- Enantiospecific total synthesis of the important biogenetic intermediates along the ajmaline pathway, (+)-polyneuridine and (+)-polyneuridine aldehyde, as well as 16-epivellosimine and Macusine A
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The first stereospecific synthesis of polyneuridine aldehyde (6), 16-epivellosimine (7), (+)-polyneuridine (8), and (+)-macusine A (9) has been accomplished from commercially available d-(+)-tryptophan methyl ester. d-(+)-Tryptophan has served here both as the chiral auxiliary and the starting material for the synthesis of the common intermediate, (+)-vellosimine (13). This alkaloid was available in enantiospecific fashion in seven reaction vessels in 27% overall yield from d-(+)-trytophan methyl ester (14) via a combination of the asymmetric Pictet-Spengler reaction, Dieckmann cyclization, and a stereocontrolled intramolecular enolate-driven palladium-mediated cross-coupling reaction. A new process for this stereocontrolled intramolecular cross-coupling has been developed via a copper-mediated process. The initial results of this investigation indicated that an enolate-driven palladium-mediated cross-coupling reaction can be accomplished by a copper-mediated process which is less expensive and much easier to work up. An enantiospecific total synthesis of (+)-polyneuridine aldehyde (6), which has been proposed as an important biogenetic intermediate in the biosynthesis of quebrachidine (2), was then accomplished in an overall yield of 14.1% in 13 reaction vessels from d-(+)-tryptophan methyl ester (14). Aldehyde 13 was protected as the N a-Boc aldehyde 32 and then converted into the prochiral C(16)-quaternary diol 12 via the practical Tollens reaction and deprotection. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps to provide a versatile entry into the three alkaloids polyneuridine aldehyde (6), polyneuridine (8), and macusine A (9) from the quarternary diol 12. The oxidation of the 16-hydroxymethyl group present in the axial position was achieved with the Corey-Kim reagent to provide the desired β-axial aldehydes, polyneuridine aldehyde (6), and 16-epivellosimine (7) with 100% diastereoselectivity.
- Yin, Wenyuan,Kabir, M. Shahjahan,Wang, Zhijian,Rallapalli, Sundari K.,Ma, Jun,Cook, James M.
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- First enantiospecific total synthesis of the important biogenetic intermediates, (+)-polyneuridme and (+)-polyneuridine aldehyde, as well as 16-epi-vellosimine and macusine A
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(Chemical Equation Presented) The first enantiospecific total synthesis of the alkaloids 16-epi-vellosimine (1), (+)-polyneuridine (2), (+)-polyneuridine aldehyde (3), and macusine A (4) is reported. The key oxidation was accomplished with the Corey-Kim reagent to provide the important biogenetic intermediates, 16-epi-vellosimine (1) and polyneuridine aldehyde (3), the latter of which is required for the conversion of the sarpagan skeleton into the ajmalan system in the biosynthesis of quebrachidine.
- Yin, Wenyuan,Jun, Ma.,Rivas, Felix M.,Cook, James M.
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- Stereospecific, Enantiospecific Total Synthesis of the Sarpagine Indole Alkaloids (E)16-Epiaffinisine, (E)16-Epinormacusine B, and Dehydro-16-epiaffinisine
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(Matrix Presented) The first stereospecific total synthesis of the sarpagine indole alkaloids (E)16-epiaffinisine (1), (E)16-epinormacusine B (2), and dehydro-16-epiaffinisine (4) has been completed; this method has also resulted in the synthesis of dehydro-16-epinormacusine B (5). The formation of the required ether in both 4 and 5 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF in 98% and 95% yields, respectively.
- Yu, Jianming,Liao, Xuebin,Cook, James M.
