- Total Synthesis of (±)-Thebainone A by Intramolecular Nitrone Cycloaddition
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Using an intramolecular nitrone cycloaddition and a Heck cyclization as the crucial transformations, a total synthesis of the racemic morphine alkaloid thebainone A was accomplished in 22 steps commencing with isovanillin.
- Hahn, Christian,Hennig, André,J?ger, Anne,Küttler, Thomas,Metz, Peter,Wang, Yuzhou
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- Synthesis, biological evaluation and molecular modeling studies of substitutedN-benzyl-2-phenylethanamines as cholinesterase inhibitors
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In this work, we report the synthesis of a series of derivatives ofN-benzyl-2-phenylethanamine which is the framework of norbelladine, the natural common precursor of the Amaryllidaceae alkaloids. These compounds were assessed in the inhibition of both AChE and BChE which are the enzymes responsible for the breakdown of acetylcholine and hence they constitute targets in the palliative treatment of Alzheimer's disease. In particular, brominated derivatives exhibited the lowest IC50values against AChE. Interestingly, the presence of iodine in one of the aromatic rings highly increased the inhibition of BChE compared to its analogues, with an IC50value similar to that of galantamine, which is the reference compound currently used in the treatment of AD. A possible mechanism of action for these compounds was determined by molecular modeling studies using combined techniques of docking and molecular dynamics simulations.
- Carmona-Viglianco, Florencia,Enriz, Ricardo D.,Feresin, Gabriela E.,Garro, Adriana,Kurina-Sanz, Marcela,Orden, Alejandro A.,Parravicini, Oscar,Zaragoza-Puchol, Daniel
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p. 9466 - 9476
(2020/06/17)
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- Enantioselective Synthesis and Racemization of (?)-Sinoracutine
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Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers
- Volpin, Giulio,Vep?ek, Nynke A.,Bellan, Andreas B.,Trauner, Dirk
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supporting information
p. 897 - 901
(2017/01/14)
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- Synthesis of 2,3,9,10-Tetraoxygenated benzo[c]phenanthridine derivatives via palladiummediated aryl-Aryl coupling reaction
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Two 2,3,9,10-Tetraoxygenated benzo[c]phenanthridine alkaloids, 1 2, originally reported as zanthoxyline and broussonpapyrine, respectively, were synthesized using the Pd-mediated intramolecular aryl-Aryl coupling reaction as the key step.
- Abe, Hitoshi,Kobayashi, Naoko,Kadoshima, Yutaka,Takeuchi, Yasuo,Harayama, Takashi,Horino, Yoshikazu
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p. 673 - 684
(2017/04/10)
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- Synthesis of a functionalized benzofuran as a synthon for salvianolic acid C analogues as potential LDL Antioxidants
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A palladium mediated synthesis of a common synthon for the syntheses of antioxidant analogues of naturally occurring salvianolic acids is presented. The synthetic route may be used to obtain analogues with a balanced lipophilicity/hydrophilicity which may
- López-Frías, Gabriela,Camacho-Dávila, Alejandro A.,Chávez-Flores, David,Zaragoza-Galán, Gerardo,Ramos-Sánchez, Víctor H.
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p. 8654 - 8665
(2016/09/04)
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- AMPHIPATHIC AND OTHER DOUBLE-SIDED ALPHA-HELIX MIMETICS BASED ON A 1,2-DIPHENYLACETYLENE SCAFFOLD
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Small-molecule scaffolds based on 1,2-diphenylacetylene that accurately replicate the spatial and angular projections of several side chains on both faces of an α-helix, specifically the i and i+7 side chains on one face, and the i and i+2 side chains on the other. The amphipathic α-helix mimetic can be used to disrupt disease-promoting protein-protein interactions that are mediated by α-helices.
