- Synthesis of Tetramic Acid Fragments Derived from Vancoresmycin Showing Inhibitory Effects towards S. aureus
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An efficient route to various vancoresmycin-type tetramic acids has been developed. The modular route is based on an effective Fries-type rearrangement to introduce various appending acetyl residues. The minimum inhibitory concentration (MIC) values of the new tetramic acids against Staphylococcus aureus and Escherichia coli were determined, revealing that three of the new compounds exhibit antimicrobial activity against S. aureus. These bioactive compounds were structurally most closely related to the authentic vancoresmycin building block. Additionally, the compounds induced a lial-lux bioreporter, which responds to cell wall stress induced by antibiotics that interfere with the lipid II biosynthesis cycle. These data suggest the tetramic acid moiety to be a part of the vancoresmycin pharmacophore.
- Wingen, Lukas Martin,Rausch, Marvin,Schneider, Tanja,Menche, Dirk
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- Asymmetric Synthesis of ent-Fissistigmatin C
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The asymmetric synthesis of ent-fissistigmatin C is successively accomplished in 12 steps (longest linear sequence (LLS)). Relying on the enantioselective coupling of aliphatic aldehyde with 2-hydroxychalcone promoted by cooperative organocatalysts, the pivotal linkage of ent-fissistigmatin C between the flavonoid and the sesquiterpenoid fragment was stereoselectively established. An unprecedented final-stage radical cascade was also featured in this synthesis, which enabled the simultaneous establishment of the trans-decalin framework via forging two consecutive C-C bonds in one step.
- Xu, Dongyang,Hu, Jiadong,Chen, Le,Chen, Lu,Su, Jiang,Yang, Jinjin,Deng, Siyu,Zhang, Hongli,Xie, Weiqing
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- Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship
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The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular
- Bemis, Christopher Y.,Ungarean, Chad N.,Shved, Alexander S.,Jamieson, Cooper S.,Hwang, Taehwan,Lee, Ken S.,Houk,Sarlah, David
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- Diene-transmissive cycloadditions: Control of monocycloaddition by self-assembly on a lewis acid template
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The sequential control of diene-transmissive Diels-Alder reactions to expand their versatility for natural product synthesis and the preparation of diversity oriented libraries is described. Self-assembly of the components (trienol 5 and methyl acrylate) via a Lewis acid template proceeds with regio-, diastereo-, and enantioselective [(S)-BINOL added] control to the monoadduct. In contrast, no cycloaddition reaction occurred at 22°C in the absence of catalyst. This protocol obliterates the necessity of tether installation for an intramolecular cyclization.
- Souweha, Michael Santos,Arab, Akram,ApSimon, Megan,Fallis, Alex G.
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- Approach to the homoerythrina alkaloids using a tandem N-alkylation/ azomethine ylide cycloaddition
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(Chemical Equation Presented) Synthetic efforts toward the homoerythrina alkaloids 1-3 are described. Two separate model systems guided the pivotal [3 + 2] azomethine ylide cycloaddition cascade to form the A-C rings of these alkaloids. The cycloaddition
- Pearson, William H.,Kropf, Jeffrey E.,Choy, Allison L.,Ill, Young Lee,Kampf, Jeff W.
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- Mechanistic Details of Asymmetric Bromocyclization with BINAP Monoxide: Identification of Chiral Proton-Bridged Bisphosphine Oxide Complex and Its Application to Parallel Kinetic Resolution
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The mechanism of our previously reported catalytic asymmetric bromocyclization reactions using 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) monoxide was examined in detail by the means of control experiments, NMR studies, X-ray structure analysis, and CryoSpray electrospray ionization mass spectrometry (ESI-MS) analysis. The chiral BINAP monoxide was transformed to a key catalyst precursor, proton-bridged bisphosphine oxide complex (POHOP·Br), in the presence of N-bromosuccinimide (NBS) and contaminating water. The thus-formed POHOP further reacts with NBS to afford BINAP dioxide and molecular bromine (Br2) simultaneously in equimolar amounts. While the resulting Br2 is activated by NBS to form a more reactive brominating reagent (Br2─NBS), BINAP dioxide serves as a bifunctional catalyst, acting as both a Lewis base that reacts with Br2─NBS to form a chiral brominating agent (P═O+─Br) and also as a Br?nsted base for the activation of the substrate. By taking advantage of this novel concerted Lewis/Br?nsted base catalysis by BINAP dioxide, we achieved the first regio- and chemodivergent parallel kinetic resolutions (PKRs) of racemic unsymmetrical bisallylic amides via bromocyclization.
