- Enantioselective Synthesis of (+)-Peganumine A
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A gram-scale enantioselective total synthesis of (+)-peganumine A was accomplished in 7 steps from commercially available 6-methoxytryptamine. Key steps included (a) a Liebeskind-Srogl cross-coupling; (b) a one-pot construction of the tetracyclic skeleton from an ω-isocyano-γ-oxo-aldehyde via a sequence of an unprecedented C-C bond forming lactamization and a transannular condensation; (c) a one-pot organocatalytic process merging two achiral building blocks into an octacyclic structure via a sequence of enantioselective Pictet-Spengler reaction followed by a transannular cyclization. This last reaction created two spirocycles and a 2,7-diazabicyclo[2.2.1]heptan-3-one unit with excellent control of both the absolute and relative stereochemistry of the two newly created quaternary stereocenters.
- Piemontesi, Cyril,Wang, Qian,Zhu, Jieping
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Read Online
- Continuous-flow synthesis of thioureas, enabled by aqueous polysulfide solution
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We have developed the continuous-flow synthesis of thioureas in a multicomponent reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution enabled the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the mother liquid. Presenting a wide range of thioureas synthesized by this procedure confirms the utility of the convenient continuous-flow application of sulfur.
- ábrányi-Balogh, Péter,Keser?, Gy?rgy M.,Mándity, István M.,Németh, András Gy.,Orsy, Gy?rgy,Szabó, Renáta
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supporting information
(2021/06/25)
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- Structural simplification of evodiamine: Discovery of novel tetrahydro-β-carboline derivatives as potent antitumor agents
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Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure–activity relationships of evodiamine.
- Ma, Zonglin,Huang, Yahui,Wan, Kun,Zhu, Fugui,Sheng, Chunquan,Chen, Shuqiang,Liu, Dan,Dong, Guoqiang
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- Production process of evodiamine and method for recycling solvent in production
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The invention relates to the field of organic synthesis, in particular to a production process of evodiamine and a method for recycling a solvent in production. According to the method, tryptamine isadopted as a raw material, evodiamine is obtained through formylation, cyclization and condensation ring closing, phosgene and ethyl chloroformate are prevented from being used in the whole process, the safety risk in the production process is reduced, and the reaction steps are greatly simplified. Meanwhile, a solvent application process in production is realized, so that the production cost is greatly reduced, and the method has an industrial popularization value.
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Paragraph 0018; 0042-0044; 0052-0054
(2021/02/24)
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- Design, synthesis, and biological evaluation of 3′,4′,5′-trimethoxy evodiamine derivatives as potential antitumor agents
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A series of compounds bearing 3′,4′,5′-trimethoxy module into the core structure of evodiamine were designed and synthesized. The synthesized compounds were screened in vitro for their antitumor potential. MTT results showed that compounds 14a–14c and 14i–14j had significant effects, with compound 14h being the most prominent, with an IC50 value of 3.3 ± 1.5?μM, which was lower than evodiamine and 5-Fu. Subsequent experiments further confirmed that compound 14h could inhibit cell proliferation and migration, and induce G2/M phase arrest to inhibit the proliferation of HGC-27 cells, which is consistent with the results of the cytotoxicity experiment. Besides, 14h could inhibit microtubule assembly and might kill tumor cells by inhibiting VEGF and glycolysis. All experimental results indicate that compound 14h might be a potential drug candidate for the treatment of gastric cancer and was worthy of further study.
- Peng, Yijiao,Xiong, Runde,Li, Zhen,Peng, Junmei,Xie, Zhi-Zhong,Lei, Xiao-Yong,He, Dongxiu,Tang, Guotao
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p. 1021 - 1032
(2021/02/26)
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- Facile access to: N-formyl imide as an N-formylating agent for the direct synthesis of N-formamides, benzimidazoles and quinazolinones
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N-Formamide synthesis using N-formyl imide with primary and secondary amines with catalytic amounts of p-toluenesulfonic acid monohydrate (TsOH·H2O) is described. This reaction is performed in water without the use of surfactants. Moreover, N-formyl imide is efficiently synthesized using acylamidines with TsOH·H2O in water. In addition, N-formyl imide was successfully used as a carbonyl source in the synthesis of benzimidazole and quinazolinone derivatives. Notable features of N-formylation of amines by using N-formyl imide include operational simplicity, oxidant- A nd metal-free conditions, structurally diverse products, and easy applicability to gram-scale operation.
