Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (-)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl] -1H-indole-1-carboxylate

Article abstract of DOI:10.1016/j.tetasy.2011.01.020

We have successfully synthesized enantiomerically pure (+)- and (-)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]- 1H-indole-1-carboxylate (+)-1 and (-)-1, which are key intermediates of non-steroidal glucocorticoid receptor m

Full text of DOI:10.1016/j.tetasy.2011.01.020

Tetrahedron: Asymmetry 22 (2011) 153–160
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal
glucocorticoid receptor modulators using (+)- and (ꢀ)-tert-butyl
6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-
carboxylate
⇑
Takaaki Sumiyoshi, Kengo Tojo, Daisuke Urabe, Masanori Tobe
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki, Suita, Osaka 564-0053, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have successfully synthesized enantiomerically pure (+)- and (ꢀ)-tert-butyl 6-cyano-3-[3-ethoxy-
1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (ꢀ)-1, which are key
intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid cat-
alyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to
large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (ꢀ)-1, enantiomerically pure
glucocorticoid receptor modulators (+)-3 and (ꢀ)-3 can be synthesized (>99% ee for both compounds).
The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoro-
methyl alcohol moiety; compound (ꢀ)-3 showed a higher binding affinity compared to (+)-3.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 November 2010
Accepted 10 January 2011
Available online 1 March 2011
1. Introduction
tal-catalyzed ones for the following reasons: (1) lack of sensitivity
to moisture and oxygen; (2) low cost and low toxicity and (3) they
A number of non-steroidal glucocorticoid receptor modulators,
containing the trifluoromethyl alcohol structure and possessing
the anti-inflammatory effects of a glucocorticoid but with reduced
adverse effects, have been explored as potential therapeutics for a
variety of inflammatory diseases, such as asthma, rheumatoid
arthritis, and allergic rhinitis.1–3 Recently, we have also disclosed
novel indole derivatives, such as 2 and 3, which have the trifluoro-
methyl alcohol structure as glucocorticoid receptor modulators.4
Moreover, it has been reported that the absolute configuration of
the hydroxyl group in the trifluoromethyl alcohol structure greatly
influences the anti-inflammatory effects of glucocorticoid receptor
modulators.3 These findings led us to prepare enantiomerically
pure indole derivatives in our glucocorticoid receptor modulator
program. In view of the retrosynthesis of our glucocorticoid recep-
tor modulators, enantiomerically pure 1 was considered to be a key
intermediate (Fig. 1). In order to obtain enantiomerically pure 1
from enantiomerically pure 4, we conducted catalytic asymmetric
synthesis, which involved the asymmetric construction of the
quarternary carbon center in the trifluoromethyl alcohol moiety.
Catalytic asymmetric synthesis, which is one of the important
methodologies in modern synthetic chemistry for the preparation
of enantiomerically enriched compounds, has been developed by
using metal catalysts or organocatalysts.5 Organocatalytic asym-
metric reactions have several significant advantages over the me-
are recyclable and reusable catalysts.6–8 Therefore, organocatalysts
are expected to be very useful in both the pharmaceutical and chem-
ical industries.
Several researchers have reported the organocatalytic asymmet-
ric addition of indole derivatives to ethyl trifluoropyruvate 6.9 Ma
et al. reported the chiral Brønsted acid catalyzed reaction, which
afforded the corresponding products with modest ee.9g Jørgensen
et al. described their discovery of chiral sulfonamides, which pro-
vided the product with 23% ee.9d Török et al. reported that cinchona
alkaloids used as organocatalysts gave products quantitatively with
high enantioselectivity.9c Among them, cinchona alkaloids, which
represent a class of natural products possessing useful features as
asymmetric organocatalysts, are inexpensive and readily available
for bulk-scale synthesis.10
From the aforementioned information, we selected cinchona
alkaloids as organocatalysts and prepared enantiomerically pure 4
by using a cinchona alkaloid catalyzed asymmetric addition on the
basis of the previous report by Török’s. Herein we report an efficient
and practical synthesis of enantiomerically pure 4 employing a cin-
chona alkaloid catalyzed asymmetric addition of 6-cyanoindole 5 to
6. We also demonstrate that an efficient procedure for the prepara-
tion of enantiomerically pure 1 from enantiomerically pure 4, which
is appropriate for use in large-scale synthesis with simple manipula-
tions. Additionally, we report the asymmetric synthesis of glucocor-
ticoid receptor modulators (+)-3 and (ꢀ)-3 by using the
corresponding enantiomerically pure 1 and present their compara-
tive glucocorticoid receptor binding affinity.
⇑
Corresponding author. Tel.: +81 6 6337 5913; fax: +81 6 6337 6010.
E-mail address: masanori-tobe@ds-pharma.co.jp (M. Tobe).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.020

154
T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
HO
F3C
CO2Et
O
+
F3C
CO2Et
N
H
NC
N
H
NC
6
5
4
6-Cyanoindole
Ethyl trifluoropyruvate
Trifluoromethyl
alcohol structure
HO
F3C
HO
CO2Et
F3C
CO2Et
N
NC
Boc
N
1
NC
Key intermediate
2
glucocorticoid receptor
modulator
HO
F3C
HO
F3C
N
CO2Et
OH
HN
CO2Et
O
+
O
OMe
N
N
Boc
NC
NC
OMe
H
Trifluoromethyl alcohol structure
HO
HO
F3C
N
CO2Et
F3C
N
CO2H
O
O
OMe
N
NC
OMe
N
NC
3
Figure 1. Retrosynthesis of glucocorticoid receptor modulators having the trifluoromethyl alcohol structure, such as 2 and 3, via the key intermediate 1.
Table 1
Effects of reaction temperature on cinchona alkaloids catalyzed asymmetric addition of 5 to 6
HO
CO2Et
F3C
O
catalyst (5 mol%)
Et2O, 24 h
+
N
H
NC
F3C
CO2Et
N
H
NC
1.5 eq.
