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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：Bromphycolide A的总合成是一个值得付出的努力的目标，因为大环内酯类作为抗癌剂的潜力很高，但目前对于整个科学界来说，它目前却无法使用。据我们所知，库巴内克和同事只能使用它。一旦获得合成方法，就可以研究Bromphycolide A作为抗癌药物的全部潜力。它的合成对合成化学家构成了一些独特的挑战。它的三溴15人戒指具有二萜和苯甲酸酯骨骼，它们以一种新颖有趣的大花环结构融合在一起。这些因素需要新颖的方法克服了这种结构固有的困难。我们提出了新的关键方法，这些方法具有非常实际的潜力，不仅使Bromophycolide的总体合成是现实，还可以增强天然产品化学的合成曲目。作为该提案的亮点，提出了两种新的非对称溴化方法，它们使用手性亲电的溴化剂来促进：1）酮的对映选择性和区域性选择性1-酮的对映射和区域性选择性。和2）烯烃具有潜在范围的串联循环的烯烃的对映选择性和区域选择性。两种新方法都将具有广泛的实用性，因为它们将为非常有用的合成中间体提供最有效的途径。公共卫生相关性：Bromophycolide A的总合成是一个值得付出的努力的目标，因为海洋天然产品作为抗癌剂具有很高的潜力，但尚未合成，目前对整个科学界都无法使用。一旦获得合成方法，并且通过提出的合成途径，我们认为我们可以提供此方法，可以研究Bromphycolide A作为抗癌药物的全部潜力。此外，我们的建议包括开发新方法，这些方法对有机化学家非常有用，尤其是在海洋天然产物合成领域。