Mappicine

The Henegar modification of the Friedlander reaction has been recently reported. The A-Boc protected derivative of o-aminobenzaldehyde (25, in this case prepared via directed ortho metallation of 24) is a stable, crystalline compound that can be stored for extended periods (in contrast with 4, which typically is freshly prepared). Treatment of 25 with ketone 26 in acetic acid results in deprotection of the aniline in situ and subsequent formation of 27, an intermediate in the synthesis of mappicine. 

Indolizino-quinoline 250, the ring system present in camphotecine and mappicine, has been prepared using classical Friedlander reaction under microwave irradiation conditions [160]. The reaction was successfully carried out in AcOH as the solvent and gave good results even with unstable o-amino benzaldehydes 248 (Scheme 92). 

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]. 

In a study reported in 2001, Curran described research designed to synthesize a library of analogs of a natural product called map-picine. A ketone derivative of mappicine had been shown to be effective in the treatment of the herpes virus and cytomegalovirus. Curran s research team was interested in determining whether there were analogs of mappicine that also display antiviral action. 

Fluoro-3-iodopyridine 212 was used by Comins and Saha as the starting material in a synthesis of mappicine. The first-formed organolithium 213 rearranges to 214 and a quench gives 215. Iodine-lithium exchange allows introduction of the C-4 hydroxypropyl substituent of 216 (Scheme 104). 

The enzymatic conversion of a 9-methoxycamptothecin derivative to 9-meth-oxy-20-(S)-mappicine should be mentioned as it is a short, simple and unusual process which uses microwave irradiation and baker s yeast as catalyst [91]. 

The Indian tree Nothapodytes foetida (syn. Mappia foetida) is an important source of camptothecin, the DNA topoisomerase I inhibitor possessing anti-cancer and anti-HIV activity of significant therapeutic importance. One of the minor components of the plant has been identified as 9-methoxy-20-(S)-mappicine, a tetracyclic derivative of the pentacyclic camptothecin. When the latter compound was treated for a short-time (7 min) with microwave irradiation, it was converted into 9-methoxymappicine ketone with an exceptionally high yield of 95%. This ketone was then easily transformed by baker s yeast into the target compound 9-methoxy-20-(S)-mappicine as illustrated in Fig. 15 [91]. 

Fig. 15 The two-step formation of 9-methoxy-20-(S)-mappicine from 9-methoxycamptothecin by microwave irradiation and Saccharomyces cerevisiae...

Fig. 7. Synthesis of a library containing 100 mappicine derivatives with fluorous tags (Rf) efficient separation on fluorous reversed-phase silica gel is possible on the basis of the fluorine content of the tag [44].

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. 

Radical precursors with a five-membered heteroarene for ring D of the important anticancer and antiviral alkaloids (Camptothecin, Mappicine, Nothapodytine B, and Nothapodytine A), l-(2-halo-3-phenylprop-2-en-l-yl]-l//-pyrrole-2-carbonitriles 163, ( )/(Z) mixture, were synthesized in high yields (87-96%) by alkylation of l//-pyrrole-2-carbonitrile with the cinnamyl bromides 162 using KOH in DME (Equation 30) <2002J(P1)58>. 

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