- Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs
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Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
- Balazs, Amber,Barratt, Derek,Bista, Michal,Chuba, Matthew D.,Cosulich, Sabina,Critchlow, Susan E.,Degorce, Sébastien L.,Di Fruscia, Paolo,Edmondson, Scott D.,Embrey, Kevin,Fawell, Stephen,Ghosh, Avipsa,Gill, Sonja J.,Gunnarsson, Anders,Hande, Sudhir M.,Heightman, Tom D.,Hemsley, Paul,Illuzzi, Giuditta,Johannes, Jeffrey W.,Lane, Jordan,Larner, Carrie,Leo, Elisabetta,Liu, Lina,Madin, Andrew,Martin, Scott,McWilliams, Lisa,O'Connor, Mark J.,Orme, Jonathan P.,Pachl, Fiona,Packer, Martin J.,Pei, Xiaohui,Pike, Andrew,Schimpl, Marianne,She, Hongyao,Staniszewska, Anna D.,Talbot, Verity,Underwood, Elizabeth,Varnes, Jeffrey G.,Xue, Lin,Yao, Tieguang,Zhang, Andrew X.,Zhang, Ke,Zheng, Xiaolan
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supporting information
p. 14498 - 14512
(2021/10/20)
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- Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application
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The invention relates to a compound for inhibiting the activity of Bcl-2/BCL-XL anti-apoptotic protein, a composition containing the compound and application of the compound serving as a synthetic drug, in particular to application of the compound serving as a drug for synthesizing a Bcl-2/BCL-XL anti-apoptotic protein inhibitor and application of the compound to cancer.
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Paragraph 0045-0048; 0050; 0052-0053
(2020/11/12)
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- NHC-Mediated Synthesis of Tricyclic Spirocarbocycles via an Intramolecular Stetter Reaction of Cyclic Enal-Enones
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A general and efficient method for the synthesis of tricyclic spirocarbocycles is described. Various cyclic enal-enones were reacted with an N-heterocyclic carbene, and an intramolecular Stetter reaction proceeded smoothly to give various tricyclic spiro-
- Hsu, Day-Shin,Liang, Suz-Ping
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p. 1270 - 1278
(2019/12/30)
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- Mechanistic Divergence in the Hydrogenative Synthesis of Furans and Butenolides: Ruthenium Carbenes Formed by gem-Hydrogenation or through Carbophilic Activation of Alkynes
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Enynes with a tethered carbonyl substituent are converted into substituted furan derivatives upon hydrogenation using [Cp*RuCl]4 as the catalyst. Paradoxically, this transformation can occur along two distinct pathways, each of which proceeds via discrete pianostool ruthenium carbenes. In the first case, hydrogenation and carbene formation are synchronized (“gem-hydrogenation”), whereas the second pathway comprises carbene formation by carbophilic activation of the triple bond, followed by hydrogenative catalyst recycling. Representative carbene intermediates of either route were characterized by X-ray crystallography; the structural data prove that the attack of the carbonyl group on the electrophilic carbene center follows a Bürgi–Dunitz trajectory.
- Peil, Sebastian,Fürstner, Alois
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supporting information
p. 18476 - 18481
(2019/11/14)
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- Controlling the Selectivity Patterns of Au-Catalyzed Cyclization-Migration Reactions
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As little as 2 mol % of (XPhos)AuNTf2 catalyzes the transformation of a broad range of o-acetylene-substituted styrenes into 1,2-dihydronaphthalenes. Our data suggests that this transformation occurs via a gold-stabilized cyclopropyl carbinyl cation, which triggers either a [1,2] carboxylate shift or a less favorable [1,2] aryl shift. The relative rates of these migrations can be controlled by the identity of the ligand or by stabilizing the mesomeric cation.
- Chen, Mo,Su, Naijing,Deng, Tianning,Wink, Donald J.,Zhao, Yingwei,Driver, Tom G.
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supporting information
p. 1555 - 1558
(2019/03/20)
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- Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction
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Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed.
