A short enantioselective synthesis of the antiepileptic agent, levetiracetam based on proline-catalyzed asymmetric α-aminooxylation

Article abstract of DOI:10.1016/j.tetlet.2006.07.061

An efficient enantioselective synthesis of a new antiepileptic drug, levetiracetam is described, in high optical purity (>99.5% ee), using proline-catalyzed α-aminooxylation of n-butyraldehyde as the key step.

Full text of DOI:10.1016/j.tetlet.2006.07.061

Tetrahedron Letters 47 (2006) 6813–6815
A short enantioselective synthesis of the antiepileptic agent,
levetiracetam based on proline-catalyzed asymmetric
a-aminooxylation
Shriram P. Kotkar and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 1 June 2006; revised 30 June 2006; accepted 14 July 2006
Available online 4 August 2006
Abstract—An efficient enantioselective synthesis of a new antiepileptic drug, levetiracetam is described, in high optical purity
(>99.5% ee), using proline-catalyzed a-aminooxylation of n-butyraldehyde as the key step.
Ó 2006 Elsevier Ltd. All rights reserved.
Epilepsy is a chronic neurological disorder that consists
of repeated occurrences of spontaneous seizures. Leveti-
racetam, [(S)-a-ethyl-2-oxopyrrolidine acetamide, 1],
has recently been approved as an add-on therapy for
the treatment of refractory epilepsy.1 The (S)-enantio-
mer of Etiracetam (levetiracetam), has shown outstand-
ing pharmacokinetic and pharmacological activity
which has led to the rapid approval of this antiepileptic
drug by the FDA. Levetiracetam offers several advanta-
ges over traditional therapy, including twice daily dos-
ing, a wide margin of safety with no requirements for
serum drug concentration monitoring, no interactions
with other anticonvulsants and has less adverse effects
than traditional treatments.2
The field of asymmetric organocatalysis in organic syn-
thesis is rapidly growing and has provided several new
methods for obtaining chiral compounds in an environ-
mentally benign manner.9 In this connection, proline, an
abundant, inexpensive amino acid available in both
enantiomeric forms, has emerged as arguably the most
practical and versatile organocatalyst.10 Proline has also
been found to be an excellent asymmetric catalyst for
a-functionalization8 of aldehydes and ketones. We
employed proline-catalyzed a-aminooxylation coupled
with SN2 displacement of an O-mesyl group with 2-pyr-
rolidone in achieving the enantioselective synthesis of
levetiracetam 1.
The literature methods for the synthesis of levetiracetam
typically involve chiral pool approaches starting from
enantiopure a-amino acids,3 resolution of Etiracetam
or advanced racemic intermediates,3a,4 asymmetric
hydrogenation over Rh(I) or Ru(II) complexes,5 and
deracemization of 2-bromobutyric acid using N-phenyl-
pantolactam as a chiral auxiliary.6 As a part of our
research program aimed at developing stereocontrolled
syntheses of bioactive molecules,7 we report a highly effi-
O
N
NH2
O
1 Levetiracetam
Our synthesis started with a-aminooxylation8a of n-
butyraldehyde which was carried out using nitrosobenz-
ene and L-proline (25 mol %) at ꢀ20 °C to furnish the
aminooxy aldehyde which was reduced in situ with
sodium borohydride to afford (R)-a-aminooxy alcohol
cient synthesis of levetiracetam
1 using proline-
catalyzed a-aminooxylation8 of n-butyraldehyde as the
25
25
key step (Scheme 1).
2 in 85% yield; ½aꢁD +20.7 (c 1, CHCl3), {lit.8e ½aꢁD
+20.5 (c 1, CHCl3)}. The protected alcohol 2 was then
hydrogenated over Pd/C (10 mol %) to furnish (R)-1,2-
butanediol 3 in 90% yield. Selective monobenzylation
*
of diol 3 was carried out using Bu2SnO and benzyl
bromide to give 4 in 95% yield; ½aꢁD ꢀ10 (c 1, CHCl3).
Corresponding author. Tel.: +91 20 25902174; fax: +91 20
25902676; e-mail: a.sudalai@ncl.res.in
25
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.061

