Total synthesis of (+)-discodermolide: an improved endgame exploiting a Still-Gennari-type olefination with a C1-C8 beta-ketophosphonate fragment

[structure: see text] An improved, third-generation, total synthesis of (+)-discodermolide, a potent microtubule-stabilizing anticancer agent of marine sponge origin, is achieved in 11.1% yield over 21 steps. Key steps include a Still-Gennari HWE olefination, performed using NaH as the base, between C1-C8 beta-ketophosphonate 7 and C9-C24 aldehyde 8, introducing the (8Z)-alkene with 10:1 selectivity, and K-Selectride reduction of the derived enone 16, installing the (7S)-configuration.     

Investigation of the metabolic fate of 2-, 3- and 4-bromobenzoic acids in bile-duct-cannulated rats by inductively coupled plasma mass spectrometry and high-performance liquid chromatography/inductively coupled plasma mass spectrometry/electrospray mass spectrometry

Inductively coupled plasma mass spectrometry (ICPMS) has been used to determine the rate and routes of excretion of bromine following the intraperitoneal administration (50 mg kg(-1)) of 2-, 3- and 4-bromobenzoic acids to male bile-duct-cannulated rats. Analysis of urine and bile for (79/81)Br using ICPMS showed that all three bromobenzoic acids were rapidly excreted (82-98%) within 48 h of dosing, primarily via the urine. High-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC/ICPMS) was then used to obtain metabolite profiles for bile and urine. These profiles revealed that extensive metabolism had taken place, with the unchanged bromobenzoic acids forming a minor part of the total of compound-related material detected. Concomitant MS studies, supplemented by alkaline hydrolysis, enabled the identification of the major metabolite of all three of the bromobenzoic acids as a glycine conjugate. Ester glucuronide conjugates were also identified, but formed only a small proportion of total.     

Synthesis and catalytic activity of a fluorous-tagged TEMPO radical

A fluorous-tagged TEMPO radical has been prepared and its catalytic activity in the chemoselective oxidation of alcohols to carbonyl compounds has been investigated. The new fluorous radical proved to be an efficient, selective and easily recoverable catalyst, which can be conveniently used in standard organic solvents and then isolated and recycled by fluorous liquid-liquid extraction.     

Synthesis of a simplified bryostatin C-ring analogue that binds to the CRD2 of human PKC-alpha and construction of a novel BC-analogue by an unusual Julia olefination process

[structure: see text] The synthesis of two truncated bryostatin analogues 2 and 3 is described. High-field NMR measurements on the C-ring analogue 3 in C(2)H(3)CN containing 25% (2)H(2)O have shown that it binds to the CRD2 of human PKC-alpha at virtually the same position as phorbol-13-acetate (PA) and bryostatin 1 (1). NMR titration studies have also revealed that 3 binds to the CRD2 with a potency similar in magnitude to PA but much less potently than 1.     

A rapid synthesis of 2-aryl-5-substituted-2,3-dihydrobenzofurans

[reaction: see text] An effective strategy has been developed for the rapid and efficient one-pot synthesis of 2-aryl-5-substituted-2,3-dihydrobenzofurans from readily available o-nitrotoluenes and aromatic aldehydes. This strategy allows access to a structurally diverse array of products for further manipulation.     

Extent of complex participation in the rate of copolymerization of styrene with maleic anhydride in methyl ethyl ketone

Georgiev and Shirota's simplified terminal complex model was applied to the dilatometrically measured initial rate of copolymerization of sytrene (ST) with maleic anhydride (MA) in methyl ethyl ketone (MEK) at 50°C. The rate was maximum at the feed MA mole fractions of 0.752, 0.769, and 0.806 at the total monomer concentrations of 2M, 1.5M, and 0.5M, respectively. Shirota's method gave the following ratios of propagation rate constants: β_A=k_AC/k_AD = 8.25 and β_D = k_DC/k_DA = 2.70. Georgiev's method gave β_A = 14, β_D = 2.7, and α = k_AD/k_DA = 22. The equilibrium constant of the donor-acceptor complexation between ST and MA in MEK was measured to be 0.045 dm³/mol at room temperature.     

The equilibrium properties and folding kinetics of an all-atom Go model of the Trp-cage

The ultrafast-folding 20-residue Trp-cage protein is quickly becoming a new benchmark for molecular dynamics studies. Already several all-atom simulations have probed its equilibrium and kinetic properties. In this work an all-atom Go model is used to accurately represent the side-chain packing and native atomic contacts of the Trp-cage. The model reproduces the hallmark thermodynamics cooperativity of small proteins. Folding simulations observe that in the fast-folding dominant pathway, partial alpha-helical structure forms before hydrophobic core collapse. In the slow-folding secondary pathway, partial core collapse occurs before helical structure. The slow-folding rate of the secondary pathway is attributed to the loss of side-chain rotational freedom, due to the early core collapse, which impedes the helix formation. A major finding is the observation of a low-temperature kinetic intermediate stabilized by a salt bridge between residues Asp-9 and Arg-16. Similar observations [R. Zhou, Proc. Natl. Acad. Sci. U.S.A. 100, 13280 (2003)] were reported in a recent study using an all-atom model of the Trp-cage in explicit water, in which the salt-bridge stabilized intermediate was hypothesized to be the origin of the ultrafast-folding mechanism. A theoretical mutation that eliminates the Asp-9-Arg-16 salt bridge, but leaves the residues intact, is performed. Folding simulations of the mutant Trp-cage observe a two-state free-energy landscape with no kinetic intermediate and a significant decrease in the folding rate, in support of the hypothesis.     

Enthalpies of dilution of aqueous solutions of amides and alcohols

Enthalpies of dilution of aqueous systems containing formamide, dimethyl-formamide, the mixture of these amides, and each amide separately with mannitol, inositol, and cyclohexanol have been determined at 25°C. The data have been treated in terms of the Savage-Wood additivity principle and in combination with literature data. New values for the methylene-amide, carbinol-amide, and amide-amide group interaction enthalpies are presented. These may be used with data on a wider variety of solute systems to obtain interaction enthalpies for new groups.     

Effect of pressure on coupled electronic ground and excited states determined from luminescence spectra of trans-dioxorhenium(V) complexes

Pressure-dependent luminescence spectra of trans-dioxo complexes of rhenium(V) with ancillary ethylenediamine ligands exhibit resolved vibronic structure in the O=Re=O symmetric stretching mode at room temperature. The intensity distribution within the vibronic progression changes with pressure, leading to band shapes that are also pressure-dependent. These spectroscopic features arise from coupled electronic states and depend on the energy differences between ground and excited states, which vary by 2500 cm(-1) for the three complexes with ethylenediamine, tetramethylethylenediamine, and tetraethylethylenediamine ancillary ligands. We describe the pressure-dependent vibronic structure and band shapes with anharmonic adiabatic potential energy surfaces for the ground states of all complexes. The calculated spectra reveal the pressure dependence of the energies of electronic origins, luminescence band maximums, offsets between ground- and emitting-state potential minimums, and vibrational frequencies. The largest pressure effects are observed where the coupled electronic states are close in energy.