Synthesis of Phostones via Phosphono Substituted Metal Allyl Intermediates

在这项由化学系化学合成计划资助的项目中，密苏里大学圣路易斯分校的克里斯托弗·D·斯皮林教授正在开发新的碳-碳键形成反应，并将其应用于合成医学上相关的磷酸取代糖。磷酸基团是所有生命系统的基本成分，对分子复制、细胞生物化学、细胞信号通路和代谢过程中的激活都很重要。这项研究建立在之前以磷为基础的研究基础上，开发新的镍基工艺来获得重要的碳支架。该项目更广泛的影响在于开发有机合成的新工具，以及本科生和研究生的培训。特别强调本科生参与研究，以提供合成有机化学技术的扎实培训。培训将帮助提供熟练的工人来支持美国的制药研究和相关的化学工业。智力优势集中在开发基于新的有机磷化学的合成方法上。由环氧乙烯基膦酸酯、1-和2-取代膦-1，3-二烯和膦-烯丙基碳酸酯等前体衍生的金属烯丙基中间体为立体选择性C-C和C-杂原子键的形成提供了独特的方法。这些反应允许以互补的方法合成具有新的生物学特性并可作为药物化学的先导化合物的磷结石和磷糖。这种从头开始的方法提供了独特的取代模式和立体化学，与容易获得的(常见)碳水化合物不同，这种碳水化合物非常适合合成潜在的类脂A拮抗剂。

AbstractIn this project, funded by the Chemical Synthesis Program of the Chemistry Division, Professor Christopher D. Spilling of the University of Missouri St. Louis is developing new carbon-carbon bond forming reactions with applications in the synthesis of medicinally relevant phosphate-substituted sugars. The phosphate group is a fundamental component of all living systems, and is important for molecular replication, cell biochemistry, cell signalling pathways, and activation in metabolic processes. The research builds on prior phosphorous-based research developing new nickel-based processes to access important carbon scaffolds. The broader impact of this program lies in developing new tools for organic synthesis and the training of undergraduate and graduate students. A particular emphasis is placed on undergraduate participation in research to provide a solid training in the techniques of synthetic organic chemistry. The training will help provide skilled workers to support pharmaceutical research and related chemical industry in the US.The intellectual merit is focused on developing synthetic methods based on new organophosphorous chemistry. Metal allyl intermediates derived from precursors such as epoxy-vinyl phosphonates, 1- and 2- substituted phosphono-1,3-dienes and phosphono allylic carbonates provide unique methods of stereoselective C-C and C-heteroatom bond forming reactions. These reactions allow complimentary approaches to the synthesis of phostones and phosphonosugars that have novel biological properties and may serve as lead compounds for medicinal chemistry. This de novo approach provides phostones with unique substitution patterns and stereochemistry which deviate from the readily available (common) carbohydrates that is ideally suited to the synthesis of potential antagonists of lipid A.