- A Radical Cascade Enabling Collective Syntheses of Natural Products
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Natural products have long been important inspirations for the development of chemical methodologies, theories, and technologies, and ultimately, discoveries of new drugs and materials. Chemical syntheses have traditionally yielded individual or small groups of natural products; however, methodology development allowing the synthesis of a large collection of natural products remains scarce. Here, we report an efficient photocatalytic radical cascade method that enables access to libraries of chiral and multiple-ring-fused tetrahydrocarbolinones. The radical cascade can controllably introduce complexity and functionality into products with excellent chemo-, regio-, and diastereoselectivity. The power of this distinct method has been demonstrated by the efficient syntheses of 33 monoterpenoid indole alkaloids belonging to four families.
- Wang, Xiaobei,Xia, Dongliang,Qin, Wenfang,Zhou, Ruijie,Zhou, Xiaohan,Zhou, Qilong,Liu, Wentao,Dai, Xiang,Wang, Huijing,Wang, Shuqing,Tan, Ling,Zhang, Dan,Song, Hao,Liu, Xiao-Yu,Qin, Yong
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p. 803 - 816
(2017/06/13)
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- ENANTIOSELECTIVE SYNTHESES OF HETEROYOHIMBINE NATURAL PRODUCT INTERMEDIATES
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Enantioselective syntheses of cis- and trans-bicyclic dihydropyran compounds, and other intermediates, en route to heteroyohimbine alkaloids.
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Paragraph 00072; 00073
(2016/11/21)
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- Enantioselective syntheses of heteroyohimbine natural products: A unified approach through cooperative catalysis
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Alstonine and serpentine are pentacyclic indoloquinolizidine alkaloids (referred to as "anhydronium bases") containing three contiguous stereocenters. Each possesses interesting biological activity, with alstonine being the major component of a plant-based remedy to treat psychosis and other nervous system disorders. This work describes the enantioselective total syntheses of these natural products with a cooperative hydrogen bonding/enamine-catalyzed Michael addition as the key step. The enantioselective total syntheses of the natural products alstonine and serpentine are presented. They proceed through a sequence with a cooperative hydrogen bonding/enamine-catalyzed Michael addition as the key step.
- Younai, Ashkaan,Zeng, Bi-Shun,Meltzer, Herbert Y.,Scheidt, Karl A.
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p. 6900 - 6904
(2015/06/08)
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- Short stereoselective syntheses of (-)-ajmalicine, (-)-3-iso-ajmalicine and their 5-methoxycarbonyl derivatives from secologanin
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Enzymatic hydrolysis of secologanin ethylene acetal at pH 5.0 resulted in stereoselective rearrangement of its aglucone to a dihydropyran aldehyde, which on reductive amination with tryptamine and cyclisation afforded 3-iso-ajmalicine, subsequently inverted to ajmalicine; analogous use of methyl S-tryptophanate gave 5S-methoxycarbonyl-3-iso-ajmalicine, whereas the R-enantiomer rather surprisingly yielded the ajmalicine derivative, whose anomalous CD spectrum has been rationalised.
- Brown, Richard T.,Dauda, Bukar E.N.,Pratt, Simon B.,Richards, Paul
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- Biomimetic synthesis of monoterpenoid indole alkaloids from aglucones of secologanin derivatives: pH controlled product selectivity
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Variation of the pH for hydrolysis of secologanin derivatives with β-glucosidase controls rearrangement of the aglucone to afford different products, and hence stercoselective syntheses of heteroyohimbine, yohimbine and Aspidosperma-type alkaloids; with baker's yeast chemoselective reduction can also be achieved to give a precursor for antirhine and related alkaloids.
- Brown
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p. 609 - 616
(2007/10/03)
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- Mannich biscyclizations. Total synthesis of (-)-ajmalicine
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A concise enantioselective total synthesis of the cardiovascular agent (-)-ajmalicine and an approach toward the synthesis of (+)-19-epiajmalicine are described. The key step of the (-)-ajmalicine synthesis is a carboxylate-terminated N-acyliminium ion biscyclization (74 → 67), which assembles the D and E rings of this heteroyohimbine alkaloid in one step. A related carboxylate-terminated iminium ion biscyclization (28 → 29) is the central step in the approach to (+)-epiajmalicine.
- L?gers, Michael,Overman, Larry E.,Welmaker, Gregory S.
