Threo Configuration Research Articles

Ring Opening of Aziridines by Pendant Silanols Allows for Stereospecific Preparations of 1'-Amino-tetrahydrofurans.

We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf)3 and 1 equivalent of NaHCO3 in CH2Cl2 is mild and compatible with a range of activating aziridine N-substituents (including tosylates, mesylates, and carbamates) and functional groups on the alkyl chains (including substituted aryl rings, alkyl bromides, and alkyl ethers). In all cases examined, trans di-substituted aziridine silanols give products with an erythro configuration; conversely, cis di-substituted aziridine silanols give products with a threo configuration. While literature syntheses of 1'-amino-tetrahydrofurans exist, only one example, contemporaneous with our work, uses a similar cyclization for their construction. Control experiments demonstrate that, for this transformation, the silanol is not particularly privileged, and a variety of protecting groups on the alcohol (including other silicon protecting groups, benzyl ethers, and MOM ethers) are compatible with product formation.

Dancing Silanols: Stereospecific Rearrangements of Silanol Epoxides into Silanoxy-Tetrahydrofurans and Silanoxy-Tetrahydropyrans.

We have developed highly stereospecific rearrangements of silanol epoxides into 1'-silanoxy-tetrahydrofurans and 1'-silanoxy-tetrahydropyrans. Upon treatment with Ph3CBF4 and NaHCO3 in CH2Cl2, di-substituted trans-epoxide silanols rearrange into products with an erythro configuration; di-substituted cis-epoxide silanols give products with a threo configuration. We have used these reactions as key steps in the syntheses of (±)-solerone and (±)-muricatacin.

Rapid Approaches for Assignment of the Relative Configuration in 1-Oxygenated 1,2-Diarylpropan-3-ols by 1H NMR Spectroscopy.

The structural elucidation of chiral molecules with more than one stereocenter is usually a tricky problem. In this paper, efficient 1H NMR spectroscopic approaches for assigning the erythro and threo configurations of 1-oxygenated 1,2-diarylpropan-3-ols were developed. By analysis of the chemical shift differences of diastereotopic methylene H2-3 (Δδ3) in CDCl3 or the chemical shift differences of H-1 and H-2 (Δδ1,2) in methanol-d4, deuterated dimethyl sulfoxide, and acetone-d6, the configurations of 1-oxygenated 1,2-diarylpropan-3-ols can be rapidly and conveniently determined.

New 8-O-4' Neolignans and Their Antibacterial Activity from the Whole Plants of Clematis lasiandra.

Four new 8-O-4′ neolignans, characterized at methoxy or ethoxy groups substituted at C-7, namely, (±) lasiandranins A–D (1–4), and two known analogs (±) pinnatifidanin BV (5) and (±) pinnatifidanin BVI (6) were isolated from the whole plants of Clematis lasiandra Maxim. The structures of 1–6 were determined by spectroscopic methods including 1D, 2D NMR, ECD, and HRESIMS analysis. Compounds 1 and 5 were determined as erythro configuration, while 2–4 and 6 were determined as threo configuration based on the chemical shift difference of H-9a and H-9b in CD3OD. The 8-O-4′ neolignans were found from the genus Clematis for the first time. Compounds 1–6 were evaluated for their antibacterial activity against three plant pathogenic bacteria Pseudomonas syringae pv. actinidiae, Ralstonia solanacearum, and Erwinia carotovora by agar and broth dilution methods. Compounds 1–6 showed potent antibacterial activity against R. solanacearum with MIC values of 25–50 μg/mL and relatively lower activity against P. syringae pv. actinidiae with MIC values of 50–100 μg/mL, while they were inactive to E. carotovora.

Chemoenzymatic Synthesis and Pharmacological Characterization of Functionalized Aspartate Analogues As Novel Excitatory Amino Acid Transporter Inhibitors.

