Mechanistic study on the cleavage and reorganization of C(sp3)-H and C=N bonds in carbodiimides: synthesis of 1,2-dihydrothiopyrimidines and 2,3-dihydropyrimidinthiones through four-component coupling.

This study sheds light on the cleavage and reorganization of C(sp(3))-H and C=N bonds of carbodiimides in a three-component reaction of terminal alkynes, sulfur, and carbodiimides by a combination of methods including 1) isolation and X-ray analysis of six-membered-ring lithium species 2-S, 2) trapping of the oxygen-analogues (B-O and D-O) of both four-membered-ring intermediate B-S and ring-opening intermediate D-S, 3) deuterium labeling studies, and 4) theoretical studies. These results show that 1) the reaction rate-determining step is [2+2] cycloaddition, 2) the C=N bond cleavage takes place before C(sp(3))-H bond cleavage, 3) the hydrogen attached to C6 in 2-S originates from the carbodiimide, and 4) three types of new aza-heterocycles, such as 1,2-dihydrothiopyrimidines, N-acyl 2,3-dihydropyrimidinthiones, and 1,2-dihydropyrimidinamino acids are constructed efficiently based on 2-S. All results strongly support the idea that the reaction proceeds through [2+2] cycloaddition/4π electrocyclic ring-opening/1,5-H shift/6π electrocyclic ring-closing as key steps. The research strategy on the synthesis, isolation, and reactivity investigation of important intermediates in metal-mediated reactions not only helps achieve an in-depth understanding of reaction mechanisms but also leads to the discovery of new synthetically useful reactions based on the important intermediates.

Copper(I)-catalyzed [3+1] cycloaddition of alkenyldiazoacetates and iminoiodinanes: easy access to substituted 2-azetines.

The copper(I)-catalyzed reaction of alkenyldiazoacetates and iminoiodinanes affords functionalized azetine derivatives. This process is consistent with the formation of an aziridinyldiazoacetate intermediate, which gives rise to the four-membered heterocycles by metal-catalyzed ring expansion. The resulting azetine structure is a direct precursor of azeditine-2-carboxylic acid derivatives (EWG = electron-withdrawing group).

Catalyst-controlled torquoselectivity switch in the 4π ring-opening reaction of 2-amino-2-azetines giving ß-substituted α,ß-unsaturated amidines.

The torquoselectivity of the 4π electrocyclic ring-opening reaction of 2-azetines can be controlled by the Brønsted acidity of the catalyst and the polarity of the solvent. DFT calculations provided insight into the mechanism of this remarkable switch. Anti and syn stereoisomers of α,ß-unsaturated amidines were selectively synthesized from ynamides and aldimines in the presence of Tf(2)NH and CSA, respectively.

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.

Antimycobacterial and phototoxic evaluation of novel 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.

Several newer 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids (10-11a-q) were synthesised from 3,4-difluoro aniline and 3-fluoro-4-nitro aniline by nine-step synthesis. The compounds were evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) as well as being tested for their ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesised compounds, 7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-nitro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (11l) was found to be the most active compound in vitro, with minimum inhibitory concentrations (MICs) of 0.09 microM and <0.09 microM against MTB and MTR-TB, respectively. Compound 11l was found to be 4 times and >506 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model, 11l decreased the bacterial load in lung and spleen tissues by 30% and 42%, respectively, at a dose of 50 mg/kg body weight.

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.

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.

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.

Simultaneous determination of hyzetimibe and its main active metabolite in plasma by LC-MS/MS and its application in PK study.

BACKGROUND: Hyzetimibe is a new compound belonging to a novel class of selective cholesterol absorption inhibitors. A simple, highly sensitive LC-MS/MS method has been developed for the quantification of hyzetimibe and its main active metabolite, hyzetimibe-glucuronide, in human plasma. RESULTS: Analytical samples were prepared using a protein precipitation method coupled with a concentration process. The linearity of this method was established for concentrations in the ranges of 0.05-50 and 0.5-500 ng/ml for hyzetimibe and hyzetimibe-glucuronide, respectively. The accuracy and precision of the method varied from 97.9 to 105% and 2.6 to 7.4%, respectively. CONCLUSION: This study represents the first reported example of an LC-MS/MS assay for the simultaneous quantification of hyzetimibe and its main active metabolite, hyzetimibe-glucuronide, in human plasma. Furthermore, this method has been successfully applied to a PK study.

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.

Modular approach to substituted Boc-protected 4-(aminomethyl)pyrroles.

The radical addition of various α-xanthyl ketones to Boc-protected azetine gives adducts which, when treated with ammonia or primary amines, furnish 2,4-disubstituted, 2,3,4-trisubstituted, and polycyclic pyrroles having a protected aminomethyl group at position 4. An unusual ring-opening was observed in the case of a cyclobutanone precursor.

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.

Amino acid-azetidine chimeras: synthesis of enantiopure 3-substituted azetidine-2-carboxylic acids.

