OF4949 I

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.

The polar extract of the Vanuatu sponge Reniera n. sp., which showed immunomodulating activity in preliminary tests, was found to contain a cyclic tripeptide, which we named renieramide (1). This metabolite is identical to a synthetic derivative mentioned in a patent concerning the preparation of cyclic peptides of the OF4949 family of anticancer agents. We describe here the first isolation of this metabolite from natural sources and its complete characterization by spectroscopic and chemical approaches. Renieramide (1) possesses a 17-membered cyclic side-chain-linked biphenyl ether skeleton, typical of the class that includes the natural products OF4949 I-IV, K13, and eurypamides. A tridimensional model of 1, obtained by NMR restrained molecular mechanics and dynamics, is also presented.

Syntheses of the cyclic tripeptides OF4949-III 1 and K-13 2 are reported, in which the key steps are intermolecular and intramolecular Negishi cross-coupling reactions, respectively. In addition, the synthesis of a protected isomer of K-13 25 is reported. The synthesis of K-13 features a tripeptidic organozinc reagent 11, one of the most highly functionalized such reagents to be described. An O-aryltyrosine derivative 15, prepared by S(N)Ar reaction between Boc-tyrosine and 2-fluorobenzaldehyde, followed by Dakin reaction, iodination, and methylation, is used as a common intermediate for all of the syntheses described. The routes to this class of cyclic tripeptide are among the shortest reported to date and demonstrate the high functional group tolerance of the carbon-zinc bond toward peptide derivatives.