Synthesis of a 14-Membered Cyclic Peptide Model of the CFG Rings of Ristocetin A and Observations on Atropdiastereoisomerism

Abstract

Two routes for the synthesis of a 14-membered heterodetic cyclic peptide as a model for the CFG ring system of the antibiotic ristocetin A (2) are described. The key aryl ether bonds for this molecule were constructed by using the reaction of phenoxides from (hydroxyaryl)glycine derivatives with tricarbonyl(3-methoxy-2-methylchlorobenzene)manganese hexafluorophosphate (11). This coupling reaction can be performed in the presence of protected amino acids and dipeptides without racemization of the sensitive arylglycine. Stereoselective introduction of the F-ring glycine side chain was accomplished by reaction of the aryl ether manganese complexes with Schollkopf's bislactim glycine enolate equivalent. The product(s) from this reaction were demetalated and aromatized by treatment with N-bromosuccinimide. Deprotection of tha aromatized compounds followed by cycloamidation furnished two atrodiastereomeric cyclic peptides corresponding to the target molecule, the structures of which were assigned on the basis of 2D-NMR NOESY experiments coupled with molecular modeling. One of the product molecules corresponds closely to the structure that has been proposed for the CFG ring system of ristocetin, except for the orientation of the w 3 amide group