First asymmetric synthesis of (R)-(-)-α-phenyl δ-amino valeric acid

Article abstract of DOI:10.1016/S0957-4166(00)00077-X

An efficient synthesis of the (R)-(-)-α-phenyl δ-amino valeric acid 1 is described starting from commercially available compounds. The key intermediate in this synthesis is the corresponding totally protected prochiral ketene. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00077-X

Tetrahedron: Asymmetry 11 (2000) 1263±1266
First asymmetric synthesis of (R)-(^)-a-phenyl
d-amino valeric acid
Monique Calmes,* Francoise Escale, Emmanuelle Juan,
Marc Rolland and Jean Martinez
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Laboratoire des Aminoacides, Peptides et Proteines, UMR-CNRS 5810-Universites Montpellier I et II, UM II,
Place E. Bataillon, 34095 Montpellier cedex 5, France
Received 7 February 2000; accepted 22 February 2000
Abstract
An ecient synthesis of the (R)-(^)-a-phenyl d-amino valeric acid 1 is described starting from commer-
cially available compounds. The key intermediate in this synthesis is the corresponding totally protected
prochiral ketene. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
d-Amino acids and their derivatives are an important group of compounds particularly in the
development of the corresponding functionalized d-lactams1,2 and new peptidomimetics.3 More-
over, the anticonvulsant e€ects of 3-mono- or 3-di-substituted d-lactams have recently been
described2 and underline the special interest of the stereoselective synthesis of their a-substituted
d-amino acid precursors.
We have recently developed a convenient and e€ective deracemization reaction4 involving
prochiral ketenes, which is well adapted to the synthesis of optically active a-phenyl substituted
carboxylic acids. We decided to examine this method for the asymmetric preparation of the a-
phenyl d-amino valeric acid 1. To our knowledge, only the racemic a-phenyl d-amino valeric acid
has been described previously and used for the preparation of a new semisynthetic penicillin
analogue5 or more recently as a new potential GABAB receptor antagonist.6
* Corresponding author. Fax: 04 67 14 48 66; e-mail: monique@ampir1.univ-montp2.fr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00077-X

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2. Results and discussion
The synthesis was performed through the asymmetric transformation of the racemic mixture of
the N-phthalyl d-amino acid derivative 2 by stereoselective addition of a chiral alcohol to the
corresponding prochiral ketene 4 (Scheme 2). The (R)-pantolactone, a very ecient commercially
available auxiliary,4,7 was used as the chiral alcohol. The phthalimido group, which totally pro-
tects the amine function, avoids the NH addition to the intermediate ketene and has the advan-
tage of being easily introduced and removed.
The racemic N-phthalyl d-amino acid derivative 2 was easily obtained by alkylation by N-bromo-
propylphthalimide of the phenylacetic acid benzyl ester prepared from the cheap commercially
available corresponding acid (Scheme 1). This reaction was achieved in good yield (80% after
puri®cation) by using lithium diisopropylamide as base and DMPU as co-solvent at low temp-
erature. Under these conditions we never observed dehydrobromination of the electrophile with
formation of N-allyl phthalimide, as described previously when using diethyl phenylmalonate as
the starting compound.6,8
Scheme 1. Synthesis of racemic N-phthalyl a-phenyl d-amino valeric acid 2
Scheme 2. Stereoselective synthesis of (R)-(^)-a-phenyl d-amino valeric acid 1
After cleavage of the benzyl ester by hydrogenolysis, the corresponding acid chloride 3 was
quantitatively obtained by treatment with oxalyl chloride at room temperature (Scheme 2). The
ketene 4 was next formed in situ by treatment of 3 with triethylamine (1.1 equivalents) for 1 h at
room temperature. The subsequent addition of (R)-pantolactone (1.1 equivalents) at the same
temperature a€orded the N-phthalyl pantolactonyl ester 5 in high chemical yield (78%) and with
a high diastereoisomeric excess (94%).9 Although the reaction was not totally diastereoselective,

