STEREOSELECTIVE UMPOLUNG REACTIONS WITH METALATED P-CHIRAL CYANOHYDRIN PHOSPHATES-ENANTIOSELECTIVE SYNTHESIS OF TERTIARY CYANOHYDRINS

We present the first cyanohydrin derivative 4 that allows diastereosel ective umpolung reactions. In 4 the OH group of the cyanohydrin is lin ked with a chiral phosphate, which can be removed hydrolytically after asymmetric synthesis. Cyclization of pseudoephedrine 1d with POCl3 ga ve 2d. This was followed by addition of racemic benzaldehyde cyanohydr in 3 to give the key intermediate 4d with complete retention of the co nfiguration at phosphorus. Deprotonation of 4d, followed by addition o f a wide variety of electrophiles afforded the crystalline products 5 with high diastereomeric excesses (de up to 94%). High asymmetric indu ction was also achieved for the reaction of 4(-)Li(+) with acyl halide s, alpha-bromoacetates, 2-cycloalkenones, alpha,beta-unsaturated ester s, and gamma-bromoacetates. Lewis acid assisted hydrolysis proceeded w ithout racemization and gave high yields of ketone cyanohydrins 6. Fro m 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, whi ch circumvents the substrate limitations of enzymatic synthesis.