An efficient procedure for the resolution of α-cyano-α-fluoro- p-tolylacetic acid (CFTA) via the diastereomeric N-carbobenzyloxy-cis-1-amino-2- indanol esters

Article abstract of DOI:10.1016/j.tetasy.2003.12.024

Development of a new, efficient resolution method of α-cyano-α- fluoro-p-tolylacetic acid (CFTA) 2a has been successfully achieved, which has been troublesome to obtain by conventional methods, in spite of its outstanding ability as an NMR chiral derivatizing agent. Fractional recrystallization of a mixture of the diastereomeric CFTA esters prepared from racemic CFTA chloride and (1R,2S)-N-carbobenzyloxy-cis-1-amino-2-indanol (-)-B afforded the less-soluble diastereomer, which was hydrolyzed to give (S)-2a. It has also been demonstrated that optically active N-acetyl-cis-1-amino-2-indanol is effective for the chromatographic resolution of α-arylacetic acids including ibuprofen and naproxen.

Full text of DOI:10.1016/j.tetasy.2003.12.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 555–563
An efficient procedure for the resolution of a-cyano-a-fluoro-
p-tolylacetic acid (CFTA) via the diastereomeric
N-carbobenzyloxy-cis-1-amino-2-indanol esters
Tomoya Fujiwara,a, Masaki Sasaki,a Kenji Omata,a Chizuko Kabuto,a
Kuninobu Kabutoa,* and Yoshio Takeuchib
aDepartment of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
bFaculty of Pharmaceutical Science, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 12 November 2003; accepted 8 December 2003
Abstract—Development of a new, efficient resolution method of a-cyano-a-fluoro-p-tolylacetic acid (CFTA) 2a has been success-
fully achieved, which has been troublesome to obtain by conventional methods, in spite of its outstanding ability as an NMR chiral
derivatizing agent. Fractional recrystallization of a mixture of the diastereomeric CFTA esters prepared from racemic CFTA
chloride and (1R,2S)-N-carbobenzyloxy-cis-1-amino-2-indanol ())-B afforded the less-soluble diastereomer, which was hydrolyzed
to give (S)-2a. It has also been demonstrated that optically active N-acetyl-cis-1-amino-2-indanol is effective for the chromato-
graphic resolution of a-arylacetic acids including ibuprofen and naproxen.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
CFPA chloride (CFPA-Cl) 1b can react with pinacolyl
alcohol 500 times faster than MTPA chloride.2b Such
high reactivity would eliminate or minimize any kinetic
resolution that may occur during derivatization, which
is desirable for obtaining accurate % ee values. Addi-
tionally, 19F chemical shift differences (DdF) between a
diastereomeric pair of CFPA or CFTA esters and
amides are 5–50 times greater than those of MTPA
derivatives. Values for % ee can be determined, even for
alcohols that have the stereogenic center located seven
bonds from the functionality.2a
One of the most convenient and reliable methods for the
determination of enantiomeric excess (% ee) and abso-
lute configuration of chiral molecules is NMR spectro-
scopic analysis of the diastereomers obtained
by condensation with chiral derivatizing agent (CDA)
such as a-methoxy-a-trifluoromethylphenylacetic acid
(MTPA).1 Among various CDAs developed to date for
this purpose, a-cyano-a-fluorophenylacetic acid (CFPA)
1a2 and a-cyano-a-fluoro-p-tolylacetic acid (CFTA) 2a3
have been found to be particularly effective from the
viewpoint of both reactivity and NMR resolution abil-
ity. Thus, owing to the strong electron-withdrawing
character of both fluorine and cyano groups on the
a-carbon of the acetate structure, the corresponding acid
chlorides of these acids are highly reactive such as to
allow condensation with even sterically hindered alco-
hols and amines. For example, it has been shown that
The CFTA method using 2a has also been applied for
assigning the absolute configurations of secondary
alcohols4 and primary amines.5 1H chemical shift dif-
ferences (DdH) between the diastereomeric pairs of
CFTA derivatives were greater than those for MTPA
derivatives. Moreover, the signs of DdH were consis-
tently correlated with the absolute configurations of the
substrates. It has been demonstrated that the 19F
chemical shift nonequivalence between the two CFTA
diastereomers are useful in assigning the absolute con-
figuration for a-amino esters.6 Similarly, the use of 19F
chemical shift nonequivalence is highly promising for
assignment of the absolute configurations of secondary
alcohols.3a
* Corresponding author. Tel./fax: +81-22-217-7716; e-mail: kabuto@
funorg.chem.tohoku.ac.jp
Present address: Faculty of Pharmaceutical Science, Toyama Med-
ical and Pharmaceutical University, Sugitani 2630, Toyama 930-
0194, Japan.
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.024

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T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
As a chiral auxiliary, ())-N-acetyl-(1R,2S)-cis-1-amino-
F
CN
2-indanol ())-A was initially examined. Reaction of
())-A with an equimolar of racemic CFTA chloride rac-
2b, prepared from rac-CFTA ethyl ester 2c, proceeded
smoothly to give the diastereomeric esters in quantitative
yield. However, contrary to our expectation, separation
of the diastereomers was not observed by HPTLC using
various solvent systems. The diastereomers were instead
separated by fractional recrystallizations from hexane/
CHCl3; five repeated recrystallizations afforded the less-
soluble isomer in a diastereomerically pure form.
CFPA 1a: R = H, X = OH
CFPA-Cl 1b: R = H, X = Cl
CFTA 2a: R = CH3, X = OH
CFTA-Cl 2b: R = CH3, X = Cl
COX
R
NHR
1
R = Ac: (-)-A
R = Cbz: (-)-B; (1S,2R): (+)-B
R
S
HO
2
Following similar methods as described above for the
acetyl derivative, ())-N-Cbz-(1R,2S)-cis-1-amino-2-ind-
anol ())-B was used to prepare the diastereomeric esters
of CFTA in 83% yield. The separation of the resulting
diastereomers was relatively simpler (Scheme 1); only
two recrystallizations were required to afford less-solu-
ble isomer 2dL as a diastereomerically pure form. The
mother liquor was subsequently concentrated and sub-
jected to repeated recrystallizations. The combined yield
of diastereomerically pure 2dL was 36% (based on the
starting ester 2c). Attempted hydrolysis of the ester 2dL
with LiOH successfully produced the acid (S)-2a in al-
most quantitative yield, accompanied by 80% recovery
of the resolving agents, ())-B and its deprotected com-
pound (+)-(1R,2S)-cis-1-amino-2-indanol. The rather
unstable acid (S)-2a thus obtained was converted to the
acid chloride (S)-2b in a usual way to give in 83% yield
after distillation.
Despite the advantages of 1a and 2a over existing
CDAs, including MTPA, utilization of 1a and 2a has
been limited, primarily due to the rather involved syn-
thetic steps in obtaining the optically active agents. The
enantiomers of CFTA have been obtained by enzymatic
resolution using Candida rugosa lipase pretreated with
2-propanol.3b Although this method is effective in
affording enantiomerically pure (R)-CFTA on a gram
scale, the (S)-isomer is obtained in rather low yields.
Furthermore, the pretreatment procedure of enzyme is
generally unfamiliar to organic chemists, and therefore,
development of a simple, effective method for enantio-
meric separation of CFTA is highly desirable for those
chemists currently engaged in recent asymmetric and
natural product synthesis. Since CFTA itself decom-
poses slowly at room temperature, the resolution of
CFTA must be carried out as its stable chiral derivative.
For a laboratory-scale production of both enantiomers
of CFTA, we anticipated that the chromatographic
separation of the CFTA diastereomers, by monitoring
the extent of purity, would be more practicable than the
fractional recrystallization of the diastereomeric amine
salts.
