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Chemistry Letters Vol.38, No.7 (2009)
Enantioselective Reduction of Aliphatic Ketones Using Oxazaborolidine Catalyst Generated
In Situ from Chiral Lactam Alcohol and Phenoxyborane
Yasuhiro Kawanami,Ã Yudai Mikami, Katsuhiro Hoshino, Mikiko Suzue, and Izumi Kajihara
Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kagawa 761-0795
(Received May 7, 2009; CL-090434; E-mail: kawanami@ag.kagawa-u.ac.jp)
Oxazaborolidine catalyst generated in situ from chiral lac-
tam alcohol 3 and p-iodophenoxyborane at room temperature
was found to catalyze the enantioselective borane reduction of
various prochiral aliphatic ketones at À20 ꢀC with high enantio-
selectivity up to 98% ee.
Table 1. Asymmetric reduction of benzylacetone using 2 or 3a
Ar
Ar
O
N
H
OH
(10 mol%)
BH3-THF, R-OH
O
OH
The asymmetric synthesis of enantiomerically pure secon-
dary alcohols has exceedingly become important in modern syn-
thetic chemistry because chiral secondary alcohols are involved
in many natural products and are important synthetic intermedi-
ate for converting to various other functionalities. Oxazaboroli-
dine-catalyzed asymmetric borane reduction of prochiral ke-
tones (CBS reduction) is one of the most efficient methods for
the synthesis of chiral secondary alcohols with predictable abso-
lute stereochemistry and, therefore, has been extensively inves-
tigated since the reports of Itsuno et al.1 and Corey et al.2
As an alternative method, we have already reported that the
oxazaborolidine catalyst could be generated in situ from chiral
lactam alcohol 2 (Figure 1) and BH3–THF at room temperature,
and the resulting oxazaborolidine was found to catalyze the bo-
rane reduction of various ketones with high enantioselectivities
up to 98% ee.3 This reduction method has also an advantage that
the lactam alcohol 2 is stable, inexpensive, and easy to handle
compared to Me-CBS. Although the reduction of most aromatic
ketones proceeded with high enantioselectivities, those of ali-
phatic ketones are generally moderate except for tertiary alkyl
ketone (pinacoline: 1a, 94% ee;3 1b, 97% ee2). For example,
the enantioselectivity in the reduction of benzylacetone as a pri-
mary aliphatic ketone catalyzed by 1a generated in situ from 2
and BH3–THF is only 69% ee and that of Me-CBS 1b is also
64% ee under the same reaction conditions. Thus, the develop-
ment of catalytic enantioselective reduction of aliphatic ketones
is a challenging problem. In this communication, we describe a
practical enantioselective reduction of aliphatic ketones using
chiral lactam alcohol 3 and p-iodophenoxyborane.4
Entry
Ar
R
Yield/%b ee/%c Config.d
1
2
3
4
5
6
7
8
9
Ph
3,5-Me2Ph
—
—
Me
i-Pr
90
88
90
89
86
74
88
85
81
86
69
75
64
69
71
69
70
72
73
79
R
R
R
R
R
R
R
R
R
R
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MeOPh
p-CF3Ph
p-BrPh
p-IPh
p-IPh
10 3,5-Me2Ph
aAll reactions were carried out with 10 mol % of 2 or 3 and
1.2 equiv of BH3–THF and ROH at room temperature.
bIsolated yield. cDetermined by HPLC analysis using a
Chiralcel OD column. dDetermined by comparison of optical
rotation with the literature value, Ref. 7.
ity of CBS reduction via the B–OMe oxazaborolidine 1c. First,
we examined the substituent effect of boron of oxazaborolidine
on the enantioselectivity in the reduction of aliphatic ketones. A
BH3–THF solution was added dropwise to various alcohols or
phenols in THF and stirred for 30 min at room temperature, at
which time the evolution of H2 was observed. Chiral lactam
alcohol 2 or 36 (10 mol %) was then added to the alkoxy- or
phenoxyborane solution and stirred further for 1 h. The reduction
was carried out by the slow addition of benzylacetone as an ali-
phatic ketone to the resulting oxazaborolidine catalyst, provid-
ing the corresponding secondary alcohols in good yield. The
results are summarized in Table 1.
Although addition of methanol and isopropanol showed no
enhancement in ee (Entries 3 and 4), addition of phenols afford-
ed slightly higher enantioselectivity depending on the electron-
withdrawing ability (70–73% ee, Entries 5–9) and the use of
p-iodophenol was found to be the best. These results suggest that
p-iodophenoxy oxazaborolidine should be more Lewis acidic
and sterically most bulky among them and therefore, would en-
hance the reactivity and enantioselectivity. Furthermore, chiral
lactam alcohol 3 that is more bulky than 2 significantly increased
the enantioselectivity from 73 to 79% ee (Entries 9 and 10).
When p-iodophenol was added to the reduction intermediate
of 3 and BH3–THF, the enantioselectivity was considerably de-
creased. This result supports that the reduction of 3 with p-iodo-
phenoxyborane would be suitable to generate B–OAr oxaza-
To improve the enantioselectivity in the reduction of ali-
phatic ketones with moderate enantioselectivities, we suppose
that electron-withdrawing and bulky substituent on boron of
oxazaborolidine catalyst should enhance the reactivity and
enatioselectivity because Masui and Shioiri5 reported that tri-
methyl borate could improve the reactivity and enantioselectiv-
Ph
O
Ar
Ph
Ar
OH
O
N
R
N
H
B
2 Ar = Ph
3 Ar = 3,5-Me2Ph
1a R = H
1b R = Me
1c R = OMe
Figure 1.
Copyright Ó 2009 The Chemical Society of Japan
Kawanami, Yasuhiro