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p. 9139 - 9150
(2007/10/02)
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- Heterocycles in Asymmetric Synthesis. Part 2. Efficient Asymmetric Approaches to Heteroyohimbine, Yohimbine and Related Alkaloids
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Asymmetric syntheses of heteroyohimbine, yohimbine, and related alkaloids are reported.The piperidine derivative ethyl (-)-(3-acetyl-1-benzylpiperidin-4-yl)acetate (-)-2, which was obtained by an asymmetric intramolecular Michael reaction of the acyclic compound ethyl 5-pent-2-enoate 1, was stereoselectively converted into the (-)-lactone methyl (1S,4aR,8aR)-3,4,4a,5,6,7,8,8a-octahydro-1-methyl-3-oxo-1H-pyranopyridine-7-carboxylate (-)-7 and (+)-olefin methyl acetate 15.The (-)-lactone (-)-7 was transformed into (-)-ajmalicine 3 in 5 steps.The (+)-olefin (+)-15 is the precursor in a published route to (-)-tetrahydroalstonine.The (-)-piperidine (-)-2 was also converted into the α,β-unsaturated ketone t-butyl (4aR,8aR)-(-)-1,2,3,4,4a,5,6,8a-octahydro-6-oxoisoquinoline-2-carboxylate (-)-30 in 6 steps.Stereoselective introduction of the methoxycarbonyl group into this last compound, followed by stereoselective reduction of the ketone moiety with L-Selectride, afforded the D/E-ring system of (+)-yohimbine.This can be converted into yohimbine by following the established sequence.The conversion of the (-)-piperidine derivative (-)-2 ethyl acetate (+)-21 for the synthesis of (-)-emetine 23 was also accomplished.
- Hirai, Yoshiro,Terada, Takashi,Yamazaki, Takao,Momose, Takefumi
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p. 517 - 524
(2007/10/02)
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- Unified strategy for synthesis of indole and 2-oxindole alkaloids
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A concise and general entry to representative indole alkaloids of the yohimboid, heteroyohimboid, corynantheoid, and 2-oxindole classes has been developed exploiting a strategy that features intramolecular Diels-Alder reactions for the facile construction of the D/E ring subunits of the target alkaloids. The efficacy of the approach is first illustrated by a two-step total synthesis of the yohimboid alkaloid oxogambirtannine (2) from 22. Thus, the Diels-Alder substrate 25, which was prepared by nucleophilic addition of vinyl ketene acetal 24 to the intermediate N-acyliminium salt formed in situ upon reaction of 22 with 23, was heated in the presence of benzoquinone to give a mixture of diastereoisomeric cycloadducts 26 and 27; these adducts underwent spontaneous oxidation to furnish 2. In another application of the strategy, the [4+2] heterocyclization of 34a, which was formed upon nucleophilic addition of 1-[(trimethylsilyl)oxy]butadiene to the N-acyliminium salt generated in situ upon treatment of 22 with crotonyl chloride, afforded a mixture (ca. 9:1) of cycloadducts 35a and 36a. The major adduct 35a was converted to 42a using a general procedure for effecting β-carbomethoxylation of enol ethers to give vinylogous carbonates. Subsequent reduction of 42a to the heteroyohimboid alkaloids (±)-tetrahydroalstonine (3) and (±)-cathenamine (4) was achieved by selective delivery of 2 or 1 equiv of hydride, respectively. When 42a was treated with sodium amide, stereoselective β-elimination ensued to give 49, which was converted by chemoselective hydride reduction into the corynantheoid alkaloid (±)-geissoschizine (5). Facile access to alkaloids of the 2-oxindole family was realized by using a new protocol for achieving stereoselective, oxidative rearrangements of β-carboline Nb lactams into 3,3-disubstituted 2-oxindoles. Thus, exposure of 42a to tert-butyl hypochlorite followed by acid and silver ion induced rearrangement of the intermediate 3-chloroindolenine gave 50, with only traces of the C(7) epimer being detected. Hydride reduction of 50 gave (±)-isopteropodine (6), acid-catalyzed isomerization of which furnished an equilibrium mixture (1:3) of 6 and (±)-pteropodine (51). The stereochemical course of the intramolecular hetero-Diels-Alder reaction of 34a to give 35a and 36a as the only isolable cycloadducts was examined by computational analysis. The geometry of the six-atom transition state was established by semiempirical methods by using the standard closed-shell, restricted Hartree-Fock (RHF) version of the AM1 method. With use of this constrained geometry for the six-membered pericyclic array, the overall conformational energies for the four possible transition states 52-55 were minimized by MM2 calculations (MacroModel). The calculated relative energies of these transition states were in the order 52 53 54 55. Since the cyclization of 34a produced only 35a and 36a in an approximately 9:1 ratio via the respective transition states 52 and 53, these calculations correlated qualitatively with the experimental results.
- Martin, Stephen F.,Benage, Brigitte,Geraci, Leo S.,Hunter, James E.,Mortimore, Michael
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p. 6161 - 6171
(2007/10/02)
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- Stereo-controlled Synthesis of (-)-Ajmalicine and (-)-Tetrahydroalstotine
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Stereo-controlled synthesis of the heteroyohimbine alkaloids, (-)-ajmalicine and (-)-tetrahydroalstotine, has been developed starting from diethyl L-tartrate by employing the intramolecular hetero-Diels-Alder reaction as the key step.
