Effect of Temperature on the Enantioselectivity in the Oxazaborolidine-Catalyzed Asymmetric Reduction of Ketones. Noncatalytic Borane Reduction, a Nonneglectable Factor in the Reduction System

Article abstract of DOI:10.1021/jo035203v

The effect of temperature on the enantioselectivity of the oxazaborolidine-catalyzed asymmetric borane reduction of ketones has been investigated carefully using alkyl aryl ketones with a variety of functional groups and a B-methoxyoxazaborolidine derived from trimethyl borate and (S)-α,α-diphenylprolinol as a catalyst. The reductions were carried out over a range of temperatures in THF and toluene with or without the catalyst. The reductive rates increase along with increasing reaction temperature with or without the catalyst by determining the conversion of the ketones to alcohols by GC analysis. However, the rates of the catalytic reductions increase faster than those without the catalyst. The results indicate that the noncatalytic borane reduction is an important factor to the enantioselectivity in the reduction. The highest enantioselectivities were usually obtained between 20 and 30 °C in the asymmetric reduction.

Full text of DOI:10.1021/jo035203v

Effect of Tem p er a tu r e on th e En a n tioselectivity in th e
Oxa za bor olid in e-Ca ta lyzed Asym m etr ic Red u ction of Keton es.
Non ca ta lytic Bor a n e Red u ction , a Non n eglecta ble F a ctor in th e
Red u ction System
J iaxi Xu,* Tiezheng Wei, and Qihan Zhang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University,
Beijing 100871, People’s Republic of China
jxxu@chem.pku.edu.cn
Received August 16, 2003
The effect of temperature on the enantioselectivity of the oxazaborolidine-catalyzed asymmetric
borane reduction of ketones has been investigated carefully using alkyl aryl ketones with a variety
of functional groups and a B-methoxyoxazaborolidine derived from trimethyl borate and (S)-R,R-
diphenylprolinol as a catalyst. The reductions were carried out over a range of temperatures in
THF and toluene with or without the catalyst. The reductive rates increase along with increasing
reaction temperature with or without the catalyst by determining the conversion of the ketones to
alcohols by GC analysis. However, the rates of the catalytic reductions increase faster than those
without the catalyst. The results indicate that the noncatalytic borane reduction is an important
factor to the enantioselectivity in the reduction. The highest enantioselectivities were usually
obtained between 20 and 30 °C in the asymmetric reduction.
In tr od u ction
Why does it show some differences in the asymmetric
borane reduction of ketones? Herein, we attempt to give
another rationale and experimental evidence for the
temperature-dependent enantioselectivity in the oxaza-
borolidine-catalyzed asymmetric borane reduction of
ketones. Noncatalytic borane reduction is a nonneglect-
able factor in the reduction system.
Enantioselective 1,3,2-oxazaborolidine-catalyzed bo-
rane reduction of prochiral ketones to chiral secondary
alcohols is an important reaction in asymmetric synthe-
ses, which has attracted much attention and was widely
used in the preparation of various secondary alcohols
during the past decade.1 Since it was pioneered by Itsuno
et al.2 and then developed by Corey’s group and is well-
known as the complete basis set reduction,3 some of the
best enantioselectivities have been achieved with chiral
1,3,2-oxazaborolidines derived from chiral vicinal amino
alcohols. In comparison with the numerous attempts to
search for new catalysts and to improve the enantiose-
lectivity, few papers have concentrated on the mecha-
nistic investigation of the catalytic reaction.3,4 Although,
many chemists have mentioned that the asymmetric
reduction shows temperature-dependent enantioselec-
tivity, and the enantioselectivity was improved with
increasing temperature.3a,b,5 It is well-known that the
enantioselectivity generally decreases with increasing
temperature in most asymmetrically catalytic reactions.
