Computational studies of Fe(III) binding to bryostatins, bryostatin analogs, siderophores and marine natural products: arguments for ferric complexes in medicinal applications

In this computational study, geometric factors are calculated by applying semi-empirical methods (PM3) that support experimental evidence from this lab where bryostatins can bind trivalent iron with six Fe-O bonds forming an octahedral geometry. The geometric factors are calculated for all 20 structures (Fe3+ bound to bryostatin 1-20) as a neutral, monovalent, and divalent species. The average Fe-O bond distances and bond angles are compared to those of known marine and terrestrial siderophores. From these two data sets, we then examined other known marine natural products (MNPs) that can form a hexavalent complex with six Fe-O bonds and draw conclusions about their potential biological role as marine siderophores. This computational data indicates that Fe(III) strongly bonds to a host of MNPs, increasing their water solubility, contracting their structure, hence allowing transport through cell membranes more readily, and in some cases, stabilizing ester bonds that are susceptible to hydrolysis. It is argued that administering medicinally bryostatin, its analogs or other MNPs as a ferric complex, holds some fundamental chemical advantages compared to its administration as a neutral uncomplexed species.     

Stereospecific Conversion of Boronic Esters into Enones using Methoxyallene: Application in the Total Synthesis of 10-Deoxymethynolide

Enones are widely utilized linchpin functional groups in chemical synthesis and molecular biology. We herein report the direct conversion of boronic esters into enones using commercially available methoxyallene as a three-carbon building block. Following boronate complex formation by reaction of the boronic ester with lithiated-methoxyallene, protonation triggers a stereospecific 1,2-migration before oxidation generates the enone. The protocol shows broad substrate scope and complete enantiospecificity is observed with chiral migrating groups. In addition, various electrophiles could be used to induce 1,2-migration and give a much broader range of α-functionalized enones. Finally, the methodology was applied to a 14-step synthesis of the enone-containing polyketide 10-deoxymethynolide.     

Photodetachment of Deprotonated R-Mandelic Acid: The Role of Proton Delocalization on the Radical Stability

The photodetachment and stability of R-Mandelate, the deprotonated form of the R-Mandelic acid, was investigated by observing the neutral species issued from either simple photodetachment or dissociative photodetachment in a cold anions set-up. R-Mandalate has the possibility to form an intramolecular ionic hydrogen-bond between adjacent hydroxyl and carboxylate groups. The potential energy surface along the proton transfer (PT) coordinate between both groups (O⁻…H⁺…⁻OCO) features a single local minima, with the proton localized on the O⁻ group (OH…⁻OCO). However, the structure with the proton localized on the ⁻OCO group (O⁻…HOCO) is also observed because it falls within the extremity of the vibrational wavefunction of the OH…⁻OCO isomer along the PT coordinate. The stability of the corresponding radicals, produced upon photodetachment, is strongly dependent on the position of the proton in the anion: the radicals produced from the OH…⁻OCO isomer decarboxylate without barrier, while the radicals produced from the O⁻…HOCO isomer are stable.     

Short Enantioselective Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assembly‐Line Synthesis

Short and highly stereoselective total syntheses of the sesquilignan natural product tatanan A and its C3 epimer are described. An assembly‐line synthesis approach, using iterative lithiation–borylation reactions, was applied to install the three contiguous stereocenters with high enantio‐ and diastereoselectivity. One of the stereocenters was installed using a configurationally labile lithiated primary benzyl benzoate, resulting in high levels of substrate‐controlled (undesired) diastereoselectivity. However, reversal of selectivity was achieved by using a novel diastereoselective Matteson homologation. Stereospecific alkynylation of a hindered secondary benzylic boronic ester enabled completion of the synthesis in a total of eight steps.     

