- Rapid Access to the Highly Oxygenated Aspidosperma Alkaloids Vindoline, Vindorosine, and Cathovaline
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A highly expedient and efficient synthesis of vindoline (1a) and vindorosine (1b), via the hitherto unknown azadienes (3a,b), is reported.
- Danieli, Bruno,Lesma, Giordano,Palmisano, Giovanni,Riva, Renata
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- Total synthesis of (?)-vindoline
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In this full paper, a stereocontrolled strategy for the total synthesis of (?)-vindoline is described. This synthetic route features: 1) rapid construction of the stereochemical center at C19 through a highly diastereoselective vinylogous Mannich addition; 2) tandem Heathcock/aza-Prins cyclization to install rings C and E in vindoline; 3) oxidative transformation of β-ketoester to enone; 4) stereoselective inversion of C4 stereochemistry with triphenylphosphine and carbon tetrabromide followed by Br?nsted acid.
- Chen, Wen,Tian, Hongchang,Tan, Wenyun,Liu, Xiaotong,Yang, Xiaodong,Zhang, Hongbin
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- Asymmetric Total Syntheses of (-)-Jerantinines A, C, and E, (-)-16-Methoxytabersonine, (-)-Vindoline, and (+)-Vinblastine
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A concise and stereocontrolled strategy for the syntheses of oxygenated Aspidosperma and Vinca alkaloids, via a stereoselective intermolecular inverse-electron-demand [4 + 2] cycloaddition, a challenging α,β-unsaturated ketone indolization rearrangement with excellent regio- and stereoselectivity, and an efficient Pd/C-catalyzed one-pot cascade reaction. The strategy has been demonstrated by the efficient asymmetric syntheses of antitumor drug (+)-vinblastine and five other oxygenated Aspidosperma alkaloids.
- Wang, Nengzhong,Liu, Jianrong,Wang, Chen,Bai, Leiyang,Jiang, Xuefeng
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- Asymmetric total synthesis of vindoline
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"Chemical equation presented" A concise asymmetric total synthesis of (-)-vindoline (1) is detailed based on a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which the tether linking the initiating dienophile and oxadiazole bears a chiral substituent that controls the facial selectivity of the initiating Diels-Alder reaction and sets absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduces three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. Implementation of the approach also required the development of a unique ring expansion reaction to provide a six-membered ring suitably functionalized for introduction of the .(6, 7)-double bond found in the core structure of vindoline and defined our use of a protected hydroxymetyl group as the substituent used to control the stereochemical course of the cycloaddition cascade.
- Kato, Daisuke,Sasaki, Yoshikazu,Boger, Dale L.
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supporting information; experimental part
p. 3685 - 3687
(2010/05/15)
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- Asymmetric total synthesis of vindorosine, vindoline, and key vinblastine analogues
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Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ6,7-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ6,7-double bond.
- Sasaki, Yoshikazu,Kato, Daisuke,Boger, Dale L.
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supporting information; experimental part
p. 13533 - 13544
(2010/12/19)
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- Total synthesis of (-)- and ent-(+)-vindoline and related alkaloids
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A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as /V-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).
- Ishikawa, Hayato,Elliott, Gregory I.,Velcicky, Juraj,Choi, Younggi,Boger, Dale L.
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p. 10596 - 10612
(2007/10/03)
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- Total synthesis of (-)- and ent-(+)-vindoline
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(Chemical Equation Presented) Two exceptionally concise total syntheses of (-)- and ent-(+)-vindoline are detailed enlisting a diastereoselective tandem [4 + 2]/[3 + 2] cycloaddition of a 1,3,4-oxadiazole. The unique reaction cascade assembles the fully functionalized pentacyclic ring system of vindoline in a single step that forms four C-C bonds and three rings while introducing all requisite functionality and setting all six stereocenters within the central ring including three contiguous and four total quaternary centers.
- Choi, Younggi,Ishikawa, Hayato,Velcicky, Juraj,Elliott, Gregory I.,Miller, Michael M.,Boger, Dale L.
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p. 4539 - 4542
(2007/10/03)
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- An efficient total synthesis of (-)-vindoline
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A highly efficient total synthesis of the title compound is described. Our synthesis features a highly efficient preparation of the key intermediate 11 using our novel indole synthesis methodology. A novel amine protecting protocol by means of 2,4-dinitrobenzenesulfonamides has been developed to ensure the formation of the elusive secodine-type intermediate 15 under very mild conditions.
- Kobayashi, Satoshi,Ueda, Toshihiro,Fukuyama, Tohru
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p. 883 - 886
(2007/10/03)
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- Novel alkaloids
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Cycloalkyl and aromatic vinblastine and vincristine derivatives useful as anti-tumor agents.
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- Biomimetic Alkaloid Syntheses. 15. Enantioselective Syntheses with Epichlorohydrin: Total Syntheses of (+)-, (-)-, and (+/-)-Vindoline and a Synthesis of (-)-Vindorosine
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Total syntheses of vindoline (1) in racemic as well as in each enantiomeric form and of (-)-vindorosine (2) are described.They were achieved by generation and diastereoselective cyclizations of 14-hydroxysecodine intermediates 6 and 7.The subsequent oxidative elaboration of ring E was also studied with 3-oxotabersonine (24), 3-oxovincadifformine (26), and 14β-hydroxyvincadifformine (15).Na-Methyltabersonine (22) was oxidized to a ring-D-contracted α-keto lactam, 23.
