Assignment Of Relative Stereochemistry Research Articles

Brønsted Acid-Promoted Cyclodimerization of α,β-Unsaturated γ-Ketoesters: Construction of Fused Pyrano-ketal-lactones and γ-Ylidene-butenolides.

Unprecedented MsOH-promoted diastereoselective cascade dimerization and intramolecular lactonization of readily accessible α,β-unsaturated γ-ketoesters are presented. The results obtained in this work, control experiments, and density functional theory (DFT) calculations suggested that the initial enolization and E to Z isomerization/equilibration of olefin (C=C) of substrate α,β-unsaturated γ-ketoesters give a Z-isomer preferentially over an E-isomer. Subsequently, the Z-isomer undergoes intermolecular annulation with α,β-unsaturated γ-ketoesters via domino Michael addition/ketalization/lactonization steps to furnish fused tetracyclic pyrano-ketal-lactone. However, the Z-isomer prefers intramolecular trans-esterification in a competing pathway and gives bicyclic γ-ylidene-butenolide. The key features of this work include simple Brønsted acid catalysis, the formation of three bonds, two rings, and three contiguous stereogenic centers in a single step, DFT calculations, and the assignment of relative stereochemistry through X-ray diffraction (XRD) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses.

Synthesis of the C28-C41 Side Chain of (Proposed) Neaumycin B: AContiguous Stereohextet.

The C28-C41 side-chain of the proposed structure of neaumycin B, which encompasses a contiguous stereohextet, is prepared in 8 steps (longest linear sequence). Convergency is maximized via Williams' Felkin-Anh-selective triorganozincate-mediated vinylation of an α,β-stereogenic aldehyde. The relative stereochemical assignment of the C33-C35 stereotriad was accomplished via the 13C NMR analysis of the related acetonide. Relative stereochemistry of C33 carbinol and C36-C37 glycidol was determined by comparative NOE analysis of the related diastereomeric furans.

Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2-trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid.

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

Relative stereochemical assignment of C-33 and C-35 in the antibiotic gladiolin

Gladiolin is a macrolide antibiotic isolated from Burkholderia gladioli BCC0238 with promising activity against Mycobacterium tuberculosis, including several multidrug resistant strains. The configuration of all but one of the stereogenic centers of gladiolin has previously been elucidated using a combination of NOESY NMR experiments and predictive sequence analysis of the polyketide synthase responsible for its assembly. However, it was not possible to assign the configuration of the C-35 methyl group using such methods. Here we report the synthesis of C-33/C-35-syn and C-33/C-35-anti mimics of the C-30 to C-38 fragment of gladiolin from (R) and (S)-citronellol, respectively. Comparison of HSQC NMR data for the mimics and the natural product showed that the C-35 methyl is anti to the C-33 hydroxyl group, indicating that gladiolin has the 35S configuration.

A synthesis-enabled relative stereochemical assignment of the C1-C28 region of hemicalide.

Through synthesising both candidate diastereomers of a model C1-C28 fragment of the potent cytotoxic marine polyketide hemicalide, an assignment of the relative configuration between the C1-C15 and C16-C26 regions has been achieved. By detailed NMR comparisons with the natural product, the relative stereochemistry between these two 1,6-related stereoclusters is elucidated as 13,18-syn rather than the previously proposed 13,18-anti relationship. A flexible and modular strategy using an advanced C1-C28 ketone fragment 22 is outlined to elucidate the remaining stereochemical features and achieve a total synthesis.

Epoxynemanione A, nemanifuranones A–F, and nemanilactones A–C, from Nemania serpens, an endophytic fungus isolated from Riesling grapevines

Ten polyketide specialized metabolites, epoxynemanione A, nemanifuranones A–F, and nemanilactones A–C, were isolated from the culture filtrate of Nemania serpens (Pers.) Grey (1821), an endophytic fungus from a Riesling grapevine (Vitis vinifera) found in Canada's Niagara region. Additionally, four known metabolites 2-(hydroxymethyl)-3-methoxy-benzoic acid, phyllostine, 5-methylmellein and a nordammarane triterpenoid were isolated. A related known metabolite 2,3-dihydro-2-hydroxy-2,4-dimethyl-5-trans-propenylfuran-3-one has also been included for structural and biological comparison to the nemanifuranones. The latter was isolated from the culture filtrates of Mollisia nigrescens, an endophytic fungus from the leaves and stems of lowbush blueberry (Vaccinium angustifolium) found in the Acadian forest of Nova Scotia, Canada. Their structures were elucidated based on 1D and 2D NMR, HRESIMS measurements, X-ray crystallographic analysis of nemanifuranone A, the nordammarane triterpenoid and 2,3-dihydro-2-hydroxy-2,4-dimethyl-5-trans-propenylfuran-3-one compounds, and comparison of NOE and vicinal 1H-1H coupling constants to literature data for relative stereochemical assignments. Nemanifuranone A possesses a rare C2 hemiacetal and was active against both Gram-negative and Gram-positive bacteria.