- Hamashima, Yoshitaka,Hirokawa, Ryo,Hisanaga, Tatsunari,Ichikawa, Mamoru,Kawato, Yuji,Nagao, Yoshihiro,Takita, Ryo,Watanabe, Kohei,Yamashita, Kenji
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p. 3913 - 3924
(2022/03/15)
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- Modular Fragment Synthesis and Bioinformatic Analysis Propose a Revised Vancoresmycin Stereoconfiguration
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Elaborate fragments of the proposed stereostructure of the complex polyketide antibiotic vancoresmycin have been synthesized in a stereoselective fashion based on a modular and convergent approach. Significant nuclear magnetic resonance differences in one of these subunits compared with the natural product question the proposed stereoconfiguration. Consequently, an extensive bioinformatics analysis of the biosynthetic gene cluster was carried out, leading to a revised stereoconfigurational proposal for this highly potent antibiotic.
- Adamek, Martina,Essig, Sebastian,Kurz, Michael,Menche, Dirk,Sch?nenbroicher, Max,Seul, Maximilian,Spindler, Stefanie,Wingen, Lukas M.,Ziemert, Nadine
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p. 1175 - 1180
(2021/01/13)
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- Synthesis of Highly Functionalized Hydrindanes via Sequential Organocatalytic Michael/Mukaiyama Aldol Addition and Telescoped Hydrozirconation/Cross-Coupling as Key Steps: En Route to the AB System of Clifednamides
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The AB ring systems of the clifednamide family, polycyclic tetramate macrolactames (PoTeMs), were prepared by a new, convergent approach employing an intramolecular Diels-Alder (IMDA) reaction. Key steps comprise an organocatalytic Michael addition (>90% enantiomeric excess (ee)), a Mukaiyama aldol reaction for the convergent installation of a diene moiety, and a telescoped hydrozirconation/cross-coupling grafting an enone. The following IMDA furnished a highly functionalized hydrindane (diastereomeric ratio (dr) = 91:1) with the same configuration as the clifednamide scaffold. Advantages of this route are only one required protecting group, 13% overall yield over 9 steps (reduced from previously 17 steps/1.3% overall), and the potential access to the key intermediates in the clifednamide biosynthesis.
- Sinast, Moritz,Claasen, Birgit,St?ckl, Yannick,Greulich, Andreas,Zens, Anna,Baro, Angelika,Laschat, Sabine
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p. 7537 - 7551
(2021/06/25)
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- Highly Regioselective 5-endo-tet Cyclization of 3,4-Epoxy Amines into 3-Hydroxypyrrolidines Catalyzed by La(OTf)3
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Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.
- Hoshino, Yoshihiko,Iwabuchi, Yoshiharu,Kuriyama, Yuse,Sasano, Yusuke,Uesugi, Shun-ichiro,Yamaichi, Aoto
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p. 1961 - 1965
(2021/01/04)
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- MACROCYCLIC DIAMINE DERIVATIVES AS ENT INHIBITORS FOR THE TREATMENT OF CANCERS, AND COMBINATION THEREOF WITH ADENOSINE RECEPTOR ANTAGONISTS
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The present invention relates to macrocyclic diamine derivatives of formula II, including pharmaceutically acceptable salts and solvates thereof. Compounds of the invention are inhibitors of ENT family transporter, especially of ENT1, and are useful as therapeutic compounds for the treatment of cancers. The invention also relates to the combined use of the macrocyclic diamine derivatives with an adenosine receptor antagonist, for the treatment of cancers.
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Paragraph 0486; 0545
(2021/10/15)
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- Dictating Thermodynamic Control through Tethering: Applications to Stereoselective Bis-Spiroketal Synthesis
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Approaches to stereocontrol that invoke thermodynamic control fail when two or more potential products are energetically similar, but rational structural perturbations can be employed to break the energetic degeneracy and provide selective transformations. This manuscript illustrates that tethering is an effective approach for the stereoselective construction of bis-spiroketals with thermodynamically similar stereoisomers, providing a new approach to set remote stereocenters and prepare complex structures that have not previously been accessed stereoselectively.
