Enantioselective Total Synthesis of Vindoline and Novel Analogs

目的/假设：我们提出开发新的化学环加成物，为构建结构多样的长春花生物碱（包括长春花碱和类似物）提供一种方法。具体目的：(1)设计并合成一个模型系统，探索以烯基硅烷为烯醇醚代物的跨环反电子需求Diels-Alder反应的效用。(2)建立对映选择性环加成级联，组装vindoline核心。(3)完成vindoline及其类似物的对映选择性全合成，为开发新型治疗剂提供机会。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。通过使用这些未开发的功能，我们的目标是开发一种方便的对映选择性合成vindoline。所提出的反应的健壮性也将允许深层结构修饰，为以前无法通过分离或合成获得的类似物的生物学评价提供机会。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，可以解决长春花生物碱的耐药性和总体毒性问题。此外，一种实际的不对称合成vindoline可以证明是目前使用的从植物材料中分离工艺的可行替代方法。

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.