- One-step route to tricyclic fused 1,2,3,4-tetrahydro-isoquinoline systems via the castagnoli–cushman protocol
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The Castagnoli–Cushman reaction of 3,4-dihydroisoquinolines with glutaric anhydride, its oxygen and sulfur analogues was investigated as a one-step approach to the benzo[a]quinolizidine system and its heterocyclic analogs. An extension towards the pyrrolo[2,1-a]isoquinoline system was achieved with the use of succinic anhydride. The results are evidence of an unexplored method for the access of the aforementioned tricyclic annelated systems incorporating a bridgehead nitrogen atom. The structures and relative configurations of the new compounds were established by means of 1D and 2D NMR techniques. The reactions between 1-methyldihydroisoquinoline and glutaric, diglycolic and succinic anhydrides yielded unexpected isoquinoline derivatives containing an exocyclic double bond. The compounds prepared bear the potential to become building blocks for future synthetic bioactive molecules.
- Burdzhiev, Nikola,Pashev, Aleksandar,Stanoeva, Elena
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- Integrating Hydrogen Production with Aqueous Selective Semi-Dehydrogenation of Tetrahydroisoquinolines over a Ni2P Bifunctional Electrode
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Exploring an alternative anodic reaction to produce value-added chemicals with high selectivity, especially integrated with promoted hydrogen generation, is desirable. Herein, a selective semi-dehydrogenation of tetrahydroisoquinolines (THIQs) is demonstrated to replace the oxygen evolution reaction (OER) for boosting H2 evolution reaction (HER) in water over a Ni2P nanosheet electrode. The value-added semi-dehydrogenation products, dihydroisoquinolines (DHIQs), can be selectively obtained with high yields at the anode. The controllable semi-dehydrogenation is attributed to the in situ formed NiII/NiIII redox active species. Such a strategy can deliver a variety of DHIQs bearing electron-withdrawing/donating groups in good yields and excellent selectivities, and can be applied to gram-scale synthesis. A two-electrode Ni2P bifunctional electrolyzer can produce both H2 and DHIQs with robust stability and high Faradaic efficiencies at a much lower cell voltage than that of overall water splitting.
- Huang, Chenqi,Huang, Yi,Liu, Cuibo,Yu, Yifu,Zhang, Bin
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- Integrating photocatalytic reduction of CO2 with selective oxidation of tetrahydroisoquinoline over InP–In2O3 Z-scheme p-n junction
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The development of a facile strategy to construct stable hierarchal porous heterogeneous photocatalysts remains a great challenge for efficient CO2 reduction. Additionally, hole-trapping sacrificial agents (e.g., triethanolamine, triethylamine, and methanol) are mostly necessary, which produce useless chemicals, and thus cause costs/environmental concerns. Therefore, utilizing oxidation ability of holes to develop an alternative photooxidation reaction to produce value-added chemicals, especially coupled with CO2 photoreduction, is highly desirable. Here, an in situ partial phosphating method of In2O3 is reported for synthesizing InP–In2O3 p-n junction. A highly selective photooxidation of tetrahydroisoquinoline (THIQ) into value-added dihydroisoquinoline (DHIQ) is to replace the hole driven oxidation of typical sacrificial agents. Meanwhile, the photoelectrons of InP–In2O3 p-n junction can induce the efficient photoreduction of CO2 to CO with high selectivity and stability. The evolution rates of DHIQ and CO are 2 and 3.8 times higher than those of the corresponding In2O3 n-type precursor, respectively. In situ irradiated X-ray photoelectron spectroscopy and electron spin resonance are utilized to confirm that the direct Z-scheme mechanism of InP–In2O3 p-n junction accelerate the efficient separation of photocarriers.
- Zhao, Bohang,Huang, Yi,Liu, Dali,Yu, Yifu,Zhang, Bin
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Read Online
- Accelerating H2 Evolution by Anodic Semi-dehydrogenation of Tetrahydroisoquinolines in Water over Co3O4 Nanoribbon Arrays Decorated Nickel Foam
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Coupling the H2 evolution reaction in water with thermodynamically favorable organic oxidation reactions is highly desirable, because it can enhance the energy conversion efficiency compared with electrocatalytic water splitting, and produce value-added chemicals instead of O2 in the anodic reaction. Herein, Co3O4 nanoribbon arrays in situ grown on nickel foam (Co3O4@NF) was employed as an effective electrocatalyst for the selective oxidation of tetrahydroisoquinolines (THIQs). Various value-added semi-dehydrogenation products including dihydroisoquinolines with electro-deficient or -rich groups could be obtained with moderate yields and faradaic efficiencies. Benefitting from the rich surface active sites of Co3O4@NF, a two-electrode (Co3O4@NF||Pt) electrolytic system drove a benchmark current density of 10 mA cm?2 at a cell voltage as low as 1.446 V in 1.0 M KOH aqueous solution containing 0.02 M THIQ, which was reduced by 174 mV in comparison with that of overall water splitting.