- Asari, Austin H.,Floreancig, Paul E.
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p. 6622 - 6626
(2020/03/04)
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- First Total Syntheses of Novel Non-Enzymatic Polyunsaturated Fatty Acid Metabolites and Their Identification in Edible Oils
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Oxidative stress (OS) is an in vivo process leading to free radical overproduction, which triggers polyunsaturated fatty acid (PUFA) peroxidation resulting in the formation of racemic non-enzymatic oxygenated metabolites. As potential biomarkers of OS, their in vivo quantification is of great interest. However, since a large number of isomeric metabolites is formed in parallel, their quantification remains difficult without primary standards. Three new PUFA-metabolites, namely 18-F3t-isoprostane (IsoP) from eicosapentaenoic acid (EPA), 20-F4t-neuroprostane (NeuroP) from docosahexaenoic acid (DHA) and 20-F3t-NeuroP from docosapentaenoic acid (DPAn-3) were synthesized by two complementary synthetic strategies. The first one relied on a racemic approach to 18(RS)-18-F3t-IsoP using an oxidative radical anion cyclization as a key step, whereas the second used an enzymatic deracemization of a bicyclo[3.3.0]octene intermediate obtained from cyclooctadiene to pursue an asymmetric synthesis. The synthesized metabolites were applied in targeted lipidomics to prove lipid peroxidation in edible oils of commercial nutraceuticals.
- Pavlí?ková, Tereza,Bultel-Poncé, Valérie,Guy, Alexandre,Rocher, Amandine,Reversat, Guillaume,Vigor, Claire,Durand, Thierry,Galano, Jean-Marie,Jahn, Ullrich,Oger, Camille
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p. 10090 - 10098
(2020/07/24)
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- Synthesis of Two Stereoisomers of Potentially Bioactive 13,19,20-Trihydroxy Derivative of Docosahexaenoic Acid
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The C16-C22 fragment with the acetylene terminus was constructed through the asymmetric dihydroxylation of the corresponding olefin, while the 15-iodo-olefin corresponding to the C11-C15 part was prepared via the asymmetric transfer hydrogenation of the corresponding acetylene ketone followed by hydrozirconation/iodination. Both pieces were joined by a Sonogashira coupling, and the product was further converted into the title compound via a Wittig reaction with the remaining C1-C10 segment and Boland reduction using Zn with TMSCl.
- Ogawa, Narihito,Sone, Shinsaku,Hong, Song,Lu, Yan,Kobayashi, Yuichi
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p. 1735 - 1739
(2020/09/02)
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- Preparation of β2-Homologous Amino Acids Bearing Polar Side Chains via a Collective Synthesis Strategy
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β-Homologous amino acids (βhAAs) are a valuable class of building blocks for novel analogues of bioactive peptides. Thus, practical methods to synthesize enantiopure βhAAs are desirable. We report the application of a collective synthesis strategy to prepare protected β2-homologous amino acids with polar side chains. In this approach, a core structure is constructed via proline-catalyzed Mannich reaction and subsequently derivatized to furnish more than one protected β2-homologous amino acid with a proteinogenic side chain.
- Gellman, Samuel H.,Liu, Shi
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- Palladium- and Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazoles
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A complementing Pd- and Rh-catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N-allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry as certified drugs and potential drug candidates. The new methods feature high chemo-, regio- and enantioselectivities aside from displaying a broad substrate scope and functional group compatibility. A mechanistic rational accounting for allene racemization and trans-alkene selectivity is discussed.
- Hilpert, Lukas J.,Sieger, Simon V.,Haydl, Alexander M.,Breit, Bernhard
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p. 3378 - 3381
(2019/02/06)
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- Spiro[3.5]nonenyl Meroterpenoid Lactones, Cryptolaevilactones G-L, an Ionone Derivative, and Total Synthesis of Cryptolaevilactone M from Cryptocarya laevigata
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A CH3OH-CH2Cl2 (1:1) extract (N025439) of the leaves and twigs of Cryptocarya laevigata furnished eight new compounds, 1-8. Based on extensive 1D and 2D NMR spectroscopic data examination, the new δ-lactone derivatives 1-6 are monoterpene-polyketide hybrids containing a unique spiro[3.5]nonenyl moiety. Their trivial names, cryptolaevilactones G-L, follow those of the related known meroterpenoids cryptolaevilactones A-F. Cryptolaevilactone L (6) contains 11,12-cis-oriented substituents, while the other cryptolaevilactones contain trans-oriented groups. The structure of the linear δ-lactone 7, cryptolaevilactone M, was characterized from various spectroscopic data analysis, and the absolute configuration was determined by total synthesis through stereoselective allylation and Grubbs olefin metathesis. Compound 8 was elucidated to be an ionone derivative with a 3,4-syn-diol functionality.
