Highly diastereo- and enantioselective reagents for aldehyde crotylation

Two new, crystalline solid, storable, and highly enantioselective reagents for aldehyde crotylation have been developed. Both (cis and trans) crotylsilane reagents are easily prepared in bulk, require trivial reaction conditions, and provide the homoallylic alcohol products with near diastereo- and enantiospecificity in many cases.     

Efficient asymmetric synthesis of (+)-SCH 351448

An efficient and stereocontrolled total synthesis of (+)-SCH 351448, a novel activator of low-density lipoprotein receptor promoter, has been achieved with a longest linear sequence of 21 steps. Key steps include applications of the recently developed asymmetric allyl- and crotylsilane reagents and a new protodesilylative version of the tandem silylformylation/allylsilylation reaction, which provides an efficient synthesis of 1,5-syn-diols. [reaction: see text]     

Stereoconvergent palladium-catalyzed carbonylation of both E and Z isomers of a 2-trifloxy-1,3-butadiene

[reaction: see text] Carbonylation of the illustrated Z-tetrasubstituted enol triflate followed by tandem silyloxy-Cope rearrangement leads to the CP-263, 114 core ring system with the all-carbon quaternary stereocenter intact in 46% yield. Subjection of the corresponding E isomer to the same conditions gives the same product in 56% yield. This observation is explained by a mechanism involving isomerization of a pi-allyl palladium species involving an allenic intermediate.     

Enantioselective friedel-crafts alkylations with benzoylhydrazones promoted by a simple strained silacycle reagent

The enantioselective Friedel-Crafts reaction of electron-rich arenes and heteroarenes with the benzoylhydrazone of isopropyl glyoxylate mediated by a simple chiral silane Lewis acid is described. The reactions are highly practical, as demonstrated by a larger scale (5 g of the hydrazone) reaction in which the recovery of the pseudoephedrine in 99% yield was achieved. A simple model is advanced to explain the observed enantioselectivity.     

An approach to the synthesis of the phomoidrides

The phomoidrides are a structurally fascinating family of natural products which possess moderate inhibitory activity against Ras farnesyl transferase and squalene synthase. Since their discovery they have inspired a great deal of attention from synthetic chemists. Our own work, culminating in an efficient synthesis of the fully elaborated tetracyclic core of phomoidrides B and D, is described herein. The synthesis relies on a late stage tandem reaction involving a novel carbonylation reaction that delivers the strained bicyclic pseudoester system, which strain in turn drives a highly efficient silyloxy-Cope rearrangement that delivers the tetracyclic core of phomoidrides B and D. Several examples of this powerful tandem reaction are presented that document its tolerance of significant structural variation. The application of this methodology to the synthesis of a phomoidride D precursor lacking only the maleic anhydride is described, and the prospects for the completion of a total synthesis are discussed.     

Thermodynamic consequences of Tyr to Trp mutations in the cation–π-mediated binding of trimethyllysine by the HP1 chromodomain

Evolution has converged on cation–π interactions for recognition of quaternary alkyl ammonium groups such as trimethyllysine (Kme3). While computational modelling indicates that Trp provides the strongest cation–π interaction of the native aromatic amino acids, there is limited corroborative data from measurements within proteins. Herein we investigate a Tyr to Trp mutation in the binding pocket of the HP1 chromodomain, a reader protein that recognizes Kme3. Binding studies demonstrate that the Trp-mediated cation–π interaction is about −5 kcal mol⁻¹ stronger, and the Y24W crystal structure shows that the mutation is not perturbing. Quantum mechanical calculations indicate that greater enthalpic binding is predominantly due to increased cation–π interactions. NMR studies indicate that differences in the unbound state of the Y24W mutation lead to enthalpy–entropy compensation. These results provide direct experimental quantification of Trp versus Tyr in a cation–π interaction and afford insight into the conservation of aromatic cage residues in Kme3 reader domains.

In this work, we experimentally validate that tryptophan provides the strongest cation–π binding interaction among aromatic amino acids and also lend insight into the importance of residue identity in trimethyllysine recognition by reader proteins.     