The more-soluble ester 2dM was obtained from the
combined filtrates in 46% yield with de of 80%. The ester
2dM was hydrolyzed and successively converted to the
acid chloride, and then was transformed to the ester of
(+)-B. Similarly to (S)-2b, diastereomerically pure
(R)-CFTA ester of (+)-B was obtained by crystalliza-
tion, followed by the conversion to enantiopure (R)-2b.
The yields of enantiopure (S)- and (R)-2b were 30% and
17% (based on rac-2c), respectively. By this procedure
several grams of optically active 2b can be easily
prepared.
2. Results and discussion
2.1. Resolution of CFTA
Since CFTA is somewhat unstable, the chiral auxiliary
used must be removed under mild conditions. Therefore,
although diastereomeric amides generally afford better
separation7 than diastereomeric esters, ester derivatives,
which can be hydrolyzed easier than amide derivatives,
were prepared. Unfortunately, due to the relatively low
polarity, separation was not detected for the diastereo-
meric CFTA esters of 1-phenylethanol, trans-2-phenyl-
cyclohexanol, menthol, and 8-phenylmenthol, as
determined by silica gel HPTLC plates. Subsequently, to
increase polarity, N-acyl-cis-1-amino-2-indanols8 were
examined as chiral auxiliaries, in which the polarity can
be adjusted by selecting a proper N-acyl group to vary
the overall chromatographic behavior. It was also
expected that cis-amide groups adjacent to the CFTA
ester groups would provide an additional site of inter-
action with the stationary phase resulting in greater
difference of chromatographic behavior between the
diastereomeric esters.
2.2. Crystal structures of 2dL and 2dM
To gain insight into the different crystallization behav-
iors of 2dL and 2dM, X-ray single-crystal analyses were
carried out on these diastereomers. Results showed that
both compounds crystallize in an acentric space group,
and that the solid-state structures of both compounds
exhibit an infinite N–H- - -O hydrogen bonding between
the Cbz groups along the shortest crystal axis, as shown
in Figure 1. Comparatively, the shorter N- - -O distance
ꢀ
of 2dL (2.793 A) indicates stronger hydrogen bonding
ꢀ
than that of 2dM (2.969 A). The longer N- - -O distance
of the latter is attributable to the steric repulsion
between cyano and p-tolyl groups that prevents compact
packing. Furthermore, weak p/p stacking between Ph/
Ph in the Cbz groups (mean interplanar dis-
ꢀ
ꢀ
tance ¼ 3.410 A, the shortest C- - -C distance ¼ 3.584 A)
was observed for 2dL. However, such p/p stacking was

T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
557
NHCbz
F
CN
F
CN
CO2Et
(COCl)2, DMF
CH2Cl2
LiOH
(-)-B, Py
CO2
rac-2a
rac-2b
THF/H2O
CH2Cl2
rac-2c
2dL + 2dM
NHCbz
F
CN
(S)-2b
LiOH
(COCl)2, DMF
CH2Cl2
(S)-2a
83% (30% from 2c)
CO2
(>99% ee)
THF/H2O
less soluble
2dL 36% from 2c
(>99% de)
1) LiOH
H2O/THF
2) (COCl)2, DMF
CH2Cl2
NHCbz
F
CN
(R)-2b
(COCl)2, DMF
CH2Cl2
36% (17% from 2c)
(R)-2a
CO2
(>99% ee)
3) (+)-B
Py
4) LiOH
H2O/THF
more soluble
2dM 46% from 2c
(~80% de)
Scheme 1. Resolution of rac-CFTA 2a.
N
H
N
H
A
O
O
A'
(a)
(b)
Figure 1. Parts of NH- - -O@C hydrogen bonding chains in the crystal. Hydrogen atoms, except for NH, are omitted for clarity. (a) Compound 2dL,
ꢀ
ꢀ
ꢀ
ꢀ
molecules are stacked along b-axis (4.904 A), O- - -N: 2.793 A, NH- - -O: 1.92 A, N–H: 0.88 A, N–H- - -O: 172.0ꢁ; (b) compound 2dM, molecules are
ꢀ
ꢀ
ꢀ
ꢀ
stacked0 along a-axis (5.100 A), O- - -N: 2.969 A, NH- - -O: 2.20 A, N–H: 0.84 A, N–H- - -O: 152.2ꢁ. Weak p/p stacking is observed between Ph/Ph
ꢀ
(A- - -A ) of the Cbz groups for the compound 2dL, centroid- - -centroid distance: 4.904 A, mean interplanar distance: 3.410 A.
ꢀ
R
not observed for 2dM. These differences in the crystal
structures explain the ease of crystallization for 2dL in
comparison to 2dM.
3: R = Me, Ar = Ph
a: X = OH
4: R = Me, Ar = 4-iBuC6H4
5: R = Me, Ar = 6-MeOC10H6
6: R = Et, Ar = Ph
b: X = Cl
c: X = 2-(1-aminoindanyl)
Ar
COX
3-7
7: R = OMe, Ar = Ph
2.3. Chromatographic resolution of a-arylacetic acids
N-Acyl-1-amino-2-indanols A and B have been shown
to be effective for the separation of CFTA enantiomers.
To investigate the range of applications, A and B were
applied for the resolution of various a-arylacetic acids
3a–7a, including well-known pharmaceutical com-
pounds, ibuprofen 4a and naproxen 5a.9
Although B was more effective than A for the resolution
of CFTA, it appeared that B was not sufficiently reactive
toward a-arylacetyl chlorides and, therefore, was not
suitable for the resolution of these acids. For example,
attempted esterification of ())-B with rac-2-phenyl-
propanoyl chloride 3b in dichloromethane was sluggish

558
T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
and afforded a mixture of diastereomeric esters 3c in low
yields. On the other hand, reaction between N-Ac
derivative ())-A and a small excess of acid chloride 3b at
room temperature for 24 h afforded the diastereomeric
esters of 3c in 81% yield (Scheme 2). Similarly, reactions
of acid chlorides 4b–7b with ())-A gave the correspond-
ing esters 4c–7c in comparable yields (see Scheme 2).
In contrast to the diastereomeric CFTA esters of ())-B,
these diastereomers showed well-resolved chromato-
graphic separation, as expected. The separation of dia-
stereomers on a silica gel TLC plate is shown in Figure
2. Preparative separation of the diastereomers of 3c was
performed by silica gel flash column chromatography.
The yields of the first-eluted 3c1st and the second-eluted
3c2nd in 43% and 35% yields (based on A), respectively.
Separation of diastereomeric esters of 4c–7c was carried
out in a similar fashion.
Figure 2. Diastereomer separation of 3c–7c using silica gel TLC
(hexane/CHCl3/AcOEt ¼ 3:3:1for 3c–5c, 2:2:1for 6c, 7c). The values
for Rf of the compounds are shown in parentheses.
Table 1. Yields of enantiomerically pure a-arylacetic acidsa
Acid
Yield (%)
Acid
Yield (%)
(S)-3a
(S)-4a
(S)-5a
(S)-6a
(S)-7a
30b (36b)
35 (42)
29 (35)
29b (35b)
31(37)
(R)-3a
(R)-4a
(R)-5a
(R)-6a
( R)-7a
20b (24b)
32 (38)
23 (27)
In order to avoid possible racemization of the acid,
which possesses an active hydrogen, hydrolysis of the
purified ester was carried out under acidic conditions.