Stability of Viscous St. Venant Roll Waves: From Onset to Infinite Froude Number Limit

We study the spectral stability of roll wave solutions of the viscous St. Venant equations modeling inclined shallow water flow, both at onset in the small Froude number or “weakly unstable” limit \(F\rightarrow 2^+\) and for general values of the Froude number F, including the limit \(F\rightarrow +\infty \). In the former, \(F\rightarrow 2^+\), limit, the shallow water equations are formally approximated by a Korteweg-de Vries/Kuramoto–Sivashinsky (KdV–KS) equation that is a singular perturbation of the standard Korteweg-de Vries (KdV) equation modeling horizontal shallow water flow. Our main analytical result is to rigorously validate this formal limit, showing that stability as \(F\rightarrow 2^+\) is equivalent to stability of the corresponding KdV–KS waves in the KdV limit. Together with recent results obtained for KdV–KS by Johnson–Noble–Rodrigues–Zumbrun and Barker, this gives not only the first rigorous verification of stability for any single viscous St. Venant roll wave, but a complete classification of stability in the weakly unstable limit. In the remainder of the paper, we investigate numerically and analytically the evolution of the stability diagram as Froude number increases to infinity. Notably, we find transition at around \(F=2.3\) from weakly unstable to different, large-F behavior, with stability determined by simple power-law relations. The latter stability criteria are potentially useful in hydraulic engineering applications, for which typically \(2.5\le F\le 6.0\).     

Epitope mapping of 7S cashew antigen in complex with antibody by solution‐phase H/D exchange monitored by FT‐ICR mass spectrometry

The potential epitope of a recombinant food allergen protein, cashew Ana o 1, reactive to monoclonal antibody, mAb 2G4, has been mapped by solution‐phase amide backbone H/D exchange (HDX) monitored by Fourier transform ion cyclotron resonance mass spectrometry (FT‐ICR MS). Purified mAb 2G4 was incubated with recombinant Ana o 1 (rAna o 1) to form antigen:monoclonal antibody (Ag:mAb) complexes. Complexed and uncomplexed (free) rAna o 1 were then subjected to HDX‐MS analysis. Five regions protected from H/D exchange upon mAb binding are identified as potential conformational epitope‐contributing segments. Copyright © 2015 John Wiley & Sons, Ltd.     

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.     

Divergent,Stereospecific Mono- and Difluoromethylation of Boronic Esters

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH₂F and CHF₂ groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α-fluoro-boronic esters. These unique intermediates can be readily transformed into the corresponding mono- or difluoromethylated compounds through proto- or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2-migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.     

Development and characterization of a variable turbulence generation system

Experimental turbulent combustion studies require systems that can simulate the turbulence intensities [u′/U ₀ ~ 20–30% (Koutmos and McGuirk in Exp Fluids 7(5):344–354, 1989)] and operating conditions of real systems. Furthermore, it is important to have systems where turbulence intensity can be varied independently of mean flow velocity, as quantities such as turbulent flame speed and turbulent flame brush thickness exhibit complex and not yet fully understood dependencies upon both U ₀ and u′. Finally, high pressure operation in a highly pre-heated environment requires systems that can be sealed, withstand high gas temperatures, and have remotely variable turbulence intensity that does not require system shut down and disassembly. This paper describes the development and characterization of a variable turbulence generation system for turbulent combustion studies. The system is capable of a wide range of turbulence intensities (10–30%) and turbulent Reynolds numbers (140–2,200) over a range of flow velocities. An important aspect of this system is the ability to vary the turbulence intensity remotely, without changing the mean flow velocity. This system is similar to the turbulence generators described by Videto and Santavicca (Combust Sci Technol 76(1):159–164, 1991) and Coppola and Gomez (Exp Therm Fluid Sci 33(7):1037–1048, 2009), where variable blockage ratio slots are located upstream of a contoured nozzle. Vortical structures from the slots impinge on the walls of the contoured nozzle to produce fine-scale turbulence. The flow field was characterized for two nozzle diameters using three-component Laser Doppler velocimetry (LDV) and hotwire anemometry for mean flow velocities from 4 to 50 m/s. This paper describes the key design features of the system, as well as the variation of mean and RMS velocity, integral length scales, and spectra with nozzle diameter, flow velocity, and turbulence generator blockage ratio.     

Feature article: High pressure kinetics: The beacon that baffled

Abstract

Experimental results may instruct or befuddle, and we rejoice or agonize accordingly. And yet, more may be learned from questions raised than from answers given. An example is described from the author's experience in high pressure kinetics, in which success did not convince but failure led to the goal. Beacon = a signal to guide mariners Baffle = to defeat by perplexing (Webster)