- Huang, Hsin-Yi,Liang, Chien-Fu,Lin, Xiu-Yi,Yen, Shih-Yao
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supporting information
p. 5726 - 5733
(2020/08/21)
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- Amino evodiamine derivative and preparation method and application thereof
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The invention discloses an amino evodiamine derivative and a preparation method and application thereof. A carboline compound and N-methyl-7-nitro isatoic anhydride are used for preparing a 2-nitro evodiamine derivative, and the 2-nitro evodiamine derivative is reduced to obtain the amino evodiamine derivative. A cytotoxicity experiment is performed by using a CCK-8 method, the anti-proliferationeffect of the compound on breast cancer MDA-MB-231 cells, colon cancer SW620 cells and normal liver LO2 cells is evaluated, and cell apoptosis detection is performed by using FITC/PI double staining;experiments show that compared with evodiamine, the compound 2-NH2-EVO has a very strong inhibition effect on breast cancer cells MDA-MB-231, the IC50 value is 0.79 uM, meanwhile, cell apoptosis can be remarkably induced, and the compound 2-NH2-EVO is expected to be developed into an anti-cancer drug with potential.
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Paragraph 0013
(2020/09/16)
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- Amino evodiamine polymer micelle as well as preparation method and application thereof
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The invention discloses an amino evodiamine polymer micelle as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing a 2-nitro evodiamine derivative from a carboline compound and N-methyl-7-nitro isatoic anhydride, reducing the 2-nitro evodiamine derivative to obtain an amino evodiamine derivative, and reacting a polymer with amino evodiamine to prepare an amino evodiamine polymer conjugate; and then carrying out self-assembly on the amino evodiamine polymer conjugate to obtain the amino evodiamine polymer micelle. The water solubility and bioavailability of a drug are improved, the drug is combined with a nanotechnology, a nano drug loading system is developed for drug delivery, and the nano drug can be passively enriched intumor tissues in a targeting manner through an EPR effect.
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Paragraph 0017
(2020/10/04)
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- Doxorubicin-loaded polymeric micelle as well as preparation method and application thereof
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The present invention discloses a doxorubicin-loaded polymeric micelle as well as a preparation method and application thereof. Novel amino evodiamine is adopted to react with polyethylene glycol, a micelle obtained by self-assembly is used as a carrier to load doxorubicin, a prepared mPEG-CO-NH-EVO micelle and a mPEG-CO-NH-EVO-OCH3 micelle have low toxicity to normal hepatocytes so that the two amphipathic polymeric micelles are used as carriers to load DOX to prepare DOX-loaded polymeric micelles, namely a mPEG-CO-NH-EVO/DOX micelle and a mPEG-CO-NH-EVO-OCH3/DOX micelle, and DOX enters hydrophobic shells of the micelles due to the dialysis effect; shapes of the micelles are represented by using a transmission electron microscope and a scanning electron microscope, and the drug loading efficiency and encapsulation efficiency of DOX are tested and calculated by using an ultraviolet spectrophotometer; and finally, evaluating the cytotoxicity by using a CCK-8 method. Shown by cytotoxicity tests, a DOX-loaded polymer has an effect on inhibiting breast cancer cells and particularly has greatly reduced toxicity to the normal hepatocytes.
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Paragraph 0014
(2020/10/04)
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- Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket
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Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 ? movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
- Zhang, Tianhua,Lai, Zengwei,Yuan, Suying,Huang, Yi-You,Dong, Guoqiang,Sheng, Chunquan,Ke, Hengming,Luo, Hai-Bin
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p. 9828 - 9837
(2020/10/19)
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- Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives
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An efficient cascade reaction of tryptamine-derived isocyanides with C,N-cyclic azomethine imines is described. The polycyclic pyrrolo[2,3-c]quinoline derivatives, which benefited from rearrangement process driven by hydrogen bonding, could be directly assembled in moderate to good yields (40–87 %) under metal-free and mild conditions. This transformation involved four new heterocyclic rings formations and uniquely, ring opening of indole as well as ring expansion of C,N-cyclic azomethine imine. Both experimental and DFT studies provided guidance on the in-depth insight into the reaction pathways and hydrogen bonding was identified to lower the free energy barrier in transition states. This work constitutes a rare example of tryptamine-derived isocyanide-based cascade reactions, and potentially could be a powerful synthetic strategy for accessing polycyclic analogues involved in natural products.
