2004 Fiscal Year Final Research Report Summary
Synthetic studies on the biologically active cyclic peptides containing unusual amino acids
| Project/Area Number |
15590001
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Chiba University |
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Principal Investigator |
MAKINO Kazuishi Chiba university, Graduate school of pharmaceutical sciences, associate professor, 大学院・薬学研究院, 助教授 (20302573)
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| Project Period (FY) |
2003 – 2004
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| Keywords | papuamide / polyoxypeptin / GE3 / halipeptin / catalytic asymmetric hydrogenation / β-hydroxy-α-amino acid / Ru / Ir |
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| Research Abstract |
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
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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
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Research Products
(15 results)