- Xiang, Ming,Xu, Zhihua,Wang, Jinghao,Yang, Xiaoqiu,Yan, Zhaoxiong
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supporting information
p. 7502 - 7506
(2021/04/21)
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- Peganumine A alkaloid structure simplifier and application thereof
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The invention discloses a Peganumine A alkaloid structure simplifier, a stereoisomer or a pharmaceutical salt thereof. The structure is shown in the following general formula: each substituent group is defined in the specification. The simplified structure of the Peganumine A alkaloid provided by the invention has a relatively obvious proliferation inhibition effect on liver cancer HepG2, lung cancer A549 and intestinal cancer HCT116, and the anti-tumor activity of part of compounds is higher than the anti-liver cancer HepG2 activity of Peganumine A reported in literatures.
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Paragraph 0037-0038; 0042-0044
(2021/06/26)
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- Enantioselective synthesis of 1-aryl tetrahydroisoquinolines by the rhodium-catalyzed reaction of 3,4-dihydroisoquinolinium tetraarylborates
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The 1-aryl tetrahydroisoquinolines (1-aryl THIQs) are omnipresent in biologically active molecules. Here we report on the direct asymmetric synthesis of these valuable compounds via the reaction of 3,4-dihydroisoquinolinium tetraarylborates. The dual roles of anionic tetraarylborates, which function as both prenucleophiles and stabilizers of 3,4-dihydroisoquinolinium cations, enable this rhodium(I)-catalyzed protocol to convergently provide enantioenriched 1-aryl THIQs in good yields (≤95%) with ≤97% ee, as demonstrated by the formal synthesis of (?)-solifenacin and the facile synthesis of (?)-Cryptostyline I.
- Li, Wei-Sian,Kuo, Ting-Shen,Wu, Ping-Yu,Chen, Chien-Tien,Wu, Hsyueh-Liang
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supporting information
p. 1141 - 1146
(2021/02/16)
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- Gold(I)-Catalyzed Cyclization-3-Aza-Cope-Mannich Cascade and Its Application to the Synthesis of Cephalotaxine
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The discovery of a new gold(I)-catalyzed cascade reaction involving cyclization onto a vinylammonium, 3-aza-Cope rearrangement, and Mannich cyclization is reported. A variety of fused nitrogen heterocycles were prepared from simple cyclic tertiary amines using 1-5 mol % of a AuCl(PPh3)/Ag[C5(CN)5] cocatalyst system. The developed reaction was used in a study aimed at synthesizing cephalotaxine. A five-step operation from norhydrastinine provided demethylcephalotaxinone in 39.1% overall yield, which was transformed to (-)-cephalotaxine in two steps.
- Sakai, Takeo,Okumura, Chise,Futamura, Masatoshi,Noda, Naotaka,Nagae, Akari,Kitamoto, Chiharu,Kamiya, Madoka,Mori, Yuji
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supporting information
p. 4391 - 4395
(2021/05/26)
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- Tetrabenazine intermediate as well as synthesis method and application thereof as, well as intermediate product for synthesis (by machine translation)
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The invention belongs to, the field of drug synthesis, and particularly relates to a butanaphenazine, intermediate and a synthesis method, thereof, as well as a synthesis: method 3,4 - thereof; and, 6,7 . (by machine translation)
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Paragraph 0082; 0086-0088; 0091; 0095-0098-0099-0100; 0103
(2020/02/14)
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- One-pot method for preparing 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride
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The invention provides a one-pot method for preparing 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride. The method comprises the following steps: with 3,4-dimethoxyphenylethylamine and a formylation reagent as raw materials, carrying out a reaction to prepare an intermediate solution, and subjecting the prepared intermediate solution to a further reaction with a solution containing oxalyl chloride; after the reaction is finished, adding phosphotungstic acid for catalytic cyclization; then adding an alcohol solvent for oxalic acid removal to obtain a target product; and finally, cooling andcrystallizing a reaction solution, carrying out filtering, leaching a filter cake, and carrying out drying to obtain the target product. According to the invention, process operation is extremely simple, and the 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (with a purity of 99.0% or above and a single impurity content of less than or equal to 0.15%) meeting the cGMP quality index requirements and having yield of 75% or above can be obtained only by cooling, filtering, leaching and drying after the one-pot reaction, so process material, manpower and equipment costs are obviously reduced;the process safety level of the method is obviously improved; waste materials are few; and good industrial application prospects are obtained.
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- Cyclopropenones in the synthesis of indolizidine, pyrrolo[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloids
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An attempted synthesis of the indolizidine natural product castanospermine resulted in the successful addition of cyclopropenone to a sugar-derived poly-hydroxylated cyclic imine to give an indolizidinone product, but with the installation of an extra hydroxy group at the castanospermine 8a-bridgehead position. This was also observed in our previous approach to the australine and hyacinthacine pyrrolizidine natural products. The same oxidative phenomenon occurred during the synthesis of pyrrolo[1,2-a]isoquinolines from the reaction of aldimine dihydroisoquinolines with cyclopropenones, whereas ketimine based dihydroisoquinolines gave pyrrolo[1,2-a]isoquinolines without bridgehead oxidation. These results may have some significance for the origins of the bridgehead hydroxy natural products jenamidine B1/B2, clazamycin A/B and legonmycin A/B. The precursor cyclic aldimine for the synthesis of the indolizino[8,7-b]indoles gave dimeric indolizino[8,7-b]indoles, whereas the corresponding cyclic ketimines behaved as expected and gave the indolizino[8,7-b]indole core after reaction with cyclopropenones.
