Intramolecular oxidative addition of C-F and C-H bonds to [Pt(dba)2]. Crystal structure of [PtCl{Me2NCH2CH2NCH(2,4,5-C6HF3)}]

The reactions of compound [Pt(dba)₂] with ligands RCHNCH₂CH₂NMe₂ (1a-1f) in which R is a fluorinated aryl ring produced activation of C-F bonds when two fluorine atoms are present in the ortho positions of the aryl ring or activation of C-H bonds for ligands containing only one fluoro substituent in ortho. Both C-F and C-H bond activation are favoured by an increase of the degree of fluorination of the ring. Further reaction with lithium halides produced cyclometallated platinum (II) compounds [PtX(Me₂NCH₂CH₂NCHR)] (X = Br, Cl) (2) containing a terdentate [C,N,N′] ligand. The obtained compounds were fully characterized including a structure determination for [PtCl{Me₂NCH₂CH₂NCH(2,4,5-C₆HF₃)}] (2d′).     

Chiral discrimination of dansyl-amino-acid enantiomers on teicoplanin phase: sucrose-perchlorate anion dependence

The chiral recognition mechanism for a series of d,l-dansyl-amino-acids (test solutes) on a teicoplanin stationary phase was investigated in reversed phase liquid chromatography (RPLC). The effect of both a surface tension modifier (sucrose) and a chaotropic agent (perchlorate anion) on the enantiomeric separation was studied by varying their concentration, c, in the mobile phase. The thermodynamic data supported the fact that the sucrose molecule acted only on the hydrophobic part of the interaction teicoplanin/dansyl-amino-acid and not on the specific chiral part. It was demonstrated that the enhancement of the separation factor observed as the perchlorate salt concentration increased in the mobile phase was enthalpically controlled owing to stereoselective bonding interactions. Such behavior was used to optimize the chromatographic conditions for separation of dansyl-amino-acids on teicoplanin.     

Synthesis of a peroxime proliferator activated receptor (PPAR) alpha/gamma agonist via stereocontrolled Williamson ether synthesis and stereospecific SN2 reaction of S-2-chloro propionic acid with phenoxides

The stereospecific synthesis of the PPAR alpha/gamma agonist 1 was accomplished via ethylation of the optically pure trihydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperature (-30 degrees C), order of addition, and solvent (DMF). The key diastereospecific SN2 reaction of the phenol 4 with S-2-chloropropionic acid is best achieved via the sodium phenoxide of 4 derived from Na0 as the reagent of choice. The structure elucidation and key purification protocols to achieve pharmaceutical purity will also be described.     

Molecular dynamics study of 2rotaxanes: influence of solvation and cation on co-conformation

The conformational preference of a [2]rotaxane system has been examined by molecular dynamics simulations. The rotaxane wheel consists of two bridged binding components: a cis-dibenzo-18-crown-6 ether and a 1,3-phenyldicarboxamide, and the penetrating axle consists of a central isophthaloyl unit with phenyltrityl capping groups. The influence of solvation on the co-conformation of the [2]rotaxane was evaluated by comparing the conformational flexibility in two solvents: chloroform and dimethyl sulfoxide. Attention was also paid to the effect of cation binding on the dynamical properties of the [2]rotaxane. The conformational stability of the [2]rotaxane was calculated using a MM/PB-SA strategy, and the occurrence of specific motions was examined by essential dynamics analysis. The changes in the co-conformational properties in the two solvents and upon cation binding are discussed in light of the available NMR data. The results indicate that in chloroform solution the [2]rotaxane system exists as a mixture of co-conformational states including some that have hydrogen bonds between axle C=O and wheel NH groups. Analysis of the simulations allow us to hypothesize that the [2]rotaxane's circumrotation motion can occur as the result of a dynamic process that combines a preliminary axle sliding step that breaks these hydrogen bonds and a conformational change in the ester group more distant from the wheel. In contrast, no hydrogen-bonded co-conformation was found in dimethyl sulfoxide, which appears to be due to the preferential formation of hydrogen bonds between the wheel NH groups with solvent molecules. Moreover, the axle experiences notable changes in anisotropic shielding, which would explain why the NMR signals are broadened in this solvent. Insertion of a sodium cation into the crown ether reduces co-conformational flexibility due to an interaction of the axle with the cation. Overall, the results reveal how both solvent and ionic atmosphere can influence the co-conformational preferences of rotaxanes.     

