New Synthetic Chemistries Enabled by Oxyallyl and 2-Aminoallyl Cations

项目摘要/摘要 这项拨款申请描述了我们在合成和合成的增值化合物的生产方面的拟议研究 生物兴趣，使用集中在不对称氧烯丙基和2-甲基-2-羟基的中间体上的新型化学物质 氨基烯丙基阳离子。羟基烯丙基和2-氨基烯丙基阳离子是结构上独特的活性物种。这些中间体有 在纳扎罗夫环合反应和环加成反应中被广泛应用于组装各种络合物 分子结构。尽管有这些众所周知的反应性，但利用亲核捕获的合成方法 区域选择性的不对称氧烯丙基和2-氨基烯丙基阳离子仍未被充分开发。这种缺乏研究的现象 因此，限制了这些多功能中间体的全部合成效用，特别是在药物发现领域。 我们研究计划的长期目标是研究不对称氧烯丙基和不对称烯丙基的合成适用性。 2-氨基烯丙基阳离子技术在化学空间中生成适合于 药物发现中的高通量筛选。这些研究可能导致保护和改善人类健康，这 是美国国立卫生研究院的最终目标。拟议研究的目的是证明不对称氧烯丙基和 2-氨基烯丙基阳离子是一种用途广泛的活性中间体，可以很容易地被利用来生成不同的 与生物和药物相关的分子支架。我们的假设是不对称的氧烯丙基和2- 氨基烯丙基阳离子可以在温和的催化条件下产生，并被广谱的亲核试剂在 通过在其各自的杂原子中引入适当的“保护”基团，以区域选择性的方式将α-碳 中锋。我们已经进行了广泛的初步研究来支持这一假设。 我们预计，拟议研究的完成将使结构新颖的小型 具有不同立体化学和功能的分子，然后可以评估它们的治疗应用。 为了筛选他们的生物学活动，我们参加了礼来公司的开放式创新药物发现(OIDD)。在……里面 事实上，将我们初步研究期间产生的合成产品提交到这个计划中已经产生了有趣的结果 结果。例如，我们的几个化合物被发现对IL-17A和PCSK9具有抑制活性 蛋白质。总体而言，我们的研究将为羟基烯丙基和2-氨基烯丙基的详细合成应用奠定基础 阳离子，使产生的结构独特的小分子作为潜在治疗剂的未来研究成为可能。

PROJECT SUMMARY/ABSTRACT This grant application describes our proposed research in the production of value-added compounds of synthetic and biological interests, using novel chemistries that are centralized in the intermediacy of unsymmetrical oxyallyl and 2- aminoallyl cations. Oxyallyl and 2-aminoallyl cations are structurally unique reactive species. These intermediates have been utilized extensively in the Nazarov-type cyclization as well as cycloaddition reactions to assemble various complex molecular architectures. Despite these well-known reactivity, synthetic methods that harness the nucleophilic capture of unsymmetrical oxyallyl and 2-aminoallyl cations in a regioselective manner remain underexplored. This lack of studies consequently limit the full synthetic utilities of these versatile intermediates particularly in the arena of drug discovery. The long-term goal of our research program is to investigate the synthetic applicability of unsymmetrical oxyallyl and 2-aminoallyl cation technology in generating a library of novel small molecules in the chemical space that are suitable for high throughput screening in drug discovery. These studies could lead to protecting and improving human health, which is the ultimate goal of the NIH. The objective of the proposed research is to demonstrate that unsymmetrical oxyallyl and 2-aminoallyl cations are highly versatile reactive intermediates that could be readily harnessed to produce diverse molecular scaffolds of biological and pharmaceutical relevance. Our hypothesis is that unsymmetrical oxyallyl and 2- aminoallyl cations could be generated under mild catalytic conditions and captured by a broad spectrum of nucleophiles at the α-carbon in a regioselective manner by introducing appropriate “protecting” groups in their respective heteroatom centers. We have conducted extensive preliminary studies to support this hypothesis. We expect that completion of the proposed research will enable the rapid production of structurally novel small molecules with diverse stereochemistry and functionalities, which can be then evaluated for their therapeutic applications. To screen their biological activities, we have participated in the Open Innovation Drug Discovery (OIDD) at Eli Lilly. In fact, submission of synthetic products generated during our preliminary studies to this program has yielded interesting results. For instance, several of our compounds were found to exhibit inhibitory activities against IL-17A and PCSK9 proteins. Overall, our research will lay the foundation for detailed synthetic applications of oxyallyl and 2-aminoallyl cations, enabling future studies of the resulting structurally unique small molecules as potential therapeutic agents.