- Cao, Wen-Bin,Ji, Shun-Jun,Lan, Yu,Li, Haiyan,Li, Shijun,Xu, Meng-Meng,Xu, Xiao-Ping
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supporting information
p. 21425 - 21430
(2020/09/23)
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- Organocatalytic Decarboxylation of Amino Acids as a Route to Bio-based Amines and Amides
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Amino acids obtained by fermentation or recovered from protein waste hydrolysates represent an excellent renewable resource for the production of bio-based chemicals. In an attempt to recycle both carbon and nitrogen, we report here on a chemocatalytic, metal-free approach for decarboxylation of amino acids, thereby providing a direct access to primary amines. In the presence of a carbonyl compound the amino acid is temporarily trapped into a Schiff base, from which the elimination of CO2 may proceed more easily. After evaluating different types of aldehydes and ketones on their activity at low catalyst loadings (≤5 mol%), isophorone was identified as powerful organocatalyst under mild conditions. After optimisation many amino acids with a neutral side chain were converted in 28–99 % yield in 2-propanol at 150 °C. When the reaction is performed in DMF, the amine is susceptible to N-formylation. This consecutive reaction is catalysed by the acidity of the amino acid reactant itself. In this way, many amino acids were efficiently transformed to the corresponding formamides in a one-pot catalytic system.
- Claes, Laurens,Janssen, Michiel,De Vos, Dirk E.
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p. 4297 - 4306
(2019/08/26)
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- Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade Dearomatization Reaction of Indoles with Propargyl Carbonate
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An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with propargyl carbonate was developed. The challenges associated with both the chemoselectivity between the carbon and nitrogen nucleophile and the enantioselective control during the formation of an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system derived from the Feringa ligand. A series of enantioenriched multiply substituted fused indolenines were provided in good yields (71–86 %) with excellent enantioselectivity (91–96 % ee) and chemoselectivity (3/4>19:1 in most cases).
- Ding, Lu,Gao, Run-Duo,You, Shu-Li
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supporting information
p. 4330 - 4334
(2019/02/25)
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- Trimethoxyphenyl-containing evodiamine derivative and application thereof
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According to the invention, the evodiamine compound is modified and optimized; wherein benzenetrimethoxy is introduced into an evodiamine skeleton; therefore, evodiamine and derivatives thereof are linked through amido bonds, and in-vitro and in-vivo antitumor activity screening experiments are carried out, so that a series of trimethoxyphenyl-containing evodiamine derivatives are synthesized, andhigh-efficiency and low-toxicity antitumor candidate drugs are screened out. The range of existing anticancer compounds is broadened, and the compounds can be used as lead compounds for continuous optimization; meanwhile, the compound has small toxic and side effects, does not have inhibitory activity on normal cells of a human body while inhibiting the growth of cancer cells, and is safer to use.
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Paragraph 0044; 0045; 0048
(2019/12/02)
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- Dual-targeting Rutaecarpine-NO donor hybrids as novel anti-hypertensive agents by promoting release of CGRP
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CGRP, known as the most potent vasodilator substance, plays an important role in hypertension initiation and development. TRPV1 and TRPA1 are critical in promoting the synthesis and release of CGRP, thereby regulating the cardiovascular tone. Rutaecarpine exhibits potent vasodilator and hypertensive effects by stimulating CGRP synthesis and release via activation of TRPV1. And NO has been shown to react with H2S in vivo to form HNO, thereby activating HNO-TRPA1-CGRP pathway. Inspired by combination therapy, 11 rutaecarpine-furoxan hybrids were designed, synthesized and evaluated. The results demonstrated that most hybrids exerted comparable or improved vasodilator activities. Among which, 13a is the most potent both ex vivo (EC50 = 13.1 nM) and in vivo. Mechanistic studies revealed that the vasodilator and anti-hypertensive effects of the hybrids might involve the promotion of CGRP release via dual activation of TRPV1 and TRPA1. This work suggests that dual-targeted hybrids might be an effective and promising approach to discover and develop novel anti-hypertensive drugs.
- Ma, Jinjin,Chen, Lan,Fan, Jinbao,Cao, Wei,Zeng, Guangyao,Wang, Yajing,Li, Yuanjian,Zhou, Yingjun,Deng, Xu
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supporting information
p. 146 - 153
(2019/02/27)
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- The base-free van Leusen reaction of cyclic imines on water: Synthesis of N-fused imidazo 6,11-dihydro β-carboline derivatives
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Construction of imidazoles has been demonstrated on water under base-free conditions. The reaction of dihydro β-carboline imines and p-toluenesulfonylmethyl isocyanides furnished the corresponding substituted N-fused imidazo 6,11-dihydro β-carboline derivatives in very good yields under ambient conditions. The use of deuterium oxide (D2O) as a solvent enabled the incorporation of deuterium isotopes in the imidazole ring.
