- Synthesis and evaluation of novel and potent protease activated receptor 4 (PAR4) antagonists based on a quinazolin-4(3H)-one scaffold
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Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC50 = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC50s > 10 μM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC50 > 3162 nM, PAR2 AP FLIPR IC50 > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy.
- Kong, Yi,Li, Shanshan,Liu, Shangde,Xie, Roujie,Yuan, Duo,Zhu, Xiong
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- Total Synthesis of (-)-Citreoisocoumarin, (-)-Citreoisocoumarinol, (-)-12-epi-Citreoisocoumarinol, and (-)-Mucorisocoumarins A and B Using a Gold(I)-Catalyzed Cyclization Strategy
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A unified and concise first asymmetric total synthesis of (-)-citreoisocoumarin (2), (-)-citreoisocoumarinol (3), 12-epi-citreoisocoumarinol (4), and (-)-mucorisocoumarins A (5) and B (6) have been accomplished from the common intermediate (-)-6-O-methyl-
- Mallampudi, N. Arjunreddy,Choudhury, Utkal Mani,Mohapatra, Debendra K.
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p. 4122 - 4129
(2020/04/10)
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- Asymmetric total syntheses of naturally occurring α,β-enone-containing RALs, L-783290 and L-783277 through intramolecular base-mediated macrolactonization reaction
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Asymmetric total synthesis of two naturally occurring α,β-enone containing RALs, L-783290 and L-783277 is described in this article. An E-selective Horner-Wadsworth-Emmons (HWE) olefination was used as a key reaction to construct the C7′-C8′ olefinic unsaturation in L-783290. An enantiopure alkyne addition to the aldehyde followed by Z-selective partial reduction was employed to construct the C7′-C8′ olefinic unsaturation in L-783277. Biomimetic lactonization reaction was used to construct the macrolactone core in both the target molecules.
- Chakraborty, Joy,Ghosh, Ankan,Nanda, Samik
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p. 2331 - 2345
(2020/04/07)
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- Asymmetric total synthesis of paecilomycin C through intramolecular nucleophilic ring opening of an epoxide
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The convergent total synthesis of naturally occurring paecilomycin C is described here for the first time. Asymmetric Brown allylation, E-selective cross metathesis, and a biomimetic carboxylate assisted intramolecular nucleophilic ring opening of an epoxide were employed to access the enantiopure γ-lactone framework of the natural product. Late stage E-selective Julia-Kocienski olefination was then employed to furnish the natural product in an efficient way.
- Chakraborty, Joy,Nanda, Samik
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p. 7369 - 7379
(2019/08/15)
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- Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy
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In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
- Miller, Michael M.,Banville, Jacques,Friends, Todd J.,Gagnon, Mark,Hangeland, Jon J.,Lavallée, Jean-Fran?ois,Martel, Alain,O'Grady, Harold,Rémillard, Roger,Ruediger, Edward,Tremblay, Fran?ois,Posy, Shana L.,Allegretto, Nick J.,Guarino, Victor R.,Harden, David G.,Harper, Timothy W.,Hartl, Karen,Josephs, Jonathan,Malmstrom, Sarah,Watson, Carol,Yang, Yanou,Zhang, Ge,Wong, Pancras,Yang, Jing,Bouvier, Michel,Seiffert, Dietmar A.,Wexler, Ruth R.,Lawrence, R. Michael,Priestley, E. Scott,Marinier, Anne
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p. 7400 - 7416
(2019/08/26)
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- Design, Synthesis, and Herbicidal Activity of Pyrimidine-Biphenyl Hybrids as Novel Acetohydroxyacid Synthase Inhibitors
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The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine-biphenyl hybrids (4aa-bb and 5aa-ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa (Ki = 0.09 μM) and 4bb (Ki = 0.02 μM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac (Ki = 0.54 μM) and flumetsulam (Ki = 0.38 μM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5-150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0.94-0.235 g ai/ha. Therefore, the pyrimidine-biphenyl motif and lead compounds 4aa and 4bb have great potential for the discovery of novel AHAS inhibitors to combat AHAS-inhibiting herbicide-resistant weeds.
- Li, Ke-Jian,Qu, Ren-Yu,Liu, Yu-Chao,Yang, Jing-Fang,Devendar, Ponnam,Chen, Qiong,Niu, Cong-Wei,Xi, Zhen,Yang, Guang-Fu
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p. 3773 - 3782
(2018/04/23)
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- First Total Syntheses of Amorfrutin C and pseudo-Amorfrutin A
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Syntheses of amorfrutin C, a natural product with potent antitumor activity, as well as pseudo-amorfrutin A were accomplished. Protected 2,4-dihydroxybenzoic acid derivative 5 was used as a common synthetic intermediate. The introduction of a prenyl moiety to 5 was achieved through bromination followed by a CuCN-meditated alkylation reaction. Interestingly, N-bromosuccinimide promoted monobromination at the 6-position, leading to pseudo-amorfrutin A; 1,3-dibromo-5,5-dimethylhydantoin triggered bromination at both the 6- and 8-positions, leading to naturally occurring amorfrutin C.
