Stereochemical Variation Research Articles

Expanding Complex Morpholines Using Systematic Chemical Diversity.

The morpholine heterocycle is a structural unit found in many bioactive compounds and FDA-approved drugs, but the generation of more complex C-functionalized morpholine derivatives remains considerably underexplored. Using systematic chemical diversity (SCD), a concept that guides the expansion of saturated drug-like scaffolds through regiochemical and stereochemical variation, we describe the synthesis of a collection of methyl-substituted morpholine acetic acid esters starting from enantiomerically pure amino acids and amino alcohols. In total, 24 diverse substituted morpholines were produced that vary systematically in regiochemistry and stereochemistry (relative and absolute). These diverse C-substituted morpholines can be directly applied in fragment screening or incorporated as building blocks in medicinal chemistry and library synthesis.

Chirality Bias Tissue Homeostasis by Manipulating Immunological Response.

The physiological chirality of extracellular environments is substantially affected by pathological diseases. However, how this stereochemical variation drives host immunity remains poorly understood. Here, it is reported that pathology-mimetic M-nanofibrils-but not physiology-mimetic P-nanofibrils-act as a defense mechanism that helps to restore tissue homeostasis by manipulating immunological response. Quantitative multi-omics in vivo and in vitro shows that M-nanofibrils significantly inhibit inflammation and promote tissue regeneration by upregulating M2 macrophage polarization and downstream immune signaling compared with P-nanofibrils. Molecular analysis and theoretical simulation demonstrate that M-chirality displays higher stereo-affinity to cellular binding, which induces higher cellular contractile stress and activates mechanosensitive ion channel PIEZOl to conduct Ca2+ influx. In turn, the nuclear transfer of STAT is biased by Ca2+ influx to promote M2 polarization. These findings underscore the structural mechanisms of disease, providing design basis for immunotherapy with bionic functional materials.

Semi-automated separation of the epimeric dehydropyrrolizidine alkaloids lycopsamine and intermedine: preparation of their N-oxides and NMR comparison with diastereoisomeric rinderine and echinatine.

The diversity of structure and, particularly, stereochemical variation of the dehydropyrrolizidine alkaloids can present challenges for analysis and the isolation of pure compounds for the preparation of analytical standards and for toxicology studies. To investigate methods for the separation of gram-scale quantities of the epimeric dehydropyrrolizidine alkaloids lycopsamine and intermedine and to compare their NMR spectroscopic data with those of their heliotridine-based analogues echinatine and rinderine. Lycopsamine and intermedine were extracted, predominantly as their N-oxides and along with their acetylated derivatives, from commercial samples of comfrey (Symphytum officinale) root. Alkaloid enrichment involved liquid-liquid partitioning of the crude methanol extract between dilute aqueous acid and n-butanol, reduction of N-oxides and subsequent continuous liquid-liquid extraction of free base alkaloids into CHCl3 . The alkaloid-rich fraction was further subjected to semi-automated flash chromatography using boronated soda glass beads or boronated quartz sand. Boronated soda glass beads (or quartz sand) chromatography adapted to a Biotage Isolera Flash Chromatography System enabled large-scale separation (at least up to 1-2 g quantities) of lycopsamine and intermedine. The structures were confirmed using one- and two-dimensional (1) H- and (13) C-NMR spectroscopy. Examination of the NMR data for lycopsamine, intermedine and their heliotridine-based analogues echinatine and rinderine allowed for some amendments of literature data and provided useful comparisons for determining relative configurations in monoester dehydropyrrolizidine alkaloids. A similar NMR comparison of lycopsamine and intermedine with their N-oxides showed the effects of N-oxidation on some key chemical shifts. A levorotatory shift in specific rotation from +3.29° to -1.5° was observed for lycopsamine when dissolved in ethanol or methanol respectively. A semi-automated flash chromatographic process using boronated soda glass beads was standardised and confirmed as a useful, larger scale preparative approach for separating the epimers lycopsamine and intermedine. The useful NMR correlations to stereochemical arrangements within this specific class of dehydropyrrolizidine alkaloid cannot be confidently extrapolated to other similar dehydropyrrolizidine alkaloids. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Modification of bipolar lipid conformation at the air/water interface by a single stereochemical variation

