A One‐Pot “Triple‐C” Multicyclization Methodology for the Synthesis of Highly Constrained Isomerically Pure Tetracyclic Peptides

A broadly applicable one‐pot methodology for the facile transformation of linear peptides into tetracyclic peptides through a chemoenzymatic peptide synthesis/chemical ligation of peptides onto scaffolds/copper(I)‐catalyzed reaction (CEPS/CLIPS/CuAAC; “triple‐C”) locking methodology is reported. Linear peptides with varying lengths (≥14 amino acids), comprising two cysteines and two azidohomoalanines (Aha), were efficiently cyclized head‐to‐tail by using the peptiligase variant omniligase‐1 (CEPS). Subsequent ligation–cyclization with tetravalent (T4_1/2) scaffolds containing two bromomethyl groups (CLIPS) and two alkyne functionalities (CuAAC) yielded isomerically pure tetracyclic peptides. Sixteen different functional tetracycles, derived from bicyclic inhibitors against urokinase plasminogen activator (uPA) and coagulation factor XIIa (FXIIa), were successfully synthesized and their bioactivities evaluated. Two of these (FF‐T4_1/2) exhibited increased inhibitory activity against FXIIa, compared with a bicyclic control peptide. The corresponding hetero‐bifunctional variants (UF/FU‐T4_1/2), with a single copy of each inhibitory sequence, exhibited micromolar activities against both uPA and FXIIa; thus illustrating the potential of the “bifunctional tetracyclic peptide” inhibitor concept.     

Rh-Catalyzed Cycloaddition of C60 with Enynes: Unveiling the Mechanistic Pathway

In this study we present a method for functionalizing C₆₀ through a Rh-catalyzed cyclization reaction with 1,6-enynes, resulting in the formation of a fused bicyclic structure. Additionally, fullerene derivatives are further functionalized through regioselective photooxygenation reactions. Our DFT calculations reveal two distinct reaction pathways: one involving rhodium-catalyzed cycloisomerization of the enyne followed by Diels-Alder with C₆₀, and the other featuring a rhodium-catalyzed [2+2+2] cycloaddition of enyne and C₆₀ followed by isomerization. Surprisingly, both pathways exhibit nearly identical energy barriers. However, experimental tests indicate that the predominant pathway varies depending on the substitution motifs of the substrates.     

Synthesis of the Ladder Polymers by the Reaction of Catalytic Dehydrocondensation

Abstract

The heterofunctional condensation of cis-1,3.5,7-tetrahydroxy-1,3,5,7-tetraphenylcyclotetrasiloxane with dimethylchlorosilane has been studied.

It was established that when the reaction proceeds under mild conditions tetraphenylcyclotetrasiloxane incompletely substituted with dimethylsiloxy groups is obtained, i.e., 1,3,5-tris(dimethylsiloxy)-7-hydroxy-1,3,5,7-tetraphenylcyclotetrasiloxane, while under certain conditions 1,3,5,7-tetrakis(dimethylsiloxy)-1,3,5,7-tetraphenylcyclotetrasiloxane is formed.

The catalytic dehydrocondensation of 1,3,5-tris(dimethylsiloxy)-7-hydroxy-1,3,5,7-tetraphenylcyclotetrasiloxane both in a dilute and concentrated solutions in the presence of platinochlorohydric acid as a catalyst has been studied. It was shown that the reaction proceeds both by the mechanism of intramolecular cyclization with formation of a bicyclic compound and intermolecularly with formation of a tricyclic compound.

The catalytic dehydrocondensation of 1,3,5,7-tetrakis-(hydriddimethylsiloxy)-1,3,5,7-tetraphenylcyclotetrasiloxane with cis-1,3,5,7-tetrahydroxy-1,3,5,7-tetraphenylcyclotetrasiloxane and with oligotetrols (m = 5, 10) was also studied. The reaction order, activation energies and dehydrocondensation rate constants were found.

