Mappicine libraries

Scheme 13.13 Seven-component FMS of a 560-membered mappicine library.

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. 

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].

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.)... 

The power of FMS has been further demonstrated in the preparation of a 560-member library of mappicine analogues (see Scheme 13.13) [25], In this case, the fluorous tags encoded substrates with different substitutions rather than substrates with different... 

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. 

Another approach is the use of multicomponent reactions (MCRs) to rapidly and efficiently construct structurally complex and varied polycyclic natural product-like compounds (Figure 1.5). A number of synthetic transformations played a key role in the rapid assembly of such molecules including isocyanide-based reactions, aza- and non-aza [4+2] cycloadditions, [3+2] cycloadditions, and dansition-metal-catalyzed reactions. Using isocyanide-based MCRs, pyrrolopyridines exemplified by mappicine represent an atttactive library target for their biological activity. Furthermore, the furoquinoline alkaloid tecleabine represents a common quinoline alkaloid core similar to strnctnres fonnd in a polycyclic library. ... 

Zhang W et al (2002) Solution-phase preparation of a 560-compoimd library of individual pure mappicine analogues by fluorous mixture synthesis. J Am Chem Soc 124 10443-10450... 

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