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Page/Page column
(2014/09/29)
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- Amphipathic α-helix mimetics based on a 1,2-diphenylacetylene scaffold
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In order to mimic amphipathic α-helices, a novel scaffold based on a 1,2-diphenylacetylene was designed. NMR and computational modeling confirmed that an intramolecular hydrogen bond favors conformations of the 1,2-diphenylacetylene that allow for accurat
- Jung, Kwan-Young,Vanommeslaeghe, Kenno,Lanning, Maryanna E.,Yap, Jeremy L.,Gordon, Caryn,Wilder, Paul T.,Mackerell, Alexander D.,Fletcher, Steven
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supporting information
p. 3234 - 3237
(2013/07/26)
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- A concise route to dihydrobenzo[b]furans: Formal total synthesis of (+)-lithospermic acid
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A sequence of Sonogashira coupling, Pd(II)-catalyzed carbonylative annulation, and benzofuran reduction (Mg, MeOH, NH4Cl) provides a convergent and modular synthetic route to trans-2-aryl-2,3-dihydrobenzo[b]furan- 3-carboxylates, which are a structural feature of numerous biologically active natural products. This versatile strategy was applied to the formal total synthesis of the anti-HIV natural product (+)-lithospermic acid.
- Fischer, Joshua,Savage, G. Paul,Coster, Mark J.
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supporting information; experimental part
p. 3376 - 3379
(2011/09/12)
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- Synthetic applications of the nickel-catalyzed cyclization of alkynes combined with addition reactions in a domino process
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Carbonickelations of alkynes and functionalization of the resulting vinylnickel moiety have been performed efficiently in a nickel-catalyzed domino cyclization-condensation process. This reaction, which does not require the preparation of any other organometallic reagent, proceeds only by exo-dig cyclization. This convenient and mild method constitutes a one-pot synthesis of substituted dihydrobenzofurans, chromans, isochromans, indoles, or indanes. Theses valuable products are generally obtained in good yields and high stereoselectivity. They are shown to be useful synthons for rapid access to functionalized polycyclic skeletons. Yes nickel can! Carbonickelation of alkynes and functionalization of the resulting vinylnickel moiety occurs efficiently. Overall, a domino cyclization-condensation process propagated by substoichiometric nickel catalysis takes place (see scheme). This one-pot synthesis provides substituted polyheterocyclic compounds in good yields and high stereoselectivity.
- Durandetti, Muriel,Hardou, Lucie,Lhermet, Rudy,Rouen, Mathieu,Maddaluno, Jacques
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supporting information; experimental part
p. 12773 - 12783
(2011/12/04)
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- Total synthesis of (±)-Galanthamine via a C3-selective stille coupling and IMDA cycloaddition cascade of 3,5-dibromo-2-pyrone
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Figure presented A new efficient synthetic route to (±)-galanthamine was devised by using a tandem C3-selective Stille coupling-IMDA cascade of 3,5-dibromo-2-pyrone as a key strategy.
- Chang, Jay Hyok,Kang, Ho-Ung,Jung, In-Hak,Cho, Cheon-Gyu
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supporting information; experimental part
p. 2016 - 2018
(2010/06/21)
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- PROCESS FOR PRODUCTION OF PHENOL DERIVATIVES SUBSTITUTED WITH IODINE AT ORTHO POSITION
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A process in which a phenol derivative is iodinated to produce a 2-iodophenol or 2,6-diiodophenol derivative substituted with iodine at an ortho position thereof is provided, which does not require any step of recovery of iodine but can produce it at low cost, in high yield and with high quality. A phenol derivative is mixed with a pyridine and hydrogen peroxide or iodic acid as an oxidizing agent, and reacted with molecular iodine. As a result, iodination can be performed very efficiently with iodine in an amount close to the theoretical amount relative to the phenol derivative, and the 2-iodophenol or 2,6-diiodophenol derivative can be obtained in high yield and with high quality.
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Page/Page column 6; 7
(2010/07/06)
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- Total synthesis of (-)-morphine
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We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1-one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N-methyl-DNsamide moiety.
- Koizumi, Hifumi,Yokoshima, Satoshi,Fukuyama, Tohru
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supporting information; experimental part
p. 2192 - 2198
(2011/06/19)
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- Synthesis of santiagonamine
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The first total synthesis of santiagonamine (1) is achieved in 12 steps from isovanillin. A palladium-catalyzed Ullmann cross-coupling reaction and a photocyclization are the key steps in the synthesis.
