- Biosynthesis of lipstatin. Incorporation of multiply deuterium-labeled (5Z,8Z)-tetradeca-5,8-dienoic acid and octanoic acid
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Fermentation experiments with Streptomyces toxytricini were performed using (5Z,8Z)-[10,11,12,12-2H]tetradeca-5,8-dienoic acid or a mixture of [2,2-2H2]- and [8,8,8-2H3]octanoic acid as supplements. 2H NMR and mass spectroscopy confirmed the incorporation of (5Z,8Z)-[10,11,12,12-2H]tetradeca-5,8-dienoic acid into the C13 side chain as well as into the C6 side chain of lipstatin. Moreover, deuterium was incorporated into the C6 side chain of lipstatin from the 8-position but not from the 2-position of octanoate. The data establish that the β-lactone moiety of lipstatin is formed by condensation of a C8 and a C14 fatty acid with a concomitant exchange of the H-2 atoms of the C8 fatty acid.
- Goese,Eisenreich,Kupfer,Stohler,Weber,Leuenberger,Bacher
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Read Online
- Cross-Selective Aza-Pinacol Coupling via Atom Transfer Catalysis
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A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable β-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.
- Nagib, David A.,Rafferty, Sean M.,Rutherford, Joy E.,Wang, Lu,Zhang, Lumin
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supporting information
p. 5622 - 5628
(2021/05/07)
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- Enantioselective Total Synthesis of (+)-Heilonine
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Chemical transformations that rapidly and efficiently construct a high level of molecular complexity in a single step are perhaps the most valuable in total synthesis. Among such transformations is the transition metal catalyzed [2 + 2 + 2] cycloisomerization reaction, which forges three new C-C bonds and one or more rings in a single synthetic operation. We report here a strategy that leverages this transformation to open de novo access to the Veratrum family of alkaloids. The highly convergent approach described herein includes (i) the enantioselective synthesis of a diyne fragment containing the steroidal A/B rings, (ii) the asymmetric synthesis of a propargyl-substituted piperidinone (F ring) unit, (iii) the high-yielding union of the above fragments, and (iv) the intramolecular [2 + 2 + 2] cycloisomerization reaction of the resulting carbon framework to construct in a single step the remaining three rings (C/D/E) of the hexacyclic cevanine skeleton. Efficient late-stage maneuvers culminated in the first total synthesis of heilonine (1), achieved in 21 steps starting from ethyl vinyl ketone.
- Cassaidy, Kyle J.,Rawal, Viresh H.
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supporting information
p. 16394 - 16400
(2021/10/20)
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- Exploiting Synergistic Catalysis for an Ambient Temperature Photocycloaddition to Pyrazoles
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Sydnone-based cycloaddition reactions are a versatile platform for pyrazole synthesis, however they operate under harsh conditions (high temperature and long reaction times). Herein we report a strategy that addresses this limitation utilizing the synergistic combination of organocatalysis and visible-light photocatalysis. This new approach proceeds under ambient conditions and with excellent levels of regiocontrol. Mechanistic studies suggest that photoactivation of sydnones, rather than enamines, is key to the successful implementation of this process.
- Lakeland, Christopher P.,Watson, David W.,Harrity, Joseph P. A.
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supporting information
p. 155 - 159
(2019/12/11)
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- Bisheterocycle substituted oxa-spiro derivative, and preparation method and medical application thereof
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The invention relates to a bisheterocyclic substituted oxa-spiro derivative, and a preparation method and medical application thereof. Specifically, the invention discloses compounds of formula (I) and formula (II) or pharmaceutically acceptable salts, stereoisomers or solvates thereof, and a preparation method and application thereof. Each group in the formulas is as defined in the specificationand claims in detail.
- -
-
Paragraph 0406-0408
(2020/09/23)
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- Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
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A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ- or δ,δ-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
- Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
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supporting information
(2019/07/03)
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- Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
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A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η 3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ-or ?,?-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
- Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
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supporting information
p. 10048 - 10059
(2019/07/04)
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- COMPOUNDS, SALTS THEREOF AND METHODS FOR TREATMENT OF DISEASES
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The present disclosure relates to compounds according to Formula (I), treating diseases.
- -
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Paragraph 00311-00312
(2019/03/12)
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- Asymmetric one-pot synthesis of five- and six-membered lactones via dynamic covalent kinetic resolution: Exploring the regio- and stereoselectivities of lipase
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Cascade lipase-catalyzed lactonization has been applied to dynamic hemithioacetal formation, leading to efficient five- and six-membered lactone synthesis as well as chiral discrimination. Solvent-dependent regioselectivity was observed for the selective formation of 1,3-oxathiolan-5-one and γ-butyrolactone derivatives.
- Xu, Jintao,Hu, Lei
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supporting information
p. 868 - 871
(2019/02/24)
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- Total Synthesis of (+)-Guadinomic Acid via Hydroxyl-Directed Guanidylation
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Protecting-group-free total synthesis of (+)-guadinomic acid is reported using δ-valerolactone as a readily available starting material. The protocol utilizes the recent hydroxyl-directed guanidylation of unactivated alkenes as an approach for direct stereoselective incorporation of the guanidine unit furnishing the natural product in 7 steps.
