Drug creation involving hybrid type of low molecular weight biomolecules as lead compounds

涉及混合型低分子量生物分子作为先导化合物的药物生产

• 批准号: 12672079
• 负责人: NAITO Takeaki
• 金额: $ 2.11万
• 依托单位: Kobe Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672079/
• 关键词: sugar; amino acid; radical; oxime ether; Dysiherbaine; Wittig rearrangement; 核酸塩基; ワンポット; デシヘルベイン

Research for exploring new lead compounds for new drugs has focused to one component of biological compounds and not to hybrid components so far. We started our project to develop the most efficient and practical synthetic method for biological hybrid compounds which consist of amino acids, sugars, and nucleic bases.New synthetic method for amino acids and the related peptides has been developed via the route involving radical addition-cyclization of oxime ethers connected with olefins. The products were converted smoothly into β-amino acids.We also investigated construction of sugar parts by the radical reactions of the unprotected natural sugars. Stannyl radical addition-cyclization of oxime ethers connected with the carbonyl group proceeded smoothly to afford cyclic amino alcohols which were converted into aminocyclitols. The radical reaction was found to proceed via the most stable transition state involving minimum 1, 3-allylic strain.Formal synthesis of Dysiherbine was completed via two key reactions which are 1, 2-Wittig rearrangement and asymmetric hydroxylation respectively.

到目前为止，探索用于新药的新先导化合物的研究主要集中在生物化合物的一种成分上，而不是杂化成分。我们的项目是开发由氨基酸、糖和核酸碱基组成的最高效、最实用的生物杂化化合物的合成方法，通过与烯烃连接的肟醚的自由基加成-环化路线，开发了氨基酸及其相关多肽的新合成方法。产物顺利地转化为β-氨基酸。我们还研究了未受保护的天然糖通过自由基反应构建糖部分。通过锡基自由基加成-环化反应顺利地得到了环氨基醇，并转化为氨基环醇。自由基反应通过最稳定的过渡态进行，最小的1，3-烯丙基应变。Dysiherbine的正常合成分别通过1，2-Wittig重排和不对称羟基化两个关键反应完成。

项目成果

宮部豪人: "Asymmetric Synthesis of α-Amino Acids Based on Carbon Radical Addition to Glyoxylic Oxime Ether"J. Org. Chem.. 65. 176-185 (2000)

Goto Miyabe：“基于乙醛肟醚碳自由基加成的 α-氨基酸的不对称合成”J. Org. 65. 176-185 (2000)

内藤猛章: "Radical Cyclization of Oxime Ethers Derived from Monosaccharides Aiming at the Synthesis of Dysiherbaine and Related Stereoisomers"Heterocycles. 53. 2611-2615 (2000)

Takeaki Naito：“单糖衍生的肟醚的自由基环化旨在合成 Dysiherbaine 和相关立体体”杂环。 53. 2611-2615 (2000)

内藤猛章: "Heteroatom Radical Addition-Cyclization and Its Synthetic Application"Heterocycles. 50(1). 505-541 (1999)

Takeaki Naito：“杂原子自由基加成-环化及其合成应用”杂环50(1)。

Hideto Miyabe, Akiyoshi Nishiki, and Takeaki Naito: "Synthesis of Aminocyclohexitol via Carbon-Carbon Bond-Forming Radical Cyclization of Oxime Ether."Chem. Pharm. Bull.. 51. 100-103 (2003)

Hideto Miyabe、Akiyoshi Nishiki 和 Takeaki Naito：“通过肟醚碳-碳键形成自由基环化合成氨基环己醇。”Chem。

宮田興子: "Radical cyclization in heterocycle synthesis. 13. Sulfanyl radical addition-cyclization of oxime ethers and hydrazones connected with........"Tetrahedron. 58. 4459-4479 (2002)

Koko Miyata：“杂环合成中的自由基环化。13.与......连接的肟醚和腙的磺基加成环化”Tetrahedron。58。4459-4479（2002）