Synthesis, structure, and glutathione peroxidase-like activity of amino acid containing ebselen analogues and diaryl diselenides

The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds.     

Application of the Cleavable Isocyanide in Efficient Approach to Pyroglutamic Acid Analogues with Potential Biological Activity

Two efficient procedures have been developed for the synthesis of pyroglutamic acid analogues 28, 29, and 34. According to the first method the Ugi (4C3C) reaction is followed by a post-transformation reaction, and the second method involves the Michael addition reaction. The present methodologies demonstrate the applicability of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (15) as a cleavable isocyanide in the Ugi/ post-transformation reaction and a strong nucleophile in the Michael addition reaction. The framework of pyroglutamic acid analogues has been constructed by the selective cleavage of the C-terminal amide bond and nucleophilic addition to the activated α,β-unsaturated carbonyl group.

     

Synthesis of Substituted 2‐Amino‐1,3‐oxazoles via Copper‐Catalyzed Oxidative Cyclization of Enamines and N,N‐Dialkyl Formamides

A facile synthesis of 2‐amino‐1,3‐oxazoles via Cu^I‐catalyzed oxidative cyclization of enamines and N ,N ‐dialkyl formamides has been developed. The reaction proceeds through an oxidative C−N bond formation, followed by an intramolecular C(sp²)−H bond functionalization/C−O cyclization in one pot. This protocol provides direct access to useful 2‐amino‐1,3‐oxazoles and features protecting‐group‐free nitrogen sources, readily available starting materials, a broad substrate scope and mild reaction conditions.     

Synthesis of 3,3‐Dimethylglutamic Acid Derivatives as DPP‐IV Inhibitors and Evaluation of Their Chemical Stability

A novel five‐step synthesis of Boc‐3,3‐dimethylglutamic acid α‐ethyl ester 11 is reported. All the steps are high yielding and simple to carry out. By use of the 3,3‐dimethylglutamic acid building block, we successfully discovered a novel class of DPP‐IV inhibitors, Glu‐Pro‐Nitrile dipeptide mimics 2 , with high potency (IC₅₀ < 40 nM). The consequence of 3,3‐dimethyl substituent on the rate of intramolecular cyclization between N‐terminal amine and 5‐position amide bond in different buffer solutions was also evaluated.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Oxygen- and Nitrogen-Embedded Zigzag Hydrocarbon Belts

Despite the aesthetically appealing structures and tantalizing physical and chemical properties, zigzag hydrocarbon belts and their heteroatom-embedded analogues remain challenging synthetic targets. We report herein the synthesis of diverse O/N-doped zigzag hydrocarbon belts based on selective bridging of the fjords of resorcin[4]arene derivatives through intramolecular S_NAr and palladium-catalyzed intermolecular C−N bond formation reactions. Preorganized conformations of mono-macrocyclic, half-belt and quasi-belt compounds were revealed to facilitate cyclization reactions to construct heteroatom-linked octahydrobelt[8]arenes. The acquired products had strained square-prism-shaped belt structures in which all six-membered heterocyclic rings adopted an unusual boat conformation with equatorially configured alkyl groups. The unprecedented heteroatom-bearing belts also exhibited different photophysical and redox properties to those of octahydrobelt[8]arene analogues.     

One-pot tandem complexity-generating reaction based on Ugi four component condensation and intramolecular cyclization

A novel complexity-generating reaction is described, which can be used in a high-throughput parallel solution-phase combinatorial format. The synthetic pathway features the Ugi four component reaction followed by intramolecular cyclization via C-C bond formation. Starting from readily available initial reactants, the described approach leads to generation of novel 3-oxoisoindoline-1-carboxamides with four points of diversity around the core scaffold. The scope and limitations of the involved chemistry and some chemical transformations of the synthesized compounds are discussed.     

