14C-labeling of a novel carbapenem antibiotic SM-7338

(1R,5S,6S)-2- [(3S,5S)-5-Dimethylaminocarbonylpyrrolidin-3-ylthio]-6- [(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid trihydrate (SM-7338), a novel 1 β-methyl carbapenem antibiotic, was labeled with carbon-14 at the C3 position of the carbapenem nucleus for use in metabolic studies. The synthesis was achieved according to the scheme illustrated in Fig. 3. Selective esterification of [2-14C]malonic acid (2) with 4-nitrobenzyl bromide (3) gave its monoester (4). Condensation of the magnesium salt of 4 with the imidazolide derived from the azetidinone carboxylic acid (5) provided the β-keto ester (6), which was desililated with hydrochloric acid to give the alcohol (7). Treatment of 7 with carboxybenzenesulfonyl azide followed by decomposition of the resulting diazo intermediate (8) in the presence of a rhodium catalyst produced the bicyclic keto ester (9). Reaction of 9 with diphenyl chlorophosphate in the presence of N,N-diisopropylethylamine and subsequent displacement reaction of the vinyl phosphate (10) with mercaptopyrrolidine (11) gave bis-protected SM-7338 (12). Catalytic hydrogenolysis of 12 afforded [carbapenem-3-14C]-SM-7338 (1). The overall yield of 1 was 5.8% from 2.