Total synthesis of analogues of the β-lactam antibiotics. Part 3. 2-Ethoxycarbonyl derivatives of carbapen-1-em-3-exo-carboxylates and carbapenam-3-exo-carboxylates

Abstract

t-Butyl 2-ethoxycarbonylcarbapen-1-em-3-exo-carboxylate (7a) has been synthesised by a strategy involving final closure of the 1,2-bond using an intramolecular Wittig condensation. Hydroxyalkylation of the azetidinone nitrogen of 4-vinylazetidin-2-one with t-butyl α,α-dihydroxyacetate followed by treatment of the product (12a) with thionyl chloride–2,6-dimethylpyridine gave t-butyl α-chloro-α(2-oxo-4-vinylazetidin-1-yl)acetate (12b) which underwent chlorine displacement with ethyl (triphenylphosphoranylidene)acetate (10b). The resultant phosphorane (9a) was converted into the carbapen-1-em (7a) by sequential treatment with trifluoroacetic acid, ozone, dimethyl sulphide, and potassium hydrogen carbonate. A similar reaction sequence was used to prepare p-nitrobenzyl 2-ethoxycarbonylcarbapen-1-em-3-exo-carboxylate (7b).

An attempt to deprotect the t-butyl ester moiety of compound (7a) with trifluoroacetic acid resulted in β-lactam cleavage to give α-[(2SR,5RS)-4-ethoxycarbonyl-5-t-butoxycarbonyl-1-trifluoroacetyl-2,5-dihydropyrrol-2-yl]acetic acid (21a). Hydrogenolysis of the carbapen-1-em (7b) in the presence of sodium hydrogen carbonate gave initially the sodium salt (7c) and then sodium 2-ethoxycarbonylcarbapenam-3-exo-carboxylate as a 1 : 2 mixture of 2-endo-(24a) and 2-exo-isomers (25a).

Whereas hydrogen added predominantly to the endo-face of the alkene moiety of the carbapen-1-em (7a) to give mainly compound (25c), diazomethane attacked largely from the exo-face to give mainly the cycloadduct (32). Under thermal conditions, the last-cited compound was transformed into t-butyl 2-ethoxycarbonyl-1-methylcarbapen-1-em-3-exo-carboxylate (33).

Under conditions in which the carbapen-1-em (7a) underwent complete deuterium exchange at position 3, the relative (33) underwent ca. 25% deuterium exchange at position 3.