- Jamshaid, Faisal,Kondakal, Vishnu V.R.,Newman, C. Declan,Dobson, Rhianne,Jo?o, Heidi,Rice, Craig R.,Mwansa, Joseph M.,Thapa, Bimod,Hemming, Karl
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supporting information
(2020/09/18)
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- A Visible-Light Promoted Amine Oxidation Catalyzed by a Cp*Ir Complex
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Through a rapid screening of Cp*Ir complexes based on a turn-on type fluorescence readout, a [Cp*Ir(dipyrido[3,2-a : 2’,3’-c]phenazine)Cl]+ complex was found to catalyze the blue-light promoted dehydrogenation of N-heterocycles under physiological conditions. In the dehydrogenation of tetrahydroisoquinolines, the catalyst preferentially yielded the monodehydrogenated product, accompanying H2O2 generation. We surmise that this mechanism may be reminiscent of flavin-dependent oxidases.
- Davis, Holly Jane,H?ussinger, Daniel,Ward, Thomas R.,Okamoto, Yasunori
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p. 4512 - 4516
(2020/07/27)
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- 3-(Phenethylamino)demethyl(oxy)aaptamine as an anti-dormant mycobacterial substance: Isolation, evaluation and total synthesis
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3-(Phenethylamino)demethyl(oxy)aaptamine (1) was re-discovered from the marine sponge of Aaptos sp. as an anti-dormant mycobacterial substance through the bioassay-guided separation. Compound 1 showed potent anti-microbial activity against Mycobacterium bovis BCG with a minimum inhibitory concentration of 0.75 μg/mL under both aerobic conditions and hypoxic conditions inducing dormant state. Compound 1 was also effective against pathogenic M. tuberculosis strains including clinical multidrug-resistant strains. Furthermore, the successful total syntheses of 1 and its analog 3-aminodemethyl(oxy)aaptamine (2) afford sufficient quantities for further biological studies.
- Arai, Masayoshi,Han, Chisu,Jacobs, William R.,Kamiya, Kentaro,Kotoku, Naoyuki,Setiawan, Andi,Sumii, Yuji,Vilchèze, Catherine
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- Mechanistic Studies on Bioinspired Aerobic C-H Oxidation of Amines with an ortho-Quinone Catalyst
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We report herein our mechanistic studies of the ortho-quinone-catalyzed aerobic oxidation of primary, secondary, and tertiary amines. Two different catalytic pathways were discovered for the reductive half reactions: for primary amines, the reaction was found to proceed via a transamination pathway, while the reactions with secondary amines and tertiary amines proceeded via hydride transfer. We also found that the amine substrates could significantly promote the regeneration of the ortho-quinone catalyst in the oxidative half reaction, in which a proton transfer occurs between the amine substrates and catechol derivatives (the reduced form of the ortho-quinone catalyst).
- Zhang, Ruipu,Qin, Yan,Zhang, Long,Luo, Sanzhong
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supporting information
p. 2542 - 2555
(2019/03/08)
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- Dehydrogenative C(sp3)-H bond functionalization of tetrahydroisoquinolines mediated by organic oxidants under mild conditions
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The organocatalyzed Mannich reaction of unsubstituted and N-aryl-substituted tetrahydroisoquinolines (THIQs) and the Strecker reaction of several N-aryl-substituted THIQs through dehydrogenative C(sp3)-H bond functionalization (cross-dehydrogenative coupling) promoted by organic single electron oxidants DDQ and IBX are presented. The C-H oxidation/Mannich reaction of less reactive N-aryl substituted pyrrolidines is achieved via metal catalyzed photoredox catalysis. Operationally simple procedures provide desired products in an effective and time preserving manner.
- D?ambaski, Zdravko,Bond?i?, Bojan P.
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supporting information
p. 6420 - 6425
(2019/07/09)
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- Synthesis of 3,4-dihydroisoquinolines using nitroalkanes in polyphosphoric acid
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A new method for the synthesis of 6,7-dimethoxy-3,4-dihydroisoquinoline based on the reaction of 2-(3,4-dimethoxyphenyl)ethan-1-amine (homoveratrylamine) with aliphatic nitro compounds in polyphosphoric acid (PPA) was developed.
- Aksenov,Malyuga,Abakarov,Aksenov,Voskressensky,Aksenov
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p. 1047 - 1051
(2019/06/18)
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- Aza-Nazarov Cyclization Reactions via Anion Exchange Catalysis
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A catalytic aza-Nazarov cyclization between 3,4-dihydroisoquinolines and α,β-unsaturated acyl chlorides has been developed to access α-methylene-γ-lactam products in good yields (up to 79%) as single diastereomers. The reactions proceed efficiently when AgOTf is used as an anion exchange catalyst with a 20 mol % loading at 80 °C. Computational studies were performed to investigate the reaction mechanism, and the findings support the role of the -TMS group in reducing the reaction barrier of the key cyclization step.
