Mappicine ketone

The same methodology was also used for the synthesis of (S)-mappicine (3-213), which can be oxidized to produce mappicine ketone, an antiviral lead compound... 

Also in this case, Curran and coworkers produced a library of 64 mappicine analogues by automated solution-phase combinatorial synthesis, as well as a 48-mem-ber library of mappicine ketone derivatives [88]. Furthermore, these authors were successful in building up a 115-member library of rac-homosilatecans 3-216 using different iodopyridones 3-214 and aryl isocyanides as substrates 3-215 (Scheme 3.56) [89]. 

B. Das et al. have also elaborated the microwave-assisted synthesis of Mappicine ketone, a potent antiviral lead compound derived from the natural product Camptothecin. The naturally occurring pyrrolo [ 3,4-6 ] quinoline... 

Camptothecin was irradiated under solvent-free conditions for 7 min at the full power of the microwave oven (Scheme 28). The product, Mappicine ketone, was isolated in 96% yield without a trace of undesired side products, which clearly exhibits the potential of microwave-assisted chemistry. In comparison, when the reaction was run at rt in THF and in the presence of BF3 x Et20, Mappicine ketone was isolated in a mere 65% yield. 

Scheme 28 Microwave-assisted conversion of Camptothecin into Mappicine ketone...

A second example for a sulfur-directed cyclization, in which even two thio-phenyl groups were present as substituents on the target alkene 36, is shown in Scheme 14 [85]. This substitution pattern is capable of reversing the usual regios-electivity observed for aryl radical additions to enamides. In the presence of a fivefold excess of tributyltin hydride, one sulfur group is removed immediately after the cyclization step. The resulting tricyclic thioether 37 was further converted to mappicine ketone 38. 

Scheme 14 Radical cyclization as key step towards mappicine ketone 38 [85]...

Figure 15.6 Combinatorial approach to mappicine and mappicine ketone analogs of de Frutos and Curran [17].

Das, B., Madhusudhan, P, and Kashinatham, A. 2000. Unprecedented adducts formed by camptothecin and mappicine ketone with maleic anhydride under microwave radiation. Indian Journal of Chemistry, 39B 326. 

This product was used by Comins in his synthesis of mappicine. The antiviral alkaloid is the alcohol formed by borohydride reduction of mappicine ketone 124. Strategic disconnections 124 split the molecule into a quinoline 125 and a pyridone 126 and correspond to a simple SN2 and a Heck reaction. If the Heck reaction is performed last it will be intramolecular and hence regioselective. 

Product 214 arose from 5-exo radical addition and partial desulphur-isation of substrate 213, which was a precursor used in the s)mthesis of the bioactive natural compound mappicine ketone. 

A naturally occurring pyrrolo[3,4-Z)]quinoline alkaloid 415, named camptothecin, has a promising antineoplastic activity in animal tumor models. When 415 was irradiated with MW under solvent-free conditions, it gave mappicine ketone 416 in 96% yield within 7 min (Scheme 83) 416 was found to be an antiviral lead compound. Under conventional conditions, 415 reacted with borontrifluoride etherate in THF at room temperature for 1.5 h to give 416 in 65% yield (98TL431). 

An efficient synthesis of the naturally occurring oxoindolizino quinoline mappicine ketone 62 has been carried out by Greene and coworkers (2003AGE5059) by making use of pyridone 57a as a key intermediate. The synthesis of 62 began with formation of the known cycloadduct 57a... 

Frutos, O. and Curran, D.P., Solution-phase synthesis of bbraries of polycycbc natural product analogs by cascade radical annulation synthesis of a 64-member bbrary of mappicine analogs and a 48-Member bbrary of mappicine ketone analogs, J. Comb. Chem., 2, 639, 2000. 

Besides camptothecines, structurally related (having the same tetracyclic ll//-indolizino[l,2-b]qumolme-9-one core) alkaloids such as 18,19-dehydro-CPT 16, mappicine 17 [86], nothapodytine, A and mappicine ketone 18 [87] (Fig. 22.4) and their hydroxylated or methoxylated derivatives and glucosides were isolated from Nothapodytes foetida (Icacinaceae) [65, 71, 76, 78, 81, 82],... 

Das et al. [59] described the Diels-Alder reaction of the naturally occurring alkaloids, camptochedn (48) and mappicine ketone (49) with maleic anhydride (50) under solvent-free for 9 min of MWl in a commercial domestic oven (Scheme 6.20). Two unprecedented adducts, (51) and (52) were produced with yields of 81 % and 14%, respectively. The first adduct was formed by the involvement of B-ring of camptochedn with maleic anlydride (50) while the second was formed by the involvement of the C-ring of the alkaloid with the dienophile. Mappicine ketone (49) also underwent similar reaction with maleic anhydride under MWl (9 min) to produce the same adducts (51) and (52) probably through a Diels-Alder reaction of intermediate (53). 

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