- Preparation of Some 2,3-Dideoxylactones by an Unusual Catalytic Hydrogenolysis
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Hydrogenolysis of 2-bromo-2-deoxyaldono-1,4-lactones in ethanol solution with palladium as catalyst gives good yields of the corresponding 2,3-dideoxylactones with removal of not only the bromine atom but also the C-3 hydroxy group.
- Lundt, Inge,Pedersen, Christian
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- Stereospecific synthesis of (+)-muricatacin: A biologically active acetogenin derivative
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(+)-muricatacin and analogs have been synthesized without ambiguity about the absolute configuration at the C-4 and C-5 centres. The observed [α](D) are reported as well as the results obtained for the cytotoxicity assay with KB and VERO cell lines.
- Figadere,Harmange,Laurens,Cave
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- Organic solvent- and catalyst-free Baeyer-Villiger oxidation of levoglucosenone and dihydrolevoglucosenone (Cyrene): A sustainable route to (: S)-γ-hydroxymethyl-α,β-butenolide and (S)-γ-hydroxymethyl-γ-butyrolactone
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A straightforward and sustainable route to (S)-γ-hydroxymethyl-α,β-butenolide (HBO) and (S)-γ-hydroxymethyl-α,β-butyrolactone (2H-HBO), two valuable chemical platforms for the synthesis of fine chemicals such as drugs, pheromones, flavors and fragrances, has been optimized using renewable cellulose-based levoglucosenone (LGO) and Cyrene as starting materials and aqueous H2O2 as both a solvent and an oxidizing agent. Combined with short-path distillation, this procedure provides enantiopure HBO and 2H-HBO in yield as high as 72% at the kilo scale.
- Bonneau, Guillaume,Peru, Aurélien A. M.,Flourat, Amandine L.,Allais, Florent
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- Chemo-enzymatic synthesis of key intermediates (S)-γ-hydroxymethyl-α,β-butenolide and (S)-γ-hydroxymethyl-γ-butyrolactone via lipase-mediated Baeyer-Villiger oxidation of levoglucosenone
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Levoglucosenone (LGO), a valuable chiral platform chemical that can be efficiently produced from catalytic fast pyrolysis of cellulose, has been efficiently converted into optically pure (S)-γ-hydroxymethyl-α,β-butenolide (HBO) using a two-step sequence involving a lipase-mediated Baeyer-Villiger oxidation and an acid hydrolysis. In the same fashion, (S)-γ-hydroxymethyl-γ-butyrolactone (2H-HBO) was successfully obtained through a three-step sequence (Baeyer-Villiger, palladium-catalysed hydrogenation and acid hydrolysis). The use of solid buffers in the lipase-mediated Baeyer-Villiger oxidation has proved beneficial in two ways: not only the reaction time and the enzymatic load were both reduced four-fold (from 8 to 2 hours and 464 to 113 U mmol?1) to reach conversions ≥83%, but solid buffers also prevented lipase from denaturation, thus preserving its enzymatic activity and allowing its use for further oxidation cycles.
- Flourat,Peru,Teixeira,Brunissen,Allais
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- Asymmetric synthesis of enantiopure (+)-(1S,2S) methyl 2-formylcyclopropanecarboxylate and corresponding (Z) and (E) didehydroamino acid derivatives
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The title cyclopropane aldehyde and didehydroamino acids have been synthesised from (S)-(+)-γ-butyrolactone-γ-carboxylic acid as a chiral precursor.
- Le Corre,Hercouet,Bessieres
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- Molecular basis for the enantio-and diastereoselectivity of burkholderia cepacia lipase toward γ-butyrolactone primary alcohols
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Burkholderia cepacia lipase (BCL) shows high enantioselectivity toward chiral primary alcohols, but this enantioselectivity is often unpredictable, especially for substrates that contain an oxygen at the stereocenter. For example, BCL resolves bsubstituted-g-acetyloxymethyl-g-butyrolactones (acetates of a chiral primary alcohol) by hydrolysis of the acetate, but the enantioselectivity varies with the nature and orientation of the b-alkyl substituent. BCL favors the (R)-primary alcohol when the balkyl substituent is hydrogen (E=30) or trans methyl (E=38), but the (S)-primary alcohol when it is cis methyl (E=145). To rationalize this unusual selectivity, we used a combination of experiments to show the importance of polar interactions and modeling to reveal differences in orientations of the enantiomers. Removal of either the lactone carbonyl in the substrate or the polar side chains in the enzyme by using a related enzyme without these side chains decreased the enantioselectivity at least four-fold. Modeling revealed that the slow enantiomers do not bind by exchanging the location of two substituents relative to the fast enantiomer. Instead, three substituents remain in the same region, but the fourth substituent, hydrogen, inverts to a new location, like an umbrella in a strong wind. In this orientation the favored stereoisomers have similar shapes, thus accounting for the unusual stereoselectivity. The ratio of catalytically productive orientations for the fast vs. slow enantiomers in a molecular dynamic simulation correlated (R2=0.82) with the degree of enantioselectivity including the case where the enantioselectivity reversed. Weighting this ratio by the ratio of Hbonds in the polar interaction to account for different binding strengths improved the correlation with the measured enantioselectivity to R2=0.97. The modeling identifies key interactions responsible for high enantioselectivity in this class of substrates.
