Chemoenzymatic synthesis of calcilytic agent NPS-2143 employing a lipase-mediated resolution protocol

Article abstract of DOI:10.1016/j.tetasy.2005.07.022

The kinetic resolution of chlorohydrin (±)-6 has been successfully carried out via a lipase-mediated transesterification with vinyl acetate in organic as well as ionic liquid media to yield (R)-alcohol 6 and (S)-acetate 7 in high enantioselectivity. An en

Full text of DOI:10.1016/j.tetasy.2005.07.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2784–2789
Chemoenzymatic synthesis of calcilytic agent NPS-2143
employing a lipase-mediated resolution protocol
Ahmed Kamal* and Gagan Chouhan
Biotransformations Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 June 2005; accepted 21 July 2005
Available online 16 August 2005
Abstract—The kinetic resolution of chlorohydrin ( )-6 has been successfully carried out via a lipase-mediated transesterification
with vinyl acetate in organic as well as ionic liquid media to yield (R)-alcohol 6 and (S)-acetate 7 in high enantioselectivity. An
enantioconvergent synthesis has also been achieved by a Mitsunobu esterification of a mixture of (R)-alcohol 6 and (S)-acetate 7
in one pot to convert the (R)-alcohol 6 to (S)-acetate 7. (S)-Acetate 7 has been hydrolyzed by LiOHÆH2O to give epoxide (R)-2. This
enantiopure epoxide has been used as a chiral precursor for the synthesis of calcilytic agent NPS-2143.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
levels are associated with bone formation,3 hence CaSR
antagonists could provide a practical approach to the
treatment of osteoporosis; such compounds are known
as calcilytic agents. NPS-2143 is an orally active low
molecular weight calcilytic agent that stimulates the
secretion of endogenous PTH by antagonizing the CaSR
on the surface of parathyroid cells,4 resulting in the stim-
ulation of new bone growth. Studies have suggested that
the (R)-enantiomer of NPS-2143 is 10- to 100-fold more
potent than the corresponding (S)-enantiomer.5 To the
best of our knowledge, there has been only one report
for the preparation6 of NPS-2143 that involves the
synthesis of enantiomerically pure (S)-oxirane and its
coupling with 1,1-dimethyl-2-(2-naphthyl)ethylamine 3.
Osteoporosis is becoming a major disease that affects
over 28 million people, especially post-menopausal
women. Presently, anti-resorptive agents such as estro-
gen, bisphosphonates, calcitonin and selective estrogen
receptor modulators (SERMs) are used in the treatment
of osteoporosis. These anti-resorptive agents can pre-
vent bone loss but have limited effects on new bone for-
mation and each has been associated with efficacy,
safety, tolerability and/or cost limitation. A synthetic
1–34 amino acid peptide fragment of human parathy-
roid hormone (PTH), has been used to treat severe oste-
oporosis as an alternative subcutaneous injection.1 As
an alternative to a daily PTH injection, one could envi-
sion stimulating the release of endogenous PTH from
the parathyroid glands. It is well established that PTH
secretion is inversely related to plasma calcium concen-
tration2 and regulated by the extracellular calcium-sens-
ing receptor (CaSR). Thus, the compound that blocks
the activity of the CaSR (CaSR ꢀantagonistsꢁ) leads to
increased plasma levels of PTH. These increased PTH
In an effort to develop an efficient preparation of enan-
tiomerically pure NPS-2143, we considered enantiomeri-
cally pure chlorohydrin 6 as one of a number of suitable
precursors for the synthesis of this compound.7 In con-
tinuation of our previous studies towards the prepara-
tion of biologically important chiral compounds or
their intermediates by the application of enzymes,8 we
CN
CN
OH
H
O
Cl
O
Cl
O
N
H2N
+
(NPS-2143)
1
(R)-2
3
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189; e-mail: ahmedkamal@iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.022

A. Kamal, G. Chouhan / Tetrahedron: Asymmetry 16 (2005) 2784–2789
2785
Table 1. Transesterification of chlorohydrin ( )-6 with various lipases
herein report a lipase-mediated kinetic resolution of
chlorohydrin ( )-6 and its application in the synthesis
of optically active calcilytic agent NPS-2143 1.
