Syntheses of Amino Acids and Amino Phosphonic Acids

描述(申请人提供)：α-氨基酸是多肽和蛋白质的基本组成成分，它们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，用于许多生物和药理活性化合物的不对称结构。非蛋白生成的例子越来越多地被用于研究酶的机制以及修饰和增强蛋白质的活性。α-氨基膦酸是氨基酸的结构类似物，因此具有广泛的生物活性：酶抑制剂、抗肿瘤药物、抗细菌药物和杀菌剂。 本工作的主要目的是利用CN和亚磷酸阴离子与手性非外消旋亚氨基亚胺[N-亚磺酰亚胺，R‘s(O)N=Cr2R3]的非对映选择性加成反应，开发实用有效的方法来合成功能化的α-氨基酸和α-氨基膦酸类化合物。N-亚磺基赋予的重要优点包括(I)强大的立体定向效应，(Ii)C-N双键向加成方向的激活，以及(Iii)在非常温和的条件下，N-亚磺基α-氨基腈和α-氨基膦酸易被辅助移除和水解成氨基酸和氨基膦酸，这种条件非常温和，不会发生外消旋。 辅助性研究将侧重于作为新型α-氨基膦酸源的N-亚磺酰氮杂环丙烷2-膦酸酯的合成、区域选择性和立体选择性开环反应。2H-氮杂环膦的亚氨基-Diels-Alder反应是一种新型的手性双烯亲和剂，可作为合成新型氮杂二环盐和氮杂二环类化合物的来源，后者是重要的手性结构单元，具有广泛的生物活性。这类研究有望提供有关与羧酸酯相比，膦酸基的化学反应性/选择性的新信息。 同时，我们将利用这种化学方法合成生物相关的、功能化的α-氨基酸和α-氨基膦酸盐，这些是很难或不可能通过其他方法制备的。目标包括环状、不饱和和β取代的衍生物(β氨基、β羟基和β氟)。

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).