Bacillus subtilis epoxide hydrolase-catalyzed preparation of enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and its application to expeditious synthesis of (R)-bicalutamide

Article abstract of DOI:10.1016/j.tetlet.2006.12.011

Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic epoxide (7) to provide the above starting material in highly enantiomerically enriched state.

Full text of DOI:10.1016/j.tetlet.2006.12.011

Tetrahedron Letters 48 (2007) 979–983
Bacillus subtilis epoxide hydrolase-catalyzed preparation of
enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and
its application to expeditious synthesis of (R)-bicalutamide
Aya Fujino,a Masayoshi Asano,a Hitomi Yamaguchi,b Naoki Shirasaka,b Akiko Sakoda,b
Masaya Ikunaka,b Rika Obata,a Shigeru Nishiyamaa and Takeshi Sugaia,*
aDepartment of Chemistry, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
bResearch and Development Center, Nagase & Co., 2-2-3, Murotani, Nishi-ku, Kobe 651-2241, Japan
Received 1 November 2006; revised 4 December 2006; accepted 5 December 2006
Available online 22 December 2006
Abstract—Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol
monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic
epoxide (7) to provide the above starting material in highly enantiomerically enriched state.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Being a potent antiandrogen of a non-steroidal struc-
ture, bicalutamide [Casodexꢁ, (1)]1 has been used in
drug therapy to treat prostate cancer (Fig. 1). While
the clinically prescribed entity is a racemic mixture,1,2
its (R)-isomer was deduced to be an active principle
from the following experimental evidences:3 the (R)-iso-
mer of 1 exhibited higher affinity to androgen receptors4
and was less susceptible to metabolic degradation com-
pared to the antipodal (S)-isomer.5
So far, (R)-1 and analogs thereof were assembled using
two kinds of enantiomerically enriched 2-methyl-2-
hydroxypropanoic acid derivatives: (1) (R)-3-bromo-2-
hydroxy-2-methylpropanoic acid (2) prepared via
asymmetric bromolactonization effected under the influ-
ence of D-proline as chiral auxiliary;6–9 (2) (S)-citramalic
acid (3) obtained by resolution.10 Once its latent symme-
try was recognized with 1, terminally differentiated
2-methylpropane-1,2,3-triol, (R)-4, might well serve the
synthesis of (R)-1 providing that thiophenol (5) and ani-
line (6) could be installed at the proper ends of (R)-4
(Fig. 1).
CO2H
O
Br
O
S
HO
F
N
CN
CF3
2
H
HO
Preparation of an enantiomerically enriched form of 4
has been known by epoxide hydrolase (EH)-catalyzed
enantioselective hydrolysis11 of easily accessible racemic
epoxide 7.12 While diverse catalytic activities and stereo-
chemical courses have been reported,13 we chose an
O
CO2H
(R
)-bicalutamide 1
HO2C
HO
3
BnO
SH
OH
H2N
CN
F
HO
)-4
OH2
BnO
CF3
BnO
OH
(
R
5
6
O
HO
)-4
a)
(fast)
(S
)-7
( )-7
Figure 1.
(
R
OBn
O
(slow)
Keywords: Epoxide hydrolase; (R)-1-Benzyloxy-2-methylpropane-2,3-
diol; Kinetic resolution; Diol; Bicalutamide.
(R)-7
*
Scheme 1. Reagents and conditions: (a) B. subtilis epoxide hydrolase,
30 ꢂC, 7 days, conv. 52%; (R)-4: 46%, 79.0% ee; (R)-7: 37%, 100% ee.
Corresponding author. Tel.: +81 45 566 1709; fax: +81 45 566 1697;
e-mail: sugai@chem.keio.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.011

980
A. Fujino et al. / Tetrahedron Letters 48 (2007) 979–983
BnO OH
a,b)
b)
a,b)
BnO
BnO
OH
BnO
O
O
HO
HO
)-4
(82.3% ee)
( )-7
(R
)-4
(S)-7
(68.1% ee)
(
R
(68.1% ee)
OH2
OBn
c)
HO
OBn
BnO
OH
OBn
)-7
O
c)
+
HO
O
HO
)-4
(100% ee)
(R
)-7
(R)-4
(R
(R
+
(
)-4
(R
)-4
R
Scheme 3. Reagents and conditions: (a) TsCl, pyridine; (b) K2CO3,
MeOH, 94%; (c) B. subtilis epoxide hydrolase, 30 ꢂC, 2 days, conv.
