Asymmetric Reaction Technologies for the Synthesis of Chemotherapeutic Agents

描述(申请人提供)：基于小分子的药物继续为开发治疗大多数人类疾病的治疗策略提供基础。因此，药物化学中很大一部分药物开发工作致力于化合物的合成，以筛选候选药物。无论药物开发是针对特定的生物活性靶点还是合成选定的衍生物库，这些努力的成功都关键取决于有机合成方法学的同步发展，这种方法学允许有效和经济地制备目标材料。认识到化学和工业药物开发之间存在的协同作用，该提案详细说明了开发新的有机反应方法，旨在高效和经济地获取具有生物活性的有机化合物。为了实现这一目标，我们将开发必要的反应技术，以实现聚丙酸酯衍生天然产物的催化合成的一般策略。聚酮的组成为重复的醋酸或丙酸单元，这使得模块化合成策略成为一种有吸引力的合成策略，它利用了同源单体单元的迭代安装。因此，我们将开发一种用于催化不对称构建立体化学多样性的聚丙酸酯网络的模块化策略。这些反应发展活动与药物研究和人类健康问题的相关性在高选择性细胞凋亡调节剂Aoptolidin C的从头合成的对映选择性全合成中得到了例证。杂环小分子是新药、重要的先导化合物和商业可用药物最普遍的特征之一。[4+2]和[2+2]环加成反应分别用于高取代哌啶和2-内酰胺衍生物的不对称合成，这是受到杂环在药物开发中的中心作用的启发而发展起来的。此外，开发这些环加成反应的催化不对称变体的努力旨在最大限度地利用这些反应在工业、医药和过程化学研究中的效用。项目叙述基于小分子的药物继续为开发治疗大多数人类疾病的治疗策略提供基础。因此，药物化学中很大一部分药物开发工作致力于化合物的合成，以筛选候选药物。基于这些考虑，我们将开发新的反应技术来加速小分子化疗药物的合成，并使新的靶向和多样性定向合成策略成为可能。

DESCRIPTION (provided by applicant): Small molecule-based drugs continue to provide the foundation for developing therapeutic strategies for treating of most human illnesses. A substantial portion of drug development efforts within medicinal chemistry is, therefore, devoted to the synthesis of compounds for screening as drug candidates. Whether drug development efforts are directed toward specific bioactive targets or the synthesis of a library of selected derivatives, success in these endeavors is critically dependent on concurrent developments in organic synthesis methodology that allows the efficient and economical preparation of the targeted materials. Recognizing the synergism existing between chemistry and industrial drug development, this proposal details the development of new organic reaction methodology designed to access biologically active organic compounds efficiently and economically. Toward this goal, we will develop the reaction technology necessary to realize a general strategy for the catalytic synthesis of polypropionate-derived natural products. The composition of polyketides as repeating acetic or propionic acid units makes a modular synthesis strategy exploiting iterative installation of homologous monomer units an attractive synthesis strategy. Thus, we will develop a modular strategy for the catalytic asymmetric construction of stereochemically diverse polypropionate networks. The relevance of these reaction development activities to medicinal research and human health issues is exemplified in a de novo enantioselective total synthesis of the highly selective apoptosis regulator apoptolidin C. Heterocyclic small molecules are among the most ubiquitous features of new drug hits, important lead compounds, and commercially available pharmaceuticals. The development of a novel family of [4+2] and [2+2] cycloadditions for the asymmetric synthesis of highly substituted piperidine and 2-lactam derivatives, respectively, is inspired by the central role heterocycles play in pharmaceutical drug development efforts. Furthermore, efforts to develop catalytic asymmetric variants of these cycloadditions are intended to maximize the utility of these reactions in industrial medicinal and process chemical research.4.4.7. PROJECT NARRATIVE Small molecule-based drugs continue to provide the foundation for developing therapeutic strategies for treating of most human illnesses. A substantial portion of drug development efforts within medicinal chemistry is, therefore, devoted to the synthesis of compounds for screening as drug candidates. Based on these considerations, we will develop new reaction technologies for accelerating the synthesis of small molecule chemotherapeutic agents and that enable new strategies for target- and diversity-oriented synthesis.