- Donmez, Selin E.,Soyda?, Emine,Aydln, G?k?en,?ahin, Onur,Bozkaya, Ugur,Türkmen, Yunus E.
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supporting information
(2019/01/21)
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- Aza-Nazarov Cyclization Reactions via Anion Exchange Catalysis
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A catalytic aza-Nazarov cyclization between 3,4-dihydroisoquinolines and α,β-unsaturated acyl chlorides has been developed to access α-methylene-?-lactam products in good yields (up to 79%) as single diastereomers. The reactions proceed efficiently when AgOTf is used as an anion exchange catalyst with a 20 mol % loading at 80 °C. Computational studies were performed to investigate the reaction mechanism, and the findings support the role of the ?TMS group in reducing the reaction barrier of the key cyclization step.
- Donmez, Selin E.,Soyda?, Emine,Aydln, G?k?en,?ahin, Onur,Bozkaya, U?ur,Türkmen, Yunus E.
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supporting information
p. 554 - 558
(2019/01/24)
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- Synthesis of Lamellarin G Trimethyl Ether by von Miller–Pl?chl-Type Cyclocondensation
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A concise synthesis of lamellarin G trimethyl ether based on a von Miller–Pl?chl-type cyclocondensation of a deprotonated α-amino nitrile with an α,β-unsaturated ketone as the key step was developed. The general strategy does not rely on molecular symmetry and allows for the independent variation of the substitution pattern.
- Colligs, Vanessa C.,Dialer, Clemens,Opatz, Till
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p. 4064 - 4070
(2018/07/31)
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- CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed Mechanistic and Kinetic Studies
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CO2-catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept, various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups such as nitrile, nitro, ester, halogen, ether, thioether, and carbonyl or carboxylic acid moieties. At the end, the CO2-catalyzed synthesis of pharmaceutical drugs has been achieved. The CO2 radical has been detected by EPR spectroscopy using DMPO, and the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidence.
- Riemer, Daniel,Schilling, Waldemar,Goetz, Anne,Zhang, Yu,Gehrke, Sascha,Tkach, Igor,Hollóczki, Oldamur,Das, Shoubhik
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p. 11679 - 11687
(2018/11/23)
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- Reactions of 3,4-dihydroisoquinolines and dihydrothieno[3,2-c]pyridines with benzyne
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Cyanomethyl-substituted tetrahydroisoquinolines and tetrahydrothieno[3,2-c]pyridines were synthesized by multicomponent reaction of the dihydro analogues of aforesaid systems with benzyne and acetonitrile. The products obtained relate to alkaloids of isoq
- Guranova, Natalia I.,Varlamov, Alexey V.,Ilyushenkova, Valentina V.,Sokolova, Ekaterina A.,Borisova, Tatiana N.,Aksenov, Alexander V.,Khrustalev, Viktor N.,Voskressensky, Leonid G.
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p. 506 - 508
(2017/10/05)
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- Dehydrogenation of Nitrogen Heterocycles Using Graphene Oxide as a Versatile Metal-Free Catalyst under Air
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Graphene oxide (GO) has been developed as an inexpensive, environmental friendly, metal-free carbocatalyst for the dehydrogenation of nitrogen heterocycles. Valuable compounds, such as quinoline, 3,4-dihydroisoquinoline, quinazoline, and indole derivatives, have been successfully used as substrates. The investigation of various oxygen-containing molecules with different conjugated systems indicated that both the oxygen-containing groups and large π-conjugated system in GO sheets are essential for this reaction. (Figure presented.).
- Zhang, Jingyu,Chen, Shiya,Chen, Fangfang,Xu, Wensheng,Deng, Guo-Jun,Gong, Hang
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supporting information
p. 2358 - 2363
(2017/07/22)
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- O-Naphthoquinone-Catalyzed Aerobic Oxidation of Amines to (Ket)imines: A Modular Catalyst Approach
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A modular aerobic oxidation of amines to imines has been achieved using an ortho-naphthoquinone (o-NQ) catalyst. The cooperative catalyst system of o-NQ and Cu(OAc)2 enabled the formation of homocoupled imines from benzylamines, while the presence of TFA helped the formation of cross-coupled imines in excellent yields. The current mild aerobic oxidation protocol could also be applied to the oxidation of secondary amines to imines or ketimines with the help of cocatalyst, Ag2CO3, with excellent yields.
- Goriya, Yogesh,Kim, Hun Young,Oh, Kyungsoo
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supporting information
p. 5174 - 5177
(2016/10/14)
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- Bioinspired organocatalytic aerobic C-H oxidation of amines with an ortho -quinone catalyst
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A simple bioinspired ortho-quinone catalyst for the aerobic oxidative dehydrogenation of amines to imines is reported. Without any metal cocatalysts, the identified optimal ortho-quinone catalyst enables the oxidations of α-branched primary amines and cyclic secondary amines. Mechanistic studies have disclosed the origins of different performances of ortho-quinone vs para-quinone in biomimetic amine oxidations.
