Synthesis of Amaryllidaceae Alkaloids via Palladium Catalysis

钯催化合成石蒜科生物碱

• 批准号: 7473984
• 负责人: Amanda Catherine Jones
• 金额: $ 4.68万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-02 至 2010-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473984
• 关键词: Alkaloids; Alkenes; Amaryllidaceae Alkaloids; Amines; Antineoplastic Agents; Biological Factors; Breathing; Bromides; Carbon; Catalysis; Complex; Condition; Coupling; Electrons; Family; Figs - dietary; Galantamine; Goals; Isomerism; Lead; Ligands; Malignant Neoplasms; Materials Testing; Mediating; Methodology; Methods; Modeling; Natural Resources; Numbers; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Phenols; Preparation; Reaction; Research; Site; Source; Standards of Weights and Measures; Structure; Testing; Therapeutic; analog; cancer cell; cancer therapy; chemotherapeutic agent; cyclohexadienone; cytotoxic; drug development; maritidine; method development; pretazettine

DESCRIPTION (provided by applicant): Project Summary: Stoichiometric palladium has been found to be capable of mediating the dearomatization of an aromatic precursor to form spirocyclic dienones. There was seen a potential for this reaction to be used in the synthesis of Amaryllidaceae alkaloids that are characterized by a unique spirocyclic framework containing a chiral quaternary carbon. The total syntheses proposed herein would utilize a catalytic version of this method. The syntheses are simple, straightforward and rely on inexpensive starting materials. The proposed methodology presents an advantage over current methods, because it is economical and likely capable of proceeding in an asymmetric fashion if chiral ligands on palladium are used. Cationic palladium centers in complexes containing bulky, chiral, monodentate ligands are proposed to be electrophilic enough to coordinate to an aromatic ring and thus activate it towards dearomatization. Specifically, this proposal aims to (1) develop an asymmetric palladium-catalyzed spirocycle forming dearomatization reaction and (2) utilize the method in the total synthesis of cytotoxic alkaloids of the Amaryllidaceae family. First, catalytic palladium conditions will be optimized for use with simple model substrates. Once catalytic conditions have been established, the reaction will be tested on a number of other related substrates in order to broaden the scope of the reaction. Finally, the natural product precursors will be prepared and the methodology applied to the synthesis of four Amaryllidaceae alkaloids. Relevance: Cancer treatment and drug development rely on a steady source of drug candidates and material for testing against cancer cells. Inspiration for drug treatment by Pharmaceuticals comes from the structures of naturally occurring cytotoxic compounds, but their availability through standard isolation methods is often limited. These studies will contribute to our ability to synthesize potential cancer therapeutics that contain a spirocyclic framework. The methodology may also be extended to the synthesis of other structurally related chemotherapeutic agents in addition to the targeted alkaloids.

描述（由申请人提供）：项目摘要：已发现化学计量的钯能够介导芳族前体的脱芳构化以形成螺环二烯酮。该反应具有合成石蒜科生物碱的潜力，石蒜科生物碱的特征在于含有手性季碳的独特螺环框架。本文提出的全合成将利用该方法的催化形式。这些合成方法简单、直接，并且依赖于廉价的起始原料。所提出的方法比目前的方法具有优势，因为它是经济的，并且如果使用钯上的手性配体，则可能能够以不对称方式进行。在含有庞大的，手性的，单齿配体的配合物中的阳离子钯中心被建议是亲电的足以协调到芳环，从而激活它对脱芳构化。具体而言，该提议旨在（1）开发不对称钯催化的螺环形成脱芳构化反应和（2）利用该方法全合成石蒜科的细胞毒性生物碱。首先，催化钯条件将被优化用于简单的模型基板。一旦确定了催化条件，将在许多其他相关底物上测试反应，以扩大反应范围。最后，将天然产物前体的制备方法应用于石蒜科生物碱的合成。相关性：癌症治疗和药物开发依赖于稳定的候选药物来源和用于测试癌细胞的材料。制药公司药物治疗的灵感来自于天然存在的细胞毒性化合物的结构，但通过标准分离方法获得它们的可能性往往有限。这些研究将有助于我们合成含有螺环框架的潜在癌症治疗剂的能力。该方法还可以扩展到合成除了靶向生物碱之外的其他结构相关的化疗剂。