5
6
(+)-4
Entry
Catalyst
Temperature (°C)
Yield (%)
ee (%)
1
2
3
4
5
Cinchonidine
Quinine
Cinchonidine
Cinchonidine
Cinchonidine
ꢀ10
ꢀ10
ꢀ20
ꢀ40
ꢀ78
88
81
89
71
4
90
87
91
94
97
Thus, our initial efforts focused on investigating the effects of the
cyano group at the C(6)-position of the indole ring by using cincho-
nidine under Török’s experimental conditions (Table 1). As a result,
the reaction of 5 with 6 in diethyl ether (Et2O) afforded the product
(+)-4 with 90% ee in 88% yield (entry 1). These results suggest that
2. Results and discussion
Török et al. have reported the cinchona alkaloids catalyzed
asymmetric addition of several indole derivatives to 6. However,
the reaction of 5 with 6 has not been included in that report.9c

T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
155
Table 2
Solvent screening for the cinchonidine catalyzed asymmetric addition of 5 to 6
HO
F3C
CO2Et
cinchonidine (7.5 mol%)
solvent, —10°C
O
+
N
NC
F3C
CO2Et
H
N
H
NC
5
1.5 eq.
6
(+)-4
Entry
Solvent
Et2O
Diisopropyl ether
Cyclopentyl methyl ether
MTBE
n-Hexane
n-Heptane
MeCN
EtOAc
Toluene
Time (h)
Conversiona (%)
Yield (%)
ee (%)
1 h
24 h
1
2
3
4
5
6
7
8
9
24
24
24
24
24
24
24
24
1
65
64
61
54
4
95
97
97
95
41
41
70
94
—
89
93
90
90
29
31
59
88
96
89
90
88
87
56
52
70
80
83
6
43
49
98
a
Conversion was determined on the basis of area % by HPLC (254 nm).
the cyano group at the C(6)-position of the indole ring contributes
to maintaining good yield and enantioselectivity. The reaction time
of unsubstituted indole was 2 h,9c while that of 6-cyanoindole was
24 h. From these results, it was found that the low reactivity of the
C(3)-position of the indole ring may be caused by the electron-
withdrawing effect of the cyano group. Quinine, belonging to the
cinchona alkaloids, also provided product (+)-4 with 87% ee in
81% yield (entry 2). We then examined the effects of temperature
on both the yield and enantioselectivity. Running the reaction at
ꢀ20 °C resulted in both the yield and enantioselectivity being com-
parable to those at ꢀ10 °C (entries 1 and 3). Lower temperatures
(<ꢀ20 °C) resulted in a decrease of the yield but an increase in
enantioselectivity (entries 4 and 5).
As the reaction proceeded slowly at very low temperatures with
decreased yield, we investigated the effects of solvents at ꢀ10 °C
on the reaction outcome. The results of this investigation are sum-
marized in Table 2. The reaction proceeded well in ethers, such as
diethyl ether (Et2O), diisopropyl ether, cyclopentyl methyl ether,
and methyl t-butyl ether (MTBE) (entries 1–4), while both yield
and enantioselectivity of the reaction were significantly decreased
when n-hexane or n-heptane was used (entries 5 and 6). Acetoni-
trile (MeCN) proved unsuccessful in improving the reaction results,
affording the product with 70% ee in 59% yield (entry 7). The yield
of the reaction when using ethyl acetate (EtOAc) was equal to that
of Et2O, while the ee was slightly diminished (entry 8). Among the
solvents tested, toluene clearly provided the best reaction rate and
yield with 83% ee (entry 9).
On the basis of these findings, we selected toluene as the sol-
vent and conducted further optimization of the reaction by exam-
ining the effect of the reaction temperature and the amount of
catalyst (Table 3). Although the yield was maintained with increas-
ing reaction temperature, the enantioselectivity decreased (entries
1–5). For example, carrying out the reaction at 40 °C for 1 h affor-
ded the product in 92% yield with a significantly lower ee (71% ee).
On the other hand, the use of 2.5 mol % of catalyst was comparable
to 7.5 mol % of one in the yield and enantioselectivity (entries 3
and 6). When the amount of catalyst was reduced to 1 mol %, the
yield and enantioselectivity decreased significantly to 53% and
Table 3
Optimization of reaction temperature and the amount of catalysts in toluene
HO
CO2Et
F3C
O
catalyst
toluene
+
N
H
F3C
CO2Et
NC
N
1.5 eq.
NC
5
H
6
(+)-4
Entry
Catalyst (mol %)
Temperature (°C)
Time (h)
Conversiona (%)
24 h
Yield (%)
ee (%)
1 h
1
2
3
4
5
6
7
8
Cinchonidine (7.5 mol %)
Cinchonidine (7.5 mol %)
Cinchonidine (7.5 mol %)
Cinchonidine (7.5 mol %)
Cinchonidine (7.5 mol %)
Cinchonidine (2.5 mol %)
Cinchonidine (1 mol %)
Cinchonine (7.5 mol %)
ꢀ40
ꢀ10
0
25
40
0
24
1
1
1
1
3
24
24
24
98
98
99
98
92
13
85
99
—
—
—
—
—
61
97
95
96
96
96
92
93
53
89
86
83
80
76
71
81
52
0
0
79b
a
Conversion was determined on the basis of area % by HPLC (254 nm).
The (ꢀ)-enantiomer was obtained as the major product.
b

156
T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
52%, respectively (entry 7). Carrying out the reaction with cincho-
nine as catalyst afforded the corresponding product (ꢀ)-4 with 79%
ee, in 89% yield (entry 8).
this suspension formed depended on the solubility of the product
(+)-4 in toluene (data not shown). The product (+)-4 was obtained
by simple filtration of the suspension with 90% ee, in 84% yield
(Scheme 2). On the other hand, (+)-4 in the filtrate showed a low
degree of enantioselectivity (27% ee). The purification of (+)-4 by
filtration of the suspension system with 90% ee was superior to
the result obtained by silica gel column chromatography with
81% ee (Table 3, entry 6). From these results, we considered that
the reason for the high enantioselectivity obtained by this proce-
dure was due to the crystallization of (+)-4 in the suspension.