It was established that with an increase in the length (m) of the oligotetrols the degree of catalytic dehydrocondensation is reduced. It was shown that if the platinochlorohydric acid catalyst is replaced by anhydrous powdered caustic potassium a different configuration of the cyclotetrasiloxane skeleton is realized in polymers.     

Product Distributions of Cytochrome P450 OleTJE with Phenyl-Substituted Fatty Acids: A Computational Study

There are two types of cytochrome P450 enzymes in nature, namely, the monooxygenases and the peroxygenases. Both enzyme classes participate in substrate biodegradation or biosynthesis reactions in nature, but the P450 monooxygenases use dioxygen, while the peroxygenases take H₂O₂ in their catalytic cycle instead. By contrast to the P450 monooxygenases, the P450 peroxygenases do not require an external redox partner to deliver electrons during the catalytic cycle, and also no external proton source is needed. Therefore, they are fully self-sufficient, which affords them opportunities in biotechnological applications. One specific P450 peroxygenase, namely, P450 OleT_JE, reacts with long-chain linear fatty acids through oxidative decarboxylation to form hydrocarbons and, as such, has been implicated as a suitable source for the biosynthesis of biofuels. Unfortunately, the reactions were shown to produce a considerable amount of side products originating from C^α and C^β hydroxylation and desaturation. These product distributions were found to be strongly dependent on whether the substrate had substituents on the C^α and/or C^β atoms. To understand the bifurcation pathways of substrate activation by P450 OleT_JE leading to decarboxylation, C^α hydroxylation, C^β hydroxylation and C^α–C^β desaturation, we performed a computational study using 3-phenylpropionate and 2-phenylbutyrate as substrates. We set up large cluster models containing the heme, the substrate and the key features of the substrate binding pocket and calculated (using density functional theory) the pathways leading to the four possible products. This work predicts that the two substrates will react with different reaction rates due to accessibility differences of the substrates to the active oxidant, and, as a consequence, these two substrates will also generate different products. This work explains how the substrate binding pocket of P450 OleT_JE guides a reaction to a chemoselectivity.     

Efficient Room‐Temperature Oxidation of Hydrocarbons Mediated by Tricopper Cluster Complexes with Different Ligands

Six tricopper cluster complexes of the type [Cu^ICu^ICu^I( L )]¹⁺ supported by a series of multidentate ligands ( L ) have been developed as oxidation catalysts. These complexes are capable of mediating the facile oxygen‐atom transfer to hydrocarbon substrates like cyclohexane, benzene, and styrene (C₆H₁₂, C₆H₆ and C₈H₈) upon activation by hydrogen peroxide at room temperature. The processes are catalytic with high turnover frequencies (TOF), efficiently oxidizing the substrates to their corresponding alcohols, aldehydes, and ketones in moderate to high yields. The catalysts are robust with turnover numbers (TON) limited only by the availability of hydrogen peroxide used to drive the catalytic turnover. The TON is independent of the substrate concentration and the TOF depends linearly on the hydrogen peroxide concentration when the oxidation of the substrate mediated by the activated tricopper complex is rapid. At low substrate concentrations, the catalytic system exhibits abortive cycling resulting from competing reduction of the activated catalyst by hydrogen peroxide. This behaviour of the system is consistent with activation of the tricopper complex by hydrogen peroxide to generate a strong oxidizing intermediate capable of a facile direct “oxygen‐atom” transfer to the substrate upon formation of a transient complex between the activated catalyst and the substrate. Some substrate specificity has also been noted by varying the ligand design. These properties of the tricopper catalyst are characteristic of many enzyme systems, such as cytochrome P450, which participate in biological oxidations.     