This article describes the design and the synthesis of two analogues of archaeal bipolar lipids that differ only by the configuration of a single stereogenic centre on a glyceryl moiety. The corresponding comparative physicochemical study by tensiometry/ellipsometry and atomic force microscopy provided a set of data that points out the effect of this single stereochemical variation. The two epimers revealed different conformations at the air/water interface resulting in a more or less tendency for a bent or a stretched conformation. It strengthens the importance of the stereochemistry in such bipolar lipid packing.

Sesquiterpene lactone stereochemistry influences herbivore resistance and plant fitness in the field.

Stereochemical variation is widely known to influence the bioactivity of compounds in the context of pharmacology and pesticide science, but our understanding of its importance in mediating plant-herbivore interactions is limited, particularly in field settings. Similarly, sesquiterpene lactones are a broadly distributed class of putative defensive compounds, but little is known about their activities in the field. Natural variation in sesquiterpene lactones of the common cocklebur, Xanthium strumarium (Asteraceae), was used in conjunction with a series of common garden experiments to examine relationships between stereochemical variation, herbivore damage and plant fitness. The stereochemistry of sesquiterpene lactone ring junctions helped to explain variation in plant herbivore resistance. Plants producing cis-fused sesquiterpene lactones experienced significantly higher damage than plants producing trans-fused sesquiterpene lactones. Experiments manipulating herbivore damage above and below ambient levels found that herbivore damage was negatively correlated with plant fitness. This pattern translated into significant fitness differences between chemotypes under ambient levels of herbivore attack, but not when attack was experimentally reduced via pesticide. To our knowledge, this work represents only the second study to examine sesquiterpene lactones as defensive compounds in the field, the first to document herbivore-mediated natural selection on sesquiterpene lactone variation and the first to investigate the ecological significance of the stereochemistry of the lactone ring junction. The results indicate that subtle differences in stereochemistry may be a major determinant of the protective role of secondary metabolites and thus of plant fitness. As stereochemical variation is widespread in many groups of secondary metabolites, these findings suggest the possibility of dynamic evolutionary histories within the Asteraceae and other plant families showing extensive stereochemical variation.

Stereochemistry affects sesquiterpene lactone bioactivity against an herbivorous grasshopper

Sesquiterpene lactones are defensive compounds which protect plants against a variety of herbivores and other natural enemies. Sesquiterpene lactones from higher plants can be divided into two groups based on the stereochemistry of their lactone ring junction, either cis-fused or trans-fused. It is unclear whether and how this variation affects potentially important ecological interactions. To investigate whether stereochemical variation in sesquiterpene lactone ring junctions can influence resistance to herbivorous insects, we performed controlled feeding trials with two pairs of diastereomeric sesquiterpene lactones and examined the deterrent effect of each compound on feeding by the polyphagous grasshopper Schistocerca americana (Drury). Sesquiterpene lactone stereochemistry and concentration significantly influenced feeding behavior with grasshoppers consuming less of the trans-fused compounds than the cis-fused compounds. To our knowledge, this is the first demonstration that sesquiterpene lactone ring junction stereochemistry influences the feeding behavior of herbivores. Because this stereochemical trait polymorphism is widely distributed in nature, it could have substantial consequences for the ecology and evolution of large groups of plants, particularly the Asteraceae.