The N-Boc protection of the nitrogen atom of (+)-4 with Boc2O fol-
lowed by the purification using trituration with diisopropyl ether-
n-hexane gave product (+)-1 (158 g) with over 99% ee, in 80% yield.
Using these simple manipulations, the large-scale synthesis of
100 g of the product was successfully achieved. The total yield
(67%) was much better than using the chiral resolution method.
Similarly to the procedure for (+)-1, N-Boc protection of the nitro-
gen atom of (ꢀ)-4 provided enantiomerically pure (ꢀ)-1 (>99% ee,
19.3 g, 73% yield). The total yield of (ꢀ)-1 from 5 was 65%.
We also found that the cinchonidine recovered from the reac-
tion mixture following a simple procedure, as shown in Figure 2,
gave almost the same result as the original one with 81% ee, in
95% yield (Scheme 1). The reaction mixture was extracted with
aqueous 0.2 M HCl and the cinchonidine was separated into the
aqueous layer. This was basified by aqueous 4 M NaOH at pH above
10, and the precipitate produced was filtered to recover cinchoni-
dine in 96% yield (Fig. 2).
Separation of the reaction mixture
Aqueous layer
Organic layer
Basified and filtrated
Finally, we conducted the asymmetric synthesis of the gluco-
corticoid receptor modulator 3 from enantiomerically pure (+)-1
and (ꢀ)-1 (Scheme 3). Reduction of ester (+)-1 and (ꢀ)-1 with
LiBH4 gave the corresponding alcohol (+)-7 and (ꢀ)-7, respectively.
Compounds (ꢀ)-8 and (+)-8 were prepared by tosylation of (+)-7
and (ꢀ)-7, respectively. Epoxidation of (ꢀ)-8 and (+)-8 with aque-
ous 1 M NaOH in THF, respectively, yielded (+)-9 and (ꢀ)-9. Mits-
unobu reaction of 10 with 11 afforded phenoxy piperidine 12.
The ring-opening reaction of the corresponding (+)-9 and (ꢀ)-9
with 12 followed by deprotection of the Boc group provided (+)-
13 and (ꢀ)-13, respectively. Alkylation of (+)-13 and (ꢀ)-13 with
cyclohexylmethyl bromide followed by hydrolysis of the corre-
sponding esters gave enantiomerically pure (ꢀ)-3 and (+)-3
(>99% ee for both compounds). Racemization was not observed
in all steps. The glucocorticoid receptor binding affinity for enanti-
omerically pure (+)-3 and (ꢀ)-3 was examined. The affinity of (ꢀ)-
3 was higher than that of (+)-3 [(ꢀ)-3: 95% at 10 nM; (+)-3: 17% at
10 nM]. These results suggested that the glucocorticoid receptor
HO
F3C
CO2Et
Recovered cinchonidine
(yield 96%)
N
H
NC
(+)-4
Figure 2. Procedure to recover cinchonidine.
Furthermore, we examined the large-scale synthesis of enanti-
omerically pure 1 and 4. With the aforementioned findings in
mind, toluene as solvent, 2.5 mol % catalyst, and 0 °C were chosen
as the optimal conditions for the large-scale synthesis of enantio-
merically pure 4. To a mixture of 5 (100 g) and cinchonidine
(5.18 g) in dry toluene (800 mL) that was allowed to stir at 0 °C
for 1 h was slowly added 6 (132 g) in dry toluene (200 mL). At this
stage, the reaction appeared as a suspension. The degree to which
HO
CO2Et
recovered cinchonidine
(7.5 mol%)
F3C
O
+
N
H
NC
F3C
CO2Et
toluene
0°C, 3 h
N
H
NC
5
1.5 eq.
6
(+)-4: yield 95%, 81% ee
Scheme 1. Reaction using recovered cinchonidine.
HO
CO2Et
F3C
O
cinchonidine (2.5 mol%)
+
N
toluene
NC
F3C
CO2Et
H
N
H
0°C, 6 h
NC
5: 100 g
1.2 eq.
6
(+)-4: 184 g (yield 84%, 90% ee)
HO
F3C
CO2Et
Boc2O (1.02 eq.)
DMAP (0.1 eq.)
Et3N (1.2 eq.)
(+)-4: 150 g, 90% ee
THF
N
0°C, 1 h
NC
Boc
(+)-1: 158 g (yield 80%, >99% ee)
Scheme 2. Large-scale synthesis of the enantiopure (+)-1.

T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
157
HO
F3C
HO
F3C
HO
F3C
O
CO2Et
F3C
OH
OTs
b
a
c
N
Boc
N
Boc
N
Boc
N
Boc
NC
NC
NC
NC
(+)-1 (>99% ee)
(−)-1 (>99% ee)
(+)-7: yield 85%
(−)-7: yield 80%
(−)-8: yield 90%
(+)-8: yield 85%
(+)-9: yield 94%
(−)-9: yield 90%
OH
CO2Et
HN
CO2Et
d, e
+
HO
O
N
f, g
OMe
OMe
Boc
11
10
12
HO
F3C
N
CO2H
HO
F3C
N
CO2Et
h, i
NC
O
OMe
O
N
NC
OMe
N
H
(+)-13: yield 85%
(−)-13: yield 87%
(−)-3: y. 77%, >99% ee (glucocorticoid receptor binding affinity: 95% at 10 nM)
(+)-3: y. 81%, >99% ee (glucocorticoid receptor binding affinity: 17% at 10 nM)
Scheme 3. Synthesis of the glucocorticoid receptor modulators (ꢀ)-3 and (+)-3. Reagents and conditions: (a) LiBH4, THF, EtOH, 0 °C, 1 h; (b) TsCl, pyridine, rt, 20 h; (c) 1 M
NaOH aq, THF, 0 °C, 10 min; (d) diisopropyl azodicarboxylate, PPh3, THF, rt, 15 h; (e) 4 M HCl in 1,4-dioxane, CHCl3, rt, 1 h; (f) Et3N, 2-propanol, 70 °C, 14 h; (g) TFA, CH2Cl2, rt,
1 h; (h) cyclohexylmethyl bromide, K2CO3, DMF, 70 °C, 15 h; (i) 1 M NaOH aq, THF, MeOH, rt, 5 h.
