Glucosamine-based primary amines as organocatalysts for the asymmetric aldol reaction

Article abstract of DOI:10.1021/jo1023156

Glucosamine derivatives have been synthesized starting from commercially available N-acetyl-D-glucosamine/glucosamine hydrochloride and have been employed successfully as efficient organocatalysts for the direct asymmetric aldol reaction between cyclohexa

Full text of DOI:10.1021/jo1023156

NOTE
pubs.acs.org/joc
Glucosamine-Based Primary Amines as Organocatalysts for the
Asymmetric Aldol Reaction
Jyoti Agarwal and Rama Krishna Peddinti*
Department of Chemistry, Indian Institute of Technology, Roorkee 247 667, Uttarakhand, India
S Supporting Information
b
ABSTRACT: Glucosamine derivatives have been synthesized
starting from commercially available N-acetyl-D-glucosamine/
glucosamine hydrochloride and have been employed success-
fully as efficient organocatalysts for the direct asymmetric aldol
reaction between cyclohexanone and aryl aldehydes having
diversified substituents. Furthermore, the anomeric effect of
various groups present at the anomeric position on the catalytic
activity of these organocatalysts was also studied.
arbohydrates have been widely used as chiral templates for
introducing chirality in synthetic asymmetric processes
configuration to allow rapid fine-tuning of their function. For
our study, we chose the asymmetric direct intermolecular aldol
reaction between aryl aldehydes and cyclohexanone.
C
owing to their rigid structure with high degree of functionaliza-
tion and the presence of several contiguous stereogenic centers.1
These molecules have been used in many reactions as chiral
reagents or ligands and found to be superior to many other
molecules.2 Many metals such as Zn, Ti, Gd, Rh, etc. were
complexed with these carbohydrate-based chiral ligands and their
catalytic activity has been explored for numerous asymmetric
transformations like Reformatsky reaction,3 hydrogenation
process,4 Strecker reactions,5 and alkylation of aldehydes.6 In
recent years, these sugar-based molecules have also been devel-
oped as organocatalysts in asymmetric synthesis. In these reports,
mono- or disaccharides were employed as a chiral scaffold to
obtain high optical yields. These sugar units were coupled either
with a pyrrolidine ring through an amide bond7 or to other chiral
moieties through urea8 /thiourea9 linkage, where pyrrolidine -
NH or another functional group such as the -NH2 group was
actively participating to catalyze the reaction through enamine/
iminium catalysis and/or hydrogen bonding. However, to the
best of our knowledge, these sugar-based molecules had never
been used independently as bifunctional organocatalysts in
asymmetric synthesis without attaching other chiral moieties
such as proline and cyclohexyldiamine or metal ion except one
report wherein commercially available glucosamine was em-
ployed for aldol reaction to obtain almost racemic products in
most of the cases.10
Herein, we report the results of our studies on the effect of
bulkiness as well as configuration (R- or β-) of the groups present
at the anomeric position of the sugar catalyst on the enantio-
selectivity of the aldol product and the catalytic activity of fully
protected sugar-based primary amine except at the C3 position
on the asymmetric induction of the aldol reaction.
Initially, we synthesized catalyst 1a according to the literature
procedure3a,12 as outlined in Scheme 1. N-Acetyl-D-glucosamine
was converted to methyl N-acetyl-D-glucosamine by refluxing it
in anhydrous MeOH with amberlyst IRN 120 Hþ resin,12 which
was further reacted with benzaldehyde dimethyl acetal followed
by ethanolic KOH to obtain 1a.3a
As a prelude to our objective, we evaluated glucosamine
derivative 1a as an organocatalyst for the aldol reaction between
3-nitrobenzaldehyde and cyclohexanone. As water is a green
solvent, we used water as a medium for the aldol reaction. Thus
the reaction was completed within 1 day with 91% yield but only
18% and 12% ee was obtained for syn- and anti-products,
respectively (entry 5, Table 1). Then we screened other polar
and nonpolar solvents to affect this transformation. The perfor-
mance in terms of optical induction of the reactions carried out at
room temperature was not encouraging. However, the reaction
was found to be very fast when it was performed in neat
conditions. Thus the reaction was completed within 3 h to yield
95% aldol adduct with 15% and 32% ee for the syn- and anti-
products, respectively (entry 11, Table 1).