Dimer acid structures. The thermal dimer of normal linoleate,methyl 9-cis, 12-cis octadecadienoate

The thermal dimer (290C) of normal methyl linoleate and its hydrogenated form have been examined by mass spectrometry. Parent mass peaks of the hydrogenated dimer show the presence of monocyclic, bicyclic, and tricyclic structures. The monocyclic structure is formed via the conjugation-Diels-Alder mechanism. The bicyclic structure is best explained by an extension of the hydrogen transfer free radical coupling mechanism. The noncyclic dehydrodimer resulting from free radical coupling undergoes a relatively rapid intramolecular cyclization to a bicyclic structure, probably by an interval Diels-Alder reaction. A model noncyclic dehydro-linoleate dimer was shown to give a bicyclic dimer as the predominant structure under thermal dimerization conditions. The tricyclic dimer may result from intramolecular alkylation of the bicyclic structures. Presented at the AOCS Meeting, Philadelphia, October 1966. Journal Series No. 450, General Mills Research Laboratories.     

Innovative Membrane-Based Catalytic Process for Environmentally Friendly Synthesis of Oxygenates

Synthesis of liquid oxygenates from light alkanes (C₁--C₃) is achieved in a multifunctional three-phase catalytic membrane reactor (3PCMR) operating under mild conditions (T_R, 80-120 °C; P_R, 140 kPa). The features of superacid catalytic membranes mediated by the Meⁿ⁺/H₂O₂ Fenton system in activating C₁-C₃ alkanes are presented. The effect of operating conditions ([H₂O₂], [Meⁿ⁺]) on the catalyst activity is outlined. A general reaction pathway accounting for the activation of the CH bond of the alkane molecule on the superacid sites and the subsequent reaction of the activated alkane with primary reactive intermediates, generated from the Meⁿ⁺/H₂O₂ system, is proposed. The suitability of the 3PCMR in enabling simultaneous reaction and product separation is discussed.     

Role of Long-Range Protein Dynamics in Different Thymidylate Synthase Catalyzed Reactions

Recent studies of Escherichia coli thymidylate synthase (ecTSase) showed that a highly conserved residue, Y209, that is located 8 Å away from the reaction site, plays a key role in the protein’s dynamics. Those crystallographic studies indicated that Y209W mutant is a structurally identical but dynamically altered relative to the wild type (WT) enzyme, and that its turnover catalytic rate governed by a slow hydride-transfer has been affected. The most challenging test of an examination of a fast chemical conversion that precedes the rate-limiting step has been achieved here. The physical nature of both fast and slow C-H bond activations have been compared between the WT and mutant by means of observed and intrinsic kinetic isotope effects (KIEs) and their temperature dependence. The findings indicate that the proton abstraction step has not been altered as much as the hydride transfer step. Additionally, the comparison indicated that other kinetic steps in the TSase catalyzed reaction were substantially affected, including the order of the substrate binding. Enigmatically, although Y209 is H-bonded to 3''-OH of 2''-deoxyuridine-5''-mono­phosphate (dUMP), its altered dynamics is more pronounced on the binding of the remote cofactor, (6R)-N⁵,N¹⁰-methylene-5,6,7,8-tetrahydrofolate (CH₂H₄folate), revealing the importance of long-range dynamics of the enzymatic complex and its catalytic function.     

Screening and Profiling of Hydrocarbon Components and Squalene in Developing Tunisian Cultivars and Wild Arachis hypogaea L. Species

Total hydrocarbon composition and content of whole peanuts from three Tunisian varieties of peanut (two cultivars: AraC (Virginia type), AraT (Valencia type) and a wild one: AraA) were investigated during maturation. The results show that 30 hydrocarbons were identified from the wild AraA species, while only 27 hydrocarbon were detected in the cultivar ones. The hydrocarbon fraction is essentially composed of squalene, n-alkenes especially nC₁₄₌, nC₁₆₌, nC₁₈₌, nC₂₀₌ and nC₂₂₌, n-alkanes such as nC₁₆, nC₁₇, nC₁₈, nC₂₅, nC₂₆ and nC₂₇, and branched saturated hydrocarbon noted (HC₁, HC₂ and HC₃). Among the hydrocarbon components, generally the wild variety AraA presents the highest content of phytochemical squalene during maturation, whereas a maximum was detected from cultivar AraT at 12 days after podding (815.45 mg/100 g of oil). At maturity, the maximum level is reached at about 346.74 mg/100 g of oil for AraA. During maturity, wild AraA is considered to be an excellent source of squalene like olive and pumpkin oil.     

