Asymmetric Reaction Technologies for the Synthesis of Chemotherapeutic Agents

描述（由申请人提供）：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，药物化学中药物开发工作的很大一部分是致力于合成用于筛选候选药物的化合物。无论药物开发工作是针对特定的生物活性靶点，还是针对选定的衍生物库的合成，这些努力的成功都严重依赖于有机合成方法的同步发展，这种方法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，本提案详细介绍了新的有机反应方法的发展，旨在有效和经济地获得生物活性有机化合物。为了实现这一目标，我们将开发必要的反应技术，以实现催化合成聚丙酸衍生天然产物的总体策略。作为重复乙酸或丙酸单元的聚酮化合物的组成使得利用同源单体单元迭代安装的模块化合成策略成为一种有吸引力的合成策略。因此，我们将开发一种模块化策略，用于催化不对称构建立体化学多样化的聚丙酸网络。这些反应发展活动与医学研究和人类健康问题的相关性在高选择性凋亡调节剂apoptolidin c的从头对映选择性全合成中得到了例证。杂环小分子是新药、重要先导化合物和市售药物中最普遍存在的特征之一。由于杂环在药物开发中的核心作用，新的[4+2]和[2+2]环加成化合物家族的发展分别用于高取代哌啶和2-内酰胺衍生物的不对称合成。此外，努力开发这些环加成的催化不对称变体旨在最大限度地利用这些反应在工业药物和过程化学研究中。4.4.7。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，药物化学中药物开发工作的很大一部分是致力于合成用于筛选候选药物的化合物。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，并为靶向和多样性导向的合成提供新的策略。

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.