Stereoselective Synthesis of (Z)-Alkene-Containing Proline Dipeptide Mimetics

Citations Over TimeTop 17% of 2006 papers

Abstract

In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This feature greatly influences the structure and function of the proline-containing peptides and proteins. Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio- and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described. The key steps of this synthesis are to introduce a C3 unit onto a gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactam with an organocopper-mediated anti-S(N)2' reaction and subsequently construct a five-membered proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere. The presented synthetic methodology should be applicable to the general syntheses of other cis-aminoacylproline type (Z)-alkene dipeptide mimetics.

Related Papers

• → Synthesis of potent β-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure–activity relationship studies(2003)57 cited
• → Synthesis of a Gln-Phe Hydroxy-ethylene Dipeptide Isostere(2004)26 cited
• → Synthesis and γ-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres(2003)22 cited
• → Stereoselective synthesis of a hydroxyethylene dipeptide isostere(1993)25 cited
• → Renin inhibitors based on dipeptide analogs. Incorporation of the hydroxyethylene isostere at the P2/P3 sites(1990)15 cited