- Miao, Qi,Li, Yunzhi,Xu, Jinyi,Lin, Aijun,Tanabe, Genzoh,Muraoka, Osamu,Wu, Xiaoming,Xie, Weijia
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p. 1443 - 1448
(2018/04/06)
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- Electrochemical Intramolecular C—H/O—H Cross-Coupling of 2-Arylbenzoic Acids
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A synthetic protocol to lactones by electro-oxidative induced C—H activation of 2-arylbenzoic acids has been developed. By using Na2SO4 aqueous solution as a cheap and green supporting electrolyte, different 2-arylbenzoic acids could provide the corresponding lactones in 30%—90% yields. This reaction could be conducted on a gram scale with a good efficiency as well as a high utility for natural product synthesis.
- Shao, Ailong,Li, Na,Gao, Yong,Zhan, Jirui,Chiang, Chien-Wei,Lei, Aiwen
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p. 619 - 624
(2018/05/30)
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- Synthetic technology of natural product aAmorfrutin C with anti-cancer activity
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The invention belongs to the field of chemical synthesis, and particularly relates to a fully synthetic method of extracting a natural product 2-hydroxyl-4-methoxyl-3,5-di(3-methyl butyl-2-alkene-1-base)-6-bibenzylcarboxylic acid (Amorfrutin C) from a plant Glycyrrhiza foetida. The method comprises the step that 2,4,6-trihydroxybenzoic acid purchased commercially is subjected to multi-step reaction to synthesize the natural product 2-hydroxyl-4-methoxyl-3,5-di(3-methyl butyl-2-alkene-1-base)-6-bibenzylcarboxylic acid (Amorfrutin C) extracted from the plant Glycyrrhiza foetida.
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- Gold(I)-Catalyzed Cyclization for the Synthesis of 8-Hydroxy-3- substituted Isocoumarins: Total Synthesis of Exserolide F
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A highly regioselective gold(I)-catalyzed 6-endo-dig cyclization of 2,2-dimethyl-5-(alkynyl)-4H-benzo[d][1,3]dioxin-4-ones for the synthesis of 8-hydroxy-3-substituted isocoumarins is described. Key features of the reaction include the broad substrate scope, scalability, and tolerance for protecting groups. The synthetic utility of this novel method is demonstrated by the first total synthesis of exserolide F, an isocoumarin-containing polyol natural product.
- Mallampudi, N. Arjunreddy,Reddy, G. Sudhakar,Maity, Saurabh,Mohapatra, Debendra K.
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p. 2074 - 2077
(2017/04/28)
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- Organocatalytic Enantioselective Michael-Acetalization-Reduction-Nef Reaction for a One-Pot Entry to the Functionalized Aflatoxin System. Total Synthesis of (-)- Dihydroaflatoxin D2 and (-)- and (+)-Microminutinin
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An efficient method has been developed for the enantioselective synthesis of the aflatoxin system with multiple stereocenters via a sequence of organocatalytic Michael-acetalization-reduction-Nef reactions that proceed with high enantioselectivities (90-99% ee). The one-pot reaction sequence provides a facile entry to the aflatoxin system, including dihydroaflatoxin D2, which includes a formal total synthesis of aflatoxin B2. The first total synthesis of (-)- and (+)-microminutinin was also achieved via this protocol.
- Huang, Wei-Lun,Raja, Arun,Hong, Bor-Cherng,Lee, Gene-Hsiang
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p. 3494 - 3497
(2017/07/15)
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- A Short and Efficient Approach for the Total Synthesis of (S)-Zearalenone and (R)-De-O-methyllasiodiplodin by Using Stille and RCM Protocols
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A concise, flexible, and linear approach has been devised for the total synthesis of the resorcinylic acid lactones (S)-zearalenone (2) and (R)-de-O-methyllasiodiplodin (4) by using a Stille cross-coupling strategy. The other key steps of the synthesis include a ring-closing metathesis (RCM), a chemoselective reduction of an α,β-unsaturated ketone, and a transesterification reaction.
- Kumar Dey, Sujit,Ataur Rahman, Mohammad,Alkhazim Alghamdi, Ahmad,Reddy, Basi V. Subba,Yadav, Jhillu S.
