An efficient diastereo- and enantioselective Mannich-type/cyclization cascade reaction of α-substituted isocyanoacetates and cyclic trifluoromethyl ketimines cooperatively catalyzed by cinchona alkaloid-derived multi-hydrogen-bonding donor squaramide and AgOAc has been investigated, affording the optically active trifluoromethyl-substituted tetrahydroimidazo[1,5-c]quinazoline derivatives in excellent yields (up to 99%) and good to excellent stereoselectivities (up to >15:1 dr, up to 98% ee) under mild conditions.