C4,C4'-BIS-BETA-LACTAM TO FUSED BIS-GAMMA-LACTAM REARRANGEMENT

Optically pure cis,cis-C4,C4'-bis-beta-lactams 1a-d are obtained in go od to excellent yields, in a single step, following two different appr oaches. Staudinger reaction of (S)-(4-phenyl-2-oxooxazolidinyl)acetyl chloride (2a) and p-anisyldiimine gave the corresponding bis-beta-lact am la as a single enantiomer. The reaction of glyoxal diimine derived from (S)-alpha-phenylethylamine and different alkoxy-substituted acid chlorides gave diastereomeric mixtures of cis,cis-bis-beta-lactams 1b- d, enantiomers at the bicyclic skeleton. The configuration of all comp ounds has been determined by X-ray diffraction analysis of enantiomeri cally pure aldehyde 4a and bis-beta-lactam Ib-a. The remaining bicycli c lactams have been chemically correlated to compound 1b-alpha and the ir configurations assigned. Starting from enantiomerically pure 4-form yl-2-azetidinone 4b, sequential imine formation and ketene cycloadditi on allowed the synthesis of differently substituted, optically pure ci s,cis-C4,C4'-bis-beta-lactams If-i in good overall yields. C4,C4'-Bis- beta-lactams smoothly rearranged to fused trans,trans-bis-gamma-lactam s 7 upon basic treatment (NaOMe/MeOH) in a totally stereoselective pro cess. The presence of alkyl groups attached to the lactam nitrogen inh ibits the rearrangement. Differently substituted (aryl and alkyl subst ituents in either rings) bicyclic p-lactam systems gave the selective opening of the ring with the aromatic substituent attached to the lact am nitrogen. Monocyclic 2-azetidinones 8 with an amino ester side chai n at C4 are then obtained. The synthesis of trans,cis-C4,C4'-bis-beta- lactam Ij and trans,trans-C4,C4'-bis-beta-lactam 11 has also been effe cted in the racemic form. Compound Ij with a trans,cis stereochemistry rearranged to cis,trans-bis-gamma-lactam 7d in the presence of base w hile the trans,trans-bicycle 11 gave monocyclic 2-azetidinone 8c with an amino ester side chain. Finally, trans,trans-bis-gamma-lactam 11 ca n be synthesized in a single step from glyoxal diimine 3a employing an excess of lithium isovalerate. A reaction pathway to account for all the observed data is proposed.