- Markey, Michael D.,Ying, Fu,Kelly, T. Ross
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p. 3255 - 3257
(2008/02/11)
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- The synthesis of a combretastatin A-4 based library and discovery of new cooperative ortho-effects in Wittig reactions leading to (Z)-stilbenes
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A synthesis of combretastatin A-4 and a small library of analogues led to the discovery of some new cooperative orthoeffects allowing (Z)-stilbenes to be prepared in high yield and diastereomeric ratio. Georg Thieme Verlag Stuttgart.
- Harrowven, David C.,Guy, Ian L.,Howell, Melanie,Packham, Graham
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p. 2977 - 2980
(2008/03/13)
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- Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine
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An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.
- Trost, Barry M.,Tang, Weiping,Toste, F. Dean
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p. 14785 - 14803
(2007/10/03)
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- Intramolecular Heck cyclization to the galanthamine-type alkaloids: Total synthesis of (±)-lycoramine
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A novel approach towards the construction of the galanthamine skeleton was demonstrated by the total synthesis of (±)-lycoramine. The key steps include a Pd-catalyzed intramolecular cyclization to form the seven-membered azepane ring and a spontaneous int
- Liang, Pi-Hui,Liu, Jing-Ping,Hsin, Ling-Wei,Cheng, Chen-Yu
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p. 11655 - 11660
(2007/10/03)
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- Asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine
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An asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine (1R and 1S) is presented. Trifluoromethylation involves nucleophilic aromatic substitution of halobenzene 4 most likely via a copper mediated CF3 anion equivalent generated in
- Dong, Lun-Cong,Crowe, Michael,West, Jonathan,Ammann, Jeffrey R.
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p. 2731 - 2733
(2007/10/03)
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- Novel trifluoromethylepinephrine compounds and methods of making and using thereof
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Disclosed herein are trifluoromethylepinephrine compounds having the following structural formula (I) wherein R1-R5 are each independently selected from the group consisting of H, alkyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, acyl, thioacyl, sulfonyl mercapto, alkylthio, carboxy, amino, alkylamino dialkylamino, carbamoyl, arylthio, and heteroarylthio; wherein X, Y, and Z are each independently selected from the group consisting of H or trifluoromethyl with the proviso that at least one of which is trifluoromethyl. Also disclosed are pharmaceutical compositions comprising the trifluoromethylepinephrine compounds and methods of making and using thereof. Novel trifluoroepinephrine intermediates are also disclosed.
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- Synthesis of ring-halogenated 3,4-dimethoxyphenylethanolamine derivatives: New β-adrenoceptor antagonists
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A series of ring-halogenated derivatives (bromo and iodo) of [2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]isopropylamine and [2-(3,4-dimethoxyphenyl)-2-methoxyethyl]isopropylamine was synthesized from benzaldehyde derivatives, via (halo-3,4-dimethoxyphenyl)ethylene oxide compounds. The compounds were tested as β-adrenoceptor antagonists on isolated guinea-pig tracheal (β2-adrenoceptors) and guinea-pig atrial (β1-adrenoceptors) muscle strips. Compounds halogenated in the 2-and 5-positions of the aromatic ring are potent β2-adrenoceptor antagonists, whereas halogenation of the 6-position of the aromatic ring leads to compounds which are weak β-adrenoceptor antagonists. β1-Selective drugs of very low potency were obtained when the β-hydroxyl group was replaced by a methoxy group.
- Venter, Daniel P.,Langenhoven, Jan H.
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- Synthesis of halogenated trimetoquinol derivatives and evaluation of their β-agonist and thromboxane A2 (TXA2) antagonist activities
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The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate β1 (guinea pig atria) and β2 (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A2 (TXA2) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both β-adrenergic systems and gave a rank order of stimulatory potency of 1 >> 6 ≥ 5. Similarly, iodine substitution at either position also caused a reduction in TXA2 antagonist activity with a rank order potency of 1 > 6 >> 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On β-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5- position of TMQ completely abolished both β1- and β2-adrenergic agonist activities while imparting weak antagonist activity on β1 receptors. On TXA2 systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8- (trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on β-adrenergic systems and TXA2 systems. On β-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)- 8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA2-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.
- Markovich,Tantishaiyakul,Hamada,Miller,Romstedt,Shams,Shin,Fraundorfer,Doyle,Feller
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p. 466 - 479
(2007/10/02)
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