Resu lts a n d Discu ssion
A lot of catalysts have been developed for the borane
asymmetric reduction of ketones until now.1,5 Among
them, (S)-2-substituted 4,4-diphenyl-3,1,2-oxazaboro-
[3.3.0]octanes 1 (Scheme 1), derived from (S)-2-(diphe-
nylhydroxymethyl)pyrrolidine, with several different sub-
stituents (such as H for 1a , Me for 1b, Bu for 1c, MeO
for 1d , and Ph for 1e) on the B atom, have been proven
to be a series of effective catalysts in the asymmetric
reduction with excellent yields and enantioselectivities
for a wide variety of ketones. However, 1a -1c have not
(5) Brunel, J . M.; Maffei, M.; Buono, G. Tetrahedron: Asymmetry
1993, 4, 2255-2260. (b) Stone, G. B. Tetrahedron: Asymmetry 1994,
5, 465-472. (c) J iang, Y. Z.; Qin, Y.; Mi, A. Q. Chin. Chem. Lett. 1995,
6, 9-12. (d) Prasad, K. R. K.; J oshi, N. N. Tetrahedron: Asymmetry
1996, 7, 3147-3152. (e) Zhao, J . K.; Bao, X. H.; Liu, X. M.; Wan, B. S.;
Han, X. W.; Yang, C. G.; Hang, J . F.; Feng, Y.; J iang, B. Tetrahedron:
Asymmetry 2000, 11, 3351-3359. (f) Santhi, V.; Rao, J . M. Tetrahe-
dron: Asymmetry 2000, 11, 3553-3560. (g) Garrett, C. E.; Prasad, K.;
Repic, O.; Blacklock, T. J . Tetrahedron: Asymmetry 2002, 13, 1347-
1349. (h) Fu, X. Y.; McAllister, T. L.; Thiruvengadam, T. K.; Tann,
C.-H.; Su, D. Tetrahedron Lett. 2003, 44, 801-804. (i) Huertas, R. E.;
Corella, J . A.; Soderquist, J . A. Tetrahedron Lett. 2003, 44, 4435-4437.
(j) Li, X. S.; Yeung, C. H.; Chan, A. S. C.; Yang, T. K. Tetrahedron:
Asymmetry 1999, 10, 759-763.
(1) For recent reviews, see: (a) Wallbaum, S.; Martens, J . Tetrahe-
dron: Asymmetry 1992, 3, 1475-1504. (b) Singh, V. K. Synthesis 1992,
605-617. (c) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763-784.
(d) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
(2) Itsuno, S.; Sakurai, Y.; Ito, K.; Hirao, A.; Nakahama, S. Bull.
Chem. Soc. J pn. 1987, 60, 395-396.
(3) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc. 1987,
109, 5551-5553. (b) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.;
Singh, V. K. J . Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E.
J .; Link, J . O. Tetrahedron Lett. 1989, 30, 6275-6278.
(4) Nevalainen, V. Tetrahedron: Asymmetry 1991, 2, 63-74, 429-
435, 827-842, and 1133-1155.
10.1021/jo035203v CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003
10146
J . Org. Chem. 2003, 68, 10146-10151

Oxazaboralidine-Catalyzed Asymmetric Reduction
SCHEME 1
been entirely satisfactory, particularly for large-scale
productions, owing to the necessity of relatively expensive
reagents, such as trimethylboroxin, methylboronic acid,
or n-butylboronic acid, for their preparation,3 and the
necessity of preparation before catalytic reactions in order
to get excellent and stable enantioselectivity. Further-
more, the catalyst 1a is air and moisture sensitive.3 The
catalyst 1d , modified by the catalyst 1b, was developed
and applied successfully in the enantioselective reduc-
tion.6 The advantage of the catalyst 1d is that it can be
prepared from (S)-2-(diphenylhydroxymethyl)pyrrolidine
and inexpensive trimethyl borate and used directly
without any further separation and purification.
F IGURE 1. Effect of temperature on the enantioselectivity
in the oxazaborolidine-catalyzed borane reduction of ketones.
enantioselectivity, while heteroatom-containing ketones
2f, 2n , and 2o show a significant effect of temperature
on the enantioselectivities under our reaction conditions.
Reduction of nitrogen, oxygen, and sulfur heteroatom-
containing ketones provided relatively low enantioselec-
tivity at low temperatures (below 20 °C) and at high
temperatures (over 30 °C) because the noncatalyzed
reduction can also occur by hydrogen transfer from the
borane coordinated to these three heteroatoms. The
noncatalyzed reaction pathways were added because of
the existence of the heteroatoms.6a,7
When we optimized the reduction temperature for
obtaining the highest enantioselectivity, we found that
the reduction time became shorter with increasing tem-
perature. We rationalized that the enantioselectivity
increases with the increasing reduction temperature, in
most cases below 20-30 °C, partly because of the increase
of the catalytic reduction rate; as Prasad et al. said, the
faster the rate of the catalyzed reduction, the better the
selectivity.9 As the catalytic reduction became faster with
the increasing temperature, the enantioselectivity be-
came more highly improved. However, when the reduc-
tion temperature was increased over 30 °C, generally,
the free borane (including other noncatalyst-coordinated
borane, such as coordinated complexes of BH3 with Me2S,
THF, etc., with the same meaning in the following)
reduction became an important factor to the enantiose-
lectivity. The rate of the free borane reduction increases
more heavily with increasing reduction temperature over
30 °C. Thus, the enantioselectivity decreases somewhat
with increasing temperature, in most cases, over 30 °C.