Aspartate (Asp) derivatives are privileged compounds for investigating the roles governed by excitatory amino acid transporters (EAATs) in glutamatergic neurotransmission. Here, we report the synthesis of various Asp derivatives with (cyclo)alkyloxy and (hetero)aryloxy substituents at C-3. Their pharmacological properties were characterized at the EAAT1–4 subtypes. The l-threo-3-substituted Asp derivatives 13a–e and 13g–k were nonsubstrate inhibitors, exhibiting pan activity at EAAT1–4 with IC50 values ranging from 0.49 to 15 μM. Comparisons between (dl-threo)-19a–c and (dl-erythro)-19a–c Asp analogues confirmed that the threo configuration is crucial for the EAAT1–4 inhibitory activities. Analogues (3b–e) of l-TFB-TBOA (3a) were shown to be potent EAAT1–4 inhibitors, with IC50 values ranging from 5 to 530 nM. Hybridization of the nonselective EAAT inhibitor l-TBOA with EAAT2-selective inhibitor WAY-213613 or EAAT3-preferring inhibitor NBI-59159 yielded compounds 8 and 9, respectively, which were nonselective EAAT inhibitors displaying considerably lower IC50 values at EAAT1–4 (11–140 nM) than those displayed by the respective parent molecules.

Structure-activity relationship of annonaceous acetogenins against multidrug resistant human hepatic carcinoma cell line SMMC-7721/ADR

The present research was launched to investigate the effects of 12 annonaceous acetogenins (ACGs) on human hepatic carcinoma cell line SMMC-7721/ADR, and to find out their structure-activity relationship. SMMC-7721/ADR cells were treated with 12 ACGs including annosquamin A(1)，annosquamin B(2)，annotemoyin-1(3)，uvariamicin Ⅱ(4)，annosquacin D(5)，annosquacin B(6)，isodesacetyluvaricin(7)，uvarigrandin A(8)，squamostatin D(9)，squamostatin E(10)，squamostatin A(11)，and 12,15-cis-squamostatin A(12) for 24 h, and the different expression of the target gene NDUFV2 were detected by quantitative real-time PCR. All the tested compounds made the expression of the target gene NDUFV2 decreased on human hepatic carcinoma cell line SMMC-7721/ADR, of which the bistetrahydrofuran ACGs showed the best activity,which the non-adjacent bistetrahydrofuran ACGs displayed the worst activity.The ACGs with the reducing number of carbons between γ-unsaturated lactone and the close tetrahydrofuran (THF) ring are more potent. For bistetrahydrofuran ACGs with the same nucleus skeleton,they would be more active as more hydroxyls on aliphatic chain, which for the non-adjacent bistetrahydrofuran ACGs with less hydroxyls on aliphatic chain that would be more active. ACGs with 3 hydroxyls on aliphatic chain would be more active. ACGs with threo configuration are more active than erythro configurotion, and the compounds with cis THF ring seem to be superior to those of trans THF ring. Furthermore, the ACGs with the reducing number of carbons between terminal methyl and the close tetrahydrofuran (THF) ring are more potent.

Convergent synthesis of stereoisomers of THF ring moiety of acetogenin thiophene analogue and their antiproliferative activities against human cancer cell lines

The convergent synthesis of thiophene-3-carboxamide analogues of annonaceous acetogenins was accomplished through the asymmetric alkynylation of a 2-formyl THF ring fragment with an alkyne having a thiophene ring as the key step. Eight stereoisomers of the THF ring moiety were synthesized by this convergent route and their antiproliferative activities against 39 human cancer cell lines were evaluated. It was revealed that derivatives having the threo configuration between C17–C18 positions showed more potent activities than the corresponding erythro ones.

Direct Assignment of the Threo and Erythro Configurations in Polyacetylene Glycosides by 1H NMR Spectroscopy.

An approach for discriminating the threo and erythro configurations of polyacetylene glycosides by 1H NMR spectroscopy was developed. Using acetic acid-d4/D2O as the solvent, a relatively larger 3JHH value (7.0 Hz) for the acyclic vicinal diol group was unambiguously assigned to the threo configuration, whereas the smaller value (3.5 Hz) was assigned to the erythro configuration. This convenient method requires no hydrolysis or derivatization and is suitable for micromolar concentrations of polyacetylene glycosides. The underlying mechanism is discussed via visualized conformations.

