Synthetic studies on the biologically active cyclic peptides containing unusual amino acids

本研究的目的是合成具有生物活性的环状多肽、木瓜酰胺、多氧多肽、GE3、金枪鱼多肽和钙多肽。这些化合物含有结构上有趣的不寻常的(非蛋白生成的)氨基酸。发展合成方法将这些氨基酸构建为空间纯净的形式，不仅是实现环脱肽的全合成的关键问题，也是提供重要的医药化合物，如酶和受体抑制剂的关键问题。在本研究项目中，我们成功地开发了一种制备几类常见氨基酸的新方法，即反β-羟基-α-氨基酸、吡喃酸和3-羟基-3-甲基丙氨酸。β-羟基-α-氨基酸是一类具有生物活性的天然产物和重要的药用化合物。因此，立体选择性合成抗β-羟基-α-氨基酸仍然是一个巨大的挑战。我们已经开发了一款…以Ru或Ir轴向手性膦为催化剂，通过动态动力学拆分(DKR)直接反选择加氢的新合成方法。该方法被应用于合成各种脂族和芳香族反β-羟基-α-氨基酸，如b-羟基亮氨酸和b-甲氧基酪氨酸。(R)-和(S)-哌嗪酸，环状a-肼酸，不仅是多氧肽和Ge_3的组成部分，本身也是具有生物活性的化合物。我们用两种不同的方法合成了(R)-和(S)-哌扎酸，一种是脯氨酸催化的不对称α-酰肼反应，另一种是不对称氮杂Diels-Alder反应。前者是以易得的溴醛为原料，以80%的总收率合成(R)-和(S)-哌嗪酸的一种高效方法。在后一种方法中，我们发现四氯化钛的用量对不对称氮杂Diels-Alder环加成反应的非对映选择性有显著的影响。我们探索了一条简洁的合成路线，在结构上新颖的(2S，3R)-3-羟基-3-甲基-3-羟基丙氨酸是一种通过诱导抗细胞凋亡的人胰腺癌细胞ASPC-1显示出强大的抗癌活性。利用邻苯二甲酸二丁酯催化的串联Mchael-Aldol反应一步合成了多取代吡咯烷环，并实现了外消旋(2S^*，3R^*)-3-羟基-3-甲基脯氨酸的快速合成。以(-)-辛可尼定为拆分试剂，通过对其β-内酯衍生物的重结晶，得到了对映体纯度较高的(2S，3R)-3-羟基-3-甲基脯氨酸。较少

The purpose of this research is the synthetic studies on biologically active cyclic depsipeptides, papuamide, polyoxypeptins, GE3, halipeptins, and callipeptins. Theses compounds contain structurally interesting unusual (non-proteogenic) amino acids. The development of synthetic methodologies to construct these amino acids as a sterically pure form is critical issue not only to attain total synthesis of the cyclic depsipeptides but also to supply medicinally important compounds such as enzyme and receptor inhibitors. We have succeeded in developing a new method for preparation of some classes of usual amino acids, anti-β-hydroxy-α-amino acids, piprazic acids, and 3-hyclroxy-3-methylproln in the term of this research project.β-Hydroxy-α-amino acids are valuable constituents of a variety of biologically active natural products and medicinally important compounds. Therefore, stereoselective synthesis of anti-β-hydroxy-α-amino acids still remains a formidable challenge. We have developed a … More new synthetic method of directly anti-selective hydrogenation through a dynamic kinetic resolution(DKR) using Ru or Ir axially chiral phosphine catalyst. This methodology was applied to the synthesis of various aliphatic and aromatic anti-β-hydroxy-α-amino acids such as b-hydroxyleucine and b-methoxytyrosine.(R)-and (S)-Piperazic acids, cylclic a-hydrazino acids, are not only a component of polyoxypeptins and GE3, are biologically active compounds their self. We have synthesized (R)-and (S)-piperazic acids by different two approaches, one is proline-catalyzed asymmetric α-hydrazination reaction and the other is asymmetric aza Diels-Alder reaction. The former is a highly efficient method for the synthesis of (R)-and (S)-piperazic acids from readily avairable bromoaldehyde in 80% overall yield and six steps, In the course of the latter approach, we found remarkable effects of the quantity of titanium tetrachloride on diastereoselectivity of asymmetric aza Diels-Alder cycloaddition.We explored a concise synthetic route to a structurally novel (2S,3R)-3-hydroxy-3-methylproline in a component of polyoxypeptins, which exhibit strong anticancer activity through the induction of apoptosis against apoptosis-resistant human pancreatic adenocarcinoma AsPC-1 cells. We have developed a method to construct the multi-substituted pyrrolidine ring in one step using a tandem Mchael-aldol reaction catalyzed by DBU, and achieved a short-step synthesis of racemic (2S^*,3R^*)-3-hydroxy-3-methylproline The enantiometically pure (2S,3R)-3-hydroxy-3-methylproline was obtained by partial optical resolution using (-)-cinchonidine and enantiometical emrichiment by the recrystallization of its β-lactone derivatives. Less