- Seefeld, Mark A.,Lin, Hong,Holenz, Joerg,Downie, Dave,Donovan, Brian,Fu, Tingting,Pasikanti, Kishore,Zhen, Wei,Cato, Matthew,Chaudhary, Khuram W.,Brady, Pat,Bakshi, Tania,Morrow, Dwight,Rajagopal, Sridharan,Samanta, Swapan Kumar,Madhyastha, Naveena,Kuppusamy, Bharathi Mohan,Dougherty, Robert W.,Bhamidipati, Ravi,Mohd, Zainuddin,Higgins, Guy A.,Chapman, Mark,Rouget, Céline,Lluel, Philippe,Matsuoka, Yasuji
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p. 3793 - 3797
(2018/10/20)
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- Achieving Site Selectivity in Metal-Catalyzed Electron-Rich Carbene Transfer Reactions from N-Tosylhydrazones
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Catalyst control of the site-selectivity of electron-rich alkyl, aryl disubstituted carbenes generated in situ from o-alkenyl-substituted N-tosylhydrazones was achieved in this study. Exposure of these substrates to copper iodide triggered the formation of α-alkoxy 2H-naphthalenones. This investigation established that changing the catalyst to a rhodium(II) carboxylate turned off cyclization and migration of the electron-rich metal carbene with the β-carboxylate and turned on allylic C-H bond functionalization to diastereoselectively afford 1H-indenes. Examination of the scope of this reaction revealed that ethereal, aminomethylene, and unactivated 2° C-H bonds could be functionalized.
- Su, Naijing,Deng, Tianning,Wink, Donald J.,Driver, Tom G.
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supporting information
p. 3990 - 3993
(2017/08/15)
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- A Pd-catalyzed, boron ester-mediated, reductive cross-coupling of two aryl halides to synthesize tricyclic biaryls
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Tricyclic biaryls are important scaffold structures in many natural products and lead compounds in drug discovery. The formation of a biaryl unit is often the key step for the synthesis of tricyclic biaryls. Despite significant progress toward the synthesis of biaryl compounds in recent years, the direct cross-coupling of two different aryl halides is still challenging and robust methods are lacking. Herein we report a direct cross-coupling of two different aryl halides in the presence of a palladium catalyst and boron ester, which provides a new and useful complementary method to synthesize tricyclic biaryls.
- Chen, Zhilong,Wang, Xiaodong
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supporting information
p. 5790 - 5796
(2017/07/22)
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- Control of the Chemoselectivity of Metal N-Aryl Nitrene Reactivity: C-H Bond Amination versus Electrocyclization
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A mechanism study to identify the elements that control the chemoselectivity of metal-catalyzed N-atom transfer reactions of styryl azides is presented. Our studies show that the proclivity of the metal N-aryl nitrene to participate in sp3-C-H bond amination or electrocyclization reactions can be controlled by either the substrate or the catalyst. Electrocyclization is favored for mono-β-substituted and sterically noncongested styryl azides, whereas sp3-C-H bond amination through an H-atom abstraction-radical recombination mechanism is preferred when a tertiary allylic reaction center is present. Even when a weakened allylic C-H bond is present, our data suggest that the indole is still formed through an electrocyclization instead of a common allyl radical intermediate. The site selectivity of metal N-aryl nitrenes was found to be controlled by the choice of catalyst: Ir(I)-alkene complexes trigger electrocyclization processes while Fe(III) porphyrin complexes catalyze sp3-C-H bond amination in substrates where Rh2(II) carboxylate catalysts provide both products.
- Kong, Chen,Jana, Navendu,Jones, Crystalann,Driver, Tom G.
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supporting information
p. 13271 - 13280
(2016/10/22)
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- Rh2(II)-catalyzed ester migration to afford 3 H-indoles from trisubstituted styryl azides
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Rh2(II)-Complexes trigger the formation of 3H-indoles from ortho-alkenyl substituted aryl azides. This reaction occurs through a 4π-electron-5-atom electrocyclization of the rhodium N-aryl nitrene followed by a [1,2]-migration to afford only 3H-indoles. The selectivity of the migration is dependent on the identity of the β-styryl substituent.
- Kong, Chen,Driver, Tom G.
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supporting information
p. 802 - 805
(2015/04/27)
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- Promoting reductive tandem reactions of nitrostyrenes with Mo(CO)6 and a palladium catalyst to produce 3 h -indoles
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The combination of Mo(CO)6 and 10 mol % of palladium acetate catalyzes the transformation of 2-nitroarenes to 3H-indoles through a tandem cyclization-[1,2] shift reaction of in situ generated nitrosoarenes. Mo(CO)6 appears to have dual roles in this transformation: generate CO and promote C-N bond formation to increase the yield of the N-heterocycle product.