- Qin, Yan,Zhang, Long,Lv, Jian,Luo, Sanzhong,Cheng, Jin-Pei
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p. 1469 - 1472
(2015/03/30)
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- A one-pot cascade to protoberberine alkaloids via stevens rearrangement of nitrile-stabilized ammonium ylides
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A facile one-pot synthesis of protoberberines from readily accessible 1,2,3,4-tetrahydroisoquinoline-1-carbonitriles and 1,2-bis(bromomethyl)arenes is described. The reaction cascade comprises four consecutive transformations, all of which can be effected under a single set of conditions. Ten protoberberines, including the alkaloids pseudopalmatine and pseudoepiberberine, were prepared in yields up to 86% according to this strategy. No chromatographic purification of the products is required, and the route is devoid of any protecting group manipulations.
- Lahm, Günther,Deichmann, Jan-Gernot,Rauen, Anna Lisa,Opatz, Till
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p. 2010 - 2016
(2015/02/19)
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- Xylochemistry - Making Natural Products Entirely from Wood
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The first total synthesis of the dimeric berberine alkaloid ilicifoline (ilicifoline B) is reported. Its carbon skeleton is constructed from ferulic acid, veratrole, and methanol. The synthesis reported herein employs starting materials solely derived from wood. The natural product is thus constructed entirely from renewable resources. The same strategy is applied to a formal total synthesis of morphinan alkaloids. The use of wood-derived building blocks (xylochemicals) instead of the conventional petrochemicals represents a sustainable alternative to classical synthetic approaches.
- Stubba, Daniel,Lahm, Günther,Geffe, Mario,Runyon, Jason W.,Arduengo, Anthony J.,Opatz, Till
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supporting information
p. 14187 - 14189
(2016/01/25)
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- Bioinspired aerobic oxidation of secondary amines and nitrogen heterocycles with a bifunctional quinone catalyst
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Copper amine oxidases are a family of enzymes with quinone cofactors that oxidize primary amines to aldehydes. The native mechanism proceeds via an iminoquinone intermediate that promotes high selectivity for reactions with primary amines, thereby constraining the scope of potential biomimetic synthetic applications. Here we report a novel bioinspired quinone catalyst system consisting of 1,10-phenanthroline-5,6-dione/ZnI2 that bypasses these constraints via an abiological pathway involving a hemiaminal intermediate. Efficient aerobic dehydrogenation of non-native secondary amine substrates, including pharmaceutically relevant nitrogen heterocycles, is demonstrated. The ZnI2 cocatalyst activates the quinone toward amine oxidation and provides a source of iodide, which plays an important redox-mediator role to promote aerobic catalytic turnover. These findings provide a valuable foundation for broader development of aerobic oxidation reactions employing quinone-based catalysts.
- Wendlandt, Alison E.,Stahl, Shannon S.
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p. 506 - 512
(2014/01/23)
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- Efficient asymmetric synthesis of 1-cyano-tetrahydroisoquinolines from lipase dual activity and opposite enantioselectivities in α-aminonitrile resolution
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Dual promiscuous racemization/amidation activities of lipases leading to efficient dynamic kinetic resolution protocols of racemic α-aminonitrile compounds are described. α-Amidonitrile products of high enantiomeric purity could be formed in high yields. Several lipases from different sources were shown to exhibit the dual catalytic activities, where opposite enantioselectivities could be recorded for certain substrates. Dynamic chemistry: Dual promiscuous racemization/amidation activities of lipases leading to efficient dynamic kinetic resolution protocols of racemic α-aminonitrile compounds are described. α-Amidonitrile products of high enantiomeric purity could be formed in high yields. Several lipases from different sources were shown to exhibit the dual catalytic activities, in which opposite enantioselectivities could be recorded for certain substrates (see scheme).
- Sakulsombat, Morakot,Vongvilai, Pornrapee,Ramstr?m, Olof
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supporting information
p. 11322 - 11325
(2014/10/15)
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- Synthesis of alkaloids by stevens rearrangement of nitrile-stabilized ammonium ylides: (±)-laudanosine, (±)-laudanidine, (±)-armepavine, (±)-7-methoxycryptopleurine, and (±)-xylopinine
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The Stevens rearrangement of nitrile-stabilized ammonium ylides in conjunction with the reductive removal of the nitrile function permits the facile construction of α-branched amines from α-aminonitriles. We employed this reaction sequence for the preparation of (±)-laudanosine, (±)-laudanidine and (±)-armepavine, (±)-7- methoxycryptopleurine, and (±)-xylopinine from two closely related and readily accessible bicyclic α-aminonitriles. The final products were obtained in high to almost quantitative yields (71-98%) from the quaternary ammonium salts obtained by N-alkylation of these starting materials.
- Orejarena Pacheco, Julio Cesar,Lahm, Günther,Opatz, Till
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p. 4985 - 4992
(2013/06/27)
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- Enantioselective formal aza-Diels-Alder reactions of enones with cyclic imines catalyzed by primary aminothioureas
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A highly enantio- and diastereoselective synthesis of indolo- and benzoquinolizidine compounds has been developed through the formal aza-Diels-Alder reaction of enones with cyclic imines. This transformation is catalyzed by a new bifunctional primary aminothiourea that achieves simultaneous activation of both the enone and imine reaction components.