Collapsed bipolar glycolipids at the air/water interface: Effect of the stereochemistry on the stretched/bent conformations

This article describes a comparative study of several bipolar lipids derived from tetraether structures. The sole structural difference between the main two glycolipids is a unique stereochemical variation on a cyclopentyl ring placed in the middle of the lipids. We discuss the comparative results obtained at the air/water interface on the basis of tensiometry and ellipsometry. Langmuir-Blodgett depositions during lipid film compressions and decompressions were also analyzed by AFM. The lactosylated tetraether (bipolar) lipid structures involved the formation of highly stable multilayers, which are still present at 10 mN m(-1) during decompression. This study suggests also that the stereochemistry of a central cyclopentyl ring dramatically drives the conformation of the corresponding bipolar lipids. Both isomers (trans and cis) adopt a U-shaped (bent) conformation at the air/water interface but the trans cyclopentyl ring induces a much more frustration within this type of conformation. Consequently, this bipolar lipid (trans-tetraether) undergoes a flip of one polar head-group (lactosyl) leading to a stretched conformation during collapse.

Highly Diastereoselective Total Syntheses of (+)‐7‐Epigoniodiol, (−)‐8‐Epigoniodiol, and (+)‐9‐Deoxygoniopypyrone

AbstractAn expedient concise total synthesis of (+)‐7‐epigoniodiol, (−)‐8‐epigoniodiol, and (+)‐9‐deoxygoniopypyrone is accomplished. The key transformations include a catalytic hydroxylation and base‐mediated N‐(acetyl)oxazolidinone addition reactions, which could set the consecutive OH motif that is either syn,syn or syn,anti with high diastereoselectivity. Moreover, this approach envisioned to facilitate the synthesis of other representatives of the family with structural and stereochemical variation.

Functional characterization of wheat copalyl diphosphate synthases sheds light on the early evolution of labdane-related diterpenoid metabolism in the cereals

Two of the most agriculturally important cereal crop plants are wheat (Triticum aestivum) and rice (Oryza sativa). Rice has been shown to produce a number of diterpenoid natural products as phytoalexins and/or allelochemicals--specifically, labdane-related diterpenoids, whose biosynthesis proceeds via formation of an eponymous labdadienyl/copalyl diphosphate (CPP) intermediate (e.g., the ent-CPP of gibberellin phytohormone biosynthesis). Similar to rice, wheat encodes a number of CPP synthases (CPS), and the three CPS characterized to date (TaCPS1-3) all have been suggested to produce ent-CPP. However, several of the downstream diterpene synthases will only react with CPP intermediate of normal or syn, but not ent, stereochemistry, as described in the accompanying report. Investigation of additional CPS did not resolve this issue, as the only other functional synthase (TaCPS4) also produced ent-CPP. Chiral product characterization of all the TaCPS then established that TaCPS2 uniquely produces normal, rather than ent-, CPP, thus, providing a suitable substrate source for the downstream diterpene synthases. Notably, TaCPS2 is most homologous to the similarly stereochemically differentiated syn-CPP synthase from rice (OsCPS4), while the non-inducible TaCPS3 and TaCPS4 cluster with the rice OsCPS1 required for gibberellin phytohormone biosynthesis, as well as with a barley (Hordeum vulgare) CPS (HvCPS1) that also is characterized here as similarly producing ent-CPP. These results suggest that diversification of labdane-related diterpenoid metabolism beyond the ancestral gibberellins occurred early in cereal evolution, and included the type of stereochemical variation demonstrated here.

A flexible organocatalytic enantioselective synthesis of heptadeca-1-ene-4,6-diyne-3S,8R,9S,10S-tetrol and its congeners

A unified enantioselective route is developed for the synthesis of heptadeca-1-ene-4,6-diyne-3S,8R,9S,10S-tetrol and its synthetic congeners. A proline-catalyzed aminoxylation, cross-metathesis, Wittig reaction, and catalytic dihydroxylation are key steps of this synthesis. This new approach is envisioned to facilitate the synthesis of every representative member of the family with skeletal and stereochemical variation.

Regioselective Intramolecular Dipolar Cycloaddition of Azides and Unsymmetrical Alkynes

Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions, resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient access to compounds containing significant structural and stereochemical variation.

