Aspidospermidine Derivatives

A pentacyclic alkaloid, so far unnamed, isolated (90) from the leaves of Voacanga africana Stapf, is the epoxide 75 of a degraded aspidospermane base in which C-5 and C-6 of the original tryptamine ethanamine chain have been lost this is the first recorded occurrence of this ring system. 

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Part 2. Aspidospermidine derivatives bearing a earbomethoxyl group at C 3... 

A number of new sources of the known aspidospermidine derivatives (24-50) have been revealed in recent years 5,6,9,10,13,38,54-65,71,74-78) and are listed in Table 1. Fourteen new alkaloids have been isolated including (-i-)-l,2-didehydroaspidospermidine N-oxide (51), which is a constituent of the roots of R. stricta 66). Its structure was deduced from its spectroscopic properties, but an attempt to assign the absolute stereochemistry by removal of the A-oxide function by reduction or reaction with phosphorus trichloride met with failure, the product obtained being an unidentified indole derivative. 

Strictanine (56) is another aspidospermidine derivative obtained from R. stricta this alkaloid occurs in the fruits 42). Isolated in insufficient quantity for complete study, strictanine appears, from its mass and proton NMR spectra, to be A-formyl-lfia-hydroxyaspidospermidine. The coupling constant for H-2 (72,16 = 7.03 Hz) is appropriate for a trans-diaxial coupling. 

Ban s synthesis of quebrachamine (5) (282-284) (Scheme 44) was readily modified to afford syntheses of several aspidospermidine derivatives. Thus, angular alkylation of the tetracyclic lactam 478, followed by appropriate reduction and cyclization stages, afforded ( )-lV-acetylaspidospermidine (26), whereas acylation at the future C-20 by means of oxalic ester provided a route to ( )-deoxylimapodine (479) and ( )-N-acetylaspidoalbidine (480). ( )-Deoxyaspidodispermine (481) was obtained by C-20 hydroxyla-tion of 478 by means of oxygen and LDA, followed by reduction and cyclization stages (4,282-284). 

Several aspidospermidine derivatives containing additional substituents in the ring system have also been the target of synthesis. Ban and collaborators synthesized 301) ( )-eburcine (513) and ( )-16-epi-eburcine (514) from 1,2-didehydroaspidospermidine (27), which was protected as its... 

Several of the synthetic approaches to the aspidofractinine skeleton involve Diels-Alder addition to a ring C diene system in an aspidospermidine derivative. This is the situation in Magnus and co-workers first enantio-selective approach in this area (4,362), which resulted in the first syntheses of (-)-kopsinine (149) and (-)-kopsinilam (5-oxokopsinine). The same... 

Absohjte Configuration of Some Naturally Occurring Aspidospermidine Derivatives... 

The reisolation of a number of simple aspidospermidine derivatives, previously found in A. qtiebracho-bianco Schlecht (Volume VIII), has been reported from Vallesia dichotoma Ruiz et Pav. 12 Table I). Alkaloid 5 from this plant has a mass spectrum similar to that of N -methylaspidospermidine (LXXXc) but differs from this alkaloid in having the C-21 terminal methyl triplet at 0.88 instead of 0.6 ppm. The... 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

The three alkaloids named in the title (XXXII, XXXIII, and XXXIV) are respectively the A -formyl, -acetyl, and -propionyl derivatives of aspidospermidine (Section II, E). Demethoxypalosine (XXXIV) has been isolated from Aspidosperma limae (40) and A. discolor (40a) and was characterized as an iVa-acyldihydroindole by its UV-spectrum (Table III) and IR-absorption at 5.89 p. A strong band in the IR-spectrum at 13.1 p indicated an unsubstituted benzene ring. The foregoing information was confirmed and the substance was shown to belong to the aspidospermine group by NMR- and mass spectrometry. In the NMR-spectrum (Table IV) the 17-proton absorption is found at 8.13 well downfield from the three-proton multiplet due to the other aromatic protons which is centered at 7.07 8. This shift is due to the proximity of the carbonyl group of the iVa-propionyl group. In the aliphatic part of the spectrum, absorptions which are characteristic of the... 

By comparison, a number of minor alkaloids occurring together with aspidospermine in the bark of Quebracho bianco were identified as iVft-acetyl and/or methoxyl derivatives of aspidospermidine.122... 

Magnus et al. (153,154) reported total synthesis of ( )-aspidospermidine (330) by applying the intramolecular Diels-Alder reaction to the enamide 329 prepared from the 2-methylindole derivative 328 (Scheme 118). 

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). 

Aspidospermidose (53) (69) and aspidospermiose (54) (70), two derivatives of aspidospermidine isolated from the leaves of R. stricta, contain a carbohydrate unit attached to the indoline nitrogen. In the case of aspidospermidose this is a glucose unit, but in aspidospermiose it is an unidentified pentose. Both alkaloids are depicted as being derivatives of (-)-aspidospermidine, apparently without supporting evidence. 

Epoxy -16 - hydroxy -16 - methoxycarbony 1 - 3 - oxo -1,2- didehydro-aspidospermidine (127) has been extracted from the seeds of Amsonia elliptica (101). However, this is almost certainly an artifact, derived by aerial oxidation of 3-oxotabersonine (107), which occurs in the same plant, or its epoxide. 

The second synthesis was a brief, six-step synthesis of iVa-benzyl-aspidospermidine (505), from the amine 506, which was readily prepared from A -benzylaniline and cyclohexan-l,3-dione (298,299). A double alkylation of506gave the intermediate 507, which was cyclized by photochemical means to a mixture of epimers of the hexahydrocarbazolone 508, which contains a irons B/C ring junction. However, alkylation of the derived anion... 

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