The first synthesis of secondary sugar sulfonic acids by nucleophilic displacement reactions

Article abstract of DOI:10.1016/j.tetlet.2003.11.025

The 4-deoxy-4-C-sulfonic acid and 6-deoxy-6-C-sulfonic acid derivatives of methyl α-D-gluco- and α-D-galactopyranosides were prepared by triflate-mediated nucleophilic displacement reactions, either with NaHSO ₃ or with AcSK. The triflate ester

Full text of DOI:10.1016/j.tetlet.2003.11.025

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 839–842
The first synthesis of secondary sugar sulfonic acids by nucleophilic
displacement reactions
a,
Andras Liptak, Edit Balla, Lorant Janossy, Ferenc Sajtos and Laszlo Szilagyi
a
b
a
c
*
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ ꢀ
ꢀ
aResearch Group for Carbohydrates of the Hungarian Academy of Sciences, H-4010 Debrecen, PO Box 55, Hungary
bDepartment of Biochemistry, Faculty of Science, University of Debrecen, H-4010 Debrecen, PO Box 55, Hungary
cDepartment of Organic Chemistry, Faculty of Science, University of Debrecen, H-4010 Debrecen, PO Box 20, Hungary
Received 16 September 2003; revised 31 October 2003; accepted 6 November 2003
ꢀ ꢀ ꢀ
Dedicated to Professor Pal Nanasi on the occasion of his 80th birthday
Abstract—The 4-deoxy-4-C-sulfonic acid and 6-deoxy-6-C-sulfonic acid derivatives of methyl a-
D
-gluco- and a-
D
-galactopyrano-
sides were prepared by triflate-mediated nucleophilic displacement reactions, either with NaHSO3 or with AcSK. The triflate esters of
methyl 2,3,4-tri-O-benzyl- 1, methyl 2,3,6-tri-O-benzyl-a- -glucopyranoside 9 and methyl 2,3,6-tri-O-benzyl-a- -galactopyrano-
side 5 provided methyl 6-deoxy-6-C-sulfo-a- -glucopyranoside 4, methyl 4-deoxy-4-C-sulfo-a- -galactopyranoside 12 and
a- -glucopyranoside 8, respectively. The triflate derivative of methyl 2,3,4-tri-O-benzyl-a- -galactopyranoside 13 gave methyl
3,6-anhydro-2,4-di-O-benzyl-a- -galactopyranoside 14. Formation of the 3,6-anhydro derivative was prevented by using 3,4-O-
isopropylidene acetal protection to obtain methyl 6-deoxy-6-C-sulfo-a- -galactopyranoside 19. The aim of the research is to replace
D
D
D
D
D
D
D
D
the sulfate esters by sulfonic acids in the repeating oligosaccharide units of glycosaminoglycans or in different oligosaccharide
ligands.
ꢀ 2003 Elsevier Ltd. All rights reserved.
In 1959 Benson et al.1 isolated a sulfur-containing gly-
colipid from the photosynthetic tissues of plants and
microorganisms. The sugar component of this glycolipid
0.1–1 lg/mL) were isolated from various cyanobacterial
(blue-green algae) media,4 and four compounds were
also synthesized.5 The sulfonic acid moiety was intro-
duced at position 6 by the oxidation of a thioacetate
group with oxone. Later, 2-amino-2,3-dideoxyhexose-
3-C-sulfonic acid was identified6 in the hydrolysates of
sulfite-treated glycoproteins, and 2-amino-2,6-dideoxy-
6-C-sulfonic acid was found in the cell-wall hydrolysates
of Halococcus sp., strain 24.
proved to be 6-deoxy-6-C-sulfo-
was synthesized by the same authors2 from 1,2-O-iso-
propylidene-6-O-tosyl-a- -glucofuranose. The primary
D-glucopyranose, which
D
sulfonate group underwent a replacement reaction with
sodium sulfite to afford 6-deoxy-1,2-O-isopropylidene-
6-C-sulfo-a-D-glucofuranose. Acid hydrolysis resulted
in 6-sulfo- -quinovose.