6814
S. P. Kotkar, A. Sudalai / Tetrahedron Letters 47 (2006) 6813–6815
ONHPh
OH
OH
b
a
d
OR
CHO
2
3 R = H
c
4 R = Bn
O
O
O
OMs
N
N
N
g
h
e
OBn
NH2
OR
OH
5
O
O
6 R = Bn
7 R = H
8
f
Levetiracetam 1
Scheme 1. Reagents and conditions: (a) PhNO, L-proline (25 mol %), ꢀ20 °C, 24 h then MeOH, NaBH4, 85%; (b) H2 (1 atm), Pd/C (10%), MeOH,
12 h, 90%; (c) Bu2SnO, toluene, reflux, 12 h then Bu4NBr, BnBr, reflux, 24 h, 95%; (d) MsCl, Et3N, CH2Cl2, 0–25 °C, 4 h, 92%; (e) 2-pyrrolidone,
NaH, DMF, 130 °C, 3 h, 62%; (f) H2 (1 atm), Pd/C (10%), MeOH, 6 h, 97%; (g) TEMPO (7 mol %), NaClO–NaClO2, acetonitrile, phosphate buffer
(pH 6.8), 25 °C, 6 h, 90%; (h) ClCO2Et, Et3N, THF, 0 °C, 30 min then NH4OH, 16 h, 75%, 99.5% ee.
Shorvon, S. D.; van Rijckevorsel, K. J. Neurol. Neurosurg.
Psychiatry 2002, 72, 426.
Unfortunately, direct displacement of the secondary
hydroxyl group in 4 with 2-pyrrolidone under Mitsun-
obu conditions was unsuccessful. Hence, alcohol 4 was
treated with methanesulfonyl chloride and triethylamine
to give mesylate 5 in 92% yield. Nucleophilic displace-
ment of mesylate 5 with 2-pyrrolidone in dry DMF at
130 °C proceeded smoothly to give the benzyl ether
(S)-611 in 62% yield. Debenzylation of 6 was carried
out by catalytic hydrogenation over Pd/C (10 mol %)
followed by oxidation of the resulting alcohol 7 with so-
dium hypochlorite–sodium chlorite in the presence of a
catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO)12 in acetonitrile–phosphate buffer (pH 6.8) to
afford the corresponding acid 8 in 88% overall yield.
Acid 8, on treatment with ethyl chloroformate and
ammonium hydroxide,3a produced levetiracetam13 1 in
82% yield (75% after recrystallization from acetone)
and >99.5% ee (determined by chiral HPLC analysis
of the recrystallized sample).14
3. (a) Gobert, J.; Greets, J. P.; Bodson, G. Eur. Pat. Appl.
E0162036; Chem. Abstr. 105, 018467; (b) Dolityzky, B. Z.
PCT Int. Appl. WO 2004/069796; Chem. Abstr. 133,
183002; (c) Ates, C.; Surtees, J.; Burteau, A. C.; Marmon,
V.; Cavoy, E. PCT Int. Appl. WO 2003/014080; Chem.
Abstr. 138, 170071; (d) Cossement, E.; Motte, G.; Greets,
J. P.; Gobert, J. UK Pat. Appl., GB 2225322; Chem. Abstr.
113, 191151.
4. (a) Futagawa, T.; Canvat, J. P.; Cavoy, E.; Deleers, M.;
Hamende, M.; Zimmermann, V. US Patent 2000/6107492;
Chem. Abstr., 133, 183002; (b) Cavoy, E.; Hamende, M.;
Deleers, M.; Canvat, J. P.; Zimmermann, V. US Patent
2000/6124473; Chem. Abstr. 133, 268549.
5. (a) Surtees, J.; Marmon, V; Differding, E.; Zimmermann,
V. PCT Int. Appl. WO 2001/64367; (b) Boaz, N. W.;
Debenham, S. D. PCT Int. Appl. WO 2002/26705; Chem.
Abstr. 136, 279566.
6. Boschi, F.; Camps, P.; Comes-Franchini, M.; Munoz-
Torrero, D.; Riccib, A.; Sancheza, L. Tetrahedron: Asym-
metry 2005, 16, 3739.
7. (a) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62,
5756; (b) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006,
62, 4907; (c) Sayyed, I. A.; Thakur, V. V.; Nikalje, M. D.;
Dewkar, G. K.; Kotkar, S. P.; Sudalai, A. Tetrahedron
2005, 61, 2831; (d) Sayyed, I. A.; Sudalai, A. Tetrahedron:
Asymmetry 2004, 15, 3111; (e) Thakur, V. V.; Nikalje, M.
D.; Sudalai, A. Tetrahedron: Asymmetry 2003, 14, 581; (f)
Sayyed, I. A.; Sudalai, A. Tetrahedron Lett. 2002, 43,
5435.
8. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293; (b) Zhong, G. Angew.
Chem., Int. Ed. 2003, 42, 4247; (c) Hayashi, Y.; Yama-
guchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.
2003, 43, 1112; (d) List, B. J. Am. Chem. Soc. 2002, 125,
5656; (e) Cordova, A.; Sunden, H.; Bøgevig, A.; Johans-
son, M.; Himo, F. Chem. Eur. J. 2004, 10, 3673.
9. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138; (c) Houk, K. N., List, B., Eds. Acc.
Chem. Res. 2004, 37, 487; (d) List, B., Bolm, C., Eds. Adv.
Synth. Catal. 2004, 346; (e) List, B.; Seayad, J. Org.
Biomol. Chem. 2005, 3, 719.
In conclusion, a practical and short enantioselective
synthesis of levetiracetam, 1, has been achieved success-
fully by employing a proline-catalyzed a-aminooxy-
lation strategy. The reactions are rapid and require a
relatively low amount of the inexpensive and nontoxic
proline as a catalyst which is available in both enantio-
meric forms. The merit of the synthesis is that leveti-
racetam has been obtained with high enantioselectivity
(>99.5% ee) and in a good overall yield (29.7%).
Acknowledgements
S.P.K. thanks CSIR, New Delhi, for the award of
research fellowships. The authors are thankful to Dr.
B. D. Kulkarni, Head, CEPD, for his support and
encouragement.
References and notes
10. For a review of proline-catalyzed asymmetric reactions,
see: List, B. Tetrahedron 2002, 58, 5573.
1. Hurtado, B.; Koepp, M. J.; Sander, J. W.; Thompson, P.
J. Epilepsy Behav. 2006, 8, 588.
2. (a) Dooley, M.; Plosker, G. L. Drugs 2000, 60, 871; (b)
Hovinga, C. A. Pharmacotherapy 2001, 21, 1375; (c)
25
11. Spectral data for 6: ½aꢁD ꢀ35.0 (c 1, CHCl3); 1H NMR
(200 MHz, CDCl3): d 0.88 (t, J = 7.4 Hz, 3H), 1.46–1.63
(m, 2H), 1.93–2.05 (m, 2H), 2.38 (t, J = 8.4 Hz, 2H), 3.27–

