Highly Enantio- and Diastereoselective l -Proline Derived Acetylglucose Amide Catalyzed Aldol Reaction of Ketones to Aldehydes under Solvent-Free Conditions

Article abstract of DOI:10.1055/s-0035-1560701

A novel organocatalyst was developed from d-glucosamine and l-proline, which was shown to catalyze the direct aldol reaction of ketones with aldehydes in a highly diastereoselective and enantioselective manner under solvent-free conditions. The presence o

Full text of DOI:10.1055/s-0035-1560701

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2858–2862
letter
2858
X. Han et al.
Letter
Synlett
Highly Enantio- and Diastereoselective L-Proline Derived Acetyl-
glucose Amide Catalyzed Aldol Reaction of Ketones to Aldehydes
under Solvent-Free Conditions
Xiaoyu Han*a
Yongjiang Wanga
Xikun Gaia
Xiaofei Zeng*b
AcO
O
OH
O
O
O
O
catalyst (10 mol%)
H neat, –20 °C
OAc
+
Ar
N
H
Ar
NH
a Zhejiang Provincial Key Laboratory for Chemical &
Biological Processing Technology of Farm Products,
School of Biological and Chemical Engineering,
Zhejiang University of Science and Technology, No.
318 Liuhe Road, Hangzhou, 310023, P. R. of China
chemhanxy@zust.edu.cn
b College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University,
Hangzhou 310036, P. R. of China
OAc
OAc
16 examples
up to 99% yield
dr 97:3 to >99:1
88 to >99% ee
catalyst
chemzxf@hznu.edu.cn
Received: 12.07.2015
Accepted after revision: 05.09.2015
Published online: 21.10.2015
the uses of additives such as acids, bases, or inorganic salts,
or a large excess of donor is necessary, thereby reducing the
atom economy of these reactions. In this context, the design
of new, versatile catalysts, and the development of highly
efficient organocatalyzed direct aldol reactions in more
economic ways are still needed.
DOI: 10.1055/s-0035-1560701; Art ID: st-2015-w0538-l
Abstract A novel organocatalyst was developed from D-glucosamine
and L-proline, which was shown to catalyze the direct aldol reaction of
ketones with aldehydes in a highly diastereoselective and enantioselec-
tive manner under solvent-free conditions. The presence of 10 mol%
catalyst could promote the reaction effectively, affording the desired al-
dol products in high yields (70–99%) and excellent selectivities (up to
>99:1 dr and up to >99% ee).
D-Glucosamine, which is usually used as the chiral tem-
plate for the synthesis of glycopeptides and other types of
biologically active and important compounds, is an inex-
pensive and abundant chiral source in organic chemistry.7
Machinami and co-workers reported the first sugar-based
prolinamide organocatalysts and their application in the di-
rect aldol reaction of acetone with aldehydes in water. Al-
though moderate to high yields of the products were attain-
able, the enantioselectivities of the reaction was low.8 Later,
Peddinti et al. developed benzyl-protected glucosamine-de-
rived prolinamide and made good use of it in the aldol reac-
tion.6k In this work, we investigate the influence of protect-
ing group on the glucosamine on the efficiency of the cata-
lyst for the aldol reactions under solvent-free conditions.
We reasoned that the combination of newly protected glu-
cosamine with the L-proline scaffold may be more effective
in inducing asymmetry for the projected direct cross-aldol
reaction.
In our catalyst design, the bulky acetyl-protected D-glu-
cosamine motif could be easily introduced to the L-proline
backbone through a one-step amide coupling, and the weak
Brønsted acid of the N–H moiety in acetylglucose amide
catalyst might form hydrogen bonds with the approaching
reactant. This protecting group is expected to perform bet-
ter as a steric shielding group and thus induce high stereo-
selectivity (Figure 1). Furthermore, this novel chiral second-
ary amine catalyst 1 could be easily accessed with high
Key words organocatalyst, stereoselectivity, enantioselectivity, aldol
reaction, solvent-free
The aldol reaction, which is one of the most useful C–C
bond-formation reactions in organic chemistry, has been
extensively studied in recent years.1 Although enantioselec-
tive aldol reactions involving enol or enolate derivatives as
donors have been investigated in detail,2 atom-efficient di-
rect aldol reactions were rarely reported before List and co-
workers published their L-proline catalyzed direct aldol re-
action of acetones with aldehydes in 2000.3 After this semi-
nal work, the development of chiral secondary amines as
organocatalysts became popular, and a large number of cat-
alysts derived from different amino acids such as prolin-
amides, prolinethioamides, sulfonamides, and peptides
were designed and successfully applied in direct aldol reac-
tions, with good to excellent yields, and with high diaste-
reo- and enantioselectivities.4,5 Nevertheless, most organo-
catalytic direct aldol reactions involve the use of organic
solvents as the reaction medium. With respect to solvent-
free protocols, the reaction conditions are usually accompa-
nied by the use of ball-milling techniques.6 In many cases,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2858–2862

