Simple approach to the synthesis of novel tricyclic BACE1 inhibitor warhead through β-lactam opening

A novel methodology for the synthesis of potential β-secretase 1 (BACE-1) inhibitors has been elaborated from a β-lactam precursor obtained by a Staudinger reaction. Ring opening of the β-lactam gave access to a key intermediate trisubstituted tetrahydrofuran after a sequential reduction/Mitsunobu etherification. This strategy allowed a partial control of the stereochemistry through epimerization of the β-lactam. Finally, the amidine was further modified by introducing an amide linker in order to deliver a putative BACE-1 inhibitor.