To confirm our rationalization, we determined the
conversion rates of the two ketones, one with a heteroa-
tom O [BuOPhCOEt (2f)] and the other without a
heteroatom [AmPhCOEt (2c)], in both free borane reduc-
tion and 1,3,2-oxazaborolidine (1d )-catalyzed borane
reduction conditions at different temperatures by GC
analyses. The results are shown in Figures 2-7.
On the basis of the published results,1,6 borane asym-
metric reduction of ketones catalyzed by (S)-2-substituted
4,4-diphenyl-3,1,2-oxazaboro[3.3.0]octanes 1 in THF or
toluene is the best reaction condition in most cases.
However, for the reduction temperature, different re-
search groups gave different suggestions. To develop a
practical and efficient method for the preparation of
various chiral secondary alcohols with excellent yields
and enantioselectivity, it is better to understand this
reaction and to investigate in detail the optimal reaction
conditions. In previous papers,6a,7,8 it was found that the
heteroatoms (O, S, and N) in ketones show an obvious
effect on the enantioselectivity in the asymmetric reduc-
tion. For comparison, we selected four ketones, one
without a heteroatom and others containing a heteroa-
tom, O, S, or N, to investigate the effect of temperature
on enantioselectivity in the asymmetric reduction. We
also found that the enantioselectivity of acetophenone is
too high in the reduction and that the enantioselectivities
of alkyl aryl ketones decrease with increasing lengths of
both the alkyl chain and the alkyl substituent on the aryl
group.7 To observe an obvious effect, we designed four
ketones with some long-chained alkyl group and the
substituent of the aryl group to determine the effect. In
our asymmetric reduction, the catalyst 1d was prepared
in situ by the addition of trimethyl borate into a solution
of (S)-2-(diphenylhydroxymethyl)pyrrolidine in toluene
(or THF). After the resulting mixture was stirred for 2 h
and borane was added, a ketone was added dropwise for
1 h at the desired reduction temperature. After the
reaction mixture was quenched with methanol and the
usual workup, the ee value was determined using a chiral
column on HPLC. The results are shown in Figure 1.
From Figure 1, a remarkable effect of the reaction
temperature on the enantioselectivity was found, and
turnovers of enantioselectivities are from 20 to 30 °C for
all of these four ketones. Nonheteroatom-containing
ketone 2c shows a lesser effect of temperature on the
To investigate the effect of the solvent, we chose two
widely used solvents, THF and toluene, for the asym-
metric reduction to tracing the reduction conversion. The
results indicate that the conversion rates of ketone 2f to
the corresponding alcohol under catalytic conditions
increase faster than those under noncatalytic conditions
at each of the same temperatures, and the catalytic rates
in toluene increase more obviously than those in THF
because THF as a Lewis basic solvent can coordinate with
borane. The coordinated borane can cause noncatalytic
reduction (Figures 2, 4 and 3, 5).5e For nonheteroatom-
(6) Masui, M.; Shioiri, T. Synlett 1997, 273-274. (b) Prasad, K. R.
K.; J oshi, N. N. Tetrahedron: Asymmetry 1996, 7, 3147-3152.
(7) Xu, J . X.; Su, X. B.; Zhang, Q. H. Tetrahedron: Asymmetry 2003,
14, 1781-1786.
(8) Shi, Y. J .; Cai, D. W.; Dolling, U.-H.; Douglas, A. W.; Tschaen,
D. M.; Verhoeven, T. R. Tetrahedron Lett. 1994, 35, 6409-6412.
(9) Prasad, K. R. K.; J oshi, N. N. J . Org. Chem. 1996, 61, 3888-
3889.
J . Org. Chem, Vol. 68, No. 26, 2003 10147

Xu et al.
F IGURE 7. Oxazaborolidine-catalyzed borane reduction of
1-(4-pentylphenyl)ethanone 2c in toluene.
F IGURE 2. Free borane reduction of 1-(4-butoxyphenyl)-
ethanone 2f in THF.
with the increasing amount of BH3‚THF above 0.6
equiv.3a The enantioselectivity decreases because the free
borane reduction increases with the increasing amount
of BH3‚THF. This is in accordance with our observations.
