First asymmetric synthesis of the antiepileptic drug Lacosamide (Vimpat) based on a hydrolytic kinetic resolution strategy

Article abstract of DOI:10.1016/j.tetasy.2011.07.024

An efficient asymmetric synthesis of the new antiepileptic drug, Lacosamide is described in high enantiopurity (>98% ee), using Jacobsen's hydrolytic kinetic resolution strategy as a key step.

Full text of DOI:10.1016/j.tetasy.2011.07.024

Tetrahedron: Asymmetry 22 (2011) 1353–1357
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First asymmetric synthesis of the antiepileptic drug Lacosamide (VimpatÒ)
based on a hydrolytic kinetic resolution strategy
⇑
M. Muthukrishnan , M. Mujahid, M. Sasikumar, P. Mujumdar
Division of Organic Chemistry, National Chemical Laboratory (NCL), CSIR, 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:
An efficient asymmetric synthesis of the new antiepileptic drug, Lacosamide is described in high enantio-
purity (>98% ee), using Jacobsen’s hydrolytic kinetic resolution strategy as a key step.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 June 2011
Accepted 25 July 2011
Available online 22 August 2011
1. Introduction
2. Results and discussion
Epilepsy is a complex neurological disorder characterized by
recurrent spontaneous seizures and affects almost 50 million
people worldwide.1 The life time prevalence of this disease is 1%
and it affects individuals of all ages regardless of gender or socio-
economic status. Further, epilepsy requires prolonged and some-
times lifelong drug therapy. Lacosamide 12,3 is the (R)-enantiomer
of N-benzyl-2-acetamido-3-methoxypropionamide, recently ap-
proved by FDA (Oct, 2008) as an add-on therapy for partial-onset
seizures in adults with epilepsy (Trade Name: VimpatÒ owned by
UCB Pharma). Although the mechanism of action of Lacosamide
is not yet clearly understood, but it is believed that it enhances
slow inactivation of voltage-gated Na+ channels and binds to dihy-
dropyrimidinase-related protein 2 (CRMP 2), and thus controls the
seizures.2a Due to this unique mode of action, it differs from other
antiepileptic drugs (AEDs). Commercially, Lacosamide is prepared
using a chiral pool approach starting from unnatural amino acid
A retrosynthetic analysis of Lacosamide is outlined in Scheme 1.
We envisaged that the azido compound (R)-5 would serve as a key
intermediate for the synthesis. It can be elaborated to the advanced
acid precursor (R)-7 by simple hydrogenation, hydrogenolysis, and
oxidation sequences followed by amidation to give the target mole-
cule 1. Compound(R)-5 canalsobe accessedfrom(S)-benzyl glycidyl
ether (S)-3a by employing regioselective ring opening as well as
Mitsunobu reaction protocols. (S)-Benzyl glycidyl ether (S)-3a can
be easily obtained with high enantiopurity from its racemic benzyl
glycidyl ether 3 using Jacobsen’s hydrolytic kinetic resolution
strategy.
The reaction of benzyl alcohol 2 with rac-epichlorohydrin in
the presence of NaOH as a base gave rac-benzyl glycidyl ether 3
in 91% yield (Scheme 2). The rac- benzyl glycidyl ether 3 was sub-
jected to Jacobsen’s hydrolytic kinetic resolution conditions with
0.55 equiv of water using the catalyst (R,R)-Salen Co(III)OAc
(0.5 mol %) at ambient temperature for 30 h. After completion of
the reaction, the reaction mixture was chromatographed over sil-
ica gel column to give enantiomerically pure epoxide (S)-3a from
D
-serine and its derivatives.2,3 To the best of our knowledge, there
has been no asymmetric synthesis of this molecule reported.
the racemic mixture in 47% yield and >99% ee {½a D
ꢀ ¼ þ8:1 (c 0.4,
O
EtOH); lit.6
½
a
ꢀD ¼ þ7:8 (c 0.4, EtOH)} along with its diol (R)-3b in
NH
H
43% yield. The epoxide (S)-3a was subjected to regioselective ring
opening with methanol in the presence of KOH as a base to give
the corresponding secondary alcohol (S)-4 in 98% yield (Scheme 2).