- Kuehne, Martin E.,Podhorez, David E.,Mulamba, Tshilundu,Bornmann, William G.
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p. 347 - 353
(2007/10/02)
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- A New Efficient Total Synthesis of Vindorosine and Vindoline
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Highly stereoselective total syntheses of indole alkaloids vindorosine (1a) and vindoline (1b) are described.An imino Diels-Alder reaction, a stereospecific alkylation, and a rearrangement induced by the Pummerer reaction are the key steps of these short and high overall yield sequences.
- Andriamialisoa, Ratremaniaina Zo,Langlois, Nicole,Langlois, Yves
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p. 961 - 967
(2007/10/02)
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- Studies in plant tissue culture. The synthesis and biosynthesis of indole alkaloids
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Studies involving plant tissue cultures of Catharanthus roseus are described. Investigations concerning the propagation of cell lines of this plant for the purposes of producing indole alkaloids within the Corynanthe, Aspdiosperma and Iboga families are presented. The utilization of such tissue culture systems for studies in biosyntheses and isolation of enzymes are also discussed.
- Kutney,Aweryn,Choi,et al.
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p. 3781 - 3795
(2007/10/02)
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- Investigations of the Biosynthesis of Indole Alkaloids. Feeding Experiments with Synthetic Radioactively Labelled Hydroxyloganin Derivatives.
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Hydroxyloganin (4a) and 6-epihydroxyloganin (5a) were synthesized with a radioactive label to check the hypothesis that these compounds lie directly on the biosynthetic pathways to secologanin (2a) and the indole alkaloids.The labels were introduced by reduction of the keto acid 6 with sodium borohydride and esterification of the hydroxy acids 9* or 11 with diazomethane.According to feeding experiments with Catharanthus roseus G.Don it is highly improbable that 4a and 5a are precursors of 2a and the indole alkaloids.Moreover, isolation experiments showed that 4a is not a naturally occuring iridoid glycoside in Menyanthes trifoliata plants.
- Battersby, Alan R.,Westcott, Neil D.,Gluesenkamp, Karl-Heinz,Tietze, Lutz-F.
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p. 3439 - 3447
(2007/10/02)
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- Investigations of the Biosynthesis of Indole Alkaloids. Feeding Experiments with Synthetic Radioactively Labelled Monoterpene Aldehydes
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Oxidation of citral (8a/8b) with selenium oxide using different reaction conditions gave the hydroxy aldehydes 4a/4b and the dialdehydes 5a/b.Reduction of 5a/b with potassium borohydride in the presence of LiCl led to the hydroxy aldehyes 4c/d.Feeding experiments with the corresponding tritiated compounds 4a - d and 5a/b to Catharanthus roseus G.Don indicate that 4a/b, 4c/d, and 5a/b are biogenetic precursors of secologanin (3) and the indole alkaloids of the Corynanthe, Aspidosperma, and Iboga type.
- Battersby, Alan R.,Thompson, Mervyn,Gluesenkamp, Karl-Heinz,Tietze, Lutz-F.
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p. 3430 - 3438
(2007/10/02)
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- Process for the isolation of alkaloid components from the plant Vinca Rosea L.
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Tumor inhibiting alkaloids are recovered from Vinca Rosea L. by a method which comprises extracting the dried leaves with a solvent selected from the group consisting of an alkanol having 1 to 5 carbon atoms, a mixture of an alkanol having 1 to 5 carbon atoms and a dilute, aqueous solution, benzene and benzene homologs; subsequently purifying the alkaloid extract obtained by a phase-change method between immiscible solvents, precipitating the main amount of dimeric alkaloids in form of their sulphuric acid addition salts, isolating leurosine, vincistine, vinblastine, desacetoxy-vinblastine, N-desmethyl-vinblastine and desacetyl-vinblastine from the salt mixture obtained, and then completing the separation and isolation of the remaining alkaloids by separation and isolation by adjusting the pH-value of the mother liquor, after precipitation and removal of the salt mixture, to 5.5 to 10, extracting the solution with a water-immiscible organic solvent and separating vindoline, catharantine, 3',4' -anhydrovinblastine and leurosine from the extract by chromatography, extracting vindoline in the pH-range of 2.5 to 3.5 and catharantine 3',4'-anhydrovinblastine and leurosine in the pH-range of 5 to 6 with benzene or a benzene homologue, from the mother liquor obtained when isolating the salt mixture, and separating a mixture of leurosine and 3',4'-anhydrovinblastine by crystallization, epoxidizing this mixture with an oxygen source, or separating the mixture into its components by chromatography, and subsequently epoxidizing the 3',4'-anhydrovinblastine component to leurosine, and isolating catharantine remaining from the mother liquor obtained when separating the crystalline mixture, or separating the extract containing catharantine, 3',4'-anhydrovinblastine and leurosine into its components by chromatography.
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