Asymmetric borane reduction of prochiral ketone using chiral bis(α,α-diphenyl-2-pyrrolidinemethanol) carbonate

Article abstract of DOI:10.1248/cpb.51.221

Chiral bis(α,α-diphenyl-2-pyrrolidinemethanol) carbonate (DPP₂·H₂CO₃) is a useful asymmetric auxiliary for the asymmetric borane reduction of prochiral ketones. Chiral DPP₂·H₂CO₃ is recover

Full text of DOI:10.1248/cpb.51.221

February 2003
Notes
Chem. Pharm. Bull. 51(2) 221—223 (2003)
221
Asymmetric Borane Reduction of Prochiral Ketone Using Chiral
a a
Bis( , -diphenyl-2-pyrrolidinemethanol) Carbonate
Takashi YANAGI, ,a Ken KIKUCHI,a Hideki TAKEUCHI,a Takehiro ISHIKAWA,a Toshihiro NISHIMURA,a
*
b
Minoru KUBOTA,a and Iwao YAMAMOTO
a Central Research Laboratories, Kissei Pharmaceutical Co., Ltd.; Hotaka, Minamiazumi, Nagano 399–8304, Japan: and
b Faculty of Textile Science and Technology, Shinshu University; Ueda, Nagano 386–8567, Japan.
Received October 16, 2002; accepted November 29, 2002
Chiral bis(a,a-diphenyl-2-pyrrolidinemethanol) carbonate (DPP2·H2CO3) is a useful asymmetric auxiliary
for the asymmetric borane reduction of prochiral ketones. Chiral DPP2·H2CO3 is recoverable from the reaction
and directly reusable for the reaction. The intermediate of KUR-1246, which we are developing as a new uterine
relaxant, was synthesized using the methodology.
Key words asymmetric borane reduction; a,a-diphenyl-2-pyrrolidinemethanol; carbonate; KUR-1246
Several asymmetric borane reductions of prochiral ketones generated from (S)-DPP (0.5 mmol) and BH3·Me2S (5 mmol)
using a chiral oxazaborolidine catalyst prepared from a chiral in each solvent (5 ml) by stirring at room temperature for 1 h.
b-amino alcohol have been reported.1—6) Especially, the use A solution of acetophenone (5 mmol) in each solvent (10 ml)
of the oxazaborolidine, MeCBS or HCBS, prepared from was then added dropwise to the catalyst solution via a sy-
chiral a,a-diphenyl-2-pyrrolidinemethanol (DPP) for the ringe pump at room temperature over 1 h. The reaction solu-
asymmetric borane reduction of various ketones showed high tion was stirred until the acetophenone disappeared based on
enantioselectivities (Fig. 1). HCBS could be synthesized TLC. The resulting solution was quenched with 1 mol/l HCl.
from DPP and a reducing reagent such as the borane–di- The usual workup provided (1R)-1-phenylethanol. These re-
methyl sulfide complex (BH3·Me2S) or the borane–tetrahy- sults are shown in Table 1. The reaction in THF, ether, or
drofuran complex. However, the synthesis of HCBS requires hexane gave (1R)-1-phenylethanol with high optical purity
a long reaction time in tetrahydrofuran (THF).3) Masui and (Ͼ98% ee). On the other hand, when toluene or CH2Cl2 was
Shioiri reported the asymmetric reduction by BH3·Me2S used as the solvent, the enantioselectivities were inadequate.
using a catalyst easily generated in situ from chiral DPP and It became evident that the solvent influenced this method of
trimethyl borate.7) We have also reported the efficient catalyst using HCBS generated in situ.
prepared from aluminum triethoxide8) and DPP for asymmet-
Next we intended to recover and reuse the catalyst. Corey
ric borane reduction. However, the additive, trimethyl borate et al. reported a method for the recovery of DPP as the hy-
or aluminum triethoxide, is necessary to prepare the catalysts drochloride salt 1.3) When we used (R)-MeCBS in the asym-
in these methods. Mathre et al. tried to prepare a borane metric borane reduction of a ketone, we found that (R)-DPP
complex of HCBS in toluene by the same procedure used to
prepare a borane complex of MeCBS (Fig. 1), but they ob-
tained only a dimer complex.5) Salunkhe and Burkhardt re-
ported that the complex generated from the chiral DPP and
borane in toluene included the dimer complex.6) Efforts to
use the dimer complex as a catalyst resulted in a low enan-
tioselectivity for the reduction of acetophenone.