- Eum, Heesung,Kazlauskas, Romas J.,Ha, Hyun-Joon
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- Elucidating the interaction of γ-hydroxymethyl-γ-butyrolactone substituents with model membranes and protein kinase C-C1 domains
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The protein kinase C (PKC) family of proteins is an attractive drug target. Dysregulation of PKC-dependent signalling pathways is related to several human diseases like cancer, immunological and other diseases. We approached the problem of altering PKC activities by developing C1 domain-based PKC ligands. In this report γ-hydroxymethyl-γ-butyrolactone (HGL) substituents were investigated in an effort to develop small molecule-based PKC regulators with higher specificity for C1 domain than the endogenous diacylglycerols (DAGs). Extensive analysis of membrane-ligands interaction measurements revealed that the membrane-active compounds strongly interact with the lipid bilayers and the hydrophilic parts of compounds localize at the bilayer/water interface. The pharmacophores like hydroxymethyl, carbonyl groups and acyl-chain length of the compounds are crucial for their interaction with the C1 domain proteins. The potent compounds showed more than 17-fold stronger binding affinity for the C1 domains than DAG under similar experimental conditions. Nonradioactive kinase assay confirmed that these potent compounds have similar or better PKC dependent phosphorylation capabilities than DAG under similar experimental conditions. Hence, our findings reveal that these HGL analogues represent an attractive group of structurally simple C1 domain ligands that can be further structurally altered to improve their potencies.
- Borah, Rituparna,Mamidi, Narsimha,Panda, Subhankar,Gorai, Sukhamoy,Pathak, Suraj Kumar,Manna, Debasis
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- A transition metal-catalyzed enyne metathesis for the preparation of pyrrolizidine alkaloid core: Application towards the total synthesis of stemaphylline
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In this paper, we disclose an efficient route for the synthesis of pyrrolizidine alkaloid core and its application towards the total synthesis of stemaphylline. The key pyrrolizidine core was achieved with Ru-carbene catalyzed ring closing enyne metathesis (RCEM). The effect of different types and amounts of Ru-carbene catalysts, solvents and temperature were systematically studied. The advantage of this method includes the construction of pyrrolizidine alkaloid core in a single operation.
- Kumar, Praveen,Rahman, Md. Ataur,Haque, Ashanul,Singh Yadav, Jhillu
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- New phenolic glycosides from Anemone chinensis Bunge and their antioxidant activity
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ABATRACT: Nine compounds, five phenolic glycosides (1, 2, 4–6), three phenylpropanoids (7–9), and a furanone glycoside (3), were isolated from aqueous soluble extract of the dried roots of Anemone chinensis Bunge. The structures of new compounds (1–4) were elucidated by comprehensive spectroscopic data analysis as well as chemical evidence. Pulsatillanin A (1) demonstrated significant antioxidant effects through scavenging free radical in DPPH assay, and relieved the oxidative stress in LPS-induced RAW 264.7 cells by reducing ROS production, enhancing antioxidant enzyme SOD activity, replenishing depleted GSH in a dose-dependent manner. Western blot analysis revealed that 1 showed antioxidant activity via activating Nrf2 signaling pathway.
- Zhang, Zeng-Guang,Li, Yuan-Yuan,Lin, Bin,Guan, Pei-Pei,Mu, Yu,Qiao, Wen-Jun,Zhang, Jing-Sheng,Huang, Xue-Shi,Han, Li
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supporting information
(2021/05/10)
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- Synthesis and anti-HIV activity of l-2′,3′-Dideoxy-4′-selenonucleosides (l-4′-Se-ddNs)
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Based on the potent anti-HIV activity of l-2′,3′-dideoxycytidine (l-ddC), l-2′,3′-dideoxy-4′-selenonucleosides (l-4′-Se-ddNs) have been synthesized from natural chiral template, l-glutamic acid, using Pummerer-type condensation as a key step. All synthesized compounds were assayed for anti-HIV-1 activity, but none of them did show any significant antiviral activity up to 100?μM, probably due to conformational differences between l-ddC and l-4′-Se-ddC, induced by the bulky selenium atom, which might play an important role in phosphorylation by cellular kinase.
- Yu, Jinha,Kim, Gyudong,Jarhad, Dnyandev B.,Kim, Hong-Rae,Jeong, Lak Shin
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p. 780 - 789
(2019/05/15)
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- Multi-Gram Scale Synthesis of Chiral 3-Methyl-2,5-trans-tetrahydrofurans
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In this article, we report the rapid and facile synthesis of chiral 3-methyl-2,5-trans-tetrahydrofurans. This reaction utilizes cheap and easily available starting materials. A domino hydrolysis and intramolecular Michael-type ring closure reaction was the key step. As a result, synthesis of the desired 3-methyl-2,5-trans-tetrahydrofurans could be achieved in gram-scale over seven linear steps with high chemical yield and high diastereoselectivity.
