Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)(3) to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1]pentylamine in terms of scalability, yield, safety, and cost.     

Novel electrochemical deoxygenation reaction using diphenylphosphinates

The electrochemical reduction of diphenylphosphinate esters leads smoothly and in high yields to the corresponding deoxygenated products. In comparison with the previously developed methodologies, the electrolysis could be performed at lower temperature and with a higher current density, resulting in a shorter reaction time.     

Synthesis of α,α-disubstituted aryl amines by rhodium-catalyzed amination of tertiary allylic trichloroacetimidates

The rhodium-catalyzed regioselective amination of tertiary allylic trichloroacetimidates with unactivated aromatic amines is a direct and efficient approach to the preparation of α,α-disubstituted allylic aryl amines in good yield and with excellent regioselectivity. This method is applicable to a variety of unactivated primary and secondary amines and allows for the preparation of reverse prenylated indoles in two steps.     

Copper(I) catalyzed regioselective asymmetric alkoxyamination of aryl enamide derivatives

The copper(I) catalyzed reaction of an enamide with an iminoiodane, in the presence of an alcohol, triggers the direct alkoxyamination of the double bond. This transformation represents a straightforward access to α-amino aminals in a completely regio- and diastereoselective manner. Use of a chiral Box ligand allows this reaction to be carried out in an enantioselective fashion.     

Interactions of halichondrin B and eribulin with tubulin

Compounds that modulate microtubule dynamics include highly effective anticancer drugs, leading to continuing efforts to identify new agents and improve the activity of established ones. Here, we demonstrate that [(3)H]-labeled halichondrin B (HB), a complex, sponge-derived natural product, is bound to and dissociated from tubulin rapidly at one binding site per αβ-heterodimer, with an apparent K(d) of 0.31 μM. We found no HB-induced aggregation of tubulin by high-performance liquid chromatography, even following column equilibration with HB. Binding of [(3)H]HB was competitively inhibited by a newly approved clinical agent, the truncated HB analogue eribulin (apparent K(i), 0.80 μM) and noncompetitively by dolastatin 10 and vincristine (apparent K(i)'s, 0.35 and 5.4 μM, respectively). Our earlier studies demonstrated that HB inhibits nucleotide exchange on β-tubulin, and this, together with the results presented here, indicated the HB site is located on β-tubulin. Using molecular dynamics simulations, we determined complementary conformations of HB and β-tubulin that delineated in atomic detail binding interactions of HB with only β-tubulin, with no involvement of the α-subunit in the binding interaction. Moreover, the HB model served as a template for an eribulin binding model that furthered our understanding of the properties of eribulin as a drug. Overall, these results established a mechanistic basis for the antimitotic activity of the halichondrin class of compounds.     

Study of Tamiflu sensitivity to variants of A/H5N1 virus using different force fields

An accurate estimation of binding free energy of a ligand to receptor ΔG(bind) is one of the most important problems in drug design. The success of solution of this problem is expected to depend on force fields used for modeling a ligand-receptor complex. In this paper, we consider the impact of four main force fields, AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L, on the binding affinity of Oseltamivir carboxylate to the wild-type and Y252H, N294S, and H274Y mutants of glycoprotein neuraminidase from the pandemic A/H5N1 virus. Having used the molecular mechanic-Poisson-Boltzmann surface area method, we have shown that ΔG(bind), obtained by AMBER99SB, OPLS-AA/L, and CHARMM27, shows the high correlation with the available experimental data. They correctly capture the binding ranking Y252H → WT → N294S → H274Y observed in experiments (Collins, P. J. et al. Nature 2008, 453, 1258). In terms of absolute values of binding scores, results obtained by AMBER99SB are in the nearest range with experiments, while OPLS-AA/L, which is applied to study binding of Oseltamivir to the influenza virus for the first time, gives rather big negative values for ΔG(bind). GROMOS96 43a1 provides a lower correlation as it supports Oseltamivir to be more resistant to N294S than H274Y. Our study suggests that force fields have pronounced influence on theoretical estimations of binding free energy of a ligand to receptor. The effect of all-atom models on dynamics of the binding pocket as well as on the hydrogen-bond network between Oseltamivir and receptors is studied in detail. The hydrogen network, obtained by GROMOS, is weakest among four studied force fields.     

