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

本研究的目的是对具有生物活性的环状沉积肽、木瓜酰胺、多氧肽、GE3、哈利肽和卡利肽的合成进行研究。这些化合物含有结构上有趣的不寻常（非蛋白质源性）氨基酸。发展以立体纯形式构建这些氨基酸的合成方法不仅对实现环沉积肽的全合成，而且对提供诸如酶和受体抑制剂等重要药用化合物至关重要。本课题成功开发了几种常用氨基酸、抗β-羟基-α-氨基酸、吡嗪酸和3-羟基-3-甲基脯氨酸的制备新方法。β-羟基-α-氨基酸是多种具有生物活性的天然产物和重要的药用化合物的重要成分。因此，立体选择性合成抗β-羟基-α-氨基酸仍然是一个艰巨的挑战。采用Ru或Ir轴向手性膦催化剂，通过动态动力学分解（DKR）直接合成了一种新的反选择性加氢方法。应用该方法合成了b-羟基亮氨酸和b-甲氧基酪氨酸等多种脂肪族和芳香族抗β-羟基α-氨基酸。(R)和(S)-哌酸是一种环a-肼酸，不仅是多羟肽和GE3的组成部分，而且本身也是具有生物活性的化合物。采用脯氨酸催化的不对称α-肼化反应和不对称aza Diels-Alder反应合成了(R)-哌酸和(S)-哌酸。前者是由易得溴醛合成(R)和(S)-哌嗪酸的高效方法，总收率为80%，共6步。在后一种方法中，我们发现四氯化钛的量对不对称Diels-Alder环加成的非对对选择性有显著影响。我们探索了一种简洁的合成途径，以合成结构新颖的(2S,3R)-3-羟基-3-甲基脯氨酸，它是多羟肽的一个组成部分，它通过诱导细胞凋亡对抗凋亡的人胰腺腺癌AsPC-1细胞表现出很强的抗癌活性。利用DBU催化的串联michael -aldol反应，一步构建了多取代吡咯烷环，并实现了外消旋(2S^*,3R^*)-3-羟基-3-甲基脯氨酸的短步合成。利用(-)-cinchonidine和其β-内酯衍生物的重结晶，通过部分光学分辨和对映富集得到了对映纯的(2S,3R)-3-羟基-3-甲基脯氨酸。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