Three-Step Metal-Promoted Allene-Based Preparation of Bis(heterocyclic) Cyclophanes from Carbonyl Compounds

A straightforward metal-mediated method for the synthesis of bis­(dihydrofuryl) cyclophane scaffolds from carbonyl compounds has been developed. The combination of the dihydrofuran moiety with different heterocycles such as β-lactams and sugars allows high levels of skeletal diversity. The process comprises indium-promoted one-pot carbonyl bis­(allenylation) and gold- or palladium-catalyzed double cyclization in the resulting bis­(allenols), followed by selective ruthenium-catalyzed macrocyclization. In some cases, the method has been successfully applied to the synthesis of the challenging Z-isomers. The E- versus Z-stereochemistry of the metathesis-formed double bonds could not be assigned taking into consideration the usual coupling constants criteria, but a diagnostic based on the chemical shifts of the two olefinic protons located at the macrocyclic double bond was established.