- Photocatalytic Cascade Radical Cyclization Approach to Bioactive Indoline-Alkaloids over Donor-Acceptor Type Conjugated Microporous Polymer
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Herein, we describe a visible-light-induced radical strategy for the 1,2-formylarylation of N-arylacrylamides via the C-H activation of 1,3-dioxolane using a carbazolic-cyano conjugated microporous polymer (CC-CMP) as a metal-free photocatalyst. This process provides an efficient and mild approach for constructing highly functionalized formyl-substituted oxindoles, which are valuable building blocks that allow rapid access to various important heterocycle-fused and spirocyclic indole alkaloids. Utilizing this strategy, bioactive alkaloids, such as (±)-desoxyeseroline, (±)-esermethole, and (±)-N-Me-coerulescine, have been concisely synthesized in up to 74% overall yield from low-cost acrylamides and 1,3-dioxolane. The overall yields of our approach are much higher than those of conventional multistep methods. Gram-scale syntheses of natural alkaloids have been demonstrated, highlighting the practical utility of this protocol. The use of CC-CMP photocatalysts, which are metal-free, flexible, stable, effective, and reusable, making this strategy appealing to advanced chemical manufacturing.
- Ou, Wei,Zhang, Guoqiang,Wu, Jie,Su, Chenliang
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- Total Synthesis of (±)-Phenserine via [4+1] Cyclization of a Bis(alkylthio)carbene and an Indole Isocyanate
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Figure presented A total synthesis of acetylcholine blocking agent, phenserine, has been achieved by employing a [4+1] cyclization between an appropriately substituted indole isocyanate and a bis(alkylthio)carbene.
- Rigby, James H.,Sidique, Shyama
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- An efficient synthesis of optically active physostigmine from tryptophan via alkylative cyclization
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(Equation Presented) Physostigmine A new and efficient synthetic route to physostigmine is described. Corey-Kim reagent reacted with tryptamine or tryptophan carbamates to give 3a-(methylthiomethyl)hexahydropyrrolo[2,3-b]indole skeletons. Formal total synthesis of racemic and chiral physostigmine was accomplished in excellent overall yields, in short steps.
- Kawahara, Michiaki,Nishida, Atsushi,Nakagawa, Masako
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- The photocatalysis synthetic alkaloid (by machine translation)
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The present invention provides a catalytic synthesis method of living beings, the alkaloid comprises indole fused ring class and indole spiro compound, the process is as follows: in order to nitrogen aryl acrylamide as raw materials in under the photocatalysis with peroxide synthesis 3 - acetal 2 - indole compound, obtained through hydrolysis 3 - formyl - 2 - indole compound, further reducing synthetic alkaloid, the method routes mild, efficiency is high-efficient. The reaction in the illumination can occur under the room temperature, mild condition, has better substrate versatility and functional group tolerant. (by machine translation)
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Paragraph 0126; 0127; 0128
(2018/11/22)
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- Pd(0)-Catalyzed Chemoselective Deacylative Alkylations (DaA) of N-Acyl 2-Oxindoles: Total Syntheses of Pyrrolidino[2,3- b]indoline Alkaloids, (±)-Deoxyeseroline, and (±)-Esermethole
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We report an efficient Pd(0)-catalyzed deacylative allylation of N-acyl 3-substituted 2-oxindoles via the coupling of in situ generated nucleophiles (3 and 4) with allyl electrophiles for the synthesis of a variety of 2-oxindoles with C3-quaternary centers. Gratifyingly, this alkylation process is found to be highly chemoselective in nature, where a C-C bond formation is completely predominant over a C-N bond formation. A variety of key intermediates were synthesized utilizing an aforementioned methodology.
- Kumar, Nivesh,Gavit, Vipin R.,Maity, Arindam,Bisai, Alakesh
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p. 10709 - 10735
(2018/09/29)
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- Metal-Free Synthesis of Oxazolidine-2,4-diones and 3,3-Disubstituted Oxindoles via ICl-Induced Cyclization
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A metal-free method for the construction of oxazolidine-2,4-diones and oxindoles was discussed. Using iodine monochloride (ICl) as both the reaction promoter and iodide source, the iodolactonization of N-Boc acrylamides proceeded readily and provided the corresponding iodo oxazolidine-2,4-diones and oxazolidin-2-ones in good isolated yields. The obtained oxazolidine-2,4-diones can be used as key intermediates in the synthesis of toloxatone. When N-alkyl-N-arylacrylamide derivatives were subjected to the same reaction, iodocarbocyclization products 3,3-disubstituted oxindoles were obtained. The obtained oxindoles can be used as key intermediates in the synthesis of the alkaloids (±)-esermethole and (±)-physostigmine.