binding affinity had a marked influence on the configuration at the
trifluoromethyl alcohol moiety.
used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double
doublet and dq = double quartet. IR spectra were recorded as KBr
pellets using a PerkinElmer Spectrum One. Optical rotations were
recorded on a JASCO Polarimeter P-1020. Melting points were re-
corded on a Stanford Research Systems OptiMelt MPA100 without
correction. Low-resolution mass spectra were recorded on a SHIMA-
DZU LCMS-2010EV instrument under electron spray ionization (ESI)
conditions. Elemental analyses were obtained on a CE Instruments
EA1110. Reaction progress was monitored by HPLC at room temper-
ature using a HITACHI L-7100 pump equipped with a HITACHI L-
7400 UV detector with a KANTO Myghtysil RP-18 GP column
3. Conclusion
We have in this study optimized the asymmetric addition of 6-
cyanoindole 5 to ethyl trifluoropyruvate 6 and developed an effi-
cient synthesis of enantiomerically pure (+)-1 (>99% ee) using eas-
ily available, recyclable, and inexpensive cinchona alkaloids as
catalysts. All steps are operationally simple and applicable to
100 g scale synthesis. By using (+)-1 and (ꢀ)-1, the corresponding
glucocorticoid receptor modulators (ꢀ)-3 and (+)-3 have been suc-
cessfully synthesized without racemization in all steps (>99% ee for
both compounds). The glucocorticoid receptor binding affinities of
(ꢀ)-3 and (+)-3 have been evaluated. Compound (ꢀ)-3 showed a
more potent binding affinity compared with (+)-3, indicating a ste-
reochemical preference of the trifluoromethyl alcohol structure for
glucocorticoid receptor binding affinity. At present, we are contin-
uing our studies to obtain enantiomerically pure glucocorticoid
receptor modulators using (+)-1 as a key intermediate.
(3 mm ꢁ 150 mm, 5
lm), eluted at 1.0 mL/min with a 30 min gradi-
ent (from 30% B to 95% B), where solvent A is water (0.05% TFA solu-
tion) and solvent B is acetonitrile (0.05% TFA solution). Enantiomeric
excess was measured by chiral HPLC at 30 °C using a SHIMADZU LC-
10AS pump equipped with a SHIMADZU SPD-10A UV detector with
a DAICEL Chiralpak AD-H column (4.6 mm ꢁ 250 mm, 5
lm). The
following abbreviations are used for reagents and solvents: TFA (tri-
fluoroacetic acid), DMF (N,N-dimethylformamide), DMAP (4-
dimethylaminopyridine), Boc2O (di-tert-butyl dicarbonate), EtOAc
(ethyl acetate), THF (tetrahydrofuran), diisopropyl ether.
4. Experimental
4.2. (+)-Ethyl 2-(6-cyano-1H-indol-3-yl)-3,3,3-trifluoro-2-
hydroxypropanoate (+)-4
4.1. General information
To a mixture of 6-cyanoindole 5 (213 mg, 1.5 mmol) and
All reagents and solvents were used as obtained from commer-
cial suppliers without further purification. All reactions were car-
ried out under an atmosphere of N2. Monitoring of reactions was
carried out using a MERCK 60 F254 silica gel, glass-supported TLC
plates, and visualization with UV light (254 nm). NMR spectra were
recorded on a VARIAN Mercury-400 spectrometer at room temper-
ature. Chemical shifts are given in d values (ppm) using tetrameth-
ylsilane as the internal standard, and following abbreviations were
cinchonidine (11.0 mg, 37.5
ethyl trifluoropyruvate 6 (298
l
mol) in dry toluene (7 mL) was added
L, 2.25 mmol) in dry toluene (2 mL)
l
dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h.
The mixture was quenched with MeOH (20 mL) and DMF (2 mL)
and stirred at room temperature over 30 min. The mixture was
concentrated and the residue purified by silica gel chromatography
(EtOAc/n-hexane = 1/2) to afford (+)-4 (435 mg, 93%, 81% ee) as a
pale purple solid; [Anal. Calcd for C14H11F3N2O3: C, 53.85; H,

158
T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
3.55; N, 8.97. Found: C, 53.91; H, 3.58; N, 9.06]; ½a D25
ꢂ
¼ þ1:2 (c
n-hexane (500 mL) at 0 °C and filtered to give (+)-1 (158 g, 80%,
99% ee) as a pale yellow solid; [Anal. Calcd for C19H19F3N2O5: C,
55.34; H, 4.64; N, 6.79. Found: 55.11; H, 4.65; N, 6.74];
1.98, CHCl3); mp 127–129 °C; 1H NMR (400 MHz, DMSO-d6) d
11.94 (s, 1H, NH), 7.94 (dd, J = 1.6, 0.6 Hz, 1H), 7.88 (d, J = 8.6 Hz,
1H), 7.75 (d, J = 2.7 Hz, 1H), 7.65 (s, 1H, OH), 7.40 (dd, J = 8.6,
1.6 Hz, 1H), 4.32 (dq, J = 10.7, 7.1 Hz, 1H), 4.27 (dq, J = 10.7,
7.1 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6)
½
a 2D5
ꢂ
¼ þ1:6 (c 2.02, CHCl3); mp 77–79 °C; 1H NMR (400 MHz,
DMSO-d6) d 8.46 (s, 1H), 8.10 (s, 1H, OH), 7.98 (s, 1H), 7.95 (d,
J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4, 1.3 Hz, 1H), 4.34 (dq, J = 10.7,
7.1 Hz, 1H), 4.31 (dq, J = 10.7, 7.1 Hz, 1H), 1.67 (s, 9H), 1.23 (t,
J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) d 166.3, 147.5,
1
d 167.2, 134.9, 129.0, 127.8, 123.8 (q, JC–F = 286 Hz), 121.7,
2
121.3, 119.9, 116.6, 109.0, 102.9, 76.3 (q, JC–F = 29.8 Hz), 62.1,
1
13.8; IR (KBr)
m
3439, 3366, 2230, 1750, 1459, 1348, 1283, 1231,
133.6, 130.2, 128.5, 125.7, 123.3 (q, JC–F = 286 Hz), 122.3, 119.0,
1178, 1115, 1019 cmꢀ1; MS (ESI) m/z 335 (M+Na)+; Enantiomeric
excess was determined by HPLC [Chiralpak AD-H, EtOH/n-hex-
ane = 8/92, flow rate 1.0 mL/min, k = 254 nm, retention times:
(+)-isomer 16.2 min, (ꢀ)-isomer 28.7 min].
