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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.

This paper reports on the preparation of 4-(trifluoromethyl)azetidin-2-ones and their synthetic potential as eligible new building blocks for the construction of CF3-containing azetidines, diaminopropanes, aminopropanol derivatives, 1,3-oxazinanes, and 1,3-oxazinan-2-ones. This β-lactam building block approach provides a convenient new entry into trifluoromethylated scaffolds as useful synthetic intermediates en route to a variety of CF3-functionalized target structures.

(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.

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.

This paper reports on the preparation of 4-(trifluoromethyl)azetidin-2-ones and their synthetic potential as eligible new building blocks for the construction of CF3-containing azetidines, diaminopropanes, aminopropanol derivatives, 1,3-oxazinanes, and 1,3-oxazinan-2-ones. This β-lactam building block approach provides a convenient new entry into trifluoromethylated scaffolds as useful synthetic intermediates en route to a variety of CF3-functionalized target structures.

cis-3-Benzyloxy-4-(2-mesyloxyethyl)azetidin-2-ones were shown to be useful starting products for the synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones in high overall yields and purity upon hydrogenolysis of the benzyl ether substituent followed by intramolecular nucleophilic substitution using sodium hydride in THF. These unconventionally C-fused bicyclic β-lactams were easily converted into the corresponding methyl cis-3-aminotetrahydrofuran-2-carboxylates via acidic methanolysis. This methodology constitutes a convenient alternative for the known preparation of cis-4,4-dimethyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones and methyl cis-3-amino-4,4-dimethyltetrahydrofuran-2-carboxylates, as their 4,4-nor-dimethyl variants are usually considered to be more promising compounds within the field of drug design.

A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH(4)-promoted reductive ring-opening of cis-3-alkoxy-4-aryl-beta-lactams in Et(2)O. The latter gamma-aminoalcohols were easily converted into cis-5-alkoxy-4-aryl-1,3-oxazinanes using formaldehyde in THF. Both series of compounds were evaluated against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for almost all representatives. Eleven compounds exhibited antimalarial activity with IC(50) values ofor=30 microM, and the majority of these compounds did not show cytotoxicity at the concentrations tested.

This chapter focuses on the importance of aziridinium ions as intermediates in organic chemistry. The principal aim is to gain insight into the factors to take into account for the selective synthesis of a variety of functionalized amines via aziridinium salts, such as the nature of the aziridinium ion (ring strain and N- and C-substituents of the aziridine ring), the nucleophile, and the solvent environment. Molecular modeling is used to investigate kinetics, electrostatics, and frontier molecular orbitals of reactions involving intermediate aziridinium ions, such as the nucleophilic ring opening of aziridines, the ring expansion of nitrogen heterocycles, and the ene reactions with triazolinedione. Open image in new window

The title compounds (IV) are transformed into variable mixtures of 4-[aryl(alkylamino)methyl]butyrolactones and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones by KOH-mediated hydrolysis of the cyano group, followed by ring expansion.

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.

This chapter focuses on the importance of aziridinium ions as intermediates in organic chemistry. The principal aim is to gain insight into the factors to take into account for the selective synthesis of a variety of functionalized amines via aziridinium salts, such as the nature of the aziridinium ion (ring strain and N- and C-substituents of the aziridine ring), the nucleophile, and the solvent environment. Molecular modeling is used to investigate kinetics, electrostatics, and frontier molecular orbitals of reactions involving intermediate aziridinium ions, such as the nucleophilic ring opening of aziridines, the ring expansion of nitrogen heterocycles, and the ene reactions with triazolinedione. Open image in new window

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.

For the first time the full conversion of functionalized azetidines into piperidin-4-ones is reported.

Azetidines (IV), synthesized by monochloroalane reduction of β-lactams (III), constitute suitable building blocks for the synthesis of highly functionalized piperidines.

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.

Treatment of the azetidinones (I) with an excess of LiAlH4 allows a new access to amino alcohols of type (III).

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 LiAlH4 in Et2O. 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 LiAlH4 and by MeOH, respectively. cis-2-Aryl-3-(hydroxymethyl)aziridines were shown to be highly reluctant to undergo ring opening by LiAlH4 and MeOH under similar reaction conditions.

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.