CHIRAL SYNTHON: 1,2-OXAPHOSPHETANE 2-OXIDES

描述：（主要研究者的摘要） α-氨基-α-烷基膦酸及其类似物的活性 包括蛋白酶过渡态类似物抑制剂、抗体半抗原 生产、杀虫剂、除草剂、杀真菌剂和生长控制调节剂。 这些天然蛋白质氨基的结构磷基类似物 酸将继续在药物设计中发挥不可或缺的作用， 特别是重要蛋白酶抑制剂的设计。尽管 优雅的方法来合成对映体纯的化合物，存在一种 需要一种方法，可以快速合成各种侧链， 具有已知的、预定的绝对构型的链状类似物。的 这项研究的目的是开发一种方法， 将多种侧链转化为“手性合成子”前体; 1，2-氧代磷杂环丁烷 2-氧化物;并评估亲核试剂加成的区域选择性。我们提出 通过利用可用的方法来开发和利用这个合成子， 合成对映体纯（D）-和（L）-膦酰丝氨酸。的合成 系列对映体纯膦酰丝氨酸单酯，闭环评价 1，2-氧杂磷杂环己烷系列的稳定性测定 2-氧化物，使用变温P31 NMR，和评价的 通过各种亲核试剂进行开环的区域选择性。 这项研究的最终长期目标是综合一个图书馆 α-氨基-α-烷基膦酸用于掺入各种 包括CaaX肽的蛋白酶底物，用于测试作为 重组Ras-和α-因子CaaX转化酶。

DESCRIPTION: (Principal Investigator's Abstract) The diverse biological activities of alpha-amino-alpha-alkylphosphonic acids and their analogues include transition state analogue inhibitors of proteases, haptens for antibody production, pesticides, herbicides, fungicides and growth control regulators. These structural phosphorus based analogues of the natural proteinogenic amino acids will continue to play an integral role in the design of drugs, in pariticular the design of inhibitors of important protease enzymes. Despite the elegant methods to synthesize enantiomerically pure compounds, there exists a need for methodology that will allow the rapid synthesis of a variety of side chain analogues with a known, predetermined absolute configuration. The objective of this proposed research is to develop methodology to introduce a variety of side chains into a "chiral synthon" precursor; 1 ,2-oxaphosphetane 2-oxide; and evaluate the regioselectivity of nucleophile additions. We propose to develop and exploite this synthon by leveraging the available methods to synthesize enantiomerically pure (D)- and (L)-phosphonoserine. Synthesis of a series of enantiopure phosphonoserine monoesters, evaluation of ring closure conditions, stability determination of the series of 1 ,2-oxaphosphetane 2-oxides using variable temperature P31 NMR, and evaluation of the regioselectivity of ring opening by various nucleophiles will be undertaken. The ultimate long-range objective of this research is to synthesize a library of alpha-amino-alpha alkylphosphonic acids for incorporation into a variety of protease substrates including CaaX peptides for testing as inhibitors of recombinant Ras- and a-Factor CaaX converting enzymes.