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p. 1684 - 1692
(2016/04/05)
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- First stereoselective total synthesis of paecilomycin G
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The stereoselective total synthesis of resorcylic acid lactone, paecilomycin G (1) has been accomplished. The key steps involved are the Corey-Fuchs reaction, Sharpless asymmetric dihydroxylation, Jacobsen hydrolytic kinetic resolution, Stille coupling, Mitsunobu reaction, and Ring-closing metathesis (RCM) reaction.
- Bujaranipalli, Sheshurao,Das, Saibal
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p. 2800 - 2802
(2016/06/09)
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- Carbohydrate-Based Studies Toward the Synthesis of Hamigeromycin E: A Stereoselective Total Synthesis of an Isomer of Zeaenol
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A stereoselective synthesis of 14-membered macrolide hamigeromycin E (6) has been studied by employing ortho-lithiated formylation, Barbier allylation, Julia–Kocienski olefination, Mitsunobu esterification, and ring-closing metathesis (RCM) reactions. The
- Saidachary, Gannerla,China Raju, Bhimapaka
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p. 425 - 435
(2016/07/06)
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- Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki-Hiyama-Kishi Macrocyclization Reaction
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The natural products cochliomycin A (1) and cochliomycin B (2), two resorcylic acid lactones obtained from marine sources, have been prepared in a concise and stereocontrolled manner from the readily accessible building blocks 4-6. Olefin cross-metathesis
- Bolte, Benoit,Basutto, Jose A.,Bryan, Christopher S.,Garson, Mary J.,Banwell, Martin G.,Ward, Jas S.
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p. 460 - 470
(2015/08/11)
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- A Carbohydrate Approach for the First Total Synthesis of Cochliomycin C: Stereoselective Total Synthesis of Paecilomycin E, Paecilomycin F and 6′-epi-Cochliomycin C
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The first total synthesis of the chlorinated resorcylic acid lactone cochliomycin C is achieved starting from the readily available sugar D-lyxose. The strategy has also lead to the total synthesis of natural resorcylic acid lactones paecilomycin E, paecilomycin F and a synthetic analogue 6-epi-cochliomycin C. The key reactions include Ohira-Bestmann alkynylation, ring closing metathesis and regioselective methylation under Mitsunobu conditions. The first total synthesis of the chlorinated resorcylic acid lactone cochliomycin C is achieved starting from the readily available sugar D-lyxose. The strategy has also lead to the total synthesis of paecilomycin E, paecilomycin F and 6′-epi-cochliomycin C. The key reactions include Ohira-Bestmann alkynylation, ring closing metathesis and regioselective methylation under Mitsunobu conditions.
- Mahankali, Bakkolla,Srihari, Pabbaraja
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p. 3983 - 3993
(2015/06/30)
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- RESORCYLIC ACID LACTONE COMPOUNDS
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Disclosed are a novel resorcyclic acid lactone compound with inhibitory activity against protein kinases, a pharmaceutically acceptable salt thereof, a method for the synthesis thereof, and a pharmaceutical composition for the treatment and prevention of
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- Synthesis and biological studies of a triazole analogue of resorcylic acid lactone LL-Z1640-2
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A highly convergent and concise synthesis of a triazole analogue of resorcylic acid lactone natural product LL-Z1640-2 has been achieved from easily accessible starting materials in six linear steps in 18% overall yield. Biological evaluationconfirmed the enone system of the natural product is crucial for its activity. The triazole analogue showed good activity (IC50 7.2 μM) against MNK2 kinase, which is an emerging target for cancer chemotherapy.
