Enantioselective synthesis of the carbacephem antibiotic loracarbef via Mitsunobu and Dieckmann cyclization from an unnatural amino acid

The nucleus of the carbacephem antibiotic loracarbef was synthesized in a highly efficient and enantioselective fashion from 2S,3S-2-amino-3-hydroxy-6-heptenoic acid (AHHA), which was derived from enzyme-catalyzed condensation of glycine and 4-pentenaldehyde. The bicyclic framework of this compound was established through sequential Mitsunobu reaction and aldol condensations.     

Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione, the B,C,D ring core of the shermilamine alkaloids

Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione (4), from N-(4-bromo-2,5-dimethoxyphenyl)acetamide (23) is described. Oxidative cyclisation of 2,2'-disulfanediylbis[N-(2,5-dimethoxyphenyl)acetamide] (19) to 5,8-dimethoxy-2H-1,4-benzothiazin-3(4H)-one (7b) is also reported.     

Material Design in Poly(Lactic Acid) Systems: Block Copolymers,Star Homo- and Copolymers,and Stereocomplexes

Abstract

This paper gives a general overview of several approaches we have investigated for designing new PLA-based polymers with a broad range of properties and improved processability. These approaches include: copolymerization (block and stereoblock copolymers), microstructure and architecture control, and stereocomplexation. Multiblock copolymers with alternating “soft” and “hard” segments, synthesized over a broad range of chemical compositions, show properties ranging from hard plastics to elastomers. Stereoblock copolymers with alternating amorphous and semicrystalline PLA blocks combine the advantages of PLA homopolymers (crystallinity) and random copolymers (processability). Independent control of polymer architecture and microstructure allows for the synthesis of star polymers with various arm morphologies. A new method for stereocomplex formation between L-PLA and D-PLA, which combines in-situ polymerization with stereocomplexation, is also described. For the synthesis of these new materials we took advantage of: 1) chirality of lactide monomer, 2) retention of configuration during polymerization, 3) living nature of the ring-opening polymerization (ROP) of lactide in the presence of active hydrogen groups such as OH and NH₂, and 4) control of the level of transesterification reactions.     

A unique mechanism for base catalyzed hydrolysis of pentaaminecobalt(III) complexes containing picolyl residues

A novel [Co(pentaamine)Cl](2+) complex having all tertiary amine or pyridine donors has been synthesized (pentaamine = 1,4-bis(2'-pyridyl)-7-methyl-1,4,7-triazacyclononane). This asym-[Co(dmpmetacn)Cl](2+) species has been completely characterized through 1D and 2D NMR studies, and through the X-ray structure for the ZnCl(4)(2)(-) salt. Despite the lack of an activating NH center, remarkably its hydrolysis to [Co(pentaamine)OH](2+) is base catalyzed (k(OH) 0.70 M(-)(1) s(-)(1), 25 degrees C, I = 1.0 M, NaCl). Detailed NMR studies reveal that the base catalyzed substitution leads to the exchange of just one deuterium in one of the two -CH(2)- pyridyl arms, that is approximately trans to the leaving group, and this occurs during and not after base hydrolysis. Quenching experiments for the reaction of asym-[Co(dmpmetacn)Cl](2+) and control experiments on H/D exchange for the product asym-[Co(dmpmetacn)OD](2+) in OD(-) show that each act of deprotonation at the acidic methylene leads to loss of Cl(-). This is the first established case of base catalyzed substitution for a complex where the effective site of deprotonation is at a pyridyl group. A pronounced kinetic isotope effect is observed for the species perdeuterated at the pyridyl methylenes (k(H)/k(D) = 5.0), consistent with rate limiting deprotonation which is a rare event in Co(III) substitution chemistry. The activation afforded by the carbanion is discussed in terms of a new process coined the pseudo-aminate mechanism.     

Lanthanide transport in stabilized zirconias: interrelation between ionic radius and diffusion coefficient

The diffusion of all stable lanthanides was measured both in calcia stabilized zirconia (CSZ) and in yttria stabilized zirconia (YSZ) in the temperature range between 1,286 and 1,600 degrees C. The lanthanide diffusion coefficients obtained increase with increasing ionic radius. The experimental activation enthalpy of diffusion is near 6 eV for CSZ and between 4 and 5 eV for YSZ and is not strongly affected by the type of lanthanide. The results were correlated with defect energy calculations of the lanthanide diffusion enthalpy using the Mott-Littleton approach. An association enthalpy of cation vacancies with oxygen vacancies of about 1 eV (96 kJ/mol) was deduced in the case of CSZ, while there is no association in the case of YSZ. Furthermore, the change in diffusion coefficients can be correlated to the interaction parameter for the interaction between the lanthanide oxide with zirconia: The higher the interaction parameter, the higher the lanthanide diffusion coefficient.     

