A proline-catalyzed aldol approach to the synthesis of 1-N-iminosugars of the d-glucuronic acid type

Article abstract of DOI:10.1016/j.tetlet.2007.11.153

A new synthetic route to 1-N-iminosugars of glucuronic acid type (e.g., 1) has been developed employing proline-catalyzed aldol reaction as a key step.

Full text of DOI:10.1016/j.tetlet.2007.11.153

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 672–674
A proline-catalyzed aldol approach to the synthesis
of 1-N-iminosugars of the D-glucuronic acid type
Chen Chen, Biao Yu *
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 20 October 2007; revised 19 November 2007; accepted 21 November 2007
Abstract
A new synthetic route to 1-N-iminosugars of glucuronic acid type (e.g., 1) has been developed employing proline-catalyzed aldol reac-
tion as a key step.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: 1-N-Iminosugar; Aldol reaction; Proline-catalyzed; Glucuronidase inhibitor; Synthesis
1-N-Iminosugars, saccharide analogs with a nitrogen in
place of the anomeric carbon, have been disclosed as
potent inhibitors of b-glycosidases, due to their good mimi-
cry of the transition state involving in equatorial glycoside
cleavage.1–4 Thus, the D-glucuronic acid (GlcA)-type 1-N-
iminosugar (1) is found to be a potent and specific inhibitor
of b-D-glucuronidase from bovine liver (Ki = 79 nM).2
Incorporation of this GlcA mimic into the reducing end
of a heparan sulfate (HS) oligosaccharide could provide a
potent and specific inhibitor of heparanase,5 the unique
mammalian endo-b-D-glucuronidase, which has become a
promising target of anticancer therapy.6 To this end, we
first required a properly protected derivative of the 1-N-
iminosugar 1 (e.g., 2, with only the 4-OH free). Concise
approaches to the synthesis of compound 1 have been
reported by Ichikawa and co-workers2c and Ganem and
co-workers;3 and a number of synthetic approaches toward
the analogous 1-N-iminosugars are available in the litera-
tures;4 however, modification of these methods to the syn-
thesis of compound 2 requires lengthy transformations.
Herein, we report a new and concise approach to the syn-
thesis of 1-N-iminosugars, as exemplified by the synthesis
of compounds 1 and 2, using proline-catalyzed aldol reac-
tion as a key step.
OH
O
OH
OBn
O
O
O
HO
HO
HO
HO
HO
BnO
OH
NHHCl
NHCbz
OH
β-D-GlcA
1
2
Organocatalyzed enantioselective aldol reaction has
recently been an intensive research topic, which provides
a biomimetic approach to the synthesis of saccharides.7
Applying this new technology to the preparation of 1-N-
iminosugars (e.g., 1 and 2) would require the aldol coupling
of a b-amino-aldehyde and a glyceric aldehyde (e.g., 3 and
4, for the preparation of the GlcA-type 1 and 2). Thus,
direct cross aldol condensation of aldehydes 38 and 49
was examined in the presence of proline (Scheme 1). The
use of 0.1 equiv of proline in DMF at room temperature
gave the best results (Table 1, entry 2): the mechanistically
expected anti-product 5 was predominately formed in a 6:1
ratio to a stereoisomer (6) in a total yield of 48%. Oxida-
tion of the unstable aldols 5 and 6 with sodium chlorite
followed by benzyl ester formation provided esters 7 and
8, which were separated by careful chromatography on
silica gel. However, the exact stereochemistry in these
products was not determined at this stage.
*
Corresponding author. Tel.: +86 21 54925131; fax: +86 21 64166128.