in diisopropyl ethera
Lipaseb Amount
(equiv w/w)
Time (h) cc (%) ee6 (%) ee7 (%)
d
d
PS-D
PS
PS-C
AK
CCL
PF
0.5
1
0.5
1
1
3
24
3
24
24
24
50
46
49
27
19
13
96
84
77
30
18
15
93
98
80
82
74
99
2. Results and discussion
2.1. Synthesis of racemic epoxide ( )-2 and chlorohydrin
( )-6
1
a Conditions: 0.25 mmol of ( )-6, 2.5 mL of solvent, 0.75 mmol vinyl
acetate at 35 ꢁC.
Racemic epoxide ( )-2 was prepared by a reaction with
excess of epichlorohydrin in the presence of K2CO3 and
18-crown-6 in refluxing acetone (Scheme 1). Upon com-
pletion of the reaction, the solids were filtered and the
filtrate evaporated under vacuum. The resulting crude
epoxide ( )-2 was then purified by column chromato-
graphy. Ring opening of the epoxide ( )-2 by LiCl
and CuCl2 in tetrahydrofuran afforded the desired
chlorohydrin ( )-6.9 Additionally, this reaction has also
been carried out in ionic liquid [bmim]PF6. Interestingly,
the use of ionic liquid media not only provides a quan-
titative yield with regioselectivity but has potential for
its reuse and recycle in further runs.10,11
b PS-D (Pseudomonas cepacia lipase immobilized on diatomite), PS
(Pseudomonas cepacia lipase), PS-C (Pseudomonas cepacia lipase
immobilized on ceramic particles), AK (Amano 20), CCL (Candida
cylindracea lipase from Sigma), PF (Pseudomonas fluorescens lipase
immobilized in sol–gel–AK on sintered glass).
c Conversions were calculated from the enantiomeric excess of sub-
strate 6 (ees) and product 7 (eep) using the formula: Conv. = ees/
(ees + eep).
d Determined by HPLC analysis (Daicel chiralcel AD-H column)
90:10; hexane/2-propanol, 0.5 mL/min flow rate at 254 nm.
2.2.2. Effect of solvents. In order to investigate the ef-
fect of solvents on the transesterification reaction pro-
cess, different organic solvents as well as ionic liquids
(Fig. 1) were studied by using vinyl acetate as acyl donor
with lipase PS-D with the results described in Table 2.
Hydrophobic solvents diisopropyl ether and toluene
gave excellent results when compared with hydrophilic
solvents such as tetrahydrofuran. Water-immiscible ionic
liquids have been shown to be excellent non-aqueous
media for enzyme-catalyzed reactions (especially for lip-
ases), not only because of the high level of activity and
stereoselectivity displayed by enzymes in chemical trans-
formations,12,13 such as ester synthesis, kinetic resolu-
tion of sec-alcohols, etc., but also because of their now
well identified stabilization effects on the biocata-
lysts.14,15 In continuation of our interest in the area of
biocatalysis, particularly in the use of ionic liquid as a
medium,9 we investigated the effect of different ionic
liquids on this transesterification process. Four ionic
liquids containing different cations/anions were utilized
for the transesterification of chlorohydrin ( )-6 using
vinyl acetate employing lipase PS-D.
2.2. Lipase-mediated resolution of racemic chlorohydrin
( )-6
Enantiomerically pure epoxide (R)-2 is an important
precursor towards the synthesis of NPS-2143 and other
related calcium-sensing receptor antagonists.7 In the lit-
erature, there have been some reports on the prepara-
tion of optically active epoxide 2 in its (R)-form.6,7
Herein, we have resolved the racemic chlorohydrin
( )-6 by employing various lipases (Scheme 2).
2.2.1. Screening of lipases. The primary requirement
for a successful kinetic resolution is the selection of a
suitable lipase and solvent. Initially, six different
commercially available lipases were screened for the
transesterification of 2-chloro-6-(3-chloro-2-hydroxy-
propoxy)benzonitrile ( )-6 with vinyl acetate in diiso-
propyl ether with the results being summarized in
Table 1. Amongst the lipases screened, lipase from Pseu-
domonas cepacia, that is, PS and PS-D gave good con-
version and high enantioselectivity.
