Enantioselective reduction of α-keto esters to 1,2-diols using the NaBH4/Me3SiCl system catalyzed by polymer-supported chiral sulfonamide

Article abstract of DOI:10.1016/j.tetasy.2004.01.009

In the presence of 25mol% of a polymer-supported chiral sulfonamide, a variety of α-keto esters can be reduced into the corresponding 1,2-diols in good yields and high enantioselectivities using the NaBH₄/Me ₃SiCl reducing system.

Full text of DOI:10.1016/j.tetasy.2004.01.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 807–810
Enantioselective reduction of a-keto esters to 1,2-diols using the
NaBH4/Me3SiCl system catalyzed by polymer-supported
chiral sulfonamide
Guang-yin Wang, Jian-bing Hu and Gang Zhao*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 20 November 2003; revised 7 January 2004; accepted 8 January 2004
Abstract—In the presence of 25 mol % of a polymer-supported chiral sulfonamide, a variety of a-keto esters can be reduced into the
corresponding 1,2-diols in good yields and high enantioselectivities using the NaBH4/Me3SiCl reducing system.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
thesis of optically active secondary alcohols. Herein, we
report the enantioselective synthesis of optically active
1,2-diols by the polymer-supported sulfonamide cata-
lyzed asymmetric reduction of a-keto esters.
Optically active terminal 1,2-diols are versatile and
important chiral building blocks in organic synthesis1
and have found numerous applications as chiral auxil-
iaries or ligands for asymmetric synthesis.2 Many meth-
ods aimed at the enantioselective synthesis of these
compounds have been reported, such as the asymmetric
dihydroxylation of olefins,3 reduction of a-hydroxy
ketones protected as their silylethers in a CBS system,4
and many biological transformations.5 However some of
these cases suffer from inherent drawbacks: For example,
dihydroxylation involves the use of toxic OsO4,3 while
the CBS-oxazaborolidine-catalyzed borane reduction of
protected a-hydroxy ketones needs two extra steps of
protection and deprotection.4 Thus, the development
of an efficient, economical and environmentally friendly
methodology for the synthesis of optically active 1,2-
diols is still required. In the past decade, several groups
have reported the preparation and application of poly-
mer-supported catalysts derived from chiral amino
alcohols for enantioselective reduction.6 Recently, we
have developed a new class of polymer-supported sul-
fonamides and applied them to the enantioselective
2. Results and discussion
As shown in our previous papers, the enantioselective
reduction of prochiral ketones and b-keto sulfones with
NaBH4/Me3SiCl can be achieved with optimal results
when the reactions were carried out in refluxing THF
with 25 mol % polymer-supported sulfonamide 1 (200–
400 mesh, 2% DVB, 2.29 mmol/g N) as the catalyst.9
Under these same reaction conditions, we first examined
the effect of the amount of the reducing system on the
reduction of phenyl-glyoxylic acid ethyl ester using
25 mol % of catalyst 1. In this study, when using an
amount of NaBH4/Me3SiCl less than 3 equiv to the
substrate, the reaction would not go to completion.
Surprisingly, under our experimental conditions we
obtained the product 1-phenyl-ethane-1,2-diol instead of
the desired a-hydroxy ester. The amount of the reducing
agent used had no influence on the enantioselectivity
(Table 1).
7
reduction of prochiral ketones via BH3ÆSMe2 or
NaBH4/Me3SiCl (or BF3ÆOEt2).8 In these studies we
found that the reducing systems of NaBH4/Me3SiCl and
NaBH4/BF3ÆOEt2 could provide an efficient, economical
and environmentally friendly methodology for the syn-
To extend this synthetic procedure to the preparation of
1,2-diols, we investigated further the reaction of a vari-
ety of a-keto esters (Table 2). The reductions afforded
the corresponding 1,2-diols in good to excellent chemi-
cal yields. It is noteworthy that aromatic a-keto esters
were reduced with excellent enantioselectivities (94–98%
* Corresponding author. Fax: +86-021-64166128; e-mail: zhaog@
mail.sioc.ac.cn
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.009