- Jana, Navendu,Zhou, Fei,Driver, Tom G.
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supporting information
p. 6738 - 6741
(2015/06/16)
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- The profound effect of the ring size in the electrocyclic opening of cyclobutene-fused bicyclic systems
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Fused cyclobutenes, prepared by the photocycloaddition of propargyl alcohols to cyclic anhydride chromophores, undergo facile thermochemical ring opening to fused γ-lactones. The size of the fused ring profoundly influences the temperature that is required to facilitate the ring opening (from 50°C to 180°C) and the nature of the product that is formed. Our studies provide new insights into the mechanistic course of these reactions and have been extended to facilitate the preparation of lactams fused to medium-sized rings.
- Ralph, Michael J.,Harrowven, David C.,Gaulier, Steven,Ng, Sean,Booker-Milburn, Kevin I.
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supporting information
p. 1527 - 1531
(2015/01/30)
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- Copper-Catalyzed Formation of α-Alkoxycycloalkenones from N-Tosylhydrazones
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The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized α-alkoxy 2H-naphthalenones from readily available N-tosylhydrazones. The data suggests that this transformation occurs through cycloaddition of a copper carbenoid with an ester, followed by a Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate. The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized α-alkoxy 2H-naphthalenones from readily available N-tosylhydrazones. The reaction proceeds by the cycloaddition of a copper carbenoid with an ester, and a subsequent Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate.
- Su, Naijing,Theorell, Juliana A.,Wink, Donald J.,Driver, Tom G.
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supporting information
p. 12942 - 12946
(2015/11/02)
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- Enantioselective synthesis of cis-1,2-disubstituted cyclopentanes and cyclohexanes by Suzuki-Miyaura cross-coupling and iridium-catalyzed asymmetric hydrogenation
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A series of 1,2-disubstituted cyclohexene derivatives was prepared through Suzuki-Miyaura cross-coupling of 2-bromo-1-cyclohexenecarbaldehyde or 2-carbomethoxy-1-cyclohexen-1-yl triflate with arylboronates. These tetra-substituted cyclic alkenes were subjected to Ir-catalyzed asymmetric hydrogenation. In this way cis-1-methoxymethyl-2-arylcyclohexanes were obtained in high yield with excellent enantio- and diastereoselectivities (up to >99%ee, >99%cis) by using phosphinomethyloxazolines as ligands. Asymmetric hydrogenation of analogous cyclopentene derivatives, prepared by Suzuki-Miyaura cross-coupling, proved to be more difficult and proceeded with lower enantioselectivities of up to 88%ee. The synthetic potential of this cross-coupling/asymmetric-hydrogenation strategy was demonstrated by an enantioselective route to chiral hexahydrofluorenones. Alkene interest: Starting from arylboronates, a variety of cyclic, tetra-substituted olefins was prepared by Suzuki-Miyaura cross-coupling (see scheme). Subsequent Ir-catalyzed asymmetric hydrogenation with phosphanylmethyloxazoline ligand complexes led to cis-disubstituted cycloalkane derivatives in high yield and excellent enantio- and distereoselectivities. Copyright
- Schumacher, Andreas,Schrems, Marcus G.,Pfaltz, Andreas
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supporting information; experimental part
p. 13502 - 13509
(2012/01/05)
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- Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions
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SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ40 lowering model.
- Su, Jing,Tang, Haiqun,McKittrick, Brian A.,Xu, Ruo,Clader, John W.,Greenlee, William J.,Hyde, Lynn,Zhang, Lili
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scheme or table
p. 3447 - 3451
(2011/07/07)
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- Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): A potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate
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Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR 109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
- Shen, Hong C.,Ding, Fa-Xiang,Raghavan, Subharekha,Deng, Qiaolin,Luell, Silvi,Forrest, Michael J.,Carballo-Jane, Ester,Wilsie, Larissa C.,Krsmanovic, Mihajlo L.,Taggart, Andrew K.,Wu, Kenneth K.,Wu, Tsuei-Ju,Cheng, Kang,Ren, Nina,Cai, Tian-Quan,Chen, Qing,Wang, Junying,Wolff, Michael S.,Tong, Xinchun,Holt, Tom G.,Waters, M.Gerard,Hammond, Milton L.,Tata, James R.,Colletti, Steven L.