CN
CN
OH
CN
CN
O
Cl
O
Cl
O
Cl
Cl
F
Cl
OH
i
iii
iv
ii
( )-2
( )-6
4
5
Scheme 1. Reagents and conditions: (i) KOAc, 18-crown-6, CH3CN, reflux 24 h; (ii) NaOH, H2O, rt, 1 h; (iii) epichlorohydrin, K2CO3, 18-crown-6,
acetone, reflux 24 h; (iv) CuCl2/LiCl, THF, rt, 14 h, or CuCl2/LiCl, [bmim]PF6, 65 ꢁC, 5 h.
CN
OAc
CN
OH
Cl
O
Cl
Cl
O
Cl
i
( )-6
+
(S)-7
(R)-6
Scheme 2. Reagents: (i) lipase, vinyl acetate.

2786
A. Kamal, G. Chouhan / Tetrahedron: Asymmetry 16 (2005) 2784–2789
transesterification processes by recycling it for 2–3
subsequent runs without any appreciable effect on the
conversion or the enantioselectivity.
N
N
N
X
PF6
[bmpyr]PF6
2.2.3. Mitsunobu esterification and synthesis of enantio-
pure epoxide (R)-2. A mixture of (R)-alcohol 6 and (S)-
acetate 7 was dissolved in dry THF and treated with
PPh3 and acetic acid followed by DEAD for 24 h, to
give (S)-acetate 7 in 80% yield and 94% ee. The hydro-
lysis of acetate (S)-7 with LiOHÆH2O in ethanol gave
the corresponding epoxide (R)-2 in an almost quantita-
tive yield (>95%) and good enantiomeric excess (>95%
ee) (Scheme 3).
X = BF4, PF6, MeSO4
Figure 1.
Table 2. The effect of solvent and ionic liquid on the enantioselectivity
in the resolution of chlorohydrin ( )-6 with lipase PS-Da
Time (h) cb (%)
ee6 (%) ee7 (%) E d
c
c
Solvent
DIPE
THF
Hexane
Toluene
[bmpyr]PF6
[bmim]PF6
3
5
5
6
9
9
50
23
35
50
36
48
96
30
53
98
53
92
93
99
99
99
94
98
108
>200
>200
>200
54
CN
OAc
CN
O
Cl
O
Cl
Cl
O
i
>200
a Conditions: 0.25 mmol of ( )-6, 2.5 mL of solvent, 0.5 mL ionic
liquid, lipase (0.5 equiv w/w), 0.75 mmol vinyl acetate at 35 ꢁC,
PS-D = Pseudomonas cepacia lipase immobilized on diatomite.
b Conversions were calculated from the enantiomeric excess of sub-
strate 6 (ees) and product 7 (eep) using the formula: Conv. = ees/
(ees + eep).
c Determined by HPLC analysis (Daicel chiralcel AD-H column)
90:10; hexane/2-propanol, 0.5 mL/min flow rate at 254 nm.
d E values were calculated using the formula: E = [ln(1 ꢀ c)(1 ꢀ ees)]/
[ln(1 ꢀ c)(1 + ees)].
(R)-2
(S)-7
Scheme 3. Reagents and conditions: (i) LiOHÆH2O, EtOH, 20 min.
2.3. Synthesis of NPS-2143
NPS-2143 was synthesized by the coupling of 2-chloro-
6-[2-(R)-oxiranylmethoxy]benzonitrile (R)-2 with 1,1-di-
methyl-2-(2-naphthyl)ethylamine 3 in ethanol. Amine 3
was prepared by treatment of 2-(aminomethyl)naphthal-
ene 8 with 2,4,6-triphenylpyrylium tetrafluoroborate 9 in
ethanol. The resulting compound was dissolved in
DMSO and treated with the sodium salt of 2-nitropro-
pane 10 to give the nitro derivative 11,16 which on reduc-
tion by hydrogenation over Pd/C in ethanol gave the
amine 3 (Scheme 4).