- Reid, Bradley T.,Mailyan, Artur K.,Zakarian, Armen
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p. 9492 - 9496
(2018/06/22)
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- Dynamic kinetic resolution of 2-methyl-2-nitrocyclohexanol: Combining the intramolecular nitroaldol (Henry) reaction & lipase-catalysed resolution
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Efforts to combine the intramolecular nitroaldol reaction with lipase-catalysed resolution of the resulting nitroaldol adduct in a one-pot dynamic kinetic resolution (DKR) are described. Significant challenges were encountered in the combination of the two systems. trans-2-Methyl-2-nitrocyclohexyl acetate (±)-3b was isolated in excellent enantiopurity (>98% ee) via a sequential DKR sequence where the lipase-mediated resolution and base-mediated interconversion of 2-methyl-2-nitrocyclohexanol 2 were effected alternately, demonstrating the feasibility of this approach initially. Further work showed, for the first time, evidence that a DKR-type system is possible for 2. Reaction engineering allowed the design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity.
- Foley, Aoife M.,Gavin, Declan P.,Deasy, Rebecca E.,Milner, Sinéad E.,Moody, Thomas S.,Eccles, Kevin S.,Lawrence, Simon E.,Maguire, Anita R.
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p. 1435 - 1443
(2018/02/23)
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- One-pot chemoenzymatic synthesis of trolline and tetrahydroisoquinoline analogues
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Chemoenzymatic reaction cascades can provide access to chiral compounds from low-cost starting materials in one pot. Here we describe one-pot asymmetric routes to tetrahydroisoquinoline alkaloids (THIAs) using the Pictet-Spenglerase norcoclaurine synthase (NCS) followed by a cyclisation, to give alkaloids with two new heterocyclic rings. These reactions operated with a high atom economy to generate THIAs in high yields.
- Zhao, Jianxiong,Lichman, Benjamin R.,Ward, John M.,Hailes, Helen C.
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supporting information
p. 1323 - 1326
(2018/02/14)
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- Synthesis and Structure-Activity Relationship Studies of Anti-Inflammatory Epoxyisoprostane Analogues
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The lactone derivative of the epoxyisoprostane EC is a highly effective inhibitor of the secretion of the proinflammatory cytokine IL-6. Herein, a modular synthesis of analogues is described, allowing flexible variations of the cyclic side chain of the parent lactone. A structure-activity relationship study identified a lactam analogue that retains the high activity. Furthermore, the exocyclic allylic alcohol was shown to be crucial for the observed effect.
- Wolleb, Helene,Ogawa, Seiji,Schneider, Michael,Shemet, Andrej,Muri, Jonathan,Kopf, Manfred,Carreira, Erick M.
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supporting information
p. 3014 - 3016
(2018/05/28)
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- Intramolecular [2 + 2] Cycloadditions of Alkyl(phenylthio)ketenes: Total Synthesis of (+)-Sphaerodiol
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Asymmetric total synthesis of (+)-sphaerodiol (2) has been achieved. A key step is an intramolecular [2 + 2] cycloaddition of alkyl(phenylthio)ketene for rapid assembly of the decalin ring.
- Wu, Xiang,Wang, Hai-Jun,Huang, Yong-Shuang,Li, Wei-Dong Z.
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supporting information
p. 1871 - 1874
(2018/04/16)
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- Catalytic asymmetric synthesis of Leukotriene B4
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Leukotriene B4 1 was prepared from two chiral synthons 8 and 14. The chiral secondary alcohols of 8 and 14 were constructed by BINOL/Ti(OiPr)4 catalyzed enantioselective alkynylzinc addition to aldehydes.
- Yang, Pengfei,Zhong, Jiangchun,Ji, Kaijie,Yin, Jingwei,Li, Shuoning,Wei, Siyuan,Zhou, Yun,Wang, Lifeng,Wang, Min,Bian, Qinghua
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p. 1596 - 1601
(2017/10/20)
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- Microwave-Assisted Synthesis of Heterocycles by Rhodium(III)-Catalyzed Annulation of N-Methoxyamides with α-Chloroaldehydes
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α-Chloroaldehydes have been used as alkyne equivalents in rhodium-catalyzed syntheses of isoquinolones and 3,4-dihydroisoquinolins starting from N-methoxyamides. Compared to the existing technology, a complementary regioselectivity is achieved. Mechanistic investigations have been performed, and it was found that steric effects of both substrate and additive determine the product selectivity. Various other heterocycles, such as isoquinolines and lactones, can be prepared by transformation of the obtained products.
