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

SBIR一期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挑战性的合成化合物。这些化合物属于聚丙酸酯类，以其在制药、农化和兽医行业的多种适应症中具有多样化和强大的生物活性而闻名。聚丙酸酯类的高影响受到当前化学工艺效率低下的阻碍，无法充分处理其复杂的结构。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，需要改进化学性质，提高效率，以成功识别具有高影响的候选物，以便进一步开发。此外，新工具是聚酮化合物的优良底物。{加强药物发现。该项目是与NCI/NIH合作开发一种新型化合物的前奏，用于治疗癌症中罕见和未满足的需求。这类癌症给医疗保健系统和整体经济带来了巨大的负担。受NSF使命的启发，该项目描述了一种创新的化学过程，可以提供高价值的化合物。这种方法将加速发现多种医药和农用化学品的需求。该项目旨在提供所有16种可能的立体四聚体构建块（以手性内酯的形式），用于实际规模的聚丙酸酯构建。这些手性构建块可以作为聚丙酸酯合成的共同前体，作为合理设计和结构活性关系（SAR）研究的工具，或作为更多样化和复杂的类似物库的入口。用于生产这些积木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大规模经济合成各种复杂的聚丙酸构建块。该统一工艺经过精心设计，采用高度非对映选择性的底物定向转化，同时避免昂贵和不切实际的手性辅助开销或昂贵的催化剂。转换的高效率允许消除繁琐和昂贵的净化，如柱色谱法。关键中间体的结晶性质使大规模生产变得容易，并且允许平台使用的合成路线很容易被工业大规模生产所采用。这确保了在几个行业（例如制药和农化领域）开发复杂手性产品的这些构建块的充分供应。

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).