The conversion is negligible when using the ionic liquids
1-butyl-3-methylimidazolium tetrafluoroborate [bmim]-
BF4 and 1-butyl-3-methylimidazolium methane sulfo-
nate [bmim]MeSO4. However, the use of the ionic
liquid 1-butyl-1-methyl-pyrrolidinium hexafluorophos-
phate [bmpyr]PF6 gave about 36% conversion in 9 h with
>94% ee of (S)-7. Interestingly, the ionic liquid 1-butyl-
3-methylimidazolium hexafluorophosphate [bmim]PF6
not only provides good conversion but also high enantio-
selectivity for both the (R)-alcohol 6 and (S)-acetate 7
as shown in Table 2. Moreover, the recyclability of the
ionic liquid-lipase system was also investigated for this
3. Conclusion
In summary, we have developed an efficient method for
the resolution of chlorohydrin ( )-6 in good yield and
NH2
i
N
+
O
BF4
8
BF4
9
ii
NO2
CH3
H3C
10
H2N
O2N
iv
iii
1
(NPS-2143)
3
11
Scheme 4. Reagents and conditions: (i) EtOH, Et3N, overnight; (ii) NaH, MeOH; (iii) Pd/C, H2; (iv) (R)-2, EtOH, 60 ꢁC.

A. Kamal, G. Chouhan / Tetrahedron: Asymmetry 16 (2005) 2784–2789
2787
high enantioselectivity employing lipase-mediated
transesterification process. Moreover, an enantioconver-
gent strategy has also been used by the Mitsunobu ester-
ification of alcohol 6. Furthermore, we have utilized this
enantiopure (S)-chlorohydrin 7 for the preparation of
the calcilytic drug NPS-2143. Additionally, the effect
of using ionic liquids on this transesterification process
has also been investigated.
gen for 24 h, and then cooled to room temperature. So-
dium hydroxide (4 mL of a 10 M solution, 40 mmol)
and water (10 mL) were added, and the reaction mixture
stirred at room temperature for 2 h. The acetonitrile was
removed on a rotary evaporator, and the residue was ta-
ken up in diethyl ether and water. The basic aqueous
layer was washed three times with diethyl ether. The
aqueous layer was then made acidic with HCl, and the
product extracted into ether. The combined diethyl ether
layers were dried over anhydrous sodium sulfate, fil-
tered, and concentrated to give 2.20 g of 3-chloro-2-
cyanophenol 5. This was dissolved in acetone (60 mL)
and treated with potassium carbonate (5.96 g,
43.13 mmol), 18-crown-6 (3.79 g, 14.37 mmol), and re-
fluxed under nitrogen for 15 min. Epichlorohydrin
(6.53 g, 70.6 mmol) was then added by syringe, and
the mixture was refluxed for 24 h. The mixture was
cooled and filtered and the filtrate evaporated to dry-
ness. The residue was partitioned between ether/water,
and the layers separated. The diethyl ether layer was
washed with saturated NaCl, dried over anhydrous so-
dium sulfate, concentrated under reduced pressure and
purified by silica gel column chromatography [eluent:
ethyl acetate/n-hexane (20:80)] to give ( )-2 as a white
solid; yield: 2.7 g (90%); mp 119–120 ꢁC; IR: 3421,
4. Experimental
4.1. Material and methods
Enzymatic reactions were carried out on a ꢀLabline
Environ-shakerꢁ at 170 rpm. 1H NMR spectra were
recorded at 200 MHz or 300 MHz, chemical shifts are
given in d units relative to the tetramethylsilane (TMS)
signal as an internal reference in CDCl3. Coupling con-
stants (J) are reported in Hertz (Hz). Electron-impact
(EI) mass spectra were recorded in the form of m/z
(intensity relative to base 100) on a VG 7070H Micro-
mass mass spectrometer at 200 ꢁC, 70 eV, with a trop
current of 200 lA and 4 kV acceleration. FAB+ mass
spectra were recorded on AutoSpec mass spectrometer
with 7 kV acceleration voltage and 25 kV gun voltage.
