Progettazione e sintesi di nuovi derivati azetidinonici biologicamente attivi

In this PhD-thesis new synthetic approaches towards new azetidinone derivatives are described. In particular, 4-alkyliden-?-lactams were used as starting materials for the preparation of new biologically active compounds. The carbapenem Thienamycin has got a broad spectrum of activity as antibiotic. It has got 3 stereocenters and apart of one epimer, all isomers have been synthesized. Using the 4-alkyliden-?-lactam benzilyc ester as precursor, we developed a synthesis for this missing epimer, which is described in chapter II. Biological tests in order to establish its biological activity are under way. The Hunsdiecker-Borodine reaction was extensively studied for the preparation of the mono halogenated and †" surprisingly †" the dihalogenated derivative from the 4-alkyliden-azetidinone carboxylic acid. The herein described synthetic procedures allowed the preparation of chloro-, bromo- and iodo derivatives in good to excellent yield. Furthermore, the reaction mechanism was investigated by NMR-experiments and is described in detail in chapter III. In chapter IV, synthetic approaches towards new ?-lactam derivatives for inhibition of the histone deacetylase enzymes (HDACs) are reported. In collaboration with the company Sigma-Tau (Rome), 14 new ?-lactams were synthesized. The new ?-lactams were evaluated for the activity showing a promising activity??particulary, 10 of the? ?-lactams synthesized were evaluated for the in vitro inhibitory activity against the 11 human HDACs isoforms and they showed a selective inhibition of HDAC6 or HDAC8 in micromolar range. Finally, preliminary studies were conducted for the employment of 4-alkyliden-?-lactams as precursors for the synthesis of chiral ?-amino acids by an opening of the ?-lactam ring. In chapter V is described the ring opening reaction catalyzed by the enzyme lipase Cal-B. Preliminary results have shown that the enzyme not only catalyzes the ring opening of the ?-lactam precursor, moreover, it leads to the formation of a cyclic dimer by the reaction of two molecules of ?-amino acid obtained.