Camptothecin Curran synthesis

An asymmetric cyanosilylation followed by hydrolysis and cyclization has been used by Curran and co-workers as the key step in the asymmetric synthesis of camptothecin <2001JA9908, 2003F1(59)369>. 

Curran s synthesis (Scheme 5) is an instructive example of applied radical chemistry. His racemic synthesis [10, 11] of camptothecin starts with compound 30. Via 31, the D ring building block is reached by some standard steps. Treatment of... 

BusSnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [51]. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [52]. Curran introduced [4-1-1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 54]. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b]. The vinyl radical 29 then reacts in a 1,6-cyclization followed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-... 

Intermolecular events can also intervene in spectacular radical cascades. Curran used isonitriles as versatile partners for the preparation of eyclopentaquinolines. This was applied to the synthesis of the antitumor agent (20S)-camptothecin (Scheme 3) [4]. 

Radical reactions have developed into indispensable methods in organic synthesis [1] and are often used as key steps in the construction of complex natural products. Impressive demonstrations are found in the following examples taken from the current literature the dactomelyne synthesis by Lee et al [2] the camptothecin synthesis by Curran et al., [3] and of (7)-deoxypancratistatin by Keck et al.,... 

The potent antitumor agents camptothecin (11) and its derivatives are targets of extensive synthetic activities. [7] A major contribution to this research area came from the laboratory of D. R Curran [3] in Pittsburgh with a total synthesis of camptothecin relying on radical chemistry. In the key step of his synthesis (Scheme 2) the iodoalkyne 9 was allowed to react with phenyl isonitrile to provide the target compound 11. 

Intermolecular radical bond formations with companally high yields and stereoselectivities are still very rare in the total synthesis of bioactive compounds. One exception is Curran s camptothecin synthesis. However, progress in acyclic stereoselection of radical reactions [11] should soon help to formulate new solutions for these synthetic challenges. 

As part of the scope of this review, the extensive studies by Curran towards the synthesis of camptothecin and its analogues by radical... 

Alvarez-Builla (02SL1093) presented the only example of 2-pyrazinyl radical, describing its addition to a pyridine ring, in a peculiar radical addition-rearomatisation reaction, also described for pyridyl radicals (Scheme 17). On the basis of the work developed during the camptothecin project (Scheme 54), Curran reported the synthesis of the natural alkaloid luotonin A (05SL2843), employing a 2-quinazolinonyl radical (Scheme 74). 

Scheme 13.33 Bond-sets of Danishefsky s and Curran s camptothecin synthesis...

Curran and coworkers [141] developed a palladium(0)-catalysed domino process for the synthesis of the very potent anticancer natural product (S)-camptothecin (283) [142] and its analogues (Scheme 8.70). Camptothecin (283) contains an ll//-indolizino[l,2- ]quinolin-9-one skeleton, which is also found in mappicine [143] and the promising new analogue DB-67 (287) [144]. A domino-radical reaction has been used for its construction in 40-60% yield [145]. However, the product is also accessible from the isonitrile 284... 

In 1992, novel methodology for the construction of the camptothecin molecule was reported by Curran et al [57-59]. They have applied a novel (4 + 1) radical annulation reaction to the construction of rings B and C of camptothecin. Reaction of A-propargylpyridone (11) with phenyl isonitrile and hexamethylditin under irradiation with a sunlamp gave the tetracyclic compound (12), which was readily converted to (20RS)-camptothecin (13) (Scheme 2.1) using Danishefsky s procedure [60]. The synthesis of key com-... 

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