For example, hydrolysis of ester 4c1st was complete
within 1h at 100 ꢁC using 6 M HBr/AcOH to afford acid
(S)-4a in 94% yield with 97% ee, as determined by
HPLC. Similarly, the other esters were hydrolyzed to
give the corresponding acids in good yields with slight
racemization. Upon recrystallization, acids (S)-4a, (R)-
4a, (S)-5a, (R)-5a, (S)-7a, and (R)-7a were obtained with
over 99% ee. Acids (S)-3a, (R)-3a, (S)-6a, and (R)-6a
were converted into their sodium salts, and then
recrystallized to afford salts that were nearly enantio-
pure. Overall yields of the acids and salts (based on the
acid chlorides) on 0.2 mmol-scale experiments are sum-
marized in Table 1.
27b (32b)
25 (30)
a Based on acid chloride; the values in parentheses: based on A.
b Yields of sodium salt.
2-indanol A can be an effective agent for the chro-
matographic resolution of a series of a-arylacetic acids.
3. Experimental
3.1. General
Optically active cis-1-amino-2-indanols were purchased
from Aldrich. Dichloromethane was distilled from CaH2
under argon atmosphere. Purification by flash chroma-
tography was performed on Merck 9385 silica gel. Thin
layer chromatography was performed on Merck 5715
glass plates. NMR spectra were recorded on a JEOL
GSX-400 spectrometer (400 MHz for 1H, 100 Hz for
13C, and 376 MHz for 19F) in CDCl3 at room tempera-
ture. Chemical shifts are expressed in ppm values from
The same procedure was applied for the resolution of 4a
in gram scale. Using 1.54 g (6.84 mmol) of racemic 4b
and 1.0 g (5.26 mmol) of ())-A, 350–370 mg of each
enantiomer of 4a was obtained in 32–34% yield. In this
resolution, 76% of ())-A was recovered.
In summary, a practical method for the resolution of
a-cyano-a-fluoro-p-tolylacetic acid (CFTA) 2a using
N-Cbz-cis-1-amino-2-indanol B was developed. This
method will allow wider usage of CFTA as a versatile
CDA. It was also demonstrated that N-Ac-cis-1-amino-
1
TMS, CDCl3, and CFCl3 as internal standard for H,
13C, 19F NMR, respectively. Optical rotations were
determined on a Perkin–Elmer 241polarimeter. IR
NHAc
NHAc
(-)-A
Et3N, DMAP
R
H
H
R
R
+
Ar
CO2
Ar
CO2
CH2Cl2, 24h
Ar
COCl
3b-7b
3c-7c
Yield
3: 81%
4: 88%
5: 77%
6: 90%
7: 78%
Scheme 2. Preparation of diastereomeric ())-A esters of a-arylacetic acids.

T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
559
spectra were recorded on a Shimadzu FTIR-8100M. MS
was taken on a JEOL JMS-GCMATE. HRMS was
determined on a JEOL JMS-AX505HAD. Melting
points were determined on a Yanaco MP-S3. The
enantiomeric purity of a-arylacetic acids was determined
by HPLC using Daicel Chiralcel OD or AD-H column
(0:46£ Â 250l mm); with hexane/2-propanol containing
trifluoroacetic acid as an eluent.
filtrate was concentrated to give crude racemic CFTA-Cl
rac-2b as yellow oil (3.12 g, 93%).
Crude rac-2b was dissolved in 60 mL of dried CH2Cl2
under an argon atmosphere. To the solution were added
pyridine (2.39 mL, 29.5 mmol) and N-Cbz-(1R,2S)-1-
amino-2-indanol ())-B (4.18 g, 14.8 mmol) at 0 ꢁC and
the mixture was stirred at room temperature for 15 h.
Solvent was evaporated and the residue was dissolved in
AcOEt. The solution was washed with water and brine.
The organic layer was dried over MgSO4 and evapo-
rated. Flash column chromatography (eluent: CHCl3/
AcOEt ¼ 10:1) gave the mixture of 2dL and 2dM as a pale
yellow solid. The solid was suspended in 250 mL of
hexane and the mixture was heated (80 ꢁC, bath temp).
At the temperature, CHCl3 was added until the solid
disappeared. The solution was stood at room temper-
ature overnight. Precipitate was filtered off and recrys-
tallized again to give 1.42 g of less-soluble isomer 2dL as
very thin fiber-like crystals in >99% de. The mother
liquor was concentrated and recrystallization was
repeated. The final yield of 2dL based on rac-2c was 36%
(2.58 g, >99% de as checked by 19F NMR).
3.2. Preparation of N-acyl-cis-1-amino-2-indanols
N-Acyl-cis-1-amino-2-indanols were prepared according
to the method described in the literature.10
3.2.1. N-Acetyl-(1R,2S)-cis-1-amino-2-indanol ())-A. Mp
22
182–183 ꢁC (hexane/AcOEt); ½aŠ ¼ )39.0 (c 1.0, EtOH)
D
20
D
{lit.11 ½aŠ ¼ +38.3 (c 0.84, EtOH for the enantiomer)};
1H NMR (400 MHz, CDCl3) d 2.11 (3H, s), 2.94 (1H,
dd, J ¼ 16.4, 2.4 Hz), 3.17 (1H, dd, J ¼ 16.4, 5.2 Hz),
4.62 (1H, td, J ¼ 4.4, 2.4 Hz), 5.37 (1H, dd, J ¼ 6.0,
5.2 Hz), 6.22 (1H, br d, J ¼ 6.0 Hz), 7.21–7.27 (4H, m).
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32.
Found: C, 68.83; H, 6.81; N, 7.16.
24
2dL: Mp 149–150 ꢁC (hexane/CHCl3); ½aŠ ¼ +92.4 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 2.32 (3H, s), 2.87
(1H, dd, J ¼ 17.4, 1.7 Hz), 3.18 (1H, dd, J ¼ 17.4,
5.1Hz), 5.05 (1H, br d, J ¼ 9.3 Hz), 5.16 (1H, d,
J ¼ 18.6 Hz), 5.49 (1H, dd, J ¼ 9.3, 5.1Hz), 5.73 (1H, m),
7.11–7.14 (3H, m), 7.26–7.28 (3H, m), 7.32–7.39 (7H, m);
13C NMR (100 MHz, CDCl3) d 21.22, 36.52, 57.80, 67.26,
79.34, 86.97 (d, J ¼ 198.4 Hz), 114.02 (d, J ¼ 33.5 Hz),
123.86, 124.97, 125.19 (d, J ¼ 6.1 Hz), 127.67, 128.11,
128.15 (d, J ¼ 22.9 Hz), 128.18, 128.53, 128.73, 129.87,
136.15, 138.25, 139.07, 141.60 (d, J ¼ 3.0 Hz), 156.14,
162.35 (d, J ¼ 30.5 Hz); 19F NMR (376 MHz, CDCl3)
d )147.11; IR (KBr) 3600–3200 (br), 3308, 3050–2850,
2250 (vw), 1754, 1698, 1538, 1293, 1254, 1057 cmÀ1; MS
(EI, 70 eV) m=z 458 (Mþ), 366, 341, 311, 302, 289, 265.
Anal. Calcd for C27H23FN2O4: C, 70.73; H, 5.06; N, 6.11.
Found: C, 70.81; H, 5.28; N, 6.24.
3.2.2. N-Carbobenzyloxy-(1R,2S)-cis-1-amino-2-indanol
24
())-B. Mp 129–130 ꢁC ; ½aŠ ¼ )11.2 (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3) d 2.89 (1H, dd, J ¼ 16.6,
1.7 Hz), 3.09 (1H, dd, J ¼ 16.6, 4.9 Hz), 4.55 (1H, br s),
5.10–5.19 (3H, m), 5.48 (1H, br s), 7.18–7.39 (9H, m).