Melting points were recorded on an electrothermal melt-
ing point apparatus. IR spectra were recorded on a
refractive spectrophotometer and are reported in wave
numbers (cmꢀ1). Analytical TLC of all the reactions
was performed on Merck prepared plates (silica gel 60
F-254 on glass). Column chromatography was per-
formed using Acme silica gel (100–200 mesh). HPLC
analyses were performed on ꢀShimadzu LC-10ATꢁ sys-
tem controller, and UV monitor as detector. Specific
rotations were recorded on SEPA-300 Horiba high sen-
sitive polarimeter, fixed with a sodium lamp of wave-
length 589 nm.
1
2231, 1590, 1452, 1284, 1034, 862, 778 cmꢀ1; H NMR
(200 MHz, CDCl3): d 2.75–2.82 (1H, dd, J = 2.4,
4.8 Hz), 2.86–2.93 (1H, t, J = 4 Hz), 3.25–3.30 (1H,
m), 4.03–4.14 (1H, dd, J = 5.6, 12 Hz), 4.35–4.44 (1H,
dd, J = 2.4, 11.2 Hz), 6.85–6.95 (1H, d, J =
8.8 Hz), 7.0–7.20 (1H, d, J = 8.8 Hz), 7.70–7.50 (1H, t,
J = 8.8 Hz); EIMS (m/z): 209 (M+); Anal. Calcd for
C10H8ClNO2: C, 57.3; H, 3.85; N, 6.68. Found: C,
57.21; H, 3.76, N, 6.5.
4.4. rac-2-Chloro-6-(3-chloro-2-hydroxypropoxy)benzo-
nitrile ( )-6
To a stirred solution of ( )-2 (209 mg, 1 mmol) taken in
ionic liquid [bmim]PF6 (1.5 mL) was added CuCl2
(85 mg, 0.63 mmol) and LiCl (55 mg, 1.3 mmol) at room
temperature. The reaction mixture was stirred at 60 ꢁC
for 5 h. After completion of the reaction as indicated
by TLC, diethyl ether (3 · 5 mL) was added to the reac-
tion mixture with stirring for 5 min. The mixture was
allowed to stand for a further 5 min and the clear
supernatant liquid then decanted. The combined ether
layers were dried over sodium sulfate and concentrated
in vacuum to obtain the crude product, which was puri-
fied by silica gel column chromatography [eluent: ethyl
acetate/n-hexane (15:85)] to furnish chlorohydrin ( )-
6. The ionic liquid layer was treated with phosphate buf-
fer (4 mL, 0.1 M, pH = 7), and dissolved in dichloro-
methane (1 · 5 mL), dried in high vacuum and
recycled in subsequent runs. ( )-6 white solid; yield:
240 mg (97%); mp 101–102 ꢁC; IR: 3499, 2231, 1592,
4.2. Chemicals and enzymes
All reagents were obtained from commercial sources
and used without further purification. Solvents for
extraction were of technical grade and distilled before
use. Racemic chlorohydrin acetate 7 was prepared by
the acetylation of racemic compound 6 with acetic anhy-
dride in the presence of triethylamine and catalytic
DMAP in DCM. P. cepacia lipase immobilized on diat-
omite (PS-D), P. cepacia lipase (PS), P. cepacia lipase
immobilized on ceramic particles (PS-C) and AK (Ama-
no 20) was purchased from Amano (Nagoya, Japan).
Candida cylindracea lipase (CCL) was purchased from
Sigma. Pseudomonas fluorescens lipase immobilized in
sol–gel–AK on sintered glass (PF) was purchased from
Fluka.
