An alternate synthesis of enantiomerically pure levetiracetam (Keppra)

Article abstract of DOI:10.1016/j.tetasy.2012.10.006

A simple and efficient synthesis of levetiracetam has been achieved with high enantiopurity (>99%) starting from commercially available benzyl glycidyl ether. The method is amenable for industrial scale-up.

Full text of DOI:10.1016/j.tetasy.2012.10.006

Tetrahedron: Asymmetry 23 (2012) 1512–1515
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Tetrahedron: Asymmetry
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An alternate synthesis of enantiomerically pure levetiracetam (KeppraÒ)
⇑
M. Mujahid, P. Mujumdar, M. Sasikumar, S. S. Kunte, M. Muthukrishnan
Division of Organic Chemistry, CSIR–National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 September 2012
Accepted 10 October 2012
A simple and efficient synthesis of levetiracetam has been achieved with high enantiopurity (>99%) start-
ing from commercially available benzyl glycidyl ether. The method is amenable for industrial scale-up.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
H2N
O
NH2
Enantioselectivity plays an important role in the design and
development of many drugs, especially in the development of anti-
epileptic drugs (AEDs). Hence, the selective synthesis of individual
enantiomers of targets is extremely important because the antipo-
des often display different pharmacological and physiological
N
O
N
Ph
nebracetam
O
piracetam
nootropil®
properties.1
c-Butyrolactam based analogues are an important
structural class as they find prevalent use in treating epilepsy
and brain related disorders (Fig. 1).2 Among these substances, lev-
O
N
etiracetam 1 [(S)-a
-ethyl-2-oxo-pyrrolidine acetamide, KeppraÒ]3
NH2
is a novel antiepileptic drug with a unique antiepileptic mecha-
nism of action related to an interaction with the synaptic vesicle
protein 2A (SV2A).4 The beneficial effects of levetiracetam 1 in pa-
tients with bipolar disorders, migraines, chronic or neuropathic
pain, and diabetic complications are also reported.5 As a result, it
has attracted a great deal of attention from synthetic chemists
and different methods for the preparation of levetiracetam have
been extensively investigated. Generally, the reported methods
for the preparation involve classical resolution processes6 and
asymmetric syntheses7 and some of these methods have their
own intrinsic disadvantages such as expensive chiral starting
materials and catalysts; problems associated with the installation
of the 2-pyrrolidone moiety with harsh reaction conditions which
often leads to a loss of enantiomeric purity, usage of hazardous
alkylating agents, tedious and time consuming experiments, and
so on. Hence, to overcome these disadvantages, development of
newer methods in the preparation of levetiracetam is highly
desirable.
O
levetiracetam 1
Keppra®
F
O
O
N
N
NH2
NH2
O
O
seleteracetam
brivaracetam
Figure 1. Examples of
c-butyrolactam based drugs used in epilepsy and related
disorders.
Herein we report a concise and simple synthesis of levetiracetam
1 starting from commercially available benzyl glycidyl ether,
thereby devising a new approach that would enable the synthesis
Epoxides constitute one of the most widely used functional
groups in organic transformations and serve as important building
blocks in the industrial production of a wide variety of organic
materials.8 Over the past few years, investigations in our labora-
tory have demonstrated the potential utility of these epoxides for
the synthesis of many pharmaceutically important compounds.9
of other c-butyrolactam related antiepileptic drugs in high enan-
tiomeric purity.
2. Results and discussion
A
retrosynthetic analysis of levetiracetam is outlined in
Scheme 1. As shown in Scheme 1, we envisaged that the secondary
alcohol (R)-4 would be an ideal key intermediate for the synthesis
⇑
Corresponding author. Tel.: +91 20 25902571; fax: +91 20 25902629.
E-mail address: m.muthukrishnan@ncl.res.in (M. Muthukrishnan).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.006

M. Mujahid et al. / Tetrahedron: Asymmetry 23 (2012) 1512–1515
1513
partial reduction
debenzylation
oxidation
amidation
O
O
O
N
N
O
N
OH
OBn
NH2
(S)-7
(S)-5
O
1
Mitsunobu
OH
O
Grignard
HKR
O
OBn
OBn
OBn
(R)-3a
Scheme 1. Retrosynthetic analysis of levetiracetam 1.
