Total Synthesis of Bicyclic Bioactive Diterpenoids

双环生物活性二萜类化合物的全合成

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7742659
• 关键词: Academia; Antibiotics; Applications Grants; Architecture; Area; Basic Science; Biological; Biological Factors; Biological Process; Biology; Chemical Structure; Chemicals; Collection; Complex; Cyclization; Development; Discipline; Diterpenes; Drug Industry; Evaluation; Exhibits; Future; Goals; Grant; Hybrids; Laboratories; Lead; Light; Link; Malignant Neoplasms; Medicine; Methods; Molecular; Mono-S; Organic Chemistry; Organometallic Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Play; Production; Protocols documentation; Public Health; Quinones; Research; Research Personnel; Route; Side; Source; Structure; Therapeutic; Universities; Variant; analog; base; carboxylate; design; garsubellin A; hyperforin; ketal; nemorosone; novel; programs; public health relevance; urinary gonadotropin fragment

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）：该资助申请的长期目标集中在具有有前途的生物学特性的天然产物的全合成和新合成方法的开发上。开发简单、有效和通用的新合成方法仍然是一项重要的科学追求。这些方法满足了基础科学的许多需求，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先导结构，极大地影响了公众健康。目前使用的抗生素和癌症治疗剂中有很大一部分是天然产物或天然产物的衍生物。该提案描述了设计和执行高效合成蓝图的努力，以实现几种具有独特和有前途的生物作用模式的天然产物二萜类化合物。这些合成蓝图将提供独特的天然产物混合结构的集合。这些原本无法获得的化合物集合将有助于揭示和阐明这些天然产物结构特征中的每一个所发挥的生物学意义，预计这对进一步的发展和应用至关重要。本文详述的所提出的合成路线的效率通过策略性地使用不发达的氧化脱芳构化方案来实现。这种强大的氧化脱芳构化协议的机制和范围将被严格评估，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间确定。公共卫生相关性：该资助申请的目标是完成三种不同类别的双环天然产物的全合成。在所有提出的合成方法中，我们计划在赠款期间研究和推进的一个非常合适的脱芳构化协议是基石。我们高效的合成路线将被用于创建独特的天然产物杂交集合，这将证明在解码这些天然产物的分子机制方面是非常宝贵的，这反过来又有助于促进它们的发展。提出的新合成方法将使学术界和制药工业的化学家受益，从而直接或间接地影响新药的发现，研究，开发和生产。