Synthesis of Biologically Significant Cyclopropanes

这个更新项目的中心是合成方法的发展及其在生物相关的含环丙烷靶点的合成中的应用，包括组蛋白去乙酰化酶抑制剂、组胺H3拮抗剂和抗真菌天然产物ambruticin。将研究与苯基和环丙基甲醇衍生物的阳离子环丙烷化反应，包括详细研究环闭合反应的立体化学完整性，重点是反应条件的影响（溶剂极性和离去基效应）。该方法将应用于新型环丙基取代组蛋白去乙酰化酶抑制剂的合成。研究α -杂芳烃取代对阳离子环化过程立体化学完整性的影响，并将其应用于一系列H3受体拮抗剂的合成。研究了烯丙醇的活化和环闭合，并将其应用于结构复杂的抗真菌聚酮胺的合成。通过这个奖项，有机和大分子化学项目支持圣母大学化学和生物化学系Richard E. Taylor博士的研究。泰勒教授和他的学生将设计和开发新的方法来控制合成含有环丙烷（三元环）单元的有机分子。这类化合物的合成通常需要特殊的技术，考虑到三元环上存在的菌株，但它们是许多有趣的天然化合物以及潜在的药物制剂的基础，包括治疗涉及睡眠、食物摄入、体温调节和记忆形成的疾病的药物。PI在这一领域的初步发现已经过渡到化学工业，在那里它们被用来促进新的候选药物的发现。

This renewal project centers on the development of synthetic methodology and its application towards the synthesis of biologically relevant cyclopropane-containing targets including histone deacetylase inhibitors, histamine H3 antagonists, and the anti-fungal natural product ambruticin. Cationic cyclopropanation reactions with benzylic and cyclopropylmethyl alcohol derivatives will be investigated, including a detailed study of the stereochemical integrity of the ring closure reaction, with emphasis on the effect of reaction conditions (solvent polarity and leaving group effects). This methodology will be applied in the synthesis of novel cyclopropyl-substituted histone deacetylase inhibitors. The effect of alpha-heteroaromatic substitution on the stereochemical integrity of the cation cyclization process will be investigated, and this chemistry will be applied toward the synthesis of a series of H3 receptor antagonists. The activation and ring closure of allylic alcohols will be investigated, and this chemistry will be applied toward the synthesis of the architecturally complex anti-fungal polyketide ambruticin.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Richard E. Taylor of the Department of Chemistry and Biochemistry at the University of Notre Dame. Professor Taylor and his students will devise and develop new methods for the controlled synthesis of organic molecules containing cyclopropane (three-membered ring) units. Such compounds often require special techniques for their synthesis, given the strain present in the three-membered ring, yet form the basis of a number of interesting naturally occurring compounds as well as potential pharmaceutical agents, including therapeutic agents for disorders involving sleep, food intake, thermoregulation, and memory formation. The PI's initial discoveries in this area are already transitioning into the chemical industry, where they are being used to facilitate the discovery of new drug candidates.