Stereoselective total synthesis of (2S,3R)-3-hydroxypipecolic acid

A concise, stereocontrolled synthesis of (2S,3R)-3-hydroxypipecolic acid 1 is described. Key features involve diastereoselective oxazoline formation catalyzed by palladium(0) and intramolecular cyclization by catalytic hydrogenation of an oxazoline.

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(4R,5R)-4-((tert-Butyldimethylsilyloxy)methyl)-2-phenyl-5-vinyl-4,5-dihydrooxazoleC18H27NO2Si[α]D25=+3.7 (c 1.0, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (4R,5R)

(E)-Methyl 3-((4R,5R)-4-((tert-butyldimethylsilyloxy)methyl)-2-phenyl-4,5-dihydrooxazol-5-yl)acrylateC20H29NO4Si[α]D25=-75.2 (c 1.0, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (4R,5R)

Methyl 3-((4R,5R)-4-((tert-butyldimethylsilyloxy)methyl)-2-phenyl-4,5-dihydrooxazol-5-yl)propanoateC20H31NO4Si[α]D25=+47.6 (c 1.0, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (4R,5R)

(5R,6R)-6-((tert-Butyldimethylsilyloxy)methyl)-5-hydroxypiperidin-2-oneC12H25NO3Si[α]D25=+10.0 (c 1.0, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (5R,6R)

(2R,3R)-2-((tert-Butyldimethylsilyloxy)methyl)piperidin-3-olC12H27NO2Si[α]D25=+3.0 (c 1.0, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (2R,3R)

(2R,3R)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-hydroxypiperidine-1-carboxylateC17H35NO4Si[α]D25=+29.25 (c 0.5, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (2R,3R)

(2S,3R)-3-Hydroxypiperidine-2-carboxylic acidC6H11NO3[α]D25=-53.8 (c 0.6, H2O)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (2S,3R)

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)piperidine-1-carboxylateC17H35NO4Si[α]D25=-17.1 (c 1.0, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (2R,3R)

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-((tert-butyldimethylsilyloxy)methyl)piperidine-1-carboxylateC23H49NO4Si2[α]D25=-13.6 (c 0.5, CHCl3)Source of chirality: d-serine, asymmetric synthesisAbsolute configuration: (2R,3R)