Stereoselective umpolung reactions with metalated P-chiral cyanohydrin phosphates-enantioselective synthesis of tertiary cyanohydrins

We present the first cyanohydrin derivative 4 that allows diastereoselective umpolung reactions. In 4 the OH group of the cyanohydrin is linked with a chiral phosphate, which can be removed hydrolytically after asymmetric synthesis. Cyclization of pseudoephedrine 1d with POCl3 gave 2d. This was followed by addition of racemic benzaldehyde cyanohydrin 3 to give the key intermediate 4d with complete retention of the configuration at phosphorus. Deprotonation of 4d, followed by addition of a wide variety of electrophiles afforded the crystalline products 5 with high diastereomeric excesses (de up to 94%). High asymmetric induction was also achieved for the reaction of 4(-)Li(+) with acyl halides, alpha-bromoacetates, 2-cycloalkenones, alpha,beta-unsaturated esters, and gamma-bromoacetates. Lewis acid assisted hydrolysis proceeded without racemization and gave high yields of ketone cyanohydrins 6. From the ring-opened chiral auxiliary 7, optically pure pseudoephedrine 1 was readily recovered by acid hydrolysis. Optically pure (R) and (S) ketone cyanohydrins are now accessible in a very general strategy, which circumvents the substrate limitations of enzymatic synthesis.