82%; (R)-4: 82%, 100% ee; (R)-7: 18%, 68.1% ee.
(mp 30-31 °C, 100% ee) (mother liquor)
Scheme 2. Reagents and conditions: (a) B. subtilis epoxide hydrolase,
30 ꢂC, 7 days, conv. 53%; (b) dil H2SO4, room temperature; (c)
recrystallization from Et2O at ꢀ30 ꢂC, (R)-4 as crystalline solid: 43%,
100% ee; as mother liquor, 40%, 68.1% ee.
model,16 and Figure 2 predicted ca. 80% conversion as
the critical point.
engineered enzyme, with high catalytic activity and
availability in quantity, from an origin of Bacillus sub-
tilis (BSEH).14 When harvested cells of the engineered
B. subtilis were incubated with ( )-7 at 30 ꢂC for a week,
(S)-selective hydrolysis proceeded in 52% conversion to
give (R)-4 of 79.0% ee and unconsumed (R)-7 of 100% ee
in 46% and 37% isolated yield, respectively (Scheme 1).15
For this BSEH-mediated kinetic resolution of ( )-7, the
E value16 was estimated to be as high as 73.
The progress of the actual enzymatic reaction was moni-
tored occasionally by HPLC. After 2 days, we stopped
the reaction at 82% conversion, and enantiomerically
pure (R)-4 in 82% and (R)-7 of 68.1% ee in 18% were ob-
tained (Scheme 3). In this event, two interesting observa-
tions were noted. When starting with (S)-7 of 68.1% ee,
the BSEH-catalyzed hydrolysis proceeded with slightly
higher enantioselectivity than the value of 73 that had
been estimated for the hydrolysis of ( )-7. In addition,
the reaction proceeded substantially faster with (S)-
enriched 7. This acceleration phenomenon should be
ascribed to less amounts of (R)-7 which, possessing a
Km value similar to that of (S)-7, must have worked as
a competitive inhibitor against the BSEH.
Now that BSEH had proven to be efficacious in resolv-
ing ( )-7 kinetically to (R)-epoxide (7) and its antipodal
diol (4) via (S)-selective hydrolysis on a preparative
scale, attention was turned to defining the conditions
to obtain only the hydrolysate (R)-4 from ( )-7 in a ste-
reoconvergent manner17 (Scheme 2). The above-men-
tioned cells of B. subtilis were incubated with ( )-7 in
53% conversion. The resulting mixture of (R)-4 and
(R)-7 as a whole was treated with dilute H2SO4,18 where-
by (R)-4 underwent acid-catalyzed hydrolysis with
stereochemical inversion at its quaternary stereogenic
center19,20 to afford (R)-4 of 82.3% ee in 83% overall
yield (Scheme 2). This was further crystallized from
Et2O at ꢀ30 ꢂC, and enantiomerically pure (R)-4 was
obtained as a solid in 43% yield (52% recovery).21
The combined total yield of enantiomerically pure (R)-4
as described in Schemes 2 and 3 was 74% based on the
original starting material, ( )-7. With enantiomerically
pure (R)-4 being secured in quantity, effort was directed
toward its conversion to (R)-bicalutamide (1) (Scheme
4). Selective oxidation of the diol was performed with
TEMPO-mediated oxidation to give 8 (97%),22 by
avoiding any reagents possibly causing the undesired
glycol cleavage through a cyclic intermediate by metallic
oxidants.23 For the next amide bond formation between
The mother liquor (68.1% ee) in the previous crystalliza-
tion procedure still contained the (R)-enantiomer (ca.
84% of the mixture). It was then attempted to reuse
the (R)-4, recovered with a moderate enantiomeric pur-
ity, by converting it back to (S)-epoxide (7) and subject-
ing the latter to the BSEH-catalyzed kinetic resolution
again (Scheme 3). Then, diol (R)-4 was derived to enan-
tiomerically enriched (S)-7 (68.1% ee) in two conven-
tional steps (94%).
Under the kinetically resolving conditions, pursuing
high ee of the digested products (more reactive enantio-
mers) is always somewhat more difficult than of the
unaffected substrates (less reactive enantiomers), even
with high enantioselectivity. As the desired (R)-4 is
derived from the more reactive enantiomer (S)-7,
termination of the reaction at the proper conversion is
very important. We then simulated the relationship
between conversion and ees of the digested product 4
and unaffected recovery 7 under a certain mathematical
Figure 2. Simulation for the progress of B. subtilis epoxide hydrolase-
catalyzed hydrolysis of (S)-7 (E = 73, ee0 = 68.1%).

