Asymmetric synthesis of protected γ-carboxy-L-glutamic acid

Article abstract of DOI:10.1055/s-2005-863734

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.

Full text of DOI:10.1055/s-2005-863734

LETTER
851
Asymmetric Synthesis of Protected g-Carboxy-L-glutamic Acid
A
symmetric Syn
é
d
g
-Carboxy-
L
-
i
glutam
c
A
cid Couturier,a Mélanie Liron,a Thierry Schlama,b Jieping Zhu*a
a
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
b
Société Rhodia, Centre de Recherches de Lyon, 69192 Saint-Fons Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 30 December 2004
Abstract: An asymmetric synthesis of an orthogonally protected g-
carboxy-L-glutamic acid (L-Gla) is developed featuring a key pro-
line-catalyzed Knoevenagel condensation between Garner’s alde-
hyde and Meldrum’s acid.
Key words: Garner’s aldehyde, Meldrum’s acid, Knoevenagel
condensation, proline-catalyzed
The g-carboxy-L-glutamic acid (L-Gla), a tricarboxylic
acid, is a key component of several vitamin K dependent
blood clotting factors, including prothrombin.1 L-Gla
units, mainly located at the N-terminal of this protein, was
found to be responsible for the binding of prothrombin to
Ca2+, that is necessary for its activation during the process
of blood coagulation.2 Furthermore, a suitably protected
( )-Gla has been demonstrated to be a potentially useful
building block3 in the total synthesis of quinocarcin and
related complex bioactive natural products.4
Scheme 1
previously and was solved by stepwise sequence involv-
ing low-temperature aldol condensation, mesylation and
b-elimination.17 Inspired by the earlier work of Yonemit-
su on the proline-catalyzed three-component synthesis of
functionalized indole derivatives,18,19 the proline-cata-
lyzed condensation between Meldrum’s acid and Gar-
ner’s aldehyde was next investigated.20 To our delight, the
Several routes to L-Gla have been exploited including res-
olution of racemic materials5 and asymmetric syntheses.
L-Glutamate,6 L-pyroglutamate7 and L-proline8 have been
employed as chiral pools in previous syntheses. While
alkylation of fully protected serine with dialkylmalonate
usually gave racemic product due to the formation of de-
hydroalanine intermediate,9 a racemization-free protocol
has been developed based on the use of L-N-tritylserine
derivatives.10 Diastereoselective addition of chiral oxazi-
none to the di-tert-butyl methylenemalonate has also been
reported as a valuable approach to this non-proteinogenic
amino acid.11 Herein, we report a novel and efficient syn-
thesis of L-5,5¢-dimethyl-N-(Cbz and Boc)-4-carboxy-
glutamate (2a,b) starting from readily available Garner’s
aldehyde 4 (Scheme 1).12
The Knoevenagel condensation between 4 and malonate
was first examined.13 Among various conditions exam-
ined varying the promoters [Ti(OPr)4,14 Yb(OTf)3,15 pro-
line, piperidine, HOAc], the solvents (DMF, MeCN,
toluene), and the temperature (0 °C, r.t., heating), only
piperidinium acetate16 (prepared in situ, DMF, 60 °C)
provided the desired methylene malonate 3. However,
complete racemization occurred under these conditions.
The racemization of Garner’s aldehyde under Knoevena-
gel condensation conditions has been encountered
Scheme 2 a) D,L-proline (0.05 equiv), MeCN, r.t., 15 h, 86%; b) (i)
H2, Pd/C, t-BuOH–THF (1:1), 24 h; (ii) MeOH, 70 °C, 15 h; then
CH2N2, Et2O, 61%; c) H2O–HOAc = 3:7, 40 °C, 5 h, 78%; d) Jones
oxidation, 73%.
SYNLETT 2005, No. 5, pp 0851–0853
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863734; Art ID: G47704ST
© Georg Thieme Verlag Stuttgart · New York
2
1.
0
3.
2
0
0
5

