ASYMMETRIC SYNTHESIS OF BIOACTIVE PRIMARY AMINES

（申请者摘要）含氮的手性非消旋胺在自然界中普遍存在。例子包括蛋白源性和非蛋白源性α和β氨基酸以及结构多样的生物碱。这类胺也被广泛用作手性构建块，用于对映选择性构建生物活性物质，包括氮嘧啶、β -内酰胺、肽抗生素、氨基糖和HIV-1蛋白酶抑制剂。特别重要的是绝对立体化学，生物活性往往依赖于它。本研究的主要目的是利用对映纯亚砜亚胺（R1S(O)N-CR2R3）和四种新的亚砜亚胺衍生的构建块，n -亚砜酰氮吡啶羧酸酯、异喹诺酮类、密集功能化氨基酸和乙醛酸n -亚砜亚胺，在新的方法中对映选择性合成生物学相关的α和β氨基酸和生物碱。n -亚砜基助剂的重要优点包括：(1)强大的立体定向作用；（ii） C=N键向亲核加成的活化；（iii）在温和条件下去除，不进行外聚化；AD （iv）通过分离非对映体中间体获得对映物。n -亚砜酰氮吡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α、α '取代和α取代类似物。异喹诺酮类药物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替代模式，不容易通过其他方式获得。摘要乙醛酸n -亚砜酰亚胺是一种新的手性异二烯亲和物和甘氨酸阳离子的等价物，将用于氨基酸的aza Diels-Alder和亚胺合成。第二个主要目标是阐明在三个过程中负责分子识别的因素。同时，我们将利用这种化学合成生物相关分子或其手性非外消旋前体。目标包括：(i)芳基丙氨酸、多肽成分和抗肿瘤抗生素；（ii） -羟基α -氨基酸，如万古霉素等多种肽抗生素的成分；（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；异喹啉、有药用价值的生物碱和艾滋病毒抑制剂。新的和改进的对映选择性方法有望产生这些生物活性胺。

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.