Secodine Derivatives

Since oxidized derivatives of secodine appear to be involved as late intermediates in the biosynthesis of the aspidospermidine and pseudoas-pidospermidine alkaloids, it is logical to begin with those secodine derivatives that have been found to occur naturally. Tetrahydrosecodine (1) occurs in the root bark of Aspidosperma marcgravianum Woodson (5) and has been detected in cell-suspension cultures of Rhazya stricta Decaisne (6) its demethoxycarbonyl derivative (2) also occurs in A. marcgravianum (5), and in Haplophyton crooksii L. Benson (7,8) and the roots of R. stricta (9). The two isomeric carbonyl derivatives, 2-ethyl-3-[2-(3-acetyl-V-piperidino)ethyl]indole (3) and crooksidine (4), occur, respectively, in A. marcgravianum (5) and H. crooksii (7,8). 

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The Kuehne biomimetic synthesis of alkaloids of the vincadifformine group (vide infra) proceeds via a transient secodine derivative, which is not usually isolated. However, in one of two syntheses of minovincine (265)... 

Following their recent synthesis of ( )-vincadifformine (Scheme 75) (343,344), Szantay and his collaborators have contributed another s3mthesis of pseudovincadifformine and its epimers (392). Condensation of the trypt-amine derivative 587 with the aldehydoester 698 gave, via an unstable secodine derivative, the epimeric tetracyclic esters 715, which, without separation, were subjected to debenzylation, with partial epimerization and cyclization. The product, a mixture of the two cis C/D-fused pentacyclic... 

Ibophyllidine, iboxyphylline, and their close relatives have also lent themselves to synthesis by the Kuehne biomimetic approach. The first essay in this area involved the synthesis of desethyl-ibophyllidine (674), which had recently been isolated from Tabernaemontana albiflora (380), With 4-chlorobutanal, the indoloazepine ester 560 condensed to give an epimeric mixture of intermediate quaternary salts, formulated as 727a, either of which, on reaction with triethylamine, gave desethyl-ibophyllidine (674) via a reactive secodine derivative (Scheme 108) (331). 

A novel route to secodine derivatives (Scheme 29) involves the photo-induced addition of indoline-2-thiones, e.g. (189), to methyl acrylate. The product... 

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

Secodine (394) is a fugitive substance, which readily dimerizes or cyclizes. In consequence, it and its simple derivatives are more often prepared as transient intermediates in the biomimetic synthesis of alkaloids of the... 

Since secodine is a relatively simple compound with no stereochemical complications, there is little scope for variety in approaches to its synthesis, and most attempts begin with a 3-(2-haloethyl)indole derivative, convert it into an N-pyridinium salt by reaction with 3-ethylpyridine, then partially reduce the pyridine ring, and finally introduce the indole 2-substituent. 

Later, a modified version of the synthesis was reported, in which the important secodine precursor is a tetrahydro-jS-carboline derivative, such as 557-559, rather than an indoloazepine ester, as in 560. This led to a simpler synthesis, the tetrahydro-/3-carboline derivatives required for the preparation of 557-559 being obtained directly from the appropriate trypt-amine derivative and pyruvic acid ester. By this route, ( )-vincadifformine (76), ( )-minovine (A g-methylvincadifformine) and ( ) ervinceine (87) were synthesized in comparatively high yield, and in essentially two stages from the starting tryptamine (330). 

The synthesis by Das et al. (338) started from the previously prepared protected indoleacrylic ester derivative 579, which was activated by mesyla-tion and oxidation and condensed with an appropriate aminoacetal to give the indoloazepine derivative 580. Release of the aldehyde function, followed by cyclization to the quaternary anunonium ion, fragmentation to the secodine 418b, and spontaneous cyclization, then gave vincadifformine (76) in 50% overall yield from 579 (Scheme 72) (338). 

Even closer to the postulated biogenetic intermediate are the structures of a group of alkaloids isolated from Rhazya stricta and/or R. orientalis. These are four monomers,derivatives of secodine (SD) (125a), and two dimeric groups, one based on presecamine (126) and the other on secamine " (127). ... 

Ajmalicine (139a) and 3-isoajmalicine (140a) were both converted to oxindole alkaloids, mitraphylline (167) and isomitraphylline (168) in Mitragyna parvifolia (Roxb.) Korth. (Rubiaceae)(S4). Feeding experiments on Vinca minor Linn. (Apocynaceae) had shown that vincamine (169) is biosynthesized via geissoschizine, stemmadenine, secodine, and tabersonine (85). Apparicine (170), which lacks one carbon atom of the tryptamine side chain, appears to be derived in Aspidosperma pyricollum Miiell. Arg. (Apocynaceae) from stemmadenine (86). 

The secodine group of alkaloids are interesting biosynthetically as derivatives of (11) ° or (12), which are regarded as likely intermediates in the biosynthesis of indole alkaloids with rearranged monoterpenoid units. Accordingly,... 

The validity of (6.267) as a biosynthetic intermediate is supported by the isolation of simple secodine (6.268) derivatives from plants and by the specific incorporation of labelled secodine (6.268) into vindoline (6.244) the tritium loss from (6.268) labelled in the dihydropyridine ring on transformation into vindoline (6.244) is consistent with involvement of secodine (6.268) via a more highly oxidized intermediate [as (6.267) [187]. 

Dehydrosecodine (97) is believed to be a key intermediate in the biosynthesis of the Aspidosperma and Iboga alkaloids. The dihydro-derivative, secodine (102), has now been synthesized by a route involving a Claisen ortho ester rearrangement [(98) + (99) (100)] and in situ elimination of methanol [(100) - ... 

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