(R)-4
2
of levetiracetam 1, which can be obtained easily from (R)-benzyl
glycidyl ether (R)-3a by a Grignard reaction. The key intermediate
(R)-4 can be elaborated to the advanced amide precursor (S)-7 by a
Mitsunobu reaction followed by partial reduction protocols. The
intermediate (S)-7 can be transformed into the target molecule 1
by simple oxidation and amidation reactions.
substitution of the hydroxyl group with succinimide using Bu3P
and DIAD in THF under Mitsunobu conditions. We observed that
the yield of the compound (S)-5 was very low when Ph3P was used
as a reagent. Several reaction conditions were tried for the mono
reduction of succinimido ether (S)-5 to obtain the compound (S)-
6. The mono reduction of succinimido ether (S)-5 employing a slow
addition of 1 equiv of BH3–DMS complex in anhydrous THF, condi-
tions recently reported by Ortiz-Marciales et al.,11 worked well and
afforded the compound (S)-6 in 66% yield.
It is noteworthy that installation of the 2-pyrrolidone moiety
employing a Mitsunobu reaction followed by mono reduction
using BH3–DMS is a straightforward and mild protocol when com-
pared to the harsh reaction conditions reported earlier. Compound
(S)-6 was next subjected to Pd(OH)2 catalyzed hydrogenolysis, fol-
lowed by oxidation with sodium chlorite catalyzed by TEMPO and
bleach in an acetonitrile-phosphate buffer (pH 6.8) and afforded
acid (S)-8 in 80% yield (two steps). Finally, acid (S)-8 was trans-
formed into the corresponding amide by consecutive reactions
with ethyl chloroformate and aq ammonia to give levetiracetam
Accordingly, our synthesis began with the commercially avail-
able rac-benzyl glycidyl ether 2, which was subjected to hydrolytic
kinetic resolution conditions to give enantiomerically pure epoxide
(R)-3a from the racemic mixture in 48% yield and >99% ee {½a D25
ꢀ
¼
ꢁ7:9 (c 0.4, EtOH); lit.10
[a
]
D = ꢁ5.8 (c 0.4, EtOH)} along with its
diol (S)-3b in 43% yield (Scheme 2). Next, the regioselective ring
opening of (R)-epoxide (R)-3a was carried out with MeMgI and a
catalytic amount of CuI in anhydrous THF at ꢁ20 °C to provide sec-
ondary alcohol (R)-4 in 93% yield. Installation of the 2-pyrrolidone
moiety onto secondary alcohol (R)-4 was carried out by using a two
step sequence via a Mitsunobu reaction followed by a partial
reduction. Accordingly, the secondary alcohol (R)-4 was readily
transformed into succinimido ether (S)-5 by stereospecific
OH
O
O
(S,S)-Salen-CoIII-(OAc) catalyst
OBn
HO
OBn
OBn
0.5 mol%
+
H2O, 0 °C to rt, 30 h
(S)-3b
2
(R)-3a
O
O
N
H
CuI
CH3MgI
THF
BH3.SMe2
THF
O
O
O
N
OH
N
Bu3P, DIAD
OBn
(R)-3a
OBn
OBn
-20 °C, 4 h
93%
reflux, 3h
66%
THF, rt, 8 h
82%
(R)-4
(S)-5
(S)-6
O
H2
Pd(OH)2
MeOH
Cat. TEMPO
O
N
O
N
N
ClCO2Et/Et3N
THF, 0 °C, 1 h
NaClO-NaClO2
NH2
OH
OH
rt, 24 h
92%
then
aq. NH3, rt, 16 h
80%
CH3CN:H2O
35 °C, 6 h
O
O
(S)-7
levetiracetam1
(S)-8
87%
ee > 99%
Scheme 2. Synthesis of levetiracetam 1.

1514
M. Mujahid et al. / Tetrahedron: Asymmetry 23 (2012) 1512–1515
1 in excellent enantioselectivity (>99% ee) without any additional
IR (CHCl3): mmax 3434, 3020, 1600, 1495, 1215, 1045, 1029, 929,
697 cmꢁ1 1H NMR (200 MHz, CDCl3): dH = 2.73 (t, J = 5.8 Hz, 1H,
crystallization (which is often required to obtain high enantiopuri-
;
ty in many reported methods) {½a D25
ꢀ
¼ ꢁ91:5 (c 1, acetone) {lit.6f
OH), 3.13 (d, J = 5 Hz, 1H, OH), 3.51–3.54 (dd, J = 5.4, 2.6 Hz, 2H),
3.57–3.68 (m, 2H), 3.82–3.92 (m, 1H), 4.54 (s, 2H), 7.28–7.39 (m,
5H, Ph); 13C NMR(50 MHz, CDCl3): dC = 137.6 (C), 128.4 (CH, 2 car-
bons), 127.8 (CH, 3 carbons), 73.5 (CH2), 71.6 (CH2), 70.7 (CH), 63.9
(CH2).
