Ajmalicine-type alkaloids

Schmidt, D. and Stockigt, J. (1995) Enzymic formation of the sarpagan-bridge a key step in the biosynthesis of sarpagine-ajmalicine-type alkaloids. Planta Med., 61, 254-8. 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

Alkaloids of the ajmalicine type, which differ from the tetrahydro-alstonine type only a trans D/E ring junction, show quite different spectra. Instead of the fragments of mass 251 [202] and 223 [203], they exhibit an intense peak at mass 225, thus differentiating these stereoisomeric types.49... 

Ajmalicine, 19-epi-ajmalicine and tetrahydroalstonine are formed from 4,21-dehydrogeissoschizine via cathenamine (Fig. 2.9). The enzymatic synthesis of these corynanthe-type alkaloids has been investigated using C. roseus cell suspension cultures, and the enzymes involved have been reviewed by De Luca (1993) and Ziegler and Facchini (2008). Ajmalicine can be oxidized by POD to serpentine. This reaction may take in the vacuole. 

Vindoline, an aspidosperma-type alkaloid produced by C. roseus, is a key precursor for vinblastine, an anticancer drug that is the most important pharmaceutical product of C. roseus. Vindoline, like ajmalicine and ajmaline, is produced from degly-cosylated strictosidine. Deglycosylated strictosidine is converted to tabersonine through a series of biochemical steps for which no enzymatic information exists. More details are known about... 

Fig. 261. Transformation of ajmalicine to alkaloids with Corynanthe-type, Iboga-type, and Aspidosperma-type skeletons...

Cathenamine and 4,21-dehydrogeissoschizine have both been demonstrated to be the central intermediates in the enzymatic production of heteroyohimbine-type alkaloids - ajmalicine, 19-epiajmalicine, and tetrahydroalsonine (128, 152) (Fig. 

Further elaboration of tetracycle 159c resulted in the syntheses of the racemate of indole alkaloids of the ajmalicine (61JA2594), tetrahydroalstunine (56JOC1315, 71JA5907), and akuammigine type (ajmalicinoid alkaloids). Similarly, 159d can be converted into yohimboid alkaloids (79JA5370). 

Researches carried out to the early part of 1966 have been comprehensively reviewed and the present account will set out from that point. In brief, the situation reached at that time was as follows. Despite their bewildering variety, three main groups of alkaloids had been recognised (a) the Corynanthe-Strychnos type, e.g. ajmalicine (1) and akuammicine (2) which possess the non-tryptamine unit (3), (b) the Aspidosperma type, e.g. vindoline (4), in which the non-tryptamine unit appears as (5), and (c) the Iboga type, e.g. catharanthine (6), having still a different arrangement of the non-tryptamine unit (7). 

Several important alkaloids have been isolated from Catharanthus roseus plants ajmalicine (34) and serpentine (35) from the root, and the dimeric alkaloids vinblastine (36) and vincristine (37) from the leaves. Therefore, much research has been done on production of these alkaloids by means of plant cell culture. Catharanthus roseus is, in fact, one of the most widely studied plants for the production of secondary metabolites in cell culture systems. We here discuss the two types of alkaloids separately. Table XXIX summarizes patents concerning the production of alkaloids by means of cell cultures of C. roseus. 

The pharmacological significance of ajmalicine stems from its use in the treatment of hypertension and obstructive circulatory diseases. Serpentine and ajmalicine can easily be transformed into each other by means of, respectively, simple reduction or oxidation. The yearly production of ajmalicine is estimated to be about 3600 kg (2). Ajmalicine and serpentine are the major alkaloids found in cell and tissue cultures of C. roseus. Both are representatives of corynanthean-type indole alkaliods, of which more than 25 different compounds are isolated from C. roseus cultures (592). 

The alkaloids imder discussion share a common Corynanthe-type nucleus derived from secologanin. Yohimbine is a carbocyclic variant of ajmalicine, and the enzymes that convert deglycosylated strictosidine to yohimbine have not been identified [124, 125]. Strychnine and bmcine are synthesized from the preakuammicine structure by hydrolysis, decarboxylation, and condensation reactions to aldehyde (Wieland-Gumlich), and subsequently reaction with acetyl-CoA to make a hemiacetal form of aldehyde (Wieland-Gumlich) and strychnine and brucine. Brucine is a dimethoxy form of strychnine. Ellipticine is a representative member of pyrido[4,3-b] carbozole alkaloid, and the formation of ellipticine is from ajmalicine (corynanthean skeleton) [126] (Fig. 20.8). 

The most important, indeed crucial, idea put forward on the biosynthesis of these alkaloids was that they are formed by fragmentation of a cyclopentane monoterpene [as (6.237)]. The pathway outlined in Scheme 6.43 indicates how the major skeletal types represented by ajmalicine (6.243) and akuammicine (6.242), catharan-thine (6.239), and vindoline (6.244) may be formed where one of... 

The stereochemistry of the heteroyohimbine types resembles that of the yohimbines but with an additional chiral centre at C19. It is again probable that only (155) type compounds occur naturally and there are thus again 4 basic skeletal types, normal (e.g. ajmalicine K9.7, pseudo, alio and epiallo, each of which may in addition have the (19i ) or (195) configuration [4]. ORD of heteroyohimbine alkaloids [5]. 

When the aldehyde partner of the Pictet-Spengler reaction with tryptamine is the terpene secologanin, strictosidine is formed as an entry toward the vast monoterpene indole alkaloids [32, 33]. Hydrolysis of the glucosidic part releases the strictosidine aglycone bearing an aldehyde, while imin-ium formation and further cyclization and reduction can lead to ajmalicine (from oxocyclization) or yohimbine (from car-bocyclization). These alkaloids are referred to as from the Corynanthe type, with the monoterpene carbon skeleton unmodified. Although it misses one carbon and has a very... 

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