- Yi, Wei,Fang, Xing-Xiao,Liu, Qing-Yun,Liu, Gong-Qing
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p. 6671 - 6681
(2019/01/04)
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- Preparation method for physostigmine precursor compound
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The invention relates to physostigmine and provides a preparation method for a physostigmine precursor compound. The physostigmine precursor compound is prepared with 5-methoxytryptamine as a starting raw material through amino protection, intramolecular cyclization, methylation and amide reduction. The preparation method has the advantages of simple synthesis route, usage of cheap and easily available synthesis reagents, simple synthesis operation, friendliness to environment and the like and is highly feasible in industrial production. In particular, a cyclization reagent, i.e., 1,3-dichloro-5,5-dimethylhydantoin, used in the key intramolecular cyclization is a commercial germicide and disinfectant and is cheap, easily available and friendly to environment. The physostigmine precursor compound used as a synthesis precursor or intermediate for physostigmine is also applicable as a synthesis precursor for phenserine and a variety of physostigmine derivatives and thus has good application value and development potential.
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Paragraph 0013; 0048-0051
(2017/09/13)
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- Synthesis of C3-Methyl-Substituted Pyrroloindolines and Furoindolines via Cascade Dearomatization of Indole Derivatives with Methyl Iodide
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A highly efficient method for constructing C3-methyl-substituted pyrroloindolines and furoindolines via cascade dearomatization reaction of indole derivatives with methyl iodide was developed. This protocol offers a direct approach to a wide range of C3 methyl substituted pyrroloindolines under mild conditions. The utility of this method was further demonstrated in the concise synthesis of (±)-esermethol.
- Yi, Ji-Cheng,Liu, Chuan,Dai, Li-Xin,You, Shu-Li
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p. 2975 - 2979
(2017/11/14)
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- FeCl3-Catalyzed Allylation Reactions onto 3-Hydroxy-2-oxindoles: Formal Total Syntheses of Bis-cyclotryptamine Alkaloids, (±)-Chimonanthine, and (±)-Folicanthine
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An FeCl3-catalyzed efficient strategy for the allylation reactions of 3-hydroxy-2-oxindoles with allyltrimethylsilane has been developed. The reaction affords a variety of 2-oxindoles having quaternary center at the pseudobenzylic position in an operationally simple and inexpensive procedure. Control experiments using enantioenriched 3-hydroxy-2-oxindole show that the reaction proceeds through in situ generated 2H-indol-2-one (8). The methodology presents an efficient and concise access to the pyrroloindoline alkaloids (±)-deoxyeseroline (1a), (±)-esermethole (1b), (±)-physostigmine (1c), (±)-phenserine (1d), and (±)-physovenine (1e). Eventually, we extrapolated the scope of this methodology to the formal total syntheses of dimeric cyclotyrptamine alkaloids (±)-chimonanthine (3a), (±)-folicanthine (3c), and (±)-calycanthine (4).
- Kinthada, Lakshmana K.,Medisetty, Sai Raghavendra,Parida, Amarchand,Babu, K. Naresh,Bisai, Alakesh
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p. 8548 - 8567
(2017/08/23)
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- Tert-Butyl Iodide Mediated Reductive Fischer Indolization of Conjugated Hydrazones
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A novel reductive Fischer indolization of readily available N-aryl conjugated hydrazones with tert-butyl iodide has been developed. In this reaction, tert-butyl iodide is used as anhydrous HI source, and the generated HI acts as a Br?nsted acid and a reducing agent. This operationally simple method allows access to various indole derivatives. Furthermore, the procedure can be applied to the synthesis of biologically active compounds.
