Synthesis of Amaryllidaceae Alkaloids via Palladium Catalysis

描述(由申请人提供)：项目摘要：已发现化学计量比的钯能够调节芳香族前体的脱芳构化以形成螺环二烯酮。这一反应被认为有可能用于合成石蒜科生物碱，这些生物碱的特征是含有手性季碳的独特螺环骨架。这里提出的全部合成将利用该方法的催化版本。这种合成方法简单、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，因为如果使用钯上的手性配体，它是经济的，并且可能能够以不对称的方式进行。在含有大体积、手性、单齿配体的络合物中，阳离子钯中心被认为是足够亲电的，可以配位到一个芳香环上，从而激活它走向脱芳构化。具体地说，本建议的目的是(1)开发不对称钯催化的螺环形成脱芳构化反应；(2)将该方法用于石蒜科植物细胞毒性生物碱的全合成。首先，将优化催化钯的条件，以便与简单的模型底物一起使用。一旦建立了催化条件，将在其他一些相关底物上测试该反应，以扩大反应的范围。最后，将制备天然产物前体，并将该方法应用于四种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针对癌细胞的测试材料。药物治疗的灵感来自于自然产生的细胞毒性化合物的结构，但通过标准的分离方法获得的药物往往是有限的。这些研究将有助于我们合成包含螺环框架的潜在癌症治疗药物。该方法还可以扩展到合成除靶向生物碱之外的其他结构相关的化疗药物。

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.