118.8, 114.2, 106.6, 85.7, 75.9 (q, JC–F = 30.0 Hz), 62.6, 27.4, 13.7;
2
IR (KBr)
m 3414, 2229, 1750, 1443, 1377, 1278, 1243, 1148,
1089 cmꢀ1; MS (ESI) m/z 435 (M+Na)+; Enantiomeric excess was
determined by HPLC [Chiralpak AD-H, EtOH/n-hexane = 5/95, flow
rate 1.0 mL/min, k = 254 nm, retention times: (+)-isomer 6.8 min,
(ꢀ)-isomer 10.3 min].
4.3. (ꢀ)-Ethyl 2-(6-cyano-1H-indol-3-yl)-3,3,3-trifluoro-2-
hydroxypropanoate (ꢀ)-4
4.7. (ꢀ)-tert-Butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-
hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (ꢀ)-1
To a mixture of 6-cyanoindole 5 (213 mg, 1.5 mmol) and cin-
chonine (33.1 mg, 112
lmol) in dry toluene (7 mL) was added
ethyl trifluoropyruvate 6 (298
l
L, 2.25 mmol) in dry toluene
Compound (ꢀ)-1 was prepared from (ꢀ)-4 (20.0 g, 64.1 mmol,
79% ee) using a procedure similar to that described for (+)-1; pale
yellow solid (19.3 g, 73%, 99% ee); [Anal. Calcd for C19H19F3N2O5: C,
(2 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C
for 24 h. The mixture was quenched with MeOH (20 mL) and
DMF (2 mL) and stirred at room temperature over 30 min. The mix-
ture was concentrated and the residue was purified by silica gel
chromatography (EtOAc/n-hexane = 1/2) to afford (ꢀ)-4 (418 mg,
89%, 79% ee) as a pale purple solid; [Anal. Calcd for C14H11F3N2O3:
C, 53.85; H, 3.55; N, 8.97. Found: C, 53.94; H, 3.58; N, 9.06];
55.34; H, 4.64; N, 6.79. Found: 55.50; H, 4.66; N, 6.86]; ½a D25
¼ ꢀ1:7
ꢂ
(c 2.05, CHCl3); mp 77–79 °C.
4.8. (+)-tert-Butyl 6-cyano-3-(1,1,1-trifluoro- 2,3-
dihydroxypropan-2-yl)-1H-indole-1-carboxylate (+)-7
½
a 2D5
ꢂ
¼ ꢀ1:1 (c 2.00, CHCl3); mp 127–129 °C.
To a mixture of LiBH4 (3.17 g, 146 mmol) in dry THF (120 mL)
and EtOH (15 mL) was added (+)-1 (15.0 g, 36.4 mmol, 99% ee) in
dry THF (30 mL) dropwise at 0 °C. The reaction mixture was stirred
at 0 °C for 1 h and then quenched with 5% KHSO4 solution. The
mixture was extracted with EtOAc. The organic layer was washed
with water and brine. The organic layer was dried over Na2SO4
and concentrated. The residue was purified by silica gel chroma-
tography (EtOAc/n-hexane = 1/1) to afford (+)-7 (11.5 g, 85%) as
an amorphous solid; [Anal. Calcd for C17H17F3N2O4ꢃ0.5H2O: C,
53.83; H, 4.78; N, 7.38. Found: 53.49; H, 4.49; N, 7.27];
4.4. Procedure to recover the organocatalyst from the reaction
mixture
To a mixture of 6-cyanoindole 5 (20.0 g, 141 mmol) and cincho-
nidine (3.11 g, 10.6 mmol) in dry toluene (700 mL) was added
ethyl trifluoropyruvate
6 (35.9 g, 211 mmol) in dry toluene
(140 mL) dropwise at 0 °C. The reaction mixture was quenched
by 0.2 M HCl (100 mL) and extracted with EtOAc (200 mL). The
aqueous layer was basified by 4 M NaOH to produce a pale yellow
solid. The solid was filtered, washed with water (10 mL), and dried
to give cinchonidine (3.0 g, 96%).
½
a 2D5
ꢂ
¼ þ12:9 (c 2.08, CHCl3); mp 39–40 °C; 1H NMR (400 MHz,
DMSO-d6) d 8.43 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.00 (s, 1H), 7.62
(d, J = 8.3 Hz, 1H), 6.78 (s, 1H, OH), 5.33 (t, J = 5.6 Hz, 1H, OH),
4.15–3.83 (m, 2H), 1.64 (s, 9H); 13C NMR (100 MHz, DMSO-d6) d
4.5. Large-scale synthesis of (+)-ethyl 2-(6-cyano-1H-indol-3-
yl)-3,3,3-trifluoro-2-hydroxy-propanoate (+)-4
1
148.3, 133.9, 132.1, 128.6, 125.6 (q, JC–F = 288 Hz), 125.5, 123.6,
2
119.5, 118.8, 117.3, 106.2, 85.4, 75.3 (q, JC–F = 27.0 Hz), 63.4,
To a mixture of 6-cyanoindole 5 (100 g, 703 mmol) and cincho-
nidine (5.18 g, 17.6 mmol) in dry toluene (800 mL) was added
27.5; IR (ATR) m 3432, 2228, 1740, 1615, 1553, 1475, 1440, 1371,
1317, 1257, 1147, 1094, 1048 cmꢀ1; MS (ESI) m/z 393 (M+Na)+.
ethyl trifluoropyruvate
6 (132 g, 774 mmol) in dry toluene
(200 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for
6 h. The reaction mixture was filtered. The solid was dried to give
(+)-4 (184 g, 84%, 90% ee).