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X. Han et al.
Letter
Synlett
yield after several simple transformations from the com-
mercially available and inexpensive D-glucosamine hydro-
chloride salt and L-proline.
Table 1 Aldol Reaction of 4-Nitrobenzaldehyde with Cyclohexanone
Catalyzed by 1a
O
O
O
OH
1 (10 mol%)
H
+
conditions
O2N
NO2
4a
3a
Solvent
2
Entry
Temp
(°C)
Time
(h)
Yield
dr
ee
(%)b
(anti/syn)c
(%)d
1
2
r.t.
r.t.
Neat
EtOH
CHCl3
Hexane
H2O
10
48
48
24
48
18
18
24
24
36
85
82
81
94
–
91:9
71:29
80:20
88:12
–
78
75
69
83
–
Figure 1 Novel L-proline derived acetylglucose amide catalyst
3
r.t.
4
r.t.
With the new catalyst 1 in hand, a preliminary study
was carried out to verify its efficiency for the asymmetric
direct aldol reaction of cyclohexanone with aldehydes. The
reaction of cyclohexanone with 4-nitrobenzaldehyde was
selected as the model reaction in the presence of 10 mol% 1
under different conditions (Table 1). The aldol reaction
could take place in the presence of 1 in commonly used or-
ganic solvents such as CHCl3 and hexane (entries 3 and 4),
to give the products in good yields, albeit with moderate di-
astereoselectivities. Comparable results were also obtained
by using EtOH as solvent under identical conditions (entry
2). Water was also tested, but it was found to be a poor me-
dium for this reaction; the starting materials were recov-
ered without the formation of any desired product (entry
5). To our delight, a better result was achieved when this re-
action was carried out under solvent-free conditions at
room temperature (entry 1). This prompted us to investi-
gate this reaction further under neat conditions. As expect-
ed, it was found that a further increase of the enantiomeric
excess was achieved when the reaction temperature was
decreased to –20 °C (entries 6–9). However, when the reac-
tion was performed at –40 °C, the reaction was slow and
the aldol adduct was obtained in lower yield, although com-
parable diastereo- and enantioselectivities were attained.
Further investigation of the number of equivalents of cyclo-
hexanone used in this reaction revealed that 2 equivalents
of ketone were optimal; reducing the amount of ketone fur-
ther (1.2 and 1.5 equiv) resulted in incomplete reaction.
Therefore, the best result was obtained by using 2 equiva-
lents of cyclohexanone in the presence of 10 mol% catalyst
1 under neat conditions at –20 °C (99% yield, 97:3 dr and
97% ee; entry 10).
5
r.t.
6
r.t.
neat
97
98
98
99
80
93:7
95:5
97:3
97:3
98:2
86
90
94
97
97
7
0
neat
8
–10
–20
–40
neat
9
neat
10
neat
a Reaction conditions: cyclohexanone (0.2 mmol), aldehyde (0.1 mmol),
catalyst 1 (0.01 mmol).
b Isolated yield.
c The dr was determined by 1H NMR spectroscopic analysis of the crude
product.
d The ee values were determined by HPLC analysis on a chiral stationary
phase.
enantioselectivities (88 to 99%). A wide range of functional
groups, including electron-withdrawing and electron-do-
nating groups, were well tolerated in this reaction. When
the heterocyclic thiophene-3-carbaldehyde was used, the
stereoselectivity remained, but the chemical yield was de-
creased to 70%. However, aliphatic aldehydes were found to
be unsuitable substrates for the reaction; the aldol reac-
tions between cyclohexanone and cyclohexanecarbalde-
hyde or butyraldehdye failed to afford the desired adducts.
The reusability of catalyst 1 was then investigated (Table
3). After catalyzing the aldol reaction between 4-nitrobenz-
aldehyde and cyclohexanone, catalyst 1 could be easily sep-
arated and recovered by column chromatography before re-
use in subsequent aldol reactions. Recycled 1 catalyzed the
aldol reaction for up to three runs with similar diastereose-
lectivity and enantioselectivity. The yield dropped signifi-
cantly in the 4th run, probably due to the loss of catalyst 1
during recovering.
With the optimal reaction conditions established, the
scope of the reaction was then assessed to establish the
general utility of this organocatalytic enantioselective di-
rect aldol reaction (Table 2).9 The reactions were complete
within 12–36 h in the presence of 10 mol% 1 at –20 °C, and
the desired aldol products were obtained in 70–99% yields
and with excellent diastereoselectivities (97:3 to 99:1) and
Notably, our solvent-free conditions led to extremely
high diastereoselectivities compared with those reported
previously. This may be due to more effective steric shield-
ing from the bulky acetyl D-glucosamine motif. It is pro-
posed that the transition state of this reaction occurs
through condensation of the ketone with the secondary
amine catalyst to give the enamine intermediate, followed
by hydrogen bonding between the N-H functionality on the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2858–2862

