ASYMMETRIC SYNTHESIS OF BIOACTIVE PRIMARY AMINES

手性非外消旋胺与立体生物质的结合 碳在自然界中无处不在。例子包括蛋白质和非蛋白质 α-和β-氨基酸以及烯丙基胺和高烯丙基胺。 这些胺也被广泛用作手性合成子。 包括氮杂环丙烷在内的生物活性物质的对映选择性构筑， β-内酰胺类、多肽抗生素、氨基糖、HIV-1蛋白酶抑制剂 和生物碱。特别重要的是绝对的立体化学， 这是生物活性经常严重依赖的。 拟议工作的主要目标是利用手性 非外消旋亚磺胺[Ars(O)N=CRR‘] 生物相关伯胺的对映选择性合成 (RR‘R“C-NH2)及其衍生物。为此，我们将探索 有机金属试剂和烯醇酸盐的非对映选择性加成 亚磺胺(手性氨亚胺合成子)。重要优势 由N-亚磺基赋予的包括：(I)强大的立体定向 影响，(Ii)C-N双键向加成的活化，(Iii) 亚磺酰胺产物[Ars(O)-NHCRR‘r]和[Ars(O)-NHCRR’r]的构型稳定性 (Iv)在温和的条件下去除，不消旋。第二个大调 目的是阐明影响分子水平的因素。 承认。对映体合成的新方法和改进方法 亚磺胺也将被设计出来。 补充性研究将集中在产品的化学上。 亚磺酰胺类化合物，包括N-亚磺基-α-和β-氨基酸、氮杂环丙烷、 以及烯丙基胺和高烯丙基胺。在这里，我们将调查其兼容性 具有不同官能团转化的N-亚磺基助剂 并评估其作为一个立体指导小组的用处。 同时，我们将在生物合成中利用这种化学。 相关分子或其手性非外消旋前体。目标包括 (I)乙烯基甘氨酸，抑制氨基酸脱羧酶；(Ii) α-羟基-β-氨基酸、抗真菌和抗肿瘤成分 合成β-内酰胺的试剂、中间体和 抗癌药物柔红霉素和柔红霉素的氨基糖片段 阿霉素和(Iii)N-β-羟基-α-氨基酸，其成分 大量的多肽抗生素。改进的对映选择性方法 这些生物活性的胺预计会产生。

Chiral nonracemic amines containing nitrogen attached to stereogenic carbon are ubiquitous in nature. Examples include protein and non-protein alpha- and beta-amino acids as well as allylic and homoallyic amines. These amines are also widely used as chiral synthons for the enantioselective construction of bioactive materials including aziridines, beta-lactams, peptide antibiotics, amino sugars, HIV-1 protease inhibitors and alkaloids. Of particular significance is the absolute stereochemistry, upon which biological activity often critically depends. The principal objective of the proposed work is to employ chiral nonracemic sulfinimines [ArS(O)N=CRR'] in new methodology for the enantioselective synthesis of biologically relevant primary amines (RR'R"C-NH2) and their derivatives. To this end, we will explore the diastereoselective addition of organometallic reagents and enolates to sulfinimines (chiral ammonia-imine synthons). Important advantages conferred by the N-sulfinyl group include, (i) powerful stereodirecting effects, (ii) activation of the C-N double bond toward addition, (iii) configurational stability of the sulfinamide product [ArS(O)-NHCRR'R"] and (iv) removal under mild conditions without racemization. A second major objective is the elucidation of the factors responsible for the molecular recognition. New and improved methods for the synthesis of enantiopure sulfinimines will also be devised. Complementary studies will focus on the chemistry of the product sulfinamides including N-sulfinyl alpha- and beta-amino acids, aziridines, and allylic and homoallylic amines. Here we will survey the compatibility of the N-sulfinyl auxiliary with various functional group transformations and assess its usefulness as a stereodirecting group. Concurrently we will exploit this chemistry in syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include (i) vinyl glycines, which inhibit amino acid decarboxylase enzymes, (ii) alpha-hydroxy-beta-amino acids, constituents of antifungal and antitumor agents, intermediates in the synthesis of beta-lactams and the aminosaccharide fragments of the anticancer drugs daunorubicin and adrimycin, and (iii) syn-beta-hydroxy-alpha-amino acids, components of numerous peptide antibiotics. Improved enantioselective approaches to these bioactive amines are expected to result.