Highly enantioselective reduction of ketones by chiral diol-modified lithium aluminum hydride reagents

Article abstract of DOI:10.1016/j.tetlet.2005.11.062

Some readily available chiral diols from indene and d-mannitol were investigated as chiral modifiers in lithium aluminum hydride reduction of ketones, and it was discovered that further modification of these reducing reagents by a simple a-amino alcohol resulted in a remarkable increase in optical yield. Among the investigated chiral modifiers, chiral diol 1 gave the highest enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2005.11.062

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 463–465
Highly enantioselective reduction of ketones by chiral
diol-modified lithium aluminum hydride reagents
a,b
c
a
a,b
a,
a
*
Yunlai Ren, Xinzhe Tian, Kunpeng Sun, Jian Xu, Xianlun Xu and Shijie Lu
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, 342 Tianshui Road, Lanzhou 730000, China
b
Graduate School of Chinese Academy of Sciences, Beijing 100039, China
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
c
Received 1 November 2005; accepted 11 November 2005
Available online 29 November 2005
Abstract—Some readily available chiral diols from indene and D-mannitol were investigated as chiral modifiers in lithium aluminum
hydride reduction of ketones, and it was discovered that further modification of these reducing reagents by a simple a-amino alcohol
resulted in a remarkable increase in optical yield. Among the investigated chiral modifiers, chiral diol 1 gave the highest
enantioselectivities.
Ó 2005 Elsevier Ltd. All rights reserved.
Asymmetric reduction of prochiral ketones offers an
especially attractive entry to enantiomerically pure sec-
ondary alcohols. In this field, some reagents have been
yield. Among the investigated chiral modifiers, chiral
diol 1 gave the highest enantioselectivities.
1
elaborated by the modification of LiAlH with alka-
Chiral diols 1–5 (Fig. 1) were readily obtained in one or
4
2
3
4
loid, sugars, and amino alcohols. In spite of the
numerous chiral auxiliaries available for asymmetric
lithium aluminum hydride reduction of ketones, only
three steps by standard procedures described in previous
8
literatures from commercially available indene or D-
9
mannitol. The chiral diol 1 has an interesting configura-
5
6
binaphthol (BINOL) and spiro[4,4]nonane-1,6-diol
tion and its key feature is that it possesses two phenyl
rings, which restrict its conformational flexibility. The
four stereogenic carbon centers in the backbone dictate
the orientation of the phenyl rings, and the structure is
similar to that of the axially dissymmetric BINOL
are satisfactorily employable. However, costliness of
these chiral auxiliaries always restricts their applications
in industries. Therefore, the search for new, effective and
inexpensive chiral auxiliaries is still an important
pursuit.
8
according to their molecular models.
Our interest has been focused on synthesis and applica-
tions of some chiral products from readily available nat-
ural substances, which mainly include carbohydrate
We first tested the effectiveness of the chiral diol 1 as
chiral modifier in asymmetric lithium aluminum hydride
reduction of acetophenone (Table 1, entries 1–4). With-
out further modification of this reagent by a simple
a-amino alcohol, only 14% ee was obtained. The disap-
pointing low level of asymmetric induction prompted us
to examine further modification of the reagent by a sim-
ple a-amino alcohol. Fortunately, when a simple alcohol
(N,N-dimethylethanolamine) was used, the result of the
reaction was excellent, and afforded optically active sec-
ondary alcohols with 93% ee. As bulkiness of alkyl
group attached to the amino group increased, both the
yield and enantioselectivity remarkably decreased,
which probably resulted from coordination of the amino
group to aluminum atom in the possible transition states
7
derivatives. In this letter, we report asymmetric reduc-
tion of ketones by using complexes of LiAlH with some
4
chiral diols from commercially available indene and D-
mannitol, and it was discovered that further modifica-
tion of these reducing reagents by a simple a-amino
alcohol resulted in a remarkable increase in optical
Keywords: Asymmetric reduction; Ketone; Diol; Lithium tetrahydrido-
aluminate.
*
Corresponding author. Tel.: +86 09314968217; fax: +86
9318277088; e-mail: xlxu@ns.lzb.ac.cn
0
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.062

