehydes to a β-silylmethylene malonate to form intermediates for the enantioselective synthesis of hydroxylated valerolactones and piperidines

The direct Michael addition of enolizable aldehydes to dimethyl(phenyl)silylmethylene malonate was catalysed by an (S)-diphenylprolinol trimethylsilyl ether/acetic acid combination. The adducts were formed in good yield, high diastereoselectivity and excellent enantioselectivity. Chiral valerolactone and piperidine skeletons embedded with a silyl and other functionalities have been made out of the adducts. A total synthesis (+)-simplactone B has been achieved from one of the adducts.

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(4S,5S)-5-Ethyltetrahydro-4-dimethylphenylsilyl-2H-2-pyranoneC15H22O2SiEe = 97%[α]D26=+46.0 (c 1.34, CHCl3)Source of chirality: asymmetric induction and (S)-prolineAbsolute configuration: (4S,5S)

(4S,5S)-5-Ethyltetrahydro-4-hydroxy-2H-2-pyranoneC7H12O3[α]D25=+22.3 (c 0.94, CHCl3)Source of chirality: asymmetric induction and (S)-prolineAbsolute configuration: (4S,5S)

(3R,4S,5S)-5-Ethyltetrahydro-4-dimethylphenylsilyl-3-methyl-2H-2-pyranoneC16H24O2Si[α]D26=+37.2 (c 0.78, CHCl3)Source of chirality: asymmetric induction and (S)-prolineAbsolute configuration: (3R,4S,5S)

(3R,4S,5S)-1-Benzyl-4-dimethylphenylsilyl-5-ethyl-2-oxo-piperidine-3-carboxylic acid ethyl esterC25H33NO3Si[α]D27=-19.0 (c 1.0, CHCl3)Source of chirality: asymmetric induction and (S)-prolineAbsolute configuration: (3R,4S,5S)

(3R,4S,5S)-(1-Benzyl-4-dimethylphenylsilyl-5-ethyl-piperidine-3-yl)-methanolC23H33NOSi[α]D26=+5.0 (c 2.36, CHCl3).Source of chirality: asymmetric induction and (S)-prolineAbsolute configuration: (3R,4S,5S)