Previously, several groups paid some attention to
studying the abnormal temperature-dependent enanti-
oselectivity in the oxazoborolidine-catalyzed borane asym-
metric reduction of ketones. Most of researchers searched
for the optimal reduction temperature for gaining the
highest enantioselectivity. Some of them presumed that
the enantioselectivity decreases with increasing temper-
ature because of the stability and dimerization of the
catalyst 1,3,2-oxazaborolidine3a,b,5a-c and the effect of
different solvents.5b,h Much effort has been made to
investigate the stability and dimerization of the catalysts.5a
After a survey of the investigation on the stability and
dimerization of the catalysts, we found that they are not
the major reason for the abnormal effect of the temper-
ature-dependent enantioselectivity above 0 °C or at least
above room temperature, based on our results, and they
may be the reason for the abnormal effect below room
temperature. Alternatively, Cai, Douglas, and their co-
workers investigated secondary reduction of the resulting
first intermediate monoalkoxyborane, which was ignored
in previous investigations, and found that it produced
relatively low enantioselectivity in the reduction sys-
tem.10 Less attention has been paid to free borane
reduction in the asymmetric reduction systems even
though borane reduction of aldehydes and ketones was
investigated,11 and some researchers mentioned it as a
possible reason for the abnormal effect of the tempera-
ture-dependent enantioselectivity.3b However, no experi-
mental evidence has been provided. The relation between
the free borane reduction and temperature has not yet
been taken into consideration.
F IGURE 3. Oxazaborolidine-catalyzed borane reduction of
1-(4-butoxyphenyl)ethanone 2f in THF.
F IGURE 4. Free borane reduction of 1-(4-butoxyphenyl)-
ethanone 2f in toluene.
F IGURE 5. Oxazaborolidine-catalyzed borane reduction of
1-(4-butoxyphenyl)ethanone 2f in toluene.
To further confirm the conclusion, a set of experiments
reducing ketone 2f as a model substrate in toluene was
designed and carried out. The results are tabulated in
Table 1. From Table 1, one can find that the addition
time (namely, the addition rate) has just a very slight
effect on the enantioselectivity when it is longer than 0.5
h (Table 1, entries 2 and 3 for 0 °C; entries 8-11 for 25
°C; and entries 18 and 19 for 80 °C), while it has a greater
effect when it is less than 0.5 h (Table 1, entries 1 and 2
for 0 °C; entries 6-8 for 25 °C; and entries 17 and 18 for
80 °C). However, the enantioselectivity is decreased
significantly with the increasing amount of borane (Table
F IGURE 6. Free borane reduction of 1-(4-pentylphenyl)-
ethanone 2c in toluene.
containing ketone 2c, only the conversion in toluene was
determined, and the same results were observed (Figures
6 and 7). Because reductions are almost completed after
the addition of the ketone to borane over 40 °C, the
tracing results are not shown in the figures. On the basis
of our observations (Figures 2-7), it seems that free
borane reduction is an important factor to the enanti-
oselectivity in the borane asymmetric reduction of ke-
tones. Corey et al. mentioned previously that the enan-
tioselectivity of the reduction often decreases somewhat
(10) Cai, D. W.; Tschaen, D.; Shi, Y.-J .; Verhoeven, T. R.; Reamer,
R. A.; Douglas, A. W. Tetrahedron Lett. 1993, 34, 3243-3246. (b)
Douglas, A. W.; Tschaen, D. M.; Reamer, R. A.; Shi, Y.-J . Tetrahe-
dron: Asymmetry 1996, 7, 1303-1308.
(11) Brown, H. C.; Schlesinger, H. I.; Burg, A. B. J . Am. Chem. Soc.
1939, 61, 673-680. (b) Fehlner, T. P. Inorg. Chem. 1972, 11, 252-
256.
10148 J . Org. Chem., Vol. 68, No. 26, 2003

Oxazaboralidine-Catalyzed Asymmetric Reduction
TABLE 1. Oxa za bor olid in e-Ca ta lyzed Asym m etr ic
Bor a n e Red u ction of Keton es u n d er Differ en t Con d ition s
catalyst
add.
temp loading
borane
time yield ee
entry ketone
(°C) (equiva) (equiva)
(h)
(%)
(%)
1
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2c
2n
2o
0
0
0.1
0.1
0.1
0.5
1.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.0
0.1
0.1
0.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
4.0
8.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
1
88
89
85
97
92
98
97
96
97
96
97
80
96
97
98
98
95
96
95
96
96
95
96
98
92
75
78
80
89
98
86
89
93
93
94
94
92
91
85
70
98
78
80
81
96
98
97
98
99
99
2
3
0
10
4
0
0
1
5
1
6
25
25
25
25
25
25
25
25
25
25
25
80
80
80
80
40
60
25
25
25
0
F IGURE 8. Potential energy diagram for the enantioselective
oxazaborolidine-catalyzed borane reduction of a ketone.