Reinvestigation of CS2 dissociation at 193 nm by means of product state-selective vacuum ultraviolet laser ionization and velocity imaging

A branching ratio of 1.6 +/- 0.3 for S(3P)/S(1D) is obtained for the dissociation of CS2 with very low fluence 193 nm laser (less than 2 mJ/cm2), in which the S(3P) and S(1D) have been state-selectively ionized using VUV lasers at different wavelengths. The anisotropy parameters betamax(3P) = 0.8 and betamax(1D) = 1.9 indicate that these channels are preferentially populated at different geometries and the lifetime is very short.     

Probing the 3-D Structure,Dynamics, and Stability of Bacterial Collagenase Collagen Binding Domain (apo- versus holo-) by Limited Proteolysis MALDI-TOF MS

Pairing limited proteolysis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) to probe clostridial collagenase collagen binding domain (CBD) reveals the solution dynamics and stability of the protein, as these factors are crucial to CBD effectiveness as a drug-delivery vehicle. MS analysis of proteolytic digests indicates initial cleavage sites, thereby specifying the less stable and highly accessible regions of CBD. Modulation of protein structure and stability upon metal binding is shown through MS analysis of calcium-bound and cobalt-bound CBD proteolytic digests. Previously determined X-ray crystal structures illustrate that calcium binding induces secondary structure transformation in the highly mobile N-terminal arm and increases protein stability. MS-based detection of exposed residues confirms protein flexibility, accentuates N-terminal dynamics, and demonstrates increased global protein stability exported by calcium binding. Additionally, apo- and calcium-bound CBD proteolysis sites correlate well with crystallographic B-factors, accessibility, and enzyme specificity. MS-observed cleavage sites with no clear correlations are explained either by crystal contacts of the X-ray crystal structures or by observed differences between Molecules A and B in the X-ray crystal structures. The study newly reveals the absence of the βA strand and thus the very dynamic N-terminal linker, as corroborated by the solution X-ray scattering results. Cobalt binding has a regional effect on the solution phase stability of CBD, as limited proteolysis data implies the capture of an intermediate-CBD solution structure when cobalt is bound.     

Viscosity of liquid mixtures: the Vesovic-Wakeham method for chain molecules

New expressions for the viscosity of liquid mixtures, consisting of chain-like molecules, are derived by means of Enskog-type analysis. The molecules of the fluid are modelled as chains of equally sized, tangentially joined, and rigid spheres. It is assumed that the collision dynamics in such a fluid can be approximated by instantaneous collisions. We determine the molecular size parameters from the viscosity of each pure species and show how the different effective parameters can be evaluated by extending the Vesovic-Wakeham (VW) method. We propose and implement a number of thermodynamically consistent mixing rules, taking advantage of SAFT-type analysis, in order to develop the VW method for chain molecules. The predictions of the VW-chain model have been compared in the first instance with experimental viscosity data for octane-dodecane and methane-decane mixtures, thus, illustrating that the resulting VW-chain model is capable of accurately representing the viscosity of real liquid mixtures.     

Synthesis,Crystal Structures,and in Silico Toxicity Prediction of Thienopyridine Phosphoramidates

New thieno[2,3-b]pyridine phosphoramidates compounds were synthesized and characterized by infrared; ¹H, ¹³C, and ³¹P NMR spectroscopy; and high-resolution mass spectrometry. The products were obtained in good yields (64–82%) under mild conditions by nucleophilic aromatic substitution reaction of aminoalkylphosphoramidates over 4-chlorothieno[2,3-b]pyridine-5-carbonitrile. The crystal structures of two compounds were solved by x-ray diffraction and showed a network of intermolecular interactions involving phosphoramidate groups. Druglike properties and toxicity of the new compounds were studied with the help of the software Molinspiration, Osiris, and Toxtree, and were compared with the standard drugs amphotericin B, miltefosine, benznidazole, and nifurtimox.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]