2000 Fiscal Year Final Research Report Summary
Chemical studies on vancomycin and related bioactive isodityrosine derivatives
| Project/Area Number |
10680574
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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 |
Bioorganic chemistry
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| Research Institution | Keio University |
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Principal Investigator |
NISHIYAMA Shigeru Keio Unv.Dept.of Chemistry Professor, 理工学部, 教授 (20137988)
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| Project Period (FY) |
1998 – 2000
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| Keywords | isodityrosine / vancomycin / phenolic oxidation / diaryl ether / diaryl / solid phase reaction / aldostatin / RP66453 |
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| Research Abstract |
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.
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[Publications] Takahashi, M., Konishi, H., Iida, S., Nakamura, K., Yamamura, S., Nishiyama, S.: "Phenolic oxidation of o, o'-dihalogenated phenols."Tetrahedron. 55. 5295-5302 (1999)
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[Publications] Mori, K., Takahashi, M., Yamamura, S., Nishiyama, S.: "Phenolic oxidation of halogenated phenols."New Directions in Organic Electrochemistry. (A.J.Fry and Y.Matsumura Ed.), THE ELECTROCHEMICAL SOCIETY, INC, Proceedings Vol.2000-15. 17-20 (2000)
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