- Qin, Shuanglin,Cao, Yuting,Luo, Yunhao,Jiang, Shende,Clark, J. Stephen,Wang, Xiaoji,Yang, Guang
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- Method for highly selective synthesis of multi-chiral central tetrahydrofuran ring
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The invention relates to the technical field of organic synthesis, in particular to a method for highly selective synthesis of a multi-chiral central tetrahydrofuran ring. The method has mild conditions, simple reaction steps, easy operation, high regioselectivity and high stereoselectivity. The method comprises the following steps: (a) using L-glutamic acid 1 as a starting material, and carryingout diazotization and ring-closing to obtain a lactone intermediate 2; (b) reducing the carboxyl group in the lactone intermediate 2 to obtain an intermediate 3; (c) protecting the hydroxyl group in the intermediate 3 by TBS to obtain an intermediate 4; (d) carrying out a substitution reaction of the intermediate 4 to obtain an intermediate 5; (e) reducing the intermediate 5 to obtain a precursorcompound of an intermediate 6; (f) carrying out a Wittig reaction of the precursor compound of the intermediate 6 to obtain the intermediate 6; (g) carrying out a Mitsunobu reaction of the intermediate 6 to obtain an intermediate 7; and (h) performing protective group removal and ring-closing on the intermediate 7 under the action of a base to obtain a target product 8.
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- METHOD FOR CONVERTING LEVOGLUCOSENONE INTO 4-HYDROXYMETHYL BUTYROLACTONE AND 4-HYDROXYMETHYL BUTENOLIDE WITHOUT USING ANY ORGANIC SOLVENT AND CATALYST
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The invention relates to a method for converting levoglucosenone into 4-hydroxymethyl butyrolactone and 4-hydroxymethyl butenolide without using any solvent or catalyst, wherein the oxidation and hydrolysis of the levoglucosenone or hydrogenated levoglucosenone are carried out in a single step using an aqueous solution of H2O2.
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Paragraph 0059-0062
(2019/07/23)
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- Synthesis and fungicidal activity of methylsulfanylmethyl ether derivatives of levoglucosenone
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[Figure not available: see fulltext.] A series of derivatives were synthesized on the basis of levoglucosenone that contained hydroxy groups at the С-4 atom or С-2 and С-4 atoms or a hydroxy and methyl group at the С-4 atom. In addition, 4-hydroxymethylbutanolides were synthesized. Derivatives containing hydroxy groups were obtained as methylsulfanylmethyl ethers. It was established that compounds containing a 6,8-dioxabicyclo[3.2.1]-octane ring exhibited fungicidal activity against Rhizoctonia solani. It was shown that the presence of a methylsulfanylmethyl moiety in the ring could increase the fungicidal activity of compounds.
- Sharipov, Bulat T.,Davidova, Anna N.,Ryabova, Alena S.,Galimzyanova, Nailya F.,Valeev, Farid A.
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- Ring-opened 4-hydroxy-δ-valerolactone subunit as a key structural fragment of polyesters that degrade without acid formation
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Random copolymers of ?-caprolactone with O-benzyl-protected 4-hydroxy- or 2,4-dihydroxy-δ-valerolactone after hydrogenation form γ-hydroxy functionalized polyesters that degrade via the cyclization to γ-butyrolactone fragments without carboxylic acid formation.
- Nifant'ev, Ilya E.,Shlyakhtin, Andrey V.,Bagrov, Vladimir V.,Ezhov, Roman N.,Lozhkin, Boris A.,Churakov, Andrei V.,Ivchenko, Pavel V.
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p. 629 - 631
(2018/12/13)
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- Palladium-Catalyzed Atom-Transfer Radical Cyclization at Remote Unactivated C(sp3)?H Sites: Hydrogen-Atom Transfer of Hybrid Vinyl Palladium Radical Intermediates
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A novel mild, visible-light-induced palladium-catalyzed hydrogen atom translocation/atom-transfer radical cyclization (HAT/ATRC) cascade has been developed. This protocol involves a 1,5-HAT process of previously unknown hybrid vinyl palladium radical intermediates, thus leading to iodomethyl carbo- and heterocyclic structures.
- Ratushnyy, Maxim,Parasram, Marvin,Wang, Yang,Gevorgyan, Vladimir
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p. 2712 - 2715
(2018/03/02)
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- Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest
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The assigned structure of the dinoflagellate-derived toxin belizentrin was prepared by total synthesis in form of the corresponding methyl ester for stability reasons. The successful route features an unusual solution for the preparation of a recalcitrant ylide on a C-glycosidic segment; moreover, it involves an asymmetric hetero-Diels–Alder reaction en route to the tertiary hemiacetal substructure, a Negishi cross-coupling of two elaborate building blocks, and a macrocyclization based on an intramolecular aminolysis of a spirolactone. A modified Kocienski olefination ultimately allowed the polyol side chain to be attached to the macrocycle although this transformation faced the exceptional base sensitivity of this polyunsaturated target compound.
