EFFICIENT SYNTHESIS OF ENANTIOPURE ALPHA AMINO ACIDS

对映体纯α氨基酸的高效合成

• 批准号: 2670511
• 负责人: FRANKLIN A DAVIS
• 金额: $ 15.21万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2670511
• 关键词: alkyl nitrile; aminoacid; antineoplastic antibiotics; chemical synthesis; cyclic aminoacid; glycine; piperidine; pyrrolidines; stereochemistry; stereoisomer; vancomycin

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.

描述：（主要研究者）α-氨基酸是基本的 肽和蛋白质的组成部分，它们负责 大多数生物的结构和功能。他们广泛就业 作为手性模板和亚基， 具有生物活性和抗菌活性的化合物， 在制药、农用化学品和食品行业。此外，非- 蛋白原D-和L-α-氨基酸越来越多地用于 研究酶作用机理，修饰和提高蛋白质活性。 拟议工作的主要目标是制定一个切实可行的， α-氨基酸的高效不对称Strecker合成， “Et 2AlCN/ROH”对手性非外消旋 亚磺酰亚胺（ArS（O）N= CRR ′）。N-100所带来的重要优势 亚磺酰基包括（i）强大立体定向作用;（ii） 活化C-N双键以加成;和（iii）辅助 N-亚磺酰基α-氨基腈（ARs（o）- NHC（CN）RR '）转化为α-氨基酸， 不会发生外消旋化。第二个主要目标是 阐明负责分子识别的因素， 这反过来又有助于合理设计改进的方法。 补充研究将集中在N-亚磺酰基α- 氨基腈产物（ArS（O）-NHRR'CN.我们将研究转换 （i）N-烷基α-氨基酸成分， 抗生素如万古霉素;（ii）α-烷基α-氨基酸， 蛋白质活性调节剂;和（iii）哌啶和吡咯烷， 生物碱类具有一系列重要的生物和 药用特性。 同时，我们将利用这种化学方法合成生物 难以或不可能通过其它方法制备相关氨基酸 方法论。靶标包括：（i）临床上可接受的氨基酸序列中的氨基酸。 重要的抗生素万古霉素（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， 抑制氨基酸脱羧酶;（iii）β-氨基，β-羟基 和β-氟代α-氨基酸，许多抗生素的成分 和抗肿瘤剂;（iv）环状氨基酸，例如D- 脯氨酸和D-高脯氨酸;和（v）氧代和卤代α-氨基酸， 重要的非外消旋结构单元，用于合成更复杂的 衍生物.