In the literature, there are several reports where primary
amines have been used to catalyze organic reactions.11 Such
glucosamine-based molecules have drawn our attention to study
them as organocatalysts since these are leading source of con-
tiguous stereogenic centers bearing a primary amino group
and an hydroxy group that may be readily manipulated in
Received: November 22, 2010
Published: March 21, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of Methyl-2-amino-4,6-benzylidene-2-
Scheme 2. Synthesis of Organocatalysts 2a, 2b, and 3b
deoxy-R-D-glucopyranoside (1a)
Table 1. Asymmetric Aldol Reaction between
3-Nitrobenzaldehyde and Cyclohexanone in the Presence
of Organocatalyst 1a in Various Conditionsa
eed
entry
solvent
CH3CN
temp (°C) time yieldb (%) drc syn:anti syn anti
1
2
3
4
5
6
7
8
9
rt
rt
rt
rt
rt
rt
rt
rt
0
48
48
72
48
24
96
24
96
72
68
3
94
96
92
90
91
90
88
90
88
76
95
98
91
97
1.5:1
1.5:1
0.8:1
1.2:1
0.7:1
1.3:1
2.4:1
1.5:1
1.2:1
1.3:1
1:1
20 24
CH2Cl2
0
0
4
2
MeOH
CHCl3
14 17
18 12
10 20
H2O
DMSO
DMSO:H2O (4:1)
DMSO:H2O (2:1)
CH3CN
2
8
20
16
16 58
not improved much. In general, as the reaction temperature was
lowered to -20 °C, the rate of reaction was decreased without
affecting the chemical yield much. However, further reduction in
temperature to -40 °C resulted in lower enantioselectivity of the
aldol adduct.
10 DMSO:H2O
0
2
4
11 Neat
12 Neat
13 CH2Cl2
14 H2O
rt
0
15 32
30 60
15 35
8
1.9:1
1:3
0
96
Next we examined the catalytic activity of fully O-protected
sugar-based primary amines with both configurations, i.e., R- and
β-anomers. For this purpose, we synthesized five glucosamine
derivatives 2a-4b. Chapleur reported13 the synthesis of glucos-
amine derivative 2a from R-anomer 8a. As we needed both
anomers 2a and 2b, we proceeded with the anomeric mixture 6.
Thus benzylation followed by column chromatographic separa-
tion provided R- and β-anomers 8a and 8b in 3:2 ratio. The
reaction sequence described for the synthesis of 2a was applied
for the transformation of 8b into 2b (Scheme 2). When the
protection of free hydroxyl groups of 6 with 4-tert-butylbenzyl
bromide was carried out, we could isolate R-anomer 11a only.
The R-anomer 11a was converted into glucosamine derivative 3a
following the three-step reaction sequence as shown in Scheme 2.
Since the N-protected sugar derivative 12a was less soluble in
methanol, the deprotection of the N-acetyl group was performed
in dichloromethane to furnish the corresponding R-anomer 13a
in excellent yield. The synthesis of β-anomer 4b14 was reported
by Schmidt. However, we have synthesized both the monosac-
charides 4a and 4b in 2:3 ratio from a common starting material
0
48
0.9:1
1
4
a Reactions were performed with cyclohexanone (0.4 mM) and
3-nitrobenzaldehyde (0.2 mM) in the presence of organocatalyst 1a
(0.04 mM) in 0.5 mL of solvent in entries 1-10, 13, and 14;
cyclohexanone (0.3 mL) and 3-nitrobenzaldehyde (0.2 mM) were used
in entries 11 and 12. b Yields are of pure and isolated products.
c Determined by 1H NMR of the crude sample. d Determined by HPLC
analysis (Chiralcel OD-H).
