SBIR Phase I: Novel Stereo-enriched Libraries as Commercial Complex Building Blocks for Facile Development of Biologically Active Compounds on Large Scale

SBIR第一阶段项目开发化学工具和平台，以生产有价值的化学构建块，可用于大规模生产具有合成挑战性的化合物。这些化合物属于聚丙酸酯类，在制药、农用化学品和兽医行业的多种适应症中以其多样和强大的生物活性而闻名。聚丙酸酯类的高影响力受到当前化学过程效率低下的阻碍，无法完全处理其复杂的结构。重要的是，缺乏可伸缩性给开发过程增加了另一个严重的复杂性。为了充分释放这一类别的潜力，需要以更高的效率改进化学，以成功地确定进一步开发的高影响候选对象。此外，这些新工具是聚酮？{增强药物发现的优秀底物。该项目是与NCI/NIH合作开发一类针对癌症中罕见和未得到满足的需求的新型化合物的前奏。这种癌症给医疗系统和整个经济带来了巨大的负担。受NSF任务的启发，这个项目描述了一种创新的化学过程，可以提供非常有价值的化合物。这种方法将使多种医药和农用化学品需求的加速发现成为可能。该项目旨在提供所有16种可能的立体四元组分(以手性内酯的形式)，用于在实际规模上构建聚丙酸酯。这些手性构筑块可以作为合成聚丙酸酯的常见前体，作为合理设计和构效关系(SAR)研究的工具，或者作为更多样化和更复杂的类似物库的条目。用于生产这些构建块的化学平台被称为手性碳目录(CCC)。CCC平台是一个合成工具箱，允许从简单的起始材料立体选择性地大规模经济地合成各种复杂的聚丙酸酯积木。统一的工艺经过精心设计，采用了高度非对映选择性底物定向转化，同时避免了昂贵和不切实际的手性辅助管理费用或昂贵的催化剂。转化的高效率使柱层析等繁琐和昂贵的纯化过程得以消除。关键中间体的结晶性质使规模化生产变得容易，并使该平台使用的合成路线很容易被行业采用，以进行大规模生产。这确保了在几个行业(例如，制药和农化领域)中开发复杂手性产品所需的这些构建块的充足供应。

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).