Complex indole alkaloids

Hi) Dehydrogenation. j3-Carboline derivatives may be obtained from tetrahydro-)3-carbohnes by zinc dust distillation or high temperatmre dehydrogenation with selenium or palladium black. Many of the complex indole alkaloids may be degraded, with bond cleavage, to yield simple )3-carbolines under these conditions and this approach has become a standard method in structural elucidations. Examples are numerous but outside the scope of this review. 

Pyrroles and indoles can give a wide variety of cycloaddition reactions and this area has seen vigorous activity since 1990 because of the potential of methodology for the synthesis of complex indole alkaloids. The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid. 

Although not described as such, this reactivity of silver as a Lewis acid in C-C bond formation via enamines was already known and actually described in the synthesis of complex indole alkaloids. A A-sulfonyldienamine embedded within a polycyclic indole ring system added to the trimethylsilylated propargyl arm of this system, leading in high yield to a new six-membered ring (Scheme 10.71).110... 

Although the natural occurrence of indole and the biosynthesis of the indole ring system are of importance and relevance to the wider question of the biosynthesis of the complex indole alkaloids, indole will not be discussed in detail here, as it is not an alkaloid. For a comprehensive and critical account of the occurrence of indole and its simple derivatives in plants, the reader is referred to the article by Stowe (8). 

Irinotecan (Camptosar), a more selective synthetic analogue of camptothecin (a natural, but toxic, anticancer alkaloid), acts by inhibiting topoisomerase 1, an enzyme involved in ordering the strands of DNA. Some compounds act by physical binding with vital natural polymers - the complex indole alkaloid vincristine is a classic example - it binds to tubulin, a protein essential to cell division. 

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)]... 

Ca2+ channels are inhibited by several bis-isoquinoline alkaloids (e.g., berbamine, hernandezine, liensinine, monterine, tetrandine), aporphines (e.g., glaucine, norushinsunine), complex indole alkaloids (bis-nortoxiferine, hirsutine, mitragynine, paspaline, paspalitrem, paxilline, penitrem), or other bulky alkaloids (agelasine, contotoxins, crambescidin, ryanodine). Many channel blocker occur in animal venoms it has been estimated that 10% of marine natural products have these properties [65]. 

MAO inhibitors can be classified as simple indole alkaloids (e.g., 13-carbolines, N,N-dimethyltryptamine N-methyltryptamine), simple isoquinolines (carnegine, salsolidine, salsolinol), quinoline alkaloids (e.g., quinine) and even complex indole alkaloids (e.g., vinblastine and vincristine). A structural similarity can be seen between the MAO blocker and endogenous substrates between the indole alkaloids and serotonin between the simple isoquinoline and dopamine, noradrenaline and adrenaline, which implies that these compounds bind to the active site of the enzyme. 

A techniquewhich must certainly now be regarded as moving out of its infancy in its applicability to the complex indole alkaloids is C n.m.r. indeed,... 

Some of the above considerations led to the proposal which has resulted in this compilation of plant species and the classification according to their contained indole alkaloid structural types. The key to this classification is derived from the recent biosynthetic work of Arigoni (2), Battersby 3, 3a), Leete (4), and Scott (5), and their respective co-workers which, in its infancy when Volume VIII of this series was in publication, now presents conclusive evidence concerning the origin of the complex indole alkaloids in plants 5a). 

Since tryptophan is recognized as a main constituent of plant proteins and as a common biogenetic precursor of the complex indole alkaloids, the wide occurrence of tryptamine derivatives in the plant kingdom is not unexpected. The presently known cases of these simple indole alkaloids have been ones in which a tryptamine unit formally appears as a slightly modified structure (e.g., by oxidation or methylation), as a cyclized form or a dimeric variation thereof, or as a modification which incorporates short carbon chains (e.g., C4, C2) or a simple aromatic structure (anthranilic acid) respectively. The great majority of the simple indole alkaloids are confined to the dicotyledon plants. 

It is reasonable then that the complex indole alkaloids also mainly inhabit the dicotyledones. Moreover, as has been pointed out by Le Men and Taylor 6) they occur most frequently in the Apocynaceae, Logani-aceae, and Rubiaceae plant families. A few representatives of this remarkable group have also been found in phylogenetically more remote families such as Annonaceae, Euphorbiaceae, and Sapotaceae. The questionably related Alangiaceae and Icacinaceae families are the most recent additions to the list of plants which contain complex indole alkaloids. The structural features of this class are a tryptamine unit... 