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- Asymmetric Total Synthesis of Sarpagine-Related Indole Alkaloids Hydroxygardnerine, Hydroxygardnutine, Gardnerine, (E)-16-epi-Normacusine B, and Koumine
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Sarpagine-related indole alkaloids (-)-hydroxygardnerine, (+)-hydroxygardnutine, (-)-gardnerine, (+)-(E)-16-epi-normacusine B, and (-)-koumine were divergently synthesized via a common intermediate possessing a piperidine ring with an exocyclic (E)-ethylidene side chain, which was constructed by a gold(I)-catalyzed 6-exo-dig cyclization strategy.
- Kitajima, Mariko,Watanabe, Keisuke,Maeda, Hiroyuki,Kogure, Noriyuki,Takayama, Hiromitsu
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supporting information
p. 1912 - 1915
(2016/05/19)
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- Stereospecific total synthesis of the indole alkaloid ervincidine. Establishment of the C-6 hydroxyl stereochemistry
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The total synthesis of the indole alkaloid ervincidine (3) is reported. This research provides a general entry into C-6 hydroxy-substituted indole alkaloids with either an α or a β configuration. This study corrects the errors in Glasby's book (Glasby, J. S. Encyclopedia of the Alkaloids; Plenum Press: New York, 1975) and Lounasmaa et al.'s review (Lounasmaa, M.; Hanhinen, P.; Westersund, M. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1999; Vol. 52, pp 103-195) as well as clarifies the work of Yunusov et al. (Malikov, V. M.; Sharipov, M. R.; Yunusov, S. Yu. Khim. Prir. Soedin. 1972, 8, 760-761. Rakhimov, D. A.; Sharipov, M. R.; Aripov, Kh. N.; Malikov, V. M.; Shakirov, T. T.; Yunusov, S. Yu. Khim. Prir. Soedin. 1970, 6, 724-725). It establishes the correct absolute configuration of the C-6 hydroxyl function in ervincidine. This serves as a structure proof and corrects the misassigned structure reported in the literature.
- Rallapalli, Sundari K.,Namjoshi, Ojas A.,Tiruveedhula, V. V. N. Phani Babu,Deschamps, Jeffrey R.,Cook, James M.
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supporting information
p. 3776 - 3780
(2014/05/20)
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- The first enantiospecific total synthesis of the 3-oxygenated sarpagine indole alkaloids affinine and 16-epiaffinine, as well as vobasinediol and 16-epivobasinediol
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The first enantiospecific total synthesis of the 3-oxygenated sarpagine indole alkaloids affinine (1) and 16-epiaffinine (2) as well as the synthesis of vobasinediol (3) and 16-epivobasinediol (4) was accomplished from d-(+)-tryptophan methyl ester.
- Yang, Jie,Rallapalli, Sundari K.,Cook, James M.
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scheme or table
p. 815 - 817
(2010/03/26)
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- General approach for the synthesis of 12-methoxy-substituted sarpagine indole alkaloids including (-)-12-methoxy-Nb-methylvoachalotine, (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline
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The enantiospecific synthesis of 7-methoxy-D-tryptophan ethyl ester was completed by combination of the Larock heteroannulation process with a Schoellkopf-based chiral auxiliary in good yield. This ester was then employed in the first regiospecific, stere
- Zhou, Hao,Liao, Xuebin,Yin, Wenyuan,Ma, Jun,Cook, James M.