- Tsurumi, Fumika,Miura, Yuta,Nakano, Misaki,Saito, Yohei,Fukuyoshi, Shuichi,Miyake, Katsunori,Newman, David J.,O'Keefe, Barry R.,Lee, Kuo-Hsiung,Nakagawa-Goto, Kyoko
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p. 2368 - 2378
(2019/10/02)
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- Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H Additions
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The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly observed.
- Costello, Jeff P.,Ferreira, Eric M.
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p. 9934 - 9939
(2019/12/24)
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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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- 3-(2,3-DIHYDRO-1H-INDEN-5-YL)PROPANOIC ACID DERIVATIVES AND THEIR USE AS NRF2 REGULATORS
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The present invention relates to compounds of Formula (I), and Formula (II), wherein B is benzotriazolyl, phenyl, triazolopyridinyl, or -(CH2)2-triazolyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from -C1-3 alkyl, -O-C1-3 alkyl, CN, - (CH2)2-O-(CH2)2-OR4 and halo; and D is -C(O)OH, -C(O)NHSO2CH3, -SO2NHC(O)CH3, 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl; and their use as NRF2 regulators.
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- Dihydropyrone compound and preparation method and purpose thereof
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The invention belongs to the field of drug synthesis and relates to a novel dihydropyrone compound and a preparation method and a purpose thereof. The chemical formula of the dihydropyrone compound isshown in the following general formula I, biological ex
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- TRICYCLIC COMPOUND SERVING AS IMMUNOMODULATOR
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Provided are compounds of formula I and formula II or pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. The compounds of formula I and formula II or the pharmaceutically acceptable salts of the compounds provide indole 2,3-dioxygenase (IDO) inhibitory activity and are capable of treating IDO-mediated immunosuppressive diseases, such as infectious diseases or cancer.
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- Approach to the Core Structure of 15- epi -Exiguolide
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The synthesis of seco acid 41 of the macrolactone part of 15- epi -exiguolide, containing a bis-pyran subunit and a trans double bond, is described. Key features of the synthetic strategy include a Feringa-Minnaard asymmetric organocuprate addition to uns
- Riefert, Alexander,Maier, Martin E.
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p. 3131 - 3145
(2018/08/17)
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- Design and synthesis of affinity chromatography ligands for the purification of 5-hydroxyeicosanoid dehydrogenase
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Arachidonic acid (AA) is converted to biologically active metabolites by different pathways, one of the most important of which is initiated by 5-lipoxygenase (5-LO). 5-Hydroxyeicosatetraenoic acid (5-HETE), although possessing only weak biological activity itself, is oxidized to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent chemoattractant for eosinophils and neutrophils. Our main goal is to determine how the biosynthesis of 5-oxo-ETE is regulated and to determine its pathophysiological roles. To achieve this task, we designed and synthesized affinity chromatography ligands for the purification of 5-hydroxyeicosanoid dehydrogenase (5-HEDH), the enzyme responsible for the formation of 5-oxo-ETE.
- Nagendra Reddy, Chintam,Grant, Gail E.,Ye, Qiuji,Powell, William S.,Patel, Pranav,Sivendran, Sashikala,Chourey, Shishir,Wang, Rui,Anumolu, Jaganmohan R.,Rokach, Joshua
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p. 116 - 125
(2016/12/22)
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- Stereoselective Total Syntheses of Polyacetylene Plant Metabolites via Ester-Tethered Ring Closing Metathesis
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Total syntheses of five naturally occurring polyacetylenes from three different plants are described. These natural products have in common an E,Z-configured conjugated diene linked to a di- or triyne chain. As the key method to stereoselectively establis
- Schmidt, Bernd,Aud?rsch, Stephan
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p. 1743 - 1760
(2017/02/10)
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- Total Synthesis of (-)-Marinisporolide C
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The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.
