A versatile approach to cis-5-substituted 4-hydroxy-2-pyrrolidinones: asymmetric synthesis of angiogenesis inhibitor streptopyrrolidine

A concise, flexible, and highly diastereoselective approach to cis-5-alkyl-4-hydroxy-2-pyrrolidinones 1 is described. The key step is an ammonium acetate-assisted catalytic hydrogenation of the enamides 9, derived in two steps from malimides 6a,b as we have described previously. The method was applied to the asymmetric synthesis of streptopyrrolidine 5, a natural product, which exhibited significant anti-angiogenesis activity.

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(4S,5S)-1-Benzyl-4-(benzyloxy)-5-methylpyrrolidin-2-oneC19H21NO2[α]D20=-19.8 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-1-Benzyl-4-(benzyloxy)-5-ethylpyrrolidin-2-oneC20H23NO2[α]D20=-2.7 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-1-Benzyl-4-(benzyloxy)-5-butylpyrrolidin-2-oneC22H27NO2[α]D20=+7.8 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-1-Benzyl-4-(benzyloxy)-5-pentylpyrrolidin-2-oneC23H29NO2[α]D20=+7.9 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-1-Benzyl-4-(benzyloxy)-5-isobutylpyrrolidin-2-oneC22H27NO2[α]D20=+7.3 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-1,5-Dibenzyl-4-(benzyloxy)pyrrolidin-2-oneC25H25NO2[α]D20=-4.2 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(S,E)-1-Benzyl-4-(benzyloxy)-5-octylidenepyrrolidin-2-oneC26H33NO2[α]D20=+80.0 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S)

(4S,5S)-1-Benzyl-4-(benzyloxy)-5-octylpyrrolidin-2-oneC26H35NO2[α]D20=+10.4 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(S,E)-1-Benzyl-4-(benzyloxy)-5-dodecylidenepyrrolidin-2-oneC30H43NO2[α]D20=+80.6 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S)

(4S,5S)-1-Benzyl-4-(benzyloxy)-5-dodecylpyrrolidin-2-oneC30H45NO2[α]D20=+10.5 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-1-(4-methoxybenzyl)-4-(benzyloxy)-5-Methylpyrrolidin-2-oneC20H23NO3[α]D20=-19.7 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(S,E)-5-Benzylidene-4-(benzyloxy)-1-(4-methoxybenzyl)pyrrolidin-2-oneC26H25NO3[α]D20=+291.0 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S)

(4S,5S)-5-Benzyl-4-(benzyloxy)-1-(4-methoxybenzyl)pyrrolidin-2-oneC26H27NO3[α]D20=-5.7 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-5-Benzyl-4-(benzyloxy)pyrrolidin-2-oneC18H19NO2[α]D20=-35.6 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)

(4S,5S)-5-Benzyl-4-hydroxypyrrolidin-2-oneC11H13NO2[α]D20=-43.5 (c 1.0, MeOH)Source of chirality: (S)-malic acidAbsolute configuration: (4S,5S)