Asymmetric inverse electron-demand 1,3-dipolar cycloaddition of ynolates with a chiral nitrone derived from l-serine leading to β-amino acid derivatives

Asymmetric 1,3-dipolar cycloaddition of lithium ynolates with a nitrone derived from Garner’s aldehyde is described. The cycloadducts, 5-isoxazolidinones, were obtained in good yields with high diastereoselectivity. Alkylation of the intermediates, the 5-isoxazolidinone enolates, was also achieved with high selectivity, the products of which were converted into the enantiomerically pure β-amino acids, β-lactams, and γ-lactams. In our cycloaddition, lithium ynolates proved to be much better as nucleophiles than lithium enolates.

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(3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-methylisoxazolidin-5-oneC21H30N2O5Ee = 100%[α]D23=-93.9 (c 1.16, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3S,4S)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-methylisoxazolidin-5-oneC21H30N2O5Ee = 100%[α]D25=-90.2 (c 1.05, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,4′R)

(3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-butylisoxazolidin-5-oneC24H36N2O5Ee = 100%[α]D24=-119.1 (c 1.16, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-isopropylisoxazolidin-5-oneC23H34N2O5Ee = 100%[α]D23=-125.2 (c 0.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-phenylisoxazolidin-5-oneC26H32N2O5Ee = 100%[α]D23=-86.4 (c 1.34, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3S)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-isoxazolidin-5-oneC20H28N2O5Ee = 100%[α]D25=-133.0 (c 1.16, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4′R)

(3S)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4,4-dimethylisoxazolidin-5-oneC22H33N2O5Ee = 100%[α]D25=-111.2 (c 0.93, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4′R)

(3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-butyl-4-methylisoxazolidin-5-oneC25H38N2O5Ee = 100%[α]D23=-130.1 (c 0.96, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-isopropyl-4-methylisoxazolidin-5-oneC24H36N2O5Ee = 100%[α]D24=-122.0 (c 1.06, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3S,4R)-2,4-Dibenzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-4-methylisoxazolidin-5-oneC28H36N2O5Ee = 100%[α]D24=-212.0 (c 1.13, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,4′R)

(3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-methylazetidin-2-oneC14H24N2O4Ee = 100%[α]D25=-18.2 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,4′R)

(3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-butylazetidin-2-oneC17H31N2O4Ee = 100%[α]D27=-22.3 (c 1.10, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-isopropylazetidin-2-oneC16H28N2O4Ee = 100%[α]D27=-28.3 (c 1.17, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-phenylazetidin-2-oneC19H26N2O4Ee = 100%[α]D26=-24.7 (c 1.60, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-butyl-3-methylazetidin-2-oneC18H33N2O4Ee = 100%[α]D26=-20.2 (c 1.22, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-isopropyl-3-methylazetidin-2-oneC17H30N2O4Ee = 100%[α]D26=-21.0 (c 0.91, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-methylazetidin-2-oneC21H30N2O4Ee = 100%[α]D26=+8.7 (c 1.39, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-butylazetidin-2-oneC24H36N2O4Ee = 100%[α]D27=+1.8 (c 0.92, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-isopropylazetidin-2-oneC23H34N2O4Ee = 100%[α]D27=-12.1 (c 0.84, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-phenylazetidin-2-oneC26H32N2O4Ee = 100%[α]D27=+38.1 (c 0.96, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-butyl-3-methylazetidin-2-oneC25H39N2O4Ee = 100%[α]D28=+0.2 (c 0.92, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-3-methyl-3-isopropylazetidin-2-oneC24H36N2O4Ee = 100%[α]D28=-14.3 (c 0.54, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,4′R)

(3S,4S,5R)-4-(Benzylamino)-5-(tert-butyldiphenylsiloxymethyl)-3-methylpyrrolidin-2-oneC29H36N2O2SiEe = 100%[α]D27=-48.5 (c 0.83, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5R)

(3S,4S,5R)-4-(Benzylamino)-5-(tert-butyldiphenylsiloxymethyl)-3-butylpyrrolidin-2-oneC32H42N2O2SiEe = 100%[α]D27=-45.2 (c 0.53, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5R)

(3S,4S,5R)-4-(Benzylamino)-5-(tert-butyldiphenylsiloxymethyl)-3-isopropylpyrrolidin-2-oneC31H40N2O2SiEe = 100%[α]D28=-45.2 (c 0.28, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5R)

(3S,4S,5R)-4-(Benzylamino)-5-(tert-butyldiphenylsiloxymethyl)-3-phenylpyrrolidin-2-oneC34H38N2O2SiEe = 100%[α]D27=-55.7 (c 0.19, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5R)

(3R,4S,5R)-4-(Benzylamino)-5-(hydoxymethyl)-3-isopropyl-3-methylpyrrolidin-2-oneC16H24N2O2Ee = 100%[α]D28=-59.9 (c 0.23, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S,5R)