852
C. Couturier et al.
LETTER
condensation proved to be highly efficient leading to com-
pound 6 in 85% yield (ee > 95%, Scheme 2). Under these
conditions, double alkylation resulting from the Michael
addition of Meldrum’s acid onto 6 was not observed.21,22
With this compound in hands, the subsequent transforma-
tion to 2 was straightforward. Hydrogenation followed by
methanolysis and esterification provided 7 in 61% overall
yield. Chemoselective hydrolysis of oxazolidine under
mild acidic conditions (HOAc, H2O) afforded the amino
alcohol 8, which was oxidized (Jones oxidation) to pro-
vide the protected L-Gla (2a) in 73% yield.23
Acknowledgment
We thank CNRS for financial support. Doctoral fellowships from
Rhodia to C. Couturier and from this institute to M. Liron are
gratefully acknowledged.
References
(1) (a) Howard, J. B.; Nelsestuen, G. L. Biochem. Biophys. Res.
Commun. 1974, 59, 757. (b) Nelsestuen, G. L.; Zytkovicz,
T. H. J. Biol. Chem. 1974, 249, 6347. (c) Zytkovicz, T. H.;
Nelsestuen, G. L. J. Biol. Chem. 1975, 250, 2968.
(2) Stenflo, J.; Fernlund, P.; Egan, W.; Roepstorff, P. Proc. Natl.
Acad. Sci. U.S.A. 1974, 71, 2730.
(3) Saito, H.; Hirata, T. Tetrahedron Lett. 1987, 28, 4065.
(4) For a recent review, see: Scott, J. D.; Williams, R. M. Chem.
Rev. 2002, 102, 1669.
The N-Cbz protected derivative 2b, was similarly pre-
pared from 7 in 45% overall yield (Scheme 3).
(5) (a) Märki, W.; Opplinger, M.; Thanei, P.; Schwyzer, R.
Helv. Chim. Acta 1977, 60, 798. (b) Boggs, N. T.;
Goldsmith, B.; Gawley, R. E.; Koehler, K. A.; Hiskey, R. G.
J. Org. Chem. 1979, 44, 2262. (c) Cerovsky, V.; Jost, K.
Collect. Czech. Chem. Commun. 1984, 49, 2562.
(6) (a) Zee-Cheng, R. K. Y.; Olson, R. E. Biochem. Biophys.
Res. Commun. 1980, 94, 1128. (b) Baldwin, J. E.; North,
M.; Flinn, A.; Moloney, M. G. J. Chem. Soc., Chem.
Commun. 1988, 12, 828.
(7) Danishefsky, S.; Berman, E.; Clizbe, L. A.; Hirama, M. J.
Am. Chem. Soc. 1979, 101, 4385.
(8) (a) Tanaka, K.-I.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull.
1986, 34, 3879. (b) Effenberger, F.; Müller, W.; Keller, R.;
Wild, W.; Ziegler, T. J. Org. Chem. 1990, 55, 3064.
(9) Weinstein, B.; Watrin, K. G.; Jeff Loie, H.; Martin, J. C. J.
Org. Chem. 1976, 41, 3634.
Scheme 3 a) TFA, CH2Cl2, then CbzOSu, dioxane, aq. NaHCO3,
51%; b) Jones oxidation, 92%.
(10) Dugave, C.; Menez, A. J. Org. Chem. 1996, 61, 6067.
(11) Schuerman, M. A.; Keverline, K. I.; Hiskey, R. G.
Tetrahedron Lett. 1995, 36, 825.
Both 2b and its racemic form were coupled with L-alanine
methyl ester to give 10 and 11, respectively (Figure 1).
HPLC analysis indicated that the de of 10, hence the ee of
2b is higher than 95%.
(12) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
(b) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979.
(c) Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988,
53, 4395. (d) Angrick, M. Monatsh. Chem. 1985, 116, 645.
(e) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K.
Synthesis 1998, 1707. (f) For a review, see: Liang, X.;
Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001,
2136.
(13) Recent application in the synthesis of non-proteinogenic
amino acid involving a sequence of olefination–
hydrogenation of serinal, see: (a) Xing, X.; Fichera, A.;
Kumar, K. Org. Lett. 2001, 3, 1285. (b) Ramesh Babu, I.;
Hamill, E. K.; Kumar, K. J. Org. Chem. 2004, 69, 5468.
(14) Reetz, M. T.; Röhrig, D. Angew. Chem., Int. Ed. Engl. 1989,
28, 1706.
(15) Grigg, R.; Lansdell, M. I.; Thornton-Pett, M. Tetrahedron
1999, 55, 2025.
(16) Larcheveque, M.; Tamagnan, G.; Petit, Y. J. Chem. Soc.,
Chem. Commun. 1989, 31.
Figure 1
(17) Ma, D.; Wu, Q. Tetrahedron Lett. 2000, 41, 9089.
(18) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett.
1978, 1759.
(19) List, B.; Castello, C. Synlett 2001, 1687.
(20) Dardennes, E.; Kovacs-Kulyassa, A.; Renzetti, A.; Sapi, J.;
Laronze, J.-Y. Tetrahedron Lett. 2003, 44, 221.
(21) Hedge, J. A.; Kruse, C. W.; Snyder, H. R. J. Org. Chem.
1961, 26, 3166.
In summary, we developed a straightforward synthesis of
protected L-Gla ready for peptide coupling. The synthesis
is easily scaled up and is expected to find application in
the synthesis of peptidomimetics with targeted thera-
peutic applications.24
(22) For a review on Meldrum’s acid, see: Chen, B. C.
Heterocycles 1991, 32, 529.
Synlett 2005, No. 5, 851–853 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Protected g-Carboxy-L-glutamic Acid
853
(23) Compound 2a: [a]D25 +3.3 (c 1.0, CHCl3). FT-IR (CHCl3):
3432, 3026, 3015, 1733, 1503, 1437, 1368 cm–1. 1H NMR
(250 MHz, CDCl3): d = 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,
cm–1. 1H NMR (300 MHz, CDCl3): d = 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): d = 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
J = 6.8 Hz), 2.54 (m, 1 H), 2.25 (m, 1 H), 1.43 (s, 9 H). 13
NMR (62.5 MHz, CDCl3): d = 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.
C
(24) Davies, J. S.; Enjalbal, C.; Nguyen, C.; Al-Jamri, L.;
Naumer, C. J. Chem. Soc., Perkin Trans. 1 2000, 2907.
Compound 2b: [a]D25 –2.5 (c 1.0, CHCl3). FT-IR (CHCl3):
3425, 3016, 2956, 1732, 1509, 1438, 1236, 1199, 1061
Synlett 2005, No. 5, 851–853 © Thieme Stuttgart · New York