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

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.
Figure 1