Asymmetric borane reduction of prochiral ketones catalyzed by phosphinamides prepared from L-serine

Article abstract of DOI:10.1002/hc.10145

Synthesis of several new chiral phosphinamide catalysts with a proximal hydroxyl group from L-serine was described. These compounds have been successfully used in the asymmetric catalytic borans, reduction of prochiral ketones. The optically active second

Full text of DOI:10.1002/hc.10145

Heteroatom Chemistry
Volume 14, Number 3, 2003
Asymmetric Borane Reduction of Prochiral
Ketones Catalyzed by Phosphinamides
Prepared From L-Serine
Kang-Ying Li,1 Zheng-Hong Zhou,1 Li-Xin Wang,1 Guo-Feng Zhao,1
Michael C. K.Choi,2 Qi-Lin Zhou,1 and Chu-Chi Tang1
1State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, 300071 Tianjin, People’s Republic of China
2Laboratory of Chiral Technology, Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong
Received 7 October 2002
tiomeric excess (ee) values and often have wide sub-
ABSTRACT: Synthesis of several new chiral phos-
strate scope. Other catalysts such as chiral sulfur
phinamide catalysts with a proximal hydroxyl group
reagents [3,4] and chiral phosphorus reagents [5]
from L-serine was described. These compounds have
were also used in this reaction. In recent years,
been successfully used in the asymmetric catalytic
many excellent results were achieved using chiral
borane reduction of prochiral ketones. The optically
phosphorus reagents as catalysts. According to their
active secondary alcohols were obtained with an
structure, they can be devided in two types. One
enantiomeric excess (ee) up to 81% and excellent
is chiral oxazaphospholidine borane complexes [6]
ꢀ
C
yields. 2003 Wiley Periodicals, Inc. Heteroatom Chem
and the other is chiral phosphinamides containing
an N P O unit [7]. Several research groups’ work
proved that introduction of a proximal hydroxyl
14:288–291, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10145
group in the phosphinamides was beneficial to enan-
tioselectivity. For instance, the asymmetric catalytic
reduction of prochiral ketones in presence of chiral
INTRODUCTION
The enantioselective reduction of prochiral ketones
is an important reaction for the synthesis of opti-
cally active secondary alcohols [1]. A catalytic enan-
tioselective borane reduction using oxazaborolidine
prepared from chiral amino alcohols is one of the
most efficient methods [2] which give excellent enan-
phosphinamide catalysts 1–3 reported by Kellogg [4]
and Wills [8,9], provided the optically active alcohols
with good yields and moderate to excellent ee.
Correspondence to: Chu-Chi Tang; e-mail: c.c.tang@eyou.com.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20002002 and 20272025.
Contract grant sponsor: Ph.D. Programs Foundation of Ministry
of Education of China.
In this paper, we report the preparation of several
new chiral phosphinamide catalysts with a proximal
hydroxyl group and their application to the asym-
metric borane reduction of prochiral ketones.
Contract grant sponsor: Hong Kong Polytechnic University ASD
Fund.
c
ꢀ
2003 Wiley Periodicals, Inc.
288