½
a 2D5
ꢀ
¼ ꢁ90:5 (c 0.99, acetone)}. The structure of levetiracetam 1
was confirmed by its IR, 1H NMR, 13C NMR, and mass spectroscopic
analysis. The enantiomeric purity of levetiracetam 1 was deter-
mined by chiral HPLC analysis.
4.1.2. (R)-1-(Benzyloxy)butan-2-ol (R)-4
3. Conclusion
To a pre-cooled (ꢁ20 °C) solution of epoxide (R)-3a (4.50 g,
27.4 mmol) and CuI (0.1 g) in dry THF (30 mL) was added dropwise
methyl magnesium iodide (7.5 mL, 54.8 mmol) in diethyl ether for
approximately 1 h. The reaction mixture was then allowed to re-
turn to ambient temperature and stirring continued for an addi-
tional 4 h. After completion of the reaction (as indicated by TLC),
aqueous NH4Cl was added, after which the reaction mixture was
filtered, and washed with ethylacetate. The solvent was removed
under reduced pressure and the crude product was subjected to
column chromatography (silica gel, petroleum ether/acetone,
In conclusion, we have developed a concise and efficient new
route for the synthesis of the antiepileptic drug levetiracetam,
starting from readily available benzyl glycidyl ether. High enantio-
purity (>99%) has been achieved without recrystallization of the fi-
nal product. In addition, the required 2-pyrrolidone moiety was
introduced conveniently via Mitsunobu and mono-reduction pro-
tocols. We envisage that this simple protocol may find application
in the pharmaceutical industry for the large scale production of
levetiracetum and that the strategy could be exploited further for
93:7) to yield (R)-4 as a colorless oil. (4.6 g; 93%); ½a D25
¼ ꢁ9:5 (c
ꢀ
the preparation of other pharmaceutically important
tam analogues.
c-butyrolac-
0.8, CHCl3) {lit.7c
½
a 2D5
ꢀ
¼ ꢁ10:0 (c 1, CHCl3)}; IR (CHCl3): 3435,
3020, 1601, 1422, 1118 cmꢁ1
;
1H NMR (200 MHz, CDCl3):
dH = 0.96 (t, J = 7.4 Hz, 3H), 1.42–1.56 (m, 2H), 2.35 (d, J = 3.4 Hz,
1H), 3.28–3.38 (m, 1H), 3.49–3.60 (m, 1H), 3.68–3.81 (m, 1H),
4.56 (s, 2H), 7.31–7.38 (m, 5H); 13C NMR (50 MHz, CDCl3):
dC = 138.0 (C), 128.5 (CH, 2 carbons), 127.9 (CH), 127.8 (CH, 2 car-
bons), 73.5 (CH), 72.6 (CH2), 69.9 (CH2), 26.1 (CH2), 9.3 (CH3); MS:
m/z 180 [M]+.
4. Experimental
4.1. General
Solvents were purified and dried by standard procedures prior
to use. IR spectra were obtained from Perkin–Elmer Spectrum
one spectrophotometer. 1H NMR and 13C NMR spectra were re-
corded on a Bruker AC-200 NMR spectrometer. Spectra were ob-
tained in CDCl3. Monitoring of reactions was carried out using
TLC plates Merck Silica Gel 60 F254, and visualization with UV light
(254 and 365 nm), I2, and anisaldehyde in ethanol as development
reagents. Optical rotations were measured with a JASCO P 1020
digital polarimeter. LC-ESI-MS data were obtained by injecting
the sample in Waters aquity ultra performance LC system
equipped with a PDA and SQ detector. The enantiomeric excess
was determined by chiral HPLC.
