Oxindole alkaloids synthesis

ABSTRACT The acid-catalysed epimerization reaction of bioactive indole alkaloids and their derivatives is reviewed. The three mechanisms, which have been proposed for the (J-carboline-type indole alkaloids, are discussed. Through recent developments, evidence for all three mechanisms has been obtained, which shows the complexity of the epimerization reaction. The epimerization seems to depend on structural features and reaction conditions making it difficult to define one universal mechanism. On the other hand, the isomerization mechanism of oxindole alkaloids has been widely accepted. The acid-catalysed epimerization reaction provides a powerful tool in selectively manipulating the stereochemistry at the epimeric centre and it can also have a marked effect on the pharmacology of any epimerizable compound. Therefore, examples of this reaction in die total synthesis of indole alkaloids are given and pharmacological activities of some C-3 epimeric diastereomers are compared. Finally, literature examples of acid-catalysed epimerization reactions are presented. 

Mitraphylline and rhynchophylline undergo characteristic fragmentation processes on electron impact, hence their mass spectra are markedly different from those of the tetrahydro-/3-carboline alkaloids in general, and of the heteroyohimbine alkaloids (e.g., ajmalicine) in particular. Consequently, the mass spectra of the oxindole alkaloids promise to be very valuable in the structural elucidation of new members of this subgroup the structure of one such base, carapanaubine, a constituent of Aspidosperma carapanauba M. Pichon, has already been elucidated by this method, and the structure deduced has subsequently been confirmed by partial synthesis from isoreserpiline (82). 

The isolation and synthesis of indole alkaloids containing a non-rearranged monoterpenoid unit have been reviewed <03NPR216>, as has the synthesis of spiro[pyrrolidine-3,3 -oxindoles] as building blocks for oxindole alkaloids <03EJ02209>. 

Cravotto, G., Giovenzana, G. B., Pilati, T., Sisti, M., Palmisano, G. Azomethine Ylide Cycloaddition/Reductive Heterocyclization Approach to Oxindole Alkaloids Asymmetric Synthesis of (-)-Horsfiline. J. Org. Chem. 2001, 66, 8447-8453. 

A simple and versatile method for the synthesis of aziridinium salts involves the reaction of a diazoalkane with an iminium salt (82TL285, B-83MI 102-01). The aziridinium salt thus formed was oxidized to an aminoaldehyde by DMSO (Scheme 39). A key step in the preparation of the oxindole alkaloid gelsemine (104) involves the carbonylation of the unsaturated aziridinium ion (103) with disodiumtetracarbonyl picrate-dioxane complex under a CO atmosphere followed by base-promoted epimerization and deprotonation (Scheme 40) <92JOC1035>. 

Spiro[pyrrolidine-3,3,-oxindoles] construction in the synthesis of oxindole alkaloids 03EJ02209. 

A new simple oxindole alkaloid, (-)-horsfiline (57) was obtained from Horsfieldia superba (Myristicaceae), in addition to the known alkaloids 6-methoxy-2-methyl-l,2,3,4-tetrahydro-P-carboline (58) and 5-methoxy-A, -dimethyltryptamine [59]. Horsfiline is a simple spiro-pyrrolidinyloxindole, its structure was deduced from spectral data (MS NMR) as well as by partial synthesis from 58 via oxidation with Pb(OAc)4 to the acetoxyindolenine 59, followed by acid catalysed rearrangement (MeOH/AcOH) to ( )-horsfiline (Scheme 2) [59]. 

Research on the biosynthesis of oxindole alkaloids in Mitragyna species has allowed some conclusions to be reached on their interrelationships and their sites of synthesis in the plant.These alkaloids are formed by modification of the terpenoid indole skeleton. 

The transformation of indole into corresponding oxindole alkaloids has been possible for some time now the reverse sequence has been achieved. The type of 2,3-seco-intermediate (47) arrived at by total synthesis above has been pro-duced " and then cyclized, in both heteroyohimbine (Scheme 12) and yohimbine... 

This cleavage of the oxindole alkaloids, e.g. (100), or the 2,3-seco-derivatives of type (101) to bicyclic piperidine derivatives is of considerable interest, and has provided new pathways for the partial synthesis of other alkaloids. Alternative ways of achieving the cleavage involve the application of the Hobson reaction to pteropodine (100), followed by hydrogenolysis of the intermediate (106) (Scheme 14) a similar sequence of reactions on 2,3-seco-2,3-dihydroakuammigine (101)... 

PeUegrini, C., Weber, M., Borschberg, H. J. (1996). Total synthesis of (-l-)-elacomine and (—)-isoelacomine, two hitherto unnamed oxindole alkaloids from Elaeagnus commutata. Helvetica Chimica Acta, 79, 151 — 168. 

Marti C, Carreira EM. Construction of spiro[pym)lidine-3,3 -oxindoles] - recent applications to the synthesis of oxindole alkaloids. Eur. J. Org. Chem. 2003 2209-2219. 

Although a partial synthesis of rhynchophylline from dihydrocorynantheine was accomplished in 1961 the total synthesis of this oxindole alkaloid remained incomplete for a long time. In the synthesis finally reported by Banet o/., the spiro oxindole nucleus has been established at an early stage, followed by stepwise construction of the functionalized piperidine ring D. 

The synthesis of rhynchophyllol by van Tamelen et a/P illustrates a biogenetic-type approach to oxindole alkaloids. A key feature of this synthesis is generation of the desired tetracyclic structure by an intramolecular Mannich cyclization of dialdehyde (B) produced by oxidative cleavage of the substituted cyclopentanediol (A). 

During the past two decades a great number of papers have been published on the isolation, structure elucidation, synthesis and transformation, biogenesis, chemotaxonomy, and pharmacology of indole alkaloids. In this chapter we summarize the new results that appeared from 1968 to mid 1984 for the cory-nantheine-yohimbine group of monoterpene indole alkaloids with greater emphasis on their chemistry, excluding the related oxindoles and heteroyohimbines. 

In the presence of tetramethyltin, 1-bromonauclefine reacts with CO in a Pd-catalyzed carbonylation to give the alkaloid naucletine [202], Dong and Busacca effected a new synthesis of tryptamines and tryptophols via a Rh-catalyzed hydroformylation of functionalized anilines that are prepared by a standard Heck reaction, as shown for the preparation of tryptamine sulfonamide 325 [423]. This reaction is applicable to ring-substituted tryptamines (Cl, Br, F. OMe, CF3). Likewise, the Rh-catalyzed carbonylation of o-alkynylanilines, which were prepared by a Pd-catalyzed Sonogashira coupling, leads to oxindoles (60-86% yields) [424],... 

The UV-spectrum of mitragynine differs notably from the spectra of the other Mitragyna alkaloids. Whereas the absorption of the latter indicate the presence of oxindole nuclei, the spectrum of mitragynine shows a greater resemblance to that of the ajmalicine group of alkaloids (5). The presence of an indole nucleus is also suspected from its color reactions (2) and confirmed by the isolation of indole derivatives (so far unidentified) and 5-methoxy-9-methylharman (I) from the products of zinc dust distillation (6). The identification by synthesis (51) of this degradation product is of some interest, since the alkaloid itself does not apparently contain an iV-methyl group. Moreover, this was the first demonstration of the occurrence of a 4-hydroxyindole derivative in nature. 

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