Asymmetric Borane Reduction Catalyzed by Phosphinamides 289
The chiral phosphinamides 4 could be prepared
by the process described in Scheme 1. The hydroxyl
group in L-serine methyl ester hydrochloride 5 was
protected with triphenylmethyl chloride in CH2Cl2
after the N-phosphinylation by diphenylphosphinic
chloride in presence of Et3N in a one-pot reaction.
Compound 6 was obtained with 64% yield over
two steps. Then compound 6 reacted with Grignard
reagent in dry THF which gave the target products 4
with 78–90% yield. These compounds were fully sta-
ble to the reaction conditions and could be recovered
and reused after the reduction reaction.
Firstly, the application of 4b for the synthesis of
a range of optically active alcohols through the re-
duction of ketones was examined. The reaction was
carried out in dry toluene using BH3·Me2S as reduc-
ing agent in presence of 10 mol% of catalyst 4b (see
Scheme 2). The major configuration of the obtained
secondary alcohols was S determined by comparison
with the specific rotation. The results were summa-
rized in Table 1.
As shown in Table 1, we found that temperature
had no signiciant effect on the reduction reaction.
Carrying out the reaction at 30–40◦C seemed to give
a little higher enantioselectivity in the reduction of
acetophenone. However, low temperature was bene-
ficial to ee when ꢀ-chloroacetophenone was used as
the substrate. This finding was contrary to Wills’ ob-
servation, which revealed that reduction of ketones
in toluene with catalyst 3 at 110◦C gave the best
asymmetric inductions [8,9].
In Table 2, the structure effect of the catalyst 4
on the asymmetric borane reduction of prochiral ke-
tones was shown. It revealed that the electron den-
sity of the quarternary carbon binding the hydroxyl
group has a dramatic influence on the enantiose-
lectivity. When R in catalyst 4 was an alkyl group
(R = Et, 4d), poor enantioselectivity was obtained.
It was much higher when R was an aromatic group
(4a–c). In this case, the mature of the substituent at-
tached on the benzene ring also had a marked effect
on the enantioselectivity. The electron-withdrawing
substituted catalyst 4a (R = p-F-C6H4) had a better
SCHEME 2
catalytic activity than the electron-donating substi-
tuted catalyst 4c (R = p-Me-C6H4). The catalytic abil-
ity of unsubstituted catalyst 4b (R = C6H5) was in be-
tween. These observations implied that increasing
the electron-withdrawing ability of R improved the
enantioselectivity. These findings provided useful in-
formations not only for the design of the chiral phos-
phinamide catalysts with a proximal hydroxyl group
but also interpreting the catalytic mechanism.
In conclusion, we have demonstrated that phos-
phinamides prepared from L-serine were capable of
the asymmetric reduction of ketones by borane in
high yields and selectivity (ee 81%). The effect of the
electron characteristic of the substituent R on the
catalytic activity was also discussed. Further investi-
gation of the catalytic activity and the optimal con-
ditions are still in progress and our findings will be
reported in due course.
EXPERIMENTAL
1H and 31P NMR were recorded in CDCl3 as solvent
on FX-900Q and AC-P200 instruments using TMS
1
as an internal standard for H NMR, 85% H3PO4
as external standard for 31P NMR. Elemental anal-
yses were conducted on MF-3 automatic analyzer.
Specific rotations were measured by a Perkin Elmer
241MC polarimeter.
Preparation of Compound 6
To a premixed solution of 40-ml CH2Cl2, 3.03 g
(30 mmol) Et3N, and 1.09 g (7 mmol) L-Serine methyl
ester hydrochloride, 1.66 g (7 mmol) diphenylphos-
phinic chloride in 10-ml CH2Cl2 was added dropwise
at 0–5◦C. After the addition, the reaction mixture was
SCHEME 1

