Regioselective O-sulfonylation of N,N-bis(2-hydroxyalkyl)tosylamides as a synthetic key step to enantiopure morpholines

The synthesis of enantiopure 2,6-disubstituted morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid-liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the resulting tosylamido-2,2′-diol, and cyclization to the morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new morpholine-3-carboxamide was synthesized starting from threonine.