Iboga skeleton

Coronaridine subtype alkaloids are widely spread in Tabernaemontana. The iboga skeleton is particularly susceptible to oxidation at aminomethylenes C-3 and C-5 and at benzylic C-6. Very often, the fundamental compounds are accompanied by the oxidation products at these positions. 

A rare and biogenetically interesting example of the ethyl chain functionalization of the iboga skeleton is represented by 18-hydroxycoronaridine (al-bifloranine) (128, C21H26N203, MP 192-194°C, [a]D -210°) isolated from T. albiflora (28). The base peak in its mass spectrum appeared at m/z 323 (M+--31), and this suggested that a hydroxy group was present at C-18. A detailed H-NMR study of 128 in comparison with 97 and heyneanine (122) was reported and shown in Table IV. 

The structures of cleavamine and velbanamine are considered here since they are probably derived from precursors with the iboga skeleton. Cleavamine (XLVII), mp 109°-113°, [a]D +56° (CHCI3), was obtained along with deacetylvindoline when leurosine (structure unknown but closely related to XLI) was refluxed with concentrated hydrochloric acid, stannous chloride, and tin (42). Velbanamine (XLVIII), mp 139°-141°, [a]D +56° (CHCI3), was the indolic product when vincaleuko-blastine (XLI R = Me) or leurocristine (XLI R = CHO) were treated in the same way (42). Aside from the question of the mode of fission of the dimers (XLI), the production of the new tetracyclic systems in XLVII and XLVIII can be regarded as proceeding via a reverse Mannich... 

Two alternative intramolecular Diels-Alder reactions of the putative alkaloid precursor dehy-drosecondine (70) have been postulated as a branch point in the biosynthesis of aspidosperma and iboga alkaloids <62JA98>. Reaction by path a, in which the acrylate moiety acts as the dienophile generates the iboga skeleton, (69) while path b, with the vinylindole acting as a diene, gives the aspidosperma structure (71) (Scheme 147). 

Incorporation of an cc,P-cis double bond generates dehydrosecodine, the putative biosynthetic intermediate. By using the piperidone (77) as a starting material the reaction can be directed to either the aspidosperma or iboga skeleton. The ketone (77) cyclizes to (80) but conversion to the TMS enol ether (78) results in the iboga structure (79) (Scheme 149) <86JOC2913>. 

Two new analogues of catharanthine, 753 and 754, differing from catharanthine in the fusion of the indole ring to the non-aromatic portion of the iboga skeleton have been synthesized in racemic form and their reactivity toward coupling with vindoline examined. The [2,1] fused analogues (e.g., 753) were found to give low... 

Synthesis of camptothecin (163) is another example[133]. The iboga alkaloid analog 164 has been synthesized smoothly by the intramolecular coupling of iodoindole and unsaturated ester to form an eight-membered ring. Af-Methyl protection of the indole is important for a smooth reaction[134]. An efficient construction of the multifunctionalized skeleton 165 of congeners of FR900482 has been achieved[135]. 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

Further variants on the terpenoid indole alkaloid skeleton (Figure 6.82) are found in ibogaine from Tabemanthe iboga, vincamine from Vinca minor, and ajmaline from Rauwolfia serpentina. Ibogaine is simply a C9 Iboga type alkaloid, but is of interest as an experimental drug to treat heroin addiction. In a number of European countries, vincamine is used clinically as a vasodilator to increase cerebral blood flow in cases of senility, and ajmaline for cardiac arrhythmias. Ajmaline... 

The versatility of strictosidine as a central intermediate for the biosynthesis of a variety of alkaloids is based on the highly reactive dialdehyde produced by the action of strictosidine p-D-glucosidase. This reactive intermediate is converted by uncharacterized enzymes into the major corynanthe, iboga, and aspidosperma skeletons that are elaborated into die several hundred alkaloids found in Catharanthns roseus. Since the biosynthesis of strictosidine appears to occur within plant vacuoles, there has been much speculation, but little is known, about the factors that regulate the accumulation of strictosidine within the vacuole, or which trigger its mobilization for further elaboration. It is well known that glycosides of different natural product classes are located within plant vacuoles. 

The subsequent steps from geissoschizine to form the Strychnos alkaloids, the secodines, the Aspidosperma alkaloids and the iboga alkaloids remain speculative, based on low levels of incorporation of early precursors or alkaloid time course studies. Joining C-2 and C-16 while moving C-3 to C-7, yields the strychnan skeleton... 

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 Group. In the biogenetic interrelationship of the three major mono-terpene-tryptamine alkaloid types, i.e. strychnos, aspidosperma, and iboga, the necessary changes in the aliphatic skeleton can be schematically represented... 

Subsequently, in an independent investigation, Battersby, Scott, Arigoni and their respective co-workers showed by feeding experiments on V. rosea that the unit as represented by the Cory nan the-Strychnos (136), Aspidosperma (137), and Iboga (138) skeletons in ajmalicine (139a), aku-ammicine (141), vindoline (142), and catharanthine (143), respectively, was derived from two molecules of mevalonic acid (134) (54-56). It was further... 

For reasons of brevity, some skeletal variations are not clearly defined in Figs. 2 and 3 and some have been omitted. In particular, the picraline (Volume VIII, p. 147), the echitamine (Volume VIII, p. 174) 78), and the aspidodasycarpine 53) skeletons have been merged into type If. The new alstophylline type 39, 40) is somewhat hidden in the Id reprepresentation. Gelsemine (Volume VIII, p. 95) has been included in the oxindole type Ic. Type Ila Iboga) includes several closely related rearranged alkaloids (Volume VIII, Chapter 9) which are not shown in Fig. 3. An unusually modified Aspidosperma structure 83) is related to type III6 and is listed as such. 

The C-atoms marked by in strychnine and brucine are derived from acetate. Vinblastine (vincaleucoblastine) and vincristine are dimeric alkaloids containing both the iboga and the aspidosperma skeletons... 

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

The conversion of the Corynanthe-type skeleton present in stemmadenine to the Aspidosperma or the Iboga-type skeletons requires cleavage of the bond between the two carbon atoms marked and the formation of a new bond at the o-position. In the first case the bond is formed with the carbon atom marked and in the second with the one marked ... 

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