Camptothecin total synthesis

CHEMISTRY OF CAMPTOTHECIN Isolation of camptothecin Total synthesis of camptothecin... 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

Fluorine has also been introduced on the E-ring. For instance, both epimers of 20-fluoro camptothecin, where the fluorine atom replaces the 20-hydroxyl, have been prepared by total synthesis via stereoselective fluorination with... 

A Pd-catalyzed alkoxycarbonylation of 2-chloropyridine 117 to ester 118 was reported in the synthesis of camptothecin analogs <97JOC6588>. Another Pd-catalyzed alkoxycarbonylation was the central feature in Hibino s total synthesis of oxopropaline G (121), a P-carboline isolated from Streptomyces sp G324 <98TL2341>. Triflate 119 was prepared from 2-foimyl-3-iodoindole in seven steps. The Pd-catalyzed alkoxycarbonylation of 119 provided the key intermediate, l-methoxycarbonyl-4-methylcarboline 120, which was then transformed to oxopropaline G (121) in four additional steps. 

A recently reported total synthesis of /-camptothecin was based on l-oxooctahydroindolizine-6-carboxylic acid (169).228 To accomplish the... 

The first total synthesis of racemic camptothecin was reported by Stork and Schultz as early as 1971. A number of total syntheses followed, many of which were also of racemic material 7 Enan-tiomcrically pure natural product has been prepared by the method of kinetic resolution through use of chiral auxiliaries,9 and by Sharpies dihydroxylation,J0 an example of a catalytic asymmetric route. 

The key steps in the total synthesis above of (+)-camptothecin are the pyridone-forming ring closure of the D ring together with construction of the C ring through an N-4-C-5 coupling. 

Several camptothecin relatives have been prepared, either by total synthesis or from natural 10-hydroxycamptothecin, for pharmacological evaluation.132... 

The DE ring of camptothecin has been prepared enantioselectively in six steps from 2-fluoropyridine using a halogen dance reaction <95TL(36)7995>. The first total synthesis of dimethyl sulfomycinamate (47) was reported starting from 3-hydroxy-6-methylpyridine (48) <95TL(36)5319>. 

The antitumor activity displayed by camptothecin (28) and its analogues has led to a great deal of interest in such compounds.36 Camptothecin is a complicated alkaloid to isolate, and analogues, which are of biological interest, are synthesized from the natural product itself.37 This need to access a wide range of analogues has led to a need for synthetic studies directed toward the development of a concise, yet inexpensive, total synthesis of camptothecin. 

A new synthesis170 of the tetracyclic pyridone ester (285) (Scheme 29) represents another formal total synthesis of camptothecin, since (285) has already been... 

The aza-annulation methods developed for conversion of 88 to 94 were extended to the synthesis of the antileukemic and antitumor natural product ( )-camptothecin (125, Scheme 11 ).47 Aza-annulation of 109 with 121 in the presence of NaBH4 resulted in heterocycle formation to give 122 without subsequent elimination of the malonate species. A dye sensitized photo-oxidation promoted the rearrangement of the indolo[a]quinolizinone ring to the indolizino[l,2-h]quinolone ring 123. Compound 123 was converted to 124, which constituted a formal total synthesis of camptothecin (125). 

Sugasawa et al.u in a series of model studies directed toward the total synthesis of camptothecin, allowed 2-pyrrolidinone (53) to react with diketene (54) followed by ammonium acetate in acetic acid to afford 2-methyl-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidin-4-one (56). Presumably, keto imide 55 is an intermediate in this reaction [Eq. (15)]. 

The first total synthesis of ( )-mappicine (218) (Scheme 39), a minor alkaloid of Mappia foetida, uses as starting material the potential camptothecin intermediate... 

The rearrangement has been used by Rapoport et al to obtain the fused pyridone-lactone DE ring system in a total synthesis of d/-camptothecin (5). 

Cyanosilylation of ketones (4,542-543 5,720). In a total synthesis of natural camptothecin (9), Corey et al used this f-butyldimethylsilyl derivative rather than trimethylsilyl cyanide (5, 720-722) to effect cyanosilylation of a ketone (1). Hydrolysis of the resulting cyano silyl ether to the required amide was not accompanied by desilylation with reversal of cyanohydrin formation. By use of carefully controlled conditions and with dicyclohexyl-18-crown-6-potassium cyanide as catalyst, they were able to convert (1) into the a-hydroxy... 

In a total synthesis of the alkaloid di-camptothecin, Rapoport et al. investigated the oxidation of the alcohol (1). The Pfitzner-Moffatt reagent proved... 

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. 

A radical-based quinoline ring synthesis was developed with the total synthesis " of the anti-cancer alkaloid camptothecin in mind. The sequence below shows the construction of the ring skeleton of camptothecin and suggests a mechanism for the process. 

In this case TTMSS was used instead of BusSnH, to provide increased yields. Radical cyclisation of 211 to give 212 is the key step in the total synthesis of (+)-camptothecin (02JOC7465). 

Finally, appropriate modification of an earlier synthesis of camptothecin has allowed the total synthesis of 7-methoxycamptothecin and some C-20-alkyl analogues. ... 

Analogs based on a novel template, ll-aza-(20S)-camptothecin 219, were obtained from a total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent ll-aza-(20S)-camptothecin 219 is derived by cyclization of the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine 217 and optically active tricyclic ketone 218 in 27% yield (Scheme 47) (95JMEn06). 

A total synthesis of 10-hydroxy- and 10-methoxy-camptothecins has been described, but adequate details of the work are difficult to obtain the overall route used appears to be similar to that adopted by the same group in an earlier synthesis of camptothecin. 

The cyclization proceeds in the sense of a 5-exo-trig reaction in analogy to the processes discussed above for allylic substrates. Frequently, spirocyclic products are obtained as shown in Scheme 13.P61-[2S] Another prominent example is the final step in a total synthesis of camptothecin presented in Scheme... 

Cyclizations of substructure type C (Figure 6.3) are also used in total synthesis of natural products bearing five-membered heterocycles, as shown by the example of (S)-camptothecin (83), a natural anticancer agent (Scheme 6.23) [71]. This pentacyclic alkaloid was synthesized in 10 steps, the last one being a 5-exo-intramolecular Mizoroki-Heck reaction. 

Scheme 6.23 Last step in the total synthesis of (S)-camptothecin.

There are also examples citing snbstructure F in the total synthesis of natural products containing 0-heterocycles, namely in a synthetic approach to (205 )-camptothecin [106] or in the synthesis of the Amaryllidaceae alkaloids ( )-tazettine and ( )-6a-epipretazettine (Scheme 6.39) [107]. 

H-)-Camptothecin was isolated from Chinese tree by Wall and colleagues in 1966 its potent antitumor property has attracted interest from synthetic chemists. In 1997 Murata, Sakamoto and their team reported a methodology for the functionalization of heteroaromatics, and also applied it in the total synthesis of camptothecin [57]. Palladium-catalyzed carbonylation of benzylic substrates was... 

A number of synthetic strategies for the preparation of camptothecin were developed in the 1970 s and early 1980 s [49-55], and these efforts culminated in several successful total syntheses, the first by Stork and Schultz [56], Discontinuation of the early clinical studies of camptothecin dramatically reduced the research effort devoted to investigating new methodologies for the total synthesis of this alkaloid. In the late 1980 s, however, the discovery of the unique biological mode of action of camptothecin, and the development of water-soluble derivatives such as CPT-11 [21] and topotecan [23], revived interest in the development of practical methods for the synthesis of camptothecin. 

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