In this paper, we report the asymmetric borane reduction
of a prochiral ketone using a catalyst generated in situ from
DPP and BH3·Me2S in various solvents. We also report that
the carbonate of DPP is useful for the reduction.
Fig. 1
Table 1. Asymmetric Reduction of Acetophenone Using (S)-DPP and
BH3·Me2S in Various Solventsa)
In our previous report,8) we described that the asymmetric
reduction of acetophenone using (S)-DPP and BH3·Me2S in
THF required a long reaction time (1.5 h) after the addition
of the ketone and gave (1R)-1-phenylethanol with 94.7% ee.
During the reaction, immediately after BH3·Me2S was added
to a solution of (S)-DPP in THF, the addition of the ketone to
the solution was started. We thought that if the mixture of
(S)-DPP and BH3·Me2S was stirred to prepare a catalyst for
a sufficient time before the addition of the ketone, the reac-
tion time would be shorter and the optical purity of the alco-
hol would be higher.
Entry
Solvent
Timeb)
ee/%c)
Yield/%
1
2
3
4
5
THF
Ether
Hexane
CH2Cl2
Toluene
5 min
5 min
5 min
1 h
98.3
98.6
98.6
71.5
73.8
84
99
85
97
96
o.n.d)
a) The absolute configuration of the product was assigned by comparison of the re-
tention time on an HPLC chiral column with the commercially available compound.
b) Reaction time after the addition of the ketone. c) Determined by HPLC analysis
using a chiral column (Chiralcel OJ). d) Overnight.
First we examined the asymmetric borane reduction of
acetophenone using a catalyst generated in situ from DPP
and BH3·Me2S in various solvents. A catalyst solution was
* To whom correspondence should be addressed. e-mail: takashi_yanagi@pharm.kissei.co.jp
© 2003 Pharmaceutical Society of Japan

222
Vol. 51, No. 2
Table 2. Asymmetric Borane Reduction of Acetophenone with a Catalyst
Generated in Situ from the Salt of (S)-DPP and BH3·Me2S
Salt of (S)-DPP
Chart 1
Entry
Timeb)
ee/%c)
Yeild/%
Salt
mol%a)
1
2
3
4
1
2
3
3
3
3
3
3
10 (10)
5 (10)
5 (10)
2.5 (5)
1.0 (2)
2.5 (5)
1.0 (2)
0.5 (1)
1.5 h
1.5 h
78.9
90.7
97.9
96.2
36.4
98.5
95.1
56.8
88
93
97
91
83
90
93
87
reduced both the ketone and the ester groups to give the
crude 6 with the excellent optical purity of 99.0% ee. After
crystallization, 6 was then obtained in 91% yield with
Ͼ99.9% ee.
5 min
5 min
o.n.d)
5 min
5 min
o.n.d)
5
6e)
7e)
8e)
In conclusion, the asymmetric borane reduction of a
prochiral ketone using the catalyst generated from a chiral
DPP and BH3·Me2S in situ in THF, ether, or hexane at room
temperature for 1 h gave the corresponding chiral alcohol
with an excellent optical purity. However, the optical purity
of the chiral alcohol, which was obtained from the reduction
in CH2Cl2 or toluene, was inadequate. (R)- and (S)-DPP2·
H2CO3 could be used for the catalyst as same as DPP. Fur-
thermore, they were easily recovered from the reaction. (R)-
and (S)-DPP2·H2CO3 are useful, recoverable, and reusable
catalysts for the asymmetric borane reduction of prochiral
ketones.