A. Fujino et al. / Tetrahedron Letters 48 (2007) 979–983
981
reduced to a benzylamine function. Finally, the acetyl
protective group was removed to give diol 11b (85%,
100% ee),27 which is a known precursor for (R)-128
(Scheme 4).
CO2H
b)
a)
BnO
OH
BnO
HO
HO
(R
)-4
8
O
In conclusion, large-scale preparation of diol (R)-4 as
well as epoxide (R)-7 was achieved using an engineered
BSEH-catalyzed hydrolation of racemic epoxide, and
the product was applied for an expeditious route to
(R)-bicalutamide (21% overall yield).29 Last but not
the least, a chemoenzymatic method to convert ( )-7
as a whole to diol (R)-4 was also established, which
should serve the synthesis of biologically active com-
pounds and other industrial materials, since (R)-4 can
be regarded as a desymmetrized form of 2-methylpro-
pane-1,2,3-triol with its molecular termini being differen-
tiated as a robust benzyl ether.
AcHN
CN
CF3
BnO
c)
N
H
CN
CF3
RO
10
9a
R = H
b
Ac
O
d)
HO
N
CN
CF3
9b
H
RO
11a R = Ac
f)
e)
(R)-1
b
H
Scheme 4. Reagents and conditions: (a) TEMPO, NaClO, NaClO2,
MeCN-buffer, 35 ꢂC, 24 h, 97%; (b) SOCl2, THF, 6, DMAP, room
temperature, 5 days; (c) Ac2O, pyridine, 83% from 8; (d) DDQ, hm
(352 nm, 15 W), MeCN, 85%; (e) K2CO3, MeOH, 85%; (f) lit.28
References and notes
1. Tucker, H.; Crook, J. W.; Chesterson, G. J. J. Med. Chem.
1988, 31, 954–959.
2. Chen, B.-C.; Zhao, R.; Gove, S.; Wang, B.; Sundeen, J. E.;
Salvati, M. E.; Barrish, J. C. J. Org. Chem. 2003, 68,
10181–10182.
highly sterically hindered 8 and amine 6 with very low
nucleophilicity, activation of a-hydroxy acid 8 was only
realized by way of acid chloride10 in THF. The smooth
reaction required excessive amount of amine 6, and an
assistance of DMAP (3 equiv). When this reaction was
attempted in N,N-dimethylacetamide according to the
literature procedures, formation of an a-halo acid by-
product was detected. As far as this particular amide
bond formation was concerned, the conventional
reagents for peptide synthesis, such as EDCI-HOBT,
did not work. Product 9a was obtained as an inseparable
mixture with 6, then the crude product was directly acet-
ylated so that acetate 9b (83% from 8) was separated
from 10 by SiO2 chromatography.24 For the deprotec-
tion of the O-benzyl group in 9b, DDQ oxidation under
UV irradiation conditions25 was effective, and the de-
sired alcohol 11a was obtained in 85% yield.26 By com-
parison, its exposure to catalytic hydrogenolysis caused
side reactions in which the aromatic cyano group was
3. Tucker, H.; Chesterson, G. J. J. Med. Chem. 1988, 31,
885–887.
4. Mukherjee, A.; Kirkovsky, L.; Yao, X. T.; Yates, R. C.;
Miller, D. D.; Dalton, J. T. Xenobiotica 1996, 26, 117–122.
5. McKillop, D.; Boyle, G. W.; Cockshott, I. D.; Jones, D.
C.; Phillips, P. J.; Yates, R. A. Xenobiotica 1993, 23, 1241–
1253.
6. Kirkovsky, L.; Mukherjee, A.; Yin, D.; Dalton, J. T.;
Miller, D. D. J. Med. Chem. 2000, 43, 581–590.
7. Marhefka, C. A.; Gao, W.; Chung, K.; Kim, J.; He, Y.;
Yin, D.; Bohl, C.; Dalton, J. T.; Miller, D. D. J. Med.
Chem. 2004, 47, 993–998.
8. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Fisher, S. J.;
Dalton, J. T.; Miller, D. D. Tetrahedron Lett. 2004, 45,
9475–9477.
9. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Yang, J.;
Kirkovsky, L. I.; Dalton, J. T.; Miller, D. D. Tetrahedron
Lett. 2005, 46, 4821–4823.
b)
a)
10. James, K. D.; Ekwuribe, N. N. Tetrahedron 2002, 58,
5905–5908.