Thiophene acetylenes and furanosesquiterpenes from Xanthopappus subacaulis and their antibacterial activities

In a search for naturally occurring antibacterial compounds in medicinal plants, six hitherto unknown thiophene acetylenes, named 10,11-threo-xanthopappin D, 10,11-erythro-xanthopappin D, 10,11-cis-xanthopappin B, 5-(but-4-chloro-3-hydroxy-1-ynyl)-2-(Z)-pent-3-ene-1-ynylthiophene, 5-(but-4-chloro-3-hydroxy-1-ynyl)-2-(E)-pent-3-ene-1-ynylthiophene, 5-(but-3,4-dihydroxy-1-ynyl)-2-(Z)-pent-3-ene-1-ynylthiophene and two furanosesquiterpenes, as well as fifteen known compounds, were isolated from Xanthopappus subacaulis, which has been used as a traditional Tibetan medicine in China. A biosynthetic pathway to thiophene acetylenes was proposed and, the isolated compounds were tested for their antibacterial activity against five bacteria. Within the series of thiophene acetylenes tested, 10,11-threo-xanthopappin D with a threo configuration exhibited strong activity against Bacillus subtilis, with a minimum inhibitory concentration (MIC) of 7.25μg/mL, whereas 10,11-erythro-xanthopappin D with erythro configuration possessed broad-spectrum antibacterial activity against Escherichia coli, Bacillus cereus, Staphylococcus aureus and Erwinia carotovora, with MICs of 12.5, 15.5, 7.25 and 7.25μg/mL, respectively. Meanwhile, the compounds 10,11-cis-xanthopappin B, xanthopappin B, 5-(but-4-chloro-3-hydroxy-1-ynyl)-2-(Z)-pent-3-ene-1-ynylthiophene and 5-(but-4-chloro-3-hydroxy-1-ynyl)-2-(E)-pent-3-ene-1-ynylthiophene substituted with a Cl atom at C-14 showed moderate inhibitory activity against E. coli, B. cereus, S. aureus, E. carotovora and B. subtilis, with MICs ranging from 31.25 to 62.5μg/mL. The structures of these compounds were elucidated through the comprehensive analysis of spectroscopic data, including UV, IR, MS and NMR.

Diastereotopic and Deuterium Effects in Gemini

Changing the geminal methyl groups on 1α,25-dihydroxyvitamin D3 and its analogues to the deuterio versions generally improves the bioactivity. Derivatives of 1α,25-dihydroxyvitamin D3 with two chains emanating at C20, commonly referred to as gemini, are subject to the same phenomenon. Additionally, gemini with different side chains are susceptible to bioactivity differentials where the C17-C20 threo configuration usually imparts higher activity than the corresponding erythro arrangement. In an effort to analyze the deuterium effect on gemini with minimal diastereotopic distortion, we synthesized gemini with equal side chains but introduced deuterium diastereospecifically on either chain. We solved the crystal structures of these compounds in the zebra fish zVDR ligand binding domain as complexes with NCoA-2 coactivator peptide and correlated the findings with growth inhibition in a breast cancer cell line.

Stability Study of Sennoside Standard Solution and Structure Analysis of Degradation Product

For the quantitative analysis of sennoside A (SA) and sennoside B (SB) in health tea, the stability of standard solutions prepared according to the Japanese Pharmacopoeia was investigated. Standard solutions of SA and SB began to decompose one day after preparation at room temperature. The results suggest that the instability of the standard solution may lead to uncertainty in quantification. Whereas it was difficult to confirm the degradation products of SA and SB by means of ultraviolet absorption measurements (wavelength, 366 nm), an unknown peak derived from the degradation product was detected in fluorescence measurements. Structure analysis revealed that the degradation product was rhein-8-glucoside. It was also found that SB having an erythro configuration is more unstable than SA having a threo configuration. A stability study of the standard solutions showed that such solvents as THF/water (7 : 3) prevented degradation at 4℃ storage but not at 37℃ storage. However, when 0.1% phosphoric acid/acetonitrile (4 : 1) was used, the degradation of SB was fairly suppressed even at 37℃. This solvent is considered to be more useful for the preparation of standard solutions of SA and SB than conventionally used methanol.

