The Synthesis of -Aspidospermidine

To probe this, model compounds were prepared and subjected to the reaction. Firstly, formation of the ABE ring system was modeled [14]. Diazotization of the amine 35 and reaction of the resulting diazonium salt afforded the spirocyclic product 36 in an acceptable 57% yield from the amine. This marked the first example where the radical-polar crossover reaction was terminated in an intramolecular manner. Modeling the ABCE tetracycle also worked well in preparing products 40 42. Importantly, the relative stereochemistry of 42, and by implication that of the other tetracycles, was verified by X-ray crystal structure analysis 

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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 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. 

Scheme 8. Completion of the Synthesis of aspidospermidine. Reagents and conditions (i) PCC, Si02, DCM, 18 h, 82% (ii) TMSCl, EtsN, DMF, 80°C, 48 h TiCU, paraldehyde, DCM, -78°C...

The intramolecular Diels-Alder reaction has featured in a number of elegant syntheses of natural products in the past decade, and this trend shows little sign of diminishing. A particularly pleasing illustration of this approach to synthesis is provided by the synthesis of ( )-aspidospermidine (79) by Magnus et al. whereby the key intermediate (80) was produced by way of intramolecular Diels-Alder reaction of the indole 2,3-quinodimethane (78), generated from treatment of the imine (76) with the mixed anhydride (77) in chlorobenzene at 140 °C. 

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]. 

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 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...

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

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). 

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). 

Fig. 2.19 Effective methods to generate all-carbon substituted quaternary stereocenters (a) Diels-Alder assembly of a complicated building block for the synthesis of (-tj-aspidospermidine (b) intermolecular C-acylation using a planar nucleophilic ferrocene type catalyst.

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). 

In an even more recent communication, Wenkert and Liu (295) have reported another preparation of ( )-aspidofractinine (146) by the two-stage reduction of the sulfone 495, a late intermediate in a synthesis of ( )-aspidospermidine (Scheme 89). 

The synthesis of ( )-20-epi-pseudoaspidospermidine (205-pseudo-aspidospermidine, 662) and ( )-20-epi-pseudovincadifformine (205-pseudovincadifformine, 667) by Wenkert et al. (388) consists of a remarkably brief sequence from 3-acetyl-5-ethylpyridine, which was... 

This novel strategy was applied to a synthesis of ( + )-aspidospermidine. In this approach, enantiomerically pure sulfoxide 242 was treated with trichloroacetyl chloride in the presence of zinc-copper couple (Zn-Cu) to give lactone 243 in 78% yield (Scheme 44) (02JA13398). Removal of the chloro substituents followed by the... 

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). 

These methods have proved useful in the synthesis of indole alkaloids. For example, ( )-N-benzyl aspidospermidine 237 (R = Et) was prepared via photocyclization of enaminone 234 to 235 followed by alkylation with nitroethene to 236, which was elaborated on to the alkaloid. 

The completion of the synthesis of aspidospeimidine relied on a protocol introduced by Heathcock [72] for annulating the E-ring to the ABCD-framework of 228. Thus, as shown in Scheme 23, acylation of target compound 242 with a-chloroacetyl chloride followed by a Finkelstein reaction afforded the a-iodoacetamide 243 that upon treatment with silver triflate effected an intramolecular alkylation reaction and the formation of the isoindole-based lactam 244. Finally, reduction of this last compound with hthium aluminium hydride gave the racemic modification of aspidospermidine (228) (32%). 

Another route to chiral lactones 130-a and 130-b was employed by Schultz and Pettus in the synthesis of (—)-ebumamonine and (—)-aspidospermidine [340], In the case of (—)-ebumamonine the cyclization was carried out on the aldehyde 130-A, and yielded the product with 18 1 selectivity for the desired a-stereoisomer. For (—)-aspidospermidine, the cyclization of 130-C was done in refluxing acetic acid, yielding a 1 1 mixture of stereoisomers. The product was taken on to ( )-aspido-spermine by an acid-catalyzed rearrangement (40% H2SO4, 100-110°C). The reason for the considerable difference in stereoselectivity of the two Pictet-Spengler cyclizations is not clear. 

Strempeliopidine (626) was obtained from Strempeliopsis strempelioides, a plant indigenous to Cuba (387). Acid hydrolysis gave aspidospermidine (627), while reductive cleavage (Sn/HCl) yielded dihydroeburnamenine, from which it was deduced that strempeliopidine was constituted from the union of aspidospermidine and eburnane moieties. This was supported by partial synthesis through acid-induced condensation of eburnamine (not stated which enantiomer was used) with aspidospermidine. Since... 

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