Shohei Hashiguchi

Synthesis of γ-lactam analogues of carbapenems with substituted-thio groups at the C-3 position

γ-Lactamanalogues of carbapenems{(7S)-7-acylamino-2-carboxy-3-(substituted-thio)-1-azabicyclo[3.3.0]oct-2-en-8-ones}(2) were synthesized starting from L-aspartic acid. Condensation of the oxo ester (4) with 2, 4-dimethoxybenzylamine followed by cyclization gave preferentially the E-γ-lactam (6), which was transformed into the 3, 5-cis-5-carboxymethyl-γ-lactam cis-(9)via stereoselective catalytic reduction. The major product cis-(9) and its trans-isomer were converted into compound (2)via a carbene insertion reaction. The antibacterial activity of the trans-acetamidoethylthio derivative (23) slightly exceeded that of the corresponding cis-derivative (17).

Stereoselective synthesis of sperabillins and related compounds

Bakers yeast reduction of methyl (4S)-4-(tert-butoxycarbonylamino)-3-oxopentanoate 6 stereoselectively afforded methyl (3R,4S)-erythro-4-Boc-amino-3-hydroxypentanoate 7, which was converted into the erythro keto δ-lactone 3a in three steps. The threo keto δ-lactones 3b–c were diastereoselectively prepared by cyclocondensation of N-Boc D- and L-alaninal 4 with 1 -methoxy-1, 3-bis(trimethylsiloxy)buta-1,3-diene 9 in the presence of a catalytic amount of tin(II) chloride. Recluctive amination of the keto lactones 3 using 5% platinum on carbon as catalyst in an acidic medium stereoselectively afforded the N-protected 3,6-diamino-5-hydroxyheptanoic acid lactones 1 with 3,5-anti stereochemistry. These were transformed into the enantiomerically pure sperabillin 17 and negamycin 20 derivatives in good yields. The configuration of sperabillin B and D was determined to be (3R,5R,6R) by comparison of the synthetic amino lactone 1e with a degradation product of sperabillin B and by the successful transformation of the synthetic amino lactone 1b into sperabillin D.