Synthesis of 2S,5S-and 2R,5S-5-hydroxypipecolic acid via amide-methylenation of S-5-hydroxy-2-piperidone with dimethyltitanocene.

Abstract A route to 2S,5S-and 2R,5S-hydroxypipecolic acid is presented, starting with the enantiopure 5S-5-hydroxy-piperidone 7 . The key step of this reaction sequence is the chemoselective methylenation of the amide carbonyl group of 8 with dimethyltitanocene 9 to 10 . The transformation of the exocyclic enecarbamate double bond to the carboxylic acid group is best accomplished via hydroboration/oxidation to the alcohol 11a,b . Separation and oxidation of the diastereomers 11a,b , to 14a , and 14b , and hydrolysis furnishes the diastereomeric pipecolic acids 15a and 15b in enantiopure form.