- Goh, Wendy Y. L.,Chai, Christina L. L.,Chen, Anqi
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p. 7239 - 7244
(2015/02/02)
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- Lysilactones A-C, three 6H-dibenzo[b,d]pyran-6-one glycosides from Lysimachia clethroides, total synthesis of Lysilactone A
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Three 6H-dibenzo[b,d]pyran-6-one glycosides named lysilactones A-C (1-3) were isolated from the aerial parts of Lysimachia clethroides. Their structures were elucidated using spectroscopic analysis and chemical evidence. This is the first report of 6H-dib
- Liang, Dong,Luo, Huan,Liu, Yan-Fei,Hao, Zhi-You,Wang, Yan,Zhang, Chun-Lei,Zhang, Qing-Jian,Chen, Ruo-Yun,Yu, De-Quan
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p. 2093 - 2097
(2013/03/13)
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- Structure elucidation and total synthesis of altenuic acid III and studies towards the total synthesis of altenuic acid II
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The structure of the Alternaria mycotoxin altenuic acid III was elucidated by NMR spectroscopic analysis of an authentic sample, and was confirmed by total synthesis. This compound is not a resorcylic acid lactone but a resorcylic acid substituted with a butenolide, and thus is the first member of a new class of alternaria toxins. For the total synthesis, a short and efficient access to halogenated butenolides bearing acetal-protected side-chains was carried out. Suzuki coupling of these butenolides with a highly functionalized boronate gave rise to a precursor of the natural product in high yield. The side-chain was completed by deprotection and subsequent oxidation. An unexpected cascade reaction leading to tricyclic butenolides was discovered during optimization of the deprotection protocol. Cleavage of the acetal protecting group gave altenuic acid III. Furthermore, a synthetic study towards altenuic acid II, a compound with a characteristic spirolactone structure, is described. It was planned to construct the spirocyclic lactone by using an intramolecular Michael-type addition of an aromatic carboxylate group to a butenolide moiety, but this approach was not successful. While testing the feasibility of this concept, a new and mild protocol for the well-known Pinner reaction in the presence of Lewis acids was discovered. Altenuic acid III, a major mycotoxin from Alternaria fungi, is the first member of a new class of alternaria toxins. Its structure was elucidated, and a total synthesis is given. Copyright
- Nemecek, Gregor,Thomas, Robert,Goesmann, Helmut,Feldmann, Claus,Podlech, Joachim
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p. 6420 - 6432
(2013/10/21)
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- Stereoselective total synthesis of paecilomycin e
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First total synthesis of recently isolated resorcylic acid lactone paecilomycin E has been accomplished. The key reactions include olefin metathesis, Mitsunobu reaction, Stille coupling and regioselective allylation.
- Srihari,Mahankali,Rajendraprasad
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- Total synthesis of 7-deoxy-6-o-methylfusarentin featuring a chelation-controlled 1,3-reetz-keck-type allylation
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The total synthesis of 7-deoxy-6-O-methylfusarentin (1) and a formal synthesis of 7-deoxy-6,8-O-dimethylfusarentin (2) has been successfully achieved in 10 steps. The described tactic underscores a diastereoselective strategy which incorporates a single acyclic reaction based on the initial stereocenter by means of a 1,3-chelation-controlled Reetz-Keck-type allylation.
- Trotter, Timothy N.,Albury, Aymara M. M.,Jennings, Michael P.
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p. 7688 - 7692
(2012/10/29)
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- An efficient and enantioselective total synthesis of naturally occurring L-783277
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Naturally occurring L-783277 which belongs to 14-membered resorcylic acid lactones (RALs) turned out to be a potent kinase inhibitor against MEK (MAP kinase kinase). We successfully accomplished efficient and enantioselective total synthesis of L-783277 based on convergent assembly of one aromatic unit and two chiral building blocks with efficient orthogonal protection-deprotection strategy. Three key steps composed of olefin cross metathesis, addition of acetylene derivative to aldehyde, and Yamaguchi macrolactonization were subsequently employed to construct the framework of L-783277. The optical rotation value of L-783277 is for the first time presented in this Letter.
- Choi, Hwan Geun,Son, Jung Beom,Park, Dong-Sik,Ham, Young Jin,Hah, Jung-Mi,Sim, Taebo
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scheme or table
p. 4942 - 4946
(2011/01/04)
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- Total synthesis of cruentaren B
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(Chemical Equation Presented) A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C 11 benzolacto
- Chakraborty, Tushar Kanti,Chattopadhyay, Amit Kumar
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p. 3578 - 3581
(2008/09/20)
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- Total synthesis of dehydroaltenusin
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The first total synthesis of dehydroaltenusin, a natural enzyme inhibitor, is described. The key step involves Suzuki-coupling reaction of an aryl triflate prepared from 2,4,6-trihydroxybenzoic acid with a catechol-derived boronic acid or boronic ester. T
- Kamisuki, Shinji,Takahashi, Shunya,Mizushina, Yoshiyuki,Hanashima, Shinya,Kuramochi, Kouji,Kobayashi, Susumu,Sakaguchi, Kengo,Nakata, Tadashi,Sugawara, Fumio
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p. 5695 - 5700
(2007/10/03)
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- Total synthesis of dehydroaltenusin
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First total synthesis of dehydroaltenusin, a natural enzyme inhibitor, is described. The key step involves Suzuki-couplig reaction of aryl triflate prepared from 2,4,6-trihydroxy benzoic acid with a catechol-derived boronic acid. The synthetic sample was
- Takahashi, Shunya,Kamisuki, Shinji,Mizushina, Yoshiyuki,Sakaguchi, Kengo,Sugawara, Fumio,Nakata, Tadashi
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p. 1875 - 1877
(2007/10/03)
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