Synthesis of thienamycin-like 2-iso-oxacephems with optional stereochemistry

All four trans-stereoisomers of 7-(1-hydroxyethyl)-2-iso-oxacephem-4-carboxylic acids, which are the 2-iso-oxacephem analogues of Thienamycin, have been synthesized. (αR,6R,7R)- and (αS,6S,7S)-7-(1-hydroxyethyl)-3-methyl-2-iso-oxacephem-4-carboxylic acids have been prepared starting from l- and d-threonine, the configuration at the α-position was inverted by using Mitsunobu reactions providing the (αS,6R,7R)- and (αR,6S,7S)-diastereomers of the compounds above. A synthetic route to the cis-annelated analogues was also worked out.

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(6R,7R)-7-[(1R)-1-Hydroxyethyl]-3-methyl-2-iso-oxacephem-4-carboxylic acidC10H13NO5[α]D20=-220.8(c1.0,MeOH)Source of chirality: l-threonineAbsolute configuration: (αR,6R,7R)

(6R,7R)-7-[(1S)-1-Hydroxyethyl]-3-methyl-2-iso-oxacephem-4-carboxylic acidC10H13NO5[α]D20=-232.3(c1.0,MeOH)Source of chirality: l-threonineAbsolute configuration: (αS,6R,7R)

(6S,7R)-7-[(1R)-1-Hydroxyethyl]-3-methyl-2-iso-oxacephem-4-carboxylic acidC10H13NO5[α]D25.5=+175.8(c1.0,MeOH)Source of chirality: l-threonineAbsolute configuration: (αR,6S,7R)

Benzyl (6R,7R)-7-[(1R)-1-hydroxyethyl]-3-methyl-2-iso-oxacephem-4-carboxylateC17H19NO5[α]D23.5=-184.3(c1.0,CH2Cl2)Source of chirality: l-threonineAbsolute configuration: (αR,6R,7R)

Benzyl (6R,7R)-7-[(1S)-1-hydroxyethyl]-3-methyl-2-iso-oxacephem-4-carboxylateC17H19NO5[α]D23=-190.7(c1.0,CH2Cl2)Source of chirality: l-threonineAbsolute configuration: (αS,6R,7R)

Benzyl (6S,7R)-7-[(1R)-1-hydroxyethyl]-3-methyl-2-iso-oxacephem-4-carboxylateC17H19NO5[α]D26=+103.5(c1.0,CH2Cl2)Source of chirality: l-threonineAbsolute configuration: (αR,6S,7R)