Dimer acid structures: Cyclic structures of clay catalyzed dimers of normal linoleic acid, 9-cis, 12-cis-Octadecadienoic acid

The clay catalyzed dimer of linoleic acid has been examined by mass spectrometry of the unhydrogenated, the partially hydrogenated and completely hydrogenated dimer. The results show that monocyclic, bicyclic and tricyclic structures are present. Monocyclic structures predominate, bicyclic structures are also prominent, and tricyclic structures are relatively minor. The monocyclic structure is believed to arise from a Diels-Alder type addition reaction. The bicyclic structure may result from a free radical coupling followed by intramolecular ring closure. The monocyclic structure in the unhydrogenated dimer appears to be mostly a benzene ring with saturated and unsaturated side-chains. It probably is formed by hydrogen transfer from the Diels-Alder cyclohexene structure first formed. Little, if any, of the Diels-Alder dimer structure as such is present. The catalytic linoleate dimer has a higher ratio of monocyclic to bicyclic dimer than does the noncatalytic (thermal) dimer made from normal (nonconjugated) linoleate, while the thermal dimer of a conjugatedtrans-trans linoleate is exclusively monocyclic. It is suggested that the clay catalyzes conjugation and hence favors the Diels-Alder reaction, and then catalyzes hydrogen transfer to aromatize the cyclohexene ring.     

Rationally designed inhibitors as tools for comparing the mechanism of squalene-hopene cyclase with oxidosqualene cyclase

The inhibition of squalene-hopene cyclase (SHC) (E.C. 5.4.99.-), an enzyme of bacterial membranes catalyzing the formation of pentacyclic sterol-like triterpenes, was studied by using different classes of compounds originally developed as inhibitors of oxidosqualene cyclase (OCS) (E.C. 5.4.99.7), the enzyme of eukaryotes responsible for the formation of tetracyclic precursors of sterols. The mechanism of cyclization of squalene by SHC, beginning with a protonation of the 2,3 double bond by an acidic residue of the enzyme, followed by a series of electrophilic additions of the carbocationic intermediates to the double bonds, is similar to the mechanism of cyclization of 2,3-oxidosqualene by OSC. The inhibitors studied included: (i) analogs of the carbocationic intermediates formed during cyclization, such as aza-analogs of squalene and 2,3-oxidosqualene; (ii) affinity-labeling inhibitors bearing a methylidene reactive group; and (iii) vinyldioxidosqualenes and vinylsulfide derivatives of the substrates. Comparison of the results obtained with the two enzymes, SHC and OSC, showed that many of the most effective inhibitors of OSC were also able to inhibit SHC, while some derivatives acted as specific inhibitors. Differences could be easily explained on the basis of the different substrate specificity of the two enzymes.     

Rhodium‐Catalyzed Enantioselective Intramolecular [4+2] Cycloaddition using a Chiral Phosphine‐Phosphite Ligand: Importance of Microwave‐Assisted Catalyst Conditioning

The use of modular α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐ and 1,1′‐bi‐2‐naphthol (BINOL)‐derived phosphine‐phosphite ligands (L₂*) in the asymmetric rhodium‐catalyzed intramolecular [4+2] cycloaddition (“neutral” Diels–Alder reaction) of (E,E)‐1,6,8‐decatriene derivatives (including a 4‐oxa and a 4‐aza analogue) was investigated. Initial screening of a small ligand library led to the identification of a most promising, TADDOL‐derived ligand bearing a phenyl group adjacent to the phosphite moiety at the arene backbone. In the course of further optimization studies, the formation of a new, more selective catalyst species during the reaction time was observed. By irradiating the pre‐catalyst with microwaves prior to substrate addition high enantioselectivities (up to 93% ee) were achieved. The new cyclization protocol was successfully applied to all three substrates investigated to give the bicyclic products in good yield and selectivity. ³¹P NMR and ESI‐MS measurements indicated the formation of a [Rh(L₂*)₂]⁺ species as the more selective (pre‐) catalyst.     