Azetidine-2-carboxylic acid (Aze) analogs possessing various heteroatomic side chains at the 3-position have been synthesized by modification of 1-9-(9-phenylfluorenyl) (PhF)-3-allyl-Aze tert-butyl ester (2S,3S)-1. 3-Allyl-Aze 1 was synthesized by regioselective allylation of alpha-tert-butyl beta-methyl N-(PhF)aspartate 13, followed by selective omega-carboxylate reduction, tosylation, and intramolecular N-alkylation. Removal of the PhF group and olefin reduction by hydrogenation followed by Fmoc protection produced nor-leucine-Aze chimera 2. Regioselective olefin hydroboration of (2S,3S)-1 produced primary alcohol 23, which was protected as a silyl ether, hydrogenated and N-protected to give 1-Fmoc-3-hydroxypropyl-Aze 26. Enantiopure (2S,3S)-3-(3-azidopropyl)-1-Fmoc-azetidine-2-carboxylic acid tert-butyl ester 3 was prepared as a Lys-Aze chimera by activation of 3-hydroxypropyl-Aze 26 as a methanesulfonate and displacement with sodium azide. Moreover, orthogonally protected azetidine dicarboxylic acid 4 was synthesized as an alpha-aminoadipate-Aze chimera by oxidation of alcohol 26. These orthogonally protected amino acid-Aze chimeras are designed to serve as tools for studying the influence of conformation on peptide activity.

Enantioselective synthesis of alpha-amino acids from N-tosyloxy beta-lactams derived from beta-keto esters.

A novel synthetic sequence has been developed to convert simple beta-keto esters into enantiomerically enriched alpha-amino acids. The key features of this sequence include the addition of azide to the C3 position of beta-keto ester derived N-tosyloxy-beta-lactams through a concomitant nucleophilic addition/N-O bond reduction reaction, a mild CsF-induced N1 benzylation of alpha-azido monocyclic beta-lactams, the preparation of alpha-keto-beta-lactams through a novel four-step sequence from the corresponding 3-azido-1-benzyl-beta-lactams, and TEMPO-mediated ring expansion of these compounds to the corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characterization of unusual 3-imino and 3-chloramino-beta-lactams is reported.

[Studies of in vitro and in vivo derived 1,2-diazetine and nitronylnitroxide as donors and acceptors of nitric oxide]. / Issledovaniia in vitro i in vivo proizvodnykh 1,2-diazetina i nitronilnitroksida v kachestve donorov i aktseptorov oksida azota.

The series of nitronylnitroxyl radicals (NNR) were studied as paramagnetic scavengers of nitric oxide. These radicals react with NO with rate constants of (0.6-1.1).10(4) M-1.sec-1 forming stable iminonitroxyl radicals. They can be used to assay nitric oxide in solutions by EPR spectroscopy; the sensitivity of the method is 1 microM for the detection of NO concentration and 0.3 nM/sec for the measurements of the rates of NO generation for 1 h in 0.2 ml sample. To overcome fast reduction of the radicals in biological samples, charged NNR was incorporated into the inner volume of large unilamellar phosphatidylcholine liposomes thus decreasing the rates of NNR reduction about 1000-fold. The method was used for the NO synthase activity assay in rat cerebellum cytosol. NNR was used to study the kinetics of the decomposition of 3,4-dihydro-1,2-diazete 1,2-dioxides (DD). Several DD derivatives at 5-80 microM concentrations are very effective vasodilators in perfused rat tail artery. Intraperitoneal injection of several DD (40-200 micrograms/kg weight). in hereditary hypertensive rats (ISIAH-strain) significantly (by 30%) decreased systolic arterial blood pressure whereas similar effect of trinitroglycerin was detected at significantly higher dose (900 micrograms/kg weight).

Probing the reaction pathways of DL-proline on TiO2 (001) single crystal surfaces.

The reaction of DL-Proline on O2-annealed (stoichiometric) and O-defected (sub-stoichiometric) TiO2 (001) single-crystal surfaces has been investigated. This is of significance in trying to understand the concept of how biomolecules interact with the surfaces of biomedical implants (molecular recognition). On an O2-annealed TiO2 surface, proline is found to largely adsorb then desorb intact at approximately 350 K. DFT (B3LYP) calculations of proline bound to a Ti(OH)4 cluster suggest a binding through the carboxylate functional group rather than through the NH group of the ring. In contrast, proline reaction was considerably different on the O-defected surface. First, proline was further stabilized, evidenced by a shift of its desorption temperature (during temperature-programmed desorption) to approximately 530 K. Along with proline desorption, two distinctive sets of reaction processes occurred at 530 and 630 K, respectively. The first pathway (alpha) at 530 K shows desorption of large amounts of m/e 55 (attributed to 1-azetine) and m/e 42 (attributed to ketene). At still higher temperature, 630 K, a pathway (beta) dominated by the appearance of low masses, mainly m/e 28, 27, and 26, is seen. These masses are tentatively attributed to desorption of HCN, ethylene, and/or acetylene as they represent the logical further decomposition of the different fragments of proline.