1- and 2-Azetines via Visible Light-Mediated [2 + 2]-Cycloadditions of Alkynes and Oximes.

Azetines, four-membered unsaturated nitrogen-containing heterocycles, hold great potential for drug design and development but remain underexplored due to challenges associated with their synthesis. We report an efficient, visible light-mediated approach toward 1- and 2-azetines relying on alkynes and the unique triplet state reactivity of oximes, specifically 2-isoxazolines. While 2-azetine products are accessible upon intermolecular [2 + 2]-cycloaddition via triplet energy transfer from a commercially available iridium photocatalyst, the selective formation of 1-azetines proceeds upon a second, consecutive, energy transfer process. Mechanistic studies are consistent with a stepwise reaction mechanism via N-O bond homolysis following the second energy transfer event to result in the formation of 1-azetine products. Characteristic for this method is its operational simplicity, mild conditions, and modular approach that allow for the synthesis of functionalized azetines and tetrahydrofurans (via in situ hydrolysis) from readily available precursors.

Chiral donor-acceptor azetines as powerful reactants for synthesis of amino acid derivatives.

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon-oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor-acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.

ß-lactam Structured, 4-(4-(Methylsulfonyl)phenyl)-1-pentyl-3-phenoxyazetidin-2-one: Selectively Targets Cancerous B Lymphocyte Mitochondria.

BACKGROUND: ß lactam-structured Cox-2 inhibitors, possesses anti-proliferative and anti-inflammatory effects. OBJECTIVE: In this research, the actions of a synthetic ß lactam-structured Cox-2 inhibitor with 4-(4- (Methylsulfonyl) phenyl)-1-pentyl-3-phenoxyazetidin-2-one on cellular viability of cancerous lymphoblast obtained from patients with acute lymphocytic leukemia (ALL) and normal lymphocytes obtained from healthy donors were compared. METHODS: % the cell viability of cancerouslymphoblasts and normal lymphocytes treated with ß lactam derivatives were assayed with MTT test. Early apoptosis and necrosis were detected by double staining of annexin V/ propidium iodide and activity of caspase 3 as the final mediator in apoptotic mode of cell death was evaluated by colorimetric assay. RESULTS: Our results showed that ß lactam derivatives inhibited the proliferation of cancerous lymphoblast but not normal lymphocytes in a concentration-dependent mode by inducing apoptosis. Treatment with ß lactam derivatives resulted in a rapid loss of mitochondrial trans-membrane potential and induction of reactive oxygen species (ROS) formation, and cytochrome c release in cytosol of mitochondria resulted in activation of procaspase-9 and formation of active apoptosome. CONCLUSION: These findings suggest that 4-(4-(Methylsulfonyl)phenyl)-1-pentyl-3-phenoxyazetidin-2-one as a ß lactam could induce ROS-mediated death signaling throughmitochondrial pathway that results in apoptosis in only cancerous lymphoblast cells. The stimulationof apoptosis by ß lactams may provide a pivotal mechanismfor their anticancer effect in acute lymphocytic leukemia cells.

Generation and electrophile trapping of N-Boc-2-lithio-2-azetine: synthesis of 2-substituted 2-azetines.

s-BuLi-induced α-lithiation-elimination of LiOMe from N-Boc-3-methoxyazetidine and further in situ α-lithiation generates N-Boc-2-lithio-2-azetine which can be trapped with electrophiles, either directly (carbonyl or heteroatom electrophiles) or after transmetalation to copper (allowing allylations and propargylations), providing a concise access to 2-substituted 2-azetines.

Synthesis of 1-Boc-3-fluoroazetidine-3-carboxylic acid.

Synthetic strategies toward 3-fluoroazetidine-3-carboxylic acid, a new cyclic fluorinated beta-amino acid with high potential as building block in medicinal chemistry, were evaluated. The successful pathway includes the bromofluorination of N-(diphenylmethylidene)-2-(4-methoxyphenoxymethyl)-2-propenylamine, yielding 1-diphenylmethyl-3-hydroxymethyl-3-fluoroazetidine after reduction of the imino bond, ring closure, and removal of the 4-methoxybenzyl group. Changing the N-protecting group to a Boc-group allows further oxidation to 1-Boc-3-fluoroazetidine-3-carboxylic acid, a new fluorinated heterocyclic amino acid.

Experimental and computational study of the conrotatory ring opening of various 3-chloro-2-azetines.

A combined experimental and theoretical study is presented on 2-azetines, a class of azaheterocyclic compounds, which are difficult to access but have shown a unique reactivity as strained cyclic enamines. New highly substituted 2-azetines bearing aryl substituents at the 2- and 4-position were synthesized from 3,3-dichloroazetidines. Whereas 2-aryl-3,3-dichloroazetidines gave stable 2-aryl-3-chloro-2-azetines upon treatment with sodium hydride in DMSO, 2,4-diaryl-3,3-dichloroazetidines showed a remarkably different reactivity in that they afforded benzimidoyl-substituted alkynes under similar mild treatment with base. The formation of the alkynes involves electrocyclic ring opening of intermediate 2,4-diaryl-3-chloro-2-azetines and elimination of hydrogen chloride. Ab initio theoretical calculations confirmed the experimental findings and demonstrated that the 4-aryl substituent is responsible for this remarkably enhanced reactivity of 2-azetines toward electrocyclic conrotatory ring opening by a significant decrease in reaction barrier of about 30 kJ/mol. This activation effect by an aryl group in the allylic position toward electrocyclic ring opening of unsaturated four-membered rings is of general importance since a similar increased reactivity of 4-aryloxetes, 4-arylthiete-1,1-dioxides, and 3-arylcyclobutenes has been reported in literature as well.

