COMBINATORIAL SYNTHESIS OF PHOSPHINE LIGANDS

组合化学作为发现新的候选药物的一种有价值的工具，最近突然出现在人们的视野中。合成数百种化合物进行筛选的能力是对合理药物设计的有益补充。新的治疗药物的设计与新的不对称配体的开发有许多相似之处，其中最重要的是合理设计策略的局限性。提出的研究旨在开发一种组合方法，以两类在过去已被证明是有用的配体，双膦和膦-恶唑啉配体。该提案的目标是直接的，为一组给定的反应配体的发展和间接的，发展的方法，利用平行的方法来发现磷化氢和磷化氢-恶唑啉配体一般。氨基酸构建块，将允许合成两种类型的配体已知的组合技术将被讨论。初步结果将表明，可以合成配体库，并且基于已知的β -转形序列的结构基序是不对称pi-烯丙基加成的选择性配体。提出了一种在固体载体上合成旋衍生双膦和膦-恶唑啉配体库的一般方法。一个计划的使用其他车削成形序列将提出。介绍了脯氨酸基膦-恶唑啉配体的继续开发工作。最初将筛选三个反应，钯催化的pi-烯丙基烷基化反应，Heck反应和铑催化的[4+2]环异构化反应。选择这些反应是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, bisphosphines and phosphine-oxazoline ligands. The goals of the proposal are direct, the development of ligands for a given set of reactions and indirect, develop methods for the utilization of a parallel approach to the discovery of phosphine and phosphine- oxazoline ligands in general. 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, libraries of ligands can be synthesized and that a structural motif based on a known beta- turn forming sequence is a selective ligand for asymmetric pi- allyl additions. A general method for the synthesis of libraries of turn derived bisphosphine and phosphine-oxazoline ligands on solid supports will be proposed. A plan for the use of other turn forming sequences will be presented. Work on the continuation of the development of proline based phosphine- oxazoline ligands is included. Initially three reactions will be screened, palladium catalyzed pi-allyl alkylation, the Heck reaction and a rhodium catalyzed [4+2] cycloisomerization reaction. These reactions were chosen because of their differing mechanisms and the fact that all are potentially useful carbon- carbon bond forming reactions.