Until such time when the biosynthetic pathways of the complex indole alkaloids have been completely defined their full taxonomic value cannot be appraised. However, a number of recent reviews (7, 8) indicate that chemotaxonomic considerations in this area have been aided by the rapid progress made in the chemistry and biosynthesis of the various indole alkaloids. Furthermore, the latter two disciplines have benefited from the former in the search for new alkaloids and in the elucidation of biosynthetic pathways. In the future it is expected that many advances in indole alkaloid chemistry will often arise as a result of the convergence of biochemical and chemical research efforts (9). 

The presentation of the tables follows, first of all, a major division into simple and complex indole alkaloids (Tables I and II, respectively). Each table then lists, in alphabetical order, the plant families and genera in which specific indole alkaloids are found. These, in turn, have been coded by letter, sometimes somewhat arbitrarily, into different structural t es Fig. 1 corresponds to structural types found in Table I and Figs. 2 and 3 correspond to structural types found in Table II. The appearance of question marks in the tables, either alone or after a letter, implies that... 

Table II tabulates the plant species which contain the complex indole alkaloids. The letters in this table correspond to the various structural types as coded in Figs. 2 and 3. Types I, II, and III are the major variations of the Cfl-Ci 0 unit which, in combination with tryptamine, formally elaborate the three significantly different groups of complex indole alkaloids Corynanthe, Iboga, and Aspidosperma. Such initial classification follows the outline set by Battersby [3, 3a) and others (2, 4, 5). The...

Fig. 2. The complex indole alkaloids. Schematic representations of the structural type I unit. The Roman numeral-letter combinations serve to define these skeletal variations in Table II.

The dimeric complex indole alkaloids are coded simply on the basis of the two monomeric types (Figs. 2 and 3) which are part of their architecture. In this manner no complete structural definition as to their exact interactions is possible but at least their probable biogenetic origin may be readily recognized. 

That the complex indole alkaloids contain a tryptamine unit is a requirement which is not always met at first sight. For example, some alkaloids from the Cinchona and Bemijia species (Rubiaeeae) (Volume VIII, Chapter 10 type Ij, Fig. 2) contain quinoline rings in their overall structures. Nevertheless, it has been shown that tryptophan is readily incorporated into these alkaloids and on this basis they are justly included in Table II. Furthermore, there are a number of complex alkaloids belonging to some Aspidosperma species (Apocynaceae) which seem to have lost the ethylamine side chain of a tryptamine unit (type li. Fig. 2). 

Plants and Theib Contained Indole Alkaloid Types The Complex Indole Alkaloids... 

Pyrroles and indoles can give a wide variety of cycloaddition reactions and this area has seen vigorous activity since 1990 because of the potential of this methodology for the synthesis of complex indole alkaloids. 

Abstract Total syntheses of several complex indole alkaloids having potent biological activities are discussed in detail. 

At least one thousand publications have described the isolation or synthesis of the natural products of indole in the last decade, including many complex indole alkaloids, especially those with novel skeletons, potent biological activities, or posing synthetic challenges. Manzamine A (1) (for recent isolations see [1-8] for recent syntheses see [9-11]) and vinblastine (2) (for recent isolations see [12-17] for recent syntheses see [18-22]) (Fig. 1) are two recent typical examples of great interest for both their syntheses and biological applications. 

CiiHgNj, Mr 168.20. An isonitrile antibiotic from cul-tiues of a Pseudomonas species. The compound is in discussion as a biosynthetic precursor of various complex indole alkaloids from cyanobacteria. lit. J. Aniibiot. 29, 850 (1976) Justus Liebigs Ann. Chem. 1984, 600. J. Am. Chem. Soc. 116, 9941 (1994). -[HS293990 CAS61168-06-7]... 

In the total synthesis of complex indole alkaloids, intramolecular alkenylation of the ketone 39f was carried out successfully by Cook to give 39g in 82 % yield [30]. 

Loganin (6) is a key intermediate in the biosynthetic pathway leading to other iridoid monoterpenes as well as complex indole alkaloids. Many of these additional compounds are derived by conversion of this bicyclic iridoid monoter-pene into secologanin (18). The mechanism by which ring cleavage occurs to yield secologanin is not well understood, but apparently the cleavage happens after oxidation of the... 

More intimate details of the intermediate stages of the biogenesis of the complex indole alkaloids from geraniol were exposed when it was shown by means of tritium-labelled materials [178-180] that loganin (XXXIII) [181 to 183], but not [178] the related iridoid mono terpenoids verbenalin, dihydro-... 

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