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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.

(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.

Heterocyclic naphthoquinones represent valuable scaffolds in medicinal chemistry. In the present Letter, the efficient stereoselective synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones by means of one-pot multicomponent reactions using 2-hydroxy-1,4-naphthoquinone, an aromatic aldehyde and ethyl 4,4,4-trifluoroacetoacetate or a pyridinium bromide, respectively, is described.

Azaheterocycles comprise relevant target structures within organic chemistry due to the broad diversity of biological activities associated with these scaffolds. In this review, the most important recent procedures for the preparation of functionalized six-membered azaheterocyclic compounds by ring transformation of beta-lactams are summarized and discussed.

cis-2-(2-Bromo-1,1-dimethylethyl)azetidines were transformed into novel 5,5-dimethylpiperidin-4-ones through a ring expansion–oxidation protocol upon heating in DMSO in the presence of Ag2CO3 or AgBF4. In addition, several 5,5-nor-dimethyl analogues of the latter piperidin-4-ones were synthesized in a selective way through a similar ring expansion–oxidation approach involving treatment of cis-2-(2-mesyloxyethyl)azetidines with K2CO3 in DMSO. Furthermore, both a diastereoselective and an enantioselective reduction of the carbonyl function in piperidin-4-ones were performed through a chemical and an enzymatic approach, respectively. Whereas the NaBH4-induced reduction proceeded with cis-diastereoselectivity, alcohol dehydrogenase-mediated reductions resulted in either an S- or R-enantioselectivity.

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.

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.

The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding β-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S(N)2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.

trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were unexpectedly transformed into 3-aryl-2-(ethylamino)propan-1-ols using LiAlH(4) in THF under reflux. A stepwise analysis showed that the initially formed 1-(1-aryl-2-chloro-3-hydroxypropyl)aziridines were converted into trans-2-aryl-3-(hydroxymethyl)aziridines, most probably via N-spiro bis-aziridinium intermediates, which were subsequently prone to undergo ring opening by LiAlH(4) to afford 3-aryl-2-(ethylamino)propan-1-ols.

trans- and cis-1-Alkyl-4-aryl-3-chloroazetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were transformed into the corresponding non-activated trans- and cis-2-aryl-3-(hydroxymethyl)aziridines via reductive ring contraction using LiAlH(4) in Et(2)O. Furthermore, trans-2-aryl-3-(hydroxymethyl)aziridines were transformed into 2-amino-3-arylpropan-1-ols and anti-2-amino-3-aryl-3-methoxypropan-1-ols by means of an unprecedented ring opening by LiAlH(4) and by MeOH, respectively. cis-2-Aryl-3-(hydroxymethyl)aziridines were shown to be highly reluctant to undergo ring opening by LiAlH(4) and MeOH under similar reaction conditions.

cis-2-(2-Bromo-1,1-dimethylethyl)azetidines, synthesized by monochloroalane reduction of the corresponding beta-lactams, were shown to be excellent building blocks for the synthesis of stereodefined 4-bromo-, 4-fluoro-, 4-acetoxy- and 4-hydroxypiperidines in DMSO. During these transformations, the initially formed bicyclic azetidinium intermediates underwent ring opening by a variety of nucleophiles.