A concise enantioselective synthesis of (2S,3S)-3-hydroxypipecolic acid via proline catalyzed α-aminooxylation of aldehydes and Pd-catalyzed ether directed aza-Claisen rearrangements

An efficient approach to (2S,3S)-3-hydroxypipecolic acid with an overall yield of 10.2% and 98% ee starting from 1,5-pentanediol has been developed. The key steps employed in the synthesis are the d-proline catalyzed sequential α-aminooxylation/Horner–Wadsworth–Emmons olefination of an aldehyde and the Pd-catalyzed MOM-ether directed aza-Claisen rearrangement of an allylic trichloroacetimidate.

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(S,E)-Ethyl 7-((tert-butyldimethylsilyl)oxy)-4-hydroxyhept-2-enoateC15H30O4SiEe 98% determined by chiral HPLC[α]D25 = −1.7 (c 0.86, CHCl3)Source of chirality: α-aminooxylation of aldehydeAbsolute configuration: (S)

(S,E)-Ethyl 7-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)hept-2-enoateC17H34O5Si[α]D25 = −45.3 (c 0.4, CHCl3)Source of chirality: α-aminooxylation of aldehydeAbsolute configuration: (S)

(S,E)-7-((tert-Butyldimethylsilyl)oxy)-4-(methoxymethoxy)hept-2-en-1-olC15H32O4Si[α]D25 = −69.8 (c 1.0, CHCl3)Source of chirality: α-aminooxylation of aldehydeAbsolute configuration: (S)

N-((3R,4S)-7-((tert-Butyldimethylsilyl)oxy)-4-(methoxymethoxy)hept-1-en-3-yl)-2,2,2 trichloroacetamideC17H32Cl3NO4Si[α]D25 = +29.3 (c 2.34, CHCl3)Source of chirality: α-aminooxylation of aldehyde and diastereoselective MOM-ether directed aza-Claisen rearrangementAbsolute configuration: (3R,4S)

2,2,2-Trichloro-N-((3R,4S)-7-hydroxy-4-(methoxymethoxy)hept-1-en-3-yl)acetamideC11H18Cl3NO4[α]D25 = +41.6 (c 1.0, CHCl3)Source of chirality: α-aminooxylation of aldehyde and diastereoselective MOM-ether directed aza-Claisen rearrangementAbsolute configuration: (3R,4S)

tert-Butyl ((3R,4S)-7-hydroxy-4-(methoxymethoxy)hept-1-en-3-yl)carbamateC14H27NO5[α]D25 = +23.3 (c 0.52, CHCl3)Source of chirality: α-aminooxylation of aldehyde and diastereoselective MOM-ether directed aza-Claisen rearrangementAbsolute configuration: (3R,4S)

(4S,5R)-5-((tert-Butoxycarbonyl)amino)-4-(methoxymethoxy)hept-6-en-1-yl methanesulfonateC15H29NO7S[α]D25 = +15.35 (c 0.48, CHCl3)Source of chirality: α-aminooxylation of aldehyde and diastereoselective MOM-ether directed aza-Claisen rearrangementAbsolute configuration: (4S,5R)

(2R,3S)-tert-Butyl 3-(methoxymethoxy)-2-vinylpiperidine-1-carboxylateC14H25NO4[α]D25 = +18.6 (c 0.3, CHCl3)Source of chirality: α-aminooxylation of aldehyde and diastereoselective MOM-ether directed aza-Claisen rearrangementAbsolute configuration: (2R,3S)