Subsequently, we focused our attention on the effect of
temperature on the outcome of the reaction anticipating better
selectivity by lowering the reaction temperature. It was observed
that with lowering the temperature, the enantioselectivity of the
reaction was increased. For example, in neat condition, the ee
value for the anti-product was 32% and 60% at room temperature
and 0 °C, respectively. Encouraged by these results, we further
reduced the reaction temperature and to our delight, at -20 °C
we obtained anti-product in excellent optical yield of >99% when
the reaction was performed in 15 equiv of cyclohexanone with
20 mol % catalyst loading. However, ee for the syn-product was
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Scheme 3. Synthesis of Organocatalysts 4a and 4b
Table 3. Asymmetric Aldol Reaction between
Cyclohexanone and Various Aryl Aldehydes Catalyzed by
Organocatalyst 1a
ee (%)c
temp (°C) time (h) product yielda (%) drb syn:anti syn anti
entry
R
Table 2. Screening of Various Catalysts at Different
Temperature for Aldol Reaction between Cyclohexanone
and 3-Nitrobenzaldehydea
1
2
3
4
5
6
7
8
9
2-NO2
2-NO2
3-NO2
3-NO2
4-NO2
4-Br
-20
-40
-20
-40
-20
-20
-20
-20
-20
-20
22
24
12
23
12
48
72
48
16
48
72
24
16
18a
18a
18b
18b
18c
18d
18e
18f
94
90
98
95
97
90
82
85
95
93
80
85
97
2:1
1.2:1
0.8:1
1.4:1
2:1
84 81
71 78
33 >99
16 94
26 66
39 92
90 96
62 92
11 47
37 93
20 98
27 62
14 70
1.3:1
1.6:1
1.1:1
1:1
2-Cl
4-Cl
4-CN
18g
18h
18i
ee (%)d
10 4-F
1:1
entry catalyst temp (°C) time (h) yieldb (%) drc syn:anti syn anti
11 2-OMe -20
0.9:1
1.4:1
1:1
12 3-CF3
-20
-20
18j
1
2
1a
1a
1a
2a
2a
2b
3a
3a
4a
4a
4b
0
-20
-40
0
8
16
24
30
48
72
30
48
48
72
72
98
96
98
85
80
39
83
78
80
70
51
1.9:1
0.8:1
1.4:1
1.5:1
1.2:1
4:1
30
33
16
35
60
50
38
59
30
36
30
60
99
94
40
68
38
40
65
35
42
30
13 4-CF3
18k
a Pure and column chromatographically isolated yields. b Determined by
1H NMR of the crude sample. c ee values of syn- and anti-products
determined by HPLC analysis.
3
4
5
-20
0
6
catalytic activity of catalysts 4a and 4b was tested for the reaction.
The replacement of the anomeric methyl group with the benzyl
group lowered the enantioselectivity of the reaction (Table 2,
entries 9, 10, and 11). It was observed that the catalytic activity of
R-anomers was better than that of β-anomers (Table 2). Thus,
the screening of the catalysts in various solvents and neat
condition and at different temperatures identified optimal con-
ditions and 1a as the optimal catalyst to carry out further
asymmetric aldol reaction.
To explore the versatility of the organocatalyst 1a, a variety of
aromatic aldehydes bearing diversified substituents were em-
ployed as aldol acceptors in the presence of 20 mol % catalyst 1a
at -20 °C. The reaction worked well with aromatic aldehydes
bearing both electron-releasing as well as electron-withdrawing
groups to afford aldol adducts 18a-k in high to excellent
chemical yields with high to excellent enantioselectivities for
anti-products and low to good enantioselectivities for syn-pro-
ducts. Furthermore, the rate of the reaction was found to be
dependent not only upon the elecronic nature of the substituents
on the aromatic nucleus but also on their position on the arene
moiety. For example, aldol reaction between cyclohexanone and
2-nitobezaldehyde afforded aldol product 18a in 22 h with 94%
chemical yield with 84% and 81% optical yield for syn- and anti-
adducts, respectively, at -20 °C (Table 3, entry 1). The
4-nitrobenzaldehyde gave rise to aldol product 18c in 12 h with
near-quantitative yield and moderate enantioselectivity (Table 3,
entry 5). The better asymmetric induction in the reaction of the
2-nitro derivative can be explained on the basis of steric
7
0
1.5:1
1.2:1
2.1:1
2.3:1
2.3:1
8
-20
0
9
10
11
-20
0
a Reactions were performed with 3-nitrobenzaldehyde (0.2 mM) and
cyclohexanone (0.3 mL) in the presence of organocatalyst (0.04 mM).
c
1
b Yields are of pure and isolated products. Determined by H NMR
(500 MHz) of the crude sample. d Determined by HPLC analysis
(Chiralcel OD-H).