D
Recently, it has turned out that sulfoquinovosyldiacyl
glycerol (SQDG) and sulfoquinovosylmonoacyl glycerol
(SQMG) are DNA polymerase inhibitors.7 These types
of compound were isolated from fern, alga and marine
invertebrates and they are potent inhibitors of DNA
polymerase a and b, in vitro and of human lung cancer
in vivo. SQDGs possess various biological activities
such as anti-tumour effects,8 P-selectin receptor inhibi-
tion,9 HIV-RT inhibition,10 AIDS-anti-viral4 and many
others. As a consequence, significant interest has been
aroused for the synthesis of related compounds. Con-
cerning the synthesis of secondary sugar sulfonic acids,
Musicki and Widlanski11 reported that sulfonate-stabi-
lized Horner–Emmons reagents readily react with
Structural studies identified the glycolipid as 1,2-di-
O-acyl-3-O-(6-deoxy-6-C-sulfo-a- -glucopyranosyl)-
glycerol. Fatty acid compositions in natural lipids from
various sources have been determined and a rather rich
spectrum of fatty acids has been found in most phos-
pholipids and glycolipids. Gigg et al.3 were the first to
D
L-
successfully synthesize 3-O-(6-deoxy-6-C-sulfo-a-
D-
glucopyranosyl)-1,2-di-O-hexadecanoyl- -glycerol. Sim-
L
ilar sulfolipids with very high anti-HIV-1 activity (EC50
* Corresponding author. Tel.: +36-52-512-900x2256; fax: +36-52-512-
913; e-mail: liptaka@tigris.klte.hu
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.025

840
A. Liptꢀak et al. / Tetrahedron Letters 45 (2004) 839–842
O
OH
O
S
C
CH3
SO3Na
O
SO3Na
O
O
c
a, b
BnO
BnO
d
BnO
BnO
BnO
BnO
HO
HO
53%
69%
63%
OCH3
OCH3
OCH3
OCH3
OBn
OH
OBn
OBn
1
2
3
4
Scheme 1. Reagents and conditions: (a) Tf2O/Py, CH2Cl2, )10 ꢁC, 1 h; (b) CH3COSK, DMF, 90 ꢁC, 3 h; (c) oxone, KOAc, AcOH, rt, 5 h; (d) H2/Pd–
C, AcOH, EtOH, rt, 24 h.
1,2:5,6-di-O-isopropylidene-a-
D
-ribo-3-ulofuranose to
give a mixture of cis - and trans-unsaturated sulfonates,
organic peracids17 to give 6-sulfonates. To avoid the
formation of disulfide derivatives we applied oxone–
acetic acid18 solution and compound 3 was obtained in
excellent yield. The presence of three O-benzyl groups
was advantageous for the chromatographic purification
of the sodium salt of the protected 6-sulfonate 3.
Compound 3 was hydrogenolyzed in ethanol in the
presence of 10% Pd–C catalyst to give the end product 4
(Scheme 1).
which were reduced with NaBH4 to afford the saturated
1,2:5,6-di-O-isopropylidene-a-D-allofuranose. This com-
pound is a 3-deoxy-3-methylene-sulfo derivative rather
than a 3-sulfo-sugar.
Recently, we have reported the synthesis12 of methyl 2-
deoxy-2-C-sulfo-a-
D
-manno- and -b-D-glucopyrano-
sides using a 1 fi 2 arylthio group migration in acid
sensitive thioglycosides, and to the best of our knowl-
edge, this is the first report on the preparation of a
secondary sugar sulfonic acid.
For the preparation of methyl 4-deoxy-4-C-sulfo-a-
glucopyranoside 8 we used methyl 2,3,6-tri-O-benzyl-a-
-galactopyranoside14 5, followed by the same sequence
D-
D
of reactions as was used for the preparation of 4.
The SN2-displacement reaction at C-4 resulted in the
Our aim is to replace the sulfate esters by sulfonic acids
in the repeating oligosaccharide units of glycosamino-
glycans or in different oligosaccharide ligands. We have
decided to apply nucleophilic displacement reactions for
the preparation of the appropriate sugar sulfonic acids.
