Enantioselective Total Synthesis of Vindoline and Novel Analogs

Vindoline 和新型类似物的对映选择性全合成

• 批准号: 7802667
• 负责人: Joshua G. Pierce
• 金额: $ 4.72万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802667
• 关键词: Address; Alder plant; Alkaloids; Alkenes; Amides; Area; Biological; Biological Factors; Biological Models; Breathing; Cancer Biology; Catalysis; Catharanthus roseus; Cell Line; Chemicals; Chemistry; Childhood Leukemia; Development; Diels Alder reaction; Digit structure; Electrons; Environment; Epoxy Compounds; Esters; Ethers; Evaluation; Hodgkin Disease; Indoles; Inhibitory Concentration 50; Investigation; Lactams; Left; Malignant Neoplasms; Methods; Microtubules; Mitosis; Modification; Names; Nature; Navelbine ditartrate; Organic Synthesis; Oxadiazoles; Plant Leaves; Plants; Play; Process; Reaction; Relative (related person); Research; Research Design; Resistance; Resistance development; Role; Route; Scheme; Side; Silanes; Structure; Temperature; Therapeutic Agents; Toxic effect; Variant; Vinblastine; Vinca Alkaloids; Vincristine; Vindoline; Weight; Work; analog; antitumor agent; cancer therapy; carbonyl group; chemical synthesis; cycloaddition; cytotoxicity; design; enol; fight against; functional group; human disease; innovation; novel; novel therapeutics; public health relevance; scaffold; silane; stereochemistry; success; ylide

DESCRIPTION (provided by applicant): Objective/Hypothesis: We propose the development of novel chemical cycloadditons to provide a method for the construction of structurally diverse Vinca alkaloids, including vindoline and analogs. Specific Aims: (1) Design and synthesize a model system to explore the utility of transannular inverse electron demand Diels-Alder reactions employing alkenyl silanes as enol ether surrogates. (2) Develop an enantioselective cycloaddition cascade to assemble the core of vindoline. (3) Complete an enantioselective total synthesis of vindoline and analogs, providing an opportunity for the development of novel therapeutic agents. Study design: Inspired by novel cycloaddition chemistry recently developed by Boger, we envision extending this chemistry to alkenyl silanes. Through the use of these under-explored functionalities, we aim to develop an expedient enantioselective synthesis of vindoline. The robust nature of the proposed reaction will also allow for deep-seated structural modifications that provide opportunity for biological evaluation of analogs previously unavailable by isolation or synthesis. Cancer relevance: Though the use of innovative chemical synthesis and inspiration from natural products, we can design significantly modified compounds that may address the developed resistance and overall toxicity profiles of the Vinca alkaloids. Additionally, a practical asymmetric synthesis of vindoline could prove a viable alternative to the currently used isolation process from plant materials. PUBLIC HEALTH RELEVANCE: The Vinca alkaloids have contributed significantly to the fight against aggressive cancer, but to date these efforts have been limited to the natural compounds and simple derivatives thereof. Although nature provides us with compounds possessing impressive and often unique biological activity, these structures were not evolved for the treatment of human disease. Through the use of innovative chemical synthesis and inspiration from nature's beautiful creations, we can design significantly modified compounds that may address developed resistance and overall toxicity profiles.

描述（由申请人提供）： 目的/假设：我们建议开发新型化学环加成物，以提供一种构建结构多样的长春花生物碱（包括文多灵和类似物）的方法。具体目标：（1）设计并合成一个模型系统，以探索使用烯基硅烷作为烯醇醚替代物的跨环逆电子需求狄尔斯-阿尔德反应的效用。 (2)开发对映选择性环加成级联来组装vindoline核心。 （3）完成文多林及其类似物的对映选择性全合成，为新型治疗药物的开发提供了契机。研究设计：受到 Boger 最近开发的新型环加成化学的启发，我们设想将这种化学扩展到烯基硅烷。通过使用这些尚未开发的功能，我们的目标是开发一种方便的文多林对映选择性合成方法。所提出的反应的稳健性质还将允许进行深层次的结构修饰，从而为以前无法​​通过分离或合成获得的类似物进行生物学评估提供机会。癌症相关性：通过使用创新的化学合成和天然产品的灵感，我们可以设计经过显着修饰的化合物，这些化合物可以解决长春花生物碱所产生的耐药性和总体毒性特征。此外，文多灵的实用不对称合成可以证明是目前使用的植物材料分离工艺的可行替代方案。 公共健康相关性：长春花生物碱对对抗侵袭性癌症做出了重大贡献，但迄今为止，这些努力仅限于天然化合物及其简单衍生物。尽管大自然为我们提供了具有令人印象深刻且通常独特的生物活性的化合物，但这些结构并不是为了治疗人类疾病而进化的。通过使用创新的化学合成和从大自然美丽的创造中获得的灵感，我们可以设计经过显着修饰的化合物，以解决已产生的耐药性和总体毒性特征。