Direct asymmetric aldol reactions promoted by (1R, 3S, 4S)-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid as an organocatalyst

Full text of DOI:10.1002/bkcs.10018

Note
DOI: 10.1002/bkcs.10018
BULLETIN OF THE
W.-Y. Chen
KOREAN CHEMICAL SOCIETY
Direct Asymmetric Aldol Reactions Promoted by (1R, 3S, 4S)-2-
Aza-bicyclo[2.2.1]heptane-3-carboxylic Acid as an Organocatalyst
*
Wei-Yi Chen
College of Chemistry, Chemical Engineering and Materials Science, Suzhou University,
Suzhou 215123, China. *E-mail: chenweiyi@suda.edu.cn
Received July 6, 2014, Accepted September 16, 2014, Published online January 5, 2015
Keywords: Organocatalyst, Proline, Asymmetric aldol reaction, Enantioselectivity, Exo-2-azabicyclo-
[2.2.1]heptane-3-carboxylic acid
During the last years, the field of organocatalysis has received
much attention and become a powerful tool in the field of
organic chemistry. Organic catalysts that possess both an
desired catalysts in hand, attention was next turned toward
its application in the direct asymmetric aldol reactions.
Initially, the catalytic effects of the catalyst was tested in the
model reaction of 4-nitrobenzaldehyde with acetone at room
temperature. The achieved results are shown in Table1. The
desired product could be obtained in 76% yield with 80%
enantiomeric excess smoothly following the procedure of
direct asymmetric aldol reaction (Table 1, entry 1). The aldol
reactions were tested in other solvents, but no better result
could be found; remarkably, the yields and the enentiomeric
excess values of the desired product in an ionic liquid were
lower than those in proline-induced direct asymmetric aldol
reaction intheionicliquid(Table 1, entry3). Whenthecatalyst
amount was increased, the yield and enantioselectivity of
the desired product were preserved at similar levels (Table1,
entry 5); lower yield and enantioselectivity were observed
by employing 10 mol% of the catalyst.
1
acidic and a basic/nucleophilic structural moiety constitute
an increasingly powerful platform for the development of
2
asymmetriccatalysis. Among them, thedirectcatalytic asym-
metric aldol reaction is one of the most useful carbon–carbon
bond-forming reactions and provides optically enriched
β-hydroxy carbonyl compounds smoothly. Its value has been
proven by their application in the total synthesis of natural
3
products.
4
Since thepioneeringworkofList etal., theorganocatalysts
reported in direct asymmetric aldol reactions are nearly exclu-
sively based on proline and its derivatives. Among them, pro-
line and its derivatives, with two functional groups with the
secondary amine acting as a nucleophilic enamine catalyst
and the carboxylic acid moiety as a general Brønsted catalyst,
have attracted much attention. They have promoted success-
fully many asymmetric reactions including Michael, Man-
nich, and, particularly, aldol reactions.
With the success of the above reactions, the study was con-
tinued by employing 20 mol% of catalyst for the direct asym-
metric aldol reactions of other substituted benzaldehydes with
acetone in dimethyl sulfoxide (DMSO), and the results are
summarized in Table2.
By now, many other enantioselective processes catalyzed
5
by L-proline have also been developed ; however, there are
some reports of proline-catalyzed reactions that proceed just
with only moderate enantioselectivity because of the flexibil-
ity of proline's five-membered ring.
Maybe, a potential strategy to enhance the enantioselectiv-
ity of proline-catalyzed reactions is to rigidify the five-
membered ring system. Very recently, it has been reported that
theazabicyclic prolineanalogs couldbeapplied inasymmetric7
reactions with high stereoselectivity and catalytic activity.
Inspired by these results, we tried to investigate (1R, 3S,
As shown in Table 2, all the aldehydes, including aromatic
and aliphatic ones, could furnish the desired products in mod-
erate to good yields and enantioselectivities smoothly. The
catalyst appeared to be good at inducing enantioselectivity
in all the cases, especially in the case of an aliphatic aldehyde
(Table 2, entry 11).
In summary, (1R, 3S, 4S)-2-azabicyclo-[2.2.1]heptane-3-
carboxylicacidwassuccessfullyusedtocatalyzethedirectasym-
metricaldolreactionsinDMSOatroomtemperature.Thedesired
aldolproducts, β-hydroxyketones, wereprovidedwithmoderate
to good yields and enantioselectivities smoothly. Although the
catalystdidnotexhibitany substantial improvementsrelative to
L-proline, these results open a novel way to design and synthe-
size new chiral ligands for enantioselective reactions.
4
,6
4S)-2-azabicyclo-[2.2.1]heptane-3-carboxylic acid as catalyst
in direct asymmetric aldol reaction, to determine whether rigi-
difying the proline ring structure could be a general strategy
for enhancing the enantioselectivity.
