Of aspidospermidine

Aube took advantage of an intramolecular Schmidt reaction of azide 129 to provide the fused ring heterocyclic lactam 130 as a key step in a total synthesis of (+)-aspidospermidine... 

In a synthesis of aspidospermidine [232] an alkylative rearrangement was employed to gain entry into the pentacyclic skeleton. 

Scheme 16. Application of radical-polar crossover reaction in the total synthesis of ( )-aspidospermidine...

The use of an azide as an efficient radical acceptor with concomitant nitrogen elimination has been applied for the preparation of an intermediate in aspidospermidine synthesis [95CC1409]. Reductive cyclization of 165 at reflux temperature furnished 166, the ABCE tetracyclic portion of aspidospermidine 167, in 95% yield. The cyclization establishes three contiguous chiral centers. 

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-... 

This enaminone cyclization route to indolones has been applied [76-79] for the synthesis of a variety of aspidospermidine class of alkaloids 153-155 from compound 152, which was obtained in very high yield from the photolysis of 151, as illustrated in Scheme 8.44. 

An intramolecular Michael addition has been used to effect transformation of the pyrrole 50 to the indolizidine 51, the ester group of which was later homologated by a one-carbon unit, and the acid so obtained underwent in turn an intramolecular acylation at the pyrrole C-3 giving the tricyclic structure 52, which eventually lead to a formal total synthesis of ( )-aspidospermidine after a few additional steps <02JCS(P1)2613>. 

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). 

However, in order to prepare the E ring of aspidospermidine containing the correct hetero-atom, it was found that the use of internal nitrogen nucleophiles was not efficient for such TTF-mediated cyclizations. To overcome this problem, these reactions were performed in moist acetone in order to introduce a hydroxyl group at the C ring (Scheme 9) [14]. Manipulations of this com-... 

Scheme 8. Synthesis of the ABCE tetracyclic structure of aspidospermidine.

Scheme 9. Application of the radical/polar crossover reaction to the total synthesis of aspidospermidine.

This encouraged us to proceed to elaborate the D ring of aspidospermidine. Ketone 51 was subjected to aldol reaction, and the aldol... 

The past 5 years study of the radical-polar crossover reaction has led to a rich vein of new chemistry and intriguing reactions. This type of reaction is still in its infancy, and many facets remain to be explored. However, the use of radical-polar crossover chemistry as the key reaction in the synthesis of aspidospermidine demonstrates the utility of the process in a challenging molecular setting. 

During the total synthesis of (+)-aspidospermidine by J. Aube et al., the final steps involved an efficient Fischer indolization of a complex tricyclic ketone." This ketone was unsymmetrical and the indole formation occurred regioselectively at the most substituted a-carbon in a weakly acidic medium (glacial AcOH). 

Iyengar, R., Schiidknegt, K., Aube, J. Regiocontrol in an Intramolecular Schmidt Reaction Total Synthesis of (+)-Aspidospermidine. Org. Lett. 2000, 2,1625-1627. 

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. 

The enantioselective approach to quebrachamine adopted by Fuji and collaborators (Scheme 41) (279) has also been modified to afford a new synthesis of (-)-aspidospermidine (251). Here, the lactone 446 was converted by titanium trichloride into the lactone hemiacetal 485, which, after appropriate reduction and oxidation stages, gave the acetal acid 486. Condensation with tryptamine gave the tetracyclic lactam 487, which was then rearranged by means of trifluoromethanesulfonic acid to the pentacyclic indolenine lactam 488, reduction of which gave (-)-aspidospermidine (251) (Scheme SI). 

Two further syntheses of aspidospermidine have been contributed by the Wenkert group. Both use as starting material the pentacyclic ketolactam 493, which was readily prepared from indoleacetic anhydride and 3-acetyl-... 

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