- Huang, Ji-Rong,Bolm, Carsten
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supporting information
p. 15921 - 15925
(2017/11/27)
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- Formal Synthesis of Ezetimibe Using a Proline-mediated, Asymmetric, Three-component Mannich Reaction
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The formal total synthesis of ezetimibe was accomplished using a proline-mediated, asymmetric, three-component Mannich reaction as the key step. The two stereogenic centers on the β-lactam skeleton of ezetimibe were controlled by the syn-selective asymmetric Mannich reaction, followed by isomerization.
- Shimasaki, Yasuharu,Koshino, Seitaro,Hayashi, Yujiro
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supporting information
p. 30 - 32
(2016/01/20)
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- Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs
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A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.
- Nicolaou, Kyriacos C.,Vourloumis, Dionisios,Totokotsopoulos, Sotirios,Papakyriakou, Athanasios,Karsunky, Holger,Fernando, Hanan,Gavrilyuk, Julia,Webb, Damien,Stepan, Antonia F.
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supporting information
p. 31 - 37
(2016/01/15)
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- Asymmetric synthesis of 12-hydroxyheptadecatrienoic acid and its 5,6-dihydro- and 14,15-dehydro-derivatives
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Natural 12-hydroxyheptadecatrienoic acid (12-HHT) with an S configuration was synthesised by a Suzuki-Miyaura coupling of C10-C17 iodo alcohol with C1-C9 vinylborane. The iodo alcohol was synthesised by utilising Sharpless asymmetric epoxidation of the corresponding trimethylsilyl alcohol. The method yielded more than 100 mg of 12-HHT. Similarly, syntheses of 5,6-dihydro- and 14,15-dehydro derivatives of 12-HHT, known as HHD and HHTE, respectively, were completed in a stereoselective manner.
- Kobayashi, Yuichi,Morita, Masao,Ogawa, Narihito,Kondo, Daiki,Tojo, Toshifumi
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p. 10667 - 10673
(2016/11/30)
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- Stereoselective synthesis of epoxyisoprostanes: an organocatalytic and "pot-economy" approach
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An efficient and direct synthetic route to epoxyisoprostane EC methyl ester has been accomplished in 8 steps (10% overall yield) from readily available starting materials using a series of asymmetric organocatalytic reactions and one-pot operations.
- Weng, Jiang,Wang, Sheng,Huang, Lin-Jie,Luo, Zhang-Yi,Lu, Gui
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supporting information
p. 10170 - 10173
(2015/06/22)
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- Molecular design of diene monomers containing an ester functional group for the synthesis of poly(diene sulfone)s by radical alternating copolymerization with sulfur dioxide
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Functional poly(diene sulfone)s are prepared by the radical alternating copolymerization of 1,3-diene monomers containing an ester substituent with sulfur dioxide. Methyl 3,5-hexadienoate (MH) and methyl 5,7-octadienoate (MO) with both an alkylene spacer and a terminal diene structure are suitable to produce a high-molecular-weight copolymer in a high yield, while the copolymerization of 5,7-nonadienoic acid, ethyl 2,4-pentadienoate, and ethyl 4-methyl-2,4-pentadienoate including either an alkylene spacer or a terminal diene structure lead to unsuccessful results. The 13C NMR chemical shift values of MH and MO suggest a high electron density at their reacting α-carbon for exhibiting a high copolymerization reactivity. Fluorene-containing diene monomers, 9-fluorenyl 3,5-hexadienoate (FH) and 9-fluorenyl 5,7-octadienoate (FO), are also prepared and copolymerized with sulfur dioxide. The thermal and optical properties of the poly(diene sulfone)s containing the methyl and fluorenyl ester substituents in the side chain are investigated.
- Matsumoto, Akikazu,Lee, Sungi,Okamura, Haruyuki
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p. 1000 - 1009
(2015/03/18)
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- A Domino Diels-Alder Approach toward the Tetracyclic Nicandrenone Framework
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The tetracarbocyclic framework of the nicandrenone natural products is formed in one step from a linear precursor via a domino intramolecular Diels-Alder/intramolecular furan Diels-Alder/aromatization sequence. The approach represents a new 0 → ABCD strategy for the preparation of aromatic steroids.
- MacKay, Emily G.,N?rret, Marck,Wong, Leon S.-M.,Louis, Ignace,Lawrence, Andrew L.,Willis, Anthony C.,Sherburn, Michael S.
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supporting information
p. 5517 - 5519
(2015/12/23)
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- Synthesis of substituted γ- and δ-lactams through Mannich-type reactions of solid-supported N-acyliminium ions
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We report the results of our recent investigations into the reactivity of cyclic solid-supported N-acyliminium ions. An intermolecular Mannich-type transformation of these intermediates was used to generate libraries of substituted lactams. Masked aldehyde building blocks were readily prepared and coupled to peptides immobilized on PEGA800(polyethylene glycol dimethyl acrylamide) resin through an HMBA [4-(hydroxymethyl)benzoic acid] linker. When treated with acid, the aldehyde was cleanly released and condensed with the amide backbone to form a hydroxylactam/N-acyliminium ion, which underwent intermolecular reactions with a series of nucleophilic heterocycles, such as substituted indoles, thiophenes, furans, and electron-rich benzenes. The resulting lactams were formed within a few minutes and in high purities (typically >85 %). A new and efficient method for the solid-phase synthesis of diversely substituted γ- and δ-lactams through Mannich-type reactions of cyclic N-acyliminium ions is presented. A wide range of external aromatic and heteroaromatic carbon nucleophiles could be successfully used in the sequence.
