Tryptamine bridge

The structure of the piperidine moiety and the presence of an unsubstituted tryptamine bridge in alkaloids of the mavacurine-pleiocarpamine class can be proved by a catalytic reduction to the corresponding indolines, which show very different spectra because now the main fragments contain ring D,los (212)- -(216)- -[2I7]-> [218]->[219]. The reduction of indole to indoline alkaloids seems an attractive route for the structure determination of those alkaloids.25... 

The presence of an additional ring connected to the tryptamine bridge changes the aspidospermidine fragmentation pattern drastically, as was demonstrated for kopsine142 and vindolinine.143,144... 

Reduction of minovincine (11) with sodium borohydride gave a mixture of the 19-epimers of minovincinine, (12) and (13). When each of these compounds was treated with zinc in methanolic sulfuric acid, 2,16-reduction and lactonization occurred to afford 14 and 15, respectively. From molecular models, once the stereochemistry of the tryptamine bridge and of C-20 are described, only the stereochemistry in which the C/D ring junction is cis will permit lactonization. Further work indicated that in 14 C-19 had the R configuration whereas in 15 this center was S. Interestingly, there was quite a substantial difference in the [< ]d of these two compounds (11). 

Each group proposed a slightly different mechanism for this rearrangement. The most probable mechanism would appear to be that of the French group (181), which does not involve cleavage of the tryptamine bridge but does involve loss of the C-21 carbon (Scheme 11). 

The two amines were efficiently debenzylated with Pd/C in acidic methanol at room temperature, and the remaining tryptamine bridge carbons inserted by double alkylation at the indole /3 -position and the secondary amine. Deprotonation of the resulting indolenine gives the / -anilinoacrylate, minovine (506 Scheme 27) (226, 227). 

A further example of synthetic approaches to the Aspidosperma skeleton is provided by Potier s synthesis of 5-oxo-20-deethyl vincadifformamide (579) (245). This approach differs fundamentally from the available syntheses in that it begins with a 2-substituted indole followed by cyclization in a single step to the A,B,C,D system lacking the tryptamine bridge carbons. 

The simple reaction sequence begins with the pyridylindolylacrylonitrile 575, which is reduced with sodium borohydride to a nitrile (580) and then hydrolyzed to the amide 581. Catalytic reduction under acidic conditions gave the tetracyclic amide 582 in 45% yield. This cyclization apparently gave the trans C/D ring junction stereochemistry, for insertion of the tryptamine bridge proceeded in poor yield. No further synthetic elaboration of this scheme has been reported. 

Four groups have reported their synthetic efforts in this area of indole alkaloids which apparently lack one carbon of the tryptamine bridge. The two series of compounds differ on the basis of the presence or absence of a C-16 exomethylene group. 

Previous studies of Borreria verticillata (Rubiaceae) yielded the indole alkaloid borrerine (224), and the bisindole alkaloids, borreverine (225), and is-oborreverine (226). A further investigation of this plant gave, in addition to these alkaloids, another new bisindole, spermacoceine (227), which was readily shown from the spectral data to be a derivative of borreverine, possessing a hydroxyethyl substituent at C-7, instead of the Ab-methyl tryptamine bridge in 225. The clearest departure was shown by the resonances of the oxymethylene C-5 in both the and NMR spectral data of 227 when compared to those of 225 137). 

Kristiansen K, Kroeze WK, Willins DL, et al. A highly conserved aspartic acid (Asp-155) anchors the terminal amine moiety of tryptamines and is involved in membrane targeting of the 5-HT(2A) serotonin receptor but does not participate in activation via a salt-bridge disruption mechanism. J Pharmacol Exp Ther 2000 293 735-746. 

Scorpionid secretions represent a mixture of neurotoxic polypeptide toxins, proteolytic and hemolytic enzymes (phospholipases A, acetylcholinesterases, ribonucleases, hyaluronidases), and biogenic amines (serotonin, tryptamine, histamine). The polypeptide toxins (the so-called scorpamines) contain fewer than 40 or 60-76 mostly alkaline and aromatic amino acids stabilized by four disulfide bridges.20 96... 

The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the j9-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (II), it is reasonable to expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which C-ll is substituted by the C-3 bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-ll shows as a singlet (2.82 S) in the NMR-spectrum and C-12 is therefore quaternary. 

The rotational spectra of conformers of tryptamine and tryptophol have been determined <2004PCP2806>. Two conformers of tryptamine are stabilized by an intramolecular N-H- -n bridge, formed between the amino group of the lateral chain in position 3 and the 7t-system of the pyrrole moiety, whereas the most stable conformer of tryptophol is stabilized by a similar N-H--7t bridge, between the hydroxyl hydrogen and the 7t-system of the pyrrole unit. 

Novel 5-HT2A ligands were obtained by incorporation of the tryptamine structure into a bridged y-carboline. The most potent compounds of the series are substituted on the basic nitrogen atom with a butyrophenone chain [24]. The 7S,10R enantiomer displays the highest affinity for the S-HTja receptor. The 7R,10S enantiomer is slightly less active but more selective with respect to dopamine-D2 receptors [25] (Table 10). 

Arundinine (127), was obtained from the epigeal parts, and the strueture was established by spectroscopic methods as well as by X-ray analysis. The moleeule is constituted from the union of two tryptamine moieties, a physostigmine-type unit and another tryptamine unit. The two units are linked by an ether bridge from C(3a) of the former to the aromatic C(5 ) of the other unit (79). A number of related bisindoles have been subsequently isolated from the root extract of the same plant, viz., arundamine (128) (80,81), arundacine (129) (82), arundanine (130) (83), arundavine (131) (84), arundaphine (132) (85), and arundarine (133) (86). The structures of 128,131, and 132 have also been confirmed by X-ray analysis, while the NMR spectrum of arundacine (129) showed the existence of two equilibrating con-formers due to restricted rotation about the amide C-N bond. 

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