- Takano, Seiichi,Satoh, Shigeki,Ogasawara, Kunio
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- A Mild and Chemoselective Reduction of Cyclic Iminium Salts
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N-Substituted cyclic iminium salts are conveniently reduced to the corresponding tertiary amines in good yields by reaction with tributylstannane in methanol at room temperature.A variety of functional groups (such as ketonic groups) present in the molecule are not affected under these conditions.
- Palmisano, Giovanni,Lesma Giordano,Nali, Micaela,Rindone, Bruno,Tollari, Stefano
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p. 1072 - 1074
(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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- Alkaloids of Mitragyna parvifolia (Roxb) Korth. and their Transformations
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From the basic fractions of the leaves of Mitragyna parvifolia (Roxb) Korth, three oxindole alkaloids, mitraphylline, isomitraphylline and speciophylline Nb-oxide were isolated.A novel method has been developed for the transformation of mitraphylline, the major alkaloid of this species, to the corresponding heteroyohimbinoid base, ajmalicine without disturbing any chiral centre.Mitraphylline Nb-methoiodide, when treated with triethyloxonium fluoroborate, was converted to its corresponding imino-ether which on reduction with sodium borohydride in acetic acid furnished ajmalicine Nb-methoiodide.The latter could be transformed to ajmalicine by conventional procedure.
- Chatterjee, A.,Dhara, K. P.,Banerji, J.
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p. 1360 - 1363
(2007/10/02)
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- PARTIAL PURIFICATION AND CHARACTERIZATION OF GEISSOSCHIZINE DEHYDROGENASE FROM SUSPENSION CULTURES OF CATHARANTHUS ROSEUS
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The characterization and partial purification of geissoschizine dehydrogenase from Catharanthus roseus cell suspension cultures are described.The 35-fold purified enzyme removes the 21α-hydrogen of geissoschizine in a NADP+-dependent reaction.NAD+, FAD or FMN cannot act as cofactors for the dehydrogenation.Structurally related indole alkaloids are not dehydrogenated.In comparison to enzymes of the ajmalicine pathway, geissoschizine dehydrogenase shows an extremely low specific activity. - Key Word Index: Catharanthus roseus; Apocynaceae; geissoschizine dehydrogenase; stereospecificity; biosynthesis; heteroyohimbine alkaloids; cell suspension culture.
- Pfitzner, Artur,Stoeckigt, Joachim
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p. 1585 - 1588
(2007/10/02)
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- MECHANISM OF THE BIOSYNTHETIC CONVERSION OF GEISSOSCHIZINE TO 19-EPI-AJMALICINE IN CATHARANTHUS ROSEUS
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Geissoschizine (8) is enzymatically converted to 19-epi-ajmalicine (7) first by oxidation to the 4,21-dehydro-intermediate (4) of the heteroyohimbine pathway followed by cyclisation and stereospecific reduction.
- Stoeckigt, J.,Hoefle, G.,Pfitzner, A.
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p. 1925 - 1926
(2007/10/02)
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- INTERCONVERSION OF THE ENAMINE AND IMMONIUM FORM OF CATHENAMINE
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From the amount of deuterium incorporated during the reduction of cathenamine to tetrahydroalstonine, the enamine and immonium ion form of cathenamine was demonstrated.The two forms could be interconverted depending on the presence or absence of SO4(-2).
- Heinstein, Peter,Stoeckigt, Joachim,Zenk, Meinhart H.
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p. 141 - 144
(2007/10/02)
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- GENERAL METHODS OF SYNTHESIS OF INDOLE ALKALOIDS - 14. SHORT ROUTES OF CONSTRUCTION OF YOHIMBOID AND AJMALICINOID ALKALOID SYSTEMS AND THEIR 13C NUCLEAR MAGNETIC RESONANCE SPECTRAL ANALYSIS.
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Conceptually new schemes of synthesis of indole alkaloids are introduced. The yohimboid ring system is constructed by the sequential treatment of 1-tryptophyl-3-( beta -ketobutyl)pyridinium bromide with base and acid. Hydrogenation of the product yields d,l-pseudoyohimbone. The ajmalicinoid ring system is formed by the exposure of 1-tryptophyl-3-acetylpyridinium bromide to sodio dimethyl malonate and then to acid, followed by hydrogenation. Subsequent reduction and dehydration of the products lead to the racemates of the alkaloids tetrahydroalstonine and akuammigine as well as isomers of ajmalicine. Shifts of specific carbons are found to be of stereochemically diagnostic value.
- Wenkert,Chang,Chawla,Cochran,Hagaman,King,orito
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p. 3645 - 3661
(2007/10/04)
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