Identification of the first enantiopure Rac1-Tiam1 protein-protein interaction inhibitor and its optimized synthesis via phosphine free remote group directed hydroarylation.

A phospine free hydroarylation reaction applied to norbornene derivatives is described for the first time and was exploited for the regioselective gram scale synthesis of AR-148, a known Rac1-Tiam1 PPI inhibitor. Umpolung conversion of the nitro group into free amine allowed the regiocontrol of the key arylation step via a long range effect. The effect of AR-148 in comparison with its enantiomers on Rac1 activation of has been evaluated and (-)AR-148 has been identified as the first enantiomerically pure inhibitor of Rac1-Tiam1 PPI.