Diastereoselective synthesis of (2S,5S)- and (2S,5R)-N-benzyloxycarbonyl-5-hydroxypipecolic acids from trans-4-hydroxy-l-proline

An efficient diastereoselective synthesis of cis- and trans-5-hydroxy-(2S)-N-benzyloxycarbonyl pipecolic acids, starting from trans-4-hydroxy-l-proline is described. The key synthetic strategies involve the regioisomeric ring expansion of keto ester 8 and diastereoselective reduction of ketone 11 in high selectivity and yield.

Figure optionsDownload as PowerPoint slide

N-Benzyloxycarbonyl-5-oxo-S-pipecolic acid tert-butyl esterC18H23NO5[α]D25=-4.8 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S)

N-Benzyloxycarbonyl-4-oxo-S-pipecolic acid tert-butyl esterC18H23NO5[α]D25=-15.4 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S)

N-Benzyloxycarbonyl-(2S,5S)-5-hydroxypipecolic acid tert-butyl esterC18H25NO5[α]D26=-27.9 (c 2.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5S)

N-Benzyloxycarbonyl-(2S,5R)-5-hydroxypipecolic acid tert-butyl esterC18H25NO5[α]D26=-19.6 (c 2.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5R)

N-Benzyloxycarbonyl-(2S,5S)-5-hydroxypipecolic acidC14H17NO5[α]D26=+76.5 (c 0.17, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5S)

N-Benzyloxycarbonyl-(2S,5R)-5-hydroxypipecolic acidC14H17NO5[α]D28=-7.2 (c 1.0, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5R)