a) The value inside ( ) was mol% of (S)-DPP. b) Reaction time after the addition
of the ketone. c) Determined by HPLC analysis using a chiral column (Chiralcel OJ).
d) Overnight. e) The solvent was decreased to a fifth of the original quantity.
could easily be recovered as the carbonate [(R)-DPP2·
H2CO3, 4] in 70—80%.9) If these salts can be used as the cat-
alyst for the asymmetric borane reduction, the recycling of
the catalyst will be very simple and economical. We then in-
vestigated the possibility of the carbonate, the hydrochloride,
and the sulfate of DPP as the catalyst for the asymmetric bo-
rane reduction of acetophenone using the above-mentioned
method. These results are shown in Table 2.
Using 5 mol% of the carbonate [(S)-DPP2·H2CO3, 3] of (S)-
DPP gave (1R)-1-phenylethanol with the excellent optical
purity of 97.9% ee (entry 3). When the hydrochloride 1 or
the sulfate 2 of (S)-DPP was used as the catalyst for the re-
duction, the reaction times were 1.5 h and the optical purities
of the alcohol were lower (78.9% ee and 90.7% ee, respec-
tively) (entry 1, 2). Furthermore, we examined the possibility
of decreasing the quantity of 3. Using 2.5 mol% of 3 under
these conditions led to a good result (96.2% ee, entry 4).
When the solvent was decreased to a fifth of its original
quantity, the reduction of acetophenone using 1 mol% of 3
gave (1R)-1-phenylethanol with 95.1% ee (entry 7). How-
Experimental
All melting points were determined on a Yanagimoto melting point appa-
ratus and are uncorrected. IR spectra were recorded on a Nicolet 510 FT-IR
1
spectrometer. H- and 13C-NMR spectra were recorded on a Bruker DRX-
500 using tetramethylsilane as the internal standard. Mass spectra were mea-
sured using a JEOL JMS-SX102A mass spectrometer. Optical rotations were
measured with a JASCO DIP-370 polarimeter.
General Procedure. Asymmetric Borane Reduction of Acetophenone
BH3·Me2S (10 mol/l, 0.5 ml, 5 mmol) was added to a suspension of (S)-DPP
(127 mg, 0.50 mmol) in THF (5 ml) under a N2 atmosphere, and the mixture
was stirred at room temperature for 1 h. A solution of acetophenone
(601 mg, 5 mmol) in THF (10 ml) was added dropwise over 1 h via a syringe
pump. The reaction mixture was stirred until the acetophenone disappeared
on TLC. The mixture was quenched with 1 mol/l HCl (10 ml), and extracted
with ether (3ϫ15 ml). The organic layers were combined, washed with water
(10 ml) and brine (10 ml), dried over MgSO4, and concentrated under re-
duced pressure. The resulting residue was purified using silica gel chro-
ever, a further reduction of the amount of 3 to 0.5 mol% at matography (Fuji Silysia Co. Ltd., BW-350; eluent, AcOEt : hexaneϭ1 : 10)
to give (1R)-1-phenylethanol (611 mg, 100%) as a colorless oil. The ee of
the alcohol was determined to be 97.5% by HPLC using a chiral column
[column, Chiralcel OJ 4.6 mm i.d.ϫ250 mm, Daicel Chemical Industries
Co., Ltd.; mobile phase, hexane–iso-PrOH, 95 : 5; flow rate, 1.0 ml/min; de-
the high concentration gave the alcohol with the unsatisfac-
tory optical purity of 56.8% ee (entry 8). From these results,
chiral DPP2·H2CO3 is quite useful for the asymmetric borane
reduction, and the obtained optical purity of the chiral alco-
hol is affected by the concentration of both the catalyst and
the ketone in the reaction solution.
tection, UV at 220 nm].