- Komnatnyy, Vitaly V.,Taveras, Kennedy M.,Nandurkar, Nitin S.,Le Quement, Sebastian T.,Givskov, Michael,Nielsen, Thomas E.
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p. 3524 - 3530
(2015/06/08)
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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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- Ugi 4-CR synthesis of γ- And δ-lactams providing new access to diverse enzyme interactions, a PDB analysis
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A three step synthesis of N-unsubstituted tetrazolo γ- and δ-lactams involving a key Ugi-4CR is presented. The compounds, otherwise difficult to access, are conveniently synthesized in overall good yields by our route. PDB analysis of the N-unsubstituted γ- and δ-lactam fragment reveals a strongly tri-directional hydrogen bond donor acceptor interaction with the amino acids of the binding sites.
- Boltjes, André,Liao, George P.,Zhao, Ting,Herdtweck, Eberhardt,D?mling, Alexander
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p. 949 - 952
(2014/07/08)
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- Discovery of a highly potent anti-inflammatory epoxyisoprostane-derived lactone
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Epoxyisoprostanes EI (1) and EC (2) are effective inhibitors of the secretion of proinflammatory cytokines IL-6 and IL-12. In detailed studies toward the investigation of the molecular mode of action of these structures, a highly potent lactone (3) derived from 1 was identified. The known isoprostanoids 1 and 2 are most likely precursors of 3, the product of facile intramolecular reaction between the epoxide with the carboxylic acid in 2.
- Egger, Julian,Bretscher, Peter,Freigang, Stefan,Kopf, Manfred,Carreira, Erick M.
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supporting information
p. 17382 - 17385
(2015/02/19)
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- Identification and synthesis of macrolide pheromones of the grain beetle oryzaephilus surinamensis and the frog spinomantis aglavei
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Macrolide lactones, the so called cucujolides derived from unsaturated fatty acids, are aggregation pheromones of cucujid grain beetles. Thirty years ago, Oehlschlarger etaal. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4) and the respective 12-olide (7) attract the sawtoothed grain beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5) increases the response synergistically. The frass of this beetle is attractive for its parasitoid Cephalonomia tarsalis, which potentially can be used for pest control. A GC/MS analysis of attractive frass showed the presence of 5, together with an unknown isomer. CucujolideaV was tentatively identified also in the femoral glands, pheromone-releasing structures, of the Madagascan mantelline frog Spinomantis aglavei. Therefore, a new route to synthesize doubly unsaturated macrolides allowing the flexible attachment of the side chain was developed. A straightforward method to obtain Zaconfigured macrolides involves ring-closing alkyne metathesis (RCAM) followed by Lindlar-catalyzed hydrogenation. This methodology was extended to homoconjugated diene macrolides by using RCAM after introduction of one Zaconfigured double bond in the precursor by Wittig reaction. A tungsten benzylidyne complex was used as the catalyst in the RCAM reaction, which afforded the products in high yield at room temperature. With the synthetic material at hand, the unknown isomer was identified as the new natural product (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX (8). Furthermore, the route also allowed the synthesis of cucujolideaV in good yield. The natural products were identified by the synthesis of enantiomerically pure or enriched material and gas chromatography on chiral phases. The new macrolide (R)-8 proved to be biologically active, attracting female O.asurinamensis, but no males. The synthetic material allowed the identification of (R)-5 in both the beetle and the frog. Attractive synthesis: Females of the sawtoothed grain beetle Oryzaephilus surinamensis are attracted to the new macrolide (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX, prepared by using a combination of Wittig reaction and ring-closing alkyne metathesis (RCAM; see scheme). The synthetic approach also allows the synthesis of the similar cucujolideaV, used by both the beetle and the mantellid frog Spinomantis aglavei.
- Hoetling, Susann,Haberlag, Birte,Tamm, Matthias,Collatz, Jana,Mack, Patrick,Steidle, Johannes L. M.,Vences, Miguel,Schulz, Stefan
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p. 3183 - 3191
(2014/03/21)
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- Synthesis of epoxyisoprostanes: Effects in reducing secretion of pro-inflammatory cytokines IL-6 and IL-12
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Anti-inflammatory: The efficient and general synthetic route to the elusive epoxyisoprostanoid phospholipids PECPC and PEIPC, along with the isoprostanoids EC and EI, relies on a number of stereo- and chemoselective steps, including a C-H insertion for the rapid construction of the cyclopentanone ring. The synthesized compounds display unprecedented biological activity in reducing the secretion of pro-inflammatory cytokines. Copyright
- Egger, Julian,Bretscher, Peter,Freigang, Stefan,Kopf, Manfred,Carreira, Erick M.