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p. 251 - 259
(2007/10/03)
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- General approach for the synthesis of sarpagine indole alkaloids. Enantiospecific total synthesis of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, (+)-Na-methylvellosimine, and (+)-Na-methyl-16-epipericyclivine
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The first total synthesis of (+)-Na-methyl-16-epipericyclivine (9) was completed [from D-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation [[α]D +22.8 (c 0.50, CHCl3)] obtained on this material confirmed that the reported optical rotation [[α]D 0 (c 0.50, CHCl 3)]47 was biogenetically unreasonable. The total syntheses of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, and (+)-Na-methylvellosimine are also described. Moreover, a mixed sample (1:1) of synthetic (-)-panarine and natural (-)-panarine yielded only one set of signals in the 13C NMR; this indicated that the two compounds are identical and further confirmed the correct configuration of (+)-vellosimine, (+)-normacusine B, and (-)-alkaloid Q3. In this approach, the key templates, (-)-Na-H,N b-benzyltetracyclic ketone 15a and (-)-Na-methyl,N b-benzyltetracyclic ketone 43 were synthesized on multihundred gram scale by the asymmetric Pictet-Spengler reaction and a stereocontrolled Dieckmann cyclization via improved sequences. An intramolecular palladium (enolate-mediated) coupling reaction was employed to introduce the C(19)-C(20) E-ethylidene function in the sarpagine alkaloids for the first time in stereospecific fashion.
- Yu, Jianming,Wang, Tao,Liu, Xiaoxiang,Deschamps, Jeffrey,Flippen-Anderson, Judith,Liao, Xuebin,Cook, James M.
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p. 7565 - 7581
(2007/10/03)
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- General approach for the total synthesis of the sarpagine related indole alkaloids (+)-Na-methyl-16-epipericyclivine, (-)-alkaloid Q3 and (-)-panarine via the asymmetric Pictet-Spengler reaction
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The stereospecific total synthesis of (+)-Na-methyl-16-epipericyclivine (1) was completed [from D-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation {[α]D +22.8 (c 0.50, CHCl3
- Yu, Jianming,Wearing, Xiangyu Z.,Cook, James M.
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p. 543 - 547
(2007/10/03)
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- Deoxysarpagine hydroxylase--a novel enzyme closing a short side pathway of alkaloid biosynthesis in Rauvolfia.
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Microsomal preparations from cell suspension cultures of the Indian plant Rauvolfia serpentina catalyze the hydroxylation of deoxysarpagine under formation of sarpagine. The newly discovered enzyme is dependent on NADPH and oxygen. It can be inhibited by typical cytochrome P450 inhibitors such as cytochrome c, ketoconazole, metyrapone, tetcyclacis and carbon monoxide. The CO-effect is reversible with light (450 nm). The data indicate that deoxysarpagine hydroxylase is a novel cytochrome P450-dependent monooxygenase. A pH optimum of 8.0 and a temperature optimum of 35 degrees C were determined. K(m) values were 25 microM for NADPH and 7.4 microM for deoxysarpagine. Deoxysarpagine hydroxylase activity was stable in presence of 20% sucrose at -25 degrees C for >3 months. The analysis of presence of the hydroxylase in nine cell cultures of seven different families indicates a very limited taxonomic distribution of this enzyme.
- Yu, Bingwu,Ruppert, Martin,Stoeckigt, Joachim
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p. 2479 - 2483
(2007/10/03)
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- General approach for the synthesis of sarpagine/macroline indole alkaloids. Enantiospecific total synthesis of the indole alkaloid trinervine.
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[structure: see text] The total synthesis of the indole alkaloid trinervine 1 was accomplished in enantiospecific fashion in an overall yield of 20% (from the tetracyclic ketone 8) in 10 reaction vessels (12.5% from tryptophan methyl ester). The synthesis of the N(a)-H substituted macroline equivalent 2 was also completed in high yield via the same intermediate 13. The unique protection/hydroboration process developed here should provide a method to functionalize the C(19)-C(20) double bond in similar systems.
- Liu,Cook
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p. 4023 - 4026
(2007/10/03)
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- Stereoselective Transformation of Ajmaline into Three Minor Gelsemium Alkaloids, Koumidine, (19Z)-Anhydrovobasinediol and N-Demethoxyrankinidine and their Absolute Configuration
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Ajmaline was converted into new Gelsemium alkaloids, 19Z-anhydrovobasinediol and N-demethoxyrankinidine, via koumidine along the biomimetic sequence, and the absolute configuration of these alkaloids was determined by these transformations.
