ASYMMETRIC SYNTHESIS OF BIOACTIVE PRIMARY AMINES

含氮的手性非外消旋胺连接到立体异构体上 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配体， 生物活性材料包括氮杂环丙烷的对映选择性构建， β-内酰胺类、肽类抗生素、氨基糖、HIV-1蛋白酶抑制剂 和生物碱。特别重要的是绝对立体化学， 生物活性往往严重依赖于此。 所提出的工作的主要目标是采用手性 非外消旋亚磺酰亚胺[ArS（O）N= CRR ']的新方法 生物相关伯胺的对映选择性合成 (RR“R“C-NH 2）及其衍生物。为此，我们将探讨 有机金属试剂和烯醇化物的非对映选择性加成， 亚磺酰亚胺（手性氨-亚胺配体）。重要的优点 由N-亚磺酰基赋予的功能包括，（i）强大的立体定向 影响，（ii）C-N双键的活化，（iii） 亚磺酰胺产物[ArS（O）-NHCRR 'R”]的构型稳定性和 (iv)在温和条件下除去而不发生外消旋化。第二主 目的是阐明导致分子生物学效应的因素， 识别.合成对映体纯的新方法和改进方法 还将设计亚磺亚胺。 补充研究将侧重于产品的化学性质 包括N-亚磺酰基α-和β-氨基酸的亚磺酰胺，氮杂环丙烷， 以及烯丙基胺和高烯丙基胺。在这里，我们将调查兼容性 具有各种官能团转化的N-亚磺酰基助剂 并评估其作为立体定向基团的有用性。 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。目标包括 (i)乙烯基甘氨酸，其抑制氨基酸脱羧酶，（ii） α-羟基-β-氨基酸，抗真菌和抗肿瘤的成分 β-内酰胺合成中的试剂、中间体和 抗癌药物柔红霉素的氨基糖片段， 阿霉素，和（iii）顺式-β-羟基-α-氨基酸， 许多肽抗生素。改进的对映选择性方法 预期得到这些生物活性胺。

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.