- Satyam, Killari,Murugesh,Suresh, Surisetti
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supporting information
p. 5234 - 5238
(2019/06/07)
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- Efficient syntheses and anti-cancer activity of xenortides A-D including: Ent / epi -stereoisomers
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A one-pot, two-step, total synthesis of naturally occurring xenortides A, B, C and D, (Xens A-D) isolated from the bacterium Xenorhabdus nematophila, and an entire complementary set of stereoisomers, has been achieved. Compounds were synthesized utilizing an isocyanide-based Ugi 4-CR followed by facile N-Boc deprotection. The reaction sequence took advantage of the chiral pool of N-Boc protected amino acids (l-Leu/Val and d-Leu/Val) with aryl isocyanides, phenyl acetaldehyde and methylamine giving the desired Xens A-D (A and B >98% ee) and all subsequent stereoisomers in reasonable yields upon deprotection followed by separation of diastereomers. Also, detailed mechanistic insights for diastereoselectivity of (-)-Xen A, as a model in the Ugi 4-CR, has been described. Moreover, for the first time, this focused library was screened for cytotoxicity against a panel of epithelial cancer cell lines as well as normal cell lines with an MTT proliferation assay. The structure-activity relationship (SAR) study demonstrated that tryptamides Xen B and D were more active than phenylethylamides Xen A and C. Furthermore, (-)-Xen B (IC50 = 19-25 μM) and ent-(+)-Xen D (IC50 = 21-26 μM) gave the highest cytotoxicity and they were also found to be non-toxic toward normal cells. Importantly, the SAR results indicate that the stereochemistry at C8 and C11 in (-)-Xen B and ent-(+)-Xen D play a critical role in cytotoxic activity.
- Esmati,Maddirala,Hussein,Amawi,Tiwari,Andreana
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p. 5332 - 5342
(2018/08/03)
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- A Highly Regio- and Diastereoselective Four-Component Reaction to Construct Polycyclic Bispiroindolines from 2-Isocyanoethylindoles and Isocyanates
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A one-pot multicomponent domino reaction between 2-isocyanoethylindoles and isocyanates for the diastereoselective construction of polycyclic bispiroindolines was developed. Fused polycyclic bispiroindolines containing two contiguous spiral atoms were afforded in moderate to good yields with excellent regio- and diastereoselectivities through a four-component Ugi-type reaction (U-4CR) under mild conditions.
- Li, Longhai,Liu, Jiaxin,Shi, Min
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supporting information
p. 7076 - 7079
(2018/11/21)
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- Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal Total Synthesis of Aspidofractinine
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The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chemistry. Nucleophilic addition typical
- Saya, Jordy M.,Roose, Thomas R.,Peek, Jarryt J.,Weijers, Bram,de Waal, Thomas J. S.,Vande Velde, Christophe M. L.,Orru, Romano V. A.,Ruijter, Eelco
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supporting information
p. 15232 - 15236
(2018/10/24)
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- Formyloxyacetoxyphenylmethane as an N-Formylating Reagent for Amines, Amino Acids, and Peptides
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Formyloxyacetoxyphenylmethane is a stable, water-tolerant, N-formylating reagent for primary and secondary amines that can be used under solvent-free conditions at room temperature to prepare a range of N-formamides, N-formylanilines, N-formyl-α-amino acids, N-formylpeptides, and an isocyanide.
- Chapman, Robert S. L.,Lawrence, Ruth,Williams, Jonathan M. J.,Bull, Steven D.
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supporting information
p. 4908 - 4911
(2017/09/23)
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- Oxa or thia- tetradium alkali anti-tumor derivative and its preparation method
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The invention relates to the technical field of medicines and in particular relates to oxa- or thio-evodiamine anti-tumor derivatives as well as a preparation method of the derivatives and application of the derivatives in preparation of topoisomerase inhibitors and anti-tumor drugs. The oxa- or thio-evodiamine anti-tumor derivatives are newly discovered topoisomerase I inhibitors with brand-new structures and have remarkable anti-tumor activity, and the structure of a compound is as shown in a general formula I.