- Anderl, Felix,Gr??l, Sylvester,Wirtz, Conny,Fürstner, Alois
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p. 10712 - 10717
(2018/08/17)
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- METHOD FOR SYNTHESIZING A PRECURSOR OF A SINGLE DAIRY-LACTONE ISOMER
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This disclosure provides a method for preparing a precursor of a single dairy-lactone isomer, methods of preparing a single dairy-lactone isomer, and to the organoleptic uses thereof.
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Paragraph 0045; 0046; 0058; 0059; 0060; 0061
(2018/03/25)
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- DEOXYDEHYDRATION OF SUGAR DERIVATIVES
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The disclosure provides methods for deoxydehydration of sugar-based derivatives using hydrogen gas as a reducing agent.
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Paragraph 0134; 0135; 0136
(2017/09/09)
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- Hydrogen Gas-Mediated Deoxydehydration/Hydrogenation of Sugar Acids: Catalytic Conversion of Glucarates to Adipates
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The development of a system for the operationally simple, scalable conversion of polyhydroxylated biomass into industrially relevant feedstock chemicals is described. This system includes a bimetallic Pd/Re catalyst in combination with hydrogen gas as a terminal reductant and enables the high-yielding reduction of sugar acids. This procedure has been applied to the synthesis of adipate esters, precursors for the production of Nylon-6,6, in excellent yield from biomass-derived sources.
- Larson, Reed T.,Samant, Andrew,Chen, Jianbin,Lee, Woojin,Bohn, Martin A.,Ohlmann, Dominik M.,Zuend, Stephan J.,Toste, F. Dean
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supporting information
p. 14001 - 14004
(2017/10/17)
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- Chemo-enzymatic synthesis of chiral epoxides ethyl and methyl (S)-3-(Oxiran-2-yl)propanoates from Renewable levoglucosenone: An access to enantiopure (S)-dairy lactone
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Chiral epoxides-such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S)-1a/1b)-are valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low to moderate overall yield (20%-50%). Moreover, this procedure requires some harmful reagents such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone (LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we propose a safer and more sustainable chemo-enzymatic synthetic pathway involving lipase-mediated Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3-(oxiran-2-yl)propanoates in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from LGO, the synthesis of high value-added (S)-dairy lactone was undertaken from these epoxides and provided the target in 37% overall yield from LGO.
- Peru, Aurélien A. M.,Flourat, Amandine L.,Gunawan, Christian,Raverty, Warwick,Jevric, Martyn,Greatrex, Ben W.,Allais, Florent
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- Synthesis of enantiopure cyclopropyl esters from (-)-levoglucosenone
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The biorenewable chiral synthon (-)-levoglucosenone has been converted to enantiopure cyclopropyl esters using the base-promoted carbocyclisation of 4,5-epoxyvalerates. This protocol was applied to the enantiospecific synthesis of the GABAc receptor agonist (1R,2R)-trans-2-aminomethylcyclopropanecarboxylic acid ((-)-TAMP) and its enantiomer. The process was also extended to generate 1,1,2- and 1,2,3-trisubstituted cyclopropanes resulting in a formal synthesis of the selective glutamate receptor antagonist PCCG-4.
- Stockton, Kieran P.,Greatrex, Ben W.
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p. 7520 - 7528
(2016/08/16)
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- NUCLEOTIDE AND NUCLEOSIDE COMPOSITIONS AND USES RELATED THERETO
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This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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- Concise Enantioselective Synthesis of Naturally Active (S)-3-Hydroxypiperidine
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A short and efficient enantioselective synthesis of natural product (S)-3-hydroxypiperidine has been achieved starting from commercially available raw materials employing two catalytic routes: (i) cocatalyzed hydrolytic kinetic resolution (HKR) of racemic methyl-3-(oxiran-2-yl)propanoate; (ii) proline-catalyzed α-aminooxylation followed by Horner-Wardsworth-Emmons olefination in high enantiomeric purity (97% ee) and high overall yield (38%). (Chemical Equation Presented).
- Dey, Soumen,Karabal, Pratibha U.,Sudalai, Arumugam
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supporting information
p. 1559 - 1565
(2015/06/02)
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- NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to halogenated nucleosides optionally conjugated to a phosphorus oxide or pharmaceutically acceptable salts thereof. In certain embodiments, the disclosure relates to conjugate compounds or pharmaceutically acceptable salts thereof comprising an amino acid ester or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer.
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- Design and Synthesis of New Acid Cleavable Linkers for DNA Sequencing by Synthesis
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A new kind of acid sensitive tetrahydrofuranyl (THF) linker was synthesized and then reacted with 5-(6)-carboxytetramethylrhodaminesuccinimidyl ester (5(6)-TAMRA, SE), followed by di(N-succinimidyl) carbonate (DSC) and modified 2′-deoxyuridine triphosphate (dUTP); the final product, as a reversible terminator for DNA sequencing by synthesis (DNA SBS), was given obtained and confirmed by 1H-NMR, 31P-NMR, and HRMS with purity of up to 99%. The synthesized dye-labeled terminator incorporated into DNA strand successfully, and the fluorophore was cleaved completely under acidic conditions. The preliminary results encourage us to explore more acid-sensitive linkers for DNA SBS to increase the cleavage efficiency under weakly acidic conditions.
