Enantio- and chemoselective Br?nsted-acid/Mg(nBu) 2 catalysed reduction of α-keto esters with catecholborane

Article abstract of DOI:10.1039/c4cc00427b

The first enantio- and chemoselective Br?nsted-acid catalysed reduction of α-keto esters with catecholborane has been developed. The α-hydroxy esters were obtained under mild reaction conditions in virtually quantitative yields and excellent enantioselectivities. With slight modifications both enantiomers can be obtained without any loss of selectivity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00427b

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Enantio- and chemoselective Brønsted-acid/Mg(nBu)2
catalysed reduction of a-keto esters with
catecholborane†
Cite this: Chem. Commun., 2014,
50, 4489
Received 17th January 2014,
Accepted 4th March 2014
Dieter Enders,* Bianca A. Stockel and Andreas Rembiak
¨
DOI: 10.1039/c4cc00427b
www.rsc.org/chemcomm
The first enantio- and chemoselective Brønsted-acid catalysed acid catalysts and catecholborane. We started our investigations by
reduction of a-keto esters with catecholborane has been developed. screening several Brønsted acids 4 for the reduction of the com-
The a-hydroxy esters were obtained under mild reaction conditions mercially available ethyl benzoylformate (1a) at room temperature
in virtually quantitative yields and excellent enantioselectivities. With (Table 1). Although first attempts with the phenyl substituted acid
slight modifications both enantiomers can be obtained without any 4a were not very promising, the desired a-hydroxy ester 2a was
loss of selectivity.
obtained in high yield and moderate selectivity of 61% ee with
stronger acids 4b and 4c (Table 1, entries 1–3). Increasing the steric
Enantiomerically pure a-hydroxy acids and their derivatives are demand of the aryl substituents on the BINOL backbone using
an important class of substances and play a significant role as catalysts 4d and 4e caused the enantioselectivity to decrease
chiral building blocks in the pharmaceutical and the chemical
industry.1 Therefore various synthetic methods have been
Table 1 Evaluation of the chiral Brønsted acids 4a
developed including enzymatic and biomimetic methods,2
Cannizzaro reactions,3 Friedel–Crafts reactions,4 kinetic resolutions5
and the synthesis of cyanohydrins as precursors.6 However, the
most convenient method for the asymmetric synthesis of a-hydroxy
esters is the reduction of prochiral a-keto esters by chiral boranes,7
diastereoselective reductions with chiral auxiliaries,8 homogeneous
hydrogenations and hydrogen transfer reactions9 as well as
heterogeneous enantioselective hydrogenations.10 Although
achiral boranes are widely used in the CBS-reduction of ketones
and trichloromethyl ketones,11 they have not been applied to
multifunctionalized substrates so far. Despite its high reactivity,
catecholborane shows a significant tolerance for several functional
groups like esters, sulfonates, and even terminal alkenes,12 but its
tremendous potential in the field of asymmetric catalysis has not
been recognized for a long time.13 To the best of our knowledge no
asymmetric reduction of a-keto esters employing an achiral borane
Entry
Catalyst
Yieldb (%)
eec (%)
has been developed so far without requiring toxic transition metals.
Recently we have developed the asymmetric reduction of imines
and a-imino esters by chiral BINOL based phosphorylborates and
catecholborane.14 Herein we want to describe the first transition
metal-free reduction of a-keto esters employing chiral phosphoric
1
2
3
4
5
6
7
8d
4a
4b
4c
4d
4e
4f
5
93
94
91
22
56
56
94
—
61
65
23
À33
À87
37
4g
4f
73
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany. E-mail: enders@rwth-aachen.de; Fax: +49 241-809-2127
† Electronic supplementary information (ESI) available. Experimental proce-
dures, characterization data of all products, 1H and 13C NMR spectra, and HPLC
chromatograms. See DOI: 10.1039/c4cc00427b
a
The reaction was conducted on a 0.1 mmol scale of 1a in 1.0 mL of
b
toluene. Yield of isolated 2a after flash column chromatography.
c
d
Determined by HPLC analysis on a chiral stationary phase. Catalyst
not washed with HCl after purification by flash column chromatography.
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dramatically to 23% ee and 33% ee, respectively, however, with only gave only moderate results, only the aromatic non-polar solvents
a low yield of 22% and a change in the absolute configuration of 2a were assumed to be beneficial. By increasing the hydrophobic
(Table 1, entries 4 and 5). Finally, the best results were obtained character of the solvent we achieved an enantioselectivity of
with the more sterically demanding acid 4f, furnishing the 82% with o-xylene and finally 87% ee accompanied by almost
a-hydroxy ester 2a in 87% ee and moderate yield of the opposite quantitative yield by performing the reaction in mesitylene at
enantiomer.
room temperature. Lowering the reaction temperature to 0 1C
Changing to the more acidic and thus more reactive triflylamide was ineffective leading to a slightly lower selectivity of 86% ee.
4g was ineffective (Table 1, entries 6 and 7). Interestingly, the use of With the optimized reaction conditions in hand we finally
acid 4f contaminated with metal salt impurities gave very good examined the substrate scope of the enantioselective, Brønsted-
results with an excellent yield and good enantioselectivity of 73% acid catalysed reduction of a-keto esters (Table 4). Various