Tetrofuranose nucleoside phosphonic acids: Synthesis and properties

New isoelectronic, non-isosteric phosphonate analogues of nucleoside 5′-phosphates featuring the phosphorus moiety directly attached on the sugar ring in the C4′ position are described. The analogues were synthesised by a nucleosidation reaction from tetrofuranosyl phosphonate synthons and silylated nucleobases. The pyrimidine compounds with erythro and threo configuration in both D- and L-series were prepared, and the structures were assigned by NMR spectroscopy. The results of NMR conformational studies show that all calculated conformers have a maximum pucker in the range typical for nucleosides. In all compounds, the S-type conformer is preferred and is more significant in α-D-threo-compounds. Studies on inhibition of thymidine phosphorylase revealed that one of the prepared phosphonic acids was a competitive inhibitor of the enzyme (Ki = 4 μM).

ChemInform Abstract: Hetero-Diels-Alder Reactions of Homochiral 1,2-Diaza-1,3-butadienes with Diethyl Azodicarboxylate under Microwave Irradiation. Theoretical Rationale of the Stereochemical Outcome.

The stereoselective normal electron demand Diels−Alder reactions of chiral 1,2-diaza-1,3-butadienes, derived from acyclic carbohydrates having different configurations (1−6), with diethyl azodicarboxylate (DEAD) are disclosed. Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation to form the corresponding functionalized 1,2,3,6-tetrahydro-1,2,3,4-tetrazines (7−18) in good yields. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1‘,2‘. Thus, 1,2-diazoalkenes derived from per-O-acylated sugars having threo configuration at C-1‘,2‘ give tetrazines with a high facial selectivity, whereas those having erythro configuration at C-1‘,2‘ afford products in lower diastereomeric ratios. The facial diastereoselection has been rationalized by a PM3 computational study. These results prove that in the transition structures (TSs) the reacting azoalkene exhibits formal negative charges at C-3 and N-2, the former bein...

Isolation and Characterization of Lignin from Tropical and Temperate Hardwood

Dioxane and milled wood lignins (MWL) were isolated from tropical hardwood, Nalita (Trema orientalis) and temperate hardwood, aspen. These lignins were characterized by UV, FTIR, 1H-NMR and 13C-NMR spectroscopy, alkaline nitrobenzene oxidation, molecular weight determination, elemental and methoxyl analysis. The structural analysis revealed that Nalita and aspen lignin is syringyl-guaiacyl type. Aspen lignin had higher syringyl unit than Nalita lignin. The β-O-4 type linkages are the main interunit linkages and more abundant in aspen than Nalita. Dioxane lignin showed higher free phenolic hydroxyl group than MWL in both species. The weight average molecular weight of aspen lignin was lower than that of Nalita lignin. Nalita and aspen lignins contained both erythro and threo configuration, but erythro proton gave stronger peak. A UV absorption maximum of aspen lignin was at 274 nm, whereas it was shifted to 280 nm for Nalita lignin. Keywords: Trema orientalis, Aspen, Dioxane lignin, Milled wood lignin, Syringyl-guaiacyl, β-O-4 linkages DOI: 10.3329/bjsir.v44i3.4399 Bangladesh J. Sci. Ind. Res. 44(3), 271-280, 2009

Isorhizochalin: a Minor Unprecedented Bipolar Sphingolipid of Stereodivergent Biogenesis from the Rhizochalina incrustata

Isorhizochalin (1) was isolated as its peracetate from the EtOH extract of the sponge Rhizochalina incrustata. Its structure and absolute stereochemistry were elucidated as (2S,3R,26R,27R)-2,27-diamino-3-O-beta-D: -galactopyranosyl-oxy-26-hydroxyoctacosan-18-one by extensive NMR, MS studies, chemical transformations, including micromolar-scale Baeyer-Villiger oxidation, and by analysis of CD spectra of isorhizochalinin perbenzoate (2b). Isorhizochalin is an unprecedented C-2 epimer of rhizochalin having an erythro configuration at the glycosylated 2-amino-3-alkanol alpha-terminus in contrast with a canonical threo configuration for other representatives of this structural group. Probable biogenesis of 1 is discussed in the context of known sphingolipid biosynthesis beginning with condensation of alanine with a fatty acyl CoA thioester. The aglycone, isorhizochalinin (2a), shows cytotoxicity against human leukemia HL-60 and THP-1 cells with IC(50) values of 2.90 and 2.20 microM, respectively.