- Jiang, Min,Tang, Daonian,Zhao, Xiaodong,Li, Qing,Zhuang, Yuan,Wei, Xiaofei,Li, Xiaowei,Liu, Yazhi,Wu, Xin-Yan,Shao, Zhifeng,Gong, Bing,Shen, Yu-Mei
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p. 774 - 785
(2015/10/19)
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- Molecular basis for the enantio- and diastereoselectivity of burkholderia cepacia lipase toward γ-Butyrolactone primary alcohols
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Burkholderia cepacia lipase (BCL) shows high enantioselectivity toward chiral primary alcohols, but this enantioselectivity is often unpredictable, especially for substrates that contain an oxygen at the stereocenter. For example, BCL resolves bsubstituted- g-acetyloxymethyl-g-butyrolactones (acetates of a chiral primary alcohol) by hydrolysis of the acetate, but the enantioselectivity varies with the nature and orientation of the b-alkyl substituent. BCL favors the (R)-primary alcohol when the balkyl substituent is hydrogen (E=30) or trans methyl (E=38), but the (S)-primary alcohol when it is cis methyl (E=145). To rationalize this unusual selectivity, we used a combination of experiments to show the importance of polar interactions and modeling to reveal differences in orientations of the enantiomers. Removal of either the lactone carbonyl in the substrate or the polar side chains in the enzyme by using a related enzyme without these side chains decreased the enantioselectivity at least four-fold. Modeling revealed that the slow enantiomers do not bind by exchanging the location of two substituents relative to the fast enantiomer. Instead, three substituents remain in the same region, but the fourth substituent, hydrogen, inverts to a new location, like an umbrella in a strong wind. In this orientation the favored stereoisomers have similar shapes, thus accounting for the unusual stereoselectivity. The ratio of catalytically productive orientations for the fast vs. slow enantiomers in a molecular dynamic simulation correlated (R2=0.82) with the degree of enantioselectivity including the case where the enantioselectivity reversed. Weighting this ratio by the ratio of Hbonds in the polar interaction to account for different binding strengths improved the correlation with the measured enantioselectivity to R2=0.97. The modeling identifies key interactions responsible for high enantioselectivity in this class of substrates.
- Eum, Heesung,Kazlauskas, Romas J.,Ha, Hyun-Joon
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p. 3585 - 3599
(2015/02/19)
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- Study on the total synthesis of velbanamine: Chemoselective dioxygenation of alkenes with PIFA via a stop-and-flow strategy
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A "stop-and-flow" strategy was developed for the chemoselective dioxygenation of alkenes with a PIFA-initiated cyclization. This method is conceived for the desymmetrization of seco-diene, and a series of substituted 5-hydroxymethyl-γ-lactones were constructed after hydrolysis. This strategy also differentiates terminally substituted alkenes and constitutes a potentially novel synthetic approach for the efficient synthesis toward velbanamine.
- Liu, Huili,Zheng, Kuan,Lu, Xiang,Wang, Xiaoxia,Hong, Ran
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p. 983 - 990
(2013/07/19)
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- Pyrene intercalating nucleic acids with a carbon linker
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We have synthesized a carbon linker analogue of INA (oligonucleotides containing insertions of 1-O-(1-pyrenylmethyl)glycerol). Thermal stability studies showed an increase in melting temperature in favor of the carbon linker analogue. We also synthesized a carbon linker analogue with two pyrenes geminally attached. Fluorescence studies of this intercalating nucleic acid with the pyrene moieties inserted as a bulge showed formation of an excimer band. When a mismatch was introduced at the site of the intercalator, an excimer band was formed for the destabilized duplexes whereas an exciplex band was observed when the stability of the duplex was retained. Copyright Taylor and Francis Group, LLC.
- stergaard, Michael E.,Wamberg, Michael C.,Pedersen, Erik B.