The secondary alcohol (S)-4 was converted into the desired azido
derivative (R)-5 in 83% yield using DPPA under Mitsunobu condi-
tions. Next, the azido compound (R)-5 was subjected to Pd(OH)2
catalyzed hydrogenation/hydrogenolysis followed by N-acetyla-
tion using acetyl chloride under basic conditions to give com-
pound (S)-6 (Scheme 3) in 85% yield (two steps). Having
successfully synthesized the precursor (S)-6, our next aim was
to convert (S)-6 into acid (R)-7, followed by coupling with benzyl-
amine to complete the synthesis of Lacosamide 1. However, oxida-
tion of compound (S)-6 to acid (R)-7 posed a problem. Oxidative
conditions with sodium chlorite catalyzed by TEMPO and bleach
MeO
N
O
Lacosamide (Vimpat®) 1
Over the past few years, investigations in our laboratory have
demonstrated the utility of Jacobsen’s hydrolytic kinetic resolution
strategy4 for the synthesis of many pharmaceutically important
compounds.5 In this context, we herein report the first asymmetric
synthesis of the antiepileptic drug Lacosamide.
⇑
Corresponding author. Tel.: +91 20 25902284; fax: +91 20 25902629.
E-mail address: m.muthukrishnan@ncl.res.in (M. Muthukrishnan).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.024

1354
M. Muthukrishnan et al. / Tetrahedron: Asymmetry 22 (2011) 1353–1357
O
O
NH
HN
amide formation
H
O
N
O
CO2H
O
(R)-7
(R)-Lacosamide 1
hydrogenation/
hydrogenolysis
oxidation
regioselective ring
opening followed by
Mitsunobu
N3
O
O
HKR
OBn
O
OBn
OBn
(R)-5
(RS)-3
(S)-3a
Scheme 1. Retrosynthetic analysis of Lacosamide 1.
O
Cl
(0.5 mol%)
OH
O
OH
O
(R,R)-salenCo(III)OAc
OBn
50% NaOH, TBAI
HO
OBn
OBn
+
rt, 24 h
91%
0 °C to rt, 30 h
(S)-3a
3
2
(R)-3b
47%
43%
>99% ee
DPPA
OH
N3
KOH, MeOH
DIAD, Ph3P
O
OBn
MeO
OBn
MeO
OBn
toluene
-20 °C to rt, 10 h
0 °C to rt, 8 h
98%
(S)-3a
(S)-4
(R)-5
83%
Scheme 2.
cat. TEMPO
buffer
NaOCl/NaClO2
CH3CN
O
O
i) Pd(OH)2, H2
MeOH, rt, 24 h
HN
HN
MeO
X
MeO
OH
CO2H
ii) CH3COCl, Na2CO3,
(or)
(S)-6
Jones oxidation
(R)-7
toluene, 5 °C, 1 h
85% two steps
(R)-5
cat. TEMPO
buffer
NaOCl/NaClO2
NHBoc
CO2H
NHBoc
OH
Pd(OH)2, H2
MeO
MeO
CH3CN, 35 °C, 6 h
83%
(Boc)2O, EtOAc, 36 h
86%
(S)-8
Scheme 3.
(R)-9
and Jones oxidative conditions failed to produce the desired acid
(R)-7.
an acetonitrile–phosphate buffer (pH 6.8) and afforded the corre-
sponding acid (R)-9 in 83% yield. Acid (R)-9 was then converted into
amide (R)-10 by coupling with benzylamine using a mixed anhy-
dride procedure (Scheme 4). Finally, Boc-deprotection followed by
N-acetylation using acetylchloride in the presence of Na2CO3 as a
base, completed the synthesis of Lacosamide 1 in excellent enanti-
Consequently, the azido compound (R)-5 was subjected to
Pd(OH)2 catalyzed hydrogenation/hydrogenolysis and concomitant
protection with (Boc)2O and afforded the N-Boc protected aminoal-
cohol (S)-8 in 86% yield. Compound (S)-8 underwent oxidation very
smoothly with sodium chlorite catalyzed by TEMPO and bleach in
oselectivity (>98% ee) {½a D
ꢀ
¼ þ16:1 (c 1, MeOH); lit.7
½aꢀD ¼ þ16:4

M. Muthukrishnan et al. / Tetrahedron: Asymmetry 22 (2011) 1353–1357
1355
O
i) CF3CO2H
ClCO2Bui
NMM
Boc
O
DCM, 0 °C to rt
overnight
NH
HN
H
N
H
N
MeO
(R)-9
MeO
BnNH2
THF, -78 °C, 1 h
90%
ii) CH3COCl
O
Na2CO3, toluene
(R)-1
Lacosamide
5 °C, 1 h
80%, two steps
(R)-10
Scheme 4.
