Addition of Vindoline to p-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations

Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.

Identifying conformational isomers of organic molecules in solution via unsupervised clustering

<p>We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterised by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the fast search and find of density peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that, while Sildenafil can adopt more than one hundred metastable conformational configurations, only 12 are significantly populated across all the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.</p>

Identifying conformational isomers of organic molecules in solution via unsupervised clustering

<p>We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterised by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the fast search and find of density peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that, while Sildenafil can adopt more than one hundred metastable conformational configurations, only 12 are significantly populated across all the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.</p>

A Size-Matching Strategy to Differentiate Flexible Conformers for the Discovery of Novel Cages with Twin Cavities

<p>Considerable efforts have been made to characterize the meaningful conformers that a molecule can adopt, which is of great significance for understanding the structure-property correlation in the fileds of molecular biology, drug discovery, catalysis, materials science, etc. It is however challenging to differentiate and make use of the flexible conformers in solution, as they often experience rapid interconversion due to low isomerization barrier. We herein present a novel yet simple size-matching strategy for conformation identification. As a proof of concept, we rationally designed a three-dimensional model compound, namely hexaformyl molecule <b>1 </b>exhibiting two types of conformers, <i>i.e.</i> <b>Conformer-1</b> and -<b>2</b> with different cleft positions and sizes. Aided by DFT calculations, we selected two triamino conformation capturers (denoted CC). Small-sized <b>CC-1</b> selectively captured <b>Conformer-1</b> by matching its cleft size, while large-sized <b>CC-2</b> was able to match and capture both conformers. It therefore allowed facile differentiation of the two conformations by conventional NMR and X-ray analyses. These two erstwhile inverconverting and indistinguishable conformational isomers were made use of, leading to the discovery of two novel configurational isomers, namely two novel cage-like compounds with twin cavities, one exhibiting a sandglass-shaped and another with a dumbbell form, which we coined <i>diphane.</i></p>

A Size-Matching Strategy to Differentiate Flexible Conformers for the Discovery of Novel Cages with Twin Cavities

<p>Considerable efforts have been made to characterize the meaningful conformers that a molecule can adopt, which is of great significance for understanding the structure-property correlation in the fileds of molecular biology, drug discovery, catalysis, materials science, etc. It is however challenging to differentiate and make use of the flexible conformers in solution, as they often experience rapid interconversion due to low isomerization barrier. We herein present a novel yet simple size-matching strategy for conformation identification. As a proof of concept, we rationally designed a three-dimensional model compound, namely hexaformyl molecule <b>1 </b>exhibiting two types of conformers, <i>i.e.</i> <b>Conformer-1</b> and -<b>2</b> with different cleft positions and sizes. Aided by DFT calculations, we selected two triamino conformation capturers (denoted CC). Small-sized <b>CC-1</b> selectively captured <b>Conformer-1</b> by matching its cleft size, while large-sized <b>CC-2</b> was able to match and capture both conformers. It therefore allowed facile differentiation of the two conformations by conventional NMR and X-ray analyses. These two erstwhile inverconverting and indistinguishable conformational isomers were made use of, leading to the discovery of two novel configurational isomers, namely two novel cage-like compounds with twin cavities, one exhibiting a sandglass-shaped and another with a dumbbell form, which we coined <i>diphane.</i></p>

Surface-mediated ordering of pristine Salen molecules on coinage metals

The conformational isomers of Salen molecules and their self-assembled structures on coinage metal surfaces.

Hydrogen evolution, electron-transfer, hydride-transfer reactions in a nickel-iron hydrogenase model complex: A theoretical study of the distinctive reactivities for the conformational isomers of nickel-iron hydride

Hydrogen fuel is a promising alternative to fossil fuel. Therefore, efficient hydrogen production is crucial to elucidate the distinctive reactivities of metal hydride species, the intermediates formed during hydrogen activation/evolution...