7
0.25
0.5
1
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2
10
case because 96-98% of the ee values were obtained
without free borane in the reduction system at different
temperatures. Now we can conclude that free borane
reduction is an important factor for the temperature-
dependent enantioselectivity in the asymmetric borane
reduction. The highest enantioselectivity is usually reached
at 20-30 °C for longer than the 1 h addition of the
ketone.
1
1
1
1
1
0
1
10
1
1
Rao et al. reported that good enantioselectivity was
obtained only at room temperature and the reaction led
to low enantioselectivity at -78 and +65 °C. They
assumed that the catalyst may not be stable at 65 °C and
the catalyst formation may be slow at -78 °C. In both
cases, free borane reduction may occur at a faster rate,
leading to low enantioselectivity of the product.5i Corey
et al. observed by 11B NMR analysis that the proportion
of the catalyst dimer increases with decreasing tem-
peratures.3a,b Mathre et al. isolated the dimer of the
catalyst 1a by adding excess BH3‚SMe2 to a solution of
(S)-2-(diphenylhydroxymethyl)pyrrolidine in toluene at
room temperature and found it to be not so unstable.12
Stone studied this effect in detail using catalysts 1b,
1c, and 1e and ketones, acetophenone and cyclohexyl
methyl ketone, as models used previously.5b Corey et al.
summarized this effect in their recent comprehensive
review and stated that the coordination of Me2S, THF,
etc., to borane generally did not affect the enantioselec-
tive level except at temperatures below -40 °C, while
free borane reduction affects the enantioselectivity.1d
These elucidations may be reasonable, but there are still
no definite conclusions and convincing experimental
proofs. Here we investigate the abnormal temperature-
dependent enantioselectivity again with a practical and
efficient catalyst 1d and a variety of ketones as model
substrates in the hope of gaining insight into the effect
on different ketones, and we give some useful information
on this effect.
1
1
1
1
a
Equiv of ketone.
1, entries 12-15), and it is improved obviously with the
increasing loading amount of the catalyst (Table 1,
entries 2, 4, and 5 for 0 °C; entries 9 and 16 for 25 °C;
and entries 18 and 20 for 80 °C). A total of 98% of the ee
values was obtained using the stoichiometric catalyst-
borane complex reduction from 0 to 40 °C (Table 1,
entries 5, 16, and 21), and 97% and 96% of the ee values
were obtained under the same conditions at 60 and 80
°C, respectively (Table 1, entries 22 and 20). To figure
out the generality, a series of ketones 2c, 2n , and 2o with
different substituents were also reduced using the sto-
ichiometric catalyst-borane complex, and 98-99% of the
ee values were also obtained (Table 1, entries 23-25).
According to our results, it is obvious that free borane
reduction is an important factor for the temperature-
dependent enantioselectivity in the oxazoborolidine-
catalyzed asymmetric borane reduction.
There are three possible reasons for the low enanti-
oselectivity at high temperature in the asymmetric
reduction. They include free borane reduction, secondary
reduction of the resulting first intermediate monoalkox-
yborane, and high temperatures provided by high energy,
which is higher than the energy barriers of the transition
states (both A and B) for the formation of (S)- and (R)-
alcohols, respectively. The energy barrier of transition
state A is higher than that of B in this asymmetric
reduction (shown in Figure 8). According to our results,
good enantioselectivities were also obtained at high
temperatures, even in refluxing toluene. The catalyst
should be stable and can still keep its enantioselective
ability at high temperatures, even in refluxing toluene.
High energy provided by high temperatures does not
seem to be a major reason for the decreasing enantiose-
lectivity. Secondary reduction is the main reason for the
decreasing enantioselectivity in some cases.10 However,
it does not seem to be a major reason in the current
Buono and his colleagues found that their catalyst (S)-
3,1,2-oxazaboro[3.3.0]octane, derived from prolinol and
borane, showed higher enantioselectivity with increasing
reaction temperatures and the highest enantioselectivity
in refluxing toluene.5a After isolation and NMR studies
of the dimer of the catalyst, they rationalized that the
catalyst favored dimerizing at low temperatures because
of the less steric hindrance on the C4 position, compared
with the catalysts of Corey et al., (S)-2-substituted 4,4-
diphenyl-3,1,2-oxazaboro[3.3.0]octanes 1a -c. The dimer
(12) Mathre, D. J .; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.;
Carroll, J . D.; Corley, E. G.; Grabowski, E. J . J . J . Org. Chem. 1993,
58, 2880-2888. (b) Tlahuext, H.; Contreras, R. Tetraherdon: Asym-
metry 1992, 3, 1145-1148.