1
4.3. rac-2-Chloro-6-(oxiran-2-ylmethoxy)benzonitrile
( )-2
1471, 1447, 1290, 1092, 1038, 964, 780 cmꢀ1; H NMR
(200 MHz, CDCl3): d 3.85–3.90 (2H, d, J = 5.0 Hz),
4.15–4.40 (3H, m), 6.90–7.0 (1H, d, J = 8.4 Hz), 7.10–
7.20 (1H, d, J = 7.6 Hz), 7.40–7.55 (1H, t, J = 8.4 Hz);
EIMS (m/z): 245 (M+ꢀ1); Anal. Calcd for C10H9-
Cl2NO2: C, 48.81; H, 3.69; N, 5.69. Found: C, 48.78;
H, 3.66, N, 5.5.
To a solution of 2-chloro-6-fluorobenzonitrile 4 (3.12 g,
20 mmol) in 40 mL of acetonitrile were added 18-crown-
6 (7.92 g, 30 mmol) and dry potassium acetate (2.94 g,
30 mmol) and the reaction mixture refluxed under nitro-

2788
A. Kamal, G. Chouhan / Tetrahedron: Asymmetry 16 (2005) 2784–2789
4.5. Lipase-mediated resolution: preparation of optically
active (R)-6 and (S)-7
solvent and purification by column chromatography
[eluent: ethyl acetate/n-hexane (15:85)], yields (S)-ace-
tate 7 (80%), ee = 94%.
To a solution of 2-chloro-6-(3-chloro-2-hydroxyprop-
oxy)benzonitrile ( )-6 (500 mg, 2.03 mmol), in toluene
(30 mL) were added lipase PS-D (250 mg) and vinyl
acetate (3 equiv). The suspension was shaken at
170 rpm at 35 ꢁC and monitored by HPLC analysis until
it reached 50% conversion (6 h). Then the reaction
mixture was filtered and washed with water, followed
by brine. The organic layer was dried over anhydrous
sodium sulfate, concentrated under reduced pressure
and purified by silica gel column chromatography
[eluent: ethyl acetate/n-hexane (15:85)] to give (R)-6
220 mg (45%) and (S)-7 270 mg (47%).
4.8. 2-Chloro-6-[(2R)-oxyrane-2-ylmethoxy]benzonitrile
(R)-2
To a solution of (S)-7 (144 mg, 0.5 mmol) in ethanol
(2 mL) was added LiOHÆH2O (65 mg, 1.5 mmol). The
mixture was stirred at room temperature for 20–
30 min. Evaporation of ethanol followed by dichloro-
methane extraction, water wash, drying and removal
of the solvent afforded epoxide (R)-2 as a white solid;
yield: 100 mg (95%); >95% ee [chiral HPLC analysis;
Daicel chiralcel OD (0.46 · 25 cm) column; eluent: hex-
ane/isopropanol = 90/10; flow rate: 0.5 mL/min; detec-
25
(R)-6: White solid, 98% ee [chiral HPLC analysis; Daicel
chiralcel AD-H (0.46 · 25 cm) column; eluent: hexane/
tor: 254 nm.; ½aꢁD ¼ ꢀ11.2 (c 0.5, CHCl3).
isopropanol = 90/10; flow rate: 0.5 mL/min; detector:
4.9. 1,1-Dimethyl-2-(2-naphthyl)ethylamine 3
25
254 nm; ½aꢁD ¼ ꢀ3.1 (c 1, CHCl3).
A solution of 2,4,6-triphenylpyrylium tetrafluoroborate
9 (2.51 g, 6.33 mmol) in ethanol (15 mL) was treated
with 2-(aminomethyl)naphthalene 8 (1 g, 6.33 mmol)
and Et3N (0.63 mmol). The reaction was stirred over-
night at room temperature and diluted with diethyl ether
to precipitate the product. The product was recrystal-
lized from ethanol/diethyl ether to give N-(2-methyl
naphthalene)-2,4,6-triphenylpyridinium tetrafluorobo-
rate as a tan coloured solid. This tetrafluoroborate salt
was dissolved in dimethyl sulfoxide (20 mL) and treated
with the sodium salt of 2-nitropropane 10 (prepared by
the reaction of sodium hydride (383 mg, 60% oil disper-
sion, 9.5 mmol) and 2-nitropropane 10 (0.858 mL,
9.5 mmol) in methanol (3 mL) at 0 ꢁC). The mixture
was stirred at 70 ꢁC overnight under nitrogen. The reac-
tion was diluted with water, and the product extracted
into diethyl ether. The combined ether layers were
washed with saturated NaCl and dried over sodium sul-
fate. The ether solution was treated with an Amberlyst
15 ion-exchange resin to absorb the 2,4,6-triphenylpyr-
idine. The resin was filtered and the filtrate evaporated
to give pure 2-(2-methyl-2-nitropropyl)naphthalene 11.