(S)-a,a-Diphenyl-2-pyrrolidinemethanol Hydrochloride [(S)-DPP·
HCl, 1] Ether (10 ml) was added to a solution of (S)-DPP (507 mg, 2
mmol) in 2.4 mol/l HCl/MeOH (2 ml), and the precipitate was collected by
filtration, washed with ether, and dried to give 1 (182 mg, 63%) as a white
Furthermore, we examined the recovery of the carbonate
of DPP from a reaction mixture and the reduction using the
recovered carbonate. The first asymmetric reduction of ace-
tophenone (12.02 g) using 2.5 mol% of 4 (1.42 g) gave (1S)-
1-phenylethanol with 98.1% ee after distillation and 4 was
recovered in 69% yield. We reused the recovered 4 for the
same reduction. The optical purity of the alcohol was 98.0%
ee.
solid. mp 246 °C. IR (KBr): 3251, 2885, 1448, 1393, 750, 695 cmϪ1. H-
1
NMR (DMSO-d6) d: 1.73—1.96 (4H, m), 3.13 (2H, t, Jϭ6.1 Hz), 4.88 (1H,
t, Jϭ7.3 Hz), 6.55 (1H, br s), 7.19—7.23 (2H, m), 7.30—7.36 (4H, m), 7.25
(2H, d, Jϭ7.6 Hz), 7.63 (2H, d, Jϭ8.1 Hz), 8.31 (1H, br), 9.33 (1H, br). 13C-
NMR (DMSO-d6) d: 26.53, 28.47, 49.20, 67.56, 79.58, 127.93, 128.31,
129.46, 129.67, 130.70, 130.88, 147.13, 147.55. [a]D29 ϩ57.1° (cϭ0.84,
MeOH). Anal. Calcd for C17H20ClNO: C, 70.46; H, 6.96; N, 4.83. Found: C,
70.43; H, 6.92; N, 4.85.
Bis[(S)-a,a-diphenyl-2-pyrrolidinemethanol] Sulfate [(S)-DPP2·H2SO4,
2] 1 mol/l H2SO4 (2 ml) was added to a solution of (S)-DPP (507 mg, 2
mmol) in THF (8 ml), and the precipitate was collected by filtration, washed
with water, and dried to give 2 (369 mg, 61%) as a white solid. mp 260—
Finally, we used the method for the synthesis of the bro-
mohydrine 6 as shown in Chart 1. Compound 6 is an inter-
mediate of KUR-1246 that we are developing as a uterine re-
laxant.10,11) The asymmetric borane reduction of the phenacyl
1
262 °C. IR (KBr): 3171, 2980, 1449, 1069, 699 cmϪ1. H-NMR (DMSO-d6)
bromide 5 using 2.5 mol% of 4 and 120 mol% of BH3·Me2S d: 1.06—1.77 (4H, m), 2.93—3.04 (2H, m), 4.56 (1H, t, Jϭ7.4 Hz), 7.15—

February 2003
223
7.33 (6H, m), 7.62 (2H, d, Jϭ8.5 Hz), 7.58 (2H, d, Jϭ8.5 Hz). 13C-NMR
(DMSO-d6) d: 25.24, 26.65, 47.23, 64.94, 77.58, 125.84, 126.32, 126.86,
128.34, 128.43, 146.25, 146.72. [a]D29 Ϫ22.7° (cϭ0.3, DMSO). Anal. Calcd
for C34H40N2O6S: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.42; H, 6.66; N,
4.56.
mg, 0.66 mmol) in THF (10 ml) under a N2 atmosphere, and the mixture was
stirred at room temperature for 1 h. A solution of methyl (2-benzyloxy-5-
bromoacetylphenyl)acetate (5)11) (10.00 g, 26.5 mmol) in THF (25 ml) was
added dropwise over 1 h. After 10 min, the mixture was stirred for 2 h at 50
°C, quenched with MeOH (10 ml), and concentrated under reduced pressure.