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supporting information; experimental part
p. 2666 - 2670
(2010/08/22)
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- Anthranilic acid replacements in a niacin receptor agonist
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Niacin is an effective drug for raising HDL cholesterol. However, niacin must be taken in large doses and significant side effects are often observed, including facial flushing, loss of glucose tolerance, and liver toxicity. An anthranilic acid was identified as an agonist of the niacin receptor. In order to improve efficacy and provide structural diversity, replacements for the anthranilic acid were investigated and several compounds with improved properties were identified.
- Schmidt, Darby,Smenton, Abigail,Raghavan, Subharekha,Shen, Hong,Ding, Fa-Xiang,Carballo-Jane, Ester,Luell, Silvi,Ciecko, Tanya,Holt, Tom G.,Wolff, Michael,Taggart, Andrew,Wilsie, Larissa,Krsmanovic, Mihajlo,Ren, Ning,Blom, Daniel,Cheng, Kang,McCann, Peggy E.,Waters, M.Gerard,Tata, James,Colletti, Steven
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scheme or table
p. 3426 - 3430
(2010/08/07)
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- Synthesis, inhibition and binding of simple non-nitrogen inhibitors of monoamine transporters
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A series of simple truncated analogues of phenyl tropanes, 2-arylcycloalk-1-enyl carboxylic acid methylesters, were prepared and investigated for their activity towards the dopamine, serotonin and norepinephrine transporters. The compounds were prepared f
- Petersen, Mikkel Due,Boye, Soren Valdgard,Nielsen, Erik Holm,Willumsen, Jeanette,Sinning, Steffen,Wiborg, Ove,Bols, Mikael
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p. 4159 - 4174
(2008/03/12)
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- QSAR studies and pharmacophore identification for arylsubstituted cycloalkenecarboxylic acid methyl esters with affinity for the human dopamine transporter
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Data from a series of 29 monoamine transport inhibitors were used to generate 2D and 3D QSAR models for their binding affinity to the human dopamine transporter (hDAT). Among the inhibitors were many non-nitrogen containing compounds. The 2D QSAR analysis resulted in the equation -log Ki = 4.00 - 3.93ELUMO - 0.67EHOMO - 3.24σp, which predicted the importance of electron withdrawing groups in the aromatic moiety. However, the model failed to predict the observed poor binding of nitro-substituted compounds. In contrast, a derived 3D QSAR model was capable of predicting these more correctly.
- Christensen, Helena S.,Boye, Soren V.,Thinggaard, Jacob,Sinning, Steffen,Wiborg, Ove,Schiott, Birgit,Bols, Mikael
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p. 5262 - 5274
(2008/03/15)
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- Niacin receptor agonists, compositions containing such compounds and methods of treatment
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The present invention encompasses compounds of Formula I: as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dyslipidemias and the like. Pharmaceutical compositions and methods of use are also included.
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Page/Page column 35; 36
(2010/11/25)
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- A new annulation method. Total syntheses of the sesquiterpenoids (+/-)-chiloscyphone and (+/-)-6-epi-chiloscyphone
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The efficacy of a new annulation method, developed for the construction of functionalized bicyclic compounds, is illustrated by conversion of the β-keto esters 18 and 19 into the bicyclonon-1-enes 33 and 34, respectively, and by transformation of 2-methoxycarbonylcyclopentanone (20) into the bicyclonon-6-ene 38 and the bicyclodec-7-enes 48 and 51.Application of the method to total syntheses of the structurally unusual sesquiterpenoids (+/-)-chiloscyphone (16) and (+/-)-6-epi-chiloscyphone (17) is described.
- Piers, Edward,Tse, Hoi Lun Allan
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p. 983 - 994
(2007/10/02)
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- PREPARATION AND ALKYLATION OF CYCLIC β-TRIMETHYLSTANNYL α,β-UNSATURATED ESTERS. A NEW, GENERAL ANNULATION SEQUENCE
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The key steps of a newly developed annulation method involve (a) reaction of cyclic β-trifluoromethanesulfonyloxy α,β-unsaturated esters (e.g. 14-16) with lithium(phenylthio)(trimethylstannyl)cuprate, (b) alkylation of the resultant products (e.g.17-19) with 1,ω-dihaloalkanes, and (c) transmetalation-cyclization of suitable substrates (e.g.25, 26, 28, 30) derived from the alkylation products (e.g. 20-24).
- Piers, Edward,Tse, Hoi Lun Allan
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p. 3155 - 3158
(2007/10/02)
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