Mappicine, synthesis

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. 

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]. 

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). 

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... 

The concise formal total synthesis of mappicine was accomplished using an intramolecular hetero Diels-Alder reaction as the key step by M. lhara and co-workers. Introduction of the necessary acetylenic moiety at the C2 position was achieved by the Sonogashira cross-coupling of a 2-chloroquinoline derivative with TMS-acetylene. Several substituents at the C3 position were investigated, and it was found that the unprotected hydroxymethyl substituent gave almost quantitative yield of the desired disubstituted alkyne product. 

Toyota, M., Komori, C., lhara, M. A Concise Formal Total Synthesis of Mappicine and Nothapodytine B via an Intramolecular Hetero Diels-Alder Reaction. J. Org. Chem. 2000, 65, 7110-7113. 

The synthesis of ( )-mappicine by Kametani et al. has now been published in detail. "... 

Heck reaction. An intramolecular version is exploited in closing the five-membered ring to complete the tetracyclic system of mappicine. A new synthesis of P-ketoesters is via the Heck reaction of aryl halides with the Baylis-Hillman reaction products. Additives have important influences on the products derived from aryl halides and 2,3-dihydrofuran ... 

Source Reproduced with permission from Zhang W., Luo, Z, Chen, C. H.-T. Curran, D. Solution-Phase Preparation of A 560-compound library of individually pure mappicine analogs by fluorous mixture synthesis, J. Am. Chem.Soc. (2002) 124, 10443-10450. Copyright (2002) American Chemical Society.)... 

Scheme 13.4 Quasi-racemic FMS of (S)- and (R)-pyridovericins. 13.2.2 Synthesis of Enantiomers of Mappicine...

Zhang, Q. S., Rivkin, A. and Curran, D. P. (2002) Quasiracemic synthesis concepts and implementation with a fluorous tagging strategy to make both enantiomers of pyridovericin and mappicine. J. Am. Chem. Soc., 124, 5774—5781. 

The introduction of additional substituent groups in combination with the discriminating perfluoroalkyl labels during the synthetic sequence enables convenient preparation and subsequent separation of relatively large libraries. For the library of 100 mappicine derivatives outlined in Scheme 3.20, 300 reactions would be required for the conventional, sequential approach. By application of fluorous mixture synthesis this was condensed into 26 steps. In addition, four tagging and 100 detagging operations are required to obtain the full, unprotected 100-member library from unprotected starting materials. 

A similar approach of fluorous quasi-racemic synthesis [20] was used to synthesize both enantiomers of mappicine at the same time in a coded mixture. The pyridine derivative 41 was split, and the carbonyl group was reduced enantioselectively by (+)- and (-)-DIP-Cl, respectively. The resulting enantiomerically pure alcohols were subsequently derivatized - the (1 ) enantiomer with BrSi(iPr)2CH2CH2QFi3 to yield (Ji)-4-2 and the (S) enantiomer with BrSi(iPr)2CH2CH2CgFi7 to yield the quasi-enantiomer (S)-43. The mixture of both quasi-enantiomers was then subjected to the reaction sequence leading to the fluorous mappicines (R)-44 and (S)-4S. These were separated by fluorous chromatography and deprotected to yield the two mappicine enantiomers (Scheme 3.21). 

Scheme 3.21 Fluorous quasi-racemic synthesis of both enantiomers of mappicine [20], (DIP = diisopinocampheylborane Rp is either QFn or CgFiy).

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. 

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

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... 

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... 

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