M. Calmes et al. / Tetrahedron: Asymmetry 11 (2000) 1263±1266
1265
the enantiomerically pure 5 can be obtained by simple recrystallization from ether giving colorless
plates which were subjected to X-ray crystallographic analysis10 (Fig. 1). The absolute con®g-
uration of the newly generated stereogenic center was determined to be (R) by using the (R)-
pantolactonyl moiety as internal reference.
Figure 1. ORTEP drawing of the ester (aR,30R)
Hydrolysis4 under acidic conditions of the diastereomerically pure (aR,30R) N-phthalyl panto-
lactonyl ester followed by propylene oxide treatment a€orded the corresponding free (R)-a-
phenyl d-amino valeric acid 1.11
3. Conclusion
We have described the ®rst asymmetric synthesis of the (R)-a-phenyl d-amino valeric acid via
stereoselective addition of the (R)-pantolactone to the corresponding N-phthalyl ketene which
took place with high stereoselectivity at room temperature.
References
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S. M.; Ferrendelli, J. A.; Covey, D. F. J. Med. Chem. 1997, 40, 44±49.
2. Milewska, M. J.; Byner, T.; Polonski, T. Synthesis 1997, 1485±1488.
3. Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.; Saperstein, R. Science 1980, 210, 656; Freidinger,
R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104±109.
4. (a) Calmes, M.; Daunis, J.; Jacquier, R.; Natt, F. Tetrahedron 1994, 50, 6875±6880; (b) Calmes, M.; Daunis, J.;
Jacquier, R.; Mai, N.; Natt, F. Tetrahedron Lett. 1996, 37, 379±380; (c) Calmes, M.; Daunis, J.; Mai, N.
Tetrahedron: Asymmetry 1997, 8, 1641±1648; (d) Calmes, M.; Escale, F. Tetrahedron: Asymmetry 1998, 9, 2845±
2850; (e) Bouifraden, S.; Drouot, C.; El hadrami, M.; Guenoun, F.; Lecointe, L.; Mai, N.; Paris, M.; Pothion, C.;
Sadoune, M.; Sauvagnat, B.; Amblard, M.; Aubagnac, J. L.; Calmes, M.; Chevallet, P.; Daunis, J.; Enjalbal, C.;
Fehrentz, J. A.; Lamaty, F.; Lavergne, J. P.; Lazaro, R.; Rolland, V.; Roumestant, M. L.; Viallefont, Ph.; Vidal,
Y.; Martinez, J. Amino Acids (Review Article) 1999, 16, 345.
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M. Calmes et al. / Tetrahedron: Asymmetry 11 (2000) 1263±1266
7. Durst, T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799±6802; Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1993,
34, 4473±4476.
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9. The diastereoisomeric excess (de) of 5 was determined for the crude product from the 1H NMR spectrum (CDCl3)
by integration of the 30-CH signal of the pantolactonyl moiety of the mixture of diastereoisomers.
10. (aR,30R)-5 has the following physical data: mp 86ꢀC; [ꢀ]D=^13 (c=2 in CH2Cl2); [FAB+/GT] [M+H+] 436; H
1
NMR (CDCl3): ꢁ=1.04 (s, 3H, 40-CH3); 1.12 (s, 3H, 40-CH3); 1.68±2.26 (m, 4H, CHCH2CH2CH2N); 3.74 (t,
J1=J2=6.8 Hz, 2H, CH2N); 3.78 (t, J1=J2=7.6 Hz, 1H, CHCOO); 3.98 (d, J=9.1 Hz, 1H, 50-HCH); 4.04 (d,
J=9.1 Hz, 1H, 50-HCH); 5.32 (s, 1H, 30-CH); 7.33 (m, 5H, H-phenyl); 7.72 (m, 2H, H-phthalyl); 7.85 (m, 2H,
H-phthalyl). The di€raction data were collected on an Enraf±Nonius KappaCCD automatic di€ractometer using
graphite-monochromated Mo-Ka radiation and the f-scan technique up to y=25.41. Crystal data of 5: molecular
formula C25H25NO6, molecular weight=435, orthorhombic, space group P 212121, cell constants: a=5.9045(2) A,
b=11.4802(7) A, c=32.836(2) A, ꢀ,ꢂ,ꢃ=90.0ꢀ, V=2225.8(2) A3, Z=4, Dc=1.299 mg m^3, T=298 K, ®nal
Rw=0.089. Details of crystal structure determination have been deposited at the Cambridge Crystallographic
Data Centre (deposition number CCDC138846).
11. (R)-1, 97% de determined by HPLC analysis after derivatization with Marfey's reagent,12 has the following
ꢀ
1
physical data: mp 240 C (dec.); [ꢀ]D=^87 (c=2 in 1N HCl); H NMR (D2O+Na): ꢁ=1.25 (m, 2H, CH2CH2N);
1.59 (m, 1H, HCHCH2CHCOO); 1.87 (m, 1H, HCHCH2CHCOO); 2.46 (t, J1=J2=7.1 Hz, 2H, CH2N); 3.32 (t,
J1=J2=7.4 Hz, 1H, CHCOO); 4.72 (s, 1H, 30-CH); 7.20 (m, 5H, H-phenyl).
12. Marfey, P. Carlsberg Res. Commun. 1984, 49, 591±596.