The 2-(2-methyl-2-nitropropyl)naphthalene 11 was
hydrogenated in ethanol (30 mL) in presence of 10%
Pd/C (500 mg) overnight. Removal of the catalyst by
filtration and evaporation of the solvent gave an oil,
which was purified by silica gel column chromato-
graphy [eluent: methanol/ethyl acetate (15:85)] to obtain
0.95 g of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine 3
as a clear oil. IR: 3043, 2963, 2928, 1593, 1387,
(S)-7: White solid, 99% ee [chiral HPLC analysis; Daicel
chiralcel AD-H (0.46 · 25 cm) column; eluent: hexane/
isopropanol = 90/10; flow rate: 0.5 mL/min; detector:
25
254 nm.; ½aꢁD ¼ þ33.8 (c 1.2, CHCl3); IR: 2233, 1746,
1
1591, 1451, 1375, 1236, 1046, 984, 776 cmꢀ1; H NMR
(200 MHz, CDCl3): d 2.15 (3H, s), 3.75–3.95 (2H, m),
4.3 (2H, d, J = 5.2 Hz), 5.3 (1H, quint, J = 5.2 Hz),
6.85 (2H, d, J = 8.9 Hz), 7.10 (2H, d, J = 7.4 Hz), 7.45
(2H, t, J = 8.1 Hz); FAB+ (m/z): 289 (M++1); Anal.
Calcd for C12H11Cl2NO3: C, 50.02; H, 3.85. N, 4.86.
Found: C, 49.98; H, 3.68, N, 4.74.
4.6. Lipase-mediated resolution in ionic liquid [bmim]PF6
To a stirred solution of ( )-6 (50 mg) taken in an ionic
liquid (0.5 mL) were added vinyl acetate (3 equiv) and
lipase PS-D (0.5 equiv w/w) at room temperature. The
mixture was stirred at room temperature. After about
48% conversion of the reaction as indicated by HPLC/
TLC, diethyl ether (3 · 3 mL) was added to the reaction
mixture with stirring for 5 min. The mixture was allowed
to stand for a further 5 min and the clear supernatant
liquid decanted. The combined diethyl ether layers were
concentrated in vacuum to obtain an oily residue, which
was purified by short silica gel column chromatography
[eluent: ethyl acetate/n-hexane (15:85)] to obtain the
products (R)-alcohol 6 and (S)-acetate 7. The products
were analyzed by HPLC using a chiral column to deter-
mine their enantiomeric excess (see Section 4.5).
1
782 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.2 (6H, s),
4.7. Mitsunobu esterification of the mixture (R)-alcohol 6
and (S)-acetate 7
1.60–1.85 (2H, br s), 3.15 (2H, s), 7.22–7.50 (4H, m),
7.60–7.80 (2H, m), 8.15 (1H, d, J = 8.4 Hz); FAB+
(m/z): 200 (M++1); Anal. Calcd for C14H17N: C,
84.37; H, 8.60; N, 7.03. Found: C, 84.28; H, 8.56; N,
6.85.
