New catalytic methods for the synthesis of oxazine natural products

合成恶嗪天然产物的新催化方法

• 批准号: 8667256
• 负责人: Oleg V Larionov
• 金额: $ 11.03万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-11 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667256
• 关键词: Action Potentials; Affect; Antineoplastic Agents; Area; Biological; Biological Assay; Biological Factors; Biomedical Research; Calculi; Catalysis; Categories; Cyclization; Development; Disease; Evaluation; Exhibits; FDA approved; Funding; Future; Generations; Goals; Grant; Health Sciences; Homologous Gene; Hydrogen Bonding; Hydrophobic Interactions; Inflammation; Lead; Libraries; Life; Malignant Neoplasms; Medicine; Metals; Methodology; Methods; Modification; Molecular Bank; NCI Center for Cancer Research; Oximes; Pharmaceutical Preparations; Play; Positioning Attribute; Property; Quinones; Reaction; Research; Research Personnel; Role; Route; Sampling; Source; Structure-Activity Relationship; Therapeutic; United States National Institutes of Health; analog; base; cancer therapy; career; cost; design; drug candidate; drug discovery; enantiomer; flexibility; improved; innovation; member; multidisciplinary; novel; public health relevance; repository; screening; small molecule

DESCRIPTION (provided by applicant): Natural products have played a pivotal role in the discovery and development of modern chemotherapeutics. Thus, the genesis of more than 70% of all small molecule anti-cancer medicines approved in the last 70 years can be traced to natural products. Although the key role of natural products in drug discovery remains uncontested few of them have undergone comprehensive structure-activity relationship (SAR) studies and exhaustive bioactivity screenings. This is primarily due to the prevailing scarcity of the natural products compounded with limited options for structural modifications which are necessary for the SAR studies. Synthesis of these natural products offers the opportunity to access the natural product and its numerous congeners through changes in the synthetic strategy. Due to the limited number of reliable enantioselective catalytic reactions many syntheses rely on the elaboration of chiral starting materials along circuitous synthetic routes. This affects the efficiency and narrows flexibility and applicability of the syntheses. The 1,2-oxazine natural products have been particularly affected by this shortcoming. This is a serious limitation for the discovery of new chemotherapeutics since many of these natural products possess unique and exciting biological activities. We aim to make the 1,2-oxazine core readily accessible through rational design of a novel enantioselective and catalytic cyclization reaction. We will also develop a straightforward methodology for the conversion of the cyclization products to the 1,2-oxazine natural products and their structural analogs that are unattainable using currently available methods. This methodology will then be employed for the synthesis of two 1,2-oxazine natural products that possess unique anti-cancer activities. This approach is based on the unprecedented catalytic enantioselective cyclization reaction and is innovative because (a) it has the potential to combine the undisputed efficiency and practicality of a catalytic asymmetric method with the ready availability of both precursors; and (b) the asymmetric cyclization reaction will allow rapid access to a variety of structurally related natura products by way of simple structural editing. These studies will improve our understanding of their biological properties and will potentially provide new leads for anti-cancer drug discovery.

描述（由申请人提供）：天然产品在现代化学治疗药的发现和开发中发挥了关键作用。因此，在过去70年中批准的所有小分子抗癌药物中，超过70％的起源可以追溯到天然产物。尽管天然产物在药物发现中的关键作用仍然无可争议。这主要是由于天然产物的普遍稀缺性，对SAR研究所需的结构修饰的选择有限。这些天然产品的合成提供了机会，可以通过改变合成策略来获取天然产品及其众多同类产品。由于可靠的对映选择性催化反应的数量有限，许多合成依赖于沿圆形合成途径的手性起始物质的阐述。这会影响合成的效率和范围，并缩小合成的灵活性和适用性。 1,2-恶嗪天然产品受到这种缺点的影响。这是发现新化学治疗剂的严重限制，因为这些天然产品中的许多都具有独特而令人兴奋的生物学活动。我们的目的是通过合理设计新颖的对映选择性和催化环化反应来使1,2-恶嗪核心容易访问。我们还将开发一种直接的方法，用于将环化产品转化为1,2-恶嗪天然产品及其结构类似物，这些方法是使用当前可用方法无法实现的。然后，该方法将用于合成具有独特抗癌活性的两种1,2-恶嗪天然产品。这种方法基于前所未有的催化对映选择性环化反应，并且具有创新性，因为（a）它有可能将催化不对称方法的无可争辩的效率和实用性与两个先驱者的现成可用性相结合； （b）不对称环化反应将通过简单的结构编辑方式快速访问各种结构相关的自然产品。这些研究将提高我们对其生物学特性的理解，并有可能为抗癌药物发现提供新的潜在客户。