Chiral Bisphosphorylimides as Organocatalysts for Asymmetric Friedel–Crafts Reactions

CREVELING 101

As a growing number of complex bioactive molecules flood the pharmaceutical industry, the demand for powerful enantioselective reactions and purification methods for these compounds becomes essential. Asymmetric organocatalysis is a field in organic chemistry that has emerged as a valuable synthetic tool complementary to traditional metal-catalyzed transformations. A type of organocatalyst that has been gaining notoriety is the bisphosphorylimide, which is a stronger acid and is more sterically hindered than chiral BINOL-derived phosphoric acids. This upsurge can be attributed to the simple preparation and functionalization of bisphosphorylimides. An enantioselective Friedel-Crafts reaction of electron-rich aromatic groups with Boc-protected aldimine electrophiles has been successfully accomplished using a chiral bisphosphorylimide organocatalyst. The chemical scaffold of bisphosphorylimides, which mimics the active site of an enzyme, enables the bisphosphorylimide organocatalyst to afford enantioenriched products. The use of triethyl amine as an additive was found to speed up the reaction and prevent product decomposition, resulting in excellent yields and regioselectivity. An improved synthesis of the bisphosphorylimide has also been developed using catalytic hydrogenation in a flow reactor. In addition, another bisphosphorylimide with a diphenyl modification was successfully synthesized, which generated an enantiomeric excess. The progress of catalyst development studies and planned catalyst investigations will be presented.