ee. Since phosphoric acid metal salts have already been reported to electron-rich as well as electron-deficient aromatic a-keto esters
be effective in numerous organic transformations15 we investigated with different substitution patterns were reduced with excellent
the influence of several main group metal sources in our reduction enantioselectivities and in almost quantitative yields. The
(Table 2). Among the most common main group metals tested in absolute configuration has been determined to be (S) by
our reduction magnesium showed the best results in terms of yield comparing the optical rotation values of the a-hydroxy esters
with an enantioselectivity of 16% ee (Table 2, entry 4). Because the 2a–d, 2p and 2w with those reported in the literature. While the
selectivity of the pure phosphoric acid magnesium salt was rather more flexible benzyl ester 2d was obtained only in moderate
low compared to previous results we examined different amounts selectivity of 66% ee, the more sterically demanding isopropyl
of the metal source resulting in 1.9 mol% to be the optimum ester was reduced with 91% ee (Table 4, entries 2 and 4).
amount with 99% yield and 80% ee. Interestingly, we could also Although better results have been expected for the tert-butyl
observe a change in the absolute configuration of our product by ester, the corresponding a-hydroxy ester could only be obtained
increasing the amount of the metal species. Therefore a high purity in moderate yield and good enantioselectivity even at 0 1C
of the established chiral phosphoric acid and thus its thorough presumably due to the lability of the ester moiety under the
washing with HCl is required after the purification by flash column
chromatography. Having identified chiral phosphoric acid 4f in
combination with 1.9 mol% dibutyl magnesium to be the best
Table 4 Substrate scope of the reduction of a-keto estersa
catalytic system we investigated the influence of the solvent on our
asymmetric reduction (Table 3). Since polar solvents have proven to
be unsuitable reaction media for our catalytic system14 and nhexane
Table 2 Optimization of the metal additivea
Entry
Additive (mol%)
Yieldb (%)
eec (%)
Entry
2
R1
R2
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
—
56
78
56
89
39
67
94
99
À87
0
1
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
Ph
Ph
Ph
Et
94 (56)d
93 (21)d
48
97
94
87 (À87)d
nBuLi (5.0)
2
iPr
tBu
Bn
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
91 (À89)d
81
Ca(OMe)2 (2.5)
Mg(nBu)2 (2.5)
Mg(nBu)2 (0.3)
Mg(nBu)2 (0.9)
Mg(nBu)2 (1.3)
Mg(nBu)2 (1.9)
26
16
À4
72
78
80
3e
4
66
97
95
5
6
7
8
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
2-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-F-C6H4
3-Cl-C6H4
2-F-C6H4
2-Cl-C6H4
3,5-F2-C6H3
1-Naphthyl
2-Naphthyl
6-MeO-2-naphthyl
Thienyl
499
97
97
499 (85) f
499
95
98 (97) f
96
a
9
The reaction was conducted on a 0.1 mmol scale of 1a in 1.0 mL of
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
97
95
91
93
89
95
83
88
90
94
97
96
70
74
toluene with 5 mol% of catalyst 4f. Yield of isolated 2a after flash
column chromatography. Determined by HPLC analysis on a chiral
stationary phase.
c
97
499
499
88
90
94
499
499
97
499
97
97
99
Table 3 Influence of the solvent and temperaturea
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
Toluene
99
98
98
94
56
94
80
67
82
87
72
86
s
t
u
v
w
Benzene
o-Xylene
Mesitylene
nHexane
Mesitylene
Cyclohexyl
5
tBu
6d
a
The reaction was performed on a 0.15 mmol scale of 1 in 1.5 mL of
a
b
The reaction was performed on a 0.1 mmol scale of 1a in 1.0 mL of mesitylene. Yields of isolated 2 after flash column chromatography.
toluene with 5 mol% of catalyst 4f and 1.9 mol% Mg(nBu2). b Yield of
Determined by HPLC analysis on a chiral stationary phase. The
c
d
isolated 2a after flash column chromatography. c Determined by HPLC reaction was conducted without the addition of Mg(nBu)2. e The reaction
analysis on a chiral stationary phase. d The reaction was performed at 0 1C. was performed at 0 1C. f The reaction was conducted on a 1.0 mmol scale.
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optimized conditions (Table 4, entry 3). The newly developed
method was highly efficient and appeared to be independent from
the substitution pattern as well as the substituent. Remarkably, both
enantiomers could be obtained in excellent enantioselectivities
using the same catalyst only by adding a metal source (Table 4,
entries 1 and 2). Even heteroaromatic systems could be reduced
with excellent results of 97% yield and 96% ee (Table 4, entry 21).
Aliphatic a-hydroxy esters were also obtained in high yields, albeit
with only good selectivities of 70% ee and 74% ee, respectively.
Finally our protocol was conducted on a 1.0 mmol scale furnishing
hydroxyl ester 2h with almost the same yield and stereoselectivity
(Table 4, entry 8, values in brackets).
In conclusion, a new efficient and highly enantioselective
Brønsted-acid catalysed reduction of a-keto esters has been
developed employing catecholborane as the reducing agent and
an in situ generated chiral phosphoryl borate as the catalyst.
The scalable protocol furnished the a-hydroxy esters in almost
quantitative yields and excellent enantioselectivities. Additionally,
the opposite enantiomer is accessible with only slight modifica-
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moderate yields. Further investigations utilizing this catalytic
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