3.2.3. N-Carbobenzyloxy-(1S,2R)-cis-1-amino-2-indanol
25
D
(+)-B. Mp 129–130 ꢁC (hexane/CHCl3); ½aŠ ¼ +11.3 (c
0.39, CHCl3).
3.3. Resolution of rac-CFTA rac-2a via diastereomeric
ester formation with enantiopure N-Cbz-cis-1-amino-2-
indanol and preparation of enantiopure CFTA-Cl 2b
Diastereomerically pure 2dL (1.20 g, 2.62 mmol) was
hydrolyzed with 5.2 mL of 1M lithium hydroxide
aqueous solution in 20 mL of THF/H2O (1:1) at room
temperature. After evaporation of THF under reduced
pressure, the mixture was extracted with Et2O. From the
aqueous layer, (S)-2a was obtained and then converted
to (S)-2b in the similar manner to the rac-2b. Distillation
of the crude product gave 0.46 g of enantiopure (S)-2b
(2.18 mmol, 83%). The Et2O layer was evaporated and
the residue was chromatographed (SiO2 15 g, hexane/
AcOEt ¼ 1to AcOEt). The resolving agent B was
recovered in 65% yield (0.48 g, 1.70 mmol) accompanied
by 59 mg of (1R,2S)-cis-1-amino-2-indanol (0.39 mmol,
15%).
Racemic CFTA ethyl ester rac-2c (3.49 g, 15.8 mmol)
was dissolved in 53 mL of THF/H2O (1:1). To this
solution was added 1M lithium hydroxide aqueous
solution (15.8 mL, 15.8 mmol) and the mixture was
stirred at room temperature for 15 min. After evapora-
tion of THF under reduced pressure, unreacted ester 2c
was removed by ether extraction. The aqueous layer was
acidified (pH ꢀ 1) with 10% aqueous HCl at 0 ꢁC. The
solution was saturated with NaCl and extracted with
AcOEt. The organic layer was washed with brine and
dried over MgSO4. After removal of the solvent, the
residual water was removed as azeotrope with benzene
to give crude racemic CFTA rac-2a as a colorless oil. It
was subsequently dissolved in dried CH2Cl2 (132 mL)
containing a catalytic amount of DMF (0.17 mL,
2.2 mmol) under an argon atmosphere. To the solution
was added oxalyl chloride (2.8 mL, 31.6 mmol) at 0 ꢁC
and the mixture was stirred at room temperature for 3 h.
After removal of the solvent, benzene was added to the
residue and insoluble precipitate was filtered off. The
1
(S)-2b: H NMR (400 MHz, CDCl3) d 2.43 (3H, br s),
7.34 (2H, br d, J ¼ 7.8 Hz), 7.54 (2H, br d, J ¼ 7.8 Hz);
IR (neat) 1794 cmÀ1
.
The combined mother liquor was concentrated and
crystallized from hexane/CHCl3 to give 2dM in 46% yield

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T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
3
1336.3 A , Z ¼ 2, Dc ¼ 1.436 g/cmÀ3
,
colorless
l(MoKa) ¼
ꢀ
(ꢀ80% de). In the same manner as described for 2dL,
2dM (ꢀ80% de) was converted to the acid chloride,
which was allowed to react with N-Cbz-(1S,2R)-cis-1-
amino-2-indanol (+)-B. The resulting (R)-CFTA ester of
(+)-B was purified by recrystallization and was con-
verted to the acid chloride (R)-2b (0.56 g, 2.65 mmol) in
the same way described for (S)-2b.
3.87 mmÀ1
,
T ¼ 173 K,
needles
(0.35 · 0.08 · 0.05 mm), 18,479 measured, 5724 unique,
R1 ¼ 0.068, wR2 ¼ 0.162 for all reflections (SHELX97
refinement), solvent CHCl3 is located in disorder, and
does not appear in clear shape, but molecular structure
of 2dL was well refined.
(S)- and (R)-2b were identified as (S)-1-phenylethyl-
amides prepared from (S)-1-phenylethylamine and (S)-
and (R)-2b. Spectral data of the amides were identical to
an authentic (S)-1-phenylethylamides prepared using
(S)- and (R)-2b obtained by enzymatic resolution.3a
Enantiomeric excesses (S)- and (R)-2b were determined
to be more than 99% as checked by 19F NMR spectra of
the corresponding amides.
Crystal data for 2dM: C27H23N2O4F, triclinic, P1 (no 1),
M ¼ 458:79,
a ¼ 5:1000(5),
b ¼ 10:180(2),
c ¼
ꢀ
11:760(3) A, a ¼ 73:29, b ¼ 72:270(6), c ¼ 79:44(1)ꢁ,
3
V ¼ 551:5 A , Z ¼ 1, Dc ¼ 1:380 g/cmÀ3, l(MoKa) ¼
ꢀ
0.99 mmÀ1, T ¼ 150 K, colorless prism (0.20 · 0.15 ·
0.10 mm), 5740 measured, 2403 unique, R1 ¼ 0:034,
wR2 ¼ 0:093 for all reflections (SHELX97 refinement).
Crystallographic data (excluding structure factors) for
the structures of 2dL and 2dM have been deposited with
the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC 223739 for 2dL
and CCDC 223740 for 2dM. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44-(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
3.3.1. (S)-2-Cyano-2-fluoro-N-[(S)-1-phenylethyl]-2-p-tolyl-
acetamide.3a (S)-2b (25 lL, 0.156 mmol) was reacted with
(S)-1-phenylethylamine (21 lL, 0.156 mmol) in CH2Cl2
(1mL) in the presence of pyridine (25 lL, 0.31mmol) to
give 41.8 mg (90%) of the amide. Mp 69–72 ꢁC;
27
½aŠ ¼ )88.9 (c 1.22, MeOH); 1H NMR (400 MHz,
D
CDCl3) d 1.61 (3H, d, J ¼ 7.1Hz), 2.36 (3H, d,
J ¼ 1.9 Hz), 5.16 (1H, qd, J ¼ 7.1, 6.9 Hz), 6.68 (1H, br
s), 7.22 (2H, br d, J ¼ 8.3 Hz), 7.26 (2H, m), 7.31(1H,
m), 7.33 (2H, m), 7.39 (2H, br d, J ¼ 8.3 Hz); 19F NMR
(376 MHz, CDCl3) d )140.96; IR (KBr) 3330, 2252,
1680 cmÀ1. MS (EI, 70 eV) 297 (Mþ+1), 296 (Mþ). Anal.
Calcd for C18H17FN2O: C, 72.95; H, 5.78; N, 9.45.
Found: C, 72.87; H, 5.52; N, 9.48.
3.5. Resolution of racemic 2-arylacetic acids 3a–7a
through chromatographic separation of their diastereo-
meric esters of ())-A 3c–7c
Typical example: Separation of the diastereomers of 3c:
To the suspension of ())-A (38.0 mg, 0.20 mmol) in 5 mL
of CH2Cl2 were added triethylamine (56 lL, 0.24 mmol),
racemic 2-phenylpropionyl chloride 3b (36 lL,
0.24 mmol), and catalytic amount of 4-(N,N-dimethyl-
amino)pyridine (3.0 mg, 0.024 mmol). After stirring at
room temperature for 24 h, the solvent was removed
under reduced pressure. Column chromatography of the
residue (SiO2 5 g, hexane/CHCl3/AcOEt ¼ 4:4:1) gave
28.9 mg (0.086 mmol, 43%) of 3c1st and 23.9 mg
(0.070 mmol, 35%) of 3c2nd. Other diastereomeric esters
of 4c–7c were obtained in the similar way.