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Paragraph 0074; 0075
(2017/04/21)
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- Evodiamine compounds and preparation method and application thereof
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The invention discloses evodiamine compounds and a preparation method and application thereof. The evodiamine compounds adopt structures shown as a general formula (I), and comprise racemates, d-type or l-type isomers and pharmaceutically acceptable salts thereof. Pharmacological tests prove that the evodiamine compounds have obvious phosphodiesterase PDE5 inhibiting activity, some of the evodiamine compounds have equivalent PDE5 inhibiting activity to sildenafil, and the evodiamine compounds have stronger phosphodiesterase PDE6 selectivity. The evodiamine compounds can be clinically used for improving or treating symptoms or diseases in a cardiovascular system, a cerebrovascular system and a urinary system, especially improving or treating symptoms or diseases including erectile dysfunction and pulmonary hypertension.
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Paragraph 0049
(2017/10/26)
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- 2-Isocyano glucose used in Ugi four-component reaction: An approach to enhance inhibitory effect against DNA oxidation
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The Ugi four-component-reaction (Ugi 4CR) allowed synthesizing bisamide from carboxylic acid, aldehyde, amine, and isocyanide in one-pot operation. However, introducing 2-isocyano glucose into the Ugi 4CR and investigating the inhibitory effects of Ugi adducts against radical-induced oxidation of DNA remained technical challenges. We herein applied 2-isocyano glucose (acetylation of hydroxy groups) to perform a catalyst-free Ugi 4CR at room temperature. The gallic, ferulic, caffeic, or p-hydroxybenzoic acids, aniline (or benzylamine and p-aminophenol), and formaldehyde acted as reagents. In the case of inhibiting DNA oxidations induced by 2,2’-azobis(2-amidinopropane hydrochloride) (AAPH), hydroxy radical, and Cu2+/glutathione, the Ugi adduct containing glucose moiety exhibited higher antioxidative activities than the structural analog without glucose moiety involved. It was also proved that high antioxidative property was owing to hydroxy groups in glucose moiety. Therefore, sugar-appended Ugi adducts might hold promising inhibitors for DNA oxidation.
- Zhao, Peng-Fei,Liu, Zai-Qun
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p. 458 - 466
(2017/05/05)
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- Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions
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A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral α-amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Br?nsted acidity of acetic acid. Amide bonds are reputedly difficult to activate due to their high resonance stabilization. An unusual mild activation of dimethylformamide and formamide by borinic acid 1 (see scheme), illustrated by a general formylation of a wide range of amines, including chiral α-amino esters, has been reported.
- Mohy El Dine, Tharwat,Evans, David,Rouden, Jacques,Blanchet, Jér?me
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supporting information
p. 5894 - 5898
(2016/04/26)
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- Investigation into the stability and reactivity of the pentacyclic alkaloid dehydroevodiamine and the benz-analog thereof
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Limited synthetic approaches to obtain the biologically active alkaloid dehydroevodiamine (DHED) are known to date. Undesired demethylation in the most widely applied route was found to be a hampering side reaction for the benz-DHED derivative leading to a quinazolinone, which represents a benz-rutaecarpine derivative. For rutaecarpine, a related plant alkaloid, many different synthetic approaches have been described. Alternative reaction procedures to obtain DHED such as methylation of rutaecarpine and oxidation of evodiamine were investigated to make DHED more easily accessible and the latter method proved to be the most successful one. Furthermore, the remarkable equilibrium between the ring closed quinazolinium and the ring open form of the compounds was systematically investigated by UV-vis measurements. The ring open form and the quinazolinium salt, form the same species when incubated in buffer solution for 24 h. A better soluble form, i.e., 'hydroxyevodiamine', seems to represent the biologically active form that has not yet been described.
- Wehle, Sarah,Espargaró, Alba,Sabaté, Raimon,Decker, Michael
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supporting information
p. 2535 - 2543
(2016/04/26)
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- Synthesis of Oxazolidin-2-ones by Oxidative Coupling of Isonitriles, Phenyl Vinyl Selenone, and Water
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Reaction of alkyl isocyanides, phenyl vinyl selenone, and water in the presence of a catalytic amount of Cs2CO3 afforded oxazolidin-2-ones in good yields. This unprecedented heteroannulation process created four chemical bonds in a s
- Buyck, Thomas,Pasche, Delphine,Wang, Qian,Zhu, Jieping
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supporting information
p. 2278 - 2281
(2016/02/14)
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- Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles
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We report a highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochemically complex spiroindolines from tryptamine-derived isocyanides. The reaction is facilitated by using fluorinated alcohols (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.
