COMBINATORIAL SYNTHESIS OF PHOSPHINE LIGANDS

组合化学最近突然出现， 用于发现新候选药物的工具。的能力 合成数百种化合物进行筛选是一种有益补充 to rational合理drug药物design设计.设计上有很多相似之处 新的治疗剂和新的不对称的发展 配体，其中最重要的是理性的限制， 设计策略该研究旨在开发一种组合 方法的两类配体已被证明是有用的， 过去，二膦和膦-二氢恶唑配体。氨基酸 构建模块，这将允许合成两种类型的 将讨论通过已知的组合技术的配体。 初步结果表明，氨基酸 衍生的膦/二氢恶唑配体能够给出 钯催化的β-烯丙基烷基化的选择性可以 合成了一种通用的方法来合成这两种库， 固体载体上的二膦和膦-二氢恶唑配体 将被覆盖。一种允许脱保护的方法， 膦保护基团，同时分子连接到固体上 还将提供支持。允许金属化的化学反应 的配体将被呈现。金属文库的筛选 复合体将被覆盖。最初将筛选三种反应， 钯催化的π-烯丙基烷基化，Heck反应和 铑催化的[4+2]环加成反应。这些反应 因为它们的机制不同，而且它们都是 潜在有用的碳-碳键形成反应。

Combinatorial chemistry has recently burst on the scene as a valuable tool for the discovery of new drug candidates. The ability to synthesize hundreds of compounds for screening is a useful complement to rational drug design. There are many similarities between the design of new therapeutic agents and the development of new asymmetric ligands, the most important of which is the limitation of a rational design strategy. The proposed research aims to develop a combinatorial approach to two classes of ligands that have proven to be useful in the past, diphosphines and phosphine-dihydrooxazole ligands. Amino acid building blocks that will allow for the synthesis of both types of ligands by known combinatorial technology will be discussed. Preliminary results will be presented that show that, amino acid derived phosphine/dihydrooxazole ligands capable of giving state of the art selectivities for palladium catalyzed pi-allyl alkylations, can be synthesized. A general method for the synthesis of libraries of both diphosphines and phosphine-dihydrooxazole ligands on solid supports will be covered. A method that permits the deprotection of the phosphine protecting group while the molecule is attached to the solid support will also be shown. Chemistry that allows for the metalation of the ligands will be presented. The screening of libraries of metal complexes will be covered. Initially three reactions will be screened, palladium catalyzed pi-allyl alkylation, the Heck reaction and a rhodium Catalyzed [4+2] cycloaddition reaction. These reactions were chosen because of their differing mechanisms and the fact that all are potentially useful carbon-carbon bond forming reactions.