In order to realize the promise of genome biology,chemical libraries need to modulate the new targets emerging from genomicstudies. Diversity-oriented synthesis can produce molecules with propertiescapable of targeting this new biological space. We sought to create a libraryof complex macrocycles, with properties that increase the probability ofsuccess not just in the initial discovery phase of the drug discovery processbut also in the downstream optimization and manufacturing phases. Ideally wewould want structures that could easily be modified at nearly every carbon.  Our approach was to prepare a library ofcomplex 16-membered macrocycles consisting of three fragments which can bereadily interchanged or shuffled to produce subtly different variants, whichshould provide rich SAR information during optimization studies. Our coremolecule contains five chiral centers and a complete matrix of stereoisomerswill be prepared. An intramolecular SNAr reaction was used for thekey macrocyclization step.

Fragment-based domain shuffling: An approach facilitating downstream drug discovery

240th National Meeting (2010)

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