TOTAL SYNTHESIS OF THE CYCLIC BIPHENYL ETHER PEPTIDES K-13 AND OF4949-III VIA SNAR MACROCYCLIZATION OF PEPTIDYL RUTHENIUM PI-ARENE COMPLEXES

Intramolecular nucleophilic aromatic substitution (SNAr) of preformed ruthenium cyclopentadienyl cationic peptidyl st-complexes forms cyclic biphenyl ethers in convenient, high-yielding reactions. The utility o f the method was demonstrated by the efficient convergent total synthe sis of two natural products, K-13 and OF4949-III. Several analogs of K -13 and OF494PI-IV were synthesized in high yields, and one ring syste m that could not be prepared by a macrolactamization method was formed in high yield by biaryl ether formation from peptidyl ruthenium compl exes. Direct comparisons between these two approaches are provided. Tr ansition metal pi-complexes of either N-protected or carboxyl-protecte d amino acids can be used as coupling partners in peptide coupling rea ctions. Preformed peptidyl ruthenium complexes can be used to synthesi ze cyclic biphenyl ethers in a combinatorial fashion.