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scheme or table
p. 210 - 226
(2012/04/18)
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- Stereochemical elucidation of streptorubin B
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Streptorubin B is a structurally remarkable mem-ber of the prodiginine group of antibiotics produced by several actinobacteria, including the model organism Streptomyces coelicolor A3(2). Transannular strain within the pyrrolophane structure of this molecule causes restricted rotation that gives rise to the possibility of (diastereomeric) atropisomers. Neither the relative nor the absolute stereochemistry of streptorubin B is known. NOESY NMR experiments were used to define the relative stereochemistry of the major atropisomer of streptorubin BHCl in solution as anti. We exploited this finding together with our knowledge of streptorubin B biosynthesis in S. coelicolor to determine the absolute stereochemistry of the anti atropisomer. 2-Undecylpyrrole stereoselectively labeled with deuterium at C-4′ was synthesized and fed to a mutant of S. coelicolor, which was unable to produce streptorubin B because it was blocked in 2-undecylpyrrole biosynthesis, and in which the genes responsible for the last two steps of streptorubin B biosynthesis were overexpressed. 1H and 2H NMR analysis of the stereoselectively deuterium-labeled streptorubin BHCl produced by this mutasynthesis strategy allowed us to assign the absolute stereochemistry of the major (anti) atropisomer as 7′S. HPLC analyses of streptorubin B isolated from S. coelicolor on a homochiral stationary phase and comparisons with streptorubin B derived from an enantioselective synthesis showed that the natural product consists of an approximately 88:7:5 mixture of the (7′S, anti), (7′S, syn), and (7′R, anti) stereoisomers.
- Haynes, Stuart W.,Sydor, Paulina K.,Corre, Christophe,Song, Lijiang,Challis, Gregory L.
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p. 1793 - 1798
(2011/04/12)
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- COMPOUNDS AND METHODS OF USE
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The present invention provides novel compounds useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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- Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: Potent inhibitors of heat shock protein 90
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A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (～25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (～100 nM).
- Wrona, Iwona E.,Gozman, Alexander,Taldone, Tony,Chiosis, Gabriela,Panek, James S.
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experimental part
p. 2820 - 2835
(2010/08/05)
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- Synthesis of azide-alkyne fragments for "Click" chemical applications. Part 2. Formation of oligomers from orthogonally protected chiral trialkylsilylhomopropargyl azides and homopropargyl alcohols
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(Chemical Equation Presented) A small library of chiral, β3-substituted homopropargyl alcohols and chiral β3-substituted trimethylsilylhomopropargyl azides were generated starting from natural L-amino acids. The free alkynes and azides were then coupled, using a Huisgen 1,3-dipolar cycloaddition, to provide chiral oligomeric 1,4-disubstituted-1,2,3-triazoles as potential peptidomimetic compounds. The work is an extension to the previous synthesis of racemic, orthogonally protected 1,4-disubstituted-1,2,3-triazoles from the corresponding α-substituted propargyl alcohols and α-substituted trialkylsilylpropargyl azides.
- Montagnat, Oliver D.,Lessene, Guillaume,Hughes, Andrew B.
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scheme or table
p. 390 - 398
(2010/03/30)
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- A synthetic approach to the fusicoccane A-B ring fragment based on a Pauson-Khand cycloaddition/Norrish type 1 fragmentation
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(Chemical Equation Presented) A synthetic approach to the A-B ring system within the fusicoccane family of diterpenes is presented. Key steps in this approach are a diastereoselective Pauson-Khand reaction, a Norrish 1 photofragmentation, a Charette cyclopropanation, and a ring-closing metathesis process.
- Dake, Gregory R.,Fenster, Erik E.,Patrick, Brian O.
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p. 6711 - 6715
(2008/12/22)
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- Probing the importance of the hemilabile site of bis(phosphine) monoxide ligands in the copper-catalyzed addition of diethylzinc to N-phosphinoylimines: Discovery of new effective chiral ligands
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(Chemical Equation Presented) The hemilabile ligand Me-DuPHOS(O) 2 has proven to be a successful ligand for the copper-catalyzed addition of diethylzinc to N-phosphinoylimines. The corresponding α-chiral amines were obtained in high yields (80-98%) and enantiomeric ratios (19.0:1 to 99.0:1 er). Furthermore, this Cu?2 catalytic system has been shown to be effective in the addition of diethylzinc to nitroalkenes and in the reduction of β,β-disubstituted vinyl phenyl sulfones. This paper describes a general structure/selectivity study in which the three ligand subunits (chiral phospholane-linker-labile coordinating group (Z)) are systematically modified and tested in the copper-catalyzed addition of diethylzinc to the N-phosphinoylimine 1 derived from benzaldehyde. This study led to the discovery of a new class of effective chiral ligands that combine a chiral phospholane unit and an achiral phosphine oxide.
- Bonnaventure, Isabelle,Charette, Andre B.
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p. 6330 - 6340
(2008/12/22)
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- Stereoselective Heck-Matsuda arylations of chiral dihydrofurans with arenediazonium tetrafluoroborates; an efficient enantioselective total synthesis of (-)-isoaltholactone
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The Heck-Matsuda arylation of chiral 2-(S)-hydroxymethyl dihydrofurans (endocyclic enolethers) and its derivatives, employing arenediazonium tetrafluoroborates, was developed into a highly efficient, practical and diastereoselective synthetic process. This methodology was applied to the total synthesis of the styryllactone (-)-isoaltholactone in seven steps with an overall yield of ～25%, from the readily available chiral 2-hydroxymethyldihydrofuran. The strategy permits the synthesis of several other aromatic analogues of isoaltholactone. Georg Thieme Verlag Stuttgart.
