Synthesis and conformational properties of the M(4-6)(5-7) bicyclic tetrapeptide common to the vancomycin antibiotics

The vancomycin class of antibiotics, exemplified by vancomycin and orienticin C aglycons (1) and (2), is widely used in the treatment of infections due to methicillin-resistant Staphylococcus aureus.1 The complexity of these structures, the interest in their mode of action,2 and the emergence of bacterial strains resistant to treatment by this family of antibiotics3 warrant development of reaction methodology and strategies for their synthesis.4 In pursuit of this objective, we have developed the relevant asymmetric amino acid syntheses5 and oxidative bond constructions for the synthesis of the biaryl ether-6 and biarylcontaining7 vancomycin-related cyclic tripeptide subunits. In a previous study, we also described the synthesis of the M(24)(4-6)8 bicyclic hexapeptide that was essentially a biaryl bond construction away from the complete tricyclic heptapeptide. However, subsequent investigations have revealed the difficulties in integrating these methods into a synthesis of the tricyclic heptapeptide framework. The purpose of this paper is to describe the first synthesis and conformational analysis of a fully functionalized M(4-6)(5-7) bicyclic tetrapeptide (e.g., 3). With the exception of the chlorination pattern on the 6-position â-hydroxytyrosine constituent, all members of the vancomycin family share the M(4-6)(5-7) bicyclic tetrapeptide subunit 3. Accordingly, our efforts have been directed toward the construction of this moiety followed by attachment of the N-terminal tripeptide and closure to the tricyclic heptapeptide related to the vancomycin aglycon. By inspection, there are two approaches to 3 that differ in the ordering of the macrocyclization events. Since prior studies7 demonstrated that the M(5-7) tripeptide 4 exists as a mixture of biaryl atropisomers (89:11) as well as (5-6) amide isomers (Vide infra) that complicate further development,9 attention has been directed toward a synthesis where macrocycle assemblage follows the order M(4-6) f M(5-7). Amino Acid Subunits. The 4-position amino acid was derived from commercially available D-4-hydroxyphenylglycine, while the remaining residues were synthesized using chiral imide enolate methodology previously developed for this purpose.5 A differentially protected o-phenolic substituent on ring 5 was required to lower the oxidation potential sufficiently to induce intramolecular oxidative coupling. To suppress the lability of the C-terminal amino acid constituent, the decision was made to carry the carboxyl terminus through the synthesis as the N-methyl amide with the expectation that it might be selectively cleaved through a site-selective nitrosation/thermolysis10 late in the synthesis. Preliminary experiments with derivatives of 3 and 4 suggested that this was a viable option.