Stereochemical and Skeletal Diversity Employing Pipecolate Ester Scaffolds

[structure: see text] The stereocontrolled synthesis of pyridooxazinones by Mg(OTf)2-promoted epoxide ring-opening with use of chiral pipecolates as nucleophiles is described. Pyridooxazinone products derived from azido-epoxides can be further rearranged to seven-membered pyridodiazepinones by azide reduction. The sequence of functional group interconversions generates diversity through topological and stereochemical variation.

Profiling of Carotenoids in Tomato Juice by One- and Two-Dimensional NMR

Epidemiological data have shown a link between dietary intake of tomatoes and tomato products (rich in carotenoids) and a decreased risk of chronic diseases. The carotenoid profile in tomato products depends on tomato variety as well as the thermal conditions used in processing. The final carotenoid profile may affect the bioaccessibility and bioavailability of these biomolecules. Therefore, nondestructive, reliable methods are needed to characterize the structural and stereochemical variation of carotenoids. CDCl(3) rapid extraction was used to extract carotenoids from tomato juice as an alternative rapid procedure that minimizes solvents and time consumption prior to NMR analysis. The profile of these biomolecules was characterized by application of high-resolution multidimensional NMR techniques using a cryogenic probe. The combination of homonuclear and heteronuclear two-dimensional NMR techniques served to identify (all-E)-, (5Z)-, (9Z)-, and (13Z)-lycopene isomers and other carotenoids such as (all-E)-beta-carotene and (15Z)-phytoene dissolved in the extracted lipid mixture. The use of one-dimensional NMR enabled the rapid identification of lycopene isomers, thereby minimizing further isomerization of (all-E)-lycopene as compared to HPLC data. On the basis of the assignments accomplished, the carotenoid profile of typical tomato juice was successfully determined with minimal purification procedures.

Four Orders of Magnitude Rate Increase in Artificial Enzyme-Catalyzed Aryl Glycoside Hydrolysis

[reaction: see text] (6AR,6DR)-6A,6D-Di-C-cyano-beta-cyclodextrin (1) and 6A,6D-di-C-cyano-alpha-cyclodextrin (2) were synthesized and shown to catalyze hydrolysis of aryl glycosides into glucose and phenol with a reaction following Michaelis-Menten kinetics. At pH 8.0 and 59 degrees C hydrolysis of 4-nitrophenyl alpha-glucopyranoside was catalyzed by 1 with KM = 10.5 +/- 1.5 mM, kcat = 1.42(+/-0.09) x 10(-4) s(-1), and kcat/kuncat = 7922. Catalysis was observed with a concentration of 1 as low as 10 microM. Hydrolysis of the other aryl glycosides containing stereochemical variation in the sugar-moiety and 4-nitro-, 2-nitro-, 2-aldehydo-, and 2,4-dinitro- were also catalyzed by 1 and 2 with kcat/kuncat ranging from 4 to 7100. Hydrolysis of a phenyl beta-d-glucoside or the thioglycoside tolylthio beta-D-glucoside was also catalyzed. From a series of prepared analogues of 1 it was found that the catalysis was associated with the hydroxyl groups alpha to the nitril groups. The monocyanohydrin 6-C-cyano-beta-cyclodextrin (3) was also found to catalyze the hydrolysis of 4-nitrophenyl beta-glucopyranoside with kcat/kuncat = 1356. It was proposed that the cyclodextrin cyanohydrins 1-3 catalyze the hydrolysis by general acid catalysis on the bound substrate.

