ASYMMETRIC SYNTHESIS OF BIOACTIVE PRIMARY AMINES

生物活性伯胺的不对称合成

• 批准号: 6519615
• 负责人: FRANKLIN A DAVIS
• 金额: $ 24.07万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519615
• 关键词: alkaloids; amines; aminoacid; aziridines; chemical synthesis; glycine; imines; isoquinolines; primary aminoacid; stereochemistry; stereoisomer; sulfur aminoacid; sulfur compounds

DESCRIPTION: (Applicant's Abstract) Chiral nonracemic amines containing nitrogen attached to a stereogenic carbon are ubiquitous in nature. Examples include proteinogenic and nonproteinogenic alpha and beta-amino acids and structurally diverse alkaloids. Such amines are also widely used as chiral building blocks for the enantioselective construction of bioactive materials including aziridines, beta-lactams, peptide antibiotics, amino sugars and HIV-1 protease inhibitors. Of particular significance is the absolute stereochemistry, upon which biological activity often critically depends. The principal objective of the proposed work is to employ enantiopure sulfinimines (R1S(O)N-CR2R3) and four new sulfinimine- derived building blocks, N-sulfinyl aziridine carboxylate esters, isoquinolones, densely functionalized amino acids, and glyoxylate N-sulfinyl imines, in new methodology for the enantioselective synthesis of biologically relevant alpha and beta-amino acids and alkaloids. Important advantages conferred by the N-sulfinyl auxiliary include: (i) powerful stereodirecting affects; (ii) activation of the C=N bond toward nucleophilic addition; (iii) removal under mild conditions without epimerization; ad (iv) ready availability of enantiopure products via separation of diastereomeric intermediates. Regio-and stereoselective ring- opening reactions of N-sulfinyl aziridine carboxylate esters will be used to synthesize alpha and beta-amino acids and their difficult-to-prepare beta, beta'-disubstituted and alpha- substituted analogs. Isoquinolones and densely functionalized amino acids will provide efficient entry into biologically active alkaloid systems with substitution patterns not easily accessible by other means. Glyoxlate N-sulfinyl imines, new chiral heterodinenophiles and glycne cation equivalent, will be employed in the aza Diels-Alder and imino ene synthesis of amino acids. A second major objective is the elucidation of the factors responsible for the molecular recognition in thee processes. Concurrently we will exploit this chemistry in syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include: (i) aryl alanines, constitutents of peptides and antitumor antibiotics; (ii) beta-hydroxy alpha-amino acids, components of numerous peptide antibiotics such as vancomycin; (iii) beta-amino acids, important peptidomimetics and fragments of antitumor drugs such as taxol; and (iv) isoquinolines, medicinally valuable alkaloids, and HIV inhibitors. New and improved enantioselective approaches to these bioactive amines are expected to result.

描述：(申请人摘要)手性非外消旋的胺类化合物在自然界中普遍存在。例子包括蛋白质来源的和非蛋白质来源的α-和β-氨基酸以及结构多样的生物碱。这类胺还被广泛用作手性构建块，用于对映体选择性构建生物活性材料，包括氮杂环丙烷、β-内酰胺、多肽抗生素、氨基糖和HIV-1蛋白酶抑制剂。具有特别重要意义的是绝对的立体化学，生物活动常常关键地依赖于它。这项工作的主要目的是使用对映体亚胺(R1S(O)N-CR2R3)和四个新的亚磺亚胺衍生的构筑块，N-亚磺酰氮杂环丁酸酯、异喹诺酮、致密官能化氨基酸和乙二醇酸酯N-亚磺酰亚胺，用于对映体选择性合成生物相关的α和β-氨基酸和生物碱。N-亚磺基助剂的重要优点包括：(I)强大的立体定向作用；(Ii)激活C=N键进行亲核加成；(Iii)在温和的条件下消除异构化；(Iv)通过分离非对映异构体中间体，容易获得对映体产品。N-亚磺酰氮杂环丁羧酸酯的区域和立体选择性开环反应将被用于合成α和β-氨基酸及其难以制备的β，β‘-二取代和α-取代类似物。异喹诺酮类化合物和官能化程度高的氨基酸将有效地进入生物活性生物碱系统，取代模式不容易通过其他手段获得。乙二醇酸酯N-亚磺酰亚胺是一种新型的手性杂二烯和甘氨酸阳离子当量化合物，将用于氮杂Diels-Alder和亚氨基氨基酸的合成。第二个主要目标是阐明在这些过程中负责分子识别的因素。同时，我们将在生物相关分子或它们的手性非外消旋前体的合成中利用这种化学。靶标包括：(I)芳基丙氨酸，多肽和抗肿瘤抗生素的组合物；(Ii)β-羟基α-氨基酸，许多多肽抗生素的成分，如万古霉素；(Iii)β-氨基酸，重要的多肽模拟物和抗肿瘤药物的片段，如紫杉醇；以及(Iv)异喹啉，有药用价值的生物碱和艾滋病毒抑制剂。这些生物活性胺的新的和改进的对映体选择性方法有望产生。