Enantioselective Total Synthesis of Vindoline and Novel Analogs

描述(申请人提供)：目的/假设：我们建议开发新的化学环加成化合物，以提供一种构建结构多样化的长春花碱的方法，包括长春花碱及其类似物。具体目标：(1)设计并合成一个模型体系，探索以烯基硅烷作为烯醇醚替代物的跨环反电子需求Diels-Alder反应的应用。(2)开发了一种用于组装长春花碱核心的对映体选择性环加成反应。(3)完成长春花碱及其类似物的对映选择性全合成，为开发新型治疗药物提供了机会。研究设计：受Boger最近开发的新型环加成化学的启发，我们设想将该化学扩展到烯基硅烷。通过利用这些未被开发的功能，我们的目标是开发一种简便的长春花碱的对映选择性合成方法。拟议反应的强健性质还将允许进行深层次的结构修改，为以前无法通过分离或合成获得的类似物提供生物学评价的机会。癌症相关性：通过使用创新的化学合成和来自天然产品的灵感，我们可以设计出显著修饰的化合物，可能解决长春花碱的耐药性和整体毒性特征。此外，一种实用的不对称合成长春花碱可能被证明是一种可行的替代目前使用的从植物材料中分离的方法。 与公共健康相关：长春花碱为抗击侵袭性癌症做出了重大贡献，但迄今为止，这些努力仅限于天然化合物及其简单的衍生物。尽管大自然为我们提供了具有令人印象深刻的、往往是独特的生物活性的化合物，但这些结构并不是为了治疗人类疾病而进化出来的。通过使用创新的化学合成和从大自然美丽的创造中获得的灵感，我们可以设计出显著改进的化合物，这些化合物可能会解决已形成的抵抗力和整体毒性特征。

DESCRIPTION (provided by applicant): Objective/Hypothesis: We propose the development of novel chemical cycloadditons to provide a method for the construction of structurally diverse Vinca alkaloids, including vindoline and analogs. Specific Aims: (1) Design and synthesize a model system to explore the utility of transannular inverse electron demand Diels-Alder reactions employing alkenyl silanes as enol ether surrogates. (2) Develop an enantioselective cycloaddition cascade to assemble the core of vindoline. (3) Complete an enantioselective total synthesis of vindoline and analogs, providing an opportunity for the development of novel therapeutic agents. Study design: Inspired by novel cycloaddition chemistry recently developed by Boger, we envision extending this chemistry to alkenyl silanes. Through the use of these under-explored functionalities, we aim to develop an expedient enantioselective synthesis of vindoline. The robust nature of the proposed reaction will also allow for deep-seated structural modifications that provide opportunity for biological evaluation of analogs previously unavailable by isolation or synthesis. Cancer relevance: Though the use of innovative chemical synthesis and inspiration from natural products, we can design significantly modified compounds that may address the developed resistance and overall toxicity profiles of the Vinca alkaloids. Additionally, a practical asymmetric synthesis of vindoline could prove a viable alternative to the currently used isolation process from plant materials. PUBLIC HEALTH RELEVANCE: The Vinca alkaloids have contributed significantly to the fight against aggressive cancer, but to date these efforts have been limited to the natural compounds and simple derivatives thereof. Although nature provides us with compounds possessing impressive and often unique biological activity, these structures were not evolved for the treatment of human disease. Through the use of innovative chemical synthesis and inspiration from nature's beautiful creations, we can design significantly modified compounds that may address developed resistance and overall toxicity profiles.