11. Hellstro¨m, H.; Steinreiber, A.; Mayer, S. F.; Faber, K.
Biotechnol. Lett. 2001, 23, 169–173.
F
S
OBn
OBn
(R)-7
O
F
HO
12
O
12. ( )-Epoxide (7) was prepared on a large scale according to
the following procedures: To a soln of benzyl metallyl
ether (prepared from benzyl alcohol and metallyl chloride
in a conventional manner, 5.00 g, 30.8 mmol) in MeCN
(2.5 mL) and EtOH (12.5 mL) was added a soln of
KHCO3 (0.925 g, 9.24 mmol) in H2O2 (30% in H2O,
4.78 mL, 61.6 mmol). MeCN was added to the mixture
and stirred at room temperature for 24 h. H2O2 (30% in
H2O, 1.2 mL, 15.4 mmol) was further added to the
mixture and stirred at room temperature for 2 days. The
mixture was quenched by the addition of a soln of
Na2S2O3 (12.5 g) in H2O (30 mL), and extracted with ice-
chilled hexane. The extract was conventionally worked up
and purified by SiO2 chromatography to give 7 (13.9 g,
92%). Its NMR spectrum was identical with that reported
previously.20
S
OR
HO
O
O
S
CO2H
F
13a R = Bn
d)
c)
HO
O
b
H
14
O
O
S
e)
F
N
CN
CF3
H
HO
O
(R)-bicalutamide 1
Scheme 5. Reagents and conditions: (a) Compound 5, NaH, THF,
room temperature, 90 min, 93%; (b) H2O2, AcOH, 60 ꢂC, 24 h; (c) H2,
Pd–C, EtOH, room temperature, 48 h, 91% from 12; (d) TEMPO,
NaClO, NaClO2, MeCN-buffer, 35 ꢂC, 24 h, 93%; (e) SOCl2, THF, 6,
room temperature, 5 days, 91%.
´
13. Simeo, Y.; Faber, K. Tetrahedron: Asymmetry 2006, 17,
402–409.

982
A. Fujino et al. / Tetrahedron Letters 48 (2007) 979–983
14. Yamaguchi, H.; Shirasaka, N.; Ikunaka, M. (Nagase &
Co., Ltd.), Japan, Kokai Tokkyo Koho 2004-349, 377,
2004; Chem. Abstr. 2006, 145, 59218, also orally presented;
Yamaguchi, H.; Shirasaka, N.; Sakoda, A.; Ikunaka, M.
Development of a useful biocatalyst (epoxide hydrolase)
to prepare optically active 1,2-diols. 2F2-42, the 85th
annual meeting of Chemical Society of Japan, March 26–
29, Yokohama, 2005. Experimental procedures were as
follows: Stock cultures of microorganisms were explored
from scratch for those capable of (S)-selective hydrolysis
of ( )-7, which led to identification of a wild strain of B.
subtilis (JCM 10629) as producing an EH of the required
stereoselectivity. The gene encoding epoxide hydrolase
(yfhM) was cloned from the genomic DNA of B. subtilis
by the standard method. Both amylase promoter and
terminator sequences were cloned from the genomic DNA
of Bacillus amyloliquefaciens NBRC 15535. The amylase
promoter, the epoxide hydrolase gene, and the amylase
terminator were inserted into an expression vector
pUB110 in this order. The competent cells of B. subtilis
MT-2 (deficient in neutral protease) were transformed
with the plasmid vector thus constructed and the clone
(dubbed Tamy 2 strain) was then selected which exhibited
the epoxide hydrolase activity. For the utilization of
amylase promoter, see: Saito, N.; Yamamoto, K. J.
Bacteriol. 1975, 121, 848–856.
20. Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.;
Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 1383–
1388.
21. A mixture of cell suspension (19.5 mL), glycerol (6.0 mL),
and ( )-7 (4.5 g, 25.2 mmol) was stirred at room temper-
ature for 7 days. Workup and purification provided a crude
mixture [4.74 g, (R)-4 (88.3% ee), and (R)-7 (97.9% ee),
47.4:52.6], which was diluted with H2O (86.4 mL). With an
ice-cooling, conc. H2SO4 (6.7 mL) was added dropwise,
and the resulted mixture was stirred at 0 ꢂC for 10 min and
further at room temperature for 30 min. After neutraliza-
tion, the mixture was extracted and purified in a conven-
tional SiO2 chromatography to give (R)-4 (4.10 g, 83%,
82.3% ee).