4.1.3. (S)-1-(1-(Benzyloxy)butan-2-yl)pyrrolidine-2,5-dione (S)-
5
A solution of DIAD (5.3 mL, 26.6 mmol) in dry THF (5 mL) was
added dropwise to a solution of (R)-4 (4.00 g, 22.2 mmol), succini-
mide (2.64 g, 26.6 mmol) and tributylphosphine (50% ethyl acetate
solution; 19.1 mL, 53.2 mmol) in dry THF (50 mL) under an N2
atmosphere at 0 °C. The reaction mixture was stirred at ambient
temperature for 8 h. The solvent was then removed under reduced
pressure and the residue was purified by column chromatography
(silica gel, petroleum ether/ethyl acetate, 80:20) to yield (S)-5 as a
colorless oil. (4.8 g; 82%); ½a D25
¼ þ31:5 (c 3.1, CHCl3); IR (CHCl3):
ꢀ
4.1.1. (R)-2-(Benzyloxymethyl) oxirane (R)-3a
3458, 3020, 2970, 2938, 2877, 1773, 1699, 1496, 1455, 1377,
1296, 1216, 1199, 1124, 1028, 952, 907, 820; 1H NMR (200 MHz,
CDCl3): dH = 0.85 (t, J = 7.4 Hz, 3H), 1.60–1.99 (m, 2H), 2.65 (s,
4H), 3.55–3.63 (dd, J = 9.8, 5.0 Hz, 1H), 3.98 (apparent t,
J = 9.8 Hz, 1H), 4.25–4.37 (m, 1H), 4.41–4.51 (m, 2H), 7.23–7.37
(m, 5H); 13C NMR (50 MHz, CDCl3): dC = 177.7 (CO, 2 carbons),
138.0 (C), 128.3 (CH, 2 carbons), 127.6 (CH), 127.5 (CH, 2 carbons),
72.6 (CH2), 68.7 (CH2), 53.4 (CH), 27.9 (CH2, 2 carbons), 21.1(CH2),
10.7 (CH3); MS: m/z 284 [M+Na]+.
A mixture of 2-(benzyloxymethyl)-oxirane 2 (10.00 g, 61 mmol)
and (S,S)-salen Co(III)OAc complex-A (0.09 g, 0.14 mmol) was vig-
orously stirred for 15 min, then cooled to 0 °C, and water added
(0.6 mL, 34 mmol) over a period of 15 min through a micro-syr-
inge. The reaction mixture was stirred at room temperature for
20 h, and then additional (S,S)-salen Co(III)OAc complex-A
(0.09 g, 0.14 mmol) was added and stirring was continued for an
additional 10 h. The reaction mixture was diluted with ethyl ace-
tate, dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography (silica gel,
petroleum ether/acetone (95:5). The less polar epoxide (R)-3a
4.1.4. (S)-1-(1-(Benzyloxy)butan-2-yl)pyrrolidin-2-one (S)-6
To a solution of compound (S)-5 (4.00 g, 15.3 mmol) in dry THF
(20 mL) at 0 °C was added dropwise the BH3–DMS complex
(1.4 mL, 15.3 mmol) under an N2 atmosphere. Next, the reaction
mixture was refluxed for 3 h. After completion of the reaction,
methanol (5 mL) was added carefully at 0 °C and the mixture
was then stirred for 20 min. The solvent was removed under re-
duced pressure and the residue was dissolved in ethyl acetate
(40 mL). After aqueous work-up the residue was purified by col-
umn chromatography (silica gel, petroleum ether/acetone, 70:30)
eluted first as a colorless oil (4.8 g, 48%), ½a D25
¼ ꢁ7:9 (c 0.4, EtOH)
ꢀ
{lit.10
½
a 2D0
ꢀ
¼ ꢁ5:8 (c 0.4, EtOH)}; ee > 99% [chiral HPLC analysis;
CHIRALCEL OD-H (250 ꢂ 4.6 mm) column; eluent: n-hexane/iso-
propanol = 90/10; flow rate: 0.5 mL/min; detector: 220 nm [(S)-
isomer tR = 15.25 min; (R)-isomer tR = 16.46 min]; IR (CHCl3): mmax
3418, 3020, 2401, 1719, 1603, 1523, 1495, 1421, 1216, 1094,
929, 669 cmꢁ1 lH NMR (200 MHz, CDCl3): dH = 2.60–2.64 (dd,
