PRACTICAL SYNTHETIC PROCEDURES
Transformation of L-Glutamic Acid into the g-Aldehyde
495
ally shacked by hands) for 30 min. The mixture was filtered under
vacuum on Celite and the filter cake washed with THF. The solvent
was evaporated under vacuum and the residue (9.6 g) purified by
chromatography [eluent: petroleum ether (60–80)–EtOAc, 6:1) as
previously described for compound 3. Product 4 was obtained as an
oil (6.85 g, 86% yield).
Acknowledgment
This work was financially supported by MIUR (Rome) within the
project PRIN-2003. The authors thank also Elena Cini (University
of Siena) for technical assistance.
1H NMR (200 MHz, CDCl3): d = 1.5–1.9 (m, 5 H including 1 ex-
changeable with D2O), 3.41 (t, J = 7 Hz, 1 H), 3.5 (m, 2 H), 3.58 (d,
J = 15 Hz, 2 H), 3.95 (d, J = 15 Hz, 2 H), 5.18 (AB system, 2 H),
7.1–7.5 (m, 15 H).
13C NMR (50 MHz, CDCl3): d = 25.7, 29.3, 54.6 (2 × C), 60.6, 62.3,
65.9, 127.0, 128.3 (2 × C), 128.4 (2 × C), 128.5 (2 × C), 128.8
(2 × C), 135.3, 139.3 (2 × C), 172.7.
References
(1) (a) Williams, R. M. Organic Chemistry Series, Vol. 7:
Synthesis of Optically Active a-Amino Acids; Balwin, J. E.;
Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989.
(b) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and
Biology; Wiley-VCH: Weinheim, 2002. (c) Barret, G. C.;
Davies, J. S. Amino Acids, Peptides and Proteins, Vol. 3;
The Royal Society of Chemistry: Cambridge, 2002.
(2) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b) Gelmi,
M. L.; Pocar, D. Org. Prep. Proced. Int. 2003, 35, 141.
(3) Recent examples: (a) Burkhart, D. J.; McKenzie, A. R.;
Nelson, J. K.; Myers, K. I.; Zhao, X.; Magnusson, K. R.;
Natale, N. R. Org. Lett. 2004, 6, 1285. (b) Koep, S.; Gais,
H.-J.; Raabe, G. J. Am. Chem. Soc. 2004, 125, 13243. (c)
See also: Watanabe, S.-I.; Cordova, A.; Tanaka, F.; Barbas,
C. F. I. III. Org. Lett. 2002, 4, 4519; and references therein.
(4) Olsen, R. K.; Ramasamy, K.; Emery, T. J. Org. Chem. 1984,
49, 3527.
MS (ES): m/z = 426 [M+ + Na].
Anal. Calcd for C26H29NO3 (403.21): C, 77.39; H, 7.24; N, 3.47.
Found C, 77.25; H, 7.25; N, 3.45.
2-Dibenzylamino-5-oxo-pentanoic Acid Benzyl Ester (2); Typi-
cal Procedure
A solution of anhyd DMSO (3.0 g, 38 mmol) in anhyd CH2Cl2(18
mL) was slowly added to a flask cooled to –78 °C containing oxalyl
chloride (2.56 g, 20 mmol) in anhyd CH2Cl2 (37 mL) under N2 and
magnetic stirring. The mixture was stirred for 15 min, then a solu-
tion of the alcohol 4 (6.43 g, 16 mmol) in anhyd CH2Cl2 (10 mL)
was slowly added. After stirring for 15 min, anhyd Et3N (5.3 mL)
was added and the mixture was stirred for 15 min at –78 °C. Addi-
tional Et3N (5 mL) was added and the flask was transferred into a
bath cooled to 0 °C and the mixture stirred for 15 min. Water (50
mL) was added, the mixture warmed to r.t. and the organic phase
separated. The aqueous phase was extracted several times with
CH2Cl2, all the organic fractions collected and washed with a 1 M
HCl solution, a sat. NaHCO3 solution and with brine. After drying
over anhyd Na2SO4, the solvent was evaporated to give aldehyde 2
(5) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.;
Martin, V. S. J. Org. Chem. 1998, 63, 3741.
(6) Compound 2 has been reported in the reaction schemes of
the previously cited paper without any detailed description
for its preparation. Also in a more detailed article compound
2 was cited but not described. In these papers, the reference
to the preparation of tetrabenzyl glutamic acid 2 reported to
a paper where the preparation of the corresponding
derivative of aspartic acid was described without any
experimental procedure: (a) Padron, J. M.; Kokotos, G.;
Martin, T.; Markidis, T.; Gibbons, W. A.; Martin, V. S.