This was dissolved with Et2O (82 mL), cooled slowly to
ꢀ30 ꢂC and kept at that temperature for 6 h. Mother liquor
was decanted off with suction, and the crystal was rinsed
twice with cold Et2O. The crystal was dried to afford (R)-4
(2.1 g, 52%) recovery, as colorless fine needles, mp 30–
27
31 ꢂC; ½aꢁD ꢀ7.03 (c 0.965, CH2Cl2) [lit.30 ½aꢁD ꢀ6.30 (c
0.87, CH2Cl2)]; HPLC: 100% ee. Caution: when the mixture
is kept at a temperature lower than ꢀ30 ꢂC for a prolonged
period, crystals of (R)-4 would suffer from contamination
with (S)-4.
22. A soln of (R)-4 (510 mg, 2.60 mmol), TEMPO (37.2 mg,
0.238 mmol), MeCN (13 mL), and sodium phosphate
buffer (pH 6.7, 0.67 M, 9.7 mL) was heated to 35 ꢂC.
First, a portion (20%) of the NaClO2 soln [80% NaClO2
(0.588 g) in H2O (2.6 mL), 5.20 mmol] and a portion (20%)
of the dilute bleach [10% NaOCl (39.2 lL) in H2O
(1.4 mL), 2.0 mol %] were added, and the remainder of
the NaClO2 soln and dilute bleach were added simulta-
neously over 1 h. At 24 h intervals, the same amount of
TEMPO, NaClO2 and dilute bleach were added twice to
the mixture in the same manner as described above and
the stirring was continued at 35 ꢂC for total 48 h. After
cooling to room temperature, H2O (25 mL) was added,
and the pH was adjusted to 8.0 with 2.0 M NaOH. The
reaction was quenched by the addition of ice-chilled soln
of Na2SO3 (2.1 g) in H2O (40 mL), such that the temper-
ature did not exceed 20 ꢂC. The pH of the aqueous layer
was adjusted to 9.0, and neutral, non-polar impurities
were removed by washing with MTBE (methyl t-butyl
ether, 3 mL). Acidification and extraction gave 8 (531 mg,
15. To a cell suspension of B. subtilis14 (19.5 mL) were added
glycerol (6.0 mL), ( )-7 (4.5 g, 25.2 mmol) and stirred at
room temperature for 7 days. The progress of the reaction
was monitored by HPLC analysis: [Senshu Pack PEGA-
SIL ODS, 0.46 cm · 15 cm; MeOH–H2O (3:2), 1.0 mL/
min], tR(min) = 3.8 (4), 6.8 (7). Then the broth was
centrifuged (3000 rpm), and the supernatant was saturated
with NaCl and mixed with EtOAc. The mixture was
stirred for 1 h and filtered through a pad of Celite. The
organic layer of the filtrate was separated and the aqueous
layer was further extracted with EtOAc. The cell debris
precipitated by centrifugation was mixed with acetone
(80 mL). The mixture was stirred for 1 h and filtered
through a pad of Celite. The combined organic extracts
were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The residue (4.16 g) was charged on a
silica gel column (400 mL). Elution with hexane–EtOAc
(2:1) afforded (R)-4 (2.25 g, 11.5 mmol, 46%) as a solid
and (R)-7 (1.64 g, 9.20 mmol, 37%) as an oil.
26
97%) as an oil, ½aꢁD ꢀ6.9 (c 0.805, EtOH), IR (film): 3438,
27
Compound (R)-4: ½aꢁD ꢀ4.8 (c 1.04, CH2Cl2); HPLC:
3064, 3032, 2986, 2880, 1734, 1496, 1454, 1373, 1101, 740,
1
79.0% ee [Chiralcel OD-H, 0.46 cm · 25 cm; hexane–i-
PrOH (15:1), 0.5 mL/min], tR(min) = 29.1 [(S)-, 10.5%],
31.1 [(R)-, 89.5%]. 1H NMR (CDCl3): d 7.31–7.19 (5H, m),
4.49 (2H, s), 3.58 (1H, dd, J = 4.6, 11.0 Hz), 3.45 (1H, d,
J = 9.1 Hz), 3.40 (1H, dd, J = 7.8, 11.0 Hz), 3.36 (1H, d,
J = 9.1 Hz), 2.71 (1H, s), 2.26 (1H, dd, J = 4.6, 7.8 Hz),
1.08 (3H, s). Its NMR spectrum was identical with that
reported previously.20
698 cmꢀ1. H NMR (CD3OD): d 7.23–7.16 (5H, m), 4.49
(1H, d, J = 12.1 Hz), 4.43 (1H, d, J = 12.1 Hz), 3.60 (1H,
d, J = 9.5 Hz), 3.38 (1H, d, J = 9.5 Hz), 1.24 (3H, s). 13C
NMR (CD3OD): d 177.7, 139.3, 129.1, 128.6, 128.5, 77.1,
75.8, 74.4, 22.8. For the TEMPO-mediated oxidation, see:
Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64,
2564–2566.
