TOTAL SYNTHESIS OF L,L-ISODITYROSINE AND ISODITYROSINE-DERIVED AGENTS - K-13, OF4949-III, AND OF4949-IV

Full details of the development of reaction conditions for implementation of an activated Ullmann condensation reaction that may be conducted without amino acid racemization and that have proven suitable for incorporation of the selectively protected catechol of functionalized L-Dopa derivatives are described. The application of this procedure in the total synthesis of L,L-isodityrosine (15), K-13 (1), and OF4949-III/OF4949TV (4/5) is detailed. Full details of a study of the macrocyclization reaction required for formation of the 17-membered tripeptides incorporating a diaryl ether linked meta- and paracyclophane structural subunit are provided and illustrate that the cyclization in route to K-13/OF4949-I - OF4949-IV is optimally conducted on substrates bearing a carbamate derivative of the C-15/C-9 amine and a C-4 free phenol with C11-N10/C10-N11 amide bond closure. © 1990, American Chemical Society. All rights reserved.