- Lalonde, Mathieu P.,McGowan, Meredeth A.,Rajapaksa, Naomi S.,Jacobsen, Eric N.
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supporting information
p. 1891 - 1894
(2013/04/10)
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- A high-yielding modular access to the lamellarins: Synthesis of lamellarin G trimethyl ether, lamellarin η and dihydrolamellarin η
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A deprotonated α-aminonitrile serves as a key intermediate in a highly efficient (95 % per step on average; see scheme) modular synthetic approach to the lamellarin alkaloids. Its reaction with an α,β- unsaturated aldehyde forms the central pyrrole ring in a one-pot procedure. The construction of the fused pentacyclic skeleton is completed by a microwave-assisted Ullmann-type lactone formation.
- Imbri, Dennis,Tauber, Johannes,Opatz, Till
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supporting information
p. 15080 - 15083
(2013/11/06)
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- Silver(i)-promoted oxidative cyclisation to pyrrolo[2,1-a]isoquinolines and application to the synthesis of (±)-crispine A
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The silver(i)-promoted oxidative cyclisation of 1-propargyl-substituted tetrahydroisoquinolines affords pyrrolo[2,1-a]isoquinolines. Scope and limitations of this method are described and an application to the synthesis of the natural product (±)-crispine A is presented. The Royal Society of Chemistry 2013.
- Agarwal, Sameer,Kataeva, Olga,Schmidt, Ulrike,Knoelker, Hans-Joachim
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p. 1089 - 1096
(2013/03/14)
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- PROCESS FOR PREPARING TETRABENAZINE
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A substantially pure crystalline form A of tetrabenazine compound of structural formula I and processes for the preparation thereof is provided.
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- Synthesis and biological evaluation of a series of 6,7-dimethoxy-1-(3,4- dimethoxybenzyl)-2-substituted tetrahydroisoquinoline derivatives
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Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3, 4-dimethoxybenzyl)-tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC50 values at 0.66, 0.65 and 0.96μM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively.
- Zou, Zhi-Hong,Lan, Xiao-Bu,Tang, Chun-Lei,Zhu, Xiao-Yun,Liu, Bao-Min,Qian, Hai,Huang, Wen-Long,Li, Yun-Man
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experimental part
p. 711 - 716
(2012/09/22)
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- Synthesis and evaluation of furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline as anticancer and multidrug resistance reversal agents
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Multidrug resistance in tumor cells poses a major obstacle to efficient chemotherapy. Several types of agents have been recognized as multidrug resistance inhibitors, among which the tetrahydroisoquinolines is the most studied. In current study 16 furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline were synthesized. Their cytotoxic activities and effects in reversing multidrug resistance have been evaluated. The results revealed that these compounds had moderate cytotoxic effects. Compounds 7a-f, 7h, and 7l showed higher cytotoxicities than the rest, but lower than adriamycin on K562 cell line. Compounds 7d, 7f, and 7l exhibited potent MDR reversal activities on K562/A02 cell line. The accumulation assay indicated that compounds 7d, 7f, and 7l significantly increased the intracellular accumulation of rhodamine123 in K562/A02 cells. Furthermore, these three compounds produced high concentrations of NO in K562/A02 cells. Potentially, the high concentrations of NO produced by NO donor moieties will lead to an increased cytotoxicity to K562/A02 cells. Our results suggested that compounds 7d, 7f, and 7l had anticancer effects, as well as multidrug resistance reversal effects.
- Zou, Zhi-Hong,Lan, Xiao-Bu,Qian, Hai,Huang, Wen-Long,Li, Yun-Man
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scheme or table
p. 5934 - 5938
(2011/10/09)
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- Catalytic asymmetric allylation of 3,4-dihydroisoquinolines and its application to the synthesis of isoquinoline alkaloids
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A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homolaudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A.
- Miyazaki, Michiko,Ando, Nami,Sugai, Keita,Seito, Yuki,Fukuoka, Hiromi,Kanemitsu, Takuya,Nagata, Kazuhiro,Odanaka, Yuki,Nakamura, Kazuo T.,Itoh, Takashi
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experimental part
p. 534 - 542
(2011/04/17)
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- Preparation and characterization of tetrabenazine enantiomers against vesicular monoamine transporter 2
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As a clinical medication for the treatment of hyperkinetic movement disorders, in conditions such as Huntington's disease, tetrabenazine (TBZ) has always been used in its racemic form. To establish whether or not its beneficial therapeutic actions are enantiospecific, a practical total synthetic route was developed to yield each enantiomeric form to allow their chemical and pharmacological characterization. We briefly summarize the total synthesis of TBZ and report a detailed procedure for resolution of TBZ into its enantiomers, (+)-TBZ and (-)-TBZ. This allowed determination of the optical rotation and absolute configurations of each TBZ enantiomer, based on X-ray crystallographic analysis, together with characterization of their inhibitory action at the vesicular monoamine transporter 2, where (+)-TBZ proved 3-fold more active than (-)-TBZ.
- Yu, Qian-Sheng,Luo, Weiming,Deschamps, Jeffery,Holloway, Harold W.,Kopajtic, Theresa,Katz, Jonathan L.,Brossi, Arnold,Greig, Nigel H.