J . Org. Chem, Vol. 68, No. 26, 2003 10149

Xu et al.
TABLE 2. Oxa za bor olid in e-Ca ta lyzed Asym m etr ic Bor a n e Red u ction of Keton es
yield
(%)a
ee
entry
ketone
R1
R2
(%)b
[R]20
config.
D
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
n-Bu
n-Am
n-Am
Me
Me
Et
Me
Me
Et
Et
Et
Bu
n-Bu
n-Bu
Me
Me
Et
99
99
98
99
99
97
95
97
95
98
96
99
99
99
95
98c
97c
93c
98d
97d
93e
92e
93e
92e
94e
93e
99f
+34.2 (1.6, MeOH)
+30.8 (1.5, MeOH)
+28.7 (1.8, MeOH)
+37.3 (0.80, CHCl3)
+35.1 (1.3, CHCl3)
+31.3 (2.1, MeOH)
+29.0 (1.7, MeOH)
+27.2 (1.8, MeOH)
+28.6 (2.0, MeOH)
+28.4 (2.2, MeOH)
+23.9 (2.0, MeOH)
+28.3 (1.2, CHCl3)
+24.9 (1.2, CHCl3)
+19.7 (0.90, CHCl3)
+46.6 (0.64, CHCl3)
Rh
Rh
Rh
Ri
n-BuO
n-AmO
n-BuO
n-AmO
n-HexO
n-BuO
n-AmO
n-HexO
n-BuS
n-AmS
n-BuS
Et2N
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Ri
9
10
11
12
13
14
15
>99f
94g
95c
Ri
Rh
Ri
Me
a
b
Isolated yields after column chromatography. ee values were determined by HPLC analysis using AS, OD, or OJ chiral columns
(Chiralcel) and a mixture of n-hexane and 2-propanol as an eluent. c OD column, n-hexane/2-propanol (95:5, v/v). AS column, n-hexane/
d
2-propanol (90:10, v/v). e OJ column, n-hexane/2-propanol (99:1, v/v). f AS column, n-hexane/2-propanol (95:5, v/v). g OD column, n-hexane/
h
2-propanol (99:1, v/v). Configuration was assigned according to the rotation value. In each case, a positive rotation was obtained, indicating
that the selectivity was for the R enantiomer in agreement with the reported work (ref 7, 15, and 16). Configuration was tentatively
i
assumed according to the mechanism and their rotation signs.
catalyst is inactive toward asymmetric reduction because
the Lewis acid character of the boron atom is decreased
by the strong oxygen and nitrogen donors, while when
the reaction temperature was increased, the dimer
showed a tendency to transfer predominately into the
active monomer catalyst, which is responsible for the high
enantioselectivity encountered as the major form in
refluxing toluene.5a The same temperature-dependent
enantioselectivity was also observed in borane (cat-
echolborane) asymmetric reduction of an oxygen-contain-
ing imine, 3,3,3-trifluoro-2-(4-methoxyphenylimino)pro-
pionate, in dichloromethane.13
For the difference between the results of Buono et al.5a
and our results (including Stone’s5b results) on the
temperature-dependent enantioselectivity, Martens et al.
argued against the results of Buono et al. 1 year later.
They could not repeat the results of Buono et al. under
refluxing conditions.14 Thus, there is doubt that the
highest enantioselectivity was obtained under refluxing
toluene. The enantioselctivity shows a turnover between
20 and 40 °C in Stone’s5b and our reduction system. We
rationalized that the difference was caused by the
structure of the catalysts. The catalyst of Buono et al. is
B-unsubstituted and favors dimerizing at low tempera-
tures. For their case, the dimerization of the catalyst is
an important factor in temperature-dependent enanti-
oselectivity. While for Stone’s and our case, free borane
reduction is important to the enantioselectivity at high
temperatures. According to the literature and our results,
a conclusion may be drawn that the enantioselectivity
of oxazaborolidine-catalyzed borane reduction is depend-
ent on both the catalyst structure and the temperature
under the same reduction conditions. For B-unsubsti-
tuted oxazaborolidine catalysts, the enantioselectivity
increases generally with increasing reduction tempera-
tures. While for B-substituted catalysts, the highest
enantioselectivity generally appears between 20 and
30 °C.
A series of ketones with a variety of functional groups
were reduced in high yields along with enantioselectivi-
ties utilizing our optimal catalytic asymmetric reduction
conditions. The results are summarized in Table 2.