290 Li et al.
TABLE 1 Asymmetric Borane Reduction of Prochiral Ke-
tones Catalyzed by Chiral Phosphinamide Catalyst 4b
(0.53 mmol) 6 and 10-ml THF was added dropwise
at room temperature. After the reaction was com-
plete (monitored by TLC), 2-ml saturated NH4Cl so-
lution was added slowly to destroy the excess p-
FC6H4MgBr. The insoluble material was filtered and
the solution was dried with anhydrous MgSO4. Re-
moving the solvent in vacuum gave the crude prod-
uct which was purified by column chromatography
(200–300 mesh, petroleum ether/EtOAc (1:2) as elu-
ent). A total of 0.3 g 4a was obtained as a white
X
Y
Temperature (◦C)
Yielda (%)
eeb (%)
H
H
H
H
H
H
H
H
H
H
−20–rt
30–40
60–70
Reflux
0–rt
92
83
92
92
83
92
97
41
51
42
39
78
78
63
H
Cl
Cl
Cl
−20–rt
30–40
25
solid. Yield 78.9%; m.p. 176–178◦C; [ꢀ]D = +35.0
aIsolated yield.
(c 3.0, CHCl3); 31P NMR 23.99 ppm, 1H NMR 3.39 (d,
H, CH2, 2 JHH = 2.28 Hz, 3 JHH = 9.20 Hz), 3.41 (d, H,
CH2, 2 JHH = 2.30 Hz, 3 JHH = 9.20 Hz), 3.85 (t, 1H, CH,
3 JHH = 8.90 Hz), 4.10 (s, H, NH), 5.20 (s, 1H, OH),
6.90–7.67 (m, 33, Ar H). C46H38F2NO3P Required: C
76.55, H 5.31, N 1.94. Found: C 76.63, H 5.39, N 1.93.
4b was prepared according to the above method
for 4a, using 0.56 g (1 mmol) 6 and C6H5MgBr. A total
of 0.59 g 4b was isolated as a white solid. Yield 86.0%;
bDetermined by HPLC using a Chiracel OD column using hexane/i -
PrOH as eluent.
warmed to room temperature and stirred overnight.
Then 1.95 g (7 mmol) triphenylmethyl chloride in
10-ml CH2Cl2 was added. After refluxing for 8 h, the
content was cooled to room temperature, washed
with water and saturated brine. The organic phase
was dried over with anhydrous Na2SO4. Removing
the solvent gave the crude product which was pu-
rified by column chromatography (200–300 mesh,
petroleum ether/EtOAc (1:2) as eluent). The product
6 was obtained as a white solid. Yield 64%; m.p. 125–
m.p. 183–185◦C; [ꢀ]D = +31.1 (c 0.9, CH2Cl2); 31P
25
1
2
NMR 23.22 ppm, H NMR 3.47 (d, H, CH2, JHH
=
2.29 Hz, 3 JHH = 9.20 Hz), 3.52 (d, H, CH2, 2 JHH = 2.30
Hz, 2 JHH = 9.20 Hz), 4.07 (t, 1H, CH, 3 JHH = 8.90 Hz),
4.27 (s, 1H, NH), 5.44 (s, 1H, OH), 7.24–7.76 (m, 35,
Ar H). C46H40NO3P Required: C 80.56, H 5.88, N 2.04.
Found: C 80.62, H 5.89, N 1.97.
25
127◦C; [ꢀ]D = −11.7 (c 1, CH2Cl2); 31P NMR 25.20
1
2
ppm (s), H NMR 3.35 (d, H, CH2, JHH = 2.21 Hz,
3 JHH = 8.10 Hz), 3.50 (d, H, CH2, JHH = 2.20 Hz,
2
3 JHH = 8.10 Hz), 3.74 (s, 3H, CH3), 3.82 (t, 1H, CH,
3 JHH = 8.20), 4.10 (s, 1H, NH), 7.24–7.95 (m, 25H, Ar
H). C35H32NO4P Required: C 74.85, H 5.74, N 2.49.
Found: C 74.60, H 5.72, N 2.50.
4c was prepared according to the above method
for 4a, using 0.30 g (0.53 mmol) 6 and p-Me-
C6H4MgBr. The product 4c (0.29 g) was isolated as
25
a white solid. Yield 78.4%. m.p. 109–111◦C; [ꢀ]D
=
+39.5 (c 1.9, CHCl3); 31P NMR 23.35 ppm, H NMR
1
2
2.25–2.36 (m, 6H, 2CH3), 3.39 (d, 1H, CH2, JHH
=
=
3
2
Preparation of Catalyst 4
2.30 Hz, JHH = 9.38 Hz), 3.43 (d, 1H, CH2, JHH
2.31 Hz, 3 JHH = 9.38 Hz), 4.07 (t, 1H, CH, 3 JHH = 8.90
Hz), 4.10 (s, H, NH), 4.14 (s, 1H, OH), 6.90–7.67 (m,
33, Ar H). C48H44NO3P Required: C 80.19, H 6.21, N
1.96. Found: C 79.99, H 6.24, N 1.69.
4a: To a 30-ml p-FC6H4MgBr solution prepared from
0.29 g (12 mmol) Mg and 0.92 g (6 mmol) p-FC6H4Br
in situ by the routine procedure, a mixture of 0.30 g
4d was prepared according to the above method
for 4a, using 0.40 g (0.7 mmol) 6 and EtMgBr. The
product 4d (0.37 g) was isolated as a viscous. Yield
TABLE 2 Asymmetric Borane Reduction of Prochiral Ke-
tones Catalyzed by Chiral Phosphinamide Catalysts 4a–d
25
90.0%; [ꢀ]D = +6.0 (c 3.0, CHCl3); 31P NMR 23.72
4
X
Y
Temperature (◦C)
Yielda (%)
eeb (%)
1
ppm, H NMR 0.55–0.70 (m, 6H, 2CH3), 1.24–1.39
2
a
b
c
d
a
b
c
d
a
b
c
H
H
H
H
H
H
H
H
H
H
H
−20–rt
−20–rt
−20–rt
−20–rt
−20–rt
−20–rt
−20–rt
−20–rt
30–40
30–40
30–40
92
92
97
75
83
91
97
77
93
92
92
55
41
31
0
81
78
63
7
(m, 4H, 2CH2), 3.14 (d, 2H, CH2, JHH = 2.25 Hz,
2
3 JHH = 8.24 Hz), 3.18 (d, 2H, CH2, JHH = 2.24 Hz,
3
3 JHH = 8.24 Hz), 3.72 (t, 1H, CH, JHH = 8.31 Hz),
H
4.10 (s, H, NH), 5.20 (s, 1H, OH), 7.23–7.95 (m, 25,
Ar H). C38H40NO3P Required: C 77.40, H 6.84, N 2.38.
Found: C 77.23, H 7.05, N 2.18.
Cl
Cl
Cl
Cl
H
H
H
2-Cl
2-Cl
2-Cl
45
36
22
General Procedure for the Reduction
of Prochiral Ketones
aIsolated yield.
bDetermined by HPLC using a Chiracel OD column using hexane/i -
The catalyst 4 (10% mmol) was dissolved in 2-ml
dry toluene, and then borane-methyl sulfide (2 M
PrOH as eluent.

