Total Synthesis of Bicyclic Bioactive Diterpenoids

这项赠款申请的长期目标是集中在全面综合 具有良好生物学特性的天然产物和新合成 方法.开发新的合成方法，简单，有效， 在范围上的普遍性仍然是一个基本的科学追求。这些方法有助于 基础科学的许多需求，使新药物的开发， 其他基本化学结构。天然产品极大地影响了公众 在过去的60年里，作为新药的来源或主导结构， 目前使用的抗生素和癌症治疗药物中有很大一部分是天然的 天然产物或衍生物。该提案描述了设计 并对几种天然产物二萜类化合物进行有效的合成 具有独特且有前途的生物学作用模式。这些合成蓝图 提供对独特的天然产物混合结构的集合的访问。这些 否则难以进入的复合集合将有助于解开和阐明 这些天然产物结构特征中的每一个都具有生物学意义， 预计将是进一步发展和应用的关键。的效率 本文详述的所提出的合成路线通过策略性地使用 不发达的氧化脱芳构化方案。这一机制和范围 强有力的氧化脱芳构化方案将被严格评估， 使不对称变体的开发成为可能，并为未来的 应用.使用这种方法产生的质子的反应性将是 在补助期间设立的。这个补助金申请的目标是完成三个不同类的总合成 双环天然产物。在所有提出的合成方法中， 脱芳构化协议，我们计划在资助期间研究和推进， 作为基石。我们高效的合成路线将被用来创造独特的 自然产品混合收集，将证明在解码这些自然无价的 产品的分子机制，这反过来又有助于推动他们的发展。 本文提出的新的合成方法将使学术界和化学家受益。 制药行业因此直接或间接地影响了发现，研究， 开发和生产新药。

The long term objectives of this grant application are focused on the total syntheses of natural products with promising biological profiles and the development of new synthetic methods. The development of new synthetic methods that are simple, efficient and general in scope continues to be an essential scientific pursuit. Such methods serve many needs of basic science and enable the development of new pharmaceuticals and other essential chemical structures. Natural products have greatly impacted public health over the last sixty years by serving as the source or lead structures for new drugs. A large percentage of currently used antibiotics and cancer therapeutics are natural products or derivatives of natural products. This proposal describes efforts to design and execute efficient synthetic blueprints towards several natural product diterpenoids with unique and promising biological modes of action. These synthetic blueprints will provide access to collections of unique natural product hybrid structures. These otherwise inaccessible compound collections will help unravel and shed light on the biological significance each one of these natural product structural features play, which is expected to be critical for further advancement and applications. The efficiency of the proposed synthetic routes detailed herein are enabled by strategic use of an underdeveloped oxidative dearomatization protocol. The mecahnism and scope of this powerful oxidative dearomatization protocol will be rigorously evaluated in order to enable development of asymmetric variants as well as to provide a blueprint for future applications. The reactivity of the synthons generated using this method will be established during the grant period. The goal of this grant application is to complete total syntheses of three different classes of bicyclic natural products. In all proposed synthetic approaches a perfectly suited dearomatization protocol, which we plan to study and advance during the grant period, serves as the cornerstone. Our efficient synthetic routes will be used to create unique natural product hybrid collections that will prove invaluable in decoding these natural products molecular mechanisms, which in turn should help advance their development. The new synthetic method proposed will benefit chemists both in academia and the pharmaceutical industry thus directly or indirectly impacting the discovery, study, development and production of new drugs.