- Meira, Paulo Roberto Rodrigues,Moro, Angelica Venturini,Correia, Carlos Roque Duarte
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p. 2279 - 2286
(2008/02/13)
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- Pectenotoxin-2 synthetic studies. 2. Construction and conjoining of ABC and DE eastern hemisphere subtargets
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(Chemical Equation Presented) Practical asymmetric synthesis of aldehyde 2 and tetrazolyl sulfone 3 has allowed for their coupling via Julia olefination to generate 32 as a single product. This substance possesses the entire carbon backbone of the A-E substructure of pectenotoxin-2.
- Bondar, Dmitriy,Liu, Jian,Mueller, Thomas,Paquette, Leo A.
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p. 1813 - 1816
(2007/10/03)
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- Total synthesis of reblastatin
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Enantioselective total synthesis of reblastatin is described. The synthesis highlights hydrozirconation, transmetalation, aldehyde addition sequence to install E-trisubstituted olefin and C7 stereocenter, and the first use of an intramolecular Buchwald-like amidation reaction to close the 19-membered macrolactam. Copyright
- Wrona, Iwona E.,Gabarda, Ana E.,Evano, Gwilherm,Panek, James S.
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p. 15026 - 15027
(2007/10/03)
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- Novel peptides comprising furanoid sugar amino acids for the treatment of cancer
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Anticancer peptides which incorporate furanoid sugar amino acids and compositions made using these peptides are described. Methods for synthesis of the peptides and for preparing the furanoid sugar amino acids are disclosed. The peptides and compositions made using the peptides have pharmacological applications of these peptides especially in the treatment and prevention of cancer and tumors.
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- Total synthesis and structural confirmation of (+)-longicin
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(Chemical Equation Presented) A stereocontrolled total synthesis of (+)-longicin, a representative of the class of mono-THF-acetogenins, is described. The strategy involves the utilization of D- and L-glutamic acids as chirons that correspond to two five-carbon segments harboring stereogenic centers at C4 and at C17 of the C32 polyketide-derived natural product. The use of Grubbs' RCM reaction as a novel "chain elongation" strategy for the synthesis of acetogenin-type structures and a new protocol for butenolide incorporation are also described.
- Hanessian, Stephen,Giroux, Simon,Buffat, Maxime
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p. 3989 - 3992
(2007/10/03)
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- Enantioselective synthesis of key intermediates in a novel approach towards the Iboga-alkaloid family
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Significant improvements in the realm of a recently disclosed, novel synthetic concept towards the Iboga alkaloid family are presented. The key step for the construction of the bicyclic aliphatic core consists of an intramolecular nitrone-olefin 1,3-dipolar cycloaddition reaction of a 1:1 mixture 15/16 yielding the two diastereoisomeric tricyclic isoxazolidine derivatives 17 and 18. The required nitrones were prepared from the readily available (S)-hydroxylactone 6 in twelve steps with an oyerall yield of 15% (average: 83.5% per step). The relative configuration of the minor isomer was deduced unambiguously by single-crystal X-ray analysis of the derived tricyclic carbamate 21. As four out of five asymmetric centers in the pair 17/18 have opposite configuration, destruction of the one possessing the same absolute configuration transforms the original set of diastereoisomers into a pair of enantiomers. We verified this contention by oxidizing the two alcohols 20 and 22 to yield the two antipodal forms of ketone 23. The absence of significant amounts of by-product and the high reproducibility of the crucial cycloaddition reaction represent marked improvements over our earlier attempts. In addition, the new route, which starts from L-glutamate, should provide access to both naturally occurring antipodal series of the targeted alkaloid class.
- Hoeck, Stefan,Borschberg, Hans-Juerg
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p. 1397 - 1409
(2007/10/03)
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- Synthetic approach to analogues of the original structure of sclerophytin A
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A route to analogues of the original structure of sclerophytin A is described. The β-anomer of dideoxyribosyl nitriles 10a,b (prepared from glutamic acid) was converted into the methyl ketone 11. Addition of a silylated acetylide to 11 in diethyl ether/trimethylamine gave mainly 22a. Alkylation with methallyl halide and ozonolysis gave the ketone 24, which was then converted by hydrogenation and a second ozonolysis into the keto aldehyde 26. A two-step aldol process afforded the desired 3-pyrone 27 in good overall yield. However, several methods for the conversion of this enone 27 into the desired sclerophytin analogue 2 failed.
- Jung, Michael E.,Pontillo, Joseph
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p. 6848 - 6851
(2007/10/03)
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- Synthesis of (S)-3-heteroaryl-2-hydroxy-1-propyl benzoates by 'ring switching' methodology
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(S)-5-Benzoyloxymethyl-3-[(E)-(dimethylamino)methylidene]tetrahydrofuran-2- one (6), prepared in 5 steps from L-glutamic acid (1), was used as precursor in a one step 'ring switching' synthesis of (S)-2-hydroxy-3-heteroaryl-1-propyl benzoates 13-18, 23, 24. In the reaction of 6 with 2-aminopyridine (21) and 2-amino-4,6-dimethylpyrimidine (22) the corresponding dimethylamine substitution products (25, 26) were obtained.