AcOEt (30 ml) and 1 mol/l HCl (10 ml) were added to the resulting residue,
and then the separated aqueous layer was extracted with AcOEt (20 ml). The
organic layers were combined, washed with water (10 ml), sat. NaHCO3
(10 ml), and brine (10 ml), dried over MgSO4, and concentrated under re-
duced pressure. The resulting residue was recrystallized from AcOEt–
hexane to give 6 (8.52 g, 91%) as a white solid. The ee of 6 was determined
to be Ͼ99.9% by HPLC using a chiral column [column, Chiralpak AD
4.6 mm i.d.ϫ250 mm, Daicel Chemical Industries Co., Ltd.; mobile phase,
hexane–iso-PrOH, 9 : 1; flow rate, 1.0 ml/min; detection, UV at 230 nm]. mp
Bis[(S)-a,a-diphenyl-2-pyrrolidinemethanol] Carbonate [(S)-DPP2·
H2CO3, 3] Sat. NaHCO3 (5 ml) was added to a solution of (S)-DPP (253
mg, 1 mmol) in a mixture of THF (1 ml), 1 mol/l HCl (5 ml), and H2O (10
ml). The precipitate was collected by filtration, washed with water, and dried
to give 3 (254 mg, 89%) as a white solid. mp 106—108 °C. IR (KBr) 2984,
1618, 1541, 1448, 1377, 701 cmϪ1 1H-NMR (DMSO-d6) d: 1.35—1.65
.
(4H, m), 2.79—2.97 (2H, m), 4.27 (1H, t, Jϭ7.4 Hz), 5.15 (1H, br), 7.09—
7.32 (6H, m), 7.46 (2H, d, Jϭ8.0 Hz), 7.57 (2H, d, Jϭ7.6 Hz). 13C-NMR
(DMSO-d6) d: 26.09, 27.08, 47.34, 64.23, 77.83, 125.74, 126.27, 126.38,
126.67, 128.08, 147.12, 148.48. [a]D27 Ϫ19.2° (cϭ1.0, MeOH). Anal. Calcd
for C35H40N2O5: C, 73.92; H, 7.09; N, 4.93. Found: C, 74.33; H, 7.02; N,
4.90.
1
86—87 °C. IR (KBr): 3249, 1568, 1448, 1253 cmϪ1. H-NMR (CDCl3) d:
1.85 (1H, s), 2.89—2.95 (3H, m), 3.51 (1H, dd, Jϭ8.9, 10.4 Hz), 3.57 (1H,
dd, Jϭ3.6, 10.4 Hz), 3.80—3.87 (2H, m), 4.79—4.84 (1H, m), 5.07 (2H, s),
6.90 (1H, d, Jϭ8.1 Hz), 7.15—7.20 (2H, m), 7.29—7.42 (5H, m). 13C-NMR
(CDCl3) d: 34.55, 40.53, 62.94, 70.55, 73.83, 112.19, 125.91, 127.65,
128.19, 128.44, 129.07, 129.16, 133.11, 137.22, 157.21. [a]D29 Ϫ17.6° (cϭ
1.0, MeOH). HR-MS (FAB) m/z: Calcd for C17H19BrO3 Mϩ: 350.0518.
Found: 350.0509. Anal. Calcd for C17H19BrO3: C, 58.13; H, 5.45. Found: C,
57.97; H, 5.52.
Bis[(R)-a,a-diphenyl-2-pyrrolidinemethanol] Carbonate [(R)-DPP2·
H2CO3, 4] Sat. NaHCO3 (10 ml) was added to a solution of (R)-DPP (253
mg, 1 mmol) in a mixture of THF (1 ml) and 1 mol/l HCl (5 ml). The precipi-
tate was collected by filtration, washed with water, and dried to give 4 (261
mg, 92%) as a white solid. mp 108—109 °C. IR (KBr) 2984, 1618, 1541,
1448, 1377, 701 cmϪ1. 1H-NMR (DMSO-d6) d: 1.35—1.65 (4H, m), 2.79—
2.97 (2H, m), 4.28 (1H, t, Jϭ7.7 Hz), 5.15 (1H, br), 7.09—7.32 (6H, m),
7.46 (2H, d, Jϭ8.4 Hz), 7.57 (2H, d, Jϭ8.1 Hz). 13C-NMR (DMSO-d6) d:
26.09, 27.08, 47.35, 64.23, 77.83, 125.73, 126.28, 126.38, 126.66, 128.09,
147.11, 148.47. [a]D27 ϩ17.4° (cϭ1.0, MeOH). Anal. Calcd for C35H40N2O5:
C, 73.92; H, 7.09; N, 4.93. Found: C, 73.58; H, 7.11; N, 4.80.