Use of a five-channel multiplexed electrospray quadrupole time-of-flight hybrid mass spectrometer for metabolite identification

Metabolism data provided with reduced cycle time has become of increasing importance for the early evaluation of DMPK properties of drugs in discovery. In this regard, quadrupole time-of-flight hybrid mass spectrometers (Q-TOF) can provide very reliable metabolite identification via accurate mass measurement of ions and the consequent access to the elemental composition of the metabolite. However, due to their cost, they are often used for drug metabolism studies on later stage drug candidates or to address challenging metabolism questions. A new prototype, consisting of a five-channel multiplexed electrospray ionization (ESI) source on a Q-TOF with one channel used for lock-mass compound infusion, was evaluated for metabolite identification. The goal was to increase the sample throughput of a single ESI-MS system by a factor of 4, while maintaining efficient metabolite separation in high-performance liquid chromatography (HPLC) as well as adequate sensitivity and mass accuracy, and ultimately improve the speed and quality of metabolism studies supporting drug discovery. The analytical performance of the system was assessed by evaluating the sensitivity and mass accuracy (using real in vitro and in vivo samples), inter-channel differences in retention times, MS/UV response, and cross-talk among channels. The sensitivity using the multiplexed ESI source was on average 2-fold lower than with single ESI, correlating well with previous literature data. The mass accuracy was comparable to that obtained using single ESI in both MS and MS/MS modes, making the metabolite identification process using the multiplexed ESI source as reliable as with single ESI. Compound-dependent differences in ionization efficiencies were observed among channels, and were minimized by analyzing related samples on the same channel. Finally, the level of cross-talk among channels was acceptable (around 0.3%) and comparable to levels previously published for quantitative applications using multiplexed ESI. The paper also focuses on the advantages and disadvantages of this new approach compared to other approaches in the literature in the field of metabolite identification.     

Ordered polyelectrolyte multilayers. Rules governing layering in organic binary multilayers

We study the growth and internal structure of polyelectrolyte multilayers obtained by combining three polyanions with nine polycations of the ionene family, of systematically varied chemical architecture. We find that, contrary to a generally held belief, ordered organic multilayers are by no way exceptional, provided one of the polyelectrolytes bears groups which induce structure in water, such as long hydrophobic segments or mesogenic groups. However, this condition is not sufficient, as order will or will not emerge in the multilayer depending on the specific pairing of the polyelectrolytes. The results support the notion that layering in the multilayer results from some degree of prestructuring of a water-swollen layer adsorbed during each step of deposition. These findings pave the way to new possible uses of polyelectrolyte multilayers, for example, for applications requiring preferential alignment or strong confinement of specific functional groups.     

beta-Silylcarbenes from isolable diazosilanes.

Manganese dioxide oxidation of the hydrazone derivative of tert-butyldimethylsilyl acetophenone gave 2-tert-butyldimethylsilyl-1-phenyldiazoethane (17) an isolable diazocompound. Thermal and Rh(II)-catalyzed decomposition of diazosilane 17 in cyclohexane led to 1-tert-butyldimethylsilyl-1-phenylethylene (19) as the major product. The formation of alkene 19 presumably involves (tert-butyldimethylsilyl)methylphenylcarbene (21), which undergoes preferential 1,2-silyl migration as opposed to 1,2-hydrogen migration. Thermal decomposition of 17 in cyclohexane under oxygen gave substantial amounts of tert-butyldimethylsilyl acetophenone, presumably by reaction of the intermediate carbene with oxygen. Thermal decomposition of 17 in methanol led to alkene 19 and 2-tert-butyldimethylsilyl-1-methoxy-1-phenylethane (22) as major products, along with a significant amount of trans-1-tert-butyldimethylsilyl-2-phenylethylene (20). Kinetic studies indicate that these products are not derived from acid-catalyzed decomposition of the diazocompound 17. Formation of the methyl ether product 22 suggests the involvement of a beta-silyl carbocation intermediate, and solvent isotope effect studies indicate that this cation is at least partially derived from protonation of diazocompound 17 by neutral methanol. Photochemical decomposition of 17 in methanol produced the alkene 19 (97%) along with a small amount (2.4%) of the methyl ether 22. Capture of a photochemically generated carbene 21 by methanol is the proposed origin of this minor product. Geometry optimization of trimethylsilylmethylphenylcarbene (8) and carbene 21 at the HF/6-31G computational level led to a conformation consistent with a hyperconjugative interaction between the vacant p-orbital of these carbenes and the adjacent C-Si bond. Carbenes 8 and 21 are not energy minima at the B3LYP/6-31G level, where they rearrange to alkenes without barrier via silyl migration. These theoretical findings contrast with the proposed trapping of carbene 21 by methanol and oxygen.