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Syntheses of Amino Acids and Amino Phosphonic Acids

氨基酸和氨基膦酸的合成

基本信息

批准号：
6923593
负责人：
FRANKLIN A DAVIS
金额：
$ 26.34万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2007-07-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Alpha-amino acids are the basic building blocks of peptides and proteins, which are responsible for the structure and function of most living things. They are extensively employed as chiral templates and subunits in the asymmetric construction of many biologically and pharmacologically active compounds. Nonproteinogenic examples are increasingly utilized to study enzyme mechanisms and to modify and enhance protein activity. Alpha-amino phosphonic acids are structural analogs of amino acids and as such exhibit a broad range of biological activities: enzyme inhibitors, antitumor agents, anti-bacterial agents, and fungicides. The principal objective of the proposed work is to develop practical and efficient methodology for the asymmetric synthesis of functionalized alpha amino acids and alpha amino phosphonic acids by exploiting the diastereoselective addition of CN and phosphite anions to chiral nonracemic sulfinimines [N-sulfinyl imines, R'S(o)N=CR2R3]. Important advantages conferred by the N-sulfinyl group include (i) powerful stereodirecting effects, (ii) activation of the C-N double bond toward addition, and (iii) facile auxiliary removal and hydrolysis of the N-sulfinyl alpha amino nitrile and alpha amino phosphonate to amino acids and amino phosphonic acids under such exceedingly mild conditions that racemization does not occur. Complementary studies will focus on the synthesis and regioselective and stereoselective ring-opening reactions of N-sulfinyl aziridine 2-phosphonates as sources of novel alpha amino phosphonic acids. The imino-Diels-Alder reactions of 2H-azirine phosphonates, a new chiral dienophile, will be exploited as sources of novel aziridine 2-phosphonates and azabicyclic systems; the latter compounds are important chiral building blocks and exhibit a range of biological activities. Such studies are expected to provide new information on the chemical reactivity/selectivity of the phosphonate group as compared to carboxylate esters. Concurrently we will employ this chemistry in syntheses of biologically relevant, functionalized alpha amino acids and alpha amino phosphonates that are difficult or impossible to prepare via other methodologies. Targets include cyclic, unsaturated, and, beta substituted derivatives (beta amino, beta hydroxy, and beta fluoro).

描述（由申请人提供）：α-氨基酸是肽和蛋白质的基本组成部分，负责大多数生物的结构和功能。它们被广泛用作手性模板和亚基，用于许多生物活性和生物活性化合物的不对称构建。非蛋白质的例子越来越多地用于研究酶的机制和修改和增强蛋白质的活性。α-氨基膦酸是氨基酸的结构类似物，因此表现出广泛的生物活性：酶抑制剂、抗肿瘤剂、抗菌剂和杀真菌剂。本论文的主要目的是通过手性非外消旋亚磺酰亚胺[N-sulfinyl imines，R'S（o）N= CR2 R3]与CN和亚磷酸根的非对映选择性加成反应，开发实用有效的不对称合成功能化α-氨基酸和α-氨基膦酸的方法。由N-亚磺酰基赋予的重要优点包括（i）强有力的立体定向作用，（ii）C-N双键的加成活化，和（iii）在不发生外消旋化的极其温和的条件下，N-亚磺酰基α氨基腈和α氨基膦酸酯容易辅助除去和水解成氨基酸和氨基膦酸。补充研究将集中在N-亚磺酰基氮丙啶2-膦酸酯的合成和区域选择性和立体选择性开环反应作为新的α-氨基膦酸的来源。2 H-氮杂环丙烷膦酸酯是一种新的手性亲双烯体，其亚胺基-Diels-桤木反应将被开发为新型氮杂环丙烷2-膦酸酯和氮杂双环体系的来源，后者是重要的手性结构单元，具有广泛的生物活性。这样的研究预计将提供新的信息的化学反应性/选择性的膦酸酯基团相比，羧酸酯。同时，我们将采用这种化学方法合成生物相关的，功能化的α氨基酸和α氨基膦酸酯，这是很难或不可能通过其他方法制备。靶点包括环状、不饱和和β取代衍生物（β氨基、β羟基和β氟）。