E-mail address: byu@mail.sioc.ac.cn (B. Yu).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.153

C. Chen, B. Yu / Tetrahedron Letters 49 (2008) 672–674
673
OH
OH
OHC
OHC
proline
OHC
OHC
OTBS
OTBS
OTBS
OTBS
OBn
CbzHN
OBn
OBn
CbzHN
CbzHN
4
3
5
6
OH
OH
i) NaClO2, NaH2PO4, t-BuOH,
2-methyl-2-butene, H2O, rt;
BnO2C
BnO2C
CbzHN
OTBS
OBn
OBn
ii) BnBr, KHCO3, DMF, rt, 94%
CbzHN
7
8
Scheme 1.
Table 1
Proline-catalyzed aldol reaction of aldehydes 3 and 4a
epimeric mixture was then subjected to reduction with tri-
ethylsilane/boron trifluoride diethyl etherate to provide the
fully protected 1-N-iminosugar derivative 12 in good yield
(71% for three steps). Finally, the CA group in 12 was
selectively deprotected with thiourea/2,6-lutidine, provid-
ing the desired 2 in an excellent 95% yield. It should be
noted that the removal of an acetyl group at this stage
was found problematic under either acidic or basic condi-
tions, leading to the corresponding 4,5-elimination prod-
uct. Further removal of the benzyl and Cbz protection
with Pd/C catalyzed hydrogenation afforded the known
1-N-iminosugar 1. The analytical data of 1 are identical
to those reported,2c thus confirming the proposed stereo-
chemistry in the major aldol product 5.
Entry
Solvent
Catalyst
loading
(equiv)
Temperature
Yield
(%)
5/6
1
2
3
4
5
a
DMF
DMF
DMF
DMF
DMSO
0.05
0.1
0.3
0.1
0.1
rt
rt
rt
0 °C
rt
<20
48
31
<20
45
—
6/1
1/1
3/1
5/1
For a typical operation: A solution of 3-benzyloxycarbonylamino-
propanal 3 (145 mg, 0.700 mmol) in DMF (1.5 mL) was added slowly over
a course of 24 h to a stirring suspension of 2-O-benzyl-3-O-tert-butyl-
dimethylsilyl-D-glyceraldehyde 4 (296 mg, 1.00 mmol) and L-proline (9 mg,
0.08 mmol) in DMF (1.5 mL) at room temperature. The mixture was
stirred for an additional 2 h at room temperature, and then was concen-
trated in vacuo. Flash chromatography (4:1 hexanes–ethyl acetate) affor-
ded a 6:1 mixture of diastereoisomers 5 and 6 as a colorless oil (167 mg,
48%).
The stereochemistry of the minor aldol product 6 was
implied by NOE analysis of its lactone derivative 13
(Scheme 3).10
In summary, the GlcA-type 1-N-iminosugar derivatives
(e.g., 1 and 2) were concisely synthesized from the aldol
adduct (e.g., 5) in high yields, demonstrating a new route
Conversion of compound 7 into the desired 1-N-imino-
sugars 1 and 2 was achieved concisely as shown in Scheme
2. Thus, the free hydroxyl group in 7 was protected with an
easily removable chloroacetyl (CA) group, providing 9 in
high yield. Attempts to remove the primary TBS ether in
9 with tetrabutyl ammonium fluoride (TBAF)/acetic acid
or hydrogen fluoride–pyridine complex led to the forma-
tion of the 1,5-lactone and migration of the CA group.
Hydrofluoric acid was found effective to cleave the TBS
group cleanly. The resulting alcohol 10 was then subjected
to Swern oxidation; automatic intramolecular aminal
formation afforded the piperidine derivative 11. This
H
H
4
BnO
O
HF-pyridine, CH2Cl2, 69%
3
H
13
8
O
2
OH
NHCbz
Scheme 3.
OCA
OCA
BnO2C
CbzHN
a
b
BnO2C
CbzHN
c
OTBS
OH
7
OBn
d
OBn
10
9
BnO2C
CAO
BnO2C
e
f
CAO
1
2
BnO
BnO
NCbz
OH
NCbz
12
11
Scheme 2. Reagents and conditions: (a) Chloroacetic anhydride, pyridine, DMAP, CH2Cl2, 91%; (b) HF (40%), CH3CN; (c) (COCl)2, DMSO, ꢀ65 °C,
CH2Cl2; (d) triethylsilane, BF3ꢁEt2O, CH2Cl2, 71% (3 steps); (e) thiourea, 2,6-lutidine, MeOH, 95%; (f) H2, Pd/C (10%), MeOH; then HCl (1 N), 90%.

