NEW METHODS FOR THE SYNTHESIS OF UNUSUAL AMINO ACIDS

描述：（主要研究者）本项目的主要目标 是立体选择性方法的发展， 不寻常的氨基酸我们将研究过渡金属的应用- 介导的平衡和动力学拆分方法， 1，2-氨基醇和1，2-二胺从α-氨基酸 非对映异构体纯的形式。乙烯基氨基醇是有价值的前体 γ-氨基-β-羟基氨基酸，如他汀，发现于 天然存在的天冬氨酸蛋白酶抑制剂，胃酶抑制剂。肽 含有他汀和他汀类似物，已经显示出在 治疗高血压艾滋病和癌症 该提案的第一部分描述了热力学研究 利用钯催化的环- 开环/闭环反应。所述乙烯基恶唑啉通过以下方法制备： 将乙烯基溴化镁加成到α-氨基醛中， 立体选择性异构化工艺将扩大其应用范围 通过提供一个平衡的途径来避免不良的加成反应。 更有希望的是获得非常高的选择性的潜力 通过动态的动力学分辨率。由于异构化过程 涉及快速平衡π-烯丙基钯中间体，动力学 用氮亲核试剂捕获可以得到非对映体纯的 二胺他汀的二氨基酸类似物正在成为重要的 蛋白酶抑制剂的组分，并且很少有这些酸的合成具有 被举报。 一项研究，以解决其中涉及的一些基本问题， 动态解决包括提案的第二部分。的 将用分子内亲核试剂研究动力学捕获， 好.这些产物将导致构象的合成 限制性氨基酸我们开发了一些已知的合成方法， 和新的官能化氨基酸。的 相同的乙烯基恶唑啉前体将用于制备 α，β-，β，γ-和β，γ，δ-官能化的氨基 acids.其它含烯烃的肽电子等排体的合成 还提出了酰胺键的替代物。

DESCRIPTION: (Principal Investigator's) The primary goal of this project is the development of stereoselective methods for the synthesis of unusual amino acids. We will examine the use of transition metal- mediated equilibration and kinetic resolution processes to obtain chiral 1,2-aminoalcohols and 1,2-diamines from alpha-amino acids in diastereomerically pure form. Vinylaminoalcohols are valuable precursors to gamma-amino-beta-hydroxy amino acids such as statine, found in the naturally occurring aspartic protease inhibitor, pepstatin. Peptides containing statine and analogs of statine, have shown promise in the treatment of hypertension, HIV, and cancer. The first part of the proposal describes a study of the thermodynamic equilibration of 5-vinyloxazolines utilizing a palladium-catalyzed ring- opening /ring-closing reaction. The vinyloxazolines are prepared by the addition of vinylmagnesium bromide to alpha-aminoaldehydes with poor stereoselectivity. The isomerization process will extend the application of a poor addition reaction by providing a pathway for equilibration. Even more promising is the potential for obtaining very high selectivity through a dynamic kinetic resolution. As the isomerization process involves rapidly equilibrating pi-allyl palladium intermediates, kinetic trapping with nitrogen nucleophiles can lead to diastereomerically pure diamines. Diamino acid analogs of statine are emerging as important components of protease inhibitors, and few syntheses of these acids have been reported. A study to address some of the fundamental issues involved in this dynamic resolution encompasses the second part of the proposal. The kinetic trapping will be studied with intramolecular nucleophiles as well. These products will lead to the synthesis of conformationally constrained amino acids. We develop the synthesis of a number of known and new functionalized amino acids in the remainder of the proposal. The same vinyloxazoline precursors will be utilized for the preparation of alpha,beta-, beta,gamma-, and beta,gamma,delta-functionalized amino acids. The synthesis of other peptide isosteres containing olefin replacements for amide bonds are also proposed.