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Table 2 (continued)
amide group and the aldehyde. This undisrupted hydrogen
bonding, combined with the significant steric hindrance
exerted by the glucosamine group, leads to the excellent
stereochemical control observed with this system (Figure
2). The structure of the aldol adducts were determined by
1H and 13C NMR spectroscopic analysis; the absolute config-
uration of the aldol product was confirmed by comparing
the optical rotation of the products with those of known
compounds.5n
Entry
Product
Yield (%)b dr (anti/syn)c ee (%)d
O
OH
8
96
98:2
94
Br
4h
O
OH
9
89
99
97:3
90
98
Table 2 Aldol Reaction of Aromatic Aldehydes 3 with Ketones 2 under
the Optimized Conditionsa
4i
O
OH
O
O
OH NO2
O
1 (10 mol%)
+
Ar
10
>99:1
neat, –20 °C
Ar
H
4j
2
3
4
O
OH
Entry
Product
Yield (%)b dr (anti/syn)c ee (%)d
11
12
96
98
98:2
99:1
95
97
O
OH
Cl
4k
1
99
97:3
97
O
OH
NO2
NO2
4a
O
OH
OH
CF3
2
3
96
97
97:3
99:1
>99
98
4l
O
OH CF3
4b
13
14
15
16
93
70
91
93
>99:1
97:3
98:2
–
99
95
91
88
O
Cl
4m
O
OH
4c
O
OH
S
4n
4
5
6
7
90
91
97
89
98:2
99:1
94
97
94
96
O
OH
CN
4d
O
OH OMe
OH Cl
OH
4o
O
OH
4e
O
4p
>99:1
>99:1
a Reaction conditions: ketone (0.2 mmol), aldehyde (0.1 mmol), catalyst 1
(0.01 mmol) under neat conditions at –20 °C.
b Isolated yield.
4f
c The dr was determined by 1H NMR spectroscopic analysis of the crude
product.
O
d Determined by HPLC analysis on a chiral stationary phase.
OMe
4g
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Letter
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Table 3 Reusability of Catalyst 1a
References and Notes
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O
reused 1
(10 mol%)
O
O
OH
H
+
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O2N
NO2
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2
Run
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dr (anti/syn)c
ee (%)d
1
2
3
4
99
91
78
63
97:3
97:3
96:4
96:4
97
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91
a Reaction conditions: ketone (20 mmol), aldehyde (10 mmol), catalyst 1 (1
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b Isolated yield.
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product.
d Determined by HPLC analysis on a chiral stationary phase.
O
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O
AcO
N
OAc
O
H N
AcO
AcO
R
H
Figure 2 The transition state of the aldol reaction mediated by catalyst 1
In conclusion, we have developed a novel and cost-effec-
tive secondary amine catalyst that can be easily derived
from L-proline and D-glucosamine. Our catalyst was found
to effectively promote direct aldol reaction between ke-
tones and aromatic aldehydes under solvent-free condi-
tions, affording the desired aldol products in high yields,
and with excellent diastereoselectivities and enantioselec-
tivities. Further investigations and modifications to broad-
en the substrate scope of aldol reaction catalyzed by 1 and
applications of this novel catalyst to other asymmetric reac-
tions are ongoing.
Acknowledgment
This work is financially supported by Zhejiang University of Science
and Technology and by the National Science Foundation of China
(21402177 and 2130233).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560701.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(9) Catalytic Asymmetric Aldol Reaction; Typical Procedure:
Cyclohexanone (0.2 mmol, 2.0 equiv), aldehyde (0.1 mmol, 1.0
equiv), and catalyst 1 (0.01 mmol, 10 mol%) were mixed
together at room temperature. The mixture was stirred at room
temperature until the aldehyde was consumed (reaction moni-
tored by TLC). The mixture was diluted with CH2Cl2 (0.5 mL),
and then purified directly by column chromatography on silica
gel to give the desired optically active aldol product. Analytical
data of compound 4b are given as a representative compound
(see the Supporting Information data on all products). Yield:
0.0241 g (96%); yellow solid; [α]D20 –29 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.22–8.16 (m, 2 H), 7.68 (d, J = 7.4 Hz,
1 H), 7.55 (d, J = 7.4 Hz, 1 H), 4.91 (dd, J = 2.7, 8.2 Hz, 1 H), 4.15
(d, J = 2.8 Hz, 1 H), 2.66–2.62 (m, 1 H), 2.53–2.38 (m, 2 H), 2.14–
2.11 (m, 1 H), 1.86–1.57 (m, 3 H), 1.42–1.38 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 215.0, 148.3, 143.2, 133.2, 129.3, 122.9,
122.0, 74.0, 57.1, 42.7, 30.7, 27.6, 24.6. HRMS: m/z [M+] calcd for
C
13H15NO4: 249.1001; found: 249.1099.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2858–2862