Strained silacycles in organic synthesis: a new reagent for the enantioselective allylation of aldehydes

A new reagent for the enantioselective allylation of aliphatic aldehydes has been developed. The reagent is easily prepared in a single step from commercially available materials and may be stored without significant decomposition. The reactivity of the reagent is attributed to strain-release Lewis acidity.     

Cavitation, shock waves and the invasive nature of sonoelectrochemistry

The invasive nature of electrodes placed into sound fields is examined. In particular, perturbations of the sound field due to the presence of the electrode support are explored. The effect of an electrode on the drive sound field (at approximately 23 kHz) is shown to be negligible under the conditions investigated in this paper. However, scattering of shock waves produced by cavity collapse is shown to exhibit a significant effect. To demonstrate this, multibubble sonoluminescence (MBSL) and electrochemical erosion measurements are employed. These measurements show an enhancement, due to the reflection by the solid/liquid boundary at the electrode support, of pressure pulses emitted when cavitation bubbles collapse. To first order, this effect can be accounted for by a correction factor. However, this factor requires accurate knowledge of the acoustic impedance of the interface and the electrolyte media. These are measured for two commonly employed substrates (soda glass and epoxy resin, specifically Epofix). A scattering model is developed which is able to predict the acoustic pressure as a function of position over a disk-like electrode substrate. The effects of shock wave reflection and materials employed in the electrode construction are used to clarify the interpretation of the results obtained from different sonoelectrochemical experiments. Given the widespread experimentation involving the insertion of electrodes (or other sensors) into ultrasonic fields, this work represents a significant development to aid the interpretation of the results obtained.     

The Rayleigh-Plesset equation in terms of volume with explicit shear losses

The most common nonlinear equation of motion for the damped pulsation of a spherical gas bubble in an infinite body of liquid is the Rayleigh-Plesset equation, expressed in terms of the dependency of the bubble radius on the conditions pertaining in the gas and liquid (the so-called ‘radius frame’). However over the past few decades several important analyses have been based on a heuristically derived small-amplitude expansion of the Rayleigh-Plesset equation which considers the bubble volume, instead of the radius, as the parameter of interest, and for which the dissipation term is not derived from first principles. So common is the use of this equation in some fields that the inherent differences between it and the ‘radius frame’ Rayleigh-Plesset equation are not emphasised, and it is important in comparing the results of the two equations to understand that they differ both in terms of damping, and in the extent to which they neglect higher order terms. This paper highlights these differences. Furthermore, it derives a ‘volume frame’ version of the Rayleigh-Plesset equation which contains exactly the same basic physics for dissipation, and retains terms to the same high order, as does the ‘radius frame’ Rayleigh-Plesset equation. Use of this equation will allow like-with-like comparisons between predictions in the two frames.     

The detection by sonar of difficult targets (including centimetre-scale plastic objects and optical fibres) buried in saturated sediment

This paper reports on a laboratory study into the use of sonar to detect objects, two of which exhibit a poor acoustic impedance mismatch with the water-saturated sediment in which they are buried to depth of about 30 cm. The targets are solid cylinders having diameters of 20-25 mm and 50 cm length, made of polyethylene, of telecommunications optical fibre, and of steel. Steel spheres are included for comparison. A poor acoustic impedance mismatch between the target and the host sediment is one factor that can make buried targets difficult to detect with sonar, but such detection is increasingly becoming an issue in a range of applications from archaeology to defence to telecommunications. Attention is paid to those signal processing techniques which could be of potential benefit. For this range of test objects, comparisons are made between use of optimal filtering and synthetic aperture sonar. In addition, the potential of a range of acousto-optical effects (optical time domain reflectometry, Raman and Brillouin scattering, and fibre optic hydrophones) is assessed in the Appendix for the particular application of detecting non-metallised fibre optic telecommunications cables. A web page dedicated to this paper hosts movies and reports at http://www.isvr.soton.ac.uk/fdag/uaua/target_in_sand.htm.