27
25
Compound (R)-7: ½aꢁD ꢀ11.7 (c 1.09, MeOH) [lit.20 ½aꢁD
ꢀ10.4 (c 1.26, MeOH)], HPLC: 100% ee [ChiralPak AS-H,
0.46 cm · 25 cm; hexane–i-PrOH (90:1), 0.5 mL/min],
tR(min) = 19.3 [(R)-, single peak]. No peak ascribable to
(S)-isomer [tR(min) = 20.1] was detected. Its NMR spec-
trum was identical with that of racemic sample.
16. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J.
J. Am. Chem. Soc. 1982, 104, 7294–7299.
23. Plietker, B. Synthesis 2005, 2453–2472.
24. SOCl2 (0.113 mL, 1.56 mmol) was added dropwise under
argon to a solution of 8 (32.6 mg, 0.155 mmol) in dry THF
(0.160 mL) at 0 ꢂC. The resulting mixture was stirred for
2 h under the same conditions. A solution of 6 (34.6 mg,
0.186 mmol) in dry THF (0.180 mL) was added dropwise
to the above solution. The mixture was stirred further for
2 h at 0 ꢂC, then DMAP (56.8 mg, 0.465 mmol) was
added. The mixture was stirred at room temperature for 5
days. The conventional workup and acetylation of the
17. Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asym-
metry 1999, 10, 107–117.
18. Steinreiber, A.; Hellstro¨m, H.; Mayer, S. F.; Orru, R. V.
A.; Faber, K. Synlett 2001, 111–113.
19. Orru, R. V. A.; Mayer, S. F.; Kroutil, W.; Faber, K.
Tetrahedron 1998, 54, 859–874.
23
residue provided 9b (54.1 mg, 83%) as an oil, ½aꢁD ꢀ7.4 (c
0.985, EtOH) IR (film): 3337, 3109, 3064, 3031, 2941,
2868, 2230, 1747, 1710, 1589, 1525, 1507, 1430, 1372, 1328,
1240, 1181, 1135, 752, 699 cmꢀ1. 1H NMR (CDCl3): d 8.80
(1H, s), 8.08 (1H, d, J = 1.6 Hz), 7.94 (1H, dd, J = 8.2,

A. Fujino et al. / Tetrahedron Letters 48 (2007) 979–983
983
1.6 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.36–7.27 (5H, m), 4.59
(2H, s), 4.28 (1H, d, J = 9.6 Hz), 3.63 (1H, d, J = 9.6 Hz),
2.14 (3H, s), 1.65 (3H, s). 13C NMR (CDCl3): d 169.7,
169.4, 141.6, 136.5, 135.7, 133.7 (q, 2JFC = 32.3 Hz), 128.7,
(1H, d, J = 9.1 Hz), 3.17 (1H, d, J = 13.2 Hz), 3.08 (1H, d,
J = 13.2 Hz), 2.62 (1H, s), 1.24 (3H, s). 13C NMR
1
(CDCl3): d 161.6 (d, JFC = 246.3 Hz), 137.7, 132.1 (d,
3JFC = 7.5 Hz), 131.9, 128.3, 127.7, 127.5, 115.9 (d,
2JFC = 21.6 Hz), 75.4, 73.3, 72.6, 44.5, 23.8.
1
128.4, 127.9, 122.0, 122.0 (q, JFC = 273.7 Hz), 117.3 (q,
18
3JFC = 5.0 Hz), 115.5, 104.2, 81.2, 74.1, 72.1, 21.6, 20.5.
HRMS (EI, 70 eV): calcd for C21H19F3N2O4: (M+):
420.1295; found: m/z 420.1290.
Compound 13a: ½aꢁD ꢀ12.3 (c 1.12, EtOH). IR (film):
3506, 3105, 2866, 1591, 1495, 1317, 1236, 1146, 1084, 846,
750 cmꢀ1 1H NMR (CDCl3): d 7.92 (2H, ddd, J = 8.5,
.
