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基醚键。这两种反应的联合使用将设计出一种新的有效的氧化方法。研究结果如下：以甲酚衍生物为氧化剂，考察了二卤代苯酚的氧化反应模式。氯代和溴代衍生物通过自由基物质产生相应的二芳基醚，而二芳基是通过苯酚基团邻位碘基直接氧化产生的苯基自由基获得的。在此基础上，以二酪氨酸衍生物为原料合成了醛糖还原酶抑制剂醛抑素。还产生了神经降压素拮抗剂RP 66453的合成中间体。针对卤代酚的氧化方式，研究了单卤代酚的阳极氧化。与二卤代衍生物相反，所有卤素衍生物都产生二芳基醚和二芳基，以及Pummerer酮。此外，大体积烷基取代基的存在影响两电子氧化，得到螺二烯酮衍生物。当暴露于刘易斯酸时，这些螺二烯酮转化为相应的二氢苯并吡喃。发现重排方向受溴代基团和螺环取代方式的控制。利用铊盐进行的双二卤代酚的环化反应是异酪氨酸类天然产物中的关键反应，为实现绿色化学，建立高效抗菌剂种子库，对该反应进行了固相反应。因此，在树脂上进行肽延伸反应，然后对所得三肽进行铊氧化，得到所需的环状异酪氨酸衍生物。

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.