- Mihelic, Damjana,Jakse, Renata,Svete, Jurij,Stanovnik, Branko,Grdadolnik, Simona Golic
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p. 1307 - 1312
(2007/10/03)
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- A facile entry to bicyclic systems from L-glutamic acid
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An efficient synthesis of bicyclic heterocycles has been realized from L-glutamic acid. The key step is the construction of the pyrrole ring in a single step, using tosylmethyl isocyanide (TosMIC) methodology. Structures of reaction intermediates and final products were investigated using density functional theory calculations.
- Frieman, Bryan A.,Bock, Charles W.,Bhat, Krishna L.
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p. 2099 - 2108
(2007/10/03)
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- Chemoenzymatic synthesis of optically active 4-methyl-tetrahydro-5-oxo- 2-furancarboxylic acids and esters
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Enantiomerically pure 4-methyl-tetrahydro-5-oxo-2-furancarboxylic acids and esters are prepared by enzymatic resolution of the chiral racemic esters. Their stereochemistry as well as their absolute configurations have been established by chemical correlation. The influence of the alkoxycarbonyl group at C-2 and that of the methyl group at C-4 on the sign of the Cotton effect in their CD spectra have been investigated. Formation of enantiomerically pure hydroxydiesters, precursors of the above-mentioned γ- lactones, by baker's yeast reduction of the corresponding ketodiesters was unsatisfactory. (C) 2000 Elsevier Science Ltd.
- Drioli, Sara,Forzato, Cristina,Nitti, Patrizia,Pitacco, Giuliana,Valentin, Ennio
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p. 1353 - 1366
(2007/10/03)
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- First total synthesis of Aspinolide B, a new pentaketide produced by Aspergillus ochraceus
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The first asymmetric total synthesis of Aspinolide B (1), a new 10-membered lactone discovered by chemical screening methods in the cultures of Aspergillus ochraceus, has been accomplished. The key steps included a selective Felkin-type addition of TMS-acetylene to aldehyde 3a and a Nozaki-Hiyama-Kishi coupling reaction to build the required 10-membered ring. This synthesis confirmed the absolute stereochemistry of aspinolide B, established through Helmchen's method and corrected its previously reported specific optical rotation.
- Pilli, Ronaldo A.,Victor, Mauricio M.,De Meijere, Armin
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p. 5910 - 5916
(2007/10/03)
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- Stereocontrolled synthesis of a trihydroxylated pyrrolizidine alkaloid, 7-deoxyalexine
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An enantiomerically and diastereomerically pure route has been developed for the asymmetric synthesis of (1R,2R,3R,7aS)-trihydroxylated pyrrolizidine alkaloid, 7-deoxyalexine, featuring the stereocontrolled elaboration of the functionalized homochiral lactam derived from 2,3,5-tri-O-obenzylol-β-D- arabinofuranose.
- Yoda, Hidemi,Asai, Fumihito,Takabe, Kunihiko
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p. 1001 - 1003
(2007/10/03)
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- The conversion of racemic terminal epoxides into either (+)- or (-)-diol γ- and δ-lactones
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The conversion of racemic terminal epoxides into either (+)- or (-)-diol γ-and δ-lactones was described with hydrolytic kinetic resolution (HKR). The optically active epoxide and diol were isolated together from the reaction mixture by bulb-to-bulb distillation. The HKR of racemic terminal epoxides gave active epoxides and diols which were converted into the corresponding lactones.
- Liu, Zhi-Yu,Ji, Jian-Xin,Li, Bo-Gang
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p. 3519 - 3521
(2007/10/03)
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- Synthesis of CMI-977, a potent 5-lipoxygenase inhibitor
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CMI-977 is a potent 5-lipoxygenase inhibitor that intervenes in the production of leukotrienes and is presently being developed for the treatment of chronic asthma. It is a single enantiomer with an all-trans (2S,5S) configuration. Of the four isomers of CMI-977, the S,S isomer was found to have the best biological activity and was selected for further development. The enantiomerically pure product was synthesized on a 2-kg scale from (S)-(+)-hydroxymethyl-γ-butyrolactone.
- Cai, Xiong,Chorghade, Mukund S.,Fura, Aberra,Grewal, Gurmit S.,Jauregui, Karen A.,Lounsbury, Heather A.,Scannell, Ralph T.,Yeh, C. Grace,Young, Michelle A.,Yu, Shaoxia,Guo, Liang,Moriarty, Robert M.,Penmasta, Raju,Rao, Munagala S.,Singhal, Rajesh K.,Song, Zhengzhe,Staszewski, James P.,Tuladhar, Sudersan M.,Yang, Sanmin
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- Chiral synthesis of (S)-(+)-γ-hydroxymethyl-γ-butyrolactone
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S-(+)-γ-hydroxymethyl-γ-butyrolactone has been synthesized from D- ribonolactone as chiral template.
- Salas-Reyes
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p. 2187 - 2199
(2007/10/03)
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