808
G. Wang et al. / Tetrahedron: Asymmetry 15 (2004) 807–810
Table 1. The effect of the amount of the reducing agent on the
asymmetric reactiona
enantioselectivity (Table 2, entries 6–10). Interestingly,
the ester groups R2 have little effect on the enantio-
selectivity. Although the yields decreased, different
substrate 2a–d having R2 ranging from methyl to tert-
butyl all reacted smoothly to give the same diol with the
ee over 95% (Table 2, entries 1–4). The reduction of 4-
tolyl-glyoxylic acid ester 2j and 3-tolyl-glyoxylic acid
ester 2k provided the corresponding diols in 95% and
93% ee, respectively, in contrast to 75% ee for 2-tolyl-
glyoxylic acid ester 2l (Table 2, entries 10–12). These
results indicate that the asymmetric induction was sen-
sitive to the steric effects of the substituent proximal to
carbonyl group. This is a common phenomenon in
oxazaborolidine-catalyzed reductions.4 In the case of
aliphatic analogues, the asymmetric reduction of the
a-keto esters 2m–p afforded somewhat lower enantio-
selectivities compared with those obtained from aro-
matic analogues (Table 2, entries 13–16). Notably higher
enantioselectivities were obtained when the reaction
occurred at the more hindered carbonyl group (Table 2,
entry 13). In the same reduction system, a-keto acid 2e
was also reduced to give diol 4 in 78% yield, but the
enantioselectivity proved unsatisfactory, being only 15%
ee (Table 2, entry 5).
Ph
cat.1 (25mol%)
NaBH4/Me3SiCl
OH
H
OEt
OH
O
Ph
THF, reflux
O
O2S N
HO
cat.1
Ph Ph
Entry
NaBH4/Me3SiCl
(mmol)
Yield (%)b
Ee (%)c
1
2
3
4
1.2/1.2
2.0/2.0
3.0/3.0
3.5/3.5
20
56
83
82
96
96
96
96
a The substrate was reduced on the 1 mmol scale; molar ratio: a-keto
ester/NaBH4/Me3SiCl/cat. ¼ 1/1.2–3.5/1.2–3.5/0.25.
b Isolated yield after column purification.
c Determined by chiral HPLC with a Chiralcel OB column.
ee). To gain insight into the effect of the electron density
of the aromatic ring, a series of a-keto esters bearing a
different substituents at the para position on the phenyl
group was studied. The results show that the electron
density of the aromatic rings has little effect on the
Under the above optimal reaction conditions, homoge-
neous sulfonamide 15 promoted the reduction of phe-
nyl-glyoxylic acid ethyl ester to give 84.4% ee––less than
the polymer-supported sulfonamide 1 (Table 2, entry 1),
Scheme 1.
Table 2. Asymmetric reduction of a-keto esters or acida
R1
1 ( 25mol%)
NaBH4/Me3SiCl
OH
OR2
H
R1
OH
O
THF, reflux
O
2a-p
3-14
Entry
R1
R2
a-Keto esters
Diols
Yield (%)b
Ee (%)c
Config.f
1
Ph
Ph
Et
2a
2b
2c
2d
2e
2f
3
3
83
87
74
53
78
94
67
62
67
75
71
76
88
86
71
46
40
60
96
95
97
95
15
97
98
94
95
95
93
75
94d
62d
45d
42
23
86e
S
S
S
S
S
S
S
S
S
S
––g
S
S
S
S
S
S
S
2
Me
i-Pr
t-Bu
OH
Et
3
Ph
Ph
3
4
3
5
Ph
3
6
p-F–C6H4
p-Cl–C6H4
p-Br–C6H4
p-MeO–C6H4
p-Me–C6H4
m-Me–C6H4
o-Me–C6H4
t-Bu
4
7
Et
Et
2g
2h
2I
2j
5
8
6
9
Et
Et
7
10
11
12
13
14
15
16
17
18
8
Et
Et
2k
2l
9
10
11
12
13
13
13
14
Et
Et
2m
2n
2o
2p
2q
2r
PhCH2CH2
n-Bu
n-Bu
Et
i-Pr
t-Bu
Et
n-Bu
c-Hex
a Experiments were performed on a 1 mmol scale; molar ratio: a-keto esters/NaBH4/Me3SiCl/cat. ¼ 1/3/3/0.25.
b Isolated yield after column purification.
c Determined by chiral HPLC.
d Analytical samples were converted to phenylcarbamates.
20
D
20
D
e Determined by comparison of specific rotations, ½aꢀ ¼ +4.45 (c 1.068, CHCl3)/½aꢀ (lit.4) ¼ +4.9 (c 1.05, CHCl3, 96% ee).
f The absolute configurations were determined by comparison with reported specific rotations.
g The absolute configuration was not determined.

