SNAr-Based Cycloetherification Methodology: Application in the Synthesis of Heterodectic Macrocyclic Peptides with Endo Aryl-Aryl and Aryl-Alkyl Ether

The endo aryl-aryl and aryl-alkyl ether bonds exist in a number of biologically important macrocyclic natural products, such as vancomycin family glycopeptide antibiotics ( 1 – 3 ), antitumor series RA I-XIV ( 4 ), K-13 ( 5 ), OF4949 ( 6 ), piperazinomycin ( 7 ), cyclopeptide alkaloids ( 8 , 9 ), nonpeptidic diarylheptanoids ( 10 ), and so on. Peptidomimetics incorporating, such structural features, have also been designed and synthesized as potential inhibitors of ACE ( 11 ), anti-HIV agents ( 12 ) and so on. From the view point of synthesis design ( 15 ), macrocyclization via formation of aryl-aryl or aryl-alkyl ether bond is unique, since it tackles two difficult synthetic problems, i.e., formation of ether bond and ring closure by a single operation. Intramolecular Ullmann ether synthesis ( 16 ), oxidative coupling reaction ( 17 ), and so forth, have been employed for the synthesis of type A (Fig. 1 ) compounds. Ring closure via the formation of aryl-aryl (type A) ( 18 ) and aryl-alkyl ether bonds (type B, Fig. 1 ) ( 19 ) by way of intramolecualr S _N Ar reaction ( 20 ) will be the focus of this chapter.

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