(c 1, MeOH)}. The structure of Lacosamide 1 was confirmed by its IR,
4.3. (S)-2-(Benzyloxymethyl) oxirane (S)-3a
1H NMR, 13C NMR, and mass spectroscopic analysis.
A mixture of 2-(benzyloxymethyl)-oxirane 3 (10 g, 61 mmol)
and (R,R)-salen Co(III)OAc complex-A (0.09 g, 0.14 mmol) was
vigorously 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-
syringe. The reaction mixture was stirred at room temperature for
20 h, and additional (R,R) salen Co(III)OAc complex-A (0.09 g,
0.14 mmol) was added and stirring was continued for additional
10 h. The reaction mixture was diluted with ethyl acetate, 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 (S)-3a eluted first as a color-
3. Conclusion
In conclusion, a practical and highly enantioselective synthesis
of Lacosamide 1 has been achieved using Jacobsen’s hydrolytic ki-
netic resolution method as the key step and source of chirality. The
main advantages of the present method include high enantioselec-
tivity, the ready availability of the starting material and the cata-
lyst, and the use of water (0.55 equiv) as the medium and
reactant in the key step. Moreover, the Jacobsen catalyst can be
regenerated by treatment with acetic acid and recycled.
less oil (4.7 g, 47%), ½a D25
ꢀ
¼ þ8:1 (c 0.4, EtOH) {lit.6 ½a D23
¼ þ7:8 (c 0.4,
ꢀ
EtOH)}; ee >99% [chiral HPLC analysis; CHIRALCEL OD-H
(250 ꢁ 4.6 mm) column; eluent: n-hexane/isopropanol = 90:10;
flow rate: 0.5 mL/min; detector: 220 nm [(S)-isomer tR = 15.25 min;
(R)-isomer tR = 16.46 min], followed by diol (R)-3b as a colorless oil
4. Experimental
4.1. General
(4.8 g, 43%); ½a 2D5
ꢀ
¼ ꢂ1:6 (c 3.1, EtOH) {lit.4b
½
a 2D5
ꢀ
¼ ꢂ1:4 (c 3.3,
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 recorded
on a Bruker AC-200 NMR spectrometer. Spectra were obtained in
CDCl3. The reactions were monitored by using TLC plates Merck Sil-
ica Gel 60 F254 and visualization with UV light (254 and 365 nm), I2
and anisaldehyde in ethanol as development reagents. Optical rota-
tions were measured with a JASCO P 1020 digital polarimeter. Mass
spectra were recorded at ionization energy 70 eV on API Q Star Pul-
sar spectrometer using electrospray ionization. Enantiomeric ex-
cesses were determined by chiral HPLC, performed on ‘SHIMADZU
SCL-10A unit’ system controller and UV monitor as detector.
EtOH)}; IR (CHCl3, cmꢂ1): mmax 3434, 3020, 1600, 1495, 1215,
1045, 1029, 929, 697; NMR (200 MHz, CDCl3): dH 2.73 (t,
J = 5.8 Hz, 1H, 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 carbons), 127.8 (CH, 3 carbons), 73.5 (CH2), 71.6
(CH2), 70.7 (CH), 63.9 (CH2).