Effects of introduction of α‐carboxylate,N‐methyl,and N‐formyl groups on intramolecular cyclization of o‐quinone amines: Density functional theory‐based study

o‐Quinone amines, which are relevant to various biological processes, can undergo spontaneous intramolecular cyclization (ring closure reaction by amino‐terminated hydrocarbon side chain) that deactivates them toward another possible reactions, that is, thiol binding. Density functional theory‐based calculation is employed for obtaining the potential energy curves along the C? N bond formation in the intramolecular cyclization of various o‐quinone amines, viz., dopaminequinone, dopaquinone, N‐methyl‐dopaminequinone, N‐formyl‐dopaminequinone, and the corresponding methylene‐inserted analogues. The activation barrier is decreased by introduction of α‐carboxylate and N‐methyl group whereas increased by introduction of N‐formyl group. A negative correlation between the activation barriers and the level of highest occupied molecular orbital is pointed out. Furthermore, the methylene‐inserted analogues show decreased activation barriers. This is explained by reduction of steric repulsion in the transition state.     

Cationic Pd(II) catalyzed regioselective intramolecular hydroarylation for the efficient synthesis of 4-aryl-2-quinolones

A divergent regioselective palladium (II) catalyzed approach through post Ugi cyclization is described. The Ugi adduct underwent intramolecular ortho-hydroarylation via 6-endo-dig cyclization for the direct access to 4-aryl-2-quinolones. Incorporation of iodine at the C-3 position of 2-quinolone followed by Suzuki-Miyaura coupling results into the more diversified 3,4-diaryl-2-quinolones.     

Synthesis of Novel 2‐Oxoquinoline Derivatives via Ugi‐Four‐Component‐Heck Reaction

The present study provides an efficient strategy for the preparation of novel N‐substituted‐4‐methyl‐quinolin‐1(2H)‐one derivatives via two‐step Ugi/Heck reaction. The procedure is based on the Ugi coupling between 2‐bromoanilines, various aromatic aldehydes, vinylacetic acid, and isocyanides, and then intramolecular Heck reaction, which leads to the formation of the title compounds in good yields.     

Stereocontrolled and Versatile Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids: Structural Revision of the Fungal Isolate (+)‐Asperdimin

Homo‐ and heterodimeric bispyrrolidinoindoline diketopiperazine alkaloids have been synthesized following a concise, versatile, and stereoselective route. Highlights of the sequence are a diastereoselective construction of the C3a‐bromo‐hexahydropyrrolo[2,3‐b]indole nucleus, its Co^I‐induced C3a? C3a′ dimerization, and the twofold or sequential amide‐bond formation before cyclization to the diketopiperazine of the homo‐ or heterodimeric alkaloids, respectively. Stereochemical diversity is achieved through the choice of the appropriate amino acids combined with the base‐induced epimerization of the C2‐acyl‐hexahydropyrrolo[2,3‐b]indole at C2. According to this strategy, the natural products (+)‐WIN 64821 1 , (+)‐WIN 64745 2 and (+)‐asperdimin 6 as well as analogues ( 5 , 22 , 32 , 44 ) with different relative and absolute configuration have been efficiently synthesized. The flexibility of this synthetic methodology has facilitated the structural revision of the natural product (+)‐asperdimin, whose structure has been corrected to diastereomer 6 .     

Catalyst-free synthesis of coumarin-, quinolone- and pyridine-annulated oxazole derivatives

An efficient approach for the synthesis of coumarin-, quinolone- and pyridine-annulated oxazole derivatives has been achieved by direct base-mediated intramolecular carbon–oxygen bond formation in a transition metal catalyst-free protocol. Intramolecular cyclization of o-bromoamides in DMSO in the presence of Cs₂CO₃ at 130 °C affords heterocycle-annulated oxazole derivatives in high yields via a nucleophilic addition of amide to form the C–O bond.     

Sequential Ugi/Heck cyclization strategies for the facile construction of highly functionalized N-heterocyclic scaffolds

A new strategy employing an Ugi four-component reaction and a microwave-assisted intramolecular Heck cyclization in a sequential fashion to access an array of N-containing heterocycles is reported. The two-step sequence generated compounds of significant molecular complexity from trivial starting materials in an expedient fashion with excellent yields. The route was also amenable to solid-phase chemistry demonstrating potential for library generation.     

