Total Synthesis of Bicyclic Bioactive Diterpenoids

描述(由申请人提供)：这项赠款申请的长期目标集中在具有良好生物学特性的天然产品的全合成和新合成方法的开发上。开发简单、高效和范围广泛的新的合成方法仍然是一项基本的科学追求。这种方法服务于基础科学的许多需要，并使新药物和其他基本化学结构的开发成为可能。在过去的60年里，天然产品作为新药的来源或主要结构，极大地影响了公众的健康。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产品或天然产品的衍生品。该提案描述了为几种具有独特和有前景的生物作用模式的天然产物二萜类化合物设计和执行有效合成蓝图的努力。这些合成蓝图将提供独特的天然产品混合结构的集合。这些原本难以获取的化合物收集将有助于解开和阐明这些天然产品结构特征中的每一个所起的生物学意义，预计这将是进一步发展和应用的关键。通过战略性地使用未开发的氧化脱芳构化协议，能够提高在此详述的建议合成路线的效率。将严格评估这一强大的氧化脱芳构化协议的机理和范围，以便能够开发不对称变体，并为未来的应用提供蓝图。使用这种方法产生的合成子的反应性将在授权期内确定。与公共健康相关：这项赠款申请的目标是完成三种不同类别的双环天然产品的全合成。在所有建议的合成方法中，一个非常适合的脱芳构化协议是基石，我们计划在授权期内研究和推进该协议。我们的高效合成路线将被用于创建独特的天然产品杂交收藏，这些收藏将被证明在破译这些天然产品的分子机制方面具有无价的价值，这反过来应该有助于推动它们的发展。建议的新合成方法将使学术界和制药行业的化学家受益，从而直接或间接地影响新药的发现、研究、开发和生产。

DESCRIPTION (provided by applicant): 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 mechanism 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. PUBLIC HEALTH RELEVANCE: 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.