Total Synthesis of Bicyclic Bioactive Diterpenoids

双环生物活性二萜类化合物的全合成

基本信息

批准号：
7742659
负责人：
JON T NJARDARSON
金额：
$ 26.8万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2010-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：本赠款申请的长期目标集中于具有有希望的生物学特征的天然产品的总合成和新合成方法的发展。在范围中简单，高效且普遍的新合成方法的发展仍然是一项基本的科学追求。这样的方法满足了基础科学的许多需求，并能够开发新的药物和其他必要的化学结构。在过去的六十年中，天然产品通过充当新药的来源或铅结构，极大地影响了公共卫生。当前使用的抗生素和癌症治疗中很大一部分是天然产物的天然产物或衍生物。该提案描述了针对具有独特且有前途的生物学作用模式的几种天然产物二萜类化合物设计和执行高效合成蓝图的努力。这些合成的蓝图将为独特的天然产品混合结构的收集提供访问。这些原本无法访问的复合收集将有助于解开并阐明这些天然产品结构特征的每一个生物学意义，这对于进一步的进步和应用至关重要。通过战略使用欠发达的氧化型亲爱的协议，可以实现此处详细介绍的拟议合成路线的效率。将严格评估这种强大的氧化亲爱的人的机制和范围，以便开发不对称变体，并为将来的应用提供蓝图。使用此方法生成的合成子的反应性将在赠款期间建立。公共卫生相关性：该赠款申请的目的是完成三种不同类别的双环天然产品的总合成。在所有提出的合成方法中，我们计划在赠款期间研究和进步的非常适合的亲爱的协议，都是基石。我们有效的合成路线将用于创建独特的天然产品混合集合，这在解码这些天然产品分子机制方面将是无价的，这反过来又有助于推动其发展。提出的新合成方法将使学术界和制药行业的化学家受益，从而直接或间接影响新药的发现，研究，开发和生产。