Tetrahedron: Asymmetry 1998, 3381. (b) Gmeiner, P.;
Kartner, A.; Junge, D. Tetrahedron Lett. 1993, 34, 4325.
(7) Reetz, M. T.; Drewes, M. W.; Schwickardi, R. Org. Synth.
1998, 76, 110.
1
as a pure viscous oil determined via H, 13C and ES/MS analyses.
Yield: 6.5 g, 99%.
1H NMR (200 MHz, CDCl3): d = 2.05 (m, 2 H), 2.5 (m, 2 H), 3.40
(t, J = 7 Hz, 1 H), 3.65 (d, J = 16 Hz, 2 H), 2.94 (d, J = 16 Hz, 2 H),
5.35 (AB system, 2 H), 7.1–7.4 (m, 15 H), 9.58 (ca s, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.6, 40.4, 54.5 (2 × C), 59.8, 66.2,
127.1, 128.3 (2 × C), 128.4 (2 × C), 128.5 (2 × C), 128.6 (2 × C),
128.9 (2 × C), 139.6, 172.0, 201.3.
(8) (a) We performed chromatographic separation using
standard flash chromatography procedure up to 5 g of crude
material: Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem.
1978, 43, 2923. (b) For larger scale (up to 35 g of crude
material) we used a preparative chromatographic
workstation (Sepacore® from Büchi).
MS (ES): m/z = 424 [M+ + Na].
2-Dibenzylamino-5-(2-methylpropylamino)pentanoic Acid
Benzyl Ester (5); Typical Procedure
(9) The use of ionic liquids in reductive amination will be
reported elsewhere.
Isobutyl amine (109.7 mg, 1.5 mmol) was dissolved in anhyd
[bmim][BF4] (0.8 g) and NaCNBH3 (0.077 g, 1.12 mmol) was add-
ed. A solid was formed and to this mixture aldehyde 2 (0.3 g, 0.75
mmol) was added. The mixture was stirred at r.t. overnight. Water
was added followed by EtOAc (10 mL), the organic layer was sep-
arated and washed with a sat. solution of Na2CO3. After drying and
evaporation of the organic solvent, product 5 was isolated by flash
chromatography [eluent: from petroleum ether (60–80)–EtOAc, 6:1
to pure EtOAc]. Yield: 0.2 g, 58%.
1H NMR (200 MHz, CDCl3): d = 0.80 (d, J = 7 Hz, 6 H), 1.5 (br s,
1 H), 1.5–1.8 (m, 5 H), 2.25 (d, J = 8 Hz, 2 H), 2.32 (t, J = 7 Hz,
2 H), 2.30 (t, J = 7 Hz, 1 H), 3.48 (d, J = 15 Hz, 2 H), 3.85 (d, J =
16 Hz, 2 H), 5.25 (AB System, 2 H), 7.0–7.40 (m, 15 H).
(10) Yoshida, K.; Nakajima, S.; Wamatsu, T.; Ban, Y.;
Shibasaki, M. Heterocycles 1988, 27, 1167.
(11) For the preparation of compound 7 using enzymatic
resolution and its application to the synthesis of ACE
inhibitors, see: (a) Hayashi, K.; Nunami, K. I.; Kato, N.;
Kubo, M.; Ochiai, T.; Ishida, R. J. Med. Chem. 1989, 32,
289. (b) See also: Hernandez, J. N.; Martin, V. S. J. Org.
Chem. 2004, 69, 3590.
(12) When DIBAL came from a new bottle, 2 equiv were
sufficient to obtain good yields. When DIBAL came from a
previously opened bottle, we found that it was better to use
3 equiv. It is also possible to make further additions of
DIBAL at 0 °C until the starting material disappears.
13C NMR (50 MHz, CDCl3): d = 20.8 (2 × C), 26.8, 27.5, 28.4, 43.7,
54.7, 58.1, 60.9, 66.1, 127.1, 128.4 (2 × C), 128.6 (2 × C), 128.7
(2 × C), 129.0 (2 × C), 136.3, 139.8 (2 × C), 173.0.
MS (ES): m/z = 459 [M+ + 1].
Synthesis 2005, No. 3, 493–495 © Thieme Stuttgart · New York