Asymmetric Synthesis of Protected γ-Carboxy-l-glutamic Acid

Abstract

An asymmetric synthesis of an orthogonally protected γ-carboxy-l-glutamic acid (L-Gla) is developed featuring a key proline-catalyzed Knoevenagel condensation between Garner’s aldehyde and Meldrum’s acid.

Garner’s aldehyde - Meldrum’s acid - Knoevenagel condensation - proline-catalyzed

References

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23

Compound 2a: [α]_D ²⁵ +3.3 (c 1.0, CHCl₃). FT-IR (CHCl₃): 3432, 3026, 3015, 1733, 1503, 1437, 1368 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 6.20 (br s, 1 H), 5.09 (d, 1 H, J = 7.3 Hz), 4.39 (m, 1 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.57 (t, 1 H, J = 6.8 Hz), 2.54 (m, 1 H), 2.25 (m, 1 H), 1.43 (s, 9 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 175.5, 169.0, 155.5, 80.4, 52.8, 51.7, 48.3, 31.1, 28.2 ppm. HRMS: m/z calcd for C₁₃H₂₁NNaO₈ [M + Na]: 342.1165; found: 342.1174.
Compound 2b: [α]_D ²⁵ -2.5 (c 1.0, CHCl₃). FT-IR (CHCl₃): 3425, 3016, 2956, 1732, 1509, 1438, 1236, 1199, 1061
cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.35 (m, 5 H), 5.39 (br s, 1 H), 5.11 (s, 2 H), 4.50 (m, 1 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.59 (m, 1 H), 2.60 (m, 1 H), 2.27 (m, 1 H). ¹³C NMR (300 MHz, CDCl₃): δ = 175.1, 169.5, 169.1, 156.3, 136.1, 128.8, 128.6, 128.5, 128.3, 128.2, 67.4, 52.9, 52.2, 48.4, 31.2 ppm. HRMS (ESI): m/z calcd for C₁₆H₁₉NNaO₈ [M + Na]: 376.1008; found: 376.0993

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