- Dias, Luiz C.,De Lucca, Emilio C.
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p. 3019 - 3045
(2017/03/23)
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- Synthesis of Naphthyridine Carbamate Dimer (NCD) Derivatives Modified with Alkanethiol and Binding Properties of G-G Mismatch DNA
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A series of new DNA binding molecules NCD-Cn-SH (n = 3, 4, 5, and 6) is reported, which possesses the NCD (naphthyridine carbamate dimer) domain selectively binding to the G-G mismatch in the 5′-CGG-3′/5′-CGG-3′ sequence and a thiol moiety, which undergoes spontaneous dimerization to (NCD-Cn-S)2 upon oxidation under aerobic conditions. The S-S dimer (NCD-Cn-S)2 produced the 1:1 binding complex with improved thermal stability. The dimer binding to the CGG/CGG DNA showed higher positive cooperativity than the binding of monomer and previously synthesized NCTn derivative. The dimerization of NCD-Cn-SH was selectively accelerated on the CGG repeat DNA but not on the CAG repeat DNA.
- Yamada, Takeshi,Miki, Shouta,Ul'Husna, Anisa,Michikawa, Akiko,Nakatani, Kazuhiko
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p. 4163 - 4166
(2017/08/23)
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- Multicomponent Catalytic Asymmetric Synthesis of trans-Aziridines
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A multicomponent trans-aziridination of aldehydes, amines, and diazo compounds with BOROX catalysts is developed. The optimal protocol is slightly different for aryl aldehydes than for aliphatic aldehydes. The key to the success with aryl aldehydes was allowing the catalyst, aldehyde, and amine to react for 20 min before addition of the diazo compound. A variety of 11 different electron-poor and electron-rich aryl aldehydes were screened to give trans-aziridines in 73-90% yield with 82-99% ee and trans/cis selectivities of 19:1 to >99:1. The optimal protocol for the trans-aziridination of aliphatic aldehydes did not require prereaction of the catalyst, aldehyde, and amine, and instead, the diazo compound could be added directly. The scope of the reaction is limited to unbranched aliphatic aldehydes and was tolerant of a number of functional groups including ethers, esters, epoxides, carbamates, and phthalimides. A total of 10 aliphatic aldehydes were examined and found to give trans-aziridines in 60-88% yield with 60-98% ee and trans/cis selectivities of 6:1 to >99:1. Alkenyl aldehydes did not react, but an alkynyl aldehyde gave a 71% yield and 95% ee of an aziridine that was found to be the cis- and not the trans-diastereomer. The aryl and aliphatic aldehydes both gave the trans-aziridines with the same absolute configuration with the same catalyst; however, in those cases where cis-aziridines were formed, the configuration was opposite for those formed from aryl versus aliphatic aldehydes.
- Zhou, Yubai,Gupta, Anil K.,Mukherjee, Munmun,Zheng, Li,Wulff, William D.
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p. 13121 - 13140
(2017/12/26)
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- A Boron Alkylidene–Alkene Cycloaddition Reaction: Application to the Synthesis of Aphanamal
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We describe an unusual net [2+2] cycloaddition reaction between boron alkylidenes and unactivated alkenes. This reaction provides a new method for the construction of carbocyclic ring systems bearing versatile organoboronic esters. Aside from surveying the scope of this reaction, we provide details about the mechanistic underpinnings of this process, and examine its application to the synthesis of the natural product aphanamal.
- Liu, Xun,Deaton, T. Maxwell,Haeffner, Fredrik,Morken, James P.
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supporting information
p. 11485 - 11489
(2017/09/11)
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- Gold-catalyzed three-component spirocyclization: A one-pot approach to functionalized pyrazolidines
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An efficient, highly atom economic synthesis of hitherto unknown spirocyclic pyrazolidines in a one-pot process was developed. The gold-catalyzed three-component coupling of alkynols, hydrazines and aldehydes or ketones likely proceeds via cycloisomerization of the alkynol to an exocyclic enol ether and subsequent [3 + 2]-cycloaddition of an azomethine ylide. A library of 29 derivatives with a wide range of functional groups was synthesized in up to 97% yield. With this new method, every position in the final product can be substituted which renders the method ideal for applications in combinatorial or medicinal chemistry.