The first task was to procure the chiral amino acid, (1R, 3S,
4S)-2-azabicyclo-[2.2.1]heptane-3-carboxylic acid. It was
synthesized by using dimethyl tartrate as the starting materia8l
and (R)-α-methylbenzylamine as the chiral pool (Scheme 1).
The synthetic procedures were quite straightforward and
afforded the product in 25% total yield (six steps). With the
Experimental
All solvents were distilled before use. Each compound of the
reactions was checked using thin-layer chromatography and
Bull. Korean Chem. Soc. 2015, Vol. 36, 378–380
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
Table 2. Direct asymmetric aldol reactions of substituted
a
HO
MeO C
OH
benzaldehydes with acetone.
HIO4
H
Ph
NH2 Ph
N
N
MeO C
2
CO Me
O
H
CO Me
2
2
2
CO H
2
CO Me
2
CO H
CO
HCl
CO H
Me
2
O
O
N
H
20mol%
H2
2
OH
O
N
Ph
Pd-C
N
H
+
R
H
H.HCl
DMSO
R
2
b
c
propylene oxide
Entry
Aldehyde
C H CHO
Yield (%)
ee (%)
N
H
1
2
3
4
5
6
7
8
9
65
76
80
82
82
80
82
78
45
80
56
71
80
76
82
70
60
61
70
42
71
90
6
5
p-O NC H CHO
NC H CHO
2 6 4
o-O NC H CHO
2
6 4
Scheme 1. Synthesis of the catalyst.
m-O
2
6 4
Table 1. Influence on the aldol reaction of acetone with 4-
nitrobenzaldehyde.
p-ClC H CHO
6
4
6 4
m-ClC H CHO
o-ClC H CHO
6
4
CO H
2
p-BrC H CHO
O
OH
O
6 4
N
H
6 4
p-MeC H CHO
O
H
1
1
a
0
1
2-NapthylCHO
c-C H CHO
6 11
+
O N
O N
2
2
The reaction was carried out with aldehyde (0.5 mmol) and acetone (1.0
mL) in the presence of catalyst (20 mol%) in DMSO (4.0 mL) at room
temperature.
Isolated yields after chromatography.
Determined by chiral HPLC analysis.
a
b
Cat./
mol%
Time
(h)
Yield
(%)
ee
Entry
Solvent
DMSO
(%)
b
c
1
2
3
4
5
6
a
20
20
20
20
30
10
8
8
8
120
5
12
76
64
72
80
68
69
-
81
76
3 3
CH COCH
(bmim)PF
6
concentrated under vacuum. The residual crude product was
purified via silica gel chromatography to afford the pure aldol
product (silica gel, PE/EA = 4:1, v/v). The enantiomeric
excess of the aldol product was determined by chiral HPLC
H O
Trace
80
2
DMSO
DMSO
68
Isolated yields after chromatography.
analysis.
b
Determined by HPLC analysis with chiralpak AS-H column.
1
(4R)-Hydroxy-4-phenyl-butan-2-one (Table 2, entry 1), H
NMR (CDCl , 300 MHz): δ 2.15(s, 3H), 2.74–2.90 (m, 2H),
3
1
purified by flash column chromatography before use. H
NMR spectra were recorded on a Varian-Inova-400 MHz
3
.65(s, 1H), 5.13(m, 1H), 7.23–7.44(m, 5H). Enantiomeric
excess was determined by HPLC (Daicel chiralpak AS-H,
spectrometer with Me Si as internal standard. The chemical
4
IPA/hex = 10:90), flow rate: 1 mL/min, major: t 15.6 min
R
shifts are given in ppm (δ). Enantiomeric excesses were deter-
mined by HPLC analysis with a chiralpak column.
and minor: t 18.5 min.
R
(
4R)-Hydroxy-4-(4-nitrophenyl)-butan-2-one
(Table2,
1
Synthesis of the Catalyst. The preparation of (1R, 3S, 4S)-2-
azabicyclo-[2.2.1]heptane-3-carboxylic acid was achieved
according to the known procedure almost without any modi-
entry 2), H NMR (CDCl , 300 MHz): δ 2.24 (s, 3H), 2.83
3
(m, 2H), 3.64 (d, J = 3.2 Hz 1H), 5.26 (m, 1H), 7.52 (d,
J = 7 Hz, 2H), 8.19 (d, J = 7.0 Hz, 2H). Enantiomeric excess
was determined by HPLC (Daicel chiralpak AS-H,
8
D
ꢀ
1
fication : White crystal, α = –1.6 (c = 1.2, H O); H NMR
2
5
2
(
1
400 MHz, CD OD): δ 4.12(s, 1H,), 3.50(s, 1H), 2.88(s, 1H),
.91–1.69(m, 4H), 1.61–1.56(m, 2H); C NMR (100 MHz,
IPA/hex = 10:90), flow rate: 1 mL/min, major: t 41.5 min
3
R
1
3
and minor: t 66.1 min.
R
CD OD): δ 172.9, 65.9, 59.5, 41.8, 35.1, 28.2, 26.8.
