- Five-Step Total Synthesis of (±)-Aspidospermidine by a Lactam Strategy via an Azomethine Ylide
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A five-step total synthesis of (±)-aspidospermidine (1) based on a lactam strategy is reported. Our synthesis features an iridium-catalyzed reductive Michael addition/[3+2] cycloaddition cascade to give a tricyclic ketone intermediate from a simple lactam via an azomethine ylide. The developed strategy enables easily available lactams to be used as stable surrogates of multisubstituted amines and would be applicable to a unified total synthesis of complex Aspidosperma alkaloids.
- Katahara, Seiya,Sugiyama, Yasukazu,Yamane, Mina,Komiya, Yukinori,Sato, Takaaki,Chida, Noritaka
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p. 3058 - 3063
(2021/05/04)
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- TiCl3-Mediated Synthesis of 2,3,3-Trisubstituted Indolenines: Total Synthesis of (+)-1,2-Dehydroaspidospermidine, (+)-Condyfoline, and (?)-Tubifoline
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2,3,3-Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl3-mediated reductive cyclization of tetrasubstituted alkenes bearing a 2-nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)-1,2-dehydroaspidospermidine featuring a late-stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π-electron-5-atom electrocyclization and a 1,2-alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)-condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2-alkyl shift. The exclusive formation of (+)-condyfoline indicates that the 1,2-alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro-Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)-condyfoline to (?)-tubifoline by way of a retro-Mannich/1,3-prototropy/transannular cyclization cascade are also documented.
- Delayre, Bastien,Piemontesi, Cyril,Wang, Qian,Zhu, Jieping
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supporting information
p. 13990 - 13997
(2020/06/10)
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- Asymmetric Total Synthesis of (+)-Winchinine B
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The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from commercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed transfer dehydrogenation, and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle system. A one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by our group was utilized to construct the D ring moiety.
- Liu, Zaimin,Ju, Xiaolin,Ma, Shiqiang,Du, Chenglong,Zhang, Weiwei,Li, Huilin,Wang, Xiaolei,Xie, Xingang,She, Xuegong
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p. 14994 - 15000
(2019/11/19)
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- Enantioselective Synthesis of (-)-Vallesine: Late-Stage C17-Oxidation via Complex Indole Boronation
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The first enantioselective total synthesis of (-)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (-)-vallesine, from a common intermediate.
- Antropow, Alyssa H.,Garcia, Nicholas R.,White, Kolby L.,Movassaghi, Mohammad
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supporting information
p. 3647 - 3650
(2018/06/26)
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- A unified synthesis of topologically diverse: Aspidosperma alkaloids through divergent iminium-trapping
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Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.
- Mijangos, Marco V.,Miranda, Luis D.
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p. 9409 - 9419
(2019/01/03)
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- Chiral tricyclic keto-amine compound as well as synthetic method and application thereof
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The invention discloses a chiral tricyclic keto-amine compound as well as a synthetic method and an application thereof. The invention discloses a (31S,6aR,9aR)-6a-ethyldecahydro-1H-pyrrolo-[3,2,1-ij]quinoline-9(2H)-ketone compound shown by a formula (1) and a preparation method thereof. According to the preparation method, the chiral tricyclic keto-amine compound is obtained through reactions of 5 steps of performing [4+2] cycloaddition on 3-ethyl-5-bromo-2-pyrone and (S)-2,3-dihydro-1H-pyrrole-1,2-di-tert-butyl dicarboxylate, performing decarboxylation, performing Pd/C catalytic hydrogenation and cyclization, and the like. The compound shown by the formula (1) is an advanced intermediate which can be used for preparing quebracho alkaloid, and the compound can be used for preparing the quebracho alkaloid and derivatives. The method starts from low-price and easily-available raw materials, and provides a good technical support for subsequent implementation of large-scale production and structure-activity relationship research of a quebracho alkaloid natural product.
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- Total Synthesis of (-)-Rhazinilam and Formal Synthesis of (+)-Eburenine and (+)-Aspidospermidine: Asymmetric Cu-Catalyzed Propargylic Substitution
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A total synthesis of (-)-rhazinilam and formal syntheses of (+)-eburenine and (+)-aspidospermidine that rely on a copper(I)-catalyzed asymmetric propargylic substitution as the key step are reported. A salient feature of the reaction is the asymmetric con
- Shemet, Andrej,Carreira, Erick M.