- Saya, Jordy M.,Oppelaar, Barry,Cioc, Rǎzvan C.,Van Der Heijden, Gydo,Vande Velde, Christophe M. L.,Orru, Romano V. A.,Ruijter, Eelco
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supporting information
p. 12482 - 12485
(2016/10/24)
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- Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines
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The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (-)-crispine A and (-)-harmicine.
- Fandrick, Daniel R.,Hart, Christine A.,Okafor, Ifeanyi S.,Mercadante, Michael A.,Sanyal, Sanjit,Masters, James T.,Sarvestani, Max,Fandrick, Keith R.,Stockdill, Jennifer L.,Grinberg, Nelu,Gonnella, Nina,Lee, Heewon,Senanayake, Chris H.
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supporting information
p. 6192 - 6195
(2016/12/09)
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- Asymmetric dearomatization of indoles through a Michael/Friedel-Crafts-Type cascade to construct polycyclic spiroindolines
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A highly efficient asymmetric dearomatization of indoles was realized through a cascade reaction between 2-isocyanoethylindole and alkylidene malonates catalyzed by a chiral N,N-dioxide/MgII catalyst. Fused polycyclic indolines containing three stereocenters were afforded in good yields with excellent diastereo- and enantioselectivities through a Michael/Friedel-Crafts/Mannich cascade. When 2-substituted 2-isocyanoethylindoles were used, spiroindoline derivatives were obtained through a Michael/Friedel-Crafts reaction.
- Zhao, Xiaohu,Liu, Xiaohua,Mei, Hongjiang,Guo, Jing,Lin, Lili,Feng, Xiaoming
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p. 4032 - 4035
(2015/03/30)
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- Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents
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A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. (Figure Presented).
- Wang, Shengzheng,Fang, Kun,Dong, Guoqiang,Chen, Shuqiang,Liu, Na,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
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p. 6678 - 6696
(2015/09/07)
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- Design, synthesis and biological evaluation of E-ring modified evodiamine derivatives as novel antitumor agents
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A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase I and II was evaluated by the relaxation assay. In vitro antitumor activity results revealed that compound 12 showed good antitumor activity with a broad spectrum. Its binding modes with topoisomerase I and II were clarified by molecular docking.
- Fang, Kun,Dong, Guo-Qiang,Gong, Hai,Liu, Na,Li, Zhen-Gang,Zhu, Shi-Ping,Miao, Zhen-Yuan,Yao, Jian-Zhong,Zhang, Wan-Nian,Sheng, Chun-Quan
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p. 978 - 982
(2014/08/18)
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- A cyclization-rearrangement cascade for the synthesis of structurally complex chiral gold(I)-aminocarbene complexes
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A facile synthesis of chiral cyclic alkyl aminocarbene-gold(I) complexes from gold-free 1,7-enyne substrates was developed. The novel cyclization-rearrangement reaction sequence is triggered by the addition of (Me2S)AuCl to different 1,7-enynes and leads to structurally unique carbene-gold(I) complexes in high yields. These novel complexes are catalytically active and inhibit the proliferation of different human cancer cell lines.
- Kolundzic, Filip,Murali, Annamalai,Perez-Galan, Patricia,Bauer, Jonathan O.,Strohmann, Carsten,Kumar, Kamal,Waldmann, Herbert
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supporting information
p. 8122 - 8126
(2014/08/18)
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- Formylation of amines through catalyst- and solvent-free transamidation reaction
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The transamidation between formamide and various amines proceeds under heating, without any catalyst nor solvent, providing thus green and neutral conditions for the formylation of primary and secondary amines. The resulting amide product can be directly transformed, in a one pot sequence, into monomethylamine.