4.4. (S)-1-(Benzyloxy)-3-methoxypropan-2-ol (S)-4
To a stirred solution of epoxide (S)-3a (4 g, 24.3 mmol) in meth-
anol (40 mL) was slowly added powdered KOH (4 g; 70 mmol) at
10 °C and the reaction mixture was stirred at ambient temperature
for 8 h, after which the solvent was evaporated under reduced
pressure. The residue was dissolved in ethylacetate (50 mL),
washed with water, dried over Na2SO4, and evaporated under re-
duced pressure. The crude product was purified by column chro-
matography (silica gel, petroleum ether/acetone, 90:10) to afford
(S)-1-(benzyloxy)-3-methoxypropan-2-ol (S)-4 as a colorless oil
4.2. 2-(Benzyloxymethyl) oxirane rac-3
To a stirred solution of aqueous sodium hydroxide (125 mL, 50%
w/w), epichlorohydrin (54 mL, 925 mmol), and tetrabutylammo-
nium iodide (3.4 g, 9.4 mmol) was added benzyl alcohol 2 (20 g,
185 mmol) below 25 °C and the resulting mixture was stirred at
room temperature for 24 h. After completion of the reaction, cold
water (250 mL) was added and the reaction mixture was extracted
with diethyl ether (3 ꢁ 50 mL). The combined organic phases were
washed with brine (100 mL), dried over Na2SO4, and evaporated
under reduced pressure. The residue was purified by column chro-
matography (silica gel, petroleum ether/acetone, 95:5) to afford
2-(benzyloxymethyl) oxirane 3 as a colorless oil (27.6 g, 91%); IR
(CHCl3, cmꢂ1): mmax 3418, 3020, 2401, 1719, 1603, 1523, 1495,
1421, 1216, 1094, 929, 669; 1H 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]+.
(4.6 g, 98%); ½a 2D5
ꢀ
¼ ꢂ2:0 (c 1.55, EtOH) {lit.8
½
a 2D5
ꢀ
¼ ꢂ1:3 (c 1.54,
EtOH)}; IR (CHCl3, cmꢂ1): mmax 3686, 3444, 3020, 2401, 1603,
1523, 1473, 1422, 1120, 1045, 758, 669; 1H NMR (200 MHz,
CDCl3): dH 3.38 (s, 3H), 3.43–3.47 (dd, J = 5.3, 3.4 Hz, 2H), 3.50–
3.55 (dd, J = 5.8, 3.1 Hz, 2H), 3.94–4.04 (m, 1H), 4.56 (s, 2H),
7.29–7.41 (m, 5H); 13C NMR (50 MHz, CDCl3): dC 137.9 (C), 128.4
(CH, 2 carbons), 127.7 (CH, 3 carbons), 73.8 (CH2), 73.4 (CH2),
71.3 (CH2), 69.4 (CH), 59.2 (CH3); MS: m/z 219 [M+Na]+.
4.5. (R)-((2-Azido-3-methoxypropoxy)methyl)benzene (R)-5
A solution of DIAD (3.1 mL, 15.9 mmol) in dry toluene (5 mL)
was added dropwise to a solution of (S)-4 (2.5 g, 13.2 mmol) and

1356
M. Muthukrishnan et al. / Tetrahedron: Asymmetry 22 (2011) 1353–1357
triphenylphosphine (4.1 g, 15.9 mmol) in dry toluene (50 mL)
under an N2 atmosphere at 0 °C. After 15 min, diphenylphosphoryl
azide (3.6 mL, 15.9 mmol) was added dropwise and the reaction
mixture was stirred at ambient temperature for 10 h. The solvent
was removed under reduced pressure and the residue was purified
by column chromatography (silica gel, petroleum ether/ethyl ace-
4.8. (R)-tert-Butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-
ylcarbamate (R)-10
To a solution of acid (R)-9 (0.7 g, 3.2 mmol) in dry THF was
added N-methylmorpholine (0.43 mL, 3.8 mmol) at ꢂ78 °C under
an argon atmosphere. After 5 min, isobutyl chloroformate
(0.5 mL, 3.8 mmol) was added and stirred for another 5 min. To
this reaction mixture benzylamine (0.4 mL, 3.8 mmol) was added
at ꢂ78 °C after which the reaction mixture was stirred at room
temperature for 1 h. After completion of the reaction, 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, 85:15) to yield (R)-10 as a colorless solid (0.9 g, 90%);
tate, 95:05) to yield (R)-5 as a colorless oil (2.4 g, 83%); ½a D25
¼ þ8:3
ꢀ
(c 2, CHCl3); IR (CHCl3, cmꢂ1): mmax 3392, 2969, 2878,1661, 1542,
1463, 1441, 1384, 1289, 1073, 1017, 988, 930, 756, 667; 1H NMR
(200 MHz, CDCl3): dH 3.37 (s, 3H), 3.46–3.52 (dd, J = 5.4, 3.7 Hz,
2H), 3.54–3.61 (m, 2H), 3.68–3.79 (m, 1H), 4.56 (s, 2H), 7.28–
7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): dC 137.7 (C), 128.5 (CH,
2 carbons), 127.8 (CH), 127.7 (CH, 2 carbons), 73.5 (CH2), 72.2
(CH2), 69.8 (CH2), 60.6 (CH), 59.2 (CH3); MS: m/z 244 [M+Na]+;
Anal. Calcd for C11H15N3O2: C, 59.71; H, 6.83; N, 18.99; Found: C,
59.43; H, 7.11; N, 19.20.