G. Wang et al. / Tetrahedron: Asymmetry 15 (2004) 807–810
OH
809
2 (25mol%)
Ph
O
H
Ph
NaBH4/Me3SiCl
OH
OH
OEt
O
N S
Ph
Ph
Ph
O
Ph
THF
reflux
O
H
89% yield, 84.4% ee
B
O
THF
cat.1
O
S
H
NaBH4+ Me3SiCl
BH3 THF
O
N
Ph
O2S
HO
N
Ph
Ph
N
O
H
B
O
S
H
O
H
B
O
O
Ph Ph
-
O
H
5
R1
R1
O
Scheme 1.
OR2
OR2
It is noteworthy that after the reduction was complete,
the polymer-supported sulfonamide 1 could be recov-
ered by simple filtration followed by washings with
water and ethyl acetate. Recycling of the chiral polymer
catalyst was tested by the reduction of phenyl-glyoxylic
acid ethyl ester (Table 3). The results showed that the
chiral polymeric catalyst could be reused at least five
times with little or no loss of performance.
H
OH
H-
O
B
R1
O
R1
OH
H
OR2
Scheme 2.
phenone ketyl before use. a-Keto esters were prepared
according to the reported procedure.
Table 3. The recycling of polymeric catalyst
O
1 (25mol%)
H
OH
OH
NaBH /Me3SiCl
4
OEt
Ph
THF
reflux
Ph
4.1. Typical procedure for the asymmetric reduction of
a-keto esters
O
Run
Yield (%)a
Ee (%)b
Me3SiCl (0.42 mL, 3.2 mmol) was added to a suspension
of NaBH4 (121 mg, 3.2 mmol) in THF (10 mL). The
suspension was heated under reflux and stirred for 1 h.
The polymeric catalyst 1 (106 mg, 0.25 mmol) was then
added and the reaction mixture heated under reflux for
another 0.5 h. Then a THF (10 mL) solution of phenyl-
glyoxylic acid ethyl ester (158 mg, 1 mmol) was added at
a rate of 3 mL/h by syringe pump. After the addition
was complete, the mixture was treated with water
(10 mL) and filtered. The polymeric catalyst was washed
several times with EtOAc and water. The resulting
aqueous solution was extracted with EtOAc (3 · 15 mL)
and dried over Na2SO4. The solution was evaporated
and purified by silica gel chromatography (eluent:
1
2
3
4
5
77
77
74
76
73
95.1
94.4
95.2
94.6
95.2
a Isolated yield after column purification.
b Determined by chiral HPLC.
Although the reaction mechanism is not exactly clear, a
possible mechanism for the reduction of a-keto esters
was proposed according to the reduction of a-hydroxy
esters with borane-dimethyl sulfide and catalytic sodium
tetrahydroborate (Scheme 2).10
V
Hexane/VEtOAc ¼ 1/1) to give a white solid (128 mg, 83%
yield): 1H NMR (300 MHz, CDCl3): d 2.51 (1H, s), 2.93
(1H, s), 3.64–3.75 (2H, m), 4.81 (1H, dd, J ¼ 2:8 and
7.8 Hz), 7.26–7.36 (5H, m); IR: 3235 cmꢁ1 (br, 2OH).
3. Conclusion
Anal. Calcd for C8H10O2: C, 69.55; H, 7.30. Found: C,
20
D
In conclusion, the results reported here offer a practical
and highly enantioselective methodology for the syn-
thesis of optically active 1,2-diols. Due to the efficiency,
low cost and high enantioselectivity observed, this
method represents a very useful alternative to previously
reported procedures.
69.53; H, 7.34. ½aꢀ ¼ +69.5 (c 1.025, CHCl3) {lit.9
20
½aꢀ ¼ +71.9 (c 1.04, CHCl3)}. The enantiomeric excess
D
was determined to be 96% by Chiralcel OB column
chromatography (eluent: VHexane/Vi-PrOH ¼ 9/1).
Acknowledgements
4. Experimental
We are grateful to the Ministry of Sciences and Tech-
nology, the State Key Project of Basic Research (Project
973, No. G 2000048007) and the National Natural Sci-
ence Foundation of China for financial support.
All reactions were carried out under a dry Ar atmo-
sphere. THF was freshly distilled over sodium/benzo-

810
G. Wang et al. / Tetrahedron: Asymmetry 15 (2004) 807–810
6. (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem.
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