- Lebleu, Thomas,Kotsuki, Hiyoshizo,Maddaluno, Jacques,Legros, Julien
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supporting information
p. 362 - 364
(2014/01/06)
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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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- Synthesis of the indolo[2,3-a]quinolizidine ring through the addition of 2-siloxyfurans to imines and intrinsic reaction coordinate calculations
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A concise asymmetric diastereoselective strategy for the synthesis of indolo[2,3-a]quinolizidine derivative 1 was developed using diastereoselective addition of 2-siloxyfurans 4 to imine 3 through chiral auxiliary induction. The addition of an ionic liquid as additive in the reaction favored the anti configuration in the major adduct. The stereochemical outcome of the anti/syn (threo/erythro) selectivity was rationalized based on transition state and IRC calculations at DFT (B3LYP) and MP2 theories. MP2 calculations was shown to be the method of choice in these systems, which orbital desymmetrizations were observed in the anti transition state of the addition of 4 to 3 and secondary orbital interactions allowed us to rationalize the production of the major anti-adduct 6. Furthermore, the work also suggested that 2-(triisopropylsiloxy) furan (4a) was the nucleophile of choice in this kind of Mannich reaction. Moreover, the strategy features the use of the Mitsunobu reaction to insert an amino group with the correct configuration into amine 2, key intermediate to achieve 1. The synthetic route can also be applied in the total synthesis of promising aza-β-carboline compounds. Georg Thieme Verlag Stuttgart. New York.
- Mirabal-Gallardo, Yaneris,Soriano, Maria D. P. C.,Caballero, Julio,Alzate-Morales, Jans,Simirgiotis, Mario J.,Santos, Leonardo S.
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experimental part
p. 144 - 150
(2012/03/26)
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- Synthesis of the debrominated analog of dihydroflustramine C utilizing a sulfur ylide-initiated thio-Claisen rearrangement
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In investigating the scope and limitations of the sulfur ylide initiated thio-Claisen rearrangement developed in our laboratory, we have been able to efficiently synthesize highly functionalized pyrroloindoline ring systems. This functionality is present in a variety of natural and non-natural products and here we report our synthesis of the debrominated analog of dihydroflustramine C.
- Sabahi, Amir,Rainier, Jon D.
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experimental part
p. 116 - 125
(2010/09/03)
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- Selection of evodiamine as a novel topoisomerase i inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents
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Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI inhibitors. Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate to good in vitro antitumor activity. These novel structures can be considered as good starting points for the development of new antitumor lead compounds. Hit 20 (evodiamine) was chosen for preliminary structure-activity relationship studies. Various groups, including alkyl, benzoyl, benzyl and ester, were introduced to the indole nitrogen atom of evodiamine. The substituted benzoyl groups were found to be favorable for the antitumor activity and spectrum. The 4-Cl benzoyl derivative, compound 29u, was the most active one with IC50 values in the range 0.049-2.6 μM.
- Dong, Guoqiang,Sheng, Chunquan,Wang, Shengzheng,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 7521 - 7531
(2011/02/21)
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- Efficient and diverse synthesis of indole derivatives
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(Chemical Equation Presented) A convergent 2-step procedure toward an array of indole derivatives involving an Ugi reaction and a Pictet - Spengler reaction is described. The reactions are versatile regarding different starting materials. Hexacyclic 24 can be produced with unprecedented complexity.
- Liu, Haixia,Doemling, Alexander
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supporting information; experimental part
p. 6895 - 6898
(2009/12/31)
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- Novel chemistry of β-carbolines. Expedient synthesis of polycyclic scaffolds
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Functionalization of β-carbolines is a challenge as numerous natural alkaloids with different biological activities present this heterocycle. The RCM is used herein with allyl-, vinyl-, ethynyl-, and propargyl-β-carbolines to generate additionally fused h
- González-Gómez, álvaro,Domínguez, Gema,Pérez-Castells, Javier
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supporting information; experimental part
p. 3378 - 3391
(2009/09/06)
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- Synthesis and vasodilator effects of rutaecarpine analogues which might be involved transient receptor potential vanilloid subfamily, member 1 (TRPV1)
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Rutaecarpine is the major alkaloid component of Wu-Chu-Yu, a well known Chinese herbal drug. It has been reported that rutaecarpine causes the vasodilator, hypotensive effects by stimulation of CGRP synthesis and release via activation of TRPV1. In present study, 23 rutaecarpine analogues were designed and synthesized. Then, the vasodilator effects of theses compounds were screened by rat aortic ring experiment. The result showed that the 14-N atom of rutaecarpine might be the key site for the activity. The 5-carbonyl might make lower contribution to the effect. And simple substitute in indole-ring or quinazoline-ring would not enhance the vasodilator effect unless in proper position with proper group. One of these compounds, 10-methylrutaecarpine, exhibited similar effect with rutaecarpine. Further functional experiments showed its vasodilator and hypotensive effect were related to the stimulation of CGRP release via activation of TRPV1. The vasodilator effects of these compounds were evaluated and the structure-activity relationship was elucidated for the first time. The results suggested a new direction of valuable TRPV1 agonist as anti-hypertensive drugs.