A NMR method for relative stereochemical assignments of the tricyclic core of cephalosporolides, penisporolides and related synthetic analogues

A new NMR method is developed to discriminate the four possible diastereomeric SAFLs, leading to revisions of 11 synthetic compounds.

Regio‐ and Diastereoselective CC Coupling of α‐Olefins and Styrenes to 3‐Hydroxy‐2‐oxindoles by Ru‐Catalyzed Hydrohydroxyalkylation

Regio‐ and Diastereoselective CC Coupling of α‐Olefins and Styrenes to 3‐Hydroxy‐2‐oxindoles by Ru‐Catalyzed Hydrohydroxyalkylation

Stereoselective Synthesis of the Butyrolactone and the Oxazoline/Furan Fragment of Leupyrrin A1

Stereoselective syntheses of the Northern and the Southern fragments 2 and 3 of leupyrrin A1 are reported. The convergent preparation of 2 is highlighted by a zirconocene-mediated one-pot cyclization-regioselective opening of an advanced diyne while the route to 3 involves a Krische allylation and a one-pot Sharpless dihydroxylation-cyclization. Comparison of the spectroscopic data with those reported for the natural product supports a relative stereochemical assignment within these heterocycles.

Potentially Biomimetic Total Synthesis and Relative Stereochemical Assignment of (±)‐Gracilamine

Gracil(e): The total synthesis of gracilamine features a potentially biomimetic intramolecular [3+2] cycloaddition to assemble its two fused five-membered rings and a debenzylation/ring-opening reaction to obtain the aldehyde intermediate (see scheme). The success of this synthesis provides a circumstantial evidence that supports the biosynthesis pathway of gracilamine proposed previously. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Potentially Biomimetic Total Synthesis and Relative Stereochemical Assignment of (±)‐Gracilamine

Potentially Biomimetic Total Synthesis and Relative Stereochemical Assignment of (±)‐Gracilamine

Absolute stereochemistry and conformational analysis of achaetolide isolated from Ophiobolus sp.

Achaetolide, as reported by Bodo et al. in 1983, was isolated from a fermentation broth of Ophiobolus sp. We established the absolute stereochemistry of achaetolide to be 3 S,6 R,7 S,9 R by way of relative stereochemical assignment with 1H NMR analyses employing the corresponding acetonide, determination of C3 and C9 stereochemistries by an extended Mosher method.

NMR studies of dextromethorphan in both isotropic and anisotropic states

Herein, we present the solution-state NMR studies on dextromethorphan (1) under both isotropic and anisotropic conditions. From the measurement of 22 residual dipolar couplings using a stretched polystyrene gel (PS), we show that accurate and detailed structural information is readily determined including the relative stereochemical assignments of chiral centers, validation of diastereomer configuration, and the stereospecific assignment of the seven pairs of prochiral protons. This utility of PS gels is thus showcased to obtain rapid, accurate conformational, and relative configuration information in this important class of compounds without recourse to X-ray analysis.

Dolastanes from the brown alga Dilophus spiralis: absolute stereochemistry and evaluation of cytotoxicity

Five new dolastanes ( 1– 5) were isolated from the brown alga Dilophus spiralis. The structural elucidation of the isolated compounds and the assignment of relative stereochemistry were based on analyses of their spectroscopic data. The structure proposed for 1 was confirmed by single crystal X-ray diffraction analysis, whereas its absolute stereochemistry was determined using the modified Mosher's method. The cytotoxicity of 1– 4 was evaluated against seven cell lines.

Stereochemistry of Sagittamide A from Residual Dipolar Coupling Enhanced NMR

Sagittamide A is a long-chain acyclic α,ω-dicarboxylic acid with eight stereocenters. The central hexahydroxyhexane moiety carries six of them. For this moiety, two different relative stereochemical assignments were published in 2006. In this communication, one relative configuration is clearly singled out based on NOEs, J- and residual dipolar couplings despite conformational averaging that is present in this moiety. The proposed NMR method relies on the measurement of dipolar couplings in recently introduced alignment media that are compatible with organic solvents, and cross validating the NMR determined ensemble of conformations against the residual dipolar couplings. The method is easily applicable to many other stereochemical problems.

Mooloolabenes A−E, Norsesterterpenes from the Australian Sponge Hyattella intestinalis

Five new norsesterterpenes, mooloolabenes A-E (1-5), and the new sesterterpene mooloolaldehyde (6), related to the scalarane family of compounds, were isolated from an acetone extract of the Australian sponge Hyattella intestinalis. Structural elucidation, including relative stereochemical assignment, was based on spectroscopic analysis. All compounds tested showed cytotoxic activity against the P388 cell line.