- Wagner, Bernd,Hiller, Wolf,Ohno, Hiroaki,Krause, Norbert
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p. 1579 - 1583
(2016/02/10)
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- Hydroxyl-Assisted Carbonylation of Alkenyltin Derivatives: Development and Application to a Formal Synthesis of Tubelactomicin A
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Alkenyltin derivatives flanked by a hydroxyl group are subject to methoxycarbonylation when treated with catalytic amounts of Pd(OAc)2 and Ph3As in MeOH under a CO atmosphere; key to success is the use of 1,4-benzoquinone as a stoich
- Sommer, Heiko,Fürstner, Alois
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p. 3210 - 3213
(2016/07/13)
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- Organocatalytic Asymmetric Synthesis of Chiral Dioxazinanes and Dioxazepanes with in Situ Generated Nitrones via a Tandem Reaction Pathway Using a Cooperative Cation Binding Catalyst
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Heterocyclic skeletons play major roles in pharmaceuticals and biological processes. Cycloaddition reactions are most suitable synthetic tools to efficiently construct chemically diverse sets of heterocycles with great structural complexity owing to the s
- Liu, Yidong,Ao, Jun,Paladhi, Sushovan,Song, Choong Eui,Yan, Hailong
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p. 16486 - 16492
(2016/12/27)
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- NRF2 REGULATORS
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The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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- Synthesis of a stereoisomer of wortmannilactone C - failure and success
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Abstract A diastereomer of wortmannilactone C was synthesized according to a versatile strategy from tert-butyl 3-hydroxypropanoate and ethyl (R)-3-hydroxybutanoate, by using versatile organometallic reagents to control four stereogenic centers out of five. The successful strategy consists of the construction of the C13-C17 triene by using a Liebeskind coupling and the construction of the C2-C7 triene by utilizing a Horner-Wadsworth-Emmons reaction to form the macrocycle.
- Dittoo, Aurélia,Brandt, Damien,Bellosta, Véronique,Cossy, Janine
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p. 5835 - 5848
(2015/08/03)
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- Concise total syntheses of amphidinolides C and F
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The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late-stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other p-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from d-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate.
- Valot, Galle,Mailhol, Damien,Regens, Christopher S.,O'Malley, Daniel P.,Godineau, Edouard,Takikawa, Hiroshi,Philipps, Petra,Fürstner, Alois
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p. 2398 - 2408
(2015/02/05)
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- A chiral phosphoric acid catalyst for asymmetric construction of 1,3-dioxanes
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A novel method of enantioselective 1,3-dioxane construction via a hemiacetalization/intramolecular oxy-Michael addition cascade by a chiral phosphoric acid catalyst was developed. The product was successfully transformed into an optically active 1,3-polyo
- Matsumoto, Akira,Asano, Keisuke,Matsubara, Seijiro
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p. 11693 - 11696
(2015/07/15)
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- A Magnesium-Based Diastereoselective Preparation of Pyridylic 1,3-Amino Alcohols Using the tert -Butyl Sulfinamide Auxiliary
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1,3-Amino alcohols were prepared by using a two-step approach and an interesting reversal in diastereoselectivity is discussed.
- Fjelbye, Kasper,Svenstrup, Niels,Püschl, Ask
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p. 3231 - 3240
(2015/10/19)
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- Total Synthesis of the Oxopolyene Macrolide (-)-Marinisporolide C
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The first total synthesis of (-)-marinisporolide C was performed in 25 steps (longest linear sequence) and an overall yield of 1%. Due to the high degree of convergence and robustness, the C9-C35 fragment that corresponds to the polyol portion was obtaine
- Dias, Luiz C.,De Lucca, Emílio C.
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p. 6278 - 6281
(2016/01/09)
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- Total Synthesis and Tentative Structural Elucidation of Cryptomoscatone E3: Interplay of Experimental and Computational Studies
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A successful combination of computational chemistry and total synthesis was explored to tentatively elucidate the absolute configuration of cryptomoscatone E3, a polyketide isolated from the Brazilian tree Cryptocarya mandiocanna. Two independent synthetic approaches are discussed based on asymmetric allylation, ring closing metathesis, and aldol reactions.
- Novaes, Luiz F.T.,Sarotti, Ariel M.,Pilli, Ronaldo A.