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supporting information
p. 5382 - 5385
(2013/06/26)
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- Amphidinolide B: Total synthesis, structural investigation, and biological evaluation
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The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.3 to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.
- Lu, Liang,Zhang, Wei,Nam, Sangkil,Horne, David A.,Jove, Richard,Carter, Rich G.
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p. 2213 - 2247
(2013/05/09)
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- Precise supramolecular control of selectivity in the Rh-catalyzed hydroformylation of terminal and internal alkenes
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In this study, we report a series of DIMPhos ligands L1-L3, bidentate phosphorus ligands equipped with an integral anion binding site (the DIM pocket). Coordination studies show that these ligands bind to a rhodium center in a bidentate fashion. Experiments under hydroformylation conditions confirm the formation of the mononuclear hydridobiscarbonyl rhodium complexes that are generally assumed to be active in hydroformylation. The metal complexes formed still strongly bind the anionic species in the binding site of the ligand, without affecting the metal coordination sphere. These bifunctional properties of DIMPhos are further demonstrated by the crystal structure of the rhodium complex with acetate anion bound in the binding site of the ligand. The catalytic studies demonstrate that substrate preorganization by binding in the DIM pocket of the ligand results in unprecedented selectivities in hydroformylation of terminal and internal alkenes functionalized with an anionic group. Remarkably, the selectivity controlling anionic group can be even 10 bonds away from the reactive double bond, demonstrating the potential of this supramolecular approach. Control experiments confirm the crucial role of the anion binding for the selectivity. DFT studies on the decisive intermediates reveal that the anion binding in the DIM pocket restricts the rotational freedom of the reactive double bound. As a consequence, the pathway to the undesired product is strongly hindered, whereas that for the desired product is lowered in energy. Detailed kinetic studies, together with the in situ spectroscopic measurements and isotope-labeling studies, support this mode of operation and reveal that these supramolecular systems follow enzymatic-type Michaelis-Menten kinetics, with competitive product inhibition.
- Dydio, Pawel,Detz, Remko J.,Reek, Joost N. H.
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supporting information
p. 10817 - 10828
(2013/08/23)
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- Study of the total synthesis of (-)-exiguolide
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In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.
- Cook, Cyril,Liron, Frederic,Guinchard, Xavier,Roulland, Emmanuel
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experimental part
p. 6728 - 6742
(2012/09/21)
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- Enantioselective total synthesis of (-)- Stenine
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In control: (-)-Stenine has been synthesized in 14 steps from commercially available compounds with an overall yield of 5.9 % by using a method that is based on double Michael addition. In the key step, the stereogenic centers that are required for (-)-stenine are generated in a highly stereocontrolled, asymmetric, one-pot cyclization to give a densely substituted cyclohexane core. Copyright
- Chen, Jingbo,Chen, Jingchao,Xie, Yan,Zhang, Hongbin
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supporting information; experimental part
p. 1024 - 1027
(2012/02/16)
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- Catalysis-based and protecting-group-free total syntheses of the marine oxylipins hybridalactone and the ecklonialactones A, B, and C
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Concise and protecting-group-free total syntheses of the marine oxylipins hybridalactone (1) and three members of the ecklonialactone family (2-4) were developed. They deliver these targets in optically pure form in 14 or 13 steps, respectively, in the longest linear sequence; five of these steps are metal-catalyzed and four others are metal-mediated. The route to either 1 or 2-4 diverges from the common building block 22, which is accessible in 7 steps from 2[5H]furanone by recourse to a rhodium-catalyzed asymmetric 1,4-addition reaction controlled by the carvone-derived diene ligand 35 and a ring-closing alkene metathesis (RCM) catalyzed by the ruthenium indenylidene complex 17 as the key operations. Alternatively, 22 can be made in 10 steps from furfural via a diastereoselective three-component coupling process. The further elaboration of 22 into hybridalactone as the structurally most complex target with seven contiguous chiral centers was based upon a sequence of cyclopropanation followed by a vanadium-catalyzed epoxidation, both of which were directed by the same free hydroxy group at C15. The macrocyclic scaffold was annulated to the headgroup by means of a ring-closing alkyne metathesis reaction (RCAM). In response to the unusually high propensity of the oxirane of the targeted oxylipins for ring opening, this transformation had to be performed with complexes of the type [(Ar3SiO)4Mo≡CPh] [K·OEt2] (43), which represent a new generation of exceedingly tolerant yet remarkably efficient catalysts. Their ancillary triarylsilanolate ligands temper the Lewis acidity of the molybdenum center but are not sufficiently nucleophilic to engage in the opening of the fragile epoxide ring. A final semireduction of the cycloalkyne formed in the RCAM step to the required (Z)-alkene completed the total synthesis of (-)-1. The fact that the route from the common fragment 22 to the ecklonialactones could follow a similar logic showcased the flexibility inherent to the chosen approach.