Stereoselective synthesis of quaternary center bearing azetines and their beta-amino acid derivatives.

We describe here the use of a stable, four-membered azetine heterocycle for the preparation of highly substituted beta-amino acid derivatives. Imidazolidinone chiral auxiliaries were found to eliminate a competitive reaction pathway that had been present under previously reported conditions for azetine synthesis. The ephedrine derived imidazolidin-2-one 21 was allowed to react as its chlorotitanium enolate with O-methyl or -benzyl oximes under optimized conditions to gain improved access to azetines at the gram scale. The azetines were further found to undergo alkylation with complete diastereocontrol, affording the creation of a quaternary center. Subsequent ring opening with benzoyl chloride and auxiliary cleavage provided the corresponding beta2,2,3-amino carbonyl derivatives in good yields.

Elucidation of the extraordinary 4-membered pyrrole ring-contracted azeteoporphyrinoid as an intermediate in chlorin oxidation.

Reaction of 2,3-dioxochlorins with benzeneselenic anhydride (BSA) results in the formation of unusual ring-contracted azetine derivatives that further react with BSA to afford porpholactones.

Synthesis and bioactivity of a new class of rigid glutamate analogues. Modulators of the N-methyl-D-aspartate receptor.

A variety of derivatives of azetidine-2,4-dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (10f) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-aspartate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of 10f was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine 10f are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine 10f appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50 microM.

Synthesis and platelet aggregation-inhibitory activities of novel 3-(2-oxopropylidene)azetidin-2-one derivatives. I.

Treatment of (E)-3-(2-hydroxypropylidene)-4-methyl-1-phenylazetidin-2-one (11) with 10% Pd/C gave (E)-(12), (Z)-3-(2-oxopropylidene)-4-methyl-1-phenylazetidin-2-one (13), 3,4-cis-(14a) and 3,4-trans-3-(2-oxopropyl)-4-methyl-1-phenylazetidin-2-one (14b). Among them, 12 and 13 were found to show potent inhibitory activities against rabbit platelet-rich plasma aggregation induced by adenosine diphosphate or collagen. Ring-expanded homologous derivatives and an acyclic analogue of 12 were also synthesized and tested for the biological activities. The azetidin-2-one skeleton bearing a 2-oxoalkylidene moiety at the 3 position was found to be essential for the platelet aggregation inhibitory activities of these compounds.

Heteroatom-activated beta-lactam antibiotics: considerations of differences in the biological activity of [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (oxamazins) and the corresponding sulfur analogues (thiamazins).

The considerable antibacterial activity of [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (oxamazins) in contrast to the lack of activity of the corresponding sulfur analogues (thiamazins) is examined in terms of physicochemical parameters, including electronegativity, IR carbonyl stretching frequencies, base hydrolysis rates, and three-dimensional molecular geometries. An X-ray structure determination of a protected thiamazin together with molecular graphics and molecular orbital calculations on model structures reveals that thiamazins would not fit as well as oxamazins in the active site of target bacterial transpeptidases. As a result of thiamazins' long N-S and S-C bond lengths, the pharmacophoric beta-lactam ring and carboxylate functionality cannot adopt the spatial relationship they have in penicillins and cephalosporins. The beta-lactam nitrogen of the monocyclic, crystalline thiamazin is 0.18 A out of the plane of its three substituents, and this distance (h) is predicted by computational chemistry methods to be higher in oxamazins. The rates of beta-lactam ring opening of an oxamazin, thiamazin, and aztreonam are comparable, even though the pyramidal character and IR data both indicate the electronegative oxygen analogue has reduced amide resonance. MNDO, AM1, and MINDO/3 correctly give a twofold potential for rotation about the N-S bond in model sulfenamides, with barrier heights ranging up to 12 kcal/mol.

In the search for new anticancer drugs. VII. Platinum complexes of diaziridines and azetidine.

Three new diaziridine platinum(II) complexes (4a)-(4c), and a new azetidine platinum(II) complex (3b) were synthesized and tested against the lymphocytic leukemia P388 in mice. (formula; see text) Moderate to good activity was found for all compounds as evidenced by a T/C value of 162 at a dose of 32 mg/kg for (3b), 190 at a dose of 32 mg/kg for (4a), 139 at a dose of 4 mg/kg for (4b), and 142 at a dose of 20 mg/kg for (4c).

Synthesis and biological activity of some new benzimidazolyl-azetidin-2-ones and -thiazolidin-4-ones.

Arylidene-2-aminobenzimidazoles (1) were prepared by condensation of 2-aminobenzimidazole with aromatic aldehydes. Cyclocondensation of mercaptoacetic acid, chloracetylchloride and phthaloyl glycyl chloride on 1 giving the corresponding 4-thiazolidinones (2) and azetidinones (3 and 4) respectively, in good yields. The biological activities of the prepared compounds were screened against several strains of bacteria.