Synthesis aspidospermidine

Banwell MG, Lupton DW, Willis AC. Application of the palladium(0)-catalyzed Ullmann cross-coupling reaction in a total synthesis ( )-aspidospermidine and thus representing an approach to the lower hemisphere of the binary indole-indoline alkaloid vinblastine. Aus. J. Chem. 2005 58 722-737. 

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

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... 

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 classical Harley-Mason cyclization was utilized en route to (—)-aspidospermidine 84. 9 The synthesis of 84 required 12 steps from the chiral benzamide 12 (X = SiMcs) and was carried out with an overall yield of 19%. 

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>. 

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). 

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.

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. 

Azides are highly valuable radical acceptors that form nitrogen-centered radicals after addition onto them, as in the case of the transformation of 31 into 32. This reaction opens new possibilities for making pyrrolidines. Murphy, for instance, disclosed the synthesis of ( )-horsfihne and ( )-coerulescine by tandem cyclization of iodoaryl alkenyl azides such as 29 [42]. By the same strategy and using precursor 33, formal syntheses of ( )-vindohne [43] and ( )-aspidospermidine [44] have been rendered possible (Scheme 10). 

The dipolar cycloaddition of an alkyl azide with an alkene to form an aziridine has been exploited in the total synthesis of the alkaloid ( )-aspidospermidine <20050BC213>. Enone 353 was prepared in 11 steps from 3-ethoxycyclohexenone and coupled to 2-iodo nitrobenzene under Ullman cross-coupling conditions. The acetate group of 354 was hydrolyzed and the resulting alcohol converted to an azide using standard conditions in 75% overall yield. The cycloaddition of the azide with the enone was conducted in refluxing benzene for 3 days. The fused-ring aziridine 355 was the only product isolated. None of the initial dipolar cycloadduct triazoline was observed. The... 

This methodology has also been applied to the formal synthesis of serri-conine [126]. A remarkable feature of this lactonization is the enantiospecific production of quaternary centers [119] that was later utilized in a synthesis of the alkaloid aspidospermidine [127] (Scheme 16). 

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. 

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