- Hickmann, Volker,Kondoh, Azusa,Gabor, Barbara,Alcarazo, Manuel,Fuerstner, Alois
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supporting information; experimental part
p. 13471 - 13480
(2011/10/10)
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- Remote supramolecular control of catalyst selectivity in the hydroformylation of alkenes
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In the pocket: The supramolecular interactions between a Rh phosphine catalyst equipped with an anion-binding pocket and alkenes that contain anionic functionalities (see picture) provide an excellent design concept to achieve remote control of the regioselectivity in hydroformylation reactions. The 4-pentenoate and 3-butenylphosphonate, which fit tightly between the Rh center and the pocket, were hydroformylated with unprecedented selectivity.
- Dydio, Pawea,Dzik, Wojciech I.,Lutz, Martin,De-Bruin, Bas,Reek, Joost N. H.
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supporting information; experimental part
p. 396 - 400
(2011/03/16)
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- Algal pheromone biosynthesis: Stereochemical analysis and mechanistic implications in gametes of ectocarpus siliculosus
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During sexual reproduction, female gametes or eggs of brown algae release pheromones to attract their male mating partners. The biologically active compounds comprise linear or alicyclic unsaturated hydrocarbons derived from the aliphatic terminus of C20 polyunsaturated fatty acids (PUFAs) by oxidative cleavage. The current study addresses the stereochemical course of the pheromone biosynthesis using female gametes of the marine brown alga E. siliculosus and chiral deuterium-labeled arachidonic acids. The biosynthetic sequence is likely to proceed via an intermediary 9-hydroperoxyarachidonic acid, which is cleaved with loss of the C(16)-HR into the C 11-hydrocarbon dictyopterene C and 9-oxonona-(5Z,7E)-dienoic acid.
- Rui, Fabio,Boland, Wilhelm
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supporting information; experimental part
p. 3958 - 3964
(2010/08/22)
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- METHOD FOR HYDROFORMYLATION
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The present invention relates to a process for the hydroformylation of compounds of the formula (I), where X is C, P(Rx), P(O—Rx) S or S(═O), where Rx is H, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetaryl; A is a divalent bridging group having from 1 to 4 bridging atoms; and R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or hetaryl; or salts thereof; in which the compound of the formula (I) is reacted with carbon monoxide and hydrogen in the presence of a catalyst comprising a complex of a metal of transition group VIII with a compound of the formula (II), where Pn is a pnicogen atom; W is a divalent bridging group having from 1 to 8 bridging atoms; R2 is a functional group capable of forming an intermolecular, noncovalent bond with the group —X(═O)OH; R3, R4 are each alkyl, cycloalkyl, heterocycloalkyl, aryl or hetaryl; a, b, c are each 0 or 1; and Y1, Y2 and Y3 are each O, S, NRa or SiRbRc; and also compounds of the formula (II.a), where W′ is a divalent bridging group having from 1 to 5 bridging atoms between the flanking bonds, Z is O, S, S(═O), S(═O)2, N(RIX) or C(RIX)(RX); and RI to RX are each, independently of one another, H, halogen, nitro, cyano, amino, alkyl, etc.; or two radicals RI, RII, RIV, RVI, RVIII and RIX together represent the second part of a double bond.
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Page/Page column 12
(2010/10/03)
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- Total synthesis of resolvin E2
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Resolvin E2 (2) was synthesized stereoselectively using the C1-8 and C15-20 aldehydes 6 and 9, which were connected to the C9-14 fragment by using Wittig reactions. The aldehyde 6 was prepared from the γ-silyl alcohol (S)-20 by a sequence of reactions involving ozonolysis, oxidation with NaIO4, and the Wittig reaction of the resulting aldehyde with Ph3P{double bond, long}CHCHO, whereas the aldehyde 9 was synthesized from the corresponding γ-silyl alcohol through epoxidation, reaction with Et2AlCN, and reduction with DIBAL-H.
- Kosaki, Yusuke,Ogawa, Narihito,Kobayashi, Yuichi
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scheme or table
p. 1856 - 1859
(2010/09/07)
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- Scope and limitations of the Minisci reaction for the synthesis of aza-heterocycles
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Attempts to prepare several classes of aza-heterocycles by application of the Minisci radical cyclisation reaction are described. Competing β-scission, hydrolytic cleavage and lactonisation reactions were found to be major hurdles to adopting this strategy for the synthesis of such targets.
- Burgin, Ryan N.,Jones, Simon,Tarbit
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scheme or table
p. 6772 - 6774
(2010/04/27)
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- Probing the active site of rat porphobilinogen synthase using newly developed inhibitors
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The structurally related tetrapyrrolic pigments are a group of natural products that participate in many of the fundamental biosynthetic and catabolic processes of living organisms. Porphobilinogen synthase catalyzes a rate-limiting step for the biosyntheses of tetrapyrrolic natural products. In the present study, a variety of new substrate analogs and reaction intermediate analogs were synthesized, which were used as probes for studying the active site of rat porphobilinogen synthase. The compounds 1, 3, 6, 9, 14, 16, and 28 were found to be competitive inhibitors of rat porphobilinogen synthase with inhibition constants ranging from 0.96 to 73.04 mM. Compounds 7, 10, 12, 13, 15, 17, 18, and 26 were found to be irreversible enzyme inhibitors. For irreversible inhibitors, loose-binding inhibitors were found to give stronger inactivation. The amino group and carboxyl group of the analogs were found to be important for their binding to the enzyme. This study increased our understanding of the active site of porphobilinogen synthase.
