New Cyclization Methods and Multicomponent Couplings

描述(由申请人提供)：本提案的主要目标是开发合成复杂分子的有效方法。在本项目期间将具体讨论的新方法将依赖于镍金属循环的催化生成和功能化。将开发一种新的合成策略，采用镍催化的顺序反应，应该可以获得各种碳环和杂环芳香族亚结构。还将开发利用烯前驱体和乙烯基锆前驱体的其他新的环化方法。在合成方法学开发方面的努力应该为各种合成问题提供新的根本解决方案。这项建议的目标还包括利用该计划开发的新反应来合成具有生物意义的天然产物。将追求的目标分子包括素A和B、软骨藻酸、异软骨藻酸G和H、锯齿佐菌素A和短角莲毒素341a。全合成中的这些问题将使我们能够寻求解决许多实质性合成挑战的方案，包括具有多个连续立体中心的密集官能化五元环和六元环的生成，三取代和四取代烯烃的立体选择性的生成，以及四元碳中心的立体选择性的生成。此外，这些具有生物意义的天然产物和密切相关的后期中间体的制备数量的合成将使人们能够评估它们作为潜在的药物制剂和药理学研究工具的效用。

DESCRIPTION (provided by applicant): The primary objective of this proposal is to develop powerful methods for the synthesis of complex molecules. The new methods to be specifically addressed during this project period will rely on the catalytic generation and functionalization of nickel metallacycles. A new synthetic strategy employing sequential nickel-catalyzed reactions will be developed that should provide access to a variety of carbocyclic and heterocyclic aromatic substructures. Other new cyclization methods that utilize allene precursors and vinylzirconium precursors will be developed. The efforts in synthetic methodology development should provide fundamentally new solutions to a variety of synthetic problems.The aims of this proposal also include the total syntheses of biologically interesting natural products utilizing new reactions developed in this program. The target molecules that will be pursued include testudinariols A and B, domoic acid, isodomoic acids G and H, serratezomine A, and pumiliotoxin 341A. These problems in total synthesis will allow us to pursue solutions to numerous substantial synthetic challenges including the generation of densely functionalized five and six membered rings that possess multiple contiguous stereocenters, the stereoselective generation of tri- and tetrasubstituted alkenes, and the stereoselective creation of quaternary carbon centers. Furthermore, the synthesis of preparative quantities of these biologically interesting natural products and closely related late stage intermediates will allow evaluation of their utility as potential pharmaceutical agents and as research tools in pharmacology.