674
C. Chen, B. Yu / Tetrahedron Letters 49 (2008) 672–674
´
´
Cordova, A.; Engqvist, M.; Ibrahem, I.; Casas, J.; Sunden, H. Chem.
to the synthesis of 1-N-iminosugars of biological signifi-
cance. There is certainly room for improvement in the pro-
line-catalyzed aldol coupling with aldehydes 3 and 4 and
the likes as partners, that has not been examined before.
Incorporation of the present GlcA-type 1-N-iminosugar
into the reducing end of heparan sulfate (HS) oligosaccha-
rides and the test of their heparanase inhibitions are our
current projects and will be reported in due course.
´
Commun. 2005, 2047–2049; (f) Zhao, G. L.; Liao, W. W.; Cordova, A.
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9. (a) Baggett, N.; Stribblehill, P. J. Chem. Soc., Perkin Trans. 1 1977,
1123–1126; (b) Reetz, M. T.; Kesseler, K. J. Org. Chem. 1985, 50,
5434–5436; (c) Morimoto, Y.; Mikami, A.; Kuwabe, S.; Shirahama,
H. Tetrahedron: Asymmetry 1996, 7, 3371–3390.
10. Selected data for the key compounds. Compound 1: 1H NMR (D2O,
300 MHz): d 2.79 (ddd, J = 4.2, 7.4, 7.8 Hz, 1H), 2.96 (dd, J = 7.5,
12.9 Hz, 1H), 3.26 (dd, J = 7.8, 13.2 Hz, 1H), 3.36 (dd, J = 3.9,
12.9 Hz, 1H), 3.40 (dd, J = 5.1, 13.2 Hz, 1H), 3.78 (dt, J = 3.3,
Acknowledgements
23
7.5 Hz, 1H), 3.96 (t, J = 6.9 Hz, 1H). Compound 2: ½aꢂD ꢀ18.8 (c 1.0,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 2.55–2.67 (m, 1H), 2.64 (t,
J = 11.7 Hz, 1H), 2.76–3.03 (br m, 2H), 3.21–3.39 (br m, 1H), 3.91 (t,
J = 9.3 Hz, 1H), 4.21–4.55 (br m, 2H), 4.56–4.77 (m, 2H), 5.11 (s,
2H), 5.16 (s, 2H), 7.20–7.43 (m, 15H); 13C NMR (CDCl3, 75 MHz): d
44.07, 45.39 (br), 47.99 (br), 66.71, 67.47, 72.27 (br), 73.57 (br), 77.69,
127.70, 127.84, 127.85, 127.94, 128.08, 128.19, 128.41, 128.44, 128.45,
135.27, 136.14, 137.69, 154.72, 170.85; ESIMS m/z 476.1 [M+H]+,
498.0 [M+Na]+; Anal. Calcd for C28H29NO6: C, 70.72; H, 6.15; N,
Financial support from the National Natural Science
Foundation of China (20572122 and 20621062) and the
Committee of Science and Technology of Shanghai
(06XD14026 and 04DZ19213) is gratefully acknowledged.