Asymmetric Borane Reduction Catalyzed by Phosphinamides 291
[2] (a) Delou, X. L.; Srebnik, M. Chem Rev 1993, 93(2),
763; (b) Corey, E. J.; Helal, C. J. Angew Chem, Int
Ed Engl 1998, 37, 1987; (c) Schunicht, C.; Biffis, A.;
Wulff, G. Tetrahedron 2000, 56, 6041.
[3] Bolm, C.; Felder, M. Tetrahedron Lett 1993, 34(38),
6041.
in THF, 1.2 mmol) was added under nitrogen at-
mosphere. After stirred for 30 min, the prochiral
ketone (1 mmol) in 4-ml toluene was added drop-
wise for 30 min. The reaction mixture was stirred at
required temperature until the ketone disappeared
(monitored by TLC). Ten milliliter saturated NH4Cl
solution was added and the water phase was ex-
tracted twice with CH2Cl2. The combined organic
layer was washed with water and saturated NaCl so-
lution, dried over with anhydrous MgSO4. The re-
sulting chiral secondary alcohol and chiral catalyst
were separated by column chromatography (200–
300 mesh, petroleum ether/EtOAc (5:1) as eluent).
The ee values of the purified chiral secondary alco-
hols were determined by HPLC or GC with chiral col-
umn. The recovered catalysts could be reused with
no loss of catalytic activity.
[4] Hulst, R.; Heres, H.; Peper, N. C. M. W.; Kellogg, R.
M. Tetrahedron: Asymmetry 1996, 7(5), 1373.
[5] (a) Buono, G.; Chiodi, O.; Wills, M. Synlett 1999, (4),
377; (b) Burns, B.; Studley, J. R.; Wills, M. Tetrahe-
dron Lett 1993, 34(44), 7105; (c) Burns, B.; King, N. P.;
Tye, H.; Wills, M. Tetrahedron: Asymmetry 1994, 5(5),
801; (d) Chiodi, O.; Fotiadu, F.; Sylvestre, M.; Buono,
G. Tetrahedron Lett 1996, 37(1), 39; (e) Gamble, M.
P.; Studley, J. R.; Wills, M. Tetrahedron: Asymme-
try 1996, 7(11), 3071; (f) Gamble, M. P.; Studley, J.
R.; Wills, M. Tetrahedron Lett 1996, 37(16), 2853;
(g) Peper, V.; Martens, J. Tetrahedron Lett 1996,
37(46), 8351; (h) Chen, G.-H.; Hsu, J.-L.; Yan, W.-B.;
Fang, J.-M.; Lee, G.-H.; Liu, Y.-H.; Wang, Y. J Chinese
Chem Soc 1999, 46, 797; (i) Brunnel, J. M.; Legrand,
O.; Buono, G. Eur J Org Chem 2000, 19, 3313.
[6] Brunel, J.-M.; Chiodi, O.; Faure, B.; Fotiadu, F.;
Buono, G. J Organomet Chem 1997, 529, 285.
[7] Wills, M.; Gamble, M.; Palmer, M.; Smith, A.; Studley,
J. R.; Kenny, J. J Mol Catal, A: Chem 1999, 146, 139.
[8] Burns, B.; King, N. P.; Tye, H.; Studley, J. R.; Gamble,
M.; Wills, M. J Chem Soc, Perkin Trans I 1998, 1027.
[9] Gamble, M. P.; Smith, A. R. C.; Wills, M. J Org Chem
1998, 63(17), 6068.
REFERENCES
[1] (a) Noyori, R. Asymmetric Catalysis in Organic Syn-
thesis; Wiley: New York, 1994; (b) Ojima, I. (Ed.).
Catalytic Asymmetric Synthesis; VCH Press: Berlin,
1993; (c) Singh, V. K. Synthesis 1992, 605; (d) Brown,
H. C.; Ramachandran, P. V. Acc Chem Res 1992,
25(1), 16; (e) Noyori, R. Chem Soc Rev 1989, 18, 187.