Stereocontrolled solid-phase synthesis of fluorinated partially-modified retropeptides via tandem aza-Michael/enolate-protonation

N-Acylation of Wang resin-bound l-α-amino acids with 2-trifluoromethyl-propenoyl chloride, followed by asymmetric tandem aza-Michael/enolate-protonation by a series of l-α-amino esters and final release from the resin, afforded a representative library of partially-modified retropeptides incorporating a stereodefined trifluoroalanine surrogate. The stereocontrol can be dramatically improved (up to 15:1) by using apolar solvents like carbon tetrachloride and DABCO as base.