Recover and Reuse of (R)-DPP2·H2CO3 (4) BH3·Me2S (10 mol/l, 8
ml, 80 mmol) was added to a suspension of 4 (1.42 g, 2.50 mmol) in THF
(20 ml) under a N2 atmosphere, and the mixture was stirred at room temper-
ature for 1 h. A solution of acetophenone (12.02 g, 100 mmol) in THF (40
ml) was added dropwise over 1 h. The reaction mixture was stirred until the
acetophenone disappeared on TLC (10 min). The mixture was quenched
with 1 mol/l HCl (25 ml) and extracted with AcOEt (2ϫ100 ml). The or-
ganic layers were combined, washed with water (10 ml) and brine (10 ml),
dried over MgSO4, and concentrated under reduced pressure. The obtained
oil was distilled under reduced pressure to give (1S)-1-phenylethanol
(8.39 g, 69%) as a colorless oil. The ee of the alcohol was determined to be
98.1% by HPLC using the chiral column.
References and Notes
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mun., 1983, 469—470 (1983).
2) Corey E. J., Bakshi R. K., Shibata S., J. Am. Chem. Soc., 109, 5551—
5553 (1987).
3) Corey E. J., Bakshi R. K., Shibata S., J. Org. Chem., 53, 2861—2863
(1988).
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(1998).
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J. D., Corley E. G., Grabowski E. J. J., J. Org. Chem., 58, 2880—2888
(1993).
6) Salunkhe A. M., Burkhardt E. R., Tetrahedron Lett., 38, 1523—1526
(1997).
7) Masui M., Shioiri T., Synlett, 1997, 273—274 (1997).
8) Yanagi T., Kikuchi K., Takeuchi H., Ishikawa T., Nishimura T., Kamijo
T., Chem. Lett., 1999, 1203—1204 (1999).
9) After the reaction mixture was quenched, the solution was washed
with 1 mol/l HCl. The 1 mol/l HCl washing was adjusted to pH 8 with
NaHCO3 solution, and then the precipitate was collected and dried to
give the carbonate 4.
10) Kobayashi M., Takeda K., Murata S., Kojima M., Akahane M., Inoue
Y., Kitamura K., Kawarabayashi T., J. Pharmacol. Exp. Ther., 297,
666—671 (2001).
The aqueous layers of the above procedure were combined and adjusted to
pH 8 by sat. NaHCO3. After the mixture was stirred overnight, the precipi-
tate was collected by filtration, washed with water, and dried to give 4
(0.98 g, 69%) as a white solid.
The recovered 4 (0.71 g, 1.25 mmol) was used for the asymmetric borane
reduction of acetophenone (6.01 g, 50 mmol) as the above procedure. (1S)-1-
Phenylethanol (4.92 g, 81%) was obtained, and the ee of the alcohol was de-
termined to be 98.0% by HPLC using the chiral column.
11) Yanagi T., Kikuchi K., Takeuchi H., Ishikawa T., Nishimura T., Ya-
mamoto I., Chem. Pharm. Bull., 49, 1018—1023 (2001).
(1R)-1-[4-Benzyloxy-3-(2-hydroxyethyl)phenyl]-2-bromoethan-1-ol (6)
BH3·Me2S (10 mol/l, 0.6 ml, 6 mmol) was added to a suspension of 4 (377