3.3.2.
tolylacetamide. 3a (R)-2b (25 lL, 0.156 mmol) were
reacted with (S)-1-phenylethylamine (21 lL,
(R)-2-Cyano-2-fluoro-N-[(S)-1-phenylethyl]-2-p-
0.156 mmol) in the presence of pyridine (25 lL,
0.31mmol) in CH 2Cl2 (1mL) to give 43.2 mg (93%) of
26
the amide. Mp 125–131 ꢁC; ½aŠ ¼ )89.6 (c 1.64,
D
MeOH); 1H NMR (400 MHz, CDCl3) d 1.53 (3H, d, J ¼
7.1Hz), 2.40 (3H, d, J ¼ 1.5 Hz), 5.14 (1H, qd, J ¼ 7.1,
6.8 Hz), 6.68 (1H, br s), 7.28 (2H, br d, J ¼ 7.6 Hz), 7.33
(1H, m), 7.35 (2H, m), 7.36 (2H, m), 7.50 (2H, br d,
J ¼ 7.5 Hz); 19F NMR (376 MHz, CDCl3) d )142.25; IR
(KBr) 3328, 2252, 1676 cmÀ1; MS (EI, 70 eV) 297
(Mþ+1), 296 (Mþ). Anal. Calcd for C18H17FN2O: C,
72.95; H, 5.78; N, 9.45. Found: C, 72.97; H, 5.89; N,
9.31.
24
3c1st: Mp 1 94ꢁC (hexane/CHCl3); ½aŠ ¼ +40.4 (c 1.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.46 (3H, d,
J ¼ 6.8 Hz), 1.56 (3H, s), 3.01 (1H, d, J ¼ 17.6 Hz), 3.21
(1H, J ¼ 17.6, 4.8 Hz), 3.63 (1H, q, J ¼ 6.8 Hz), 5.16
(1H, br d, J ¼ 8.0 Hz), 5.54 (1H, td, J ¼ 4.8, 0.8 Hz),
5.58 (1H, dd, J ¼ 8.0, 4.8 Hz), 7.21–7.34 (9H, m); 13C
NMR (100 MHz, CDCl3) d 17.70, 22.77, 37.61, 45.29,
55.52, 75.94, 123.60, 124.92, 127.14, 127.35 (br), 128.09,
128.94, 139.14, 140.78, 140.92, 169.96, 173.27; IR (KBr)
3600–3300 (br), 3291, 3200–2800, 1722, 1653, 1549,
1202, 1174, 752, 727, 696 cmÀ1; MS (EI, 70 eV) m=z 323
(Mþ), 263, 190, 173. Anal. Calcd for C20H21NO3: C,
74.28; H, 6.55; N, 4.33. Found: C, 74.02; H, 6.66; N,
4.29.
3.4. X-ray crystallography
Single crystals of 2dL were prepared by recrystallization
of 2dL with >99% de from hexane/CHCl3. Single crystals
of 2dM formed together with crystals of 2dL in recrys-
tallization of 2dL with ꢀ90% de from the same solvent
system.
25
3c2nd: Mp 1 71ꢁC (hexane/CHCl3); ½aŠ ¼ +68.6 (c 0.33,
D
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.48 (3H, d,
Crystal
data
for
2dL:
[C27H23N2O4F]ꢁCHCl3,
J ¼ 7.2 Hz), 1.82 (3H, s), 2.86 (1H, dd, J ¼ 16.4, 1.2 Hz),
M ¼ 577.87, monoclinic, P21 (no 4), a ¼ 14.395(6),
ꢀ
3.18 (1H, dd, J ¼ 16.4, 5.2 Hz), 3.70 (1H, q, J ¼ 7.2 Hz),
b ¼ 4.904(2), c ¼ 19.085(8) A, b ¼ 97.329(9)ꢁ, V ¼

T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
561
5.41(1H, br d, J ¼ 9.2 Hz), 5.57 (1H, td, J ¼ 5.2, 2.0 Hz),
5.63 (1H, dd, J ¼ 9.2, 5.2 Hz), 7.16–7.30 (9H, m); 13C
NMR (100 MHz, CDCl3) d 17.83, 22.83, 37.14, 45.73,
75.56, 123.58, 124.78, 127.05, 127.20, 127.24, 127.33,
128.11, 128.53, 139.19, 139.78, 140.31, 169.93, 173.27;
IR (KBr) 3700–3200 (br), 3299, 3200–2800, 1716, 1653,
1553, 1219, 1207, 1192, 754, 733, 700 cmÀ1; MS (EI,
70 eV) m=z 323 (Mþ), 321, 274, 241, 206. Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.52;
H, 6.73; N, 4.26.
J ¼ 17.1, 1.6 Hz), 3.17 (1H, dd, J ¼ 16.9, 4.8 Hz), 3.83
(1H, q, J ¼ 7.1Hz), 5.33 (1H, br d, J ¼ 9.6 Hz), 5.57 (1H,
dd, J ¼ 5.1, 1.5 Hz), 5.61 (1H, dd, J ¼ 9.1, 5.1 Hz), 7.09
(1H, d, J ¼ 2.5 Hz), 7.12–7.19 (3H, m), 7.21–7.27 (2H,
m), 7.29 (1H, dd, J ¼ 8.6, 1.9 Hz), 7.57 (1H, d,
J ¼ 1.5 Hz), 7.61 (1H, d, J ¼ 9.1Hz), 7.64 (1H, d,
J ¼ 8.6 Hz); 13C NMR (100 MHz, CDCl3) d 17.85, 22.61,
37.20, 45.78, 55.23, 55.49, 75.68, 105.43, 119.14, 123.62,
124.86, 125.89, 125.97, 127.06, 127.11, 128.14, 128.72,
129.14, 133.66, 134.82, 139.23, 140.40, 157.74, 169.90,
173.42; IR (KBr) 3700–3200 (br), 3302, 1717, 1653,
1549, 1196, 1181, 1030, 812, 758, 731 cmÀ1; MS (EI,
70 eV) m=z 403 (Mþ), 342, 229, 211; HRMS calcd for
C25H25NO4: 403.1784; found: 403.1766.
25
4c1st: Mp 207 ꢁC (hexane/CHCl3); ½aŠ ¼ +17.2 (c 1.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) d 0.90 (6H, d,
J ¼ 4.0 Hz), 1.46 (3H, d, J ¼ 6.8 Hz), 1.58 (3H, s), 1.78–
1.86 (1H, m), 2.43 (2H, d, J ¼ 7.2 Hz), 2.85 (1H, d,
J ¼ 17.2 Hz), 3.16 (1H, dd, J ¼ 17.2, 4.8 Hz), 3.66 (1H, q,
J ¼ 7.2 Hz), 5.50–5.65 (3H, m), 7.02–7.27 (8H, m); 13C
NMR (100 MHz, CDCl3) d 17.68, 22.31, 22.36, 22.72,
30.10, 37.67, 44.87, 44.91, 55.61, 75.88, 123.58, 124.92,
127.05, 127.14, 128.08, 129.63, 138.05, 139.20, 140.81,
140.86, 169.94, 173.49; IR (KBr) 3600–3200 (br), 3318,
3200–2800, 1728, 1651, 1541, 1200, 1175, 779, 762,
764 cmÀ1; MS (EI, 70 eV) m=z 379 (Mþ), 318, 205, 187,
173. Anal. Calcd for C24H29NO3: C, 75.96; H, 7.70; N,
3.69. Found: C, 75.82; H, 7.89; N, 3.63.
20
6c1st: Mp 81–82 ꢁC (hexane/CHCl3); ½aŠ ¼ +48.7 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.85 (3H, t,
J ¼ 7.3 Hz), 1.55 (3H, s), 1.77 (1H, ddq, J ¼ 13.7, 7.6,
7.3 Hz), 2.08 (1H, ddq, J ¼ 13.7, 7.6, 7.3 Hz), 2.98 (1H,
br d, J ¼ 17.1 Hz), 3.22 (1H, br dd, J ¼ 17.1, 4.9 Hz)
3.36 (1H, t, J ¼ 7.6 Hz), 5.20 (1H, br d, J ¼ 7.4 Hz), 7.16
(1H, br d, J ¼ 7.6 Hz), 7.18–7.34 (9H, m); 13C NMR
(100 MHz, CDCl3) d 11.82, 22.68, 37.69, 55.05, 55.49,
75.65, 123.58, 124.88, 127.11, 127.36, 127.72, 128.06,
128.86, 139.17, 139.39, 140.75, 169.90, 172.79; IR (KBr)
3600–3200 (br), 3332, 3200–2800, 1725, 1655, 1534,
1199, 1173, 750, 727, 694 cmÀ1; MS (EI, 70 eV) m=z 337
(Mþ), 294, 277, 249, 190, 173. Anal. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.66;
H, 7.12; N, 4.05.