(4R)-Hydroxy-4-(3-nitrophenyl)-butan-2-one (Table 2,
3
1
General Catalytic Procedure. The catalyst, (1R, 3S, 4S)-2-
azabicyclo-[2.2.1]heptane-3-carboxylic acid (14.1 mg, 0.1
mmol) was added to DMSO (4 mL) and acetone (1 mL),
and the resulting mixture was stirred for 15 min. After that,
entry 3), H NMR (CDCl
, 300 MHz): δ 2.23 (s, 3H), 2.90
3
(d, J = 5.3 Hz, 2H), 3.94 (s, 1H), 5.26 (s, 1H), 7.47–8.24
(m, 4H). Enantiomeric excess was determined by HPLC
(Daicel chiralpak AS-H, IPA/Hex = 20:80), flow rate: 1 mL/
4-nitrobenzaldehyde (755 mg, 0.5 mmol) was added, and
min, major: t
24.1 min and minor: t 32.2 min.
R R
the reaction mixture was stirred at room temperature and mon-
itored by TLC. Then, the reaction mixture was treated with a
saturated ammonium chloride solution, and extracted with
diethyl ether. The separated diethyl ether layer was collected
and the procedure was repeated until no product was detected
in diethyl ether layer. The organic solution was dried and
(4R)-Hydroxy-4-(2-nitrophenyl)-butan-2-one (Table 2,
entry 4), H NMR (CDCl , 300 MHz): δ 2.18 (s, 3H),
3
2.64–3.05 (m, 2H), 3.85 (s, 1H), 5.69 (d, J =10.7 Hz, 1H),
7.54–7.83 (m, 4H). Enantiomeric excess was determined by
HPLC (Daicel chiralpak AS-H, IPA/hex = 30:70), flow rate:
1
1 mL/min, major: t 10.1 min and minor: t 8.2 min.
R R
Bull. Korean Chem. Soc. 2015, Vol. 36, 378–380
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
379

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
(
4R)-Hydroxy-4-(4-chlorophenyl)-butan-2-one (Table2,
1.56–1.88 (m, 6H), 2.17(s, 3H), 2.53(dd, J = 17.4, 8.7 Hz,
1H), 2.61(dd, J = 17.4, 3.5 Hz, 1H), 3.76–3.82(m, 1H). Enan-
tiomeric excess was determined by HPLC (Daicel chiralpak
OD, IPA/hex = 3:97), flow rate: 1 mL/min, major: tR
1
entry 5), H NMR (CDCl , 300 MHz): δ 2.20 (s, 3H,),
3
2
.81–2.85 (m, 2H), 3.45 (s, 1H), 5.12 (s, 1H), 7.27–7.34 (
m, 4H). Enantiomeric excess was determined by HPLC
Daicel chiralpak AS-H, IPA/hex = 10:90), flow rate: 1 mL/
min, major: t 13.1 min and minor: t 15.2 min.
(
9.1 min and minor: t 10.2 min.
R
R
R
Acknowledgment. Publication cost of this paper was sup-
ported by the Korean Chemical Society.
(4R)-Hydroxy-4-(3-chlorophenyl)-butan-2-one (Table2,
1
entry 6), H NMR (CDCl , 300 MHz): δ 2.20 (s, 3H),
3
2
7
.77–2.89 (m, 2H), 3.50 (s, 1H), 5.12–5.13(m, 1H),
.21–7.34 ( m, 4H). Enantiomeric excess was determined
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3
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2
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R
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2
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3
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R
R
(
4R)-Hydroxy-4-(4-methyphenyl)-butan-2-one (Table2,
entry 9), 1H NMR (CDCl3, 300 MHz): δ 2.19 (s, 3H), 2.34
s, 3H), 2.77–2.91 (m, 2H,), 3.26 (s, 1H), 5.10–5.13(m,
H), 7.16 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H). Enan-
4
(
1
tiomeric excess was determined by HPLC (Daicel chiralpak
AS-H, IPA/hex = 10:90), flow rate: 1 mL/min, major: tR
1
7
2
9.1 min and minor: t 25.2 min.
R
4
-Hydroxy-4-naphthalen-2-yl-butan-2-one (Table2, entry
1
1
0), H NMR (CDCl , 300 MHz): δ 2.20 (s, 3H), 2.88–3.01
3
6
(m, 2H), 3.41(d, J = 2.4 Hz, 1H), 5.33(m, 1H), 7.44–7.81(m,
8
3
H), 7.82–7.86(m, 4H). Enantiomeric excess was determined
7
by HPLC (Daicel chiralpak AD, IPA/hex = 5:95), flow rate: 1
mL/min, major: t 26.1 min and minor: t 31.2 min.
R
R
4-Cyclohexyl-4-hydroxy-butan-2-one (Table2, entry 11),
1
H NMR (CDCl , 300 MHz): δ 0.89–1.51(m, 5H,),
3
Bull. Korean Chem. Soc. 2015, Vol. 36, 378–380
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
380