The transesterification processes were repeated by
reacting ( )-6 (100 mg), vinyl acetate (3 equiv) and
lipase PS-D (0.5 equiv) in toluene (10 mL). The products
(R)-alcohol 6 and (S)-acetate 7 were not separated. The
evaporated mixture was dissolved in dry THF (5 mL),
after which PPh3 (1.5 equiv), and then acetic acid
(1.5 equiv) were added. The mixture was cooled to 0–
5 ꢁC and DEAD (1.5 equiv) added. The mixture was
stirred at room temperature for 24 h. Evaporation of
4.10. Synthesis of NPS-2143
2-Chloro-6-[2-(R)-oxiranylmethoxy]benzonitrile (R)-2
(209 mg, 1 mmol) and 1,1-dimethyl-2-(2-naphthyl)ethyl-
amine 3 (300 mg, 1.5 mmol) were stirred at 60 ꢁC in eth-
anol overnight. The methanol was evaporated at

A. Kamal, G. Chouhan / Tetrahedron: Asymmetry 16 (2005) 2784–2789
2789
G. B. R.; Ramu, R.; Krishnaji, T. Tetrahedron Lett. 2003,
44, 4783; (f) Kamal, A.; Sandbhor, M. Bioorg. Med.
Chem. Lett. 2002, 12, 1735; (g) Kamal, A.; Ramana, K. V.;
Rao, M. V. J. Org. Chem. 2001, 66, 997.
reduced pressure, and the resulting thick liquid purified
by silica gel column chromatography [eluent: methanol/
25
ethyl acetate (10:90)] to furnish the NPS-2143. ½aꢁD
¼
þ13.3 (c 1.2, CHCl3); IR: 3355, 2927, 2857, 2231,
9. Hoff, B. H.; Anthosen, T. Tetrahedron: Asymmetry 1999,
10, 1410.
1590, 1451, 1377, 1285, 1038, 781 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 1.20 (6H, s), 2.90–3.20 (2H, m),
3.30 (2H, s), 4.1–4.2 (2H, m), 4.30–4.50 (2H, m), 6.85
(1H, d, J = 8.9 Hz), 6.90–7.0 (1H, d, J = 7.4 Hz), 7.20–
7.50 (5H, m), 7.60–7.80 (2H, m), 8.10–8.20 (1H, d,
J = 8.9 Hz); FAB+ (m/z): 409 (M++1); Anal. Calcd
for C24H26ClN2O2: C, 70.49; H, 6.16; N, 6.85. Found:
C, 70.38; H, 6.15; N, 6.74.
10. (a) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2005, 46,
1489; (b) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2005,
45, 8801; (c) Kamal, A.; Chouhan, G. Adv. Synth. Catal.
2004, 346, 579; (d) Kamal, A.; Chouhan, G. Tetrahedron
Lett. 2004, 13, 815.
11. For reviews see: (a) Holbrey, J. D.; Seddon, K. R. Clean.
Prod. Process 1999, 1, 223; (b) Welton, T. Chem. Rev.
1999, 99, 2071; (c) Wasserscheid, P.; Keim, W. Angew.
Chem., Int. Ed. 2000, 39, 3772; (d) Sheldon, R. Chem.
Commun. 2001, 2399; (e) Olivier-Bourbigou, H.; Magna,
L. J. Mol. Catal. A 2002, 182–183, 419; (f) Dupont, J.; de
Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667;
(g) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH: Weinheim, 2003; (h) Ionic Liquids as Green
Solvents: Progress and Prospects; Rogers, R. D., Seddon,
K. R., Eds.; ACS Symposium Series 856; ACS: Washing-
ton, 2003.
Acknowledgement
We are thankful to the Department of Science and Tech-
nology, New Delhi, for the financial assistance of the
Grants-in-Aid project under SERC (No. SR/S1/OC-
36/2003). One of the authors G.C. is thankful to CSIR,
New Delhi, for the award of senior research fellowship.
12. (a) Park, S.; Kazlauskas, R. J. Curr. Opin. Biotechnol.
2003, 14, 432; (b) Rantwijk, F. V.; Lau, R. M.; Sheldon,
R. A. Trends Biotechnol. 2003, 21, 131; (c) Kragl, U.;
Eckstein, M.; Kaftzik, N. Curr. Opin. Biotechnol. 2002, 13,
565; (d) Sheldon, R. A.; Lau, R. M.; Sorgedrager, M. J.;
Rantwijk, F. V.; Seddon, K. R. Green Chem. 2002, 4, 147;
(e) Karr, J. L.; Jesionowski, A. M.; Berberich, J. A.;
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Wiesenhofer, W.; Francio, G.; Leitner, W. Chem. Com-
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