Reactions with tosyl or mesyl esters were sluggish, so we
decided to apply triflate esters. Now, we report the
synthesis of 4-C- and 6-C-sulfonic acid derivatives of
D
-galacto fi
D-gluco-configurational change and pro-
ceeded with excellent yield and with complete stereo-
selectivity. The 4-S-acetyl intermediate 6 was oxidized to
7 by oxone, and the benzyl groups were removed by
catalytic hydrogenolysis to give the target compound 8
(Scheme 2).
methyl a-
D
-gluco- (8 and 4) and a-D-galactopyranosides
(12 and 19). The starting compounds (1,13 5,14 915 and
13) were trifluoromethylsulfonylated and treated with
CH3COSK to give crude products, which were used for
the next step without further purification. Methyl 2,3,
OH
BnO
O
O
a, b
O
OCH3
OBn
BnO
BnO
45%
4-tri-O-benzyl-6-S-acetyl-6-thio-a-D-glucopyranoside 2
was obtained from compound 1 (and characterized by
OCH3
OBn
13
14
1
its H and 13C NMR spectra). The 6-S-acetyl function-
16
Scheme 4. Reagents and conditions: (a)–(d) as for Scheme 1.
ality can be directly oxidized with H2O2 or with
OH
OBn
O
OBn
O
OBn
OH
BnO
O
C
O
O
a, b
NaO3S
c
d
96%
CH3
S
BnO
NaO3S
HO
51%
BnO
53%
OCH3
OCH3
OCH3
OCH3
OBn
OH
OBn
OBn
5
6
7
8
Scheme 2. Reagents and conditions: (a)–(d) as for Scheme 1.
O
OBn
O
OBn
O
OH
OBn
O
NaO3S
HO
NaO3S
BnO
CH3
C
S
O
c
a, b
d
95%
HO
BnO
BnO
67%
91%
OCH3
OCH3
OCH3
OCH3
OBn
OBn
OBn
OH
12
9
10
11
Scheme 3. Reagents and conditions: (a)–(d) as for Scheme 1.

A. Liptꢀak et al. / Tetrahedron Letters 45 (2004) 839–842
841
O
OH
O
S
C
CH3
O
O
O
a, b
O
O
55%
OBn
OBn
OCH3
OCH3
15
a, e
16
41%
c
83%
SO3Na
O
SO3Na
O
SO3Na
O
OH
HO
OH
HO
O
f
d
87%
O
98%
OBn
OBn
OH
OCH3
OCH3
OCH3
17
18
19
Scheme 5. Reagents and conditions: (a)–(d) as for Scheme 1; (e) Na2SO3, EtOH/H2O ¼ 1:1, reflux, 45 min; (f) 3% AcOH, CH2Cl2/H2O ¼ 99.5:0.5,
reflux, 5 h.
Table 1. Comparison of the 13C NMR data of the target compounds (4, 8, 19 and 12)22
C-1
C-2
C-3
C-4
C-5
C-6
OCH3
Solvent
4
100.83
100.77
101.50
99.24
73.41
73.75
69.98
67.76
70.18
74.97
70.00
71.42
69.30
71.96
74.91
63.49
72.43
70.92
61.87
69.41
70.00
68.55
66.62
70.37
54.98
63.98
53.47
51.91
63.50
55.95
55.80
56.06
55.19
55.77
CD3OD
CD3OD
CD3OD
D2O
8
19
12
100.82
CD3OD
Methyl 2,3,6-tri-O-benzyl-a-
D
-glucopyranoside15 9 was
Compound 17 was transformed into the methyl 6-
deoxy-6-C-sulfo-a- -galactopyranoside sodium salt 19
after removal of the isopropylidene (fi18) and benzyl
protecting groups. The structures of both intermediates
(17 and 18), as well as that of the product 19 were
confirmed by 2D NMR (Table 1).
transformed into compound 10 as described by Elhalabi
and Rice.15 The oxidation was achieved with oxone and
after catalytic hydrogenolysis compound 12 was isolated
and characterized (Scheme 3).
D
The approach used for the synthesis of compound 4 was
unsuccessful for the preparation of methyl 6-deoxy-6-C-
sulfo-a-D-galactopyranoside 19. Triflation of 13 resulted
in the 6-O-triflate derivative, but an intramolecular
displacement reaction occurred during treatment with
potassium thioacetate and methyl 3,6-anhydro-2,4-di-O-
benzyl-a-D
-galactopyranoside19 14 was formed (Scheme
4).