25
4c2nd: Mp 1 27ꢁC (hexane/CHCl3); ½aŠ ¼ +52.6 (c 1.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) d 0.88 (6H, d,
J ¼ 4.0 Hz), 1.44 (3H, d, J ¼ 7.2 Hz), 1.58 (3H, s), 1.78–
1.86 (1H, m), 2.43 (2H, d, J ¼ 7.2 Hz), 3.00 (1H, d,
J ¼ 17.6 Hz), 3.20 (1H, dd, J ¼ 17.6, 4.8 Hz), 3.60 (1H, q,
J ¼ 7.2 Hz), 5.25 (1H, br d, J ¼ 8.4 Hz), 5.50–5.63 (2H,
m), 7.02–7.27 (8H, m); 13C NMR (100 MHz, CDCl3) d
17.64, 21.89, 22.16, 29.63, 36.67, 44.41, 44.68, 55.08,
74.98, 123.22, 124.25, 126.50, 126.64, 127.52, 128.78,
136.82, 138.90, 139.98, 140.04, 169.94, 173.27; IR (KBr)
3600–3200 (br), 3314, 3200–2800, 1734, 1655, 1541,
1198, 1159, 750, 741, 729 cmÀ1. Anal. Calcd for
C24H29NO3: C, 75.96; H, 7.70; N, 3.69. Found: C, 75.92;
H, 7.85; N, 3.72.
20
6c2nd: Mp 124–126 ꢁC (hexane/AcOEt); ½aŠ ¼ +51.3 (c
D
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.88 (3H, t,
J ¼ 7.3 Hz), 1.78 (3H, s), 1.79 (1H, m), 2.02 (1H, ddq,
J ¼ 13.9, 7.6, 7.3 Hz), 2.86 (1H, br d, J ¼ 16.6 Hz), 3.17
(1H, dd, J ¼ 17.1, 4.9 Hz), 3.44 (1H, t, J ¼ 7.9 Hz), 5.46
(1H, br d, J ¼ 8.3 Hz), 5.60 (1H, dt, J ¼ 5.1, 1.2 Hz), 5.62
(1H, m), 7.16–7.30 (10H, m); 13C NMR (100 MHz,
CDCl3) d 12.05, 22.94, 37.34, 53.94, 55.55, 75.64, 123.58,
124.90, 127.14, 127.37, 127.92, 128.17, 128.64, 138.60,
139.28, 140.49, 169.89, 172.67; IR (KBr) 3600–3100 (br),
3312, 3100–2800, 1732, 1655, 1541, 1196, 1163, 738,
694 cmÀ1; MS (EI, 70 eV) m=z 337 (Mþ), 294, 277, 249,
190, 173. Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87;
N, 4.15. Found: C, 74.83; H, 6.87; N, 4.19.
24
5c1st: Mp 230 ꢁC (hexane/CHCl3); ½aŠ ¼ )14.2 (c 1.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.11 (3H, s),
1.54 (3H, d, J ¼ 7.1Hz), 3.03 (1H, d, J ¼ 17.2 Hz), 3.21
(1H, dd, J ¼ 16.9, 4.2 Hz), 3.76 (1H, q, J ¼ 7.1Hz), 3.92
(3H, s), 5.05 (1H, br d, J ¼ 8.8 Hz), 5.52–5.58 (2H, m),
7.09 (2H, m), 7.15 (1H, dd, J ¼ 9.1, 2.7 Hz), 7.15–7.28
(3H, m), 7.29 (1H, dd, J ¼ 8.3, 1.7 Hz), 7.59 (1H, d, J ¼
1.8 Hz), 7.64 (1H, d, J ¼ 9.0 Hz), 7.68 (1H, d,
J ¼ 8.8 Hz); 13C NMR (100 MHz, CDCl3) d 17.64, 22.11,
37.69, 45.20, 55.29, 55.55, 75.94, 105.48, 119.40, 123.60,
124.92, 125.76, 125.89, 127.12, 127.44, 128.08, 128.88,
129.13, 133.72, 135.88, 139.16, 140.83, 157.89, 169.91,
173.42; IR (KBr) 3700–3200 (br), 3319, 3100–2900,
1724, 1651, 1545, 1192, 1032, 855, 735 cmÀ1; MS (EI,
70 eV) m=z 403 (Mþ), 229, 211, 184, 172; HRMS calcd
for C25H25NO4: 403.1784; found: 403.1762. Anal. Calcd
for C25H25NO4: C, 74.42; H, 6.25; N, 3.47. Found: C,
74.42; H, 6.25; N, 3.51.
20
7c1st: Mp 192–194 ꢁC (hexane/AcOEt); ½aŠ ¼ +77.0 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) dD1.58 (3H, s),
3.03 (1H, br d, J ¼ 17.5 Hz), 3.22 (1H, dd, J ¼ 17.5,
4.9 Hz), 3.38 (3H, s), 4.69 (1H, s), 5.10 (1H, br d,
J ¼ 8.5 Hz), 5.61 (1H, m), 5.64 (1H, m), 7.14 (1H, br d,
J ¼ 7.4 Hz), 7.26 (4H, m), 7.35 (5H, m); 13C NMR
(100 MHz, CDCl3) d 22.72, 37.53, 55.61, 57.21, 76.68,
81.95, 123.44, 124.94, 127.14, 127.21, 128.15, 128.96,
128.98, 136.62, 138.98, 140.45, 169.40, 169.91; IR (KBr)
3600–3200 (br), 3318, 3200–2800, 1740, 1651, 1549,
1194, 1117, 997, 988, 750, 725, 698 cmÀ1; MS (EI, 70 eV)
m=z 339 (Mþ), 279, 236, 204, 173. Anal. Calcd for
C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.62;
H, 6.31; N, 4.11.