mp 63–64 °C; ½a 2D5
ꢀ
¼ ꢂ20:5 (c 0.9, CHCl3); IR (CHCl3, cmꢂ1): mmax
3683, 3431, 3020, 2931, 2401, 1714, 1523, 1496, 1368, 1165,
1119, 928, 758, 669; 1H NMR (200 MHz, CDCl3): dH 1.43 (s, 9H),
3.37 (s, 3H), 3.47–3.54 (dd, J = 9.2, 6.1 Hz, 1H), 3.82 (dd, J = 9.3,
3.7 Hz, 1H), 4.27 (m, 1H), 4.47 (d, J = 5.1 Hz, 1H), 5.41 (br s, 1H),
6.77 (m, 1H), 7.22–7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): dC
170.3 (CO), 155.5 (CO), 137.9 (C), 128.7 (CH, 2 carbons), 127.5
(CH, 3 carbons), 80.4 (C), 72.1 (CH2), 59.1 (CH3), 54.0 (CH), 43.5
(CH2), 28.3 (CH3, 3 carbons); MS: m/z 331 [M+Na]+.
4.6. (S)-tert-Butyl 1-hydroxy-3-methoxypropan-2-ylcarbamate
(S)-8
To
a solution of (R)-5 (2.0 g, 9 mmol) and Boc2O (2.1 g,
10 mmol) in ethyl acetate (30 mL) was added palladium hydroxide
on activated charcoal (200 mg, 10–20 wt %) and the reaction mix-
ture was stirred under hydrogen (60 psi) for 36 h. After completion
of the reaction (indicated by TLC), the catalyst was filtered over a
plug of Celite bed (EtOAc eluent) and the solvent was evaporated
under reduced pressure. The crude product was purified by column
chromatography (silica gel, petroleum ether/acetone, 80:20) to
4.9. (R)-2-Acetamido-N-benzyl-3-methoxypropanamide (R)-1
(Lacosamide)
To a solution of compound (R)-10 (0.6 g, 1.9 mmol) in dichloro-
methane (7 mL) was added trifluoroacetic acid (3 mL) and the reac-
tion mixture was stirred at room temperature overnight, after
which the solvent was evaporated under reduced pressure. The
residue was then dissolved in dry toluene after which Na2CO3
(0.6 g, 5.7 mmol) was added. The reaction mixture was cooled to
0 °C after which acetyl chloride (0.14 mL, 2.0 mmol) was slowly
added and the solution stirred at 5 °C for 1 h. After completion of
the reaction, the solid was filtered and the solvent was evaporated
under reduced pressure. The crude product was purified by column
chromatography (silica gel, dichloromethane/methanol, 95:05) to
afford (R)-1 (Lacosamide) as a colorless solid (0.38 g, 80%); Color-
yield (S)-8 as a colorless oil (1.6 g, 86%); ½a D25
¼ þ3:8 (c 0.95, CHCl3)
ꢀ
{lit.9
½
a 2D5
ꢀ
¼ þ26:4 (c 0.995, CHCl3)}; IR (CHCl3, cmꢂ1): mmax 3683,
3443, 3018, 2981, 2898, 1703, 1504, 1393, 1368, 1169, 1092,
928, 848, 669; 1H NMR (200 MHz, CDCl3): dH 1.45 (s, 9H), 2.94
(br s, 1H), 3.37 (s, 3H), 3.52–3.56 (apparent t, J = 3.7 Hz, 2H),
3.61–3.80 (m, 2H), 5.20 (m, 1H); 13C NMR (50 MHz, CDCl3): dC
156.1 (CO), 79.2 (C), 73.1 (CH2), 63.8 (CH2), 59.2 (CH), 51.4 (CH3),
28.3 (CH3, 3 carbons); MS: m/z 228 [M+Na]+.
