Substituent effects on aromatic stacking interactions.

Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the free energies of aromatic stacking interactions. The conformational properties of the complexes have been characterised using NMR spectroscopy in CDCl(3), and by comparison with the solid state structures of model compounds. The structural similarity of the complexes makes it possible to apply the double mutant cycle method to evaluate the magnitudes of 24 different aromatic stacking interactions. The major trends in the interaction energy can be rationalised using a simple model based on electrostatic interactions between the pi-faces of the two aromatic rings. However, electrostatic interactions between the substituents of one ring and the pi-face of the other make an additional contribution, due to the slight offset in the stacking geometry. This property makes aromatic stacking interactions particularly sensitive to changes in orientation as well as the nature and location of substituents.

Electrostatic control of aromatic stacking interactions.

A supramolecular approach has been used to investigate the free energies of intermolecular aromatic stacking interactions. Chemical double mutant cycles have been used to measure the effect of a range of substituents on face-to-face stacking interactions with phenyl and pentafluorophenyl rings. Electrostatic effects dominate the trends in interaction energy.

A single-step method for the production of sugar hydrazides: intermediates for the chemoselective preparation of glycoconjugates.

The ability to selectively conjugate carbohydrate molecules to a protein is a key step in the preparation of conjugate vaccines, while facile methods for linking carbohydrates to polymers or solid surfaces to produce diagnostic probes and functional microarrays are also sought. Here, we describe a simple, single-step method of producing glycosylhydrazides from unprotected sugars, which were then linked in a controlled manner to a desired carrier, through an appropriate linker. The method was chemoselective and did not require coupling reagents, and the native pyranose form of the reducing end residue was retained. Initially, mono- and disaccharide hydrazides were produced from the corresponding reducing sugars and linked to BSA through a bifunctional linker. Final exemplification of the procedure was demonstrated by the preparation of a LewisY tetrasaccharide protein conjugate, which was recognized by a LewisY monoclonal antibody indicating the preservation of the natural conformation of the tetrasaccharide in the final construct. It is envisaged that this method will have general applicability to a variety of functionally diverse reducing sugars and provide a route to highly defined glycoconjugates, without the need for elaborate synthetic strategies.

Experimental measurement of noncovalent interactions between halogens and aromatic rings.

Chemical double mutant cycles have been used to quantify the interactions of halogens with the faces of aromatic rings in chloroform. The halogens are forced over the face of an aromatic ring by an array of hydrogen-bonding interactions that lock the complexes in a single, well-defined conformation. These interactions can also be engineered into the crystal structures of simpler model compounds, but experiments in solution show that the halogen-aromatic interactions observed in the solid state are all unfavourable, regardless of whether the aromatic rings contain electron-withdrawing or electron-donating substituents. The halogen-aromatic interactions are repulsive by 1-3 kJ mol(-1). The interactions with fluorine are slightly less favourable than with chlorine and bromine.

Synthesis and biological activity of AM-112 and related oxapenem analogues.

Thirty five oxapenem analogues substituted with a range of tertiary groups at C-2 have been synthesised and evaluated as broad-spectrum beta-lactamase inhibitors. All analogues enhanced the activity of ceftazidime against bacterial isolates producing Class A and Class C beta-lactamases. Compounds with cyclic substituents at C-1' (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry at C-1' led to synergistic activity against beta-lactamase negative enterococci. (S) Stereochemistry at C-1' was associated with enhanced inhibition of Class A beta-lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum and not detectable following subcutaneous or oral dosing in mice. AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following oral dosing. AM-112 [(1'R,5R,6R)-2-(4-ammonio-1,1-dimethylbutyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] achieved the greatest protection of ceftazidime against Gram-negatives producing Class A or C beta-lactamases.

Novel and Efficient Isomerization of Allylic Alcohols Promoted by a Tetrapropylammonium Perruthenate Catalyst.

In the absence of an oxidant, tetrapropylammonium perruthenate (TPAP) is reduced by 2-undecanol to a low-valent ruthenium species that efficiently catalyzes the isomerization of a wide range of allylic alcohols into the corresponding saturated carbonyl derivatives [Eq. (1)]. R1, R2, R3, R4=alkyl, aryl, H.