Synthesis, hydrolysis, and evaluation of 3-acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazinecarboxylic acids and linear azadepsipeptides as potential substrates/inhibitors of beta-lactam-recognizing enzymes

The title compounds can be considered as stabilized aza analogs of previous ly studied dihydrobenzopyranones and linear depsipeptides, which behave as substrates or inhibitors of beta -lactamases. Treatment of substituted hydr azides Sb and 9b' with a phosgene substitute resulted in a series of N-meth ylated 3-acylamino-3,4-dihydro-2-oxo-2H- 1,3-benzoxazine-7-and -8-carboxyli c acids 2b and 2b'. However, in the case of the corresponding free NH hydra zide 9a(m), a competitive cyclization gave instead a stable 4H-1,3,4-oxadia zol-5-one 10a. To avoid this unwanted cyclization, an N-(p-methoxy)benzylat ed hydrazide 9b" was prepared. After formation of the benzoxazinone ring wi th carbonyldiimidazole, the removal of this new N'-hydrazide protecting gro up was achieved with methanesulfonic acid in trifluoroacetic acid to give t he expected 3-phenacetamido-3,4-dihydro-2-oxo-2H- 1,3-benzoxazine-7-carboxy lic acid 2a(m). The corresponding linear azadepsipeptides 5 were generally obtained by reaction of a hydrazide with 3 - tert- butoxycarbonylphenyl chl orocarbonate. Hydrolysis of the title compounds in buffer at neutral pH was more rapid than anticipated because of the presence of mechanisms more fac ile than the classical B(AC)2. Hydrolysis of the cyclic azadepsipeptide 2a( m), for example, involved intramolecular nucleophilic participation by the am ido side chain and a slowly hydrolyzing oxadiazolone intermediate (10a). These compounds, unlike their parent depsipeptides, were not substrates or inhibitors of beta -lactamase or DD-peptidase. This result probably arises from a combination of the poor carbonyl electrophilicity and the close to planar geometry of the nitrogen atom of the oxazin-2-one ring.