Indole alkaloid-type compounds

Scheme 41 Synthesis of polycyclic indole alkaloid-type compounds 225. The X-ray structure of compound 225D is shown in blue sticks (CCDC-749252)...

Methylation at C-4 of sterol nucleus was one of the other factors affecting activity enhancement. Thus, in general, 4-methylsterols (14,15) and 4,4-dimethylsterols (8,13) exhibited higher activity than 4-desmethylsterols. A similar structure-activity relationship was observed also in the HHPA-induced inflammation on mouse ear [35]. Whereas cholesterol (7) did not show inhibitory activity, several 4,4-dimethylcholestane derivatives, 0-12, exhibited activity. 4,4-Dimethylcholestane-3a,5a-diol (12) was the most potent inhibitor its activity was comparable to that of ursolic acid (210) [35]. Compound 12 reduced also the inflammation induced by teleocidin B (3), one of the indole alkaloid-type of tumor promoters [53]. 

Alkaloids are compounds that contain nitrogen in a heterocyclic ring and are commonly found in about 15-20% of all vascular plants. Alkaloids are subclassified on the basis of the chemical type of their nitrogen-containing ring. They are formed as secondary metabolites from amino acids and usually present a bitter taste accompanied by toxicity that should help to repel insects and herbivores. Alkaloids are found in seeds, leaves, and roots of plants such as coffee beans, guarana seeds, cocoa beans, mate tea leaves, peppermint leaves, coca leaves, and many other plant sources. The most common alkaloids are caffeine, theophylline, nicotine, codeine, and indole... 

The formation of a Reissert anion (intermediate of type 16) is usually the introductory step in a great number of synthetic routes leading to isoquinoline as well as indole alkaloids and related compounds. On the one hand, the alkylation of a Reissert anion with alkyl halide followed by alkaline hydrolysis is the most frequently used method for the synthesis of 1-alkyl- or 1-arylalkylisoquinolines (20) (Scheme 4). On the other hand, Reissert anions react with aldehydes to form... 

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. 

Hirsutine (85) is a corynantheine-type indole alkaloid with a C/D cis ring juncture (pseudo stereochemistry). This compound has recently been found to exhibit highly potent inhibition of the replication of the strains of influenza A (subtype H3N2) [63]. The EC50 of hirsutine was 11- to 20-fold more potent than that of the clinically used ribavirin. Exploration of the important structural features of this molecule revealed that the stereochemistry at C-3 (.R) and C-20 (R) as well as the presence of the Nb lone pair were essential for the anti-influenza A activity. Thus, the C-3 epimer, dihydrocorynantheine (86) (normal stereochemistry), was much less active than hirsutine (85). 

Structural features, reaction conditions and acid strength also influence the acid-catalysed epimerization reaction. For example, Mechanism 1 requires protonation at C-7, which seems to occur under strongly acidic conditions. When a P-carboline derivative was treated with a weakly acidic solution (TFA-d, 2.9 equiv., rt), deuterium incorporation did not occur, whereas refluxing of a similar compound in a DCl/MeOH solution resulted in deuterium incorporation at the epimeric centre. Therefore, it is impossible to define one universal mechanism to explain the epimerization reaction for any given compound. On the contrary, each compound type must be separately investigated under different conditions. Clearly, then, the acid-catalysed epimerization reaction of indole alkaloids is a fruitful research area. 

Started in the late 1960s, studies on enamide photocyclization and its application to the synthesis of alkaloids have been successfully accumulated and have achieved a number of total syntheses of various types of isoquinoline and indole alkaloids and related heterocyclic compounds (11). 

Streptomyces distallicus the structure elucidation and synthesis have also been made by them.165 A wide variety of porphyrins which are derivatives of porphin (125 R = H) occur in nature and exert three biological functions (a) oxygen storage and transport, as in hemoglobin, (b) cellular respiration as in the cytochromes, and (c) photosynthesis, as in the chlorophylls for detailed discussion of structures and synthesis of naturally occurring porphyrins, see references.166 Recent developments in the chemistry of polypyrrolic compounds have been reviewed.167 Several naturally occurring indole alkaloids have dimeric structures of type B,168 an example of which is c-toxiferine-I, a calabash curare alkaloid found in South American species of Strychnos.169... 

The distance between the chromophores Is approximately 21 8 as measured on molecular models and no ground state Interaction could be observed. In dioxane, the singlet energy transfer occurs by a Forster-type mechanism. On the basis of this mechanism, the distance can be calculated from the transfer efficiency. For [16a] a value of 21.211.6 X was found, while for [I6b] one obtained a value of 16.7 1.4 X. This latter discrepancy was explained on the basis of preferential orientation of the chromophores. That this phenomenon Indeed plays an Important role, was proved by Leermakers (59,60) In a series of indole alkaloids. The same author (59) also Illustrated the absence of triplet-triplet transfer at low temperature in compound [16b]. 

Adina cordifolia has yielded a pair of jS-carboline acids, cordifoline" " (43) and adifoline (44), which are closely related to the vincosides in structural type. In both compounds the carboxy-group of precursor tryptophan is retained very few monoterpene indole alkaloids have been obtained which do still retain this feature, though of course, classical methods of alkaloid isolation would automatically lose such compounds in discarded acidic fractions. 

More recently, Langlois and co-workers have adapted this methodology to total synthesis of some complex indole alkaloids.56 Cyclic imines (Scheme 2-IX) reacted thermally in good yields with methylbutadiene-1-carboxylate to afford a mixture of Diels-Alder adducts. Alkylation of the enolate derived from the mixture of isomers gave a /3, y-unsaturated ester stereospecifically. This type of compound was coverted to vindoline (28, R = OMe) and vindorosine (28, R = H). These workers found that 1-cyanobutadiene is also useful in this sort of cycloaddition [Eq. (13)]... 

In numerous reviews of the biosynthesis of indole alkaloids (2), an intermediate of the type 259 has been postulated. This skeleton remained merely a topic for chemical comment until a compound having this type of skeleton was actually isolated (115). 

The publication of Volume VIII of this treatise afforded a timely opportunity to examine the advances in indole alkaloid chemistry at a stage which was immediately preceded, in a short five years, by the most intense and productive investigations that the field had ever experienced. At that time, a cursory examination of that volume revealed that the newly discovered compounds invariably offered minor variations from the previously known indole alkaloids and that, in many cases, they lent themselves to a formal categorization according to several basic structural types. In general, the recent developments in the field tend to support this observation although some notable exceptions are recognized. 

Biogenetically, the humantenine-type oxindole alkaloids would be generated from the sarpagine-type compounds such as 19(Z)-anhydrovobasinediol (6) through p-oxidation of the indole portion and subsequent rearrangement to the oxindoles (Fig. 13). 

Sarpagine-type indole alkaloids have a structural feature bonding the C-5 and C-16 positions in the Corynanthe-typ monoterpenoid indole alkaloids. This type of compound is distributed not only in Gelsemium plants, but also in many genera in the family of Apocynaceae, Rubiaceae, and Loganiaceae. As shown in Table I, sfac sarpagine-type alkaloids 1-3, 5, 8, and 9 have been isolated from the Gelsemium plants. 

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