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

含有特殊氨基酸的生物活性环肽的合成研究

基本信息

批准号：
15590001
负责人：
MAKINO Kazuishi
金额：
$ 2.3万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590001/
关键词：
papuamide polyoxypeptin GE3 halipeptin catalytic asymmetric hydrogenation β-hydroxy-α-amino acid Ru Ir 動的速度論的分割 BINAP

项目摘要

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

本研究的目的是合成具有生物活性的环缩肽、papuamide、polyoxypeptin、GE 3、halipeptin和calipeptin。这些化合物含有结构有趣的不寻常（非蛋白质）氨基酸。开发合成方法来构建这些氨基酸作为空间纯形式是关键问题，不仅要实现环状缩肽的全合成，而且要提供医学上重要的化合物，如酶和受体抑制剂。本课题成功地开发了几类常用氨基酸、抗β-羟基-α-氨基酸、吡哌酸和3-羟基-3-甲基脯氨酸的合成新方法，β-羟基-α-氨基酸是许多具有生物活性的天然产物和药用化合物的重要组成部分。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。我们已经开发出一种 ...更多信息以Ru或Ir轴向手性膦为催化剂，通过动态动力学拆分（DKR）直接进行反选择加氢的新合成方法。该方法被应用于各种脂肪族和芳香族反-β-羟基-α-氨基酸如b-羟基亮氨酸和b-甲氧基酪氨酸的合成。（R）-和（S）-哌嗪酸，即环状α-肼基酸，不仅是多氧肽和GE 3的组分，本身也是具有生物活性的化合物。我们分别通过脯氨酸催化的不对称α-肼化反应和不对称氮杂Diels-Alder反应合成了（R）-和（S）-哌嗪酸。前者是一种由易得的溴醛经六步反应合成（R）-和（S）-哌嗪酸的高效方法，总收率80%。在后者的合成过程中，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影响。3R）-3-羟基-3-甲基脯氨酸，其通过诱导抗凋亡的人胰腺癌AsPC-1细胞的凋亡而显示出强的抗癌活性。我们发展了一种利用DBU催化的串联Mchael-aldol反应一步合成多取代吡咯烷环的方法，实现了外消旋体的一步合成。（2S，3R）-3-羟基-3-甲基脯氨酸3R）-3-羟基-3-甲基脯氨酸通过（-）-辛可尼定及其β-内酯衍生物的重结晶对映体富集。少

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stereoselective synthesis of protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins

DOI：
10.1016/j.tet.2004.06.111
发表时间：
2004-09
期刊：
Tetrahedron
影响因子：
2.1
作者：
S. Hara;K. Makino;Y. Hamada
通讯作者：
S. Hara;K. Makino;Y. Hamada

光学活性β-ヒドロキシ-α-アミノカルボン酸誘導体の製造法

光学活性β-羟基-α-氨基羧酸衍生物的制造方法

DOI：
发表时间：
2003
期刊：
影响因子：
0
作者：
通讯作者：

Stereoselective Synthesis of Prtected (2S,3S)-N-Methyl-5-hydroxyisoleucine, an Component of Halipeptins

Halipeptins 的一种成分——受保护的 (2S,3S)-N-甲基-5-羟基异亮氨酸的立体选择性合成

DOI：
发表时间：
2004
期刊：
Tetrahedron 60
影响因子：
0
作者：
Makino;K. et al.
通讯作者：
K. et al.

Efficient construction of 1,2-dihydroquinoline and 1,2,3,4-tetrahydroquinoline rings using tandem Michael-aldol reaction

DOI：
10.1016/j.tetlet.2003.10.011
发表时间：
2003-12
期刊：
Tetrahedron Letters
影响因子：
1.8
作者：
K. Makino;O. Hara;Y. Takiguchi;Takayuki Katano;Yumiko Asakawa;K. Hatano;Y. Hamada
通讯作者：
K. Makino;O. Hara;Y. Takiguchi;Takayuki Katano;Yumiko Asakawa;K. Hatano;Y. Hamada

A short-step synthesis of (2S,3R)-3-hydroxy-3-methyl-proline, a component of polyoxypeptins, using a tandem Michael-aldol reaction and optical resolution.

使用串联迈克尔醛醇反应和光学拆分，短步合成 (2S,3R)-3-羟基-3-甲基-脯氨酸（聚氧肽素的一种成分）。