25. Rahim, M. A.; Matsumura, S.; Toshima, K. Tetrahedron
Lett. 2005, 46, 7307–7309.
5.0, 2.0 Hz), 7.31 (2H, ddd, J = 9.2, 8.5, 2.0 Hz), 7.27–7.17
(5H, m), 4.48 (2H, s), 3.47 (1H, s), 3.47 (1H, d, J = 14.3
26. To a soln of 9b (30.2 mg, 0.0718 mmol) in dry MeCN
(11 mL) was added DDQ (24.4 mg, 0.108 mmol) and the
mixture was stirred at room temperature for 24 h under
irradiation by Toshiba EFD15BLB black light (UV,
352 nm, 15 W). During the reaction, the apparatus and
lamp were wrapped with aluminum foil so as to enhance
the reflection. The conventional workup and purification
Hz), 3.46 (2H, s), 3.33 (1H, d, J = 14.3 Hz), 3.36 (1H, s),
1
1.25 (3H, s). 13C NMR (CDCl3): d 165.6 (d, JFC
=
3
256.2 Hz), 137.5, 137.1, 130.5 (d, JFC = 10.0 Hz), 128.3,
127.8, 127.6, 116.5 (d, JFC = 23.2 Hz), 76.2, 73.4, 71.7,
2
62.6, 24.8.
18
Compound 13b: Mp 85.0–85.5 ꢂC. ½aꢁD ꢀ5.2 (c 1.05,
EtOH). IR (KBr): 3467, 3074, 2945, 1591, 1495, 1454,
21
afforded 11a (20.1 mg, 85%), ½aꢁD ꢀ27.1 (c 0.99, EtOH),
1315, 1203, 1144, 837 cmꢀ1 1H NMR (CDCl3): d 7.97
.
IR (film): 3446, 3339, 2925, 2858, 2231, 1732, 1613, 1579,
(2H, ddd, J = 6.8, 5.1, 1.7 Hz), 7.25 (2H, ddd, J = 8.4, 6.8,
1.7 Hz), 3.66 (1H, s), 3.62 (3H, m), 3.35 (1H, d,
J = 14.2 Hz), 3.24 (1H, d, J = 14.2 Hz), 2.45 (1H, dd,
J = 6.1 Hz, 5.9 Hz), 1.42 (3H, s). 13C NMR (CDCl3): d
165.8 (d, 1JFC = 256.2 Hz), 136.5 (d, 4JFC = 3.3 Hz), 130.5
1524, 1429, 1373, 1327, 1234, 1179, 1135, 1052, 759 cmꢀ1
.
1H NMR (CDCl3): d 9.12 (1H, s), 8.08 (1H, d, J = 1.3 Hz),
7.94 (1H, dd, J = 8.3, 1.3 Hz), 7.79 (1H, d, J = 8.3 Hz),
4.45 (1H, d, J = 11.9 Hz), 4.36 (1H, d, J = 11.9 Hz), 3.79
(1H, s), 2.10 (3H, s), 1.50 (3H, s). 13C NMR (CDCl3): d
172.5, 172.0, 141.2, 135.8, 134.0 (q, 2JFC = 32.3 Hz), 121.7,
3
2
(d, JFC = 9.1 Hz), 116.7 (d, JFC = 22.4 Hz), 72.8, 69.4,
62.5, 24.6. HRMS (EI, 70 eV): calcd for C10H14FO4S:
(M+H+): 249.0595; found: m/z 249.0587.
1
3
121.1 (q, JFC = 273.7 Hz), 117.2 (q, JFC = 5.8 Hz),
115.4, 104.7, 76.3, 69.6, 23.4, 20.8. HRMS (EI, 70 eV):
calcd for C14H11F3N2O3: (M+1+): 312.0019; found: m/z
312.0701.
Compound 14: Prisms from hexane–EtOAc, mp 132.0–
21
132.2 ꢂC, ½aꢁD ꢀ8.7 (c 1.04, EtOH). IR (KBr): 3475, 3105,
2997, 1728, 1589, 1491, 1458, 1325, 1284, 1147, 822 cmꢀ1
.