- Ito, Yuta,Ueda, Masafumi,Takeda, Norihiko,Miyata, Okiko
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supporting information
p. 2616 - 2619
(2016/02/26)
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- Synthesis of pyrroloindolines and furoindolines via cascade dearomatization of indole derivatives with carbenium ion
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A highly efficient intermolecular cascade dearomatization of substituted indoles with benzodithiolylium tetrafluoroborate has been developed. This reaction provides a novel strategy to synthesise C3 methyl-substituted pyrroloindolines and furoindolines under mild reaction conditions, the utility of which has been demonstrated by the synthesis of esermethol and physovenine in a highly concise manner.
- Liu, Chuan,Yin, Qin,Dai, Li-Xin,You, Shu-Li
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p. 5971 - 5974
(2015/03/30)
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- Formation of enehydrazine intermediates through coupling of phenylhydrazines with vinyl halides: Entry into the Fischer indole synthesis
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Cut to the chase: Direct formation of an enehydrazine, an intermediate in the classic Fischer indole synthesis, solves the regioselectivity problem associated with indolization. This approach not only achieves selective synthesis of indoles through proper selection of the vinyl halide, but also leads to quick construction of desoxyeseroline and esermethole, as well as the key structural motif in the Akuammiline alkaloid vincorine. Copyright
- Zhan, Fuxu,Liang, Guangxin
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p. 1266 - 1269
(2013/03/13)
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- Synthesis of (+)-phenserine using an interrupted Fischer indolization reaction
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A concise synthesis of the Alzheimer's therapeutic (+)-phenserine is described. The approach features an interrupted Fischer indolization to construct the pyrrolidinoindoline core, in addition to a classical resolution to arrive at phenserine in enantioenriched form.
- Schammel, Alex W.,Chiou, Grace,Garg, Neil K.
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supporting information; experimental part
p. 725 - 728
(2012/03/26)
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- Synthesis of (±)-esermethole via an intramolecular carbamoylketene-alkene [2+2] cycloaddition
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A synthesis of (±)-esermethole (2), a synthetic precursor of physostigmine (1), has been accomplished by using an intramolecular carbamoylketene-alkene [2+2] cycloaddition followed by nitrone-mediated regioselective ring expansion for the construction of the basic carbon framework of 2 as the key steps.
- Ozawa, Tsukasa,Kanematsu, Makoto,Yokoe, Hiromasa,Yoshida, Masahiro,Shishido, Kozo
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p. 2927 - 2932
(2013/02/21)
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- Efficient synthesis of esermethole and its analogues
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In this work, a general and flexible synthetic route towards the synthesis of pyrroloindoline alkaloids was developed. This new strategy features with a palladium mediated sequential arylation-allylation of o-bromoanilides and leads to the construction of oxindoles bearing a full carbon quaternary center. The cheap triphenylphosphine was proved to be a highly effective ligand for this one pot transformation. On the basis of this new method, esermethole and its analogues were synthesized.
- Zhou, Yongyun,Zhao, Yuanhong,Dai, Xiaoyong,Liu, Jianping,Li, Liang,Zhang, Hongbin
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p. 4091 - 4097
(2011/07/07)
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- A novel one-pot approach of hexahydropyrrolo[2,3-b ]indole nucleus by a cascade addition/cyclization strategy: Synthesis of (±)-esermethole
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A practical and efficient synthesis of 3-substituted hexahydropyrrolo[2,3- b]indole is described. The addition/cyclization of 3-substituted indoles with α,β-dehydroamino esters in the presence of a Lewis acid provides hexahydropyrrolo[2,3-b]indole adducts in good yields and stereoselectivities. This approach has been applied to the concise synthesis of esermethole employing an appropriately substituted indole and an N-acyl dehydroamino ester.
- Lucarini, Simone,Bartoccini, Francesca,Battistoni, Flavia,Diamantini, Giuseppe,Piersanti, Giovanni,Righi, Marika,Spadoni, Gilberto
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supporting information; experimental part
p. 3844 - 3847
(2010/12/18)
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- Intramolecular cyanoamidation of unsaturated cyanoformamides catalyzed by palladium: an efficient synthesis of multi-functionalized lactams
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The Pd(0)-catalyzed intramolecular cyanoamidation of several unsaturated cyanoformamides with alkenyl, allenyl, and alkynyl groups was investigated. In the cases of alkynyl and 1,1-disubstituted alkenyl cyanoformamides, the Pd(0)-catalyzed C-CN activation and subsequent insertion reaction proceeded smoothly and gave the corresponding lactams bearing a cyano group at the β-position in good yields. The mechanism of the reaction was also discussed.