4.7. (R)-2-(tert-Butoxycarbonylamino)-3-methoxypropanoic
acid (R)-9
less solid; mp 139–40 °C (lit.7 143–44 °C); ½a D25
ꢀ
¼ þ16:1 (c 1,
3685, 3421, 3020,
;
1H NMR (400 MHz,
MeOH) {lit.7 +16.4 (c 1, MeOH)}; IR (CHCl3):
c
1663, 1523, 1426, 1118, 1030, 929 cmꢂ1
A mixture of (S)-8 (1 g, 4.9 mmol), TEMPO (0.05 g, 0.32 mmol),
acetonitrile (20 mL), and sodium phosphate buffer (16 mL, 0.67 M,
pH 6.7) was heated to 35 °C. Next, sodium chlorite (1.32 g dissolved
in 2 mL water, 14.6 mmol) and diluted bleach (4–6%, 1 mL diluted in
2 mL water) were added simultaneously over 1 h. The reaction mix-
ture was stirred at 35 °C until the reaction was complete (6 h, TLC),
then cooled to room temperature. Water (30 mL) was added and
the pH adjusted to 8 with 2 M NaOH. The reaction was quenched
by pouring it into an ice cold Na2SO3 solution maintained at
<20 °C. After stirring for 30 min at room temperature, ethylacetate
(30 mL) was added and the stirring continued for an additional
15 min. The organic layer was separated and discarded. More ethyl-
acetate (30 mL) was added, and the aqueous layer was acidified with
M HCl to pH 3–4. The organic layer was separated, washed with
water (2 ꢁ 15 mL), brine (20 mL) and concentrated under reduced
pressure to afford the carboxylic acid (R)-9 (0.88 g, 83%);
CDCl3): d 2.05 (s, 3H, COCH3), 3.40 (s, 3H, OCH3), 3.45 (apparent
t, J = 9.7, 8.0 Hz, 1H, OCH2), 3.83 (dd, J = 9.4, 3.4 Hz, 1H, OCH2),
4.50 (d, J = 4.5 Hz, 2H, CH2Ph), 4.52–4.58 (m, 1H), 6.48 (br s, 1H,
NH), 6.78 (br s, 1H, NH), 7.26–7.38 (m, 5H, Ph);13
C NMR
(50 MHz, CDCl3): d 170.7 (CO), 170.0 (CO), 137.7 (C), 128.6 (CH, 2
carbons), 127.4 (CH, 3 carbons), 71.8 (CH2), 59.1 (CH3), 52.6 (CH),
43.6 (CH2), 23.2 (CH3); MS: m/z 273 [M+Na]+; ee >98% [The ee of
1
was determined by chiral HPLC analysis; Chiralcel OD-H
(250 ꢁ 4.6 mm) column; eluent: pet. ether/isopropanol/trifluoro-
acetic acid (60:40:0.1); flow rate 0.5 mL/min; detector: 220 nm
[(R)-isomer tR = 10.43 min; (S)-isomer tR = 11.8 min].
Acknowledgments
M. Mujahid thanks CSIR, New Delhi for a research fellowship.
We are grateful to Dr. Pradeepkumar for his support and encour-
agement. Financial support from the DST, New Delhi (Grant SR/
FTP/CS-25/2007) is also gratefully acknowledged.
½
a 2D5
ꢀ
¼ ꢂ19:2 (c 1.4, CHCl3); IR (CHCl3, cmꢂ1): mmax 3443, 3019,
2982, 2932, 1708, 1501, 1393, 1369, 1216, 1164, 1119, 1064, 927,
757, 669; 1H NMR (200 MHz, CDCl3): dH 1.46 (s, 9H), 3.38 (s, 3H),
3.59–3.66 (dd, J = 9.4, 3.7 Hz, 1H), 3.84–3.90 (dd, J = 9.6, 3.1 Hz,
1H), 4.41–4.47 (m, 1H), 5.42 (d, J = 8.2 Hz, 1H) 8.16 (br s, 1H); 13C
NMR (50 MHz, CDCl3): dC 175.4 (CO), 155.8 (CO), 80.3 (C), 72.1
(CH2), 59.3 (CH), 53.7 (CH3), 28.3 (CH3, 3 carbons); MS: m/z 242
[M+Na]+.
References
1. (a) Duncan, J. S.; Sander, J. W.; Sisodia, S. M.; Walker, M. C. Lancet 2006, 367,
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