Synthesis of Amaryllidaceae Alkaloids via Palladium Catalysis

描述（由申请人提供）：项目摘要：化学计量学钯已被发现能够介导芳香前体的脱芳，形成螺环二烯酮。该反应被认为有潜力用于合成含有手性季碳的独特螺旋环框架的Amaryllidaceae生物碱。本文提出的全合成将利用该方法的催化版本。这种合成方法简单、直接，而且依赖于廉价的起始材料。所提出的方法比目前的方法有优势，因为它是经济的，并且如果使用钯上的手性配体，可能能够以不对称的方式进行。在含有大体积、手性、单齿配体的配合物中，阳离子钯中心被认为是亲电的，足以配位到芳环上，从而激活芳环去芳化。具体而言，本提案旨在(1)开发一种不对称钯催化的螺旋环形成脱芳反应(2)将该方法用于Amaryllidaceae家族细胞毒性生物碱的全合成。首先，催化钯的条件将优化用于简单的模型底物。一旦建立了催化条件，反应将在许多其他相关底物上进行测试，以扩大反应的范围。最后，制备了天然产物前体，并将合成方法应用于四种苋菜科生物碱的合成。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检测癌细胞的材料。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旋环框架的潜在癌症疗法的能力。该方法也可以扩展到合成其他结构相关的化疗药物，除了目标生物碱。

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.