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scheme or table
p. 105 - 109
(2010/11/18)
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- BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
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The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 28
(2010/04/30)
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- Lipase-catalyzed kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-acetic acid esters
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The enantiomers of 1,2,3,4-tetrahydroisoquinoline- and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acids were prepared via Burkholderia cepacia lipase (lipase PS-D)-catalyzed kinetic resolution of the corresponding ethyl and 2-methoxyethyl esters using enantioselective (E > 200) hydrolysis in DIPE. The (S)-acids were produced enzymatically, whereas the (R)-acids were obtained via the chemical hydrolysis of the unreacted (R)-esters. The solvent and its water content had major effects on both reactivity and enantioselectivity. The methoxyethyl moiety of the ester had a key role concerning the reactivity of the substrates.
- Paal, Tihamer A.,Forro, Eniko,Fueloep, Ferenc,Liljeblad, Arto,Kanerva, Liisa T.
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body text
p. 2784 - 2788
(2009/06/18)
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- Diastereomeric reissert compounds of isoquinoline and 6,7-dimethoxy-3,4- dihydroisoquinoline in stereoselective synthesis
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(Chemical Equation Presented) Chiral acid chlorides were reacted with isoquinoline and 6,7-dimethoxy-3,4-dihydroisoquinoline to form diastereomeric Reissert compounds 8-11 and 18-21, respectively. The best diastereoselectivity (80:20) was achieved in formation of the 9-phenylmenthyl derivative 20. The diastereomers of 2-l-menthoxy-carbonyl-1,2-dihydroisoquinaldonitriles (S)-8/(R)-8), formed in equal amounts, were inseparable. However, the individual diastereomers of 2-cholesteryloxycarbonyl-1,2-dihydroisoquinaldonitriles ((R)-11 and (5)-11) and the 2-l-menthoxycarbonyl-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinaldonitriles ((S)-19/(R)-19)) were each readily purified. (S)-8/(R)-8 (1:1) via the corresponding anions (NaH, -40°C, DMF) with pivaldehyde yielded in 82:18 predominance the S-diastereomer of 1-isoquinolyl tert-butyl carbinyl l-menthyl carbonate ((S)-12), which was obtained in pure form by a single recrystallization; hydrolysis produced 99% pure S-(-)-1-isoquinolyl tert-butyl carbinol [(S)-16]. Reactions of the anions of diastereomeric Reissert compounds, either as mixtures or pure single species, with aromatic aldehydes and alkyl halides proceeded with at best modest selectivity (diastereomeric ratios up to 66:34 and 72:28, respectively). Therefore, it is concluded that the Reissert anions are either planar or rapidly inverting tetrahedral structures.
- Gibson, Harry W.,Berg, Michael A. G.,Dickson, Jennifer Clifton,Lecavalier, Pierre R.,Wang, Hong,Merola, Joseph S.
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p. 5759 - 5770
(2008/02/11)
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- Synthesis of (-)-(S)-norlaudanosine, (+)-(R)-O,O-dimethylcoclaurine, and (+)-(R)-salsolidine by alkylation of an α-aminonitrile
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A short asymmetric synthesis of 1-substituted 1,2,3,4- tetrahydroisoquinoline alkaloids by deprotonation of an unprotected α-aminonitrile and alkylation of the resulting carbanion followed by spontaneous elimination of HCN and asymmetric reduction is described. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Werner, Frank,Blank, Nancy,Opatz, Till
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p. 3911 - 3915
(2008/02/13)
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- Aerobic ruthenium-catalyzed oxidative transformation of secondary amines to imines
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Aerobic, catalytic oxidation of secondary amines is performed efficiently in the presence of a diruthenium complex catalyst Ru2(OAc) 4Cl to give the corresponding imines. The catalytic system is characterized by its high selectivity, activity, and operational simplicity. Georg Thieme Verlag Stuttgart.
- Murahashi, Shun-Ichi,Okano, Yuriko,Sato, Hideomi,Nakae, Takahiro,Komiya, Naruyoshi
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p. 1675 - 1678
(2007/12/29)
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- Protoberberines from Reissert- compounds. Part IX [1]. An alternative approach to dibenzoquinolizine- and isoquinonaphthyridin-13a-carboxylic acids, a novel synthesis of alangimarine
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3,4-Dihydroisoquinoline-Reissert-compounds were alkylated to 1-benzyl- and 1-picolyl-derivatives, which in turn could selectively be hydrolized yielding various carboxylic acids, among others certain amino acids related to 3′,4′-deoxynorlaudanosoline carboxylic acid (DNLCA). These on treating with ethanolic KOH underwent cyclization to dibenzoquinolizine- and isoquinonaphthyridine-13a-carboxylic acids. Alternatively this cyclization also could be achieved by a more convenient one-pot procedure starting from the same dihydro-Reissert-compounds. Thermal decarboxylation afforded among others the alangia alkaloids alangimarine and dihydroalangimarine. Springer-Verlag 2004.