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p. 12027 - 12037
(2016/01/09)
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- LEPTIN mRNA COMPOSITIONS AND FORMULATIONS
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A formulation comprising a modified synthetic messenger RNA and a delivery agent. The modified synthetic messenger RNA encodes a leptin protein, is non-replicating and is translation-ready. The formulation can be delivered to a subject with congenital leptin deficiency, lipodystrophy or other condition where circulating leptin level is low.
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Paragraph 0404; 0405; 0406
(2015/07/07)
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- LIPIDS AND LIPID COMPOSITIONS FOR THE DELIVERY OF ACTIVE AGENTS
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This invention provides for a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-R3, n, p, L1 and L2 are defined herein. The compounds of formula (I) and pharmaceutically acceptable salts thereof are cationic lipids useful in the delivery of biologically active agents to cells and tissues.
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Page/Page column 95
(2015/07/07)
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- Leveraging the micellar effect: Gold-catalyzed dehydrative cyclizations in water at room temperature
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The first examples of gold-catalyzed cyclizations of diols and triols to the corresponding hetero- or spirocycles in an aqueous medium are presented. These reactions take place within nanomicelles, where the hydrophobic effect is operating, thereby driving the dehydrations, notwithstanding the surrounding water. By the addition of simple salts such as sodium chloride, reaction times and catalyst loadings can be significantly decreased.
- Minkler, Stefan R. K.,Isley, Nicholas A.,Lippincott, Daniel J.,Krause, Norbert,Lipshutz, Bruce H.
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p. 724 - 726
(2014/03/21)
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- Synthesis of 2-deoxy-l-ribose via palladium(ii)-catalyzed cyclization
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We present a total synthesis of 2-deoxy-L-ribose through intramolecular palladium(II)-catalyzed cyclization of aldehyde via an unstable hemiacetal intermediate as the key step.
- Miyazawa, Masahiro,Akita, Erika,Onda, Kazusi,Narantsetseg, Magsarjav,Minabe, Haruna,Yokoyama, Hajime,Hirai, Yoshiro
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p. 399 - 412
(2014/03/21)
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- Controlling regiochemistry in the gold-catalyzed synthesis of unsaturated spiroketals
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A novel gold-catalyzed synthesis of unsaturated spiroketals that addresses regioselectivity issues commonly reported in metal-catalyzed spiroketalization of alkynes is reported. The reaction sequence is regulated by an acetonide protecting group which und
- Paioti, Paulo H. S.,Ketcham, John M.,Aponick, Aaron
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p. 5320 - 5323
(2015/01/16)
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- Spiroacetal formation through telescoped cycloaddition and carbon-hydrogen bond functionalization: Total synthesis of bistramide A
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Spiroacetals can be formed through a one-pot sequence of a hetero-Diels-Alder reaction an oxidative carbon-hydrogen bond cleavage and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramideA.
- Han, Xun,Floreancig, Paul E.
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p. 11075 - 11078
(2015/03/30)
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- Anionic polycyclization entry to tricycles related to quassinoids and terpenoids: A stereocontrolled total synthesis of (+)-cassaine
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A full account of our anionic polycyclization approach to access highly functionalized tricycles related to quassinoids and terpenoids from several optically active bicyclic enone systems and Nazarov reagents is presented. (+)-Carvone is the only chiral s
- Ravindar, Kontham,Caron, Pierre-Yves,Deslongchamps, Pierre
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p. 7979 - 7999
(2015/03/18)
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- Chroman-4-one- and chromone-based sirtuin 2 inhibitors with antiproliferative properties in cancer cells
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Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of Nε-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.
- Seifert, Tina,Malo, Marcus,Kokkola, Tarja,Engen, Karin,Fridén-Saxin, Maria,Wallén, Erik A. A.,Lahtela-Kakkonen, Maija,Jarho, Elina M.,Luthman, Kristina
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p. 9870 - 9888
(2015/02/05)
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- Total synthesis of cryptomoscatones D1 and D2: Stereochemical assignment of cryptomoscatone D1
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The first total synthesis and structural elucidation of cryptomoscatone D1, and a novel synthetic approach for cryptomoscatone D2 were achieved in 30% and 29% overall yield, respectively. The synthesis relied on the use of a key Mukaiyama aldol reaction followed by a diastereoselective carbonyl reduction that allowed the preparation of four cryptomoscatone isomers in a stereochemically divergent manner. Comparison of NMR data and CD curves of the synthetic stereoisomers and natural products confirmed the stereochemical nature of cryptomoscatone D2, and led to establishing the absolute configuration of cryptomoscatone D1.