464
Y. Ren et al. / Tetrahedron Letters 47 (2006) 463–465
R
O
O
O
O
OH
OH
O
OH
OH
OH
O
OH
H
H
H
O
HO
R
O
O
H
2
R = Ph
HO
O
1
3 R = p-MeO-Ph
4
5
Figure 1. Chiral diols used in asymmetric lithium aluminum hydride reduction of ketones.
a
4
Table 1. Asymmetric reduction of ketones by using complexes of LiAlH with chiral diol and a-amino alcohol
b
Entry
Diol
Ketone
a-Amino alcohol
Yield (%)
ee (%)
Confign
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
5
PhCOCH
PhCOCH
PhCOCH
PhCOCH
PhCO-n-C
PhCOCH(CH
PhCOC(CH
2-Naphth-COPh
p-Cl-PhCOCH
p-MeO-PhCOCH
3
3
3
3
3
100
89
83
42
86
94
93
91
81
81
85
92
78
67
88
92
14
93
84
75
96
88
83
98
76
94
18
60
23
35
12
67
S
S
S
S
S
S
S
S
S
S
R
R
S
S
S
R
(Me)
(Et) NC
(i-Bu) NC
2
NC
H
2 4
2
H
4
OH
OH
OH
2
2
2
H
4
4
H
9
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
(Me)
2
2
2
2
2
2
2
2
2
2
2
2
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
2
2
2
2
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
4
4
4
4
4
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
3 2
)
3 3
)
3
1
1
1
1
1
1
1
0
1
2
3
4
5
6
n-C
n-C
4
H
H
9
COCH
17COCH
3
8
3
2-Naphth-COPh
2-Naphth-COPh
2-Naphth-COPh
2-Naphth-COPh
a
Reaction conditions are shown in Ref. 11.
The absolute configuration was determined by optical rotation (Refs. 9 and 10).
b
6
or 7 (Fig. 2). The coordination of the amino group to
enantioselectivity. 4-Chloroacetophenone 33 only gave
76% ee, while 4-methoxyacetophenone gave 94% ee.
Asymmetric reduction of some dialkyl ketones was also
investigated, but disappointing results were obtained.
aluminum center probably accelerates the dissociation
of the hydrogen from aluminum, and simultaneously
accelerates the transfer of the hydrogen from aluminum
to carbonyl carbon. So increasing bulkiness of amino
group would hold back the coordination of amino
group to aluminum, and then results in a decrease of
the yield.
Above behaviors are slightly inconsistent with the litera-
5
ture reports, where chiral binaphthol was used as chi-
ral modifier in the reduction of alkyl phenyl ketones,
and it was found that bulkiness of alkyl group had a
remarkable effect on the enantioselectivity of the reac-
tion. However, in this letter, this kind of steric effects
are unobvious. It probably results from more flexible
configuration of the chiral diol 1 compared with BI-
NOL, the flexible configuration would be expected to
produce more complicated transition states. Moreover,
it is puzzling that asymmetric reduction of 2-naphthyl
phenyl ketone gave secondary alcohol with high enantio-
selectivity, which is almost the same as the results of
asymmetric reduction of alkyl phenyl ketones. So far,
according to the results in Table 1, we cannot affirm
the mechanism of this reaction because this reaction is
influenced by steric effects and various electronic factors.
In addition, in the possible transition states for this reac-
tion, the carbonyl function may coordinate to Li or Al
atom (Fig. 2). A further investigation of the mechanism
is underway.
A series of other ketones were then used to test the
asymmetric inductive capability of the chiral auxiliary
1
(Table 1, entries 5–12). With alkyl phenyl ketones,
the optical yield enhanced gradually in going from ace-
tophenone to the ketone bearing a long primary alkyl
group, and then decreased slightly as the bulkiness of
alkyl group increased. On the other hand, the substituent
attached to phenyl group has a remarkable effect on the
Rs
Rs
O
Al
H
Ph
O
O
N
H
Ph
O
O
Al
R
R
N
Li
O
O
R
R
O
6
7
Among the above results, 2-naphthyl phenyl ketone
gave the highest enantioselectivity (entry 8), so this sub-
strate was then used to test asymmetric inductive capa-
Figure 2. Two of the possible transition state models for the reduction
of alkyl phenyl ketones by chiral diol 1-modified lithium aluminum
hydride reagent.

Y. Ren et al. / Tetrahedron Letters 47 (2006) 463–465
465
bility of the chiral modifiers 2–5 (entries 13–16). With
chiral diol 2, a optical yield of 23% was obtained, while
the optical yield is up to 12%, as described in the previ-
Jacquet, I.; Vigneron, J. P. Tetrahedron Lett. 1974, 15,
2
065–2068; (d) Vigneron, J. P.; Jacquet, I. Tetrahedron
1
976, 32, 939–944; (e) Terashima, S.; Tanno, N.; Koga, K.
9
Chem. Lett. 1980, 981–984.
ous paper, in asymmetric reduction of some alkyl phen-
5
6
. (a) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M.
J. Am. Chem. Soc. 1984, 106, 6709–6716; (b) Noyori, R.;
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yl ketones or dialkyl ketones. Chiral diols 3–5 were also
used as auxiliaries in asymmetric reduction of 2-naph-
thyl phenyl ketone, but disappointing results were
obtained.
In conclusion, in this letter, some readily available chiral
diols from indene and D-mannitol were investigated as
chiral modifiers in lithium aluminum hydride reduction
of ketones, and it was discovered that the addition of
a simple a-amino alcohol resulted in a remarkable
increase in optical yield. Among the investigated chiral
modifiers, chiral diol 1 gave the highest enantioselectiv-
ities. In spite of the excellent enantioselectivities, it is
useful to search for readily available and inexpensive
reagents in enantioselective reduction.
7. (a) Zhou, H. Y.; Hou, J. G.; Chen, J.; Lu, S. J.; Fu, H. X.;
Wang, H. Q. J. Organomet. Chem. 1997, 543, 227–228; (b)
Zhou, H. Y.; Lu, S. J.; Hou, J. G. Chem. Lett. 1996, 339–
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(
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Acknowledgements
1
0. (a) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.;
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Chem. 1973, 38, 1870–1877.
The authors wish to thank National Nature Science
Foundation of China (No. 29933050) for financial
support.
1
1. In a typical experimental procedure, a-amino alcohol
(0.6 mmol) and chiral diol (0.6 mmol) were added to a
stirred solution of LiAlH4 (0.6 mmol) in diethyl ether
(4 mL) at room temperature. After 2 h, this solution was
cooled to À78 °C, a diethyl ether solution (0.5 mL) of
0.2 mmol of ketone was dropwise added. After the
reaction mixture was stirred for 10 h, the excess hydride
was decomposed by the dropwise addition of water at
À78 °C. Diethyl ether was removed under reduced
pressure, then the residue was dissolved in 6 N HCl and
extracted with diethyl ether. The organic layer was
References and notes
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(
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dried over Na SO . The yield and ee were determined by
GC with a chiraldex capillary column or HPLC with a
Daicel chiracel OD-H column.
2
4