New Synthetic Chemistries Enabled by Oxyallyl and 2-Aminoallyl Cations

项目概要/摘要 该资助申请描述了我们在合成和合成的增值化合物生产方面的拟议研究。 生物学的兴趣，使用新的化学集中在中间体的不对称的氧烯丙基和2- 氨基烯丙基阳离子。氧烯丙基和2-氨基烯丙基阳离子是结构独特的反应物种。这些中间体具有 在Nazarov型环合反应和环加成反应中， 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仍然存在。 不对称的氧代烯丙基和2-氨基烯丙基阳离子以区域选择性的方式仍然未被探索。缺乏研究 因此限制了这些通用中间体的完全合成应用，特别是在药物发现的竞技场中。 我们研究计划的长期目标是研究不对称氧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产生新的小分子库， 药物发现中的高通量筛选。这些研究可以保护和改善人类健康， 是NIH的终极目标提出的研究的目的是证明，不对称的氧烯丙基和 2-氨基烯丙基阳离子是高度通用的反应性中间体，其可以容易地利用以产生多种 生物和药物相关的分子支架。我们的假设是，不对称的羟烯丙基和2- 氨基烯丙基阳离子可以在温和的催化条件下产生，并被广谱亲核试剂捕获， 通过在它们各自的杂原子中引入适当的“保护”基团， 中心.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，完成拟议的研究将使快速生产结构新颖的小 分子具有不同的立体化学和功能，然后可以评估其治疗应用。 为了筛选它们的生物活性，我们参加了礼来公司的开放式创新药物发现（OIDD）。在 事实上，在我们对该计划的初步研究中产生的合成产品的提交已经产生了有趣的结果。 结果例如，发现我们的几种化合物显示出对IL-17 A和PCSK 9的抑制活性 proteins.总的来说，我们的研究将为氧烯丙基和2-氨基烯丙基的详细合成应用奠定基础 阳离子，使未来的研究所产生的结构独特的小分子作为潜在的治疗剂。

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.