24
5c2nd: Mp 203 ꢁC (hexane/CHCl3); ½aŠ ¼ +65.6 (c 1.0,
D
21
7c2nd: Mp 1 67ꢁC (hexane/CHCl3); ½aŠ ¼ +21.2 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.56 (3H, d,
D
1
J ¼ 6.8 Hz), 1.56 (1H, d, J ¼ 7.1Hz), 2.84 (1H, dd,
CHCl3); H NMR (400 MHz, CDCl3) d 1.84 (3H, s),

562
T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
2.85 (1H, br d, J ¼ 17.4 Hz), 3.19 (1H, br dd, J ¼ 17.4,
5.1 Hz), 3.36 (3H, s), 5.58–5.69 (3H, m), 7.17 (1H, ddd,
J ¼ 5.1, 3.9, 0.9 Hz), 7.20–7.28 (4H, m), 7.30–7.37 (5H,
m); 13C NMR (100 MHz, CDCl3) d 22.76, 37.06, 55.48,
57.25, 76.30, 82.69, 123.55, 124.84, 126.69, 127.14,
128.18, 128.59, 128.71, 135.95, 139.04, 140.12, 169.81,
170.09; IR (KBr) 3700–3100 (br), 3285, 3200–2800,
1748, 1651, 1541, 1204, 1172 1107, 1040, 1020, 752, 735,
696 cmÀ1; MS (EI, 70 eV) m=z 239 (Mþ), 279, 236, 204,
173. Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N,
4.13. Found: C, 70.65; H, 6.34; N, 4.09.
3.6.4. (R)-a-Phenylpropionic acid (R)-3a (hydrolysis
product of 3d2nd). Sodium salt: gradually decom-
24
D
posed at 250 ꢁC; ½aŠ ¼ )0.3 (c 1.0, H2O). Anal. Calcd
for C9H9O2Naꢁ0.2H2O: C, 61.50; H, 5.39. Found: C,
61.64; H, 5.31. Anal. Calcd for benzylthiouronium salt
of (R)-3a (C17H20N2O2S): C, 64.53; H, 6.37; N, 8.85; S,
10.11. Found: C, 64.27; H, 6.57; N, 8.85; S, 10.13.
3.6.5. (S)-(+)-Naproxen (S)-5a (hydrolysis product
of 5c1st). Mp 151–152 ꢁC (CHCl3/hexane) (lit.13 152–
21
154); ½aŠ ¼ +65.3 (c 1.0, CHCl3) [lit.13 +66 (c 1.0,
D
1
CHCl3)]; H NMR (400 MHz, CDCl3) d 1.59 (3H, d,
J ¼ 7.1Hz), 3.88 (1H, q, J ¼ 7.1Hz), 3.91 (3H, s), 7.11
(1H, br d, J ¼ 2.5 Hz), 7.13 (1H, dd, J ¼ 8.8, 2.5 Hz),
7.41(1H, dd, J ¼ 8.6, 1.7 Hz), 7.68 (1H, br s), 7.70 (1H,
br dd, J ¼ 8.8, 2.2 Hz). Anal. Calcd for C14H14O3: C,
73.03; H, 6.13. Found: C, 72.76; H, 6.24.
3.6. Hydrolysis of the esters of N-Ac-cis-1-amino-2-
indanol 3c–7c
Typical example: Ester of ibuprofen 4c1st (35.3 mg,
0.090 mmol) was dissolved in 1.9 mL of acetic acid. To
this solution, 0.95 mL of hydrobromic acid (47% aque-
ous solution) was added and the mixture was heated at
100 ꢁC for an hour. After cooling with an ice bath, brine
was added and the mixture was extracted with CHCl3.
The organic layer was washed with brine and dried over
MgSO4. The solvent was removed under reduced pres-
sure to give a pale yellow oil, which was purified by silica
gel column chromatography to give (S)-4a in 94% yield
(18.1 mg, 0.88 mmol) with 97% ee. Repeated recrystal-
lization from MeOH/H2O furnished 16.8 mg of enan-
tiopure (S)-4a (0.081mmol, 90%).
3.6.6. (R)-(+)-Naproxen (R)-5a (hydrolysis product of
21
D
5c2nd). Mp 150–151 ꢁC (CHCl3/hexane); ½aŠ ¼ )65.4 (c
1.0, CHCl3). Anal. Calcd for C14H14O3: C, 73.03; H,
6.13. Found: C, 72.76; H, 6.24.
3.6.7. (S)-a-Phenylbutyric acid (S)-6a (hydrolysis product
of 6c1st). 1H NMR (400 MHz, D2O) d 0.90 (3H, t,
J ¼ 7.4 Hz), 1.82 (1H, dqd, J ¼ 15.0, 7.4, 7.0 Hz), 2.09
(1H, ddq, J ¼ 15.0, 8.6, 7.4 Hz), 3.45 (1H, t, J ¼ 7.0 Hz),
7.28 (1H, m), 7.30–7.36 (4H, m); sodium salt: gradually
24
decomposed at 240 ꢁC; ½aŠ ¼ +0.5 (c 1.0, H2O); 1H
D
NMR (400 MHz, D2O) d 0.90 (3H, t, J ¼ 7.4 Hz), 1.74
(1H, dqd, J ¼ 15.0, 7.4, 7.0 Hz), 1.97 (1H, ddq, J ¼ 15.0,
8.6, 7.4 Hz), 3.40 (1H, dd, J ¼ 8.6, 7.0 Hz), 7.31(1H, m),
7.36–7.42 (4H, m). Anal. Calcd for C10H11-
O2Naꢁ0.3H2O: C, 62.69; H, 6.10. Found: C, 62.51; H,
6.22. Anal. Calcd for benzylthiouronium salt of (S)-6a
(C18H22N2O2S): C, 65.42; H, 6.71; N, 8.48; S, 9.70.
Found: C, 65.12; H, 6.77; N, 8.48; S, 9.88.
3.6.1. (S)-(+)-Ibuprofen (S)-4a (hydrolysis product
23
of 4c1st) . Mp 49–50 ꢁC (lit.12 50–52 ꢁC); ½aŠ ¼ +55.0 (c
D
20
1
2.0, EtOH) {lit.12 ½aŠ ¼ +59 (c 2.0, EtOH)}; H NMR
(400 MHz, CDCl3) dD0.90 (6H, d, J ¼ 6.6 Hz), 1.50 (3H,
d, J ¼ 7.1 Hz), 1.84 (1H, sept, J ¼ 6.7 Hz), 2.44 (2H, d,
J ¼ 7.1Hz), 3.71 (1H, q, J ¼ 7.1Hz), 7.10 (2H, dt,
J ¼ 8.1, 1.9 Hz), 7.21 (dt, J ¼ 8.1, 2.0 Hz). Anal. Calcd
for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.61; H,
8.79.
Hydrolyses of other esters were conducted in the same
manner.
3.6.8. (R)-a-Phenylbutyric acid (R)-6a (hydrolysis prod-
uct of 6c2nd). Sodium salt: gradually decomposed
24
D
at 230 ꢁC; ½aŠ ¼ )0.4 (c 1.0, H2O). Anal. Calcd for
C9H9O2Naꢁ0.3H2O: C, 62.69; H, 6.10. Found: C, 62.67;
H, 6.23. Anal. Calcd for benzylthiouronium salt of (R)-
6a (C18H22N2O2S): C, 65.42; H, 6.71; N, 8.48; S, 9.70.
Found: C, 65.12; H, 6.71; N, 8.48; S, 9.82.
3.6.2. (R)-())-Ibuprofen (R)-4a (hydrolysis product of
23
4c2nd). Mp 50.0–50.8 ꢁC; ½aŠ ¼ )55.0 (c 2.0, EtOH).
D
Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C,
75.43; H, 8.76.
3.6.9. (S)-a-Methoxyphenylacetic acid (S)-7a (hydrolysis
product of 7c1st). Mp 64–66 ꢁC (H2O/MeOH) (lit.14 65–
3.6.3. (S)-a-Phenylpropionic acid (S)-3a (hydrolysis prod-
uct of 3c1st). H NMR (400 MHz, D2O) d 1.52 (3H, d,
23
67 ꢁC); ½aŠ ¼ +143.8 (c 1.0, EtOH) [lit.14 +143.4 (c 1,
1
D
1
EtOH)]; H NMR (400 MHz, CDCl3) d 3.44 (3H, s),
4.79 (1H, s), 7.35–7.45 (5H, m). Anal. Calcd for
C9H9O3: C, 65.05; H, 6.07. Found: C, 65.04; H, 6.16.
