Secologanin condensation

The enzyme responsible for the stereospecific condensation of trypt-amine and secologanin 34) was called strictosidine synthase, and its presence was demonstrated by Treimer and Zenk 194) in a number of indole alkaloid-producing plants, including Amsonia salicifolia, Catharanthus roseus, Ochrosia elliptica, Rauwolfia vomitoria, Rhazya orientalis, Stem-madenia tomentosa. Vinca minor, and Voacanga africana. Enzyme activity as high as 1698 pkat/mg protein was observed for O. elliptica. No... 

Strictosidine (97) is formed by condensation of tryptamine (95) with secologanin (96), as shown in Scheme 9. The enzyme which catalyses the condensation has been isolated, purified, and characterized.27 Subsequent transformation of strictosidine (97) involves first the loss of the glucose moiety. Two strictosidine-specific glucosidases have been isolated and characterized.28... 

Terpenoid Indole Alkaloids.—Experiments in intact plants have in the past given results from which a fairly clear picture of the biosynthesis of terpenoid indole alkaloids has emerged.114 An important stage in the biosynthesis of these alkaloids is reached when tryptamine (128) condenses with secologanin (129) to give... 

Although not an alkaloid, condoxine (146) is a compound of considerable interest, and it is relevant to include it here. In contrast to dihydrosecologanin aglycone, which condenses with 2-oxotryptamine with the formation of the oxin-dole analogue (147) of dihydromancunine, secologanin aglycone reacts with 2-oxotryptamine to produce an oxindole base, condoxine, of structure (146).84 Condoxine is thus obtained by cyclization of Nb and the prospective C-7 in... 

Strictosidine synthetase catalyzes the stereospecific condensation of trypt-amine and the iridoid glucoside secologanin to form strictosidine. The product is the precursor of the monoterpenoid-derived indole and quinoline alkaloids. 

All terpenoid indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Fig. 2b). Tryptophan decarboxylase, a pyridoxal-dependent enzyme, converts tryptophan to tryptamine (62, 63). The enzyme strictosidine synthase catalyzes a stereoselective Pictet-Spengler condensation between tryptamine and secologanin to yield strictosidine. Strictosidine synthase (64) has been cloned from the plants C. roseus (65), Rauwolfla serpentine (66), and, recently, Ophiorrhiza pumila (67). A crystal structure of strictosidine synthase from R. serpentina has been reported (68, 69), and the substrate specificity of the enzyme can be modulated (70). 

Ibrahim 407) has reported a microbial transformation of emetine (1) into O-methylpsychotrine (4), which used Cunninghamella blakesleeana MR-198. The first synthesis of the alkaloid glucoside neoalangiside (48) has been achieved with the Aimi et al. 408). It started with the condensation of the brominated phenethylamine 196 with the tetra-O-acetyl derivative of secologanin (132) and proceeded through the intermediates 197 and 198. 

As for the biosynthetic pathway (b) in Scheme 1, two novel enzyme activities involved in the condensation between dopamine and secologanin (132) have been discovered by De-Eknamkul et al. 411) in the cell-free extracts prepared from the leaves of A. lamarckii. These extracts allowed dopamine to condense rapidly with 132 at pH 7.5, giving both (li )-deacetylipecoside (188) and (15)-deacetylisoipecoside (186), which could immediately undergo lactamization to form demethylalangiside (19) and demethylisoalangiside (187), respectively. 

Condensation of tryptamine with secologanin opened the way to studies of the later stages of the biosynthesis. Two basic glucosides, vincoside and... 

A highly significant result emerged when the epimeric isoquinolines (25) and (26) were tested in vivo.15 Both compounds are available from the in vitro condensation of dopamine with secologanin. [3 -14C]Desacetylipecoside (26) was found to be an efficient and specific precursor of all three alkaloids (27), (28), and (29) whereas the epimer, desacetylisoipecoside (25), was biologically inactive. 

