Chemical studies on vancomycin and related bioactive isodityrosine derivatives

万古霉素及相关生物活性异二酪氨酸衍生物的化学研究

• 批准号: 10680574
• 负责人: NISHIYAMA Shigeru
• 金额: $ 1.86万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680574/
• 关键词: isodityrosine; vancomycin; phenolic oxidation; diaryl ether; diaryl; solid phase reaction; aldostatin; RP66453; MRSA; アノード酸化; タリウム(III); プンメラーケトン; パンコマイシン; 耐性菌; ジアリールエテール; ハロゲン化フェノール; 有機電気化学

The aim of this investigation is a production of new bioactive substance related to vancomycin. The key reaction in this synthesis is a construction of the diaryl ether linkage by means of electrochemical and thallium oxidations. A new and effective oxidation methodology will be devised by the joint usage of both reactions. The results are summarized as follows.The inspection of the oxidation reaction mode of dihalogenated phenols was carried out by employing cresol derivatives. Whereas chloro and bromo derivatives produced the corresponding diaryl ethers via radical species, diaryls were obtained by the phenyl radicals produced by direct oxidation of the iodo group at ortho-positions of phenol groups. Based on these findings, aldostatin, an inhibitor of aldose reductase was synthesized from the dityrosine derivative. A synthetic intermediate of RP66453, a neurotensin antagonist, was also produced. In relation to oxidation mode of halogenated phenols, anodic oxidation of monohalogenated phenols was carried out. In contrast to dihalogenated derivatives, all halogen derivatives produced both diaryl ethers and diaryls, as well as the Pummerer ketones. Additionally, the presence of bulky alkyl substituents effected the two electron oxidation to give spirodienone derivatives. Upon exposure to Lewis acid, these spirodienones were converted into the corresponding dihydrobenzopyrans. It was observed that the direction of the rearrangement was controlled by the bromo group and substitution pattern of the spiro ring. Since the cyclization of bis-dihalogenated phenols by employing thallium (III) salts, is a crucial reaction in the isodityrosine-class natural products, solid phase reaction of this step was undertaken to realize green chemistry and to make a library as seed of effective antimicrobiral agents. Thus, peptide elongation reactions on resin, followed by the thallium oxidation of the resulted tripeptides, provided the desired cyclic isodityrosine derivative.

本研究的目的是生产与万古霉素相关的新生物活性物质。该合成中的关键反应是通过电化学和铊的氧化来构建二芳基醚的键。通过两种反应的联合使用，将设计出一种新的有效的氧化方法。主要研究结果如下：利用甲酚类化合物考察了二卤代苯酚的氧化反应模式。氯和溴的衍生物通过自由基物种生成相应的二芳基醚，而二芳基是由苯酚的邻位上的碘直接氧化产生的苯基得到的。基于这些发现，以二硫代赖氨酸为原料合成了醛糖还原酶抑制剂--醛糖抑素。还合成了神经降压素拮抗剂RP66453的合成中间体。针对卤代苯酚的氧化方式，对一卤代苯酚进行了阳极氧化。与二卤代衍生物不同的是，所有卤素衍生物都产生二芳基醚和二芳基，以及Pummerer酮。此外，大分子烷基取代基的存在影响了螺二烯酮衍生物的双电子氧化反应。当暴露在Lewis酸中时，这些螺二烯被转化为相应的二氢苯并吡喃。观察到重排的方向受溴基和螺环取代方式的控制。由于双二卤代苯酚的Tl(III)盐环化反应是异剂量酪氨酸类天然产物中的关键反应，为了实现绿色化学和建立有效抗菌剂的种子库，我们进行了这一步骤的固相反应。因此，多肽在树脂上的延伸反应，然后生成的三肽的铊氧化，提供了所需的环异剂量酪氨酸衍生物。