- Kitajima, Mariko,Takayama, Hiromitsu,Sakai, Shin-ichiro
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p. 1773 - 1779
(2007/10/02)
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- Studies on Gelsemium alkaloids. Total synthesis of (+)-koumine, (+)-taberpsychine, and (+)-koumidine
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The total synthesis of the Gelsemium alkaloids (+)-koumine (2), (+)-taberpsychine (4), and (+)-koumidine (50) has been accomplished starting from (S)-(-)-tryptophan (21), All the synthetic alkaloids are antipodal to the natural compounds. N′ -Benzyltryptophan ((-)-22) was methylated to give 23 which was reductively benzylated to provide (-)-25. Pictet-Spengler condensation of (-)-25 with 2-ketoglutaric acid followed by esterification gave a mixture of diastereomeric methyl esters 27/28. Exposure of (+)-27 and (-)-28 to Dieckmann cyclization conditions provided (+)-29 and (-)-29, respectively. Thus starting from a single enantiomer of tryptophan both antipodes of the tetracyclic β-ketoesters (+)-29/(-)-29 are available. Since (+)-29 was the more readily available antipode, subsequent reactions were conducted with this compound. Conversion of (+)-29 into (+)-31 followed conventional lines. N-Alkylation of (+)-31 with propargyl bromide gave (+)-33 which was converted into (+)-36 by treatment with t-BuMe2SiOTf/Et3N, n-BuLi/CICO2Me, and LiBF4. Exposure of (+)-36 to pyrrolidine/ trifluoroacetic acid gave the (Z)- and (E)-quinuclidines (+)-37 and (+)-38. Methylenation of 38 with Tebbe's reagent gave 39. Both E and Z isomers were taken through the series of transformations to give 43, 45, 47, and 49 and 44, 46, 48, and 50. The structures of (+)-37 and (+)-43 were conclusively established by single-crystal X-ray crystallography. Fragmentation of 49 with methyl chloroformate gave 51 which was reduced with LiAlH4 to give (+)-taberpsychine (4). Treatment of 47 with methyl chloroformate gave the 18-hydroxytaberpsychine derivative 52 which was reduced with LiAlH4 to give 53. Similarly 48 gave 55. When the Z isomer 55 was exposed to the Mitsunubo conditions, (+)-koumine (2) was formed (40%, 72% based upon recovered 55). The E isomer 53 gave (+)-koumine (2) in lower yields at a much reduced rate.
- Magnus, Philip,Mugrage, Benjamin,DeLuca, Mark R.,Cain, Gary A.
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p. 5220 - 5230
(2007/10/02)
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- CHARACTERISTICS OF VELLOSIMINE REDUCTASE, A SPECIFIC ENZYME INVOLVED IN THE BIOSYNTHESIS OF THE RAUWOLFIA ALKALOID SARPAGINE
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A plant enzyme - vellosimine reductase - has been isolated from Rauwolfia cell suspension cultures.This new enzyme has been purified (110-fold) and characterized.The reductase is a specific enzyme of the sarpagine pathway catalyzing the NADPH dependent conversion of vellosimine into 10-deoxysarpagine.The latter alkaloid is the immediate biogenetic precursor of sarpagine as shown by its high in vivo incorporation rate (86percent) into sarpagine.
- Pfitzner, Artur,Krausch, Brigitte,Stoeckigt, Joachim
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p. 1691 - 1700
(2007/10/02)
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- VELLOSIMINE REDUCTASE. A SPECIFIC ENZYME INVOLVED IN THE CELLFREE BIOSYNTHESIS OF SARPAGINE TYPE ALKALOIDS.
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Vellosimine reductase is a substrate and cofactor specific enzyme which catalyzes the NADPH-dependent reduction of vellosimine (4) forming 10-deoxy-sarpagine type alkaloids.
- Pfitzner, Arthur,Stoeckiqt, Joachim
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p. 1695 - 1698
(2007/10/02)
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