References and notes
23
2.95. Found: C, 70.79; H, 6.12; N, 2.77. Compound 7: ½aꢂD ꢀ19.2 (c
1
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Bols, M. Acc. Chem. Res. 1998, 31, 1–8; (c) Liu, H.; Liang, X.; Søhoel,
0.98, CHCl3); H NMR (CDCl3, 300 MHz): d 0.045 (s, 3H), 0.048 (s,
3H), 0.88 (s, 9H), 2.92–2.98 (m, 1H), 2.97 (d, J = 7.8 Hz, 1H), 3.48 (t,
J = 6.1 Hz, 2H), 3.52–3.58 (m, 1H), 3.73–3.86 (m, 2H), 3.90–3.97 (m,
1H), 4.50 (d, J = 11.4 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.93 (d,
J = 12.0 Hz, 1H), 5.02 (d, J = 12.0 Hz, 1H), 5.06 (s, 2H), 5.07 (br s,
1H), 7.20–7.39 (m, 15H); 13C NMR (CDCl3, 75 MHz): d ꢀ5.57,
ꢀ5.55, 18.13, 25.80, 40.66, 48.38, 62.10, 66.50, 66.65, 70.48, 72.74,
79.77, 127.73, 127.95, 128.03, 128.06, 128.14, 128.18, 128.30, 128.33,
128.42, 128.44, 128.54, 128.57, 135.51, 136.34, 137.98, 156.21, 172.90;
ESIMS m/z 608.3 [M+H]+, 630.3 [M+Na]+; Anal. Calcd for
H.; Bulow, A.; Bols, M. J. Am. Chem. Soc. 2001, 123, 5116–5117.
¨
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5. For a review on the azasugars and azasugar-containing oligosaccha-
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C
34H45NO7Si: C, 67.19; H, 7.46; N, 2.30. Found: C, 67.46; H, 7.31;
23
N, 2.42. Compound 8: ½aꢂD ꢀ20.2 (c 0.96, CHCl3); 1H NMR (CDCl3,
300 MHz): d 0.05 (s, 6H), 0.88 (s, 9H), 2.92–2.98 (m, 1H), 3.32 (d,
J = 6.6 Hz, 1H), 3.44–3.49 (m, 1H), 3.56–3.72 (m, 2H), 3.76–3.87 (m,
2H), 4.03–4.09 (m, 1H), 4.42 (d, J = 11.4 Hz, 1H), 4.62 (d,
J = 11.4 Hz, 1H), 5.01 (s, 2H), 5.07 (s, 2H), 5.28 (br t, J = 6.3 Hz,
1H), 7.22–7.33 (m, 15H); 13C NMR (CDCl3, 75 MHz): d ꢀ5.60,
ꢀ5.57, 18.09, 25.78, 39.85, 48.25, 62.65, 66.61, 66.77, 70.33, 72.85,
78.89, 127.72, 128.01, 128.05, 128.29, 128.33, 128.44, 128.52, 135.45,
136.34, 137.94, 156.68, 172.42; ESIMS m/z 608.4 [M+H]+, 630.3
[M+Na]+; Anal. Calcd for C34H45NO7Si: C, 67.19; H, 7.46; N, 2.30.
23
Found: C, 67.27; H, 7.43; N, 2.29. Compound 13: ½aꢂD ꢀ43.0 (c 1.07,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 2.56 (dt, J = 11.1, 3.0 Hz,
1H); 3.56 (ddd, J = 15.0, 4.8, 2.1 Hz, 1H), 3.78–3.89 (m, 2H), 3.92
(dd, J = 8.1, 3.6 Hz, 1H), 4.33 (d, J = 3.6 Hz, 2H), 4.63 (d,
J = 11.7 Hz, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.72 (d, J = 4.5 Hz,
1H), 5.11 (AB, 2H), 5.48 (m, 1H), 7.26–7.38 (m, 10H); 13C NMR
(CDCl3, 75 MHz): d 36.55, 47.66, 67.40, 68.40, 69.96, 71.46, 77.71,
127.79, 127.86, 128.00, 128.29, 128.44, 128.53, 135.83, 137.38, 158.43,
172.13; ESIMS m/z 408.2 [M+Na]+; ESIHRMS m/z calcd for
C21H23NO6 [M+Na]+: 408.1418; found, 408.1431.
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the synthesis of carbohydrates, see: (a) Northrup, A. B.; MacMillan,
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