Compounds used in fragment based drug discovery (FBLD) screening are predominantly composed of sp2-enriched structural elements. For practitioners of FBLD, the preponderance of sp2 based molecular motifs fails to completely capture available biological target chemical space. There remains much space to be explored, especially with sp3-enriched compounds. The dearth of sp3-enriched fragments, even from commercial sources, necessitates the development of synthetic strategies designed to provide the requisite compound library feedstocks from readily available precursors. Our lab took up the challenge of developing scalable syntheses for making sp3-enriched building blocks that can be further diversified into drug-like fragments. Specifically, we chose piperazine as the target building block due to its desirable properties that render it suitable for modification as part of a drug discovery effort. In doing this, we designed and synthesized piperazine scaffolds with systematically diverse stereochemistry and regiochemistry. We are particularly interested in a three branch family of di-substituted piperazines as starting materials for fragments: 2,3-; 2,5- and 2,6-disubstituted piperazine acetic acids. The syntheses of the 2,3- and 2,6-disubstituted piperazines have been published. The synthetic efforts towards making 2,5-disubstituted piperazines will be discussed in this talk. The key to the successful synthesis is a late stage aza-Michael ring closure. In cases where the ring closure was too diasteroselective to allow for isolation of both target products in the desired quantities, an alternative ring closure pathway was developed that gave the minor diastereomer almost exclusively.

Scalable synthesis of enantiomerically pure 5-substituted-piperazine-2-acetic acid esters as building blocks for library production

2019 Spring National Meeting

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