Search

In this study, the preparation of 4-imidoyl-, 4-oxiranyl-, and 4-propargyloxyphenyl-substituted beta-lactams as versatile building blocks in heterocyclic chemistry was realized. Efforts were made to deploy these polyvalent compounds for ensuing cyclization reactions en route to new bi- or polycyclic frameworks, which, in the case of a 3-chloro-4-propargyloxyphenyl-beta-lactam substrate, enabled the preparation of an unprecedented beta-lactam-fused benzotriazolo-oxazocane scaffold. The chemical structure of the latter polyheterocycle was unequivocally secured by means of X-ray analysis.

The reactivity of 3-oxo-β-lactams with respect to primary amines was investigated in depth. Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to selectively produce 3-imino-β-lactams (through dehydration), α-aminoamides (through CO elimination), or ethanediamides (through an unprecedented C3-C4 ring opening). In addition to the experimental results, the mechanisms and factors governing these peculiar transformations were also examined and elucidated by means of DFT calculations.

Within heterocyclic chemistry, β-lactams comprise an extraordinary class of strained compounds, recognized for their biological importance as potent antibiotics and their chemical value as flexible building blocks for the construction of diverse nitrogen-containing structures. Among the synthetic routes available to access this interesting scaffold, the carbonylation of aziridines, in which carbon monoxide is inserted into one of the ring carbon–nitrogen bonds, is praised for its efficiency and remarkable regio- and stereoselectivity. This review provides a comprehensive overview of aziridine-to-azetidin-2-one carbonylation studies. The protocols are categorized according to the different transition metals (i.e. rhodium, palladium, nickel, iron, and cobalt) that have been employed (in a catalytic or stoichiometric amount) to effect this transformation.

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.

(3R, 4S)-3-Alkoxy/aryloxy-4-(cyanomethyl) azetidin-2-ones were efficiently prepared from readily available 1,2: 5,6-di-D-isopropylidene-D-mannitol by means of a classical organic synthesis approach via 4-hydroxymethyl-beta-lactams as key intermediates. The corresponding 4-carboxymethyl-beta-lactams were subsequently obtained after selective hydrolysis of the nitrile functionality by means of a nitrilase enzyme without affecting the sensitive four-membered ring system, hence overcoming the difficulties associated with the chemical hydrolysis approach. Thus, the implementation of a biocatalytic step allows a convenient synthetic route to new 4-carboxymethyl-beta-lactams as versatile building blocks for further elaboration.

Trimethylene-tethered thymine-beta-lactam and thyminebis-beta-lactam chimeras were prepared as novel classes of hybrid systems through selective mono-or bis-N-alkylation of thymine with cis-1-(3-bromopropyl)-beta-lactams. In addition, acidic methanolysis of the beta-lactam nucleus in these systems provided an entry into the class of thymine-beta-amino ester hybrids. A selection of the newly synthesized hybrid compounds was assessed for their antiviral activity, cytotoxicity, and cytostatic activity, revealing a significant cytostatic effect of one of the derivatives against murine leukemia and human T-lymphocyte tumor cells.

The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-β-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-β-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO(4)-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-β-lactams, which exclusively leads to the corresponding 4-formyl-β-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3-ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations.

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.

β-Lactams represent versatile building blocks in heterocyclic chemistry. This chapter covers recent methodologies for the preparation of functionalized six-membered and three-membered azaheterocycles by ring transformation of azetidin-2-ones. Furthermore, emerging topics including the synthesis of biologically relevant C-fused bicyclic β-lactams and β-lactam-based hybrids are discussed.

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)methyl]butyrolactones 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 nitriles by means of a nitrilase was performed as well, interestingly providing a selective route towards the above-mentioned functionalized γ-lactams.