The Influence of Disulfide, Thioacetal and Lanthionine-Bridges on the Conformation of a Macrocyclic Peptide.

Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency and selectivity. However, a systematic comparative study of the effects of differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used the NMR deconvolution algorithm, NAMFIS, to determine the conformational ensembles, in aqueous solution, of three cyclic analogues of angiotensin(1-7), incorporating either disulfide, or non-reducible thioether or methylene thioacetal bridges. We demonstrate that the major solution conformations are conserved between the different bridged peptides, but the distribution of conformations differs appreciably. This suggests that subtle differences in ring size and bridging structure can be exploited to fine-tune the conformational properties of cyclic peptides, which may modulate their bioactivities.

Electrosynthesis of Stabilized Diazo Compounds from Hydrazones.

An electrochemical synthesis of diazo compounds from hydrazones in yields as high as 99% was performed. This method was elaborated as a useful synthetic method and demonstrated on various diazo compounds (24 examples). Apart from exhibiting an efficiency that matched that of commonly used harsh and toxic chemical oxidants, this reaction is practically simple to set up, requires mild conditions, and is highly electron efficient (3 F/mol).

Catalytic Bismuth(V)-Mediated Oxidation of Hydrazones into Diazo Compounds.

A new bismuth(V) oxidative catalytic system has been developed and applied for the conversion of hydrazones into diazo compounds. With the use of low catalytic amounts of Ph3Bi and AcOH with NaBO3·H2O as a terminal oxidant, the in situ formation of Ph3Bi(OAc)2 is capable of oxidizing hydrazones in excellent yields. The reaction was applied for the synthesis of diazocarbonyls and 2,2,2-trifluoromethyl diazoalkanes in good to excellent yields.

A direct method for the synthesis of orthogonally protected furyl- and thienyl- amino acids.

The synthesis of unnatural amino acids plays a key part in expanding the potential application of peptide-based drugs and in the total synthesis of peptide natural products. Herein, we report a direct method for the synthesis of orthogonally protected 5-membered heteroaromatic amino acids.

Oxidation in three-liquid-phase microemulsion systems using "Balanced Catalytic Surfactants".

A series of "Balanced Catalytic Surfactants" (BCS) [(Cn)2N(C1)2]2MoO4 (n = 8, 9, 10, 12) based on amphiphilic double-tailed quaternary ammonium with molybdate as a counterion has been developed for the dark singlet [4 + 2] cyclooxygenation of organic substrates in three-liquid-phase microemulsion systems. These cationic surfactants form three-liquid-phase microemulsion systems at room temperature in the presence of an appropriate organic solvent and water without addition of any cosurfactant or electrolyte. Comparative peroxidation of rubrene points out the specific advantages of these three-phase media over phase transfer catalysis in two phase systems and on conventional one-phase microemulsions based on sodium molybdate: (i) only three constituents, (ii) low amounts of surfactants, (iii) insensitivity to water dilution, (iv) fast separation of the three phases, (v) straightforward recovery of the product and the surfactant from the oil and microemulsion phases, respectively. The preparative peroxidation of alpha-terpinene and 1,4,5-trimethylnaphtalene was performed in the ternary systems [(C8)2N(C1)2]2MoO4/water/tert-butyl acetate or benzene. The reusability of the catalyst, the catalytic nature of the BCS, and the ability of the systems to oxidize poorly reactive substrates were demonstrated showing the broadness of the applicability of such systems.

Continuous process for singlet oxygenation of hydrophobic substrates in microemulsion using a pervaporation membrane.

Chemically generated singlet oxygen (1O2, 1Deltag) is able to oxidize a great deal of hydrophobic substrates from molybdate-catalyzed hydrogen peroxide decomposition, provided a suitable reaction medium such as a microemulsion system is used. However, high substrate concentrations or poorly reactive organics require large amounts of H2O2 that generate high amounts of water and thus destabilize the system. We report results obtained on combining dark singlet oxygenation of hydrophobic substrates in microemulsions with a pervaporation membrane process. To avoid composition alterations after addition of H2O2 during the peroxidation, the reaction mixture circulates through a ceramic membrane module that enables a partial and selective dewatering of the microemulsion. Optimization phase diagrams of sodium molybdate/water/alcohol/anionic surfactant/organic solvent have been elaborated to maximize the catalyst concentration and therefore the reaction rate. The membrane selectivity towards the mixture constituents has been investigated showing that a high retention is observed for the catalyst, for organic solvents and hydrophobic substrates, but not for n-propanol (cosurfactant) and water. The efficiency of such a process is illustrated with the peroxidation of a poorly reactive substrate, viz., beta-pinene.

Reactivity, chemoselectivity, and diastereoselectivity of the oxyfunctionalization of chiral allylic alcohols and derivatives in microemulsions: comparison of the chemical oxidation by the hydrogen peroxide/sodium molybdate system with the photooxygenation.

The chiral allylic alcohols 1a-d and their acetate (1e) and silyl ether (1f) derivatives have been oxidized by the H2O2/MoO4(2)- system, a convenient and efficient chemical source of singlet oxygen. This chemical peroxidation (formation of the allylic hydroperoxides 2) has been conducted in various media, which include aqueous solutions, organic solvents, and microemulsions. The reactivity, chemoselectivity, and diastereoselectivity of this chemical oxidation are compared to those of the sensitized photooxygenation, with the emphasis on preparative applications in microemulsion media. While a similar threo diastereoselectivity is observed for both modes of peroxidation, the chemoselectivity differs significantly, since in the chemical oxidation with the H2O2/MoO4(2)- system the undesirable epoxidation by the intermediary peroxomolybdate competes efficiently with the desirable peroxidation by the in situ generated singlet oxygen. A proper choice of the type of microemulsion and the reaction conditions furnishes a high chemoselectivity (up to 97%) in favor of threo-diastereoselective (up to 92%) peroxidation.

Thermodynamic insight into the origin of the inclusion of monosulfonated isomers of triphenylphosphine into the beta-cyclodextrin cavity.

Formation of inclusion complexes between the beta-cyclodextrin and the potassium salt of o-, m-, and p-substituted monosulfonated triphenylphosphine derivatives was investigated in aqueous solution by NMR spectroscopy. Titration and continuous variation plots obtained from 31P and 1H NMR data indicate the formation of a 1:1 inclusion complex for the three phosphine isomers. T-ROESY NMR experiments show that in all cases a non-sulfonated aromatic ring was included into the hydrophobic cavity of beta-cyclodextrin from the secondary hydroxyl groups side. The standard enthalpy and entropy of the inclusion process were estimated from the temperature dependence of the association constant. All inclusion complexes were enthalpy stabilized, but highly entropy destabilized.