The 1-azabicyclo[3.2.0]heptan-2-one system as a potential antibiotic

Abstract

The main body of this work consists of various synthetic approaches to the two diastereomers of bicyclic lactam I (R = H) which, possessing a non-planar amide moiety but lacking the penicillinase sensitive ß-lactam ring, present interest from the biological viewpoint. A short and efficient synthesis of pyrrolidones II and III (R = H or Me, R' = OH) is described. Base treatment of III (R = Hor Me, R' = OTs, CMs or Br) failed to effect cyclization to the azetidine. Studies concerning the possibility of ring contraction of IV to the desired carbon skeleton were carried out on a monocyclic 3-diazopyrrolid-2-one, where it was found that the carbene generated, inserts into the adjacent C-H or solvent 0-H bonds, rather than into the N-CO bond. Azetidine diester V was prepared in high yield by treating α,α'-dibromoglutaric acid diester with benzylamine. The use of different ester groups allowed selective reduction to alcohol VI (R = Bz, R' = CH2OH), which could be resolved to diastereomers by crystallization. Attempts to form the lactam ring by appropriate nitrogen acylation of VI (R = H, R' = CH2 OH) and subsequent Moffatt oxidation of the alcohol function (VI, R = COCH2 X, R' = CHO, X = carbanion stabilizing group) were unsuccessful. Chain extension was achieved by the Wittig reaction of aldehyde VI (R = CBZ, R' = CHO) with PhjPCHCC^PNB. Saturation of the resulting olefin and hydrogenolysis of the protecting groups furnished γ -amino acid VI (R = H, R' = CH2 CH2CO2 H) which, when treated with 2,2'-dipyridyl disulfide and triphenyl phosphine, lactamized to I (R = ιΒυ). Deprotection to the free acid (I, R = II) was accomplished by treatment with trifluoroacetic acid. The possibility of synthesizing I via an intramolecular [2*2] cycloaddition is briefly discussed. X-ray structure determination was performed on both diastereomers of I (R = cBu). All structural parameters considered by the various hypotheses critical for biological activity, were well within limits in the case of the cis isomer of I. However, in vivo tests, proved both trans and cis diastereomers of I (R = H) to be devoid of biological activity. This is attributed to the extreme sensitivity of I (R = H) to hydrolysis.