- Li, Nan,Chu, Xiusheng,Liu, Xiaojun,Li, Ding
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scheme or table
p. 33 - 40
(2009/05/30)
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- Studies on the mechanism, selectivity, and synthetic utility of lactone reduction using SmI2 and H2O
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Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI2, activation of the lanthanide reagent by H2O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI2-H2O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI2-H2O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.
- Parmar, Dixit,Duffy, Lorna A.,Sadasivam, Dhandapani V.,Matsubara, Hiroshi,Bradley, Paul A.,Flowers II, Robert A.,Procter, David J.
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supporting information; experimental part
p. 15467 - 15473
(2010/02/16)
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- Composition of the cloacal gland secretion of tuatara, Sphenodon punctatus
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The lipophilic content of the cloacal gland secretion of the tuatara (Sphenodon punctatus) was investigated. GC/EI-MS Analysis of CH2Cl2 extracts of the secretions revealed triacylglycerols as major glandular constituents. Twelve major medium-chain fatty acids were found to be conjugated to glycerol in different combinations, resulting in complex mixtures. These acids were identified by transesterification and subsequent derivatization of natural samples, and their structures were verified by synthesis. The natural glycerides contain predominantly three of the following acids: octanoic (A), (E)- and (Z)-oct-4-enoic (B and C, resp.), (4E,6Z)-octa-4,6-dienoic (tuataric acid;D), (R)-2,6-dimethylheptanoic (E), (R)-2,6-dimethylhept-5-enoic (F), (Z)-dec-4-enoic (G), (4Z,7Z)-deca-4,7-dienoic (H), (R)-3,7-dimethyloct-6-enoic (I), (R)-4,8-dimethylnon-7-enoic (J), (2R,6S)-2,6,10-trimethylundec-9-enoic (K), and (2R,5E)-2,6,10-trimethylundeca-5,9-dienoic acids (L). Several additional acids, occurring in trace amounts only, were tentatively identified by MS. The elucidation of the absolute configuration of the acids was performed by GC on chiral phases. Individual tuatara show specific mixtures of glycerides with up to 100 components. The individual mixtures may permit individual recognition because the bouquets seem to be stable over years.
- Flachsbarth, Birte,Fritzsche, Matthias,Weldon, Paul J.,Schulz, Stefan
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experimental part
p. 1 - 37
(2010/04/23)
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- Novel synthesis of substituted pyrrolidines and piperidines via radical addition-ionic cyclization reaction of oxime ethers
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We have developed a novel synthetic route to nitrogen-containing heterocycles via radical addition-ionic cyclization reaction. Treatment of oxime ethers carrying the tosyloxy group with Et3B and alkyl iodide in the presence of Lewis acid gave the substituted pyrrolidines and piperidines. The reaction of oxime ethers carrying the methoxycarbonyl group proceeded under the same conditions to give the amino esters, which were easily converted into the corresponding lactams by the treatment with concd HCl. On the other hand, the oxime ether bearing the phenoxycarbonyl group afforded directly alkylated lactams under the radical reaction conditions. The utility of this domino reaction was demonstrated by the synthesis of (±)-bgugaine and the formal synthesis of 5,8-disubstituted indolizidine alkaloids.
- Miyata, Okiko,Takahashi, Shinya,Tamura, Akira,Ueda, Masafumi,Naito, Takeaki
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p. 1270 - 1284
(2008/09/17)
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- Structure-activity relationship study of flowering-inducer FN against Lemna paucicostata
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FN1 (1) and FN2 (2), cycloadducts of α-ketol octadecadienoic acid (3) with norepinephrine (NE), induce flowering in Lemna paucicostata. In order to broaden our understanding of structural requirements of FN?for flower induction, nine analogs of 3 (4-12) were synthesized and reacted with NE under basic conditions. These analogs, except for 8, 10, and 12, exhibited significant activity regarding to floral induction in L. paucicostata. Similar experiments were carried out by using 3 and epinephrine, and it was demonstrated that these products also possessed biological activity.
- Kai, Kenji,Takeuchi, Jun,Kataoka, Taichi,Yokoyama, Mineyuki,Watanabe, Naoharu
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p. 6760 - 6769
(2008/12/21)
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- Total synthesis of cytotoxic macrolide amphidinolide B1 and the proposed structure of amphidinolide B2
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The first enantioselective total syntheses of cytotoxic macrolide amphidinolide B1 and the proposed structure for amphidinolide B2 have been accomplished. Key features of the syntheses include a diastereoselective aldol condensation, a spontaneous Wadsworth-Emmons macrocyclization and a directed epoxidation/elimination sequence. Copyright
- Lu, Liang,Zhang, Wei,Carter, Rich G.