Optimum conditions for the water extraction of L-theanine from green tea

Theanine is a unique non-protein amino acid found in tea (Camellia sinensis). It contributes to the favourable umami taste of tea and is linked to various beneficial effects in humans. There is an increasing interest in theanine as an important component of tea, as an ingredient for novel functional foods and as a dietary supplement. Therefore, optimal conditions for extracting theanine from tea are required for the accurate quantification of theanine in tea and as an efficient first step for its purification. This study examined the effects of four different extraction conditions on the yield of theanine from green tea using water and applied response surface methodology to further optimise the extraction conditions. The results showed that temperature, extraction time, ratio of water-to-tea and tea particle sizes had significant impacts on the extraction yield of theanine. The optimal conditions for extracting theanine from green tea using water were found to be extraction at 80 °C for 30 min with a water-to-tea ratio of 20:1 mL/g and a tea particle size of 0.5-1 mm.     

Determination of the primary structure and carboxyl p<Emphasis Type="Italic">K</Emphasis><Subscript>A</Subscript>s of heparin-derived oligosaccharides by band-selective homonuclear-decoupled two-dimensional <Superscript>1</Superscript>H NMR

Determination of the structure of heparin-derived oligosaccharides by ¹H NMR is challenging because resonances for all but the anomeric protons cover less than 2 ppm. By taking advantage of increased dispersion of resonances for the anomeric H¹ protons at low pD and the superior resolution of band-selective, homonuclear-decoupled (BASHD) two-dimensional ¹H NMR, the primary structure of the heparin-derived octasaccharide ∆UA(2S)-[(1 → 4)-GlcNS(6S)-(1 → 4)-IdoA(2S)-]₃-(1 → 4)-GlcNS(6S) has been determined, where ∆UA(2S) is 2-O-sulfated ∆^4,5-unsaturated uronic acid, GlcNS(6S) is 6-O-sulfated, N-sulfated β-d-glucosamine and IdoA(2S) is 2-O-sulfated α-l-iduronic acid. The spectrum was assigned, and the sites of N- and O-sulfation and the conformation of each uronic acid residue were established, with chemical shift data obtained from BASHD-TOCSY spectra, while the sequence of the monosaccharide residues in the octasaccharide was determined from inter-residue NOEs in BASHD-NOESY spectra. Acid dissociation constants were determined for each carboxylic acid group of the octasaccharide, as well as for related tetra- and hexasaccharides, from chemical shift–pD titration curves. Chemical shift–pD titration curves were obtained for each carboxylic acid group from sub-spectra taken from BASHD-TOCSY spectra that were measured as a function of pD. The pK _As of the carboxylic acid groups of the ∆UA(2S) residues are less than those of the IdoA(2S) residues, and the pK _As of the carboxylic acid groups of the IdoA(2S) residues for a given oligosaccharide are similar in magnitude. Relative acidities of the carboxylic acid groups of each oligosaccharide were calculated from chemical shift data by a pH-independent method.     

An improvement of the Nevanlinna-Gundersen theorem

A well-known result of Nevanlinna states that for two nonconstant meromorphic functions f and g on the complex plane C and for four distinct values aj∈C∪{∞}, if νf−aj=νg−aj for all 1?j?4, then g is a Möbius transformation of f. In 1983, Gundersen generalized the result of Nevanlinna to the case where the above condition is replaced by: min{νf−aj,1}=min{νg−aj,1} for j=1,2 and νf−aj=νg−aj for j=3,4. In this paper, we prove that the theorem of Gundersen remains valid to the case where min{νf−aj,1}=min{νg−aj,1} for j=1,2, and min{νf−aj,2}=min{νg−aj,2} for j=3,4. Furthermore, we work on the case where {aj} are small functions.