Enantioselective Total Synthesis of Vindoline and Novel Analogs

描述（由申请人提供）：目的/假设：我们提出开发新的化学环加成剂，以提供一种用于构建结构多样的阿巴拉生物碱（包括文多灵和类似物）的方法。具体目标：（1）设计并合成了一个模型体系，以探索以烯基硅烷为烯醇醚替代物的跨环反电子需求Diels-Alder反应的实用性。(2)发展一个对映选择性环加成级联反应来组装文多灵的核心。(3)完成了文多灵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，我们设想将这种化学扩展到烯基硅烷。通过使用这些未被探索的功能，我们的目标是开发一个方便的文多灵的对映选择性合成。所提出的反应的稳健性质还将允许深层结构修饰，这为以前通过分离或合成不可用的类似物的生物学评价提供了机会。癌症相关性：通过使用创新的化学合成和来自天然产物的灵感，我们可以设计出显著修饰的化合物，这些化合物可能会解决胡枝子生物碱的耐药性和整体毒性特征。此外，文多灵的实际不对称合成可以证明是目前使用的从植物材料中分离过程的可行替代方案。 公共卫生相关性：胡枝子生物碱对对抗侵袭性癌症有显著贡献，但迄今为止，这些努力仅限于天然化合物及其简单衍生物。尽管大自然为我们提供了具有令人印象深刻且通常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的。通过使用创新的化学合成和灵感来自大自然的美丽的创作，我们可以设计显着修改的化合物，可以解决发展的阻力和整体毒性概况。

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.