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p. 7253 - 7255
(2008/12/20)
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- A supramolecular catalyst for regioselective hydroformylation of unsaturated carboxylic acids
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(Chemical Equation Presented) The quest to capture the catalytic power of enzymes is one of the great challenges of modern chemistry. A novel system inspired by the principles of enzymatic catalysis combines recognition of the substrate and transition-metal catalysis (see scheme; Do = donor, FG = functional group) and mimics enzyme properties - high efficiency, substrate selectivity, and reaction-site selectivity.
- Smejkal, Tomas,Breit, Bernhard
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p. 311 - 315
(2008/09/19)
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- Thiazole analogues and uses thereof
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The present invention relates to compounds of the general formula (I) and salts and physiologically functional derivatives thereof, R2 is attached at the 4- or 5-position of the thiazole ring and is hydrogen, alkyl, halogen, cyano, alkoxy, haloalkyloxy, or alkylamino; X independently represents a divalent linkage group selected from S, O, NR4, SO, or SO2; R4 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl; is attached at the 4- or 5-position of the thiazole ring and independently represents one of the following groups of the general formula (II): wherein the dotted line represents a single or double bond; * indicates the point of attachment to the thiazole ring; n is 1,2, or 3.
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Page/Page column 19
(2008/06/13)
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- Thiazole Analogues and Uses Thereof
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Compounds of formula (I) and salts and physiologically functional derivatives thereof, wherein R2 is attached at the 4- or 5-position of the thiazole ring and is hydrogen, alkyl, halogen, cyano, alkoxy, haloalkoxy, or alkylamino; X independently represents a divalent linkage group selected from S, O, NR4, SO, or SO2; R4 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl; R1 is attached at the 4- or 5-position of the thiazole ring and independently represents a group of formula (II): ?wherein the dotted line represents a single or double bond; * indicates the point of attachment to the thiazole ring; and n is 1, 2, or 3. Also disclosed are pharmaceutical compositions comprising the above compounds and method of treatments for cancer and other diseases.
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Page/Page column 14; 15
(2008/06/13)
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- A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor: Effect of various substitutions at the primary amino function
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In an effort to establish the structural requirements for agonism, neutral antagonism, and inverse agonism at the human histamine H3 receptor (H3R) we have prepared a series of higher homologues of histamine in which the terminal nitrogen of the side chain has been either mono- or disubstituted with several aliphatic, alicyclic, and aromatic moieties or incorporated in cyclic systems. The novel ligands have been pharmacologically investigated in vitro for their affinities on the human H3R and H4R subtypes by radioligand displacement experiments and for their intrinsic H3R activities via a CRE-mediated β-galactosidase reporter gene assay. Subtle changes of the substitution pattern at the side chain nitrogen alter enormously the pharmacological activity of the ligands, resulting in a series of compounds with a wide spectrum of pharmacological activities. Among the several neutral H3R antagonists identified within this series, compounds 2b and 2h display an H3R affinity in the low nanomolar concentration range (pKi values of 8.1 and 8.4, respectively). A very potent and selective H3R agonist (11, pEC 50 = 8.9, α = 0.94) and a very potent, though not highly selective, H3R inverse agonist (2k, pIC50 = 8.9, α = -0.97) have been identified as well.
- Govoni, Marinella,Lim, Herman D.,El-Atmioui, Dris,Menge, Wiro M. P. B.,Timmerman, Henk,Bakker, Remko A.,Leurs, Rob,De Esch, Iwan J. P.
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p. 2549 - 2557
(2007/10/03)
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- Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents
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To discover novel peroxisome proliferator-activated receptor γ (PPARγ) agonists that could be used as antidiabetic agents, we designed docosahexaenoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C(4)-position, based on the crystal structure of the ligand-binding pocket of PPARγ. These compounds were synthesized via iodolactone as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPARγ transactivation higher than, or comparable to, that of pioglitazone, which is a TZD derivative used as an antidiabetic agent. DHA derivatives related to these potent compounds 2 and 3 were also synthesized to study structure-activity relationships. Furthermore, 4-OH DHA 2, which shows strong PPARγ transcriptional activity, was separated as an optically pure form.
- Itoh, Toshimasa,Murota, Itsuki,Yoshikai, Kazuyoshi,Yamada, Sachiko,Yamamoto, Keiko
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- Surveying approaches to the formation of carbon-carbon bonds between a pyran and an adjacent ring
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We have examined several methods for the stereoselective formation of carbon-carbon bonds between contiguous rings where a stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxy enones, and epimerization of several α-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have proven C2-C2′ relative stereochemistry of 1-2 via a chemical correlation.
- Frein, Jeffrey D.,Rovis, Tomislav
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p. 4573 - 4583
(2007/10/03)
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- Inhibitors of cholesteryl ester transfer protein
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This invention relates to inhibitors of CETP and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders mediated by CETP.
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Page/Page column 29
(2010/02/15)
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