Efficient and stereoselective synthesis of threo-β-hydroxy-l-glutamic acid via a tandem (Z)-olefination-conjugate addition

threo-β-Hydroxy-l-glutamic acid 1 is an attractive target as a biologically active compound and as a chiral synthon. The required β-hydroxyl group in 1 was efficiently and stereoselectively introduced via an intramolecular conjugate addition of the N-hydroxymethyl group of γ-amino-α,β-unsaturated (Z)-ester 4. While the corresponding (E)-ester 3 gave a lower selectivity of ca. 5:1 in the intramolecular conjugate addition, a selectivity of up to 70:1 was shown with (Z)-ester 4. The tandem (Z)-olefination-conjugate addition could be achieved by simply changing the reaction conditions to give a selectivity of >20:1. Thus, the target compound 1 was obtained as its hydrochloride salt in 70% overall yield over four steps from lactol 2.

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Methyl (2E,4S)-4-[(N-tert-butoxycarbonyl)-(N-hydroxymethyl)]amino-5-(tert-butyldimethylsilyloxy)pent-2-enoateC18H35NO6Si[α]D19=-3.0 (c 0.11, CHCl3)Source of chirality: d-serineAbsolute configuration: (2E,4S)

Methyl (2Z,4S)-4-[(N-tert-butoxycarbonyl)-(N-hydroxymethyl)]amino-5-(tert-butyldimethylsilyloxy)pent-2-enoateC18H35NO6Si[α]D25=-45.0 (c 0.90, CHCl3)Source of chirality: d-serineAbsolute configuration: (2Z,4S)

(4S,5R)-4-Hydroxymethyl-5-methoxycarbonylmethyl-oxazolidine-3-carboxylic acid tert-butyl esterC12H21NO6[α]D26=-22.7 (c 1.02, CHCl3)Source of chirality: d-serine and intramolecular conjugate additionAbsolute configuration: (4S,5R)

(4S,5R)-5-Methoxycarbonylmethyl-oxazolidine-3,4-dicarboxylic acid 3-tert-butyl esterC12H19NO7[α]D26=-61.0 (c 1.08, CHCl3)Source of chirality: d-serine and intramolecular conjugate additionAbsolute configuration: (4S,5R)

(2S,3R)-2-Amino-3-hydroxypentanedioic acid hydrochlorideC5H10ClNO5[α]D26=+19.7 (c 1.20, 20% aq HCl)Source of chirality: d-serine and intramolecular conjugate additionAbsolute configuration: (2S,3R)