Enantioselective Total Synthesis of Potential Anticancer Drug Bromophycolide A

潜在抗癌药物 Bromophycolide A 的对映选择性全合成

• 批准号: 8211838
• 负责人: Daniel Hohman Paull
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211838
• 关键词: Acetals; Acids; Address; Alcohols; Aldehydes; Alkenes; Amines; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Apoptotic; Area; Benzoates; Binding; Biological Factors; Boranes; Bromine; Candida albicans resistance; Cell Death; Cinchona Alkaloids; Communities; Complex; Cyclization; Cytotoxin; Development; Diterpenes; Enterococcus faecium; Exhibits; Goals; HIV; Halogens; Human; Inhibitory Concentration 50; Iodination reaction; Ions; Ketones; Macrolides; Measurable; Mercury; Methodology; Methods; Modification; Natural Products Chemistry; Nature; Oxygen; Pharmacologic Substance; Polyenes; Quinones; Red Algae; Reporting; Research; Route; Salts; Scheme; Silanes; Skeleton; Structure; System; Testing; Tumor Cell Line; Vancomycin resistant enterococcus; Work; analog; base; catalyst; chlorination; cytotoxicity; enol; infancy; interest; marine natural product; member; methicillin resistant Staphylococcus aureus; novel; programs; public health relevance; salen; silane

DESCRIPTION (provided by applicant): The total synthesis of bromophycolide A is a goal worthy of great effort because the macrolide shows a very high potential as an anticancer agent, yet it is currently unavailable to the scientific community at large; as far as we know, it is only available to Kubanek and coworkers. Once a synthetic method is available, the full potential of bromophycolide A as an anticancer drug can be investigated. Its synthesis poses several unique challenges to the synthetic chemist. Its tri-brominated, 15-member ring possesses both diterpene and benzoate skeletons, which come together in a new and interesting type of macrolide structure. These factors necessitate novel methods overcome the difficulties inherent to such a structure. We have proposed new key methods which have the very real potential not only to make the total, asymmetric synthesis of bromophycolide A a reality, but to enhance the synthetic repertoire of natural products chemistry. As a highlight of this proposal, two new methods for asymmetric bromination are proposed, which use a chiral electrophilic brominating agent to promote: 1) the enantioselective and regioselective 1-bromination of ketones; and 2) the enantioselective and regioselective bromination of olefins with tandem cyclizations of potentially vast scope. Both new methods will have widespread utility as they will provide the most efficient route to highly useful synthetic intermediates. PUBLIC HEALTH RELEVANCE: The total synthesis of bromophycolide A is a goal worthy of great effort because the marine natural product shows a very high potential as an anticancer agent, yet it has not been synthesized and is currently unavailable to the scientific community at large. Once a synthetic method is available, and by the proposed synthetic route we believe we can provide this method, the full potential of bromophycolide A as an anticancer drug can be investigated. Additionally, our proposal includes development of new methods that will be highly useful to organic chemists, particularly in the area of marine natural product synthesis.

描述(申请人提供)：完全合成溴植内酯A是一个值得付出巨大努力的目标，因为大环内酯显示出非常高的抗癌潜力，但目前科学界普遍无法获得；据我们所知，只有库巴内克和同事才能获得。一旦有了一种合成方法，就可以研究溴植酯A作为抗癌药物的全部潜力。它的合成对合成化学家提出了几个独特的挑战。它的三溴15元环同时具有二萜和苯甲酸骨架，这两种骨架聚集在一起形成了一种新的有趣的大环内酯结构。这些因素需要新的方法来克服这种结构所固有的困难。我们已经提出了新的关键方法，这些方法不仅有可能实现溴植酸酯A的完全不对称合成，而且还可以提高天然产物化学的合成能力。作为这一建议的一个亮点，提出了两种不对称溴化反应的新方法，这两种方法使用手性亲电溴化剂来促进：1)酮的对映选择性和区域选择性的1-溴化反应；2)烯烃的对映选择性和区域选择性的溴化反应。这两种新方法都将具有广泛的实用性，因为它们将提供获得高度有用的合成中间体的最有效途径。 与公共卫生相关：完全合成溴植酯A是一个值得努力的目标，因为这种海洋天然产物显示出非常高的抗癌潜力，但它还没有被合成，目前还不能为科学界所用。一旦一种合成方法可用，通过所提出的合成路线，我们相信我们可以提供这种方法，溴植酯A作为抗癌药物的全部潜力可以被研究。此外，我们的建议还包括开发对有机化学家非常有用的新方法，特别是在海洋天然产物合成领域。