T. Schrader, STEREOSELECTIVE UMPOLUNG REACTIONS WITH METALATED P-CHIRAL CYANOHYDRIN PHOSPHATES-ENANTIOSELECTIVE SYNTHESIS OF TERTIARY CYANOHYDRINS, Chemistry, 3(8), 1997, pp. 1273-1282
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.