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: 8059398
• 负责人: Daniel Hohman Paull
• 金额: $ 4.84万
• 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/8059398
• 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; 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）：溴藻内酯A的全合成是一个值得付出巨大努力的目标，因为大环内酯显示出作为抗癌剂的非常高的潜力，但目前整个科学界还无法获得；据我们所知，只有库巴内克和同事可以使用它。一旦找到了合成方法，就可以研究溴藻内酯 A 作为抗癌药物的全部潜力。它的合成给合成化学家带来了一些独特的挑战。其三溴化 15 元环同时具有二萜和苯甲酸酯骨架，它们以一种新型有趣的大环内酯结构结合在一起。这些因素需要新的方法来克服这种结构固有的困难。我们提出了新的关键方法，这些方法不仅具有真正的潜力，可以使全溴藻内酯 A 的不对称合成成为现实，而且可以增强天然产物化学的合成能力。作为该提案的一个亮点，提出了两种不对称溴化的新方法，它们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1-溴化； 2）烯烃的对映选择性和区域选择性溴化以及潜在广泛的串联环化。这两种新方法都将具有广泛的用途，因为它们将为高度有用的合成中间体提供最有效的途径。 公共健康相关性：溴藻内酯 A 的全合成是一个值得付出巨大努力的目标，因为这种海洋天然产物显示出作为抗癌剂的非常高的潜力，但它尚未被合成，目前整个科学界还无法获得。一旦合成方法可用，并且通过所提出的合成路线，我们相信我们可以提供这种方法，就可以研究溴藻内酯 A 作为抗癌药物的全部潜力。此外，我们的建议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。