- Chen, Zhuo,Hu, Gaoyun,Li, Dai,Chen, Jun,Li, Yuanjian,Zhou, Huayong,Xie, Ye
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experimental part
p. 2351 - 2359
(2009/09/08)
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- Indole derivatives with antimycobacterial activity
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1,3-Dinitro-2-(indol-3'-yl)-propanes 3 are synthesized by Michael reaction of nitromethane with the indolylnitroethenes 2. - Reaction of the aldehydes 4 and 10 with the benzylamines 12 as well as the reaction of the indolylalkylamines 6a and 9a with the benzaldehydes 11 lead to Schiff bases which are reduced to N-benzyl-(indol-3-ylmethyl)-amines 13 and N-benzyl-(indol-3-ylethyl)-amines 14, respectively; tert amines 16 are synthesized via the formamides 15, amines 18 are prepared according to Mannich. - Inhibitory effects on Mycobacterium tuberculosis H 37 Ra are investigated, a structure-activity relationship is discussed.
- Mahboobi,Grothus,Meindl
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p. 105 - 114
(2007/10/02)
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- Total Syntheses of Yohimbe Alkaloids, with Stereoselection for the Normal, Allo, and 3-Epiallo Series, Based on Annelations of 4-Methoxy-1,2-dihydropyridones
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N--2,3-dihydro-4-pyridone (31) was generated in two steps (77percent yield) from tryptamine and N-methyl-4-piperidone methiodide.Its cyclization (90percent yield) and oxidation (91percent yield) provided the tetracyclic analogue 32.O-Methylation and Robinson-type annelation of these vinylogous lactams (the latter in form of its Na-carbamate) furnished the dienones 38 (64percent) and 43 (90percent).Further elaboration by cyclization and/or reduction reactions selectively provided the 15,16-didehydroyohimbinones 7 and 44.Their reductions then led to yohimbinone (52, 20percent overall yield from tryptamine), alloyohimbinone (11, 19percent overall yield), and 3-epi-alloyohimbinone (10, 23percent overall yield), which led to yohimbine (3), β-yohimbine (9), 3-epi-alloyohimbine (53), and 3-epi-17-epi-alloyohimbine (54).
- Kuehne, Martin E.,Muth, Randy S.
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p. 2701 - 2712
(2007/10/02)
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- Reactions of Electron-Rich Heterocycles with Derivatives of Carboxylic Ortho Acids, II: Acid Catalysed Reactions of 3-Substituted Indoles with Ethyl Orthoformate
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The indoles 1a and 1b react with the diethoxycarbenium ion 2b, generated in an acidic medium, to yield the di- and triindolylmethanes 3, 4, 5 and 7.Compound 5a is oxidized to the cyanine 6a.Tryptamine (8a) undergoes formylation with 2b.When the nucleophilicity of the amino group in 8a is reduced, formation of triindolylmethane is favored, as shown in the reaction of 8b with 2b.
- Mueller, Johann,Pindur, Ulf
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p. 555 - 561
(2007/10/02)
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- Synthesis of Oxazolylindole Alkaloids from Tryptamine and Tryptophan by Oxidation with 2,3-Dichloro-5,6-dicyanobenzoquinone
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When N-acyl derivatives of tryptamine and L-tryptophan methyl ester were treated with DDQ (2 equiv) in tetrahydrofuran or other anhydrous solvents, four consecutive reactions, dehydrogenation, nucleophilic cyclization, another dehydrogenation, and isomeri
- Yoshioka, Tadao,Mohri, Kunihiko,Oikawa, Yuji,Yonemitsu, Osamu
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p. 2252 - 2281
(2007/10/02)
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- Photoinduced oxygenation of tryptamines by aromatic amine N-oxides
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Irradiation (1) (253-7 nm) of Na,Nb-dimethyltryptaimne with pyridine N-oxide or benzo[c]cinnoline N-oxide in CH2Cl2 yielded 1,8-dimethyl-3a-hydroxy-1,2,3,3a,8-8a,- hexahydropyrrolo[2,3-b]indole (19), while with visible light Nb-(4-cyanobutadienyl)-Na,Nb,- dimethyltryptamine (21) was obtained. This method was applied to trimethyltryptamine and the corresponding oxindole (34) and the N-formyl derivative (20) were obtained.
- Nakagawa,Kaneko,Yamaguchi,Kawashima,Hino
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p. 2591 - 2600
(2007/10/04)
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