β-Hydroxylation of the Aspartyl Residue in the Phytotoxin Syringomycin E: Characterization of Two Candidate Hydroxylases AspH and SyrP in Pseudomonas syringae

The pseudomonal phytotoxin syringomycin E and related nonribosomal peptides contain an L- threo-beta-hydroxyaspartyl residue at the eighth position of the lipodepsipeptide backbone as part of a conserved nonproteinogenic tripeptide motif. Informatic analysis of the P. syringae genome suggests only one putative non-heme iron hydroxylase, AspH. On heterologous expression in Escherichia coli AspH shows robust catalytic activity with free L-Asp and L-Asp thioesters to make beta-OH-Asp but yields the erythro diastereomer rather than the threo configuration that is found in syringomycin. Further analysis of the Syr gene cluster indicated that SyrP, previously annotated as the gene regulatory protein for the five-gene Syr cluster, is actually homologous to the known non-heme mononuclear iron hydroxylase TauD. Indeed, purified SyrP acts on Asp tethered as the protein-bound S-pantetheinyl thioester on the eighth module of the SyrE megasynthetase. The hydroxylation gives the anticipated L- threo-3-OH-Asp diastereomer found in syringomycin. The knockout of syrP abolishes the production of the mature syringomycin E, while knockout of aspH has no effect on syringomycin production.

Initiator selectivity during free radical copolymerizations of styrene and methyl methacrylate initiated by anaerobic copper(II) oxidation of carbon-13 labeled acetophenone

Nuclear magnetic resonance (NMR) analysis of the 13C-labeled chain ends of polystyrene, polyMMA, and styrene-MMA copolymers prepared by polymerizations initiated using 13C-labeled-phenacyl radicals were investigated. The phenacyl radicals were generated by anaerobic oxidation of acetophenone-methyl-13C using a Cu(II) octanoate-pyridine complex in the presence of triethylamine and triphenylphosphine. NMR analysis of the 13C-labeled chain ends of these polymers afforded insight into the initiation mechanism. In copolymerization experiments using 13C-labeled acetophenone initiator, the NMR spectra provided evidence that the phenacyl radical reacts 2.7 times faster with styrene than with MMA. The resonances of the labeled phenacyl carbons also showed that the sequence and stereosequence distributions of monomer units at the chain ends are nearly the same as those that prevail along the polymer chains. Styrene–styrene, styrene–MMA, and MMA–styrene enchainments at the chain ends are equally likely to have meso (erythro) or racemic(threo) configurations but the ratio of meso to racemic MMA-MMA enchainments is ∼ 3/7. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2347–2356, 2008

Tridentate [N,N,O] Schiff-base group 4 metal complexes: Synthesis, structural characterization and reactivity in olefin polymerization

New complexes LTiCl 3( 1), LZrCl 3( 2) and LHfCl 3( 3) (L = ( E)-2- tert-butyl-6[(quinoline-8-ylimino)methyl]phenolate) have been synthesized and fully characterized by multinuclear NMR, mass spectrometry and X-ray diffractometry. The three isostructural complexes show distorted octahedral geometries. Complexes 1– 3 were tested as catalysts for ethylene polymerization under a variety of experimental conditions. Reasonable productivities were achieved after activation by methylaluminoxane (MAO) under moderate temperature and pressure conditions (e.g., 50 °C and 6 atm). Complexes 1– 3 were also tested as precatalysts for the polymerization of propene. Interestingly, polymerization by 1-MAO at −20 °C afforded an isotactic polypropylene containing 5% isolated regioirregular units in threo configuration. This very unusual microstructure implicates that both primary and secondary monomer insertions occur with the same enantioface selectivity, at variance with what is observed in the case of metallocene catalysts.

Lignans from Wikstroemia hainanensis.

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Lignans fromWikstroemia hainanensis

The structures and conformations of three new lignans, wikstrone (1), wikstroemol (2), and wikstroemone (3) – isolated from the aerial parts of Wikstroemia hainanensis – were determined, together with those of twelve known compounds, including erythro-guaiacylglycerol-β-O-4′-sinapyl ether (4). The configuration of 4, falsely assigned in the literature (threo configuration), was redetermined, and the compound was identified as erythro-guaiacylglycerol-β-O-4′-sinapyl ether.