J ¼ 6.8 Hz), 3.74 (1H, q, J ¼ 6.8 Hz), 7.27 (1H, m), 7.30–
7.36 (4H, m); sodium salt: gradually decomposed over
24
D
1
250 ꢁC; ½aŠ ¼ +0.3 (c 1.0, H2O); H NMR (400 MHz,
D2O) d 1.41 (3H, d, J ¼ 7.1Hz), 3.65 (1H, q, J ¼ 7.1Hz),
7.30 (1H, tt, J ¼ 6.9, 1.8 Hz), 7.34–7.42 (4H, m). Anal.
Calcd for C9H9O2Naꢁ0.2H2O: C, 61.50; H, 5.39. Found:
C, 61.59; H, 5.32. Anal. Calcd for benzylthiouronium
salt of (S)-3a (C17H20N2O2S): C, 64.53; H, 6.37; N, 8.85;
S, 10.11. Found: C, 64.23; H, 6.55; N, 8.80; S, 10.19.
3.6.10. (R)-a-Methoxyphenylacetic acid (R)-7a (hydroly-
sis product of 7c2nd). Mp 64–65 ꢁC (H2O/MeOH);
23
½aŠ ¼ )144.2 (c 1.0, EtOH). Anal. Calcd for C9H9O3: C,
D
65.05; H, 6.07. Found: C, 65.08; H, 6.06.

T. Fujiwara et al. / Tetrahedron: Asymmetry 15 (2004) 555–563
563
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart/New York, 1995; Vol. E 21a, pp 253–
292; (c) Rothchild, R. Enantiomer 2000, 5, 457; (d) Dale, J.
A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512; (e)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H.
J. Am. Chem. Soc. 1991, 113, 4092; (f) Trost, B. M.;
Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec,
J. M. J. Org. Chem. 1986, 51, 2370.
3.6.11. Enantiomer separation of 4a in preparative scale.
A mixture of 1.00 g (5.26 mmol) of ())-A and 1.45 mL
(6.84 mmol) of triethylamine in CH2Cl2 (100 mL) was
cooled to 0 ꢁC. Then racemic 2-(4-isobutylphenyl)pro-
panoyl chloride (1.54 g, 6.84 mmol) and 64 mg
(0.52 mmol) of 4-(N,N-dimethylamino)pyridine were
added. After stirring at room temperature for 24 h, brine
was added and the mixture was extracted with CHCl3.
The organic layer was dried over MgSO4 and the solvent
was evaporated. Crude material was subjected to flash
column chromatography (SiO2 70 g, i.d. of column:
30 mm, eluent: hexane/CHCl3/AcOEt ¼ 5:5:1) to give
4c1st (0.88 g, 2.31mmol) and 4c2nd (1.04 g, 2.51 mmol) in
44% and 48% yield, respectively. The aqueous layer was
acidified with 2 M HCl and then saturated with NaCl.
The solution was extracted with CHCl3 and the organic
layer was washed with brine and dried over MgSO4. The
solvent was removed and the residue was purified by
silica gel short column to recover 4a (ibuprofen) in
64 mg (0.31mmol).
2. (a) Takeuchi, Y.; Itoh, N.; Note, H.; Koizumi, T.;
Yamaguchi, K. J. Am. Chem. Soc. 1991, 113, 6318; (b)
Takeuchi, Y.; Itoh, N.; Koizumi, T.; Yamaguchi, K.
J. Chem. Soc., Chem. Commun. 1992, 1514; (c) Takeuchi,
Y.; Itoh, N.; Koizumi, T.; Yamaguchi, K. Chem. Ind.
1992, 874; (d) Takeuchi, Y.; Itoh, N.; Satoh, T.; Koizumi,
T.; Yamaguchi, K. J. Org. Chem. 1993, 58, 1812.
3. (a) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.;
Kometani, T.; Kirk, K. L. Chem. Commun. 1998, 365; (b)
Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kirk,
K. L. Enantiomer 1999, 4, 339.
4. Takahashi, T.; Fukushima, A.; Tanaka, Y.; Takeuchi, Y.;
Kabuto, K.; Kabuto, C. Chem. Commun. 2000, 788.
5. A consistent regularity has been found between the
relative 1H chemical shifts of diastereomeric CFTA amides
and absolute configurations of various primary amines.
Details will be published elsewhere.
6. Fujiwara, T.; Omata, K.; Kabuto, K.; Kabuto, C.;
Takahashi, T.; Segawa, M.; Takeuchi, Y. Chem. Commun.
2001, 2694.
7. (a) Pirkle, W. H. In Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic: New York/London, 1983; Vol. 1, pp
87–124; (b) Lindner, W. In Houben-Weyl: Methods in
Organic Chemistry; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart/New
York, 1995; Vol. E 21a, pp 225–252.
8. Optically active cis-1-amino-2-indanols have been used
for the resolution of some carboxylic acids by diastereo-
meric salt formation: (a) Kinbara, K.; Kobayashi, Y.;
Saigo, K. J. Chem. Soc., Perkin Trans. 2 2000, 111; (b)
Kinbara, K.; Katsumata, Y.; Saigo, K. Chem. Lett. 2002,
266; (c) Sakurai, R.; Sakai, K. Tetrahedron: Asymmetry
2003, 14, 411.
9. Stahly, G. P.; Starrett, R. M. In Chirality in Industry II;
Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley:
Chichester, 1997; pp 17–40.
10. Luna, A.; Maestro, A.; Astorga, C.; Gotor, V. Tetra-
hedron: Asymmetry 1999, 10, 1969.
11. Anilkumar, A. T.; Goto, K.; Takahashi, T.; Ishizaki, K.;
Kaga, H. Tetrahedron: Asymmetry 1999, 10, 2501.
12. Cleij, M.; Archelas, A.; Furstoss, R. J. Org. Chem. 1999,
64, 5029.
A mixture of the ester 3c1st, 20 mL of aqueous 47% HBr
and 40 mL of AcOH was heated at 100 ꢁC for 1h. After
cooling to room temperature, 30 mL of brine was added
and the mixture was extracted with CHCl3. The organic
layer was washed with brine then dried over MgSO4.
After removal of the solvent, hexane was added to the
residue and insoluble precipitate of A was filtered off.
The filtrate was concentrated and chromatographed
(eluent: hexane/CH2Cl2/AcOEt ¼ 5:5:1). Removal of the
solvent afforded crude ibuprofen as crystals, which was
recrystallized from H2O/MeOH. To the aqueous layer,
2 M NaOH was added until pH of the layer slightly
exceeded 11. The solution was repeatedly extracted with
CHCl3 until the spot of A was disappeared on TLC. The
combined organic layer was dried over MgSO4 and the
solvent was removed to give crude A. Hydrolysis of the
ester 4c2nd was conducted in the same way as described
above to give (R)-4a and A. The yields of (S)- and (R)-4a
based on A were 32% (350 mg, 2.18 mmol) and 34%
(372 mg, 2.32 mmol), respectively. All A recovered from
hydrolysis of 4c1st and 4c2nd was combined and recrys-
tallized from hexane/CHCl3. The recovery of ())-A was
76% (758 mg, 3.99 mmol).
13. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.;
Roszkowski, A.; Tomolonis, A.; Fried, J. H. J. Med.
Chem. 1970, 13, 203.
References and notes
14. Moreno-Dorado, F. J.; Guerra, F. M.; Ortega, M. J.;
Zubia, E.; Massanet, G. M. Tetrahedron: Asymmetry
2003, 14, 503.
1. (a) Parker, D. Chem. Rev. 1991, 91, 1441; (b) Uray, G. In
Houben-Weyl: Methods in Organic Chemistry; Helmchen,