D-glucosamine hydrochloride following a new pathway described
in Scheme 3. The catalytic activity of these primary amine
organocatalysts was tested at 0 and -20 °C for the reaction
between cyclohexanone and 3-nitrobenzaldehyde (Table 2).
When the catalyst 2a was employed in the reaction at 0 °C,
85% yield of aldol product 18b was obtained in 30 h with 35%
and 40% ee for syn- and anti-isomers, respectively. However, in
the presence of 2b, the reaction was not complete even after 72 h
at 0 °C and yielded 39% of the product 18b with 50% and 38% ee
of syn- and anti-isomers, respectively (Table 2, entries 4 and 6).
Further, to improve the enantioselectivity of the reaction, the
reaction was performed at -20 °C in the presence of organoca-
talyst 2a to afford syn- and anti-isomers 18b in a combined yield
of 80% with 60% and 68% ee, respectively. The catalyst tri-O-(4-
tert-butylbenzyl) sugar derivative 3a did not influence the
enantioselectivity of the reaction much. At this juncture, the
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NOTE
hindrance resulting from ortho-substitution for enhanced differ-
entiation of enantiomers. The halo-substituted benzaldehydes
also provided the corresponding aldol adducts 18d,e,f,h in very
high to excellent chemical yields. The reaction of 2-chloroben-
zaldehyde (17e) was slower than that of 4-chlorobenzaldehyde
(17f); however, in both cases good to excellent enantioselec-
tivities were obtained for both syn- and anti-isomers. The
4-bromo- and 4-fluorobenzaldehydes also afforded correspond-
ing aldol adducts 18d, 18h with high enantioselectivity of anti-
products, but moderate enantioselectivity was obtained for syn-
products. In the case of electron-donating substituent, i.e. a
4-methoxy group, the reaction was completed in 72 h to provide
80% of aldol product 18i and syn- and anti-products were
obtained with 20% and 98% enantioselectivity, respectively.
The reaction between acetone and 4-nitrobenzaldehyde was
also carried out in the presence of catalyst 1a. However, the
asymmetric induction was not impressive. The reaction was
performed at 0 and -20 °C to produce the aldol product in
35% ee (18 h, 93%) and 66% ee (48 h, 85%), respectively.
In conclusion, for the first time, a bifunctional sugar-based
primary amine was employed independently as an efficient and
potential organocatalyst for the asymmetric transformation. We
observed that the sugar catalyst 1a bearing a free hydroxyl group
vicinal to primary amine functionality was the optimal catalyst for
our study and it provides the best results possibly through the
hydrogen bonding between the proton on the hydroxyl moiety
and the carbonyl group of the aldehyde. This situation could be
analogous to the functional group array of proline, especially in
light of the reduced pKa of carbohydrate hydroxyls relative to
simple secondary alcohols. We have also studied the anomeric
effect of sugar-based molecules 2a and 2b, 4a, and 4b on the rate
of reaction as well as on the optical induction of the aldol adduct
and found that R-anomers catalyze the reaction faster than the β-
anomers. As these derivatives have been shown to be promising
organocatalysts for direct asymmetric aldol reactions it provides
us an opportunity to explore their catalytic activity for other
asymmetric transformations in due course.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rkpedfcy@iitr.ernet.in.
’ ACKNOWLEDGMENT
We are grateful to DST, New Delhi for financial support
(research grant No. SR/S1/OC-15/2005). J.A. thanks UGC for
the award of a research fellowship.
’ REFERENCES
(1) Kunz, H.; Ruck, K. Angew. Chem., Intl. Ed. Engl. 1993,
32, 336–358.
(2) (a) Yu, T.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996,
118, 9806–9807. (b) Hurzeler, M.; Bernet, B.; Vasella, A. Helv. Chim.
Acta 1992, 75, 557–558. (c) Park, H.; Ranjanbabu, T. V. J. Am. Chem.
Soc. 2002, 124, 734–735.
