Synthesis of new β-lactam building blocks and their application in heterocyclic chemistry

Abstract

Within azaheterocyclic chemistry, β-lactams comprise an extraordinary class of strained compounds with diverse applications. In addition to their biological importance as potent antibiotics, azetidin-2-ones have been recognized as valuable building blocks for further elaboration toward a variety of nitrogen-containing structures. In a major part of this PhD thesis, the cobalt carbonyl-catalyzed carbonylation of different classes of non-activated aziridines was scrutinized, with special attention devoted to selectivity issues and reaction optimization. This has resulted in the regio- and stereoselective synthesis of 24 novel β-lactam target structures in high yields on a multigram scale, which were subjected to selected ring-expansion, ring-closure and side chain-functionalization protocols. In addition, other emerging topics have been covered in this thesis, including the synthesis of β-lactam-based hybrids and C-fused bicyclic β-lactams. In particular, trimethylene-tethered thymine-(bis-)β-lactam chimeras were prepared and subsequently assessed for their antiviral activity, cytotoxicity and cytostatic activity. Furthermore, 4-(3-aryloxiran-2-yl)azetidin-2-ones were synthesized in a highly diastereoselective way and converted into a novel class of 3,4-oxolane-fused bicyclic β-lactams, providing interesting leads for further β-lactamase inhibitor development. Finally, the reactivity of 3-oxo-β-lactams with respect to primary amines was explored in-depth, both experimentally and computationally. Depending on the different β-lactam substituents, this reaction was shown to selectively produce 3-imino-β-lactams (dehydration products), α-aminoamides (CO elimination products) or unprecedented ethanediamides (C3-C4 ring-opening products)