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NEW METHODS FOR THE SYNTHESIS OF UNUSUAL AMINO ACIDS

合成特殊氨基酸的新方法

基本信息

批准号：
2727333
负责人：
GREGORY RICHARD COOK
金额：
$ 9.87万
依托单位：
NORTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2001-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2727333
关键词：
alkenes aminoacid aminoacid analog aminoalcohol chemical group chemical kinetics chemical synthesis protease inhibitor stereochemistry

项目摘要

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.

描述：(首席调查员)本项目的主要目标是立体选择性合成方法的发展不寻常的氨基酸。我们将研究过渡金属的使用- 中介平衡和动力学拆分过程以获得手性 α-氨基酸中的1，2-氨基醇和1，2-二胺非对映体纯净的形态。乙烯基氨基醇是有价值的前体到伽马-氨基-β-羟基氨基酸，如他汀类，发现于天然的天冬氨酸蛋白酶抑制剂，胃抑素。肽类含有他汀类药物和他汀类药物，在治疗高血压、艾滋病毒和癌症。提案的第一部分描述了对热力学的研究用钯催化的环平衡5-乙烯基恶唑啉- 开/合环反应。乙烯基恶唑类化合物是由贫α-氨基醛中添加乙烯基溴化镁的研究立体选择性。异构化过程将扩大其应用范围通过提供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选择性的潜力通过动态动力学解析。作为异构化过程涉及到快速平衡pi-烯丙基钯中间体，动力学用氮亲核试剂捕获可导致非对映异构体纯度二胺。他汀类的二氨基酸类似物正在成为重要的蛋白水解酶抑制剂的成分，以及这些酸的很少合成已经上报了。一项研究，旨在解决与此有关的一些基本问题动态决议包含提案的第二部分。这个将研究分子内亲核试剂的动力学捕获。井。这些产物将导致构象的合成。受限制的氨基酸。我们开发了一些已知化合物的合成并在提案的其余部分添加新的官能化氨基酸。这个相同的聚氧乙烯基恶唑啉前驱体将用于制备 α、β-、β-、伽马-和β、伽马、三角功能化氨基酸。其他含烯烃的多肽异构体的合成还提出了取代酰胺键的方法。