- Kobayashi, Yusuke,Kamisaki, Haruhi,Takeda, Hiroshi,Yasui, Yoshizumi,Yanada, Reiko,Takemoto, Yoshiji
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p. 2978 - 2989
(2007/10/03)
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- Palladium-catalyzed enantioselective domino heck-cyanation sequence: Development and application to the total synthesis of esermethole and physostigmine
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An efficient synthesis of functionalized 3-alkyl-3-cyanomethyl-2-oxindole 1 by a palladium-catalyzed domino Heck-cyanation reaction has been developed. Reaction of ortho-iodoanilide 5 with potassium ferro(II)cyanide, K 4[Fe(CN)6], dissolved in DMF in the presence of palladium acetate and sodium carbonate afforded oxindole 1 in good to excellent yields. An enantioselective domino Heck-cyanation process has been developed for the first time using (S)-DIFLUORPHOS as a chiral supporting ligand, and an enantioselectivity of up to 79% ee in the enantiomerically enriched oxindole was obtained under optimized conditions. A concise total synthesis of esermethole and physostigmine, powerful inhibitors of acetyl- and butyryl-cholinesterase, is documented.
- Pinto, Artur,Jia, Yanxing,Neuville, Luc,Zhu, Jieping
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p. 961 - 967
(2007/10/03)
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- Synthesis of hexahydropyrrolo[2,3-b]indole alkaloids based on the aza-Pauson-Khand-type reaction of alkynecarbodiimides
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(Chemical Equation Presented) Upon treatment with 30 mol % of Co 2(CO)8 and 30 mol % of TMTU in toluene at 70°C, benzene-bridged alkynecarbodiimides efficiently underwent a ring-closing reaction to give the pyrrolo[2,3-b]-indol-2-ones in good yields. These conditions could nearly suppress the formation of the urea derivatives, which were consistently observed when 10 mol % of Co2(CO)8 and 60 mol % of TMTU in benzene were used. The synthesis of the eight hexahydropyrrolo[2,3-b]indole alkaloids was accomplished from the resulting pyrrolo[2,3-b]indol-2-ones via the introduction of an angular substituent at the C3a-position by treatment with NaBH4/alkyl bromide as the crucial step.
- Aburano, Daisuke,Yoshida, Tatsunori,Miyakoshi, Naoki,Mukai, Chisato
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p. 6878 - 6884
(2008/02/10)
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- Diastereoselective fischer-type pyrroloindole synthesis and its application to the synthesis of chiral pyrroloindole alkaloids
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Facile access to optically active pyrroloindoles by Fischer-type pyrroloindole synthesis is investigated. The reaction using chiral hydrazines prepared from commercially available chiral amines proceeded with diastereoselective cyclization (up to 70% de), and a short-step conversion of the cycloadducts to (-)-desoxyeseroline and pyrroloindole alkaloids was achieved.
- Nishida, Atsushi,Ushigome, Satoru,Sugimoto, Ayako,Arai, Shigeru
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p. 181 - 185
(2007/10/03)
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- Simple synthesis of racemic pyrrolo[2,3-b]indoles: Formal total synthesis of (±)-physostigmine
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Racemic pyrrolo [2,3-b]indoles were efficiently synthesized by the reaction of aromatic hydrazines with 4-chloro-2-methylbutanal. A formal total synthesis of physostigmine was achieved.
- Tsuji, Riichiro,Nakagawa, Masako,Nishida, Atsushi
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p. 587 - 593
(2007/10/03)
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- 2-Azonianorbornene-2-spiro-1'-aziridinium triflate - A novel ethylene immonium ion equivalent: Application to a synthesis of physostigmine
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A unique protocol for either the aminoethylation or the N-methyl aminoethylation of carbonyl compounds featuring the preparation and use of a novel spiroaziridinium salt, 2-azonianorbornene-2-spiro-1'-aziridinium triflate 2, is described.
- Grieco,Carroll
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p. 4401 - 4404
(2007/10/02)
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