- Reimann, Eberhard,Grasberger, Fritz
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p. 193 - 209
(2007/10/03)
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- Activation of iodosobenzene by catalytic tetrabutylammonium iodide and its application in the oxidation of some isoquinoline alkaloids
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Oxidation of N-methyltetrahydroisoquinolines with iodosylbenzene in the presence of a catalytic amount of tetrabutylammonium iodide in various solvents afforded N-methyl-2H-3,4-dihydroisoquinol-1-ones in almost quantitative yields. The application of this finding to the oxidation of other isoquinolines, including tetrahydroisoquinolines, lycorine diacetate, and benzyltetrahydroisoquinolines, also afforded the corresponding lactams in good yields, however, accompanied by a few minor byproducts. Under similar conditions, tetrahydroberberine gave a rearranged compound, berberal, as the major product, accompanied by 8-oxoberberine and berberine.
- Huang, Wei-Jan,Singh, Om V.,Chen, Chung-Hsiung,Chiou, Sheng-You,Lee, Shoei-Sheng
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p. 1069 - 1078
(2007/10/03)
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- Application of hexamethylenetetramine in a Pictet-Spengler type reaction for synthesis of isoquinoline derivatives
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Hexamethylenetetramine was used successfully as amino- and amidoalkylation cyclization reagent for the synthesis of 3,4-dihydroisoquinolines, tetrahydroisoquinolines and 1,4-dihydro-3(2H)-isoquinolinones. The reagent provides a simple and convenient pathway for the preparation of a range of these compounds.
- Ivanov, Iliyan,Venkov, Atanas
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p. 1569 - 1580
(2007/10/03)
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- Investigation of the regio- and stereoselectivity of the annelation reaction of cyclic Schiff base with structurally asymmetrical β,β′-triketones. Synthesis and properties of 17-acetoxy-8-aza-D-Homogona-12,17a-diones
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Annelation ([2+4]-cyclocondensation) of 3,4-dihydroixoquinolines and 2-acetyl-4-acetoxycyclohexane-1,3-dione gives 17-acetoxy-8-aza-D-homogona-12,17a-diones as a mixture of the C(9), C(17)-stereoisomers with the (9R, 17S: 9S, 17R) racemic pair predominating.
- Gulyakevich,Zaitsev,Mikhal'chuk
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p. 956 - 962
(2007/10/03)
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- Aryl radical cyclizations of 1-(2′-bromobenzyl)isoquinolines with AIBN-Bu3SnH: Formation of aporphines and indolo[2,1-a]isoquinolines
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(matrix presented) Radical cyclization of alkoxy-substituted 1-(2′-bromobenzyl)-3,4-dihydroisoquinolines 1 with AIBN-Bu3SnH gave 6a,7-dehydroaporphines 2 preferentially. A steric repulsion between the respective alkoxy groups at the 7- and 3′-positions gave 5,6-dihydroindolo[2,1-a]isoquinolines 3 in a disfavored 5-endo cyclization mode. Radical cyclizations of the related substrates, such as 1-(2′-bromobenzoyl)isoquinolines or 1-(2′-bromo-α-hydroxybenzyl)isoquinolines, were also found to give the corresponding oxoaporphines or oxyaporphines.
- Orito, Kazuhiko,Uchiito, Shiho,Satoh, Yoshitaka,Tatsuzawa, Takashi,Harada, Rika,Tokuda, Masao
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p. 307 - 310
(2007/10/03)
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- A concise, regio and stereoselective route to fluorinated protoberberines via tandem addition-cyclisation reactions of phthalide anions with 3,4-dihydroisoquinolines
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A series of fluorinated protoberberines have been prepared by condensing fluorinated phthalide anions with 6,7-dimethoxydihydroisoquinoline. The spectroscopy and stereochemistry of the products are discussed and the stereochemical outcome of the reactions rationalised.
- Warrener, Ronald N.,Liu, Ligong,Russell, Richard A.
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p. 7485 - 7496
(2007/10/03)
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- Identification and characterization of m4 selective muscarinic antagonists
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Our interest in the area of m4 muscarinic antagonists has led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example 1 with an IC50 value of 90.7nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82- fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of 1 are reported.
- Augelli-Szafran, Corinne E.,Jaen, Juan C.,Moreland, David W.,Nelson, Carrie B.,Penvose-Yi, Jan R.,Schwarz, Roy D.
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p. 1991 - 1996
(2007/10/03)
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- Mechanistic and synthetic aspects of amine oxidations promoted by 3-methyl-5-ethyllumiflavinium perchlorate
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Preparative and kinetic aspects of the chemistry of 3-methyl-5-ethyllumiflavinium perchlorate (1) with primary and secondary amines have been investigated. Reactions of! with primary and secondary amines leads to rapid production of modestly stable C4a-adducts. The rates of these processes, determined by stopped-flow kinetic methods, parallel amine nucleophilicities. The C4a-adducts undergo benzylamine promoted elimination reactions to produce N-benzylaldimine products with rates that parallel reactivity profiles expected for E2-elimination processes. Finally, flavinium salt 1 serves as a catalyst for oxidations of primary and secondary amines under aerobic conditions.
- Hoegy, Susan E.,Mariano, Patrick S.
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p. 5027 - 5046
(2007/10/03)
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