Although the effect of temperature on the enantiose-
lectivity has been described many times in the literature,5
no complete explanation has been reported. It is difficult
to provide a straightforward explanation, because the
enantioselectivity of this asymmetric reduction is likely
to be a result of many complex factors, such as the
structure and loading amount of the catalyst, the borane
source and amount, the order and rate of the addition,
the reduction temperature, the solvent, and the additive,
etc. Very recently, Matos et al. found that NaBH4
stabilizer in BH3‚THF can affect enantioselectivity in the
oxazaborolidine-catalyzed asymmetric reduction of
ketones with BH3‚THF as a reductant.17 Our observa-
tions just add another aspect of the reaction and hope in
(15) Su, X. B.; Zhang, Q. H.; Wu, Y. Q.; Xu, J . X. Chin. J . Org. Chem.
2002, 22, 496-500.
(16) Moriuchi, F.; Muroi, H.; Yano, Y. J pn. Kokai Tokkyo Koho J P
01,215,298 (Chem. Abstr. 1990, 112, 117388e).
(17) Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D. R.;
Corella, J . A. J . Org. Chem. 2002, 67, 2970-2976.
(13) Sakai, T.; Yan, F. Y.; Kashino, S.; Uneyama, K. Tetrahedron
1996, 52, 233-244.
(14) Mehler, T.; Behnen, W.; Wilken, J .; Martens, J . Tetraherdon:
Asymmetry 1994, 5, 185-188.
10150 J . Org. Chem., Vol. 68, No. 26, 2003

Oxazaboralidine-Catalyzed Asymmetric Reduction
2H, OCH2), 4.84 (t, J ) 6.3 Hz, 1H, CH), 6.87 (d, J ) 8.4 Hz,
2H, ArH), 7.28 (d, J ) 8.4 Hz, 2H, ArH); 13C NMR (75.5 MHz,
CDCl3) δ 13.85, 19.21, 24.95, 31.29, 67.69, 69.99, 114.39,
126.59, 137.73, 158.54; MS (EI) m/z 194 (M+, 29), 179 (62),
gaining insight into the origin of the temperature effects
on the borane reduction catalyzed by chiral oxazaboro-
lidines.
A survey of the literature reveals that a variety of
conditions have been recommended for the asymmetric
reduction. We hope that the present study has addressed
an important issue regarding the experimental aspects
of the oxazaborolidine-catalyzed asymmetric reduction of
ketones. We recommend that the present optimized
protocol should be valuable for organic chemists inter-
ested in the methodology, especially for chemists working
in the industry of large-scale production of chiral second-
ary alcohols from ketones.
151 (6), 137 (4), 123 (100), 95 (28), 77 (14), 43 (22); IR v (cm-1
)
3379 (OH), 2961, 2933, 1512, 1244. Anal. Calcd for C12H18O2
(194.27): C, 74.19; H, 9.34. Found: C, 73.86; H, 9.18.
(R)-1-(4-Bu tylth iop h en yl)eth a n ol (3l): colorless liquid;
[R]20D ) +28.3 (c 1.2, CHCl3), 99% ee value; 1H NMR (200 MHz,
CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3H), 1.46 (d, J ) 6.0 Hz, 3H),
1.21-1.66 (m, 4H), 2.90 (t, J ) 7.2 Hz, 2H), 4.83 (q, J ) 6.0
Hz, 1H), 7.18-7.28 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 13.6,
21.9, 25.0, 31.2, 33.4, 69.9, 125.9, 129.1, 143.4, 155.0; MS (EI)
m/z 210 (M+, 63), 195 (100), 167 (10), 139 (28), 123 (9), 111
(21), 77 (16), 43 (32); IR v (cm-1) 3373 (OH), 2958, 2928, 1493,
1450, 1094. Anal. Calcd for C12H18OS (210.34): C, 68.52; H,
8.63. Found: C, 68.39; H, 8.60.
Con clu sion
(R)-1-(4-P en tylth iop h en yl)eth a n ol (3m ): colorless liq-
uid; [R]20D ) +24.9 (c 1.2, CHCl3), 99% ee value; 1H NMR (300
MHz, CDCl3) δ 0.89 (t, J ) 7.2 Hz, 3H), 1.22-1.46 (m, 4H),
1.45 (d, J ) 6.3 Hz, 3H), 1.59-1.69 (m, 2H), 2.89 (t, J ) 7.2
The effect of temperature on the enantioselectivity of
the oxazaborolidine-catalyzed asymmetric borane reduc-
tion of ketones has been investigated using alkyl aryl
ketones with a variety of functional groups and (S)-2-
methoxy-4,4-diphenyl-3,1,2-oxazaboro[3.3.0]octane as a
catalyst. The results indicate that the noncatalytic borane
reduction is an important and nonneglectable factor to
the enantioselectivity in the reduction. The highest
enantioselectivities were obtained usually between 20
and 30 °C in the asymmetric reduction.
