Aspidosperma Aspidospermidine

The versatile cyclohexa-1,4-diene 32a has served as an intermediate for synthesis of (—)-eburnamonine 81 and the Aspidosperma alkaloid (—)-aspidospermidine 84 (Scheme 18).3s Butyrolactone carboxylic acids 78 and 82 were prepared from 32 by modification of the methodology outlined in Scheme 7. The key Pictet-Spengler-type cyclization of 79 under conditions of kinetic control gave an 18 1 mixture of 80 and its C(3) (3-epimer in 93% yield. Subsequent hydroboration... 

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... 

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). 

Aryldiazonium tetrahaloborates, 16 Aryl methyl ethers, 115 Arylthallium ditrifluoroacetates, 287-288 Aryl trifluoroacetates, 287 Asparagine, 102 Aspidosperma alkaloids, 196 (+)-Aspidospermidine, 196 Asymmetric synthesis, 199—200 Aurantiocladin, 7 Autoxidation, 245... 

The Harley-Mason approach to the Aspidosperma skeleton was discussed in Volume XI (p. 225), and very brief mention was made of the successful synthesis of aspidospermidine (249) using this route (241). In view of the complication involving cis/trans C/D ring stereochemistry involved in a number of other approaches, it is amazing that the Harley-Mason approach should be stereoselective. The process in question is typically reaction of the hydroxyester 560 with tryptamine to give a compound (561) having a sero-ebumane skeleton. When this compound is treated with 40% sulfuric acid or boron trifluoride etherate at 100°, the indolenine lactam 562 is produced. Lithium aluminum hydride reduction then gives racemic aspidospermidine (249 Scheme 33). 

As in the route described in Volume tryptamine oxindole serves as the starting material for a now even shorter route to the aspidosperma ring system. Scheme 23 shows the construction of ( )-aspidospermidine (109) and of ( )-vincadifTormine using this approach. 

The Aspidosperma alkaloids are a group of more than 100 monomeric and dimeric monoterpene indole alkaloids with aspidospermidine (228) representing a key member of the class and sometimes considered to be the parent [68]. Numerous total syntheses of this pentacyclic compound have been reported. Our own contributions in the area were prompted by the discovery of a new method for preparing indoles via a palladium-catalysed Ullmann cross-coupling reaction that proceeds especially efficiently at close to room temperature [69] and which we felt could serve as the centrepiece in developing a new synthesis of compound 228 and, in the longer term, syntheses of dimeric members of the indole alkaloid class such as the clinically significant alkaloids vinblastine and vincristine. 

Aspidospermidine, one of the simplest of Aspidosperma alkaloids containing a pentacyclic ring system, was isolated from Aspidosperma quebracho bianco and other Aspidosperma species. Aspidosperma is a genus of flowering plant in the family Apocynaceae. The alkaloids aspidosper-mine were first synthesized by Stork and Dolfini in 1963. " Since then the compound has had many extensive investigations, and more than 30 research groups have synthesized... 

Kozmin SA, Iwama T, Huang Y, Rawal VH. An efficient approach to Aspidosperma alkaloids via [4-1-2] cycloadditions of aminosiloxydienes stereocontrolled total synthesis of ( )-tabersonine. Gram-scale catalytic asymmetric syntheses of (-l-)-tabersonine and (-l-)-16-methoxytahersonine. Asymmetric syntheses of (-l-)-aspidospermidine and (-)-quebrachamine. J. Am. Chem. Soc. 2002 124(17) 4628-4641. 

Kutney JP, Abdurahman N, Gletsos C, Quesne PL, Piers E, Vlattas I. Total synthesis of indole and dihydroindole alkaloids. V. Total synthesis of dl-quehrachamine and dl-aspidospermidine. General entry into the aspidosperma alkaloids. J. Am. Chem. Soc. 1970 92(6) 1727-1735. 

---