;
J = 5.1, 2.7 Hz, 1H), 2.78–2.82 (dd, J = 5.3, 4.2 Hz, 1H), 3.15–3.23
(m, 1H), 3.39–3.48 (dd, J = 11.3, 5.8 Hz, 1H), 3.73–3.81 (dd,
J = 11.4, 3.0 Hz, 1H), 4.60 (s, 2H), 7.28–7.37 (m, 5H); 13C NMR
(50 MHz, CDCl3): dC = 137.8 (C), 128.4 (CH, 2 carbons), 127.7 (CH,
3 carbons), 73.3 (CH2), 70.7 (CH2), 50.8 (CH), 44.2 (CH2). MS: m/z
187 [M+Na]+, followed by diol (R)-3b as a colorless oil (4.7 g,
to yield (S)-6 as a colorless oil. (2.5 g; 66%); ½a D25
¼ ꢁ30:5 (c 1,
ꢀ
CHCl3) {lit.7c
½
a 2D5
ꢀ
¼ ꢁ35:0 (c 1, CHCl3)}; IR (CHCl3): 3421, 3019,
1670, 1461, 1425, 1288, 1216, 1093, 928 cmꢁ1
;
1H NMR
(200 MHz, CDCl3): dH = 0.88 (t, J = 7.5 Hz, 3H), 1.43–1.64 (m, 2H),
1.90–2.05 (m, 2H), 2.41 (apparent t, J = 8 Hz 2H), 3.23–3.39 (m,
2H), 3.44–3.58 (m, 2H), 4.17–4.30 (m, 1H), 4.40–4.50 (m, 2H),
43%); ½a 2D5
ꢀ
¼ ꢁ2:3 (c 6.5, CHCl3) {lit.12
½
a 2D5
ꢀ
¼ ꢁ3:6 (c 6.6, CHCl3)};

M. Mujahid et al. / Tetrahedron: Asymmetry 23 (2012) 1512–1515
1515
7.24–7.39 (m, 5H); 13C NMR (50 MHz, CDCl3): dC = 175.5 (CO),
138.2 (C), 128.3 (CH, 2 carbons), 127.6 (CH, 3 carbons), 72.7
(CH2), 70.4 (CH2), 52.1 (CH), 43.3 (CH2), 31.4 (CH2), 21.5 (CH2),
18.3 (CH2), 10.6 (CH3); MS: m/z 270 [M+Na]+.
17 °C {lit.6f mp = 115–117 °C}; ½a 2D5
ꢀ
¼ ꢁ91:5 (c 1, acetone) {lit.6f
½
a 2D5
ꢀ
¼ ꢁ90:5 (c 0.99, acetone)}; IR (CHCl3): 3409, 3019, 1670,
1523, 1422, 1215, 1045, 757 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
dH = 0.90 (t, J = 7.4 Hz, 3H), 1.60–1.79 (m, 1H), 1.85–2.14 (m, 3H),
2.38–2.47 (m, 2H), 3.33–3.52 (m, 2H), 4.42–4.50 (dd, J = 8.9,
6.7 Hz, 1H), 5.77 (br s, 1H), 6.47 (br s, 1H); 13C NMR (50 MHz,
CDCl3): dC = 176.0 (CO), 172.5 (CO), 55.9 (CH), 43.7 (CH2), 30.9
(CH2), 21.1 (CH2), 18.0 (CH2), 10.4 (CH3); MS: m/z 171 [M+1]+,
193 [M+Na]+.
4.1.5. (S)-1-(1-Hydroxybutan-2-yl)pyrrolidin-2-one (S)-7
To a solution of (S)-6 (2.00 g, 8.1 mmol) in methanol (10 mL)
was added palladium hydroxide (0.2 g, 10–20 wt %) and the reac-
tion mixture was stirred under hydrogen (60 psi) for 24 h. After
completion of the reaction (indicated by TLC), the catalyst was fil-
tered over a plug of Celite and the solvent was evaporated under
reduced pressure. The crude product was purified by column chro-
matography (silica gel, ethylacetate/methanol, 95:5) to yield (S)-7
Acknowledgements
M.M. thanks the CSIR, New Delhi for a research fellowship.
Financial support from the CSIR Network projects (NAPAHA and
ORIG-IN) are gratefully acknowledged.
as a colorless oil. (1.2 g; 92%); ½a D25
ꢀ
¼ ꢁ20:1 (c 1.1, CHCl3) {lit.7b
½
a 2D5
ꢀ
¼ ꢁ11:8 (c 0.9, CHCl3)} IR (CHCl3): 3434, 3019, 1661, 1524,
1474, 1424, 1215, 1045, 928 cmꢁ1
;
1H NMR (200 MHz, CDCL3):
dH = 0.87 (t, J = 7.4 Hz, 3H), 1.36–1.62 (m, 2H), 1.93–2.1 (m, 2H),
2.39–2.47 (m, 2H), 3.24–3.50 (m, 2H), 3.54–3.72 (m, 3H), 3.87–
4.01 (m, 1H); 13C NMR (50 MHz, CDCl3): dC = 176.8 (CO), 62.8
(CH2), 55.8 (CH), 43.7 (CH2), 31.5 (CH2), 21.1 (CH2), 18.2 (CH2),
10.6 (CH3); MS: m/z 157 [M]+, 158 [M+1]+, 180 [M+Na]+.
