Approaches to the synthesis of enantiopure α-hydroxy-β-lactams with functionalized side chains

We report a synthesis of pharmaceutically important α-hydroxy (or t-butyldimethylsilyl protected α-hydroxy)-β-lactams with functionalized chains in position 4 of the azetidinone ring. A convenient and high-yielding route to these compounds was developed and optimized. Preparation and characterization of several new enantiopure title compounds with various functional groups are discussed.

We report a synthesis of pharmaceutically important α-hydroxy (or t-butyldimethylsilyl protected α-hydroxy)-β-lactams with functionalized chains in position 4 of the azetidinone ring. A convenient and high-yielding route to these compounds was developed and optimized. Preparation and characterization of several new enantiopure title compounds with various functional groups are discussed.Figure optionsDownload as PowerPoint slide

(3S,4R)-(−)-4-(2-Benzyloxy-1,1-dimethylethyl)-3-hydroxy-1-(4-methoxyphenyl)azetidin-2-oneC21H25NO4Ee = >99%[α]D20=-77.1 (c 1.0, CH2Cl2)Source of chirality: lipase resolutionAbsolute configuration: (3S,4R)

(3R,4S)-(+)-3-Acetoxy-4-(2-benzyloxy-1,1-dimethylethyl)-1-(4-methoxyphenyl)azetidin-2-oneC23H27NO5Ee = >99%[α]D20=+51.0 (c 1.0, CH2Cl2)Source of chirality: lipase resolutionAbsolute configuration: (3R,4S)

(3R,4R)-(+)-4-(2-Benzyloxy-1,1-dimethylethyl)-3-hydroxy-1-(4-methoxyphenyl)azetidin-2-oneC21H25NO4Ee = >99%[α]D20=+39.5 (c 0.25, CH2Cl2)Source of chirality: baker’s yeast reductionAbsolute configuration: (3R,4R)

(3R,4S)-(+)-4-(2-Benzyloxy-1,1-dimethylethyl)-3-(tert-butyldimethylsilanyloxy)-1-(4-methoxyphenyl)azetidin-2-oneC27H39NO4SiEe = >99%[α]D20=+52.1 (c 1.2, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(1,1-dimethylethyl-2-hydroxyl)-1-(4-methoxyphenyl)azetidin-2-oneC20H33NO4SiEe = >99%[α]D20=+53.7 (c 1.0, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(1-formyl-1,1-dimethylmethyl)-1-(4-methoxyphenyl)azetidin-2-oneC20H31NO4SiEe = >99%[α]D20=+56.4 (c 1.05, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(1,1-dimethyl-2-morpholinoethyl)-1-(4-methoxyphenyl)azetidin-2-oneC24H40N2O4SiEe = >99%[α]D20=+48.7 (c 1.5, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-3-Hydroxy-4-(1,1-dimethyl-2-hydroxy-ethyl)-1-(4-methoxyphenyl)azetidin-2-oneC14H19NO4Ee = >99%[α]D20=+70.2 (c 1.0, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(2-(tert-butyldimethylsilanyloxy)-1,1-dimethylethyl)-1-(4-methoxyphenyl)azetidin-2-oneC26H47NO4Si2Ee = >99%[α]D20=+34.8 (c 1.0, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(2-tert-butyldimethylsilanyloxy-1,1-dimethylethyl)azetidin-2-oneC19H41NO3Si2Ee = >99%[α]D20=+47.1 (c 0.25, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)

(3R,4S)-(+)-1-(tert-Butoxycarbonyl)-3-(tert-butyldimethylsilanyloxy)-4-(2-(tert-butyldimethylsilanyloxy)-1,1-dimethylethyl)azetidin-2-oneC24H49NO5Si2Ee = >99%[α]D20=+57.1 (c 1.01, CH2Cl2)Source of chirality: enantiopure reactantAbsolute configuration: (3R,4S)