Synthesis and decarboxylation of Delta(2)-cephem-4,4-dicarboxylic acids

Citation
S. Wolfe et al., Synthesis and decarboxylation of Delta(2)-cephem-4,4-dicarboxylic acids, CAN J CHEM, 79(8), 2001, pp. 1238-1258
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry
Journal title
CANADIAN JOURNAL OF CHEMISTRY-REVUE CANADIENNE DE CHIMIE
ISSN journal
0008-4042 → ACNP
Volume
79
Issue
8
Year of publication
2001
Pages
1238 - 1258
Database
ISI
SICI code
0008-4042(200108)79:8<1238:SADODA>2.0.ZU;2-J
Abstract
Penicillin V was converted in 14 steps into Delta (2)-cephems having hydrog en at C-3, hydrogen or ethyl at C-2, and two methoxycarbonyl, two benzyloxy carbonyl, or one methoxycarbonyl and one benzyloxycarbonyl substituent at C -4. Deprotection of these Delta (2)-cephem-4,4-dicarboxylic acid esters by alkaline hydrolysis (in the case of methyl esters) or hydrogenolysis (in th e case of benzyl esters) led in all cases to rapid decarboxylation of the D elta (2)-cephem-4,4-dicarboxylic acid or delta(2)-cephem-4,4-dicarboxylic a cid monoester. With hydrogen at C-2, hydrolysis of the dimethyl ester with 1 equiv of base produced a Delta (2)-cephem. With 2 equiv of base, and with all compounds having methyl at C-2, hydrolysis or hydrogenolysis afforded 4 alpha -substituted-Delta (2)-cephems. In contrast, simpler benzyl or methyl acetamidomalonates could be deprotect ed without difficulty to afford stable malonic acids. Reasons for the diffe rences in ease of decarboxylation were examined using semiempirical (AM1) a nd ab initio (3-21G) molecular orbital calculations. The decarboxylation ba rriers of unionized cephem or acetamido malonic acids were found to be high (35-40 kcal mol(-1)). Although the monoanion of acetamidomalonic acid reta ined a high barrier, the epimeric monoanions of a Delta (2)-cephem malonic acid decarboxylated with barriers of only 2 kcal mol(-1).