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292862.
carboxylic acid (S)-8 (0.94 g, 87%); ½a D25
¼ ꢁ27:1 (c 1.1, CHCl3)
ꢀ
{lit.7a
½
a 2D5
ꢀ
¼ ꢁ23:6 (c 0.97, CHCl3)}; IR (CHCl3): 3444, 3020, 1646,
1422, 1215, 1122, 1043, 929, 759 cmꢁ1; 1H NMR (200 MHz, CDCl3):
dH = 0.94 (t, J = 7.3 Hz, 3H), 1.64–1.81 (m, 2H), 2.01–2.18 (m, 2H),
2.50 (t, J = 7.7 Hz, 2H), 3.31–3.42 (m, 1H), 3.50–3.62 (m, 1H),
4.61–4.69 (dd, J = 10.7, 5 Hz, 1H); 13C NMR (50 MHz, CDCl3):
dC = 177.1 (CO), 174.4 (CO), 55.5 (CH), 43.9 (CH2), 30.8 (CH2), 21.9
(CH2), 18.2 (CH2), 10.8 (CH3); MS: m/z 171 [M]+, 194 [M+Na]+.
4.1.7. (S)-2-(2-Oxopyrrolidin-1-yl)butanamide (levetiracetam) 1
To a solution of acid (S)-8 (0.70 g, 4.1 mmol) and triethylamine
(0.7 mL, 4.9 mmol) in dry THF (10 mL) was added ethyl chlorofor-
mate (0.4 mL, 4.5 mmol) at 0 °C under an argon atmosphere. After
1 h, ammonium hydroxide (25% w/v aqueous solution, 2.8 mL,
20.4 mmol) was added and the mixture was stirred at ambient
temperature for another 16 h. After completion of the reaction,
potassium carbonate (0.8 g, 6 mmol) was added and the reaction
mixture was filtered, and washed with ethyl acetate. The solvent
was removed under reduced pressure and the crude product was
subjected to column chromatography (silica gel, dichlorometh-
ane/methanol, 95:5) to yield 1 as a pale yellow solid (0.56 g,
80%); ee >99% [The ee was determined by chiral HPLC analysis:
DAICEL CHIRALCEL OD-H (250 ꢂ 4.6 mm) column; eluent: hex-
ane/isopropanol = 90/10; flow rate: 0.5 mL/min; detector 210 nm
[(R) isomer tR = 33.30 min; (S) isomer tR = 46.71 min]; mp = 116–
8. Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley-VCH: Weinheim,
2006.
9. (a) Muthukrishnan, M.; Mujahid, M.; Sasikumar, M.; Mujumdar, P. Tetrahedron:
Asymmetry 2011, 22, 1353; (b) Nikalje, M. D.; Sasikumar, M.; Muthukrishnan,
M. Tetrahedron: Asymmetry 2010, 21, 2825; (c) Sasikumar, M.; Nikalje, M. D.;
Muthukrishnan, M. Tetrahedron: Asymmetry 2009, 20, 2814; (d)
Muthukrishnan, M.; Garud, D. R.; Joshi, R. R.; Joshi, R. A. Tetrahedron 2007,
63, 1872; (e) Joshi, R. A.; Garud, D. R.; Muthukrishnan, M.; Joshi, R. R.; Gurjar, M.
K. Tetrahedron: Asymmetry 2005, 16, 3802.
10. Hansen, T. V.; Vaagen, V.; Partali, V.; Anthonsen, H. W.; Anthonsen, T.
Tetrahedron: Asymmetry 1995, 6, 499.
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2009, 74, 4195.
12. Thompson, A. M.; Sutherland, H. S.; Palmer, B. D.; Kmentova, I.; Blaser, A.;
Franzblau, S. G.; Wan, B.; Wang, B. –J.; Wang, Y. –H.; Ma, Z.-K. J. Med. Chem.
2011, 54, 6563.