Effects of the Nitridation of Y and USY Zeolites on their Catalytic Activity for the Base Catalyzed Knoevenagel Condensation

This contribution reports on the preparation, physicochemical characterization and catalytic performances of nitrided zeolites in the Knoevenagel condensation reaction. These basic materials were prepared by subjecting one Y zeolite (Si/Al ratio of 2.6) and two ultrastable Y zeolites (Si/Al ratio of 13 and 37) to nitridation, i.e., treatment with ammonia at high temperature. Both the amount and the chemical nature of incorporated nitrogen species were controlled by the nitridation temperature. Namely, an increase of the temperature induces an increase of the nitrogen content and the appearance of nitrogenous species in the following order of increasing temperature: NH₄ ⁺, adsorbed NH₃, –NH₂, >NH and >N–. The nitridation occurred practically in the same manner whatever the Si/Al ratio of the starting material. However, from a catalytic point of view different behavior was observed. No direct correlation was found with the nitrogen content of the samples. Nitrided zeolites were found to exhibit catalytic activity as long as the zeolitic framework was maintained.     

The use of <Superscript>1</Superscript>H NMR for yield determination in the regioselective epoxidation of squalene

¹H NMR can be used to determine the epoxide yield rapidly in the oxidation of squalene. Moreover, unequivocal distinction can be made between internal and terminal epoxide bonds. To underline the power of this technique, different stoichiometric and catalytic epoxidation procedures were carried out using squalene as substrate. They were characterized in terms of substrate conversion and regioselectivity of the epoxide fraction.     

Chemical fixation of carbon dioxide to dimethyl carbonate from propylene carbonate and methanol using ionic liquid catalysts

The synthesis of dimethyl carbonate (DMC) through the transesterification of propylene carbonate (PC) with methanol was investigated by using imidazolium salt ionic liquid catalysts. 1-alkyl-3-methyl imidazolium salts of different alkyl group (C₂, C₄, C₆, C₈) and anions (Cl⁻, Br⁻, BF₄⁻, PF₆⁻) were used for catalysts. The reaction was carried out in an autoclave at 140–180°C under carbon dioxide pressure of 1.48–5.61 MPa. The imidazolium salts of shorter alkyl group, and more nucleophilic counter anion exhibited higher catalytic activity. The conversion of PC increased as CO₂ pressure and reaction temperature increased. Kinetic studies were also performed to better understand the reaction mechanism. This paper was presented at the 6 ^th Korea-China Workshop on Clean Energy Technology held at Busan, Korea, July 4–7, 2006.     

Synthesis of coumarin derivatives by palladium complex catalyzed intramolecular Heck reaction: Preparation of a 1,2-cyclobutadiene-substituted CpCoCb diphosphine chelated palladium complex

A cobalt-sandwich diphosphine chelated palladium complex 2, [(η⁵-cyclopentadienyl)(η⁴-1,2-diphenyl-3,4-bis(diphenylphosphino-κP)cyclobutadiene)cobalt(I)]palladium(II)dichloride, was prepared from the reaction of a cyclobutadiene-substituted CpCoCb diphosphine 1, (η⁵-cyclopentadienyl) (η⁴-1,2-diphenyl-3,4-bis-diphenylphosphinocyclobutadiene)cobalt(I), with one molar equivalent of Pd(COD)Cl₂. Both compounds were characterized by spectroscopic means as well as single-crystal X-ray diffraction methods. Application of purified 2 as the catalytic precursor in intramolecular Heck cyclization reaction on 4-hydroxycoumarin resulted in the formation of several derivatives with intensity enhanced fluorescence property.     

