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。在这个项目期间，具体解决的新方法将依赖于镍金属循环的催化生成和功能化。采用顺序镍催化反应的一种新的合成策略将被开发出来，该策略将提供获得各种碳环和杂环芳香亚结构的途径。利用烯基前驱体和乙烯基锆前驱体的其他新的环化方法也将得到开发。综合方法论发展的努力应该为各种综合问题提供根本的新解决方案。该提案的目的还包括利用该计划开发的新反应完全合成生物学上有趣的天然产物。目标分子将被追求包括丁香醇A和B，软骨藻酸，异软骨藻酸G和H，锯齿zomine A，和pumiliotoxin 341A。全合成中的这些问题将使我们能够寻求许多实质性合成挑战的解决方案，包括具有多个连续立体中心的密集功能化五元和六元环的生成，三取代和四取代烯烃的立体选择性生成，以及立体选择性生成季碳中心。此外，这些生物学上有趣的天然产物和密切相关的后期中间体的制备量的合成将允许评估它们作为潜在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.