Enantioselective synthesis of cis-(2S,3R)- and trans-(2S,3S)-piperidinedicarboxylic acids using domino: allylic acetate and Ireland-Claisen rearrangements and Michael addition as the key steps

An enantioselective synthesis of (2S,3R)-piperidine-2,3-dicarboxylic acid and (2S,3S)-piperidine-2,3-dicarboxylic acid is described. This synthesis was mainly based on a δ-amino acid formation via a domino reaction: allylic acetate rearrangement, stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition protocol from a Baylis–Hillman adduct, in which the cinnamaldehyde double bond is a masked carboxylic functionality, and a cerium(IV) ammonium nitrate promoted monodebenzylation.

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(4S,5R,αR,E)-4-Methoxycarbonyl-5-(N-α-methylbenzylamino)-7-phenyl-hept-6-enoic acidC23H27NO4[α]D26=+14.3 (c 0.47, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R,αR,E)

(2R,3S,αR,E)-Methyl-6-oxo-1-(N-α-methylbenzyl)-2-styryl-piperidine-3-carboxylateC23H25NO3[α]D26=+22.7 (c 1.40, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,αR,E)

(2S,3S,αR)-Methyl-2-formyl-6-oxo-1-(N-α-methylbenzyl)-piperidine-3-carboxylateC16H19NO4[α]D26=+65.9 (c 0.78, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration; (2S,3S,αR)

(2S,3S,αR)-6-Oxo-1-(N-α-methylbenzyl)-piperidine-2,3-dicarboxylic acid 3-methyl esterC16H19NO5[α]D26=+110.7 (c 0.84, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,αR)

(2S,3S,αR)-Dimethyl-6-oxo-1-(N-α-methylbenzyl)-piperidine-2,3-dicarboxylateC17H21NO5[α]D26=+92.6 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,αR)

(2S,3S,αR)-Dimethyl-1-(N-α-methylbenzyl)-piperidine-2,3-dicarboxylateC17H23NO4[α]D26=-3.6 (c 1.07, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,αR)

(2S,3S)-Dimethyl-piperidine-2,3-dicarboxylateC9H16NO4[α]D26=+31.4 (c 1.04, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)

(2S,3S)-Piperidine-2,3-dicarboxylic acid hydrochlorideC7H11NO4[α]D26=+18.6 (c 0.62, HCl 6 M)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)

(4R,5R,αR,E)-4-Methoxycarbonyl-5-(N-α-methylbenzylamino)-7-phenyl-hept-6-enoic acidC23H27NO4[α]D26=+26.8 (c 2.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4R,5R,αR,E)

(2R,3R,αR,E)-Methyl-6-oxo-1-(N-α-methylbenzyl)-2-styryl-piperidine-3-carboxylateC23H25NO3[α]D26=+8.9 (c 1.34, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,αR,E)

(2S,3R,αR)-Methyl-2-formyl-6-oxo-1-(N-α-methylbenzyl)-piperidine-3-carboxylateC16H19NO4[α]D26=+71.5 (c 0.91, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,αR)

(2S,3R,αR)-6-Oxo-1-(N-α-methylbenzyl)-piperidine-2,3-dicarboxylic acid 3-methyl esterC16H19NO5[α]D26=+52.6 (c 1.24, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,αR)

(2S,3R,αR)-Dimethyl-6-oxo-1-(N-α-methylbenzyl)-piperidine-2,3-dicarboxylateC17H21NO5[α]D26=+53.6 (c 1.27, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,αR)

(2S,3R,αR)-Dimethyl-1-(N-α-methylbenzyl)-piperidine-2,3-dicarboxylateC17H23NO4[α]D26=-2.0 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,αR)

(2S,3R)-Dimethyl-piperidine-2,3-dicarboxylateC9H16NO4[α]D26=+0.85 (c 1.18, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

(2S,3R)-Piperidine-2,3-dicarboxylic acid hydrochlorideC7H11NO4[α]D26=+1.8 (c 0.75, HCl 6 M)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)