A spectroscopic and computational study of stereochemistry in 2-hydroxymutilin

A computational and spectroscopic study of two epimers of 2-hydroxymutilin was conducted to obtain assignments for the configuration of the carbon at the 2-position. Gas-phase structural models for ( R)- and ( S)-2-hydroxymutilin were optimized using density functional theory (DFT). These models were validated using internuclear distances measured from 1H nuclear Overhauser effect (NOE) build-up rates in CDCl 3 solution. The models were subsequently used to predict NMR parameters using the hybrid B3LYP density functional. After linear scaling, the agreement between predicted gas-phase and observed solution-state chemical shifts was sufficient for relative stereochemical assignments, with an average absolute error of 0.16 and 1.47 ppm for 1H and 13C shifts, respectively. 1H– 1H and 1H– 13C coupling constants were also predicted using the B3LYP functional with the aug-cc-p-VTZ-J basis set and compared to experimental values (measured by J-resolved and gradient J-HMBC experiments). The predicted coupling constants were within 10% of their experimental values in most cases, and like the chemical shielding, allowed for relative stereochemical assignments of the isomers. DFT prediction of coupling constants gave more useful information than empirical parameterizations. Although just one chiral center changes between the two isomers, with no consequent conformational change and only two affected NOE restraints, predictable effects on 20 different chemical shielding and J-coupling values were observed. Including these values in the stereochemical assignment allows for additional confirmation of the stereochemical results, using data already available in 1D 1H spectra and 2D 1H– 13C correlation spectra. Electronic and vibrational circular dichroism (ECD and VCD) spectra of the two isomers are also measured and compared with theoretical predictions. VCD was especially useful for determining the absolute stereochemistry of 2-hydroxymutilin and was found to be superior to ECD in this role. The combination of computational and spectroscopic work is shown to be a useful tool in the analysis of unknown mutilin derivatives or other compounds, such as those present as minor impurities or metabolites in pharmaceutical samples.

Cytotoxic Withaphysalins from the Leaves of Acnistus arborescens

Three withaphysalins, rel-(17S,20R,22R)-5 beta,6 beta:18,20-diepoxy-4 beta-hydroxy-1,18-dioxowitha-2,24-dienolide(withaphysalin M) (1), rel-(17S,20R,22R)-5 beta,6 beta:18,20-diepoxy-4 beta-hydroxy-18-ethoxy-1-oxowitha-2,24-dienolide (withaphysalin F ethyl ether, withaphysalin O) (2), and rel-(17S,20R,22R)-5 beta,6 beta:18,20-diepoxy-4 beta-hydroxy-1,18-dioxowitha-24-enolide (withaphysalin N) (3), were isolated from the leaves of Acnistus arborescens. The structures were deduced from 1D ((1)H NMR, (13)C NMR, DEPT-(13)C NMR) and 2D (COSY, HMQC, HMBC) NMR analysis and the relative stereochemical assignments based on 1D NOESY correlations and analysis of coupling constants. Compounds 1 and 2 displayed potent cytotoxic activity against a panel of human cancer cell lines.

Catalytic, Asymmetric Mannich‐Type Reactions of N‐Acylimino Esters: Reactivity, Diastereo‐ and Enantioselectivity, and Application to Synthesis of N‐Acylated Amino Acid Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Catalytic, asymmetric Mannich-type reactions of N-acylimino esters: reactivity, diastereo- and enantioselectivity, and application to synthesis of N-acylated amino acid derivatives.

In the presence of a catalytic amount of Cu(OTf)(2)-chiral diamine 3e complex, N-acylimino esters reacted with silyl enol ethers to afford the corresponding Mannich-type adducts in high yields with high enantioselectivities. A wide variety of silyl enol ethers derived from ketones, as well as esters and thioesters, reacted smoothly. In the reactions of alpha-substituted silyl enol ethers (alpha-methyl or benzyloxy), the desired syn-adducts were obtained in high yields with high diastereo- and enantioselectivities. Several intermediates for the synthesis of biologically important compounds were prepared using this novel catalytic asymmetric Mannich-type reaction, and at the same time, absolute and relative stereochemical assignments were made. In addition, it has been revealed that alkyl vinyl ethers reacted with N-acylimino esters in the presence of a catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type adducts in high yields with high enantioselectivities. This is the first example of catalytic asymmetric Mannich-type reactions with alkyl vinyl ethers. The reaction mechanism, structure of chiral catalyst-electrophile complexes, and transition states of these catalytic asymmetric reactions were assumed based on X-ray crystallographic analysis of the Cu(II)-chiral amine complex, PM3 calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of ceramide trafficking from endoplasmic reticulum to the site of sphingomyerin (SM) synthesis, has been synthesized efficiently using the present Mannich-type reaction as a key step. The synthesis involved three steps (two-pot), and total yield was 82.9%.