S. P. Kotkar, A. Sudalai / Tetrahedron Letters 47 (2006) 6813–6815
6815
3.38 (m, 2H), 3.47–3.51 (m, 2H), 4.19 (m, 1H), 4.43 (dd,
J = 12.2, 15.1 Hz, 2H), 7.28 (m, 5H); 13C NMR (50 MHz,
CDCl3): d 10.42, 18.11, 21.26, 30.92, 43.04, 51.79, 70.15,
72.41, 127.19, 127.96, 137.88, 174.58. Elemental Analysis:
C15H21NO2 requires C, 72.84; H, 8.56; N, 5.66. Found: C,
72.88; H, 8.55; N, 5.63.
(m, 3H), 2.38–2.47 (m, 2H), 3.34–3.55 (m, 2H), 4.42–4.50
(dd, J = 6.7, 8.6 Hz, 1H), 5.76 (br s, 1H), 6.52 (br s, 1H);
13C NMR (50 MHz, CDCl3): d 10.27, 17.89, 21.09,
30.81, 43.57, 55.71, 172.59, 175.75. Elemental analysis:
C8H14N2O2 requires C, 56.45; H, 8.29; N, 16.46. Found:
C, 56.49; H, 8.34; N, 16.44.
12. Zhao, M. L.; Mano, E.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J.; Reider, P. J. J. Org. Chem. 1999, 64,
2564.
14. HPLC conditions: Chiral OD-H column; hexane: i-PrOH
(90:10 v/v); flow rate 1.0 mL/min; UV – 210 nm; column
temperature 25 °C; retention time: 10.3 min (R-isomer)
and 16.3 min (S-isomer). Compared with reported condi-
tions: Rao, B. M.; Ravi, R.; Reddy, B. S.; Sivakumar, S.;
Gopi Chand, I.; Praveen Kumar, K.; Acharyulu, P. V. R.;
Om Reddy, G.; Srinivasu, M. K. J. Pharm. Biomed. Anal.
2004, 35, 1017.
13. Spectral data for levetiracetam: mp 116 °C, {lit.3a mp
25
25
117 °C}; ½aꢁD ꢀ90.3 (c 1, acetone) {lit.3a ½aꢁD ꢀ90.0 (c 1,
acetone)}; IR (CHCl3) mmax: 3672, 3332, 3009, 2463, 1668,
1422, 1288, 1043, 754 cmꢀ1, 1H NMR (200 MHz, CDCl3):
d 0.91 (t, J = 7.5 Hz, 3H), 1.60–1.75 (m, 1H), 1.90–2.09