Acknowledgements
This work was supported by the Hungarian Research
Fund (OTKA: T 38066) and by the Hungarian Acad-
emy of Sciences.
A similar reaction was observed20 earlier in the case of
benzylated or methylated galactopyranoside derivatives
bearing good leaving groups at position 6. It was also
found19 that the presence of a 3,4-O-isopropylidene ring
can prevent the 4C1 fi 4C1 conformational flip. Based on
this observation a new route was worked out for the
synthesis of compound 19.
References and notes
1. (a) Benson, A. A.; Daniel, H.; Wiser, R. Proc. Natl. Acad.
Sci. 1959, 45, 1582–1584; (b) Benson, A. A. Adv. Lipid
Res. 1963, 1, 387–394.
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G. M. L.; Boyd, M. R. J. Natl. Cancer Inst. 1989, 81,
1254–1258.
Methyl 2-O-benzyl-3,4-O-isopropylidene-a-D-galacto-
pyranoside21 15 was first treated with trifluoro-
methanesulfonic anhydride. The triflyloxy group was
then converted into a thioacetyl moiety with potassium
thioacetate in DMF to yield 16. Treatment with
NaHSO3 in ethanol–water resulted in the sodium sul-
fonate 17. Compound 17 could equally well be obtained
by the oxidation of 16 with oxone (Scheme 5).
5. Gordon, D. M.; Danishefsky, S. J. J. Am. Chem. Soc.
1992, 114, 659–663.

842
A. Liptꢀak et al. / Tetrahedron Letters 45 (2004) 839–842
6. Reistad, R. Carbohydr. Res. 1977, 54, 308–310.
7. (a) Hanashima, S.; Mizushina, Y.; Yamazaki, T.; Ohta,
22. Selected physical and spectral data for the new com-
22
pounds: 2: ½aꢀ +24.8ꢁ (c 0.24, CHCl3); 1H NMR
22
D
K.; Takahashi, S.; Koshino, H.; Sahara, H.; Sakaguchi,
K.; Sugawara, F. Tetrahedron Lett. 2000, 41, 4403–4407;
(b) Hanashima, S.; Mizushina, Y.; Yamazaki, T.; Ohta,
K.; Takahashi, S.; Sahara, H.; Sakaguchi, K.; Sugawara,
F. Bioorg. Med. Chem. 2001, 9, 367–376.
(200 MHz, CDCl3): d 2.35 (s, 3H, CH3COS–); 13C NMR
(50 MHz, CDCl3): d 30.90 (C-6), 30.47 (CH3COS–); 3: ½aꢀ
D
+41.0ꢁ (c 0.09, MeOH); 13C NMR (50 MHz, CD3OD): d
22
53.75 (C-6). 4: ½aꢀ +82.1ꢁ (c 0.29, MeOH); 1H NMR
D
(400 MHz, CD3OD): d 4.68 (d, 1H, J1;2 ¼ 3:8 Hz, H-1),
4.07 (dd, 1H, J5;6a ¼ 1:9 Hz, J5;6b ¼ 9:2 Hz, H-5), 3.65 (t,
1H, J3;4 ¼ 9:3 Hz, H-3), 3.45 (dd, 1H, J2;3 ¼ 9:7 Hz, H-2),
8. Sahara, H.; Ishikawa, M.; Takahashi, N.; Ohtani, S.; Sato,
N.; Gasa, S.; Akino, T.; Kikuchi, K. British J. Cancer
1997, 75, 324–332.
9. Golik, J.; Dickey, J. K.; Todderud, G.; Lee, D.; Alford, J.;
Huang, S.; Klohr, S.; Eustice, D.; Aruffo, A.; Agler, M. L.
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891–895.
11. Musicki, B.; Widlanski, T. S. Tetrahedron Lett. 1991, 32,
1267–1270.