21
27. Compound 11b: Mp 131.2–131.5 ꢂC. ½aꢁD ꢀ42.2 (c 0.945,
1H NMR (CD3OD): d 7.97 (2H, ddd, J = 8.7, 5.1, 2.1 Hz),
7.29 (2H, ddd, J = 9.0, 8.7, 2.1 Hz), 3.84 (1H, d,
J = 14.8 Hz), 3.65 (1H, d, J = 14.8 Hz), 1.44 (3H, s). 13C
18
MeOH) [lit.28 ½aꢁD ꢀ43.6 (c 1.0, MeOH)], IR (film): 3342,
2925, 2854, 2231, 1697, 1612, 1581, 1522, 1429, 1327, 1178,
1
1
1134, 1051, 845 cmꢀ1. H NMR (CDCl3): d 9.10 (1H, s),
NMR (CD3OD): d 176.8, 167.0 (d, JFC = 253.8 Hz),
3
2
8.09 (1H, d, J = 2.1 Hz), 7.92 (1H, dd, J = 8.4, 2.1 Hz),
7.78 (1H, d, J = 8.4 Hz), 4.14 (1H, d, J = 11.0 Hz), 3.57
(1H, d, J = 11.0 Hz), 3.40 (1H, s), 2.14 (1H, s), 1.45
(3H, s). 13C NMR (CDCl3): d 174.1, 141.7, 136.1, 134.3
138.7, 132.5 (d, JFC = 10.0 Hz), 117.0 (d, JFC
=
23.2 Hz), 73.3, 65.0, 27.6.
22
Compound (R)-1: Mp 180–181 ꢂC [lit.28 181–182 ꢂC]. ½aꢁD
18
ꢀ83.2 (c 1.04, MeOH) [lit.10 ½aꢁD ꢀ82 (c 1.0, MeOH)],
2
1
(q, JFC = 34.0 Hz), 122.3 (q, JFC = 274.5 Hz), 122.0,
HPLC: 100% ee [Chiralcel OJ-H, 0.46 cm · 25 cm; hexane–
i-PrOH (5:4), 0.5 mL/min], tR(min) = 22.4 [(R)-, 100%].
No peak ascribable to (S)-isomer [tR(min) = 27.3] was
detected. IR (KBr): 3462, 3340, 3109, 2916, 2231, 1703,
3
117.5 (q, JFC = 5.0 Hz), 115.7, 104.8, 71.7, 67.8, 22.9.
HPLC: 100% ee [Chiralcel OD-H, 0.46 cm · 25 cm; hex-
ane–i-PrOH (15:1), 0.5 mL/min], tR(min) = 53.9 [(S)-,
100%]. No peak ascribable to (S)-isomer [tR(min) = 57.2]
was detected.
1612, 1581, 1522, 1495, 1431, 1333, 1292, 1142, 845 cmꢀ1
.
1H NMR (CDCl3): d 9.07 (1H, s), 7.97 (1H, s), 7.91–7.86
28. Soros, B.; Tuba, Z.; Galik, G.; Bor, A.; Demeter, A.;
Trischler, F.; Harvath, J.; Brlik, J. WO 2001000608, 2002;
Chem. Abstr. 2002, 134, 86040.
(2H, m), 7.78 (1H, m), 7.13–7.19 (2H, m), 5.03 (1H, s),
3.96 (1H, d, J = 14.5 Hz), 3.48 (1H, d, J = 14.5 Hz), 1.58
1
(3H, s). 13C NMR (CDCl3): d 173.6, 164.7 (d, JFC
=
3
29. Alternatively, (R)-bicalutamide (1) was also synthesized
from (R)-7 as in Scheme 5.
252.1 Hz), 143.0, 137.0, 136.1, 131.3 (d, JFC = 13.3 Hz),
2
1
131.3 (q, JFC = 31.5 Hz), 122.8, 122.4 (q, JFC
=
=
22
3
2
Compound 12: ½aꢁD +5.7 (c 1.07, EtOH). IR (film): 3448,
273.7 Hz), 117.4 (q, JFC = 5.0 Hz), 116.0 (d, JFC
3089, 2862, 1589, 1491, 1369, 1227, 1092, 827, 739,
22.4 Hz), 115.7, 101.9, 73.1, 63.4, 27.2. Its IR and NMR
spectra were identical with those reported previously.10
30. Tanner, D.; Somfai, P. Tetrahedron 1986, 42, 5985–
5990.
698 cmꢀ1 1H NMR (CDCl3): d 7.38 (2H, ddd, J = 7.2,
.
5.1, 2.0 Hz), 7.35–7.25 (5H, m), 6.94 (2H, ddd, J = 8.6,
2.0, 7.2 Hz), 4.42 (2H, s), 3.43 (1H, d, J = 9.1 Hz), 3.31