The asymmetric intramolecular dipolar cycloaddition of azomethine ylides was developed for fluorinated dipolarophiles, being the RF group crucial for selectivity.

The synthesis of polycyclic fluorinated tertiary amines has been accomplished by means of an intramolecular azomethine ylide cycloaddition with fluorinated dipolarophiles. Thus, tri‐ and tetracyclic fused pyrrolidines bearing a quaternary trifluoromethyl group were obtained in moderated yields in a stereoselective manner. This is one of the few examples reported in the literature of intramolecular 1,3‐dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles. Initial attempts of the asymmetric version of the process have been performed, but low levels of diastereoselectivity were achieved.

Tolerance development caused by dopamine replacement with l -DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson’s disease. In search for selective modulators of the D 1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4′-( S -methanesulfonimidoyl)-1,1′-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D 1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances l -DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D 1 receptor as a promising therapeutic approach for Parkinson’s disease.