In view of the importance of the isoquinoline system in biosynthesis it is surprising that so little effort has been devoted in the past to the biosynthesis of the basic ring system. No doubt the success of this investigation in the peyote cactus will stimulate further work in other systems. It is likely that the normal pattern will involve condensation of a phenethylamine with the appropriate pyruvic acid. However, reference has already been made to ipecoside (27) (Scheme 3) in which the isoquinoline system is formed by condensation of the phenethylamine with an aldehyde [secologanin]. Presumably the corresponding aldehyde, rather than a pyruvic acid, will be found to serve as precursor for the phenethylisoquinolines,3 5 and also for the isoquinoline alkaloids of the Lophophora cactus such as lopho-cerine (66). 

The stereospecific condensation of tiyptamine and secologanin under the action of strictosidine synthase (STR), Fig. (4), is the first committed step in TIAs biosynthesis, and it yields the ghicoalkaloid 3-a(S)-strictosidine, which is the central biogenetic precursor of all TIAs [74-11]. 

The general biosynthetic pathway of indole alkaloids involves condensation of tryptamine with secologanin to afford strictosidine... 

The structure assigned to ipecoside (2) has been confirmed by partial synthesis. Dopamine (21), on condensation with secologanin (22) at pH 5.0, afforded a mixture of deacetylipecoside (23) and deacetylisoipecoside (24) separated by countercurrent distribution. There was a preponderance of the 5j3 isomer in the reaction. Acetylation of deacetylipecoside followed by Zemplen O-deacetylation furnished ipecoside identical with the, natural material (14). 

In a subsequent modification pure, hexa-O-acetylipecoside was readily obtained by acetylation of the crude condensation product of dopamine with secologanin followed by column chromatography over silica gel (14). 

To distinguish between these structures, a synthesis of alangiside was undertaken. Attempted condensation of 4-hydroxy-3-methoxyphenyl-ethylamine with secologanin under a variety of conditions was not successful. However, 3-hydroxy-4-methoxyphenylethylamine condensed smoothly with secologanin at pH 5.2 to afford 33 and 34. No attempts were made to obtain the individual epimers in a pure form, and the crude mixture was treated with a solution of sodium carbonate when mainly the 5/8 epimer (26) which differed from alangiside was obtained, and this on treatment with diazomethane afforded O-methylalangiside. The phenolic hydroxyl of alangiside was thus located at C-7, and structure 25 is a complete representation of the molecule (16). 

In principle there appears no reason why a condensation product of secologanin with tryptophan instead of tryptamine should not occur in nature to give a new series of carboxy terpenoid indole alkaloids parallel to the known tryptamine derivatives. A few representatives have been isolated in recent years, and probably more will follow with the adoption of isolation techniques suited to amino acids. 

An obvious inference from the structures of cordifoline and deoxycordifoline was that their biogenetic precursor would have to be a tetrahydrodeoxycordifoline (TDC) (104 and/or 105) formed by condensation between L-tryptophan and secologanin. One of these, the 3ar isomer, has subsequently been found in R. orientalis (8) and in A. rubescens (38), but the other has so far eluded isolation as a natural product. 

The isolation of cordifoline and related bases led to the prediction of the existence of a common precursor derived by condensation between tryptophan and secologanin. This tetrahydrodeoxycordifoline (TDC) could be (a) a biogenetic cul-de-sac (b) an alternative intermediate to vincoside for some terpenoid indole alkaloids, or (c) the progenitor of a novel range of acidic terpenoid indole alkaloids in which the carboxy group of tryptophan was retained. The last possibility stimulated a search for such alkaloids which was amply rewarded by the discovery in A. rubescens of adirubine (7), 5a-carboxytetrahydroalstonine (102), and 5a-carboxycorynanthine (103), shown to have the tryptophan-based Corynanthe type structures 189,190, and 191, respectively. Surely, with the adoption of modern techniques for... 

A possible clue to the explanation of the enigma of the biosynthetic use of vincoside, with a -hydrogen at C-3, in making alkaloids with a C-3 a-configura-tion, was one of the results to come out of Brown s study of the in vitro conversion (Scheme 12) of secologanin into corynantheine types. Condensation of... 

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