- Toneto Novaes, Luiz Fernando,Drekener, Roberta Lopes,Avila, Carolina Martins,Pilli, Ronaldo Aloise
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p. 6467 - 6473
(2015/03/30)
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- Synthesis of cyclic alkenylsiloxanes by semihydrogenation: A stereospecific route to (Z)-alkenyl polyenes
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Cyclic alkenylsiloxanes were synthesized by semihydrogenation of alkynylsilanes - a reaction previously plagued by poor stereoselectivity. The silanes, which can be synthesized on multigram scale, undergo Hiyama-Denmark coupling to give (Z)-alkenyl polyene motifs found in bioactive natural products. The ring size of the silane is crucial: five-membered cyclic siloxanes also couple under fluoride-free conditions, whilst their six-membered homologues do not, enabling orthogonality within this structural motif.
- Elbert, Bryony L.,Lim, Diane S. W.,Gudmundsson, Haraldur G.,O'Hanlon, Jack A.,Anderson, Edward A.
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supporting information
p. 8594 - 8598
(2014/07/21)
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- Synthesis of the C1-C11 western fragment of madeirolide A
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The stereocontrolled synthesis of a fully elaborated C1-11 subunit of madeirolide A is described, utilizing an asymmetric boron aldol reaction and a cis-selective hetero-Michael cyclization to form the tetrahydropyran ring, followed by efficient formation of the required C5 α-glycoside.
- Paterson, Ian,Haslett, Gregory W.
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supporting information
p. 1338 - 1341
(2013/05/09)
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- The cinchona primary amine-catalyzed asymmetric epoxidation and hydroperoxidation of α,β-unsaturated carbonyl compounds with hydrogen peroxide
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Using cinchona alkaloid-derived primary amines as catalysts and aqueous hydrogen peroxide as the oxidant, we have developed highly enantioselective Weitz-Scheffer-type epoxidation and hydroperoxidation reactions of α,β-unsaturated carbonyl compounds (up to 99.5:0.5 er). In this article, we present our full studies on this family of reactions, employing acyclic enones, 5-15-membered cyclic enones, and α-branched enals as substrates. In addition to an expanded scope, synthetic applications of the products are presented. We also report detailed mechanistic investigations of the catalytic intermediates, structure-activity relationships of the cinchona amine catalyst, and rationalization of the absolute stereoselectivity by NMR spectroscopic studies and DFT calculations.
- Lifchits, Olga,Mahlau, Manuel,Reisinger, Corinna M.,Lee, Anna,Fares, Christophe,Polyak, Iakov,Gopakumar, Gopinadhanpillai,Thiel, Walter,List, Benjamin
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p. 6677 - 6693
(2013/06/05)
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- Total synthesis of amphidinolide f
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Orchestrated yet nonconsonant: The challenge posed by the "umpoled" 1,4-dioxygenation pattern characteristic for the polyketide frame of amphidinolide F was mastered by a late-stage ring-closing alkyne metathesis followed by a directed transannular hydration under the aegis of a carbophilic π-acid catalyst. This concordant strategy enabled a concise total synthesis of this enticing marine natural product. Copyright
- Valot, Ga?lle,Regens, Christopher S.,O'Malley, Daniel P.,Godineau, Edouard,Takikawa, Hiroshi,Fürstner, Alois
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p. 9534 - 9538
(2013/09/23)
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- Solar photochemistry: Optimisation of the photo Friedel-Crafts acylation of naphthoquinones
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A practical and robust photo Friedel-Crafts acylation of naphthoquinones is described. Although the reaction proceeds slowly in sunlight, the optimised conditions offer a substantial improvement to those already reported, by the utilisation of a more reliable and practical 'sun-mimicking' light source, a less hazardous solvent system (trifluorotoluene) and faster reaction times. Using these conditions, the reaction scope has been expanded to include functionalised aldehyde and naphthoquinone substrates, affording the desired photo-products in acceptable to excellent yields (17-81%). Factors influencing the regiochemistry of the photo Friedel-Crafts reaction on unsymmetrical naphthoquinones have also been investigated.
- Mitchell, Lorna J.,Lewis, William,Moody, Christopher J.
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p. 2830 - 2842
(2013/10/08)
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