The absolute stereochemistry of grenadamide

3-(2S-Heptylcycloprop-1S-yl)propanoic acid 2-phenylethanamide was synthesised from cis-cyclopropan-1,2-dimethanol via enzymatic desymmetrisation of the dibutyrate; it gave identical NMR spectroscopic data to those reported for grenadamide but had an equal and opposite absolute rotation, indicating that the latter is the 2R,1R-enantiomer.     

The absolute stereochemistry of crotonitenone

The configuration at C—4 of the novel casbenoid diterpene, crotonitenone (3), was determined by Horeau's method as (R) — hence the absolute stereochemistry of the molecule is as written in (3).     

Determination of the absolute stereochemistry of Etzionin

The absolute configuration of Etzionin, a marine peptide-like compound isolated in 1989 from a red tunicate collected from the Red Sea has been determined by a combination of synthetic and spectroscopic procedures. Finally, its absolute stereochemistry has been established as 3S,3′R.     

Determination of absolute stereochemistry of panaxynol

Absolute stereochemistry of panaxynol was determined by exciton chirality method. The circular dichroism spectra of panaxynol p-bromobenzoate and p-dimethylaminobenzoate show the negative exciton chirality at λ_ext indicating the S configuration of the chiral center.     

Synthesis and absolute stereochemistry of roseophilin

The enantiospecific total synthesis of natural roseophilin has been completed in 7.0% overall yield over 15 steps by means of an asymmetric cyclopentannelation. This establishes the absolute configuration of the natural product as 22R,23R. Cyclopentenone (+)-12 was prepared in 78% yield and 86% ee in the key step.     

The absolute stereochemistry of cascarillic acid

((1S,2R)-2-Hexylcycloprop-1-yl)acetic acid has been synthesised from cis-1,2-dihydroxymethylcyclopropane and shown to be identical to cascarillic acid obtained from cascarilla essential oil.     

The effect of structural redundancy in validation sets on virtual screening performance

The performance of a classification model is often assessed in terms of how well it separates a set of known observations into appropriate classes. If the validation sets used for such analyses are redundant due to bias in sampling, the relevance of the conclusions drawn to prospective work in which new kinds of positives are sought may be compromised. In the case of the various virtual screening techniques used in modern drug discovery, such bias generally appears as over‐representation of particular structural subclasses in the test set. We show how clustering by substructural similarity, followed by applying arithmetic and harmonic weighting schemes to receiver operating characteristic (ROC) curves, can be used to identify validation sets that are biased due to such redundancies. This can be accomplished qualitatively by direct examination or quantitatively by comparing the areas under the respective linear or semilog curves (AUCs or pAUCs). Copyright © 2009 John Wiley & Sons, Ltd.     

Revised absolute stereochemistry of natural kulokekahilide-2

Kulokekahilide-2 is a potent cytotoxic depsipeptide isolated from the Hawaiian marine mollusk Philinopsis speciosa. The structure of kulokekahilide-2 was reported to be composed of five amino acids (l-Ala, l-Ile, MeGly, l-MePhe, d-Ala) and two hydroxy acids (d-Hica, 5S,6S,7S-Dtda); however, following its total synthesis, the ¹H NMR spectrum of the synthetic compound was found to be different from that of the natural one, suggesting that the stereochemistry of the reported structure was incorrect. To determine the stereochemistry of the natural compound, arrays of analogues have been prepared using different sets of chiral amino acids, and the absolute stereochemistry of kulokekahilide-2 has been unambiguously confirmed to involve the combination 21-l-Ala, 24-d-MePhe, and 43-d-Ala.     

Total synthesis and absolute stereochemistry of plakortone D

The first total synthesis of plakortone D is described and thereby establishes the structure and absolute stereochemistry of the most biologically active member of the marine-derived plakortone family. The sterically congested bicyclic lactone core results from a Pd(II)-induced hydroxycyclization-carbonylation-lactonization sequence on an enediol whose chirality was installed by AD-technology. Attachment of the side chain, also constructed using AD-methodology, was achieved by using a modified Julia coupling. The described approach enables acquisition of other plakortones and analogues, in the correct (natural) stereochemical series.     

Total synthesis and absolute stereochemistry of plakortone E

The absolute stereochemistry of plakortone E, a cytotoxic metabolite of the Caribbean sponge, was established to be 1, by the synthesis of the racemic C-8 epimer (±)-2 and then of (−)-1 itself, which was identical with the natural compound.     

On the absolute stereochemistry of C-2 and C-3 in stegobinone

By comparison of the CD-spectra of synthetic material with that of stegobinone it is established that stegobinone has the 2S, 3R-configuration. The stereochemistry at C-7 remains unknown at present.     

Computational investigation on stereochemistry in titanium-salicylaldehydes-catalyzed cyanation of benzaldehyde

Theoretical simulation on the enantioselective cyanation of benzaldehyde over titanium-salicylaldehyde catalysts is performed with B3LYP//ONIOM methods. The calculations predict that the attack of cyanide to adsorbed benzaldehyde is the rate-determining step for the entire reaction. The stereochemistry of the titled reaction might be controlled not only by the attack directions of cyanide to benzaldehyde but also by different coordination modes of benzaldehyde to the chiral catalysts. In addition, to evaluate the accuracy of the employed method, the stereoselectivities of the reactions with five different chiral ligands are theoretically predicted. The theoretical predictions are qualitatively in agreement with experiments, and a linear relationship between calculated Delta DeltaG(double dagger) and experimental ones is obtained, especially for the reactions using the ligands with a single chiral center.     

Synthesis of detoxininolactone derivatives and the revised absolute stereochemistry of detoxinine

A stereospecific synthesis of acetyl-$\text{L}$-valyl-detoxininolactone has been performed and the absolute stereochemistry of detoxinine has been revised to (2$\text{S}$, 3$\text{R}$, 1′$\text{S}$)-2-(2′-carboxy-1′-hydroxyethyl)-3-hydroxypyrrolidine.     

Total synthesis of amaminol A: establishment of the absolute stereochemistry

The first synthetic route to amaminol A with use of an organocatalytic intramolecular Diels-Alder reaction is reported. The absolute stereochemistry is proven with a crystallographic image of a cyclic carbamate of amaminol A.     

Revised structure of tetrapetalone A and its absolute stereochemistry

The chemical structure of tetrapetalone A (1), a novel lipoxygenase inhibitor from Streptomyces sp., was revised by using the ¹H-¹⁵N HMBC technique. Furthermore, the absolute stereochemistry of all the asymmetric carbons in 1 was determined based on the detailed NOE data of 1 and its derivative.     

Computational screening for active compounds targeting protein sequences: methodology and experimental validation

The three-dimensional (3D) structures of most protein targets have not been determined so far, with many of them not even having a known ligand, a truly general method to predict ligand-protein interactions in the absence of three-dimensional information would be of great potential value in drug discovery. Using the support vector machine (SVM) approach, we constructed a model for predicting ligand-protein interaction based only on the primary sequence of proteins and the structural features of small molecules. The model, trained by using 15,000 ligand-protein interactions between 626 proteins and over 10,000 active compounds, was successfully used in discovering nine novel active compounds for four pharmacologically important targets (i.e., GPR40, SIRT1, p38, and GSK-3β). To our knowledge, this is the first example of a successful sequence-based virtual screening campaign, demonstrating that our approach has the potential to discover, with a single model, active ligands for any protein.