Asymmetric synthesis of 1,3-thiazolidine-derived spiro-β-lactams via a Staudinger reaction between chiral ketenes and imines

Enantiomerically pure 1,3-thiazolidine-derived spiro-β-lactams were stereoselectively synthesised by means of a Staudinger ketene–imine reaction starting from optically active N-Boc-1,3-thiazolidine-2-carboxylic acid derivatives and imines. The reactions were stereoselective and afforded spiro-β-lactams with a relative trans-configuration. The absolute configuration of the new stereocentres was assigned on the basis of the well-accepted mechanism and confirmed by means of the X-ray crystal structure analysis. The spiro-β-lactams were transformed into enantiomerically pure chiral monocyclic β-lactams by opening the thiazolidine ring and recovering the chiral auxiliary.

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(2S,4R)-1,3-Thiazolidine-2,4-dicarboxylic acid 4-methyl esterC6H9NO4SDr = >99% [NMR][α]D20=-216.8 (c 1.03, CH3OH)Source of chirality: l-cysteine methyl esterAbsolute configuration: (2S,4R)

(2S,4R)-1,3-Thiazolidine-2,3,4-tricarboxylic acid 3-(1,1-dimethylethyl) 4-methyl esterC11H17NO6SEe >99%[α]D20=-72.7 (c 0.22, CH3OH)Absolute configuration: (2S,4R)

(4S)-4-(1-Methylethyl)-1,3-thiazolidine-2,3-dicarboxylic acid 3-(1,1-dimethylethyl) esterC12H21NO4SDr = >99% [NMR][α]D20=+56.4 (c 0.15, CH3OH)Source of chirality: l-valinolAbsolute configuration: (4S)

(2S,4R)-3-Acetyl-1,3-thiazolidine-2,4-dicarboxylic acid 4-methyl esterC8H11NO5SEe >99%[α]D20=-133.0 (c 0.79, CH3OH)Absolute configuration: (2S,4R)

(2S,4R)-3-Benzoyl-1,3-thiazolidine-2,4-dicarboxylic acid 4-methyl esterC13H13NO5SEe >99%[α]D20=+191.9 (c 1.03, CH3OH)Absolute configuration: (2S,4R)

(3R,4R,7R)-8-(tert-Butoxycarbonyl)-7-methoxycarbonyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3,4]octan-1-oneC25H28N2O5SDr = >99% [NMR][α]D20=-180.2 (c 0.95, CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration: (3R,4R,7R)

(3S,4S,7R)-8-(tert-Butoxycarbonyl)-7-methoxycarbonyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3,4]octan-1-oneC25H28N2O5SDr = >99% [NMR][α]D20=+59.6 (c 0.98, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,7R)

(3S,4S,7S)-8-(tert-Butoxycarbonyl)-7-(1-methylethyl)-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3,4]octan-1-oneC26H32N2O3SDr = >99% [NMR][α]D20=+159.2 (c 1.03, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,7S)

(3S,4R,7R)-8-Benzoyl-7-methoxycarbonyl-3-phenyl-2-(phenylsulfonyl)-5-thia-2,8-diazaspiro[3,4]octan-1-oneC26H22N2O6S2Dr = >99% [NMR][α]D20=-85.3 (c 0.30, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,7R)

(4R)-4-Phenyl-1-(phenylmethyl)azetidine-2,3-dioneC16H13NO2Ee >99% [1H NMR with (+)-Eu(hfc)3][α]D20=-21.9 (c 0.59, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4R)