4.9. (ꢀ)-tert-Butyl 6-cyano-3-(1,1,1-trifluoro-2,3-dihydroxy-
propan-2-yl)-1H-indole-1-carboxylate (ꢀ)-7
Compound (ꢀ)-7 was prepared from (ꢀ)-1 (7.00 g, 17.0 mmol,
99% ee) using a procedure similar to that described for (+)-7; amor-
4.6. Large-scale synthesis of (+)-tert-butyl 6-cyano-3-[3-ethoxy-
1,1,1- trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carb-
oxylate (+)-1
phous solid (5.03 g, 80%); ½a D25
¼ ꢀ13:3 (c 2.06, CHCl3); mp 39–
ꢂ
40 °C.
To a mixture of (+)-4 (150 g, 480 mmol, 90% ee), Et3N (58.3 g,
577 mmol) and DMAP (5.87 g, 48.0 mmol) in dry THF (720 mL)
was added Boc2O (107 g, 490 mmol) in dry THF (240 mL) dropwise
at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mix-
ture was neutralized with 5% KHSO4 solution (1500 mL). The mix-
ture was extracted with EtOAc (1000 mL). The organic layer was
washed with water (150 mL) and brine (150 mL). The organic layer
was dried over Na2SO4 and concentrated. The residue was tritu-
rated with diisopropyl ether (375 mL) and n-hexane (675 mL) at
0 °C. The mixture was filtered and the filtrate was concentrated.
The residue was triturated with diisopropyl ether (100 mL) and
4.10. (ꢀ)-tert-Butyl 6-cyano-3-(1,1,1-trifluoro-2-hydroxy-3-
{[(4-methylphenyl)sulfonyl]oxy}-propan-2-yl)-1H-indole-1-
carboxylate (ꢀ)-8
To a solution of (+)-7 (10.0 g, 27.0 mmol) in pyridine (80 mL)
was added p-toluenesulfonyl chloride (25.7 g, 135 mmol) at room
temperature. The reaction mixture was stirred at room tempera-
ture for 20 h and then concentrated. A toluene solution of the res-
idue was washed with 1 M HCl, water and then concentrated. The
crude product was purified by silica gel chromatography (EtOAc/n-
hexane = 1/3) to afford (ꢀ)-8 (12.7 g, 90%) as a white solid; [Anal.

T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
159
Calcd for C24H23F3N2O6S: C, 54.96; H, 4.42; N, 5.34. Found: 55.11;
J = 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) d 171.3, 150.9,
144.4, 129.0, 121.3, 118.3, 113.2, 70.1, 60.6, 55.5, 40.7, 39.5, 26.6,
H, 4.37; N, 5.41]; ½a D25
ꢂ
¼ ꢀ16:5 (c 2.07, CHCl3); mp 115–116 °C;
1H NMR (400 MHz, DMSO-d6) d 8.37 (s, 1H), 7.89 (s, 1H), 7.83 (d,
J = 8.3 Hz, 1H), 7.66–7.58 (m, 3H), 7.55 (d, J = 8.3 Hz, 1H), 7.28 (d,
J = 8.0 Hz, 2H), 4.62 (d, J = 10.7 Hz, 1H), 4.51 (d, J = 10.7 Hz, 1H),
2.37 (s, 3H), 1.64 (s, 9H); 13C NMR (100 MHz, DMSO-d6) d 148.0,
145.1, 133.8, 131.3, 130.8, 129.8, 128.7, 127.5, 125.7, 124.5 (q,
1JC–F = 288 Hz), 122.8, 119.3, 118.9, 114.8, 106.5, 85.7, 73.8 (q,
13.9; IR (ATR) m 2788, 1734, 1590, 1515, 1461, 1447, 1417, 1344,
1308, 1285, 1270, 1190, 1165, ,1137, 1124, 1036, 1023 cmꢀ1; MS
(ESI) m/z 294 (M+H)+.
4.15. (+)-Ethyl [4-({1-[2-(6-cyano-1H-indol-3-yl)-3,3,3-
trifluoro-2-hydroxypropyl]piperidin-4-yl}oxy)-3-methoxy-
phenyl]acetate (+)-13
2JC–F = 29.2 Hz), 69.3, 27.4, 21.1; IR (ATR)
m 3426, 2226, 1745,
1440, 1337, 1352, 1320, 1297, 1258, 1235, 1172, 1149, 1116,
1092 cmꢀ1; MS (ESI) m/z 547 (M+Na)+.
To a mixture of (+)-9 (2.00 g, 5.68 mmol) and Et3N (1.97 mL,
14.2 mmol) in 2-propanol (19 mL) was added 12 (2.06 g,
6.25 mmol) at room temperature. The reaction mixture was stirred
at 70 °C for 14 h. The reaction mixture was neutralized with 5%
KHSO4 solution and then extracted with EtOAc. The organic layer
was washed with water and brine. The organic layer was dried over
Na2SO4 and concentrated. To a CH2Cl2 (10 mL) solution of the res-
idue was added TFA (20 mL) at room temperature. The mixture
was stirred at room temperature for 1 h and then concentrated.
Next, an EtOAc solution of the residue was washed with saturated
NaHCO3 solution and brine. The organic layer was dried over
Na2SO4 and concentrated. The crude product was purified by silica
gel chromatography (EtOAc/n-hexane = 1/1) to afford (+)-13
(2.65 g, 86%) as an amorphous solid; [Anal. Calcd for C28H30F3N3O5:
C, 61.64; H, 5.54; N, 7.70. Found: 61.55; H, 5.48; N, 7.77];
4.11. (+)-tert-Butyl 6-cyano-3-(1,1,1-trifluoro-2-hydroxy-3-
{[(4-methylphenyl)sulfonyl]oxy}-propan-2-yl)-1H-indole-1-
carboxylate (+)-8
Compound (+)-8 was prepared from (ꢀ)-7 (4.80 g, 13.0 mmol)
using a procedure similar to that described for (ꢀ)-8; white solid
(5.78 g, 85%); ½a D25
¼ þ16:2 (c 2.08, CHCl3); mp 115–116 °C.
