EFFICIENT SYNTHESIS OF ENANTIOPURE ALPHA AMINO ACIDS

描述：(主要研究人员)α-氨基酸是基本的 多肽和蛋白质的积木，它们负责 大多数生物的结构和功能。他们被广泛雇用。 作为手性模板和亚基在许多不对称结构中 具有生物活性和药理活性的化合物，被广泛使用 在制药、农化和食品行业。此外，非 蛋白来源的D-氨基酸和L-α-氨基酸越来越多地被利用来 研究酶的作用机制，修饰和提高蛋白质活性。 拟议工作的主要目标是制定一项切实可行的 α-氨基酸的高效不对称Strecker合成 “Et2AlCN/ROH”与手性非外消旋的非对映选择性加成反应 亚磺胺(Ars(O)N=CRR‘)。N-赋予的重要优势- 亚磺基包括(I)强大的立体定向效应；(Ii) C-N双键向加成方向的活化；和(Iii)辅助 N-亚磺基-α-氨基腈(Ars(O)-)的脱除和水解 NHC(CN)RR‘)在极温和的条件下转化为α-氨基酸，如 这种消旋化不会发生。第二个主要目标是 阐明影响分子识别的因素， 这反过来应该允许对改进的方法进行合理的设计。 补充性研究将集中在N-亚磺酰α-的化学上。 氨基腈产品(Ars(O)-NHRR‘CN.我们将研究转换为 这些物种如下：(I)N-烷基-α-氨基酸组成 抗生素，如万古霉素；(Ii)α-烷基-α-氨基酸， 蛋白质活性修饰剂；和(Iii)哌啶类和吡咯烷类， 生物碱的一类，具有一系列重要的生物和 药用特性。 同时，我们将把这种化学应用于生物合成。 难以或不可能通过其他方法制备的相关氨基酸 方法论。目标包括：(I)临床上的氨基酸 重要抗生素万古霉素(即芳基甘氨酸、β-羟基-α- 氨基酸和双(α-氨基酸)；(Ii)乙烯基甘氨酸，它 抑制氨基酸脱羧酶；(Iii)β-氨基、β-羟基 和β-氟-α-氨基酸，这是一些抗生素的成分 和抗肿瘤药物；(Iv)环状氨基酸，如D- (V)氧和卤α-氨基酸， 合成更复杂化合物的重要非外消旋构筑块 衍生品。

DESCRIPTION: (Principal Investigator's) 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 extensive employed as chiral templates and subunits in the asymmetric construction of many biologically and pharmacologically active compounds, and are widely used in the pharmaceutical, agrochemical and food industries. In addition non- proteinogenic D- and L-alpha-amino acids are increasingly utilized to study enzyme mechanism and to modify and enhance protein activity. The principal objective of the proposed work is to develop a practical and efficient asymmetric Strecker synthesis of alpha-amino acids, exploiting the diastereoselective addition of "Et2AlCN/ROH" to chiral non-racemic sulfinimines (ArS(O)N=CRR'). 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) auxiliary removal and hydrolysis of the N-sulfinyl alpha-amino nitrile (ARs(o)- NHC(CN)RR') to alpha-amino acids under exceedingly mild conditions, such that racemization does not occur. A second major objective is the elucidation of the factors responsible for the molecular recognition, which in turn should permit the rational design of improved methodology. Complementary studies will focus on the chemistry of the N-sulfinyl alpha- amino nitrile products (ArS(O)-NHRR'CN. We will examine the conversion of these species to: (i) N-alkyl alpha-amino acids constituents of antibiotics such as vancomycin; (ii) alpha-alkyl alpha-amino acids, modifiers of protein activity; and (iii) piperidines and pyrrolidines, classes of alkaloids possessing a range of significant biological and medicinal properties. Concurrently we will employ this chemistry in syntheses of biologically relevant amino-acid that are difficult or impossible to prepare via other methodologies. Targets include: (i) the amino acids in the clinically important antibiotic vancomycin (i.e., arylglycines, beta-hydroxy alpha- amino acids, and bis(alpha-amino acids)); (ii) vinyl glycines, which inhibit amino acid decarboxylase enzymes; (iii) beta-amino, beta-hydroxy and beta-fluoro alpha-amino acids, constituents of a number of antibiotics and antitumor agents, respectively; (iv) cyclic amino acids such as D- proline and D-homoproline; and (v) oxo and halo alpha-amino acids, important non-racemic building blocks for the synthesis of more complex derivatives.