2-Alkylcyclobutanones from the radiolysis of triglycerides

A cyclic compound was isolated from the radiolytic products of each of the simple triglycerides containing C₆, C₈, C₁₀, C₁₂, C₁₄, C₁₆ and C₁₈ fatty acids. In each case the compound was identified as the 2-alkylcyclobutanone of the same carbon number as the precursor fatty acid. A mechanism is proposed for the production of these compounds which involves the formation of a six-membered ring intermediate, cyclization and cleavage at the acyl-oxy bond.     

Stimulation of hepatic squalene and triglyceride synthesis by dimethylsulfoxide,in vitro

The incorporation of [¹⁴C] mevalonate and [¹⁴C] acetate into squalene by rat liver slices was increased over 7-fold by the presence of 5% dimethylsulfoxide (DMSO) in the incubation medium. The stimulation of squalene synthesis was dose-related over the concentration range of 1–5% DMSO and did not affect the incorporation of [¹⁴C] mevalonate, into the C₂₇-sterol fraction (cholesterol) but did increase (about 50%) incorporation into C₃₀-sterol (lanosterol) at a level, of 5% DMSO. The stimulation of squalene synthesis was observed under both anaerobic (N₂ atmosphere) and aerobic (ambient air or 95% O₂/5% CO₂) conditions and may represent a direct effect of DMSO on squalene synthetase. At a level of 5%, DMSO also stimulated 7-fold the incorporation of [¹⁴C] acetate into triglycerides by liver slices; this occurred without changes in incorporation into the phospholipid or free fatty acid fractions. The disproportionate increase in lipid labeling from [¹⁴C] acetate suggests that the effects of DMSO are not simply a matter of increasing [¹⁴C] acetate entry into the tissue.     

NO2 Reduction with Nitromethane over Ag/Y: A Catalyst with High Activity over a Wide Temperature Range

Nitromethane (NM) is a very efficient reductant for converting NO₂ to N₂ over Ag/Y: Between 140 °C and 400 °C, the N₂ yield is close to 100%. This high N₂ yield results from the ability of Ag/Y to effectively catalyze the reaction between NM and NO₂. This high catalytic activity of Ag/Y is minimally affected by surface bound CN⁻, NC⁻, or acetate, all of which are stable at temperatures below ∼300 °C. At T ≥ 400 °C, there is a reaction path that yields N₂ from NM even in the absence of NO₂. However even at 400 °C, under typical deNO _x conditions, most N₂ molecules are formed as a result of the reaction of NM and NO₂.     

Thermal Isomerization of Azulene. Single-Pulse Shock Tube Investigation

The thermal isomerization of azulene was studied behind reflected shocks in a pressurized driver single-pulse shock tube. The temperature range covered was 1050–1400 K at overall densities of ∼2.5 × 10⁻⁵ mol/cm³. The main reaction of azulene under these conditions is a unimolecular isomerization to naphthalene, but it also isomerizes, although at a much lower rate, to another isomer. The suggested “tetracyclic triene” intermediate structure for the azulene-naphthalene isomerization can lead also to transition states that can describe isomerizations to 1-methylene-1H-indene and 1, 2,3-metheno-1H-indene,2,3-dihydro. Small quantities of C₂H₂, C₄H₂, C₆H₆, and C₆H₅-C≡CH were also found in the post-shock samples, particularly at high temperatures. The Arrhenius parameters of the two high pressure limit rate constants for the isomerization processes are: azulene → naphthalene, k₁ = 10^12.93 exp(–62.8 × 10³/RT) s⁻¹ azulene → second isomer, k₂ = 10^12.42 exp(–69.5 × 10³/RT) s⁻¹ A discussion of the mechanism for these isomerization processes is presented.