ꢂ
4.12. (+)-tert-Butyl 6-cyano-3-[2-(trifluoromethyl)oxiran-2-yl]-
1H-indole-1-carboxylate (+)-9
To a solution of (ꢀ)-8 (12.0 g, 22.9 mmol) in THF (115 mL) was
added 1 M NaOH (22.9 mL) at 0 °C. The reaction mixture was stir-
red at 0 °C for 10 min. The reaction mixture was neutralized with
saturated NH4Cl solution and then extracted with EtOAc. The or-
ganic layer was washed with water and brine. The organic layer
was dried over Na2SO4 and concentrated to afford (+)-9 (7.6 g,
94%) as a white solid; [Anal. Calcd for C17H15F3N2O3: C, 57.96; H,
½
a 2D5
ꢂ
¼ þ6:7 (c 2.01, CHCl3); mp 55–56 °C; 1H NMR (400 MHz,
DMSO-d6) d 11.76 (br s, 1H, NH), 7.97 (d, J = 8.4 Hz, 1H), 7.88 (dd,
J = 1.2, 0.8 Hz, 1H), 7.73 (s, 1H), 7.33 (dd, J = 8.4, 1.2 Hz, 1H), 6.85
(d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H) , 6.70 (dd, J = 8.4, 2.0 Hz,
1H), 6.24 (s, 1H, OH), 4.18–4.10 (m, 1H), 4.08 (q, J = 7.2 Hz, 2H),
3.71 (s, 3H), 3.54 (s, 2H), 3.16 (d, J = 13.6 Hz, 1H), 3.03 (d,
J = 13.6 Hz, 1H), 2.77–2.65 (m, 2H), 2.39–2.28 (m, 2H), 1.79–1.69
(m, 2H), 1.55–1.45 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, DMSO-d6) d 170.8, 149.5, 144.7, 134.8, 128.5, 128.4,
4.29; N, 7.95. Found: 57.98; H, 4.23; N, 8.02]; ½a D25
¼ þ14:0 (c
ꢂ
2.08, CHCl3); mp 103–104 °C; 1H NMR (400 MHz, CDCl3) d 8.54
(br s, 1H), 7.95 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.3,
1.5 Hz, 1H), 3.50 (d, J = 5.2 Hz, 1H), 3.09 (dq, J = 5.2, 1.7 Hz, 1H),
1.70 (s, 9H); 13C NMR (100 MHz, CDCl3) d 148.4, 134.3, 131.5,
1
127.2, 125.8 (q, JC–F = 284 Hz), 122.0, 121.0, 120.9, 120.1, 116.2,
1
2
130.0, 126.3, 123.1 (q, JC–F = 278 Hz), 121.1, 120.1, 120.0, 111.4,
116.1, 113.5, 112.9, 102.1, 73.9 (q, JC–F = 27.3 Hz), 73.1, 59.9,
2
3
108.3, 86.1, 53.7 (q, JC–F = 39.2 Hz), 50.0 (q, JC–F = 1.7 Hz), 28.1;
59.8, 55.4, 51.5, 39.7, 30.5, 14.0; IR (ATR) m 3284, 2219, 1719,
IR (ATR)
m
2225, 1749, 1617, 1476, 1442, 1395, 1370, 1316, 1259,
1511, 1458, 1408, 1338, 1264, 1202, 1176, 1141, 1035 cmꢀ1
1227, 1152, 1096, 1054 cmꢀ1; MS (ESI) m/z 375 (M+Na)+.
cmꢀ1; MS (ESI) m/z 568 (M+Na)+.
4.13. (ꢀ)-tert-Butyl 6-cyano-3-[2-(trifluoromethyl)oxiran-2-yl]-
1H-indole-1-carboxylate (ꢀ)-9
4.16. (ꢀ)-Ethyl [4-({1-[2-(6-cyano-1H-indol-3-yl)-3,3,3-tri-
fluoro-2-hydroxypropyl]piperidin-4-yl}oxy)-3-methoxy-
phenyl]acetate (ꢀ)-13
Compound (ꢀ)-9 was prepared from (+)-8 (5.00 g, 9.53 mmol)
using a procedure similar to that described for (+)-9; white solid
Compound (ꢀ)-13 was prepared from (ꢀ)-9 (2.00 g, 5.67 mmol)
using a procedure similar to that described for (+)-13; amorphous
(3.03 g, 90%); ½a D25
¼ ꢀ14:6 (c 2.03, CHCl3); mp 103–104 °C.
ꢂ
solid (2.70 g, 87%); ½a D25
¼ ꢀ6:5 (c 2.03, CHCl3); mp 55–56 °C.
ꢂ
4.14. Ethyl [3-methoxy-4-(piperidin-4-yloxy)phenyl]acetate
hydrochloride 12
4.17. (ꢀ)-{4-[(1-{2-[6-Cyano-1-(cyclohexylmethyl)-1H-indol-
3-yl]-3,3,3-trifluoro-2-hydroxy-propyl}piperidin-4-yl)oxy]-3-
methoxyphenyl}acetic acid (ꢀ)-3
To a solution of 10 (5.00 g, 23.8 mmol), 11 (6.22 g, 30.9 mmol)
and PPh3 (9.36 g, 35.7 mmol) in THF (79 mL) was added diisopro-
pyl azodicarboxylate (7.52 mL, 35.7 mmol) at room temperature.