One-pot synthesis of quinolin-2-(1H)-ones via tandem Ugi-Knoevenagel condensations

A new application of the Ugi reaction in the synthesis of heterocyclic compounds is described. Substituted quinolin-2-(1H)-ones are formed in one-pot sequential Ugi four-component condensation and intramolecular Knoevenagel cyclization between o-acylanilines, aldehydes, malonic or tosylacetic acids and cyclohexyl isocyanide.     

A DFT study for the formation of imidazo[1,2-c]pyrimidines through an intramolecular Michael addition

The formation of imidazo[1,2-c]pyrimidines through a ring closure of 2-(2-sulfonylimino-1,2-dihydro-1-pyrimidinyl) acetamides has been studied using DFT methods. Analysis of the energy results for the cyclization step shows the demand of almost an acid catalyst, which increases the electrophilicity of the dihydropyrimidine moiety, in order to make feasible the intramolecular Michael addition. The substitution on both dihydropyrimidine and amide moieties has also an influence on the cyclization step.     

Asymmetric Total Synthesis of Mycoleptodiscin A

The first total synthesis of mycoleptodiscin A, a structurally unusual indolosesquiterpenoid possessing an ortho‐benzoquinone motif, has been accomplished. A sulfone alkylation coupled two readily available fragments to give an aryl triene intermediate. The tetracyclic core of the molecule was assembled through a highly enantioselective iridium‐catalyzed polyene cyclization. The benzylic homologation was achieved by a cationic cyanation. The indole motif was constructed via a copper‐mediated intramolecular C? N bond formation at a late stage.     

Highly efficient microwave-assisted fluorous Ugi and post-condensation reactions for benzimidazoles and quinoxalinones

The efficiency of an Ugi/de-Boc/cyclization strategy for construction of heterocyclic compounds has been improved through the incorporation of microwave and fluorous technologies. In the synthesis of substituted quinoxalinones and benzimidazoles, a fluorous-Boc protected diamine is employed for the Ugi reactions. Both the Ugi and the post-condensation reaction proceed rapidly under microwave irradiation and the reaction mixtures are purified by solid-phase extraction (SPE) over FluoroFlash^TM cartridges.     

Computational studies on the conformational preference of N-(Thiazol-2-yl) benzamide

N-(Thiazol-2-yl) benzamide 1 substructures are found in some of bioactive compounds. In some of protein/ligand co-crystals, the 1 moiety adopts a conformer in which the amide O and the thiazole S atoms are close. In fact, in the crystalline structure of 1 , the O—S distance is even shorter than Van der Waals radius. Although the natural bond orbital analysis finds a weak stabilizing interaction between O and S atoms, the attractive dipole–dipole interaction between the amide N─H and thiazole N atom seems to play a more significant role. Moreover, an intramolecular O—H hydrogen bonding in dimeric forms found to have an important role in the conformation preference of 1 . Computational details for the stability of conformers have been discussed using quantum theory of atoms in molecules, natural bond orbital (NBO) and noncovalent interaction index analysis.     

Hybrid sugars as glycosidase inhibitors en route to 2-deoxy-2-amino C-glycosyl amino acids

Sugar-azasugar hybrid molecules made up of d-galactose with nojirimycin-δ-lactam and pyrrolidine analogues are synthesized using intramolecular cyclization as a key step from 2-nitro galactal and found to be glycosidase inhibitors. Further, some of the intermediate compounds are converted into 2-deoxy-2-amino C-glycosyl glycines and C-glycosyl alanines.     

Etude des composés d'addition des acides de Lewis - XXXV. Note sur les composés d'addition entre amides et,respectivement, PdCl2 et PtCl2

The adducts of dimethylformamide, diethylformamide, dimethylacetamide and diethylacetamide with PdCl₂ and PtCl₂ have been prepared and the IR. spectra of the compounds in nujol mull or in CH₂Cl · CH₂Cl solution are studied. The lowering of the carbonyl frequency (amide I) shows that the metal is linked by a dative bond to the amide oxygen atom acting as a donor; the lowering is about 33 to 59 cm^?1. The decrease of the frequency of the carbonyl group vibration, observed in these cases as for other addition compounds of Lewis acids, is due to an intramolecular electronic displacement in the direction of the amid oxygen atom.