Application of Negishi Cross-Coupling to the Synthesis of the Cyclic Tripeptides OF4949-III and K-13

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 SNAr reaction between Boc-tyrosine and 2-fluorobenzaldehyde, followed by Dakin reaction, iodination, and methylation, is used its it 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.