Chemical studies on vancomycin and related bioactive isodityrosine derivatives

本研究的目的是生产与万古霉素相关的新型生物活性物质。该合成的关键反应是通过电化学和铊氧化来构建二芳醚键。结合这两种反应，将设计出一种新的、有效的氧化方法。结果总结如下：采用甲酚衍生物对二卤代酚的氧化反应方式进行了考察。氯和溴衍生物通过自由基生成相应的二芳醚，而二芳醚是由苯酚基团邻位上的碘基直接氧化产生的苯基自由基生成的。基于这些发现，从二酪氨酸衍生物合成醛糖还原酶抑制剂醛糖抑制素。合成了神经紧张素拮抗剂RP66453的中间体。针对卤代酚的氧化方式，对单卤代酚进行了阳极氧化。与二卤衍生物相反，所有卤素衍生物都产生二芳醚和二芳，以及彭默尔酮。此外，大量烷基取代基的存在影响了双电子氧化生成螺二烯酮衍生物。暴露于路易斯酸后，这些螺二烯酮转化为相应的二氢苯并吡喃。结果表明，重排方向受溴基团和螺旋环取代模式的控制。由于利用铊（III）盐对双二卤代苯酚进行环化是异氰酸类天然产物中的一个关键反应，因此进行这一步骤的固相反应是为了实现绿色化学，并为有效的抗菌药物库提供种子。因此，树脂上的肽延伸反应，随后的铊氧化所得到的三肽，提供了所需的环异丁基酪氨酸衍生物。

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.