ASYMMETRIC SYNTHESIS OF BIOACTIVE PRIMARY AMINES

描述：（申请人的摘要）含有与立体碳连接的氮的手性非外消旋胺在自然界中普遍存在。实例包括蛋白原性和非蛋白原性α和β-氨基酸以及结构多样的生物碱。此类胺还广泛用作手性结构单元，用于生物活性材料的对映选择性构建，所述生物活性材料包括氮丙啶、β-内酰胺、肽抗生素、氨基糖和HIV-1蛋白酶抑制剂。特别重要的是绝对的立体化学，生物活性往往严重依赖于它。所提出的工作的主要目标是采用对映体纯的亚磺酰亚胺（R1 S（O）N-CR2 R3）和四种新的亚磺酰亚胺衍生的结构单元，N-亚磺酰基氮丙啶羧酸酯、异喹诺酮、密集官能化的氨基酸和乙醛酸化的N-亚磺酰亚胺，用于生物相关的α和β-氨基酸和生物碱的对映体选择性合成的新方法。由N-亚磺酰基助剂赋予的重要优点包括：（i）强大的立体定向作用;（ii）C=N键朝向亲核加成的活化;（iii）在温和条件下去除而不差向异构化;以及（iv）通过分离非对映异构体中间体容易获得对映体纯产物。N-亚磺酰基氮丙啶羧酸酯的区域和立体选择性开环反应将用于合成α和β-氨基酸及其难以制备的β，β ′-二取代和α-取代的类似物。异喹诺酮和密集功能化的氨基酸将提供有效的进入生物活性生物碱系统的取代模式不容易通过其他手段。乙二醛酸盐N-亚磺酰亚胺类化合物是一种新型的手性亲杂二烯体和甘氨酸阳离子等价物，可用于氨基酸的氮杂Diels-Alder和亚胺烯合成。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，我们将利用这种化学方法合成生物相关分子或其手性非外消旋前体。具体目标包括：（i）芳基丙氨酸，肽和抗肿瘤抗生素的成分;（ii）β-羟基α-氨基酸，许多肽抗生素如万古霉素的组分;（iii）β-氨基酸，重要的肽模拟物和抗肿瘤药物如紫杉醇的片段;和（iv）异喹啉，药用价值的生物碱和HIV抑制剂。新的和改进的对映选择性的方法，这些生物活性胺的预期结果。

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.