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

<A NAME="RG47704ST-1A">1a</A> Howard JB. Nelsestuen GL. Biochem. Biophys. Res. Commun.  1974,  59:  757 

<A NAME="RG47704ST-1B">1b</A> Nelsestuen GL. Zytkovicz TH. J. Biol. Chem.  1974,  249:  6347 

<A NAME="RG47704ST-1C">1c</A> Zytkovicz TH. Nelsestuen GL. J. Biol. Chem.  1975,  250:  2968 

<A NAME="RG47704ST-2">2</A> Stenflo J. Fernlund P. Egan W. Roepstorff P. Proc. Natl. Acad. Sci. U.S.A.  1974,  71:  2730 

<A NAME="RG47704ST-3">3</A> Saito H. Hirata T. Tetrahedron Lett.  1987,  28:  4065 

<A NAME="RG47704ST-4">4</A> For a recent review, see: Scott JD. Williams RM. Chem. Rev.  2002,  102:  1669 

<A NAME="RG47704ST-5A">5a</A> Märki W. Opplinger M. Thanei P. Schwyzer R. Helv. Chim. Acta  1977,  60:  798 

<A NAME="RG47704ST-5B">5b</A> Boggs NT. Goldsmith B. Gawley RE. Koehler KA. Hiskey RG. J. Org. Chem.  1979,  44:  2262 

<A NAME="RG47704ST-5C">5c</A> Cerovsky V. Jost K. Collect. Czech. Chem. Commun.  1984,  49:  2562 

<A NAME="RG47704ST-6A">6a</A> Zee-Cheng RKY. Olson RE. Biochem. Biophys. Res. Commun.  1980,  94:  1128 

<A NAME="RG47704ST-6B">6b</A> Baldwin JE. North M. Flinn A. Moloney MG. J. Chem. Soc., Chem. Commun.  1988,  12:  828 

<A NAME="RG47704ST-7">7</A> Danishefsky S. Berman E. Clizbe LA. Hirama M. J. Am. Chem. Soc.  1979,  101:  4385 

<A NAME="RG47704ST-8A">8a</A> Tanaka K.-I. Yoshifuji S. Nitta Y. Chem. Pharm. Bull.  1986,  34:  3879 

<A NAME="RG47704ST-8B">8b</A> Effenberger F. Müller W. Keller R. Wild W. Ziegler T. J. Org. Chem.  1990,  55:  3064 

<A NAME="RG47704ST-9">9</A> Weinstein B. Watrin KG. Jeff Loie H. Martin JC. J. Org. Chem.  1976,  41:  3634 

<A NAME="RG47704ST-10">10</A> Dugave C. Menez A. J. Org. Chem.  1996,  61:  6067 

<A NAME="RG47704ST-11">11</A> Schuerman MA. Keverline KI. Hiskey RG. Tetrahedron Lett.  1995,  36:  825 

<A NAME="RG47704ST-12A">12a</A> Garner P. Park JM. J. Org. Chem.  1987,  52:  2361 

<A NAME="RG47704ST-12B">12b</A> Garner P. Park JM. J. Org. Chem.  1988,  53:  2979 

<A NAME="RG47704ST-12C">12c</A> Garner P. Park JM. Malecki E. J. Org. Chem.  1988,  53:  4395 

<A NAME="RG47704ST-12D">12d</A> Angrick M. Monatsh. Chem.  1985,  116:  645 

<A NAME="RG47704ST-12E">12e</A> Campbell AD. Raynham TM. Taylor RJK. Synthesis  1998,  1707 

<A NAME="RG47704ST-12F">12f</A> For a review, see: Liang X. Andersch J. Bols M. J. Chem. Soc., Perkin Trans. 1  2001,  2136 

Recent application in the synthesis of non-proteinogenic amino acid involving a sequence of olefination-hydrogenation of serinal, see:

<A NAME="RG47704ST-13A">13a</A> Xing X. Fichera A. Kumar K. Org. Lett.  2001,  3:  1285 

<A NAME="RG47704ST-13B">13b</A> Ramesh Babu I. Hamill EK. Kumar K. J. Org. Chem.  2004,  69:  5468 

<A NAME="RG47704ST-14">14</A> Reetz MT. Röhrig D. Angew. Chem., Int. Ed. Engl.  1989,  28:  1706 

<A NAME="RG47704ST-15">15</A> Grigg R. Lansdell MI. Thornton-Pett M. Tetrahedron  1999,  55:  2025 

<A NAME="RG47704ST-16">16</A> Larcheveque M. Tamagnan G. Petit Y. J. Chem. Soc., Chem. Commun.  1989,  31 

<A NAME="RG47704ST-17">17</A> Ma D. Wu Q. Tetrahedron Lett.  2000,  41:  9089 

<A NAME="RG47704ST-18">18</A> Oikawa Y. Hirasawa H. Yonemitsu O. Tetrahedron Lett.  1978,  1759 

<A NAME="RG47704ST-19">19</A> List B. Castello C. Synlett  2001,  1687 

<A NAME="RG47704ST-20">20</A> Dardennes E. Kovacs-Kulyassa A. Renzetti A. Sapi J. Laronze J.-Y. Tetrahedron Lett.  2003,  44:  221 

<A NAME="RG47704ST-21">21</A> Hedge JA. Kruse CW. Snyder HR. J. Org. Chem.  1961,  26:  3166 

<A NAME="RG47704ST-22">22</A> For a review on Meldrum’s acid, see: Chen BC. Heterocycles  1991,  32:  529 

<A NAME="RG47704ST-23">23</A>

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

<A NAME="RG47704ST-24">24</A> Davies JS. Enjalbal C. Nguyen C. Al-Jamri L. Naumer C. J. Chem. Soc., Perkin Trans. 1  2000,  2907