Synthesis of a Tetrasubstituted Tetrahydronaphthalene Scaffold for α-Helix Mimicry via a MgBr2-Catalyzed Friedel-Crafts Epoxide Cycloalkylation

alpha-Helices are ubiquitous protein recognition elements that bind diverse biomolecular targets. The synthesis of a small molecule scaffold to present the side chains of an alpha-helix is described. The 1,3,5,7-tetrasubstituted 1,2,3,4-tetrahydronaphthalene scaffold, providing mimicry of the i+3, and i+4 positions of an alpha-helix, was synthesized using a novel MgBr2-catalyzed Friedel Crafts epoxide cycloalkylation as the key step. Each position may be differentiated via O-alkylation after scaffold synthesis, generating a diversity-oriented approach to readily synthesize proteomimetics for different targets.