Novel chiral pyrrolidinone scaffolds derived from threonine with antibacterial activity

The synthesis of chiral pyrrolidinones derived from threonine, making use of a Dieckmann or aldol ring closure, is described. Compounds were found to exhibit antibacterial activity, for which the correlation with various physiochemical parameters was examined. This chiral tetramate scaffold may provide a useful template for fragment-based drug design providing rapid access to novel antibacterial compound libraries.

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2-(tert-Butyl)-3-(3-ethoxy-3-oxopropanoyl)-4-methoxycarbonyl-5-methyl-oxazolidineC15H26NO6[α]D = −71.1 (c 1.6, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4S,5R)

2-(tert-Butyl)-3-(3-ethoxy-2-methyl-3-oxopropanoyl)-4-methoxycarbonyl-5-methyl-oxazolidineC16H28NO6[α]D = +87.2 (c 2.2, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2S,4S,5R,2′S)

2-(tert-Butyl)-3-(3-ethoxy-2-phenyl-3-oxopropanoyl)-4-methoxycarbonyl-5-methyl-oxazolidineC21H30NO6[α]D = −43.4 (c 2.0, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4S,5R,2′R)

2-(tert-Butyl)-3-(3-ethoxy-2-phenyl-3-oxopropanoyl)-4-methoxycarbonyl-5-methyl-oxazolidineC21H30NO6[α]D = +87.0 (c 2.0, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4S,5R,2′S)

2-(tert-Butyl)-3-(2-phenylacetyl)-5-methyl-4-methoxycarbonyl-oxazolidineC18H26NO4[α]D = −4.9 (c 1.6, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4S,5R)

2-(tert-Butyl)-3-(2-cyanoacetyl)-4-methoxycarbonyl-5-methyl-oxazolidineC13H21N2O5[α]D = −41.7 (c 1.2, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4S,5R)

3-(Acetoacetyl-2-(tert-butyl)-4-methoxycarbonyl-5-methyl-oxazolidineC15H26NO5[α]D = +11.6 (c 3.0, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4S,5R)

1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-6,8-dioxo-3-oxabicyclo[3.3.0]-octaneC13H18NO5[α]D = +47.2 (c 1.5 in MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R)

l-Aza-2-(tert-butyl)-4-methyl-6,8-dioxo-3-oxabicyclo[3.3.0]octaneC11H17NO3[α]D = +95.4 (c 1.5 in MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R)

1-Aza-2-(tert-butyl)-6-hydroxy-5-methoxycarbonyl-4-methyl-8-oxo-7-phenyl-3-oxabicyclo[3.3.0]oct-6-eneC19H22NO5[α]D = +87.2 (c 1.2, MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R)

1-Aza-2-(tert-butyl)-6-hydroxy-4-methyl-8-oxo-7-phenyl-3-oxabicyclo[3.3.0]oct-6-eneC17H21NO3[α]D = +63.2 (c 1.12, MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R)

1-Aza-6-amino-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-8-oxo-3-oxabicyclo-[3.3.0]-oct-6-eneC13H2lN2O4[α]D = +23.2 (c 1.3, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5S)

1-Aza-6-amino-2-(tert-butyl)-4-methyl-8-oxo-3-oxabicyclo-[3.3.0]-oct-6-eneC11H17N2O2[α]D = +104.6 (c 1.5, MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5S)

1-Aza-2-(tert-butyl)-6-hydroxy-5-methoxycarbonyl-4,6-dimethyl-8-oxo-3-oxabicyclo [3.3.0] octaneC14H22NO5[α]D = +38.2 (c 1.5, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R,6S)

1-Aza-2-(tert-butyl)-6-hydroxy-5-methoxycarbonyl-4,6-dimethyl-8-oxo-3-oxabicyclo [3.3.0] octaneC14H22NO5[α]D = +29.0 (c 1.35, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R,6R)

3-Hydroxy-2-(1′-hydroxyethyl)-4-phenyl-1H-pyrrol-2(5H)-oneC12H12NO3[α]D = +51.1 (c 0.9 MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,1′R)

Methyl 3-hydroxy-2-(1′-hydroxyethyl)-5-oxo-4-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylateC14H16NO5[α]D = +43.2 (c 1.0, MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,1′R)

3-Hydroxy-2-(1-hydroxyethyl)-2-methoxycarbonyl-3-methyl-5-pyrrolidinoneC9H14NO5[α]D = +79.6 (c 1.7, MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,3S,2′R)

1-Aza-2-(tert-butyl)-6-hydroxy-5-methoxycarbonyl-4,6,7-trimethyl-8-oxo-3-oxabicyclo[3.3.0]octaneC15H24NO5[α]D = +33.4 (c 1.1, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R,6S,7S)

1-Aza-2-(tert-butyl)-6-hydroxy-5-methoxycarbonyl-4,6,7-trimethyl-8-oxo-3-oxabicyclo[3.3.0]octaneC15H24NO5[α]D = +63.7 (c 1.2, CHCl3)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,4R,5R,6R,7S)

2,3-Dimethyl-3-hydroxy-2-(R-1-hydroxyethyl)-2-methoxycarbonyl-5-pyrrolidinoneC10H16NO5[α]D = +60.1 (c 0.6, MeOH)Source of chirality: l-threonine methyl esterAbsolute configuration: (2R,3R,1′R)