The reaction mixture was stirred at room temperature for 15 h
and then concentrated. The residue was purified by silica gel chro-
matography (EtOAc/n-hexane = 1/3) to afford a pale yellow oil. To a
CHCl3 (5 mL) solution of the oil was added 4 M HCl in 1,4-dioxane
(50 mL) at room temperature. The reaction mixture was stirred at
room temperature for 1 h and then concentrated. Trituration with
Et2O (40 mL) and filtration of the solid gave 12 (5.66 g, 72%) as a
white solid; [Anal. Calcd for C16H24ClNO4: C, 58.27; H, 7.33; N,
4.25. Found: 58.02; H, 7.14; N, 4.30]; mp 131–133 °C; 1H NMR
(400 MHz, DMSO-d6) d 9.59 (br s, 2H, NH), 6.85 (d, J = 8.2 Hz,
1H), 6.85 (d, J = 1.7 Hz, 1H), 6.79 (dd, J = 8.2, 1.7 Hz, 1H), 4.61–
4.51 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.56 (s, 2H),
3.54–3.39 (m, 2H), 3.36–3.21 (m, 2H), 2.32–2.06 (m, 4H), 1.27 (t,
To a mixture of (+)-13 (1.00 g, 1.83 mmol) and K2CO3 (1.52 g,
11.0 mmol) in DMF (18 mL) was added cyclohexylmethyl bromide
(972 mg, 5.49 mmol) at room temperature. The reaction mixture
was stirred at 70 °C for 15 h. The reaction mixture was diluted with
water and extracted with EtOAc. The organic layer was washed
with water and brine. The organic layer was dried over Na2SO4
and concentrated. The residue was purified by silica gel chroma-
tography (EtOAc/n-hexane = 1/3) to afford an amorphous solid.
To a solution of the amorphous solid in THF (10 mL) and MeOH
(10 mL) was added 1 M NaOH (5 mL) at room temperature. The
reaction mixture was stirred at room temperature for 5 h and then
neutralized with saturated NH4Cl solution. The mixture was
extracted with EtOAc. The organic layer was washed with
water and brine. The organic layer was dried over Na2SO4 and

160
T. Sumiyoshi et al. / Tetrahedron: Asymmetry 22 (2011) 153–160
concentrated. The crude product was purified by silica gel chroma-
tography (MeOH/CHCl3 = 1/20) to afford (ꢀ)-3 (862 mg, 77%, 99%
ee) as an amorphous solid; [Anal. Calcd for C33H38F3N3O5ꢃ0.75H2O:
C, 63.20; H, 6.35; N, 6.70. Found: 62.89; H, 6.12; N, 6.67];
References
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Opin. Ther. Patents 2010, 20, 855–873.
3. Recent reports with trifluoromethyl alcohol structures: (a) Schäcke, H.;
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H.; Hennekes, H.; Asadullah, K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 227–232;
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G. W.; Humphreys, D.; Inglis, G. G. A.; Johnston, M. J.; Jones, H. T.; House, D.;
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(c) Madauss, K. P.; Bledsoe, R. K.; Mclay, I.; Stewart, E. L.; Uings, I. J.;
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M. A.; Macdonald, S. J. F.; Madauss, K. P.; McLay, I. M.; Shipley, T. J.; Taylor, S. J.;
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6698.
½
a 2D5
ꢂ
¼ ꢀ6:2 (c 2.08, CHCl3); mp 104–106 °C; 1H NMR (400 MHz,
DMSO-d6) d 8.31 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.33
(d, J = 8.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H),
6.68 (dd, J = 8.0, 1.6 Hz, 1H), 4.22–3.96 (m, 3H), 3.68 (s, 3H), 3.44
(s, 2H), 3.16 (d, J = 13.5 Hz, 1H), 2.95 (d, J = 13.5 Hz, 1H), 2.79–
2.59 (m, 2H), 2.41–2.18 (m, 2H), 1.83–1.52 (m, 6H), 1.52–1.30
(m, 4H), 1.20–1.01 (m, 3H), 1.01–0.84 (m, 2H); 13C NMR
(100 MHz, DMSO-d6) d 172.8, 150.0, 144.9, 135.4, 132.7, 129.1,
1
128.4, 126.1 (q, JC–F = 287 Hz), 122.5, 121.4, 121.3, 120.5, 116.7,
2
115.6, 114.0, 119.9, 102.5, 74.5 (q, JC–F = 27.3 Hz), 73.4, 59.9,
55.6, 51.8, 51.6, 40.2, 38.1, 30.7, 30.6, 29.9, 29.8, 25.9, 25.1; IR
(ATR)
m 2221, 1721, 1586, 1509, 1450, 1387, 1265, 1224, 1152,
1035 cmꢀ1; MS (ESI) m/z 614 (M+H)+. Enantiomeric excess was
determined by HPLC [Chiralpak IC, 2-propanol/n-hexane/TFA/
Et2NH = 20/80/0.1/0.1, flow rate 1.0 mL/min, k = 220 nm, retention
times: (+)-isomer 25.5 min, (ꢀ)-isomer 32.7 min].
4.18. (+)-{4-[(1-{2-[6-Cyano-1-(cyclohexylmethyl)-1H-indol-3-
yl]-3,3,3-trifluoro-2-hydroxy-propyl}piperidin-4-yl)oxy]-3-
methoxyphenyl}acetic acid (+)-3
4. Sone, T.; Sawaki, R.; Nakajima, T. PCT Int. Appl. WO 040166, 2007.
5. Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH: New York, 2000. pp 1–864.
6. Special issues on asymmetric organocatalysis: (a) Houk, K. N.; List, B. Acc. Chem.
Compound (+)-3 was prepared from (ꢀ)-13 (200 mg,
0.367 mmol) using a procedure similar to that described for (ꢀ)-
ˇ
´
Res. 2004, 37, 487–631; (b) Kocovsky, P.; Malkov, A. V. Tetrahedron 2006, 62,
255–502; (c) List, B. Chem. Rev. 2007, 107, 5413–5883.
3; amorphous solid (183 mg, 81%, 99% ee); ½a D25
¼ þ6:1 (c 2.01,
ꢂ
CHCl3); mp 104–106 °C.
7. Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today
2007, 12, 8–27.
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The binding affinity was determined according to the previously
reported protocol.4
Acknowledgments
We are deeply grateful to Dr. Norio Fujiwara for his support and
encouragement. We also acknowledge Keiko Bando for elemental
analysis and Makiko Honma for NMR measurements.
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