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p. 5529 - 5532
(2017/10/25)
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- Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (-)-Quebrachamine, (+)-Aspidospermidine, (-)-Aspidospermine, (-)-Pyrifolidine, and Related Natural Products
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A uniformly strategic total synthesis of Aspidosperma alkaloids (+)-vincadifformine, (-)-quebrachamine, (+)-aspidospermidine, (-)-aspidospermine, (-)-pyrifolidine, and nine others from efficiently constructed tricyclic ketone 13 is reported. Highlights of these divergent and practical syntheses include (i) stereoselective intermolecular [4 + 2] cycloaddition to establish a C-E ring with one all-carbon quaternary stereocenter (C-5) and two bridged contiguous cis-stereocenters (C-12 and C-19), (ii) a Pd/C-catalyzed hydrogenation/deprotection/amidation cascade process to assemble the D ring, and (iii) Fischer indolization to forge the A-B ring.
- Wang, Nengzhong,Du, Shuo,Li, Dong,Jiang, Xuefeng
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p. 3167 - 3170
(2017/06/23)
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- Unified strategy to monoterpene indole alkaloids: Total syntheses of (±)-Goniomitine, (±)-1,2-Dehydroaspidospermidine, (±)-Aspidospermidine, (±)-Vincadifformine, and (±)-Kopsihainanine A
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Total syntheses of (±)-goniomitine, (±)-1,2-dehydroaspidospermidine, (±)-aspidospermidine, (±)-vincadifformine, and (±)-kopsihainanine A were achieved featuring two common key steps: (1) a palladium-catalyzed decarboxylative vinylation that provides quick access to cyclopentene intermediates containing all of the carbons present in the natural products and (2) an integrated oxidation/reduction/cyclization (iORC) sequence for skeletal reorganization that converts the cyclopentenes to the pentacyclic structures of the natural products. By incorporation of a geometric constraint to iORC substrates, both the chemoselectivity (C7 vs N1 cyclization) and the stereoselectivity (trans- vs cis-fused ring system) of the cyclization process can be controlled.
- Wagnires, Olivier,Xu, Zhengren,Wang, Qian,Zhu, Jieping
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supporting information
p. 15102 - 15108
(2014/12/11)
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- Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C-H activation: Mechanism and applications
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A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles was developed based on a norbornene-mediated regioselective cascade C-H activation. The detailed reaction mechanism was investigated by NMR spectroscopic analyses, characterization of the key intermediate, deuterium labeling experiments, and kinetic studies. The results indicate that a catalytic cycle operates, in which an N-norbornene type palladacycle is formed as the key intermediate. Oxidative addition of alkyl bromide to the Pd(II) center in this intermediate is the rate-determining step of the reaction. The synthetic utility of this indole 2-alkylation method was demonstrated by its application in natural product total synthesis. A new and general strategy to synthesize Aspidosperma alkaloids was established employing the indole 2-alkylation reaction as the key step, and two structurally different Aspidosperma alkaloids, aspidospermidine and goniomitine, were synthesized in concise routes.
- Jiao, Lei,Herdtweck, Eberhardt,Bach, Thorsten
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supporting information
p. 14563 - 14572
(2012/10/29)
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- Collective synthesis of natural products by means of organocascade catalysis
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Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.
- Jones, Spencer B.,Simmons, Bryon,Mastracchio, Anthony,MacMillan, David W. C.
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p. 183 - 188
(2012/05/20)
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- 'Aromatic ring umpolung', a rapid access to the main core of several natural products
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Treatment of various substituted phenols in the presence of (diacetoxyiodo)benzene promotes the formation of a phenoxenium ion, a very electrophilic species able to react with various nucleophiles leading rapidly to a plethora of different cores present i
- Guérard, Kimiaka C.,Sabot, Cyrille,Beaulieu, Marc-André,Giroux, Marc-André,Canesi, Sylvain
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scheme or table
p. 5893 - 5901
(2010/09/09)
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- Total synthesis of (±)-aspidospermidine starting from 3-ethyl-5-bromo-2-pyrone
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A new synthetic route to (±)-aspidospermidine was devised, starting from the cycloadduct of 3-ethyl-5-bromo-2-pyrone with vinyl sulfide through a tandem conjugate addition-alkylation sequence. The requisite 3-ethyl-5-bromo-2-pyrone was prepared via the C3-selective Pd-catalyzed coupling reaction with Et3Al-dimethylaminoethanol complex.
- Cho, Hyun-Kyu,Tam, Nguyen Thanh,Cho, Cheon-Gyu
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p. 3382 - 3384
(2012/05/20)
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- Concise total synthesis of (±)-aspidospermidine via an oxidative Hosomi-Sakurai process
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A concise total synthesis of (±)-aspidospermidine has been achieved in twelve steps from inexpensive 4-ethylphenol, based on an oxidative Hosomi-Sakurai reaction via the concept of "aromatic ring umpolung".
