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

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)

Chemoenzymatic approach toward the synthesis of 3-O-(α/β)-glucosylated 3-hydroxy-β-lactams

Glycosylation significantly alters the biological and physicochemical properties of small molecules. beta-Lactam alcohols comprise eligible substrates for such a transformation based on their distinct relevance in the chemical and medicinal community. In this framework, the unprecedented enzymatic glycosylation of the rigid and highly strained four-membered beta-lactam azaheterocycle was studied. For this purpose, cis-3-hydroxy-beta-lactams were efficiently prepared in three steps by means of a classical organic synthesis approach, while a biocatalytic step was implemented for the selective formation of the corresponding 3-O-alpha- and -beta-glucosides, hence overcoming the complexities typically encountered in synthetic glycochemistry and contributing to the increasing demand for sustainable processes in the framework of green chemistry. Two carbohydrate-active enzymes were selected based on their broad acceptor specificity and subsequently applied for the alpha- or beta-selective formation of beta-lactam-sugar adducts, using sucrose as a glucosyl donor

Use of α,ω-dichloroketimine building blocks for the construction of 1-azabicyclo[3.1.0]hexanes, piperidines, pyridines, pyrroles and tetrahydroindoles

A variety of different N-[2-chloro-4-(chloromethyl)pent-4-enylidene]amines and N-(2,6-dichlorohex-4-enylidene)amines was prepared for the first time, and their reactivity as eligible building blocks for the synthesis of biologically relevant nitrogen-containing heterocyclic compounds was studied. In this way, a convenient entry into functionalized 1-azabicyclo[3.1.0]hexanes, piperidines, pyridines, pyrroles, and tetrahydroindoles was developed, pointing to the broad synthetic flexibility of these dichlorinated imine substrates

Practical ferrioxalate actinometry for the determination of photon fluxes in production-oriented photoflow reactors

Accurate determination of the photon flux is of major importance to evaluate and characterize photochemical reactor setups. Knowing the photon flux ensures reproducible reactor operation and facilitates predictable scale-up. Over the past years, flow reactors have proven to be the key enabling technology for photochemistry to become relevant on production scales. This is mainly due to the mitigation of the limited penetration depth of photons in typical batch reactors. However, due to the practical drawbacks of the widely accepted standard for photon flux determination (ferrioxalate actinometry) concerning precipitation and gas formation at higher conversion, reliable actinometry in flow reactors is still challenging. In this paper, three practical approaches for the ferrioxalate-based determination of the photon flux are presented, which address these problems. These "dimmed emitter," "segment-based," and "time-resolved" methods thus allow photon flux determination in flow reactors with higher irradiated volumes and more powerful light sources, which is of utmost importance in the context of future scale-up

Synthesis of 2-aryl-3-(2-cyanoethyl)aziridines and their chemical and enzymatic hydrolysis towards γ-lactams and γ-lactones

Trans- and cis-2-aryl-3-(2-cyanoethyl)aziridines, prepared via alkylation of the corresponding 2-aryl-3-(tosyloxymethyl)aziridines with the sodium salt of trimethylsilylacetonitrile, were transformed into variable mixtures of 4-aryl(alkylamino)methylIbutyrolactones and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones via KOH-mediated hydrolysis of the cyano group, followed by ring expansion. In addition, next to this chemical approach, enzymatic hydrolysis of the former aziridinyl nitrites by means of a nitrilase was performed as well, interestingly providing a selective route towards the above-mentioned functionalized gamma-lactam

Diastereoselective synthesis of 3-acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones and their transformation into 3,4-oxolane-fused bicyclic β-lactams

cis-3-Acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones were prepared through a Staudinger [2+2]-cyclo-condensation between acetoxyketene and the appropriate epoxyimines in a highly diastereoselective way. Subsequent potassium carbonate-mediated acetate hydrolysis, followed by intramolecular ring closure through epoxide ring opening, afforded stereodefined 3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones as a novel class of C-fused bicyclic beta-lactams. Selective benzylic oxidation of bicyclic N-(4-methoxybenzyl)-beta-lactams with potassium persulfate and potassium dihydrogen phosphate provided the corresponding N-aroyl derivatives as interesting leads for further beta-tactamase inhibitor development