This SBIR Phase I project develops chemical tools and platforms to produce valuable chemical building blocks that can be used to produce synthetically challenging compounds on large scales. These compounds belong to the class of polypropionates which is known for its diverse and powerful biological activities across multiple indications within the pharmaceutical, agrochemical, and veterinary industries. The high impact of the polypropionate class is hampered by the inefficiencies of current chemical processes to fully tackle their complex structures. Importantly, the lack of scalability adds another severe complication to the development process. To fully unlock the potential of this class, improved chemistries with greater efficiencies are required to successfully identify high impact candidates for further development. Moreover, the new tools are excellent substrates for polyketide?{enhanced drug discovery. This project is a prelude to the development of a novel class of compounds against rare and unmet needs in cancer in collaboration with the NCI/NIH. Such cancers pose a huge burden on the healthcare system and the economy in general. Inspired by the NSF mission, this project describes an innovative chemical process that can deliver highly valuable compounds. Such an approach will enable accelerated discoveries across multiple medicinal and agrochemical needs.
This project aims to provide all sixteen possible stereotetrad building blocks (in the form of chiral lactones) for construction of polypropionates on practical scales. Those chiral building blocks can serve as common precursors for synthesis of polypropionates, as tools for rational design and structure activity relationship (SAR) studies, or as entries for more diverse and complex library of analogs. The chemistry platform used to produce those building blocks is referred to as the Chiral Carbon Catalog (CCC). The CCC platform is a synthetic tool box that allows stereoselective large scale economic synthesis of various complex polypropionate building blocks from simple starting materials. The unified process has been carefully designed to employ highly diastereoselective substrate directed transformations while avoiding expensive and impractical chiral auxiliary overheads or expensive catalysts. The high efficiencies of transformations allow the elimination of tedious and expensive purifications such as column chromatography. The crystalline natures of key intermediates enable facile production on scale and allow the synthetic routes used by the platform to be easily adopted by the industry for large scale production. This ensures adequate supply of those building blocks for development of complex chiral products within several industries (e.g. pharmaceutical and agrochemical fields).
