Adsorption to the Surface of Hemozoin Crystals: Structure-Based Design and Synthesis of Amino-Phenoxazine ß-Hematin Inhibitors.

In silico adsorption of eight antimalarials that inhibit ß-hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly π-π interactions. A good correlation (r2 =0.64, P=0.017) between adsorption energies and the logarithm of ß-hematin inhibitory activity was found for this face. Of 53 monocyclic, bicyclic and tricyclic scaffolds, the latter yielded the most favorable adsorption energies. Five new amino-phenoxazine compounds were pursued as ß-hematin inhibitors based on adsorption behaviour. The 2-substituted phenoxazines show good to moderate ß-hematin inhibitory activity (<100 µM) and Plasmodium falciparum blood stage activity against the 3D7 strain. N1 ,N1 -diethyl-N4 -(10H-phenoxazin-2-yl)pentane-1,4-diamine (P2a) is the most promising hit with IC50 values of 4.7±0.6 and 0.64±0.05 µM, respectively. Adsorption energies are predictive of ß-hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure-based development of new non-quinoline inhibitors.

Facile synthesis of a C4-symmetrical inherently chiral calix[4]arene.

Inherently chiral calix[4]arenes with C4-symmetry are extremely rare and difficult to synthesise, severely hampering any effort to expand on their potential as chiral supramolecular catalysts and building blocks. Herein we report a reaction of a tetracarbamate calix[4]arene with NBS which results in a high yield of an inherently chiral calix[4]arenes with C4-symmetry. Furthermore, employing a chiral N-Boc proline moiety allows for separation of the diastereomers formed, thus obtaining the pure enantiomers after hydrolysis. The enantiomers could be assigned based on the CD spectra and DFT calculated values.

Attempted synthesis of a meta-metalated calix[4]arene.

An evidence for the formation of a rare meta-metalated inherently chiral calix[4]arene is described. Our strategy involved using a mesoionic carbene to direct C-H activation, but proved to form an unexpectedly unstable intermediate that was identified through high-resolution mass spectrometry. On route to our target, a new optimized method to mononitrocalix[4]arenes was developed, including optimized and high yielding transformations to azide and 1,2,3-triazole derivatives which may have application in other areas of research.

Inherently Chiral Calixarenes: Synthesis and Applications.

This article looks at the chemistry surrounding the concept of inherently chiral calixarenes (ICCs), whose synthesis and application have only recently being realised. One challenge in the area of ICC chemistry is the sheer breadth and scope for installing different aspects of inherent chirality. The aim of this article is not to cover every known method, but rather to give the reader an overview of the main themes that have emerged in this area, including more recent additions to the literature. This overview will also touch on the very limited reports on the applications of ICCs which give a glimpse into the potential these compounds may have in future studies.

Correction: Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space.

[This corrects the article DOI: 10.3762/bjoc.10.291.].

Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space.

The diastereoselective oxazoline-directed lithiation of calix[4]arenes is reported with diastereoselective ratios of greater than 100:1 in some instances. Notably, it has been found that the opposite diastereomer can be accessed via this approach merely through the choice of an alkyllithium reagent. The inherently chiral oxazoline calix[4]arenes have also been preliminarily examined as ligands in the palladium-catalyzed Tsuji-Trost allylation reaction, returning results comparable to their planar chiral ferrocene counterparts pointing towards future application of these types of compounds.

Manipulating the diastereoselectivity of ortholithiation in planar chiral ferrocenes.

The sense of asymmetric ortholithiation directed by a chiral oxazoline may be inverted simply by the choice of achiral ligand. Comparison of results with a number of ferrocenyl oxazoline derivatives suggests that lithiation takes place by coordination to the oxazoline nitrogen irrespective of the ligand used.

Synthesis of inherently chiral calix[4]arenes: stereocontrol through ligand choice.

Employing a chiral oxazoline as an ortholithiation directing group allows the synthesis of inherently chiral calix[4]arenes suitable for elaboration into planar chiral molecules. An important finding has been that the diastereoselectivity of the reaction can be tuned by the choice of additive. These results have bearing on the elucidation of the general mechanism of oxazoline-directed ortholithiation.

Transient chirality in a distal-substituted resorcinarene metal complex.

A novel distal bidentate S/S resorcinarene ligand has been synthesised and a bis-mu-chloro-bridged palladium(II) complex obtained. The solid state structure for this complex represents the first crystal structure evidence for a bispalladium-mu-chloro-bridged complex bound to thioether ligands. Furthermore, solution NMR studies revealed conformational changes in the flexible resorcinarene ligand and discreet transient chirality around the sulfur centres.

An asymmetric ortholithiation approach to inherently chiral calix[4]arenes.

A general asymmetric synthesis of inherently chiral calix[4]arenes is described: using a chiral oxazoline derived from L-valine, an ortholithiation strategy is employed to give inherently chiral calix[4]arenes with high (93%) enantiomeric excesses. A crystal structure of a phosphine oxide intermediate has been obtained, unambiguously assigning the major diastereomer in the reaction; a mechanism explaining this result is proposed.