Xylopyranoside-based agonists of d- myo-inositol 1,4,5-trisphosphate receptors: synthesis and effect of stereochemistry on biological activity

The synthesis of a series of tetrahydrofuranyl α- and β-xylopyranoside trisphosphates, designed by excision of three motifs of adenophostin A is reported. The synthetic route features improved preparations of allyl α- d-xylopyranoside and its 2- O-benzyl ether, and gives access to four diastereoisomeric trisphosphates, which show a range of abilities to mobilise Ca 2+ from the intracellular stores of hepatocytes. A comparison of the potencies of the four trisphosphates provides useful information relating to the effects of stereochemical variation on the recognition of carbohydrate-based trisphosphates by d- myo-inositol 1,4,5-trisphosphate receptors. 1- O-[(3′ S,4′ R)-3-hydroxytetrahydrofuran-4-yl] α- d-xylopyranoside 3,4,3′-trisphosphate ( 8) is the most active member of the series with a potency close to Ins(1,4,5)P 3; a β-linked analogue, 1- O-[(3′ R,4′ S)-3-hydroxytetrahydrofuran-4-yl] β- d-xylopyranoside 3,4,3′-trisphosphate, is ca. 20-fold weaker than Ins(1,4,5)P 3, and the other compounds are much less active. While no compound attained a potency close to that of adenophostin A, we believe that 8 represents the minimal structure for potent Ca 2+-releasing activity in this type of carbohydrate-based analogue.

A modular synthetic approach toward exhaustively stereodiversified ligand libraries.

[structure] This report describes a modular approach to the synthesis of stereodiversified natural product-like libraries. Monomers 2 and 3 were coupled in parallel by silyl-tethered olefin metathesis to generate all 16 stereoisomers of cis-enediols 1. All 16 stereoisomers were incorporated into chimerae having flanking peptidic segments. These chimerae exhibited a broad range of hydrophobicities, raising the possibility that stereochemical variation might be used to tune the pharmacologic properties of small molecules.

The Thioesterase of the Erythromycin-Producing Polyketide Synthase: Influence of Acyl Chain Structure on the Mode of Release of Substrate Analogues from the Acyl Enzyme Intermediates.

The production of genetically engineered polyketides depends critically on thioesterase activity for product release. In vitro studies with the thioesterase from the erythromycin polyketide synthase (PKS) have demonstrated that the ability of this enzyme to act as a universal decoupler is limited, but stereochemical variation is readily tolerated. Synthetic analogues with all four stereochemical configurations of the natural substrate's 2-methyl-3-hydroxy substitution pattern (1-4; X=p-nitrophenoxy) were substrates for the enzyme.

Reagent-specific electrostatic effects on electrophilic .pi.-facial stereoselectivity. Interpretation of the stereochemical variation of electrophilic additions to 7-isopropylidenebenzonorbornenes

Electrostatic interactions account for the stereochemical variations in electrophilic additions to 7-isopropylidenebenzonorbornenes. Didferent electrophilic reagents have very different electrostatic profiles. This conclusion is supported by electrostatic potential analyses of 7-methylenenorbornene and 7-methylenebenzonorbornene or by calculations on the interactions of point charges with the two faces of the π system

A notable stereochemical variation in the 2+2+2 annulation reaction

On prepare l'epiaflavine par annelations multiples a partir du citronellol et de la methyl-4cyclohexene-2one

Stereochemical basis of anticonvulsant drug action. VI. Crystal and molecular structure of diphenylsilanediol

The crystal and molecular structure of diphenylsilanediol, a compound with recently demonstrated anticonvulsant activity, has been determined and its stereochemistry compared with other antiepileptics. Crystals of diphenylsilanediol are triclinic, space group [Formula: see text] with cell dimensions a = 9.912, b = 15.048, c = 14.519 Å, α = 120.83,β = 99.95, γ = 100.84°, Z = 6 molecules per cell (3 molecules per asymmetric unit). The structure was determined by Patterson and Fourier methods and refined to a final discrepancy value R = 0.034. The phenyl ring planes in the molecule are rotated by 80° with respect to each other, and the hydroxyl oxygen atoms are 2.66 Å apart. The molecular parameters help to delineate limits of stereochemical variation in these molecules with retention of anticonvulsant activity.