Hz, 2H), 4.82 (q, J ) 6.3 Hz, 1H), 7.24-7.30 (m, 4H, ArH); 13
C
NMR (75.5 MHz, CDCl3) δ 13.9, 22.2, 25.0, 28.8, 30.9, 33.6,
69.9, 125.9, 128.9, 135.9, 143.3; MS (EI) m/z 224 (M+, 65), 209
(100), 181 (9), 139 (33), 111 (18), 77 (16), 43 (42); IR v (cm-1
)
3357 (OH), 2958, 2928, 1599, 1494, 1094. Anal. Calcd for
C13H20OS (224.36): C, 69.59; H, 8.98. Found: C, 69.60; H, 9.16.
(R)-1-(4-N,N-Dieth yla m in op h en yl)eth a n ol (3o): color-
1
less liquid; [R]20 ) +46.6 (c 0.64, CHCl3), 95% ee value; H
D
NMR (300 MHz, CDCl3) δ 1.14 (t, J ) 6.9 Hz, 6H, 2CH3), 1.45
(d, J ) 6.3 Hz, 3H, CH3), 2.02 (s, br, OH), 3.33 (q, J ) 6.9 Hz,
4H, 2CH2), 4.75 (t, J ) 6.3 Hz, 1H, CH), 6.64 (d, J ) 8.7 Hz,
2H, ArH), 7.20 (d, J ) 8.7 Hz, 2H, ArH); 13C NMR (75.5 MHz,
CDCl3) δ 12.4, 24.5, 44.3, 69.96, 111.6, 126.6, 132.4, 147.2; MS
(EI) m/z 193 (M+, 31), 178 (100), 160 (28), 150 (6), 134 (7), 132
(7), 77 (10), 43 (5); IR v (cm-1) 3389 (OH), 2970, 1614, 1521,
1265. Anal. Calcd for C12H19NO (193.29): C, 74.57; H, 9.91;
N, 7.25. Found: C, 74.33; H, 9.60; N, 7.17.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Asym m etr ic Red u ction of
Keton es. To a solution of (S)-2-(diphenylhydroxymethyl)-
pyrrolidine (12.5 mg, 0.05 mmol) in dry toluene (2.5 mL) was
added trimethyl borate (6.0 mg, 0.06 mmol), and the mixture
was stirred under a nitrogen atmosphere at room temperature
for 2 h. After a 2 M borane-dimethyl sulfide complex in THF
(0.25 mL, 0.5 mmol) was added, a solution of ketone (0.5 mmol)
in dry toluene (2.5 mL) was added dropwise over 1 h (25 min
for the tracing conversion). The mixture was stirred at 25-30
°C (at the desired temperature for the tracing conversion) until
the ketone disappeared on GC monitoring. The resulting
mixture was quenched with methanol in an ice bath and
concentrated under reduced pressure. The residue was purified
on a silica gel column with a mixture of petroleum ether (60-
90 °C) and ethyl acetate (5:1, v/v) as an eluent to give a
colorless oil chiral secondary alcohol.
Ack n ow led gm en t. This work was supported in part
by the National Natural Science Foundation of China
(Project No. 20272002), Ministry of Education of China
(SRF for ROCS and EYTP), and Peking University
(present grant). The authors thank the reviewers’ help-
ful suggestions.
Su p p or tin g In for m a tion Ava ila ble: The chromatograms
for the determination of ee of the unknown chiral alcohols 3d ,
3l, 3m , and 3o and their 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(R)-1-(4-Bu toxyp h en yl)eth a n ol (3d ): colorless liquid;
[R]20 ) +37.3 (c 0.80, CHCl3), 98% ee value; 1H NMR (300
D
MHz, CDCl3) δ 0.94 (t, J ) 7.5 Hz, 3H, CH3), 1.47 (d, J ) 6.3
Hz, 3H, CH3), 1.49 (sextet, J ) 7.5 Hz, 2H, CH2), 1.76 (quintet,
J ) 7.5 Hz, 2H, CH2), 1.84 (s, br, 1H, OH), 3.95 (t, J ) 6.6 Hz,
J O035203V
J . Org. Chem, Vol. 68, No. 26, 2003 10151