- Sabot, Cyrille,Guerard, Kimiaka C.,Canesi, Sylvain
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supporting information; experimental part
p. 2941 - 2943
(2009/12/01)
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- Domino double Michael-Claisen cyclizations: A powerful general tool for introducing quaternary stereocenters at C(4) of cyclohexane-1,3-diones and total synthesis of diverse families of sterically congested alkaloids
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(Chemical Equation Presented) Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids of biological interest such as (+)-aspidospermidine, (±)-galanthamine, (±)-lycoramine, and (±)-mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates under thermodynamically controlled conditions.
- Ishikawa, Teruhiko,Kudo, Kazuhiro,Kuroyabu, Ken,Uchida, Satoshi,Kudoh, Takayuki,Saito, Seiki
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p. 7498 - 7508
(2008/12/22)
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- A short total synthesis of (±)-aspidospermidine
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A cascade radical cyclization starting from an amidyl radical has been used for the construction of (±)-aspidospermidine. This approach has also been developed for the preparation of a tricycle whose framework is contained in the stemona alkaloids.
- Sharp, Lisa A.,Zard, Samir Z.
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p. 831 - 834
(2007/10/03)
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- Hemisynthesis of rhazinilam analogues: Structure - Activity relationships on tubulin-microtubule system
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Semi-synthesis of derivatives of rhazinilam, an antitubulin compound, delineated some molecular features necessary for biological activity. In the course of this study, the formation of rhazinilam from 1,2-didehydroaspidospermidine is reexamined and a new mechanism is proposed.
- David, Bruno,Sevenet, Thierry,Thoison, Odile,Awang, Khalijah,Pais, Mary,Wright, Michel,Guenard, Daniel
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p. 2155 - 2158
(2007/10/03)
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- Synthetic applications of 2-(1,3-dithian-2-yl)indoles. 7. Synthesis of aspidospermidine
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A new method of synthesizing the alkaloid aspidospermidine (1), based on building ring E on the pyridocarbazole [ABCD] ring structure, is reported. The preparation of the pyridocarbazole framework of Aspidosperma alkaloids is a new three-step synthetic application of 2-(1,3-dithian-2-yl)indoles. A tandem conjugate addition-alkylation reaction starting from indolyldithiane (4), 3-methylenelactam 6, and EtI yields the adduct 17. Treatment of lactam 17 with DIBALH leads to formation of the naphthyridoindole 18. Compound 18 isomerizes in aqueous AcOH to yield pyridocarbazole 3. Finally, closure of ring E and subsequent reduction of the dithiane ring produces aspidospermidine. Pyridocarbazoles 2 and 10 were prepared as models.
- Forns, Pilar,Diez, Anna,Rubiralta, Mario
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p. 7882 - 7888
(2007/10/03)
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- Synthesis of Eburnamonine and Dehydroaspidospermidine
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The route of synthesis of γ-imino carbonyl compounds by cyclopropanation of enamides and acid-catalyzed ring opening of the resultant β-amido cyclopropanecarboxylates has been applied to the preparation of substituted 1-piperideines and therefrom to the synthesis of the alkaloids eburnamonine, dehydroaspidospermidine, and aspidospermidine.
- Wenkert, Ernest,Hudlicky, Tomas
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p. 1953 - 1957
(2007/10/02)
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- THERMAL REARRANGEMETS OF SOME INDOLE ALKALOID DERIVATIVES
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Under both static and flow thermolysis conditions, several compounds with an "aspidosperma" framework rearranged to "vinca" derivatives.Thus (-)1,2-dehydroaspidospermidine (4) rearranged to (-)aspidospermidine and compound 17 on pyrolysis (200 deg C) while flow termolysis (580 deg C) gave vincane (14).Compound 6 rearranged to vincamine (13a) and 16-epivincamine (13b) under either condition; increasing the temperature resulted in formation of apovincamine (19) (pyrolysis) or vincamone (16) (flow thermolysis).
- Hugel, Georgette,Levy, Jean
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p. 1067 - 1074
(2007/10/02)
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- A SYNTHETHIC ROAD TO THE FOREST OF STRYCHNOS, ASPIDOSPERMA, SCHIZOZYGANE AND EBURNAMINE ALKALOIDS BY WAY OF THE NOVEL PHOTOISOMERIZATION
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The novel photoisomerization of 1-acylindoles accompanied by a conversion of indole to indolenine afforded 3-acylindolenines, a so far unknown reactive species, as a major product.This reaction was thorougly investigated and applied with success to the total synthesis of Strychnos, Aspidosperma, Schizozygane and Eburnamine alkaloids through a versatile intermediate 9-membered ring system,synthesized in a one pot reaction by photolysis and the simultaneous ring enlargement.
- Ban, Yoshio,Yoshida, Kiyoshi,Goto, Jiro,Oishi, Takeshi,Takeda, Eiko,Ishigamori
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p. 3657 - 3668
(2007/10/02)
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