(3) (a) Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Tetrahedron:
Asymmetry 2005, 16, 213–221. (b) Ribeiro, C. M. R.; Santos, E. de S.;
Jardim, A. H. de O.; Maia, M. P.; Silva, F. C. da; Moreira, A. P. D.;
Ferreira, V. F. Tetrahedron: Asymmetry 2002, 13, 1703–1706. (c) Bauer,
T.; Tarasiuk, J.; Paꢀsniczek, K. Tetrahedron: Asymmetry 2002, 13, 77–82.
(4) Selke, R.; Ohff, M.; Riepe, A. Tetrahedron 1996,
52, 15079–15102.
(5) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5634–5635.
(6) (a) Cho, B. T.; Chun, Y. S.; Yang, W. K. Tetrahedron: Asymmetry
2000, 11, 2149–2157. (b) Emmerson, D. P. G.; Villard, R.; Mugnaini, C.;
Batsanov, A.; Howard, J. A. K.; Hems, W. P.; Tooze, R. P.; Davis, B. G.
Org. Biomol. Chem. 2003, 1, 3826–3838.
(7) Agarwal, J.; Peddinti, R. K. Tetrahedron: Asymmetry 2010,
21, 1906–1909.
(8) Becker, C.; Hoben, C.; Kunz, H. Adv. Synth. Catal. 2007,
349, 417–424.
(9) (a) Liu, K; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org.
Lett. 2007, 9, 923–925. (b) Wang, C. G.; Zhou, Z. H.; Tang, C. C. Org.
Lett. 2008, 10, 1707–1710. (c) Gao, P.; Wang, C. G.; Wu, Y.; Zhou,
Z. H.; Tang, C. C. Eur. J. Org. Chem. 2008, 4563–4566. (d) Lu, A.; Gao,
P.; Wu, Y.; Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem. 2009,
7, 3141–3147. (e) Wang, Y.; Yang, H.; Yu, J.; Miao, Z.; Chen, R. Adv.
Synth. Catal. 2009, 351, 3057–3062.
’ EXPERIMENTAL SECTION
General Procedure for the Aldol Reaction. To the solution of
organocatalyst 1a (0.04 mM, 20 mol %) in cyclohexanone (0.3 mL) was
added aryl aldehyde (0.2 mM) and the resulting reaction mixture was
stirred for a certain time (as mentioned in Table 3) at -20 °C. The
progress of the reaction was monitored by TLC. After completion of the
reaction, crude product was submitted to 1H NMR (500 MHz)
spectroscopy to obtain a diastereomeric ratio of syn- and anti-products.
Then the reaction mixture was subjected to silica gel chromatography to
afford the corresponding products 18a-k in pure form. The HPLC
analysis of the aldol products was performed on a chiral stationary phase
with hexane-isopropanol as the eluting solvent.
(10) Singh, N.; Pandey, J.; Tripathy, R. P. Catal. Commun. 2008,
9, 743–746.
(11) For reviews on primary amine-catalyzed reactions, see: (a)
Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1–13. (b) Xu, L.-W.;
Luo, J.; Lu, Y. Chem. Commun. 2009, 1807–1821.
(12) Bornaghi, L. F.; Poulsen, S.-A. Tetrahedron Lett. 2005,
46, 3485–3488.
(13) Henry, C.; Joly, J.-P.; Chapleur, Y. J. Carbohydr. Chem. 1999,
18, 689–695.
(14) Aly, M. R. E.; Schmidt, R. R. Eur. J. Org. Chem.
2005, 4382–4392.
’ ASSOCIATED CONTENT
’ NOTE ADDED AFTER ASAP PUBLICATION
S
This paper was published to the Web on March 21, 2011,
with errors in the abstract graphic and scheme 1. These errors
were fixed when the paper was published to the Web on
March 29, 2011.
Supporting Information. Experimental procedures,
b
characterization data of new compounds, HPLC data table and
chromatograms for aldol products, and copies of 1H (500 MHz)
and 13C (125 MHz) NMR spectra of all compounds; and 500
MHz 1H-1H COSY and 125 MHz HETCOR spectra of 4a and
4b. This material is available free of charge via the Internet at
http://pubs.acs.org.
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