The Diels-Alder cycloaddition reaction will be applied as a synthetic route for preparation of diaryl ethers. A major objective will be the preparation of optically active beta-(diaryl ether)-alpha-amino acids, such as isodityrosine and related amino acid units as present in the cyclic peptide antibiotics K-13, OF4949, bouvardin, and vancomycin. Enone and eynone dienophiles will be prepared from L- or D-serine derivatives. Cycloaddition with aryloxy functionalized 1,4-dienes and subsequent aromatization will provide the target diaryl ether amino acids. Model studies have demonstrated the potential of this method for the synthesis of isodityrosine derivatives in optically pure form. This approach also has the potential to lead to the synthesis of beta-hydroxy tyrosine derivatives, as present in the vancomycin family, by stereoselective reduction of an intermediate beta-keto tyrosine derivative. The synthesis of the peptide antibiotics K-13, OF4949-III, and the 14-membered cyclo(isodityrosine) unit of the bouvardins will be studied in which the cyclization step will involve a Diels-Alder cycloaddition to form the diaryl ether unit. These studies will involve preparation of the required tri- or dipeptide units containing in the N- and C-terminal side chains the diene and dienophile components needed for the intramolecular Diels-Alder reaction. Two routes to the synthesis of optically active phenylglycines by Diels-Alder methodology will be studied. These will involve (1) cycloaddition of 1,3-diaryloxy dienes with a serine-derived a, 6-unsaturated ester followed by a reaction sequence involving a Barton decarboxylation-phenylselenation leading to aromatic product, and (2) an inverse electron demand Diels-Alder method using a serine-derived a-pyrone and an aryloxy-substituted alkene. These methods will be applied for a synthesis of the core triaryl diether tripeptide unit of vancomycin.