3.29 (dd, 1H, J6a;6b ¼ 14:5 Hz, H-6a), 3.12 (t, 1H,
22
J4;5 ¼ 9:5 Hz, H-4), 2.95 (dd, 1H, H-6b). 6: ½aꢀ +30.2ꢁ (c
0.53, CHCl3); 1H NMR (200 MHz, CDCl3): d D2.23 (s, 3H,
CH3COS–); 13C NMR (50 MHz, CDCl3): d 45.67 (C-4),
22
30.49 (CH3COS–). 7: ½aꢀ +41.1ꢁ (c 2.3, MeOH); 1H NMR
(200 MHz, CD3OD): d D3.27 (t, 1H, J4;5 ¼ 10:5 Hz, H-4);
22
13C NMR (50 MHz, CD3OD): 63.07 (C-4). 8: ½aꢀ +87.2ꢁ
D
(c 0.92, MeOH); 1H NMR (400 MHz, CD3OD): d 4.72 (d,
1H, J1;2 ¼ 3:7 Hz, H-1), 4.15 (t, 1H, J3;4 ¼ 9:7 Hz, H-3),
4.03–3.85 (m, 3H, H-5, H-6a, H-6b), 3.53 (dd, 1H,
ꢀ
ꢀ
ꢀ
12. Liptak, A.; Sajtos, F.; Janossy, L.; Gehle, D.; Szilagyi, L.
Org. Lett. 2003, 5, 3671–3674.
ꢀ
1–11.
14. Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J.
Carbohydr. Chem. 1983, 2, 305–311.
J2;3 ¼ 9:3 Hz, H-2), 3.42 (s, 3H, OCH3), 2.96 (t, 1H,
22
J4;5 ¼ 9:8 Hz, H-4). 10: ½aꢀ +41.8ꢁ (c 0.60, CHCl3); 1H
ꢀ ꢀ ꢀ
13. Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44,
D
NMR d 4.51 (t, 1H, J4;5 ¼ 1:7 Hz, H-4), 2.39 (CH3COS–);
13C NMR (125 MHz, CDCl3): d 47.10 (C-4), 30.63
22
D
(CH3COS–). 11: ½aꢀ +97.1ꢁ (c 0.46, MeOH); 1H NMR
22
15. Elhalabi, J.; Rice, K. G. Carbohydr. Res. 2001, 335, 159–
165.
(200 MHz, CD3OD) d 4.54 (H-4); 13C NMR (50 MHz,
CD3OD): d 60.59 (C-4). 12: ½aꢀ +111.5ꢁ (c 0.52, MeOH);
D
1H NMR (400 MHz, CD3OD) d 4.83 (d, 1H, J1;2 ¼ 3:6 Hz,
H-1), 4.23 (dd, 1H, J2;3 ¼ 10:3 Hz, H-2), 4.13 (m, 1H, H-3),
4.11 (dd, 1H, J5;6a ¼ 7:8 Hz, J5;6b ¼ 4:2 Hz, H-5), 4.04 (dd,
1H, J6a;6b ¼ 12:1 Hz, H-6a), 3.92 (dd, 1H, H-6b), 3.52 (dd,
ꢀ
16. Fernandez-Bolanos, J. G.; Morales, J.; Garcia, S.; Dianez,
M. J.; Dolores Estrada, M.; Lopez-Castro, A.; Perez, S.
~
ꢀ
ꢀ
ꢀ
Carbohydr. Res. 1993, 248, 1–14.
17. Hoch, M.; Heinz, E.; Schmidt, R. R. Carbohydr. Res.
1989, 191, 21–28.
18. Reddie, R. N. Synth. Commun. 1987, 17, 1129–1139.
1H, H-4). 16: 13C NMR (50 MHz, CDCl3): d 29.70 (C-6).
22
17: ½aꢀ +80.2ꢁ (c 0.49, MeOH); 13C NMR (50 MHz,
D
22
D
19. Borbas, A.; Biro, A.; Liptak, A. ACH-Models Chem. 1994,
CD3OD): d 52.92 (C-6). 18: ½aꢀ +74.7ꢁ (c 0.95, H2O); 13
C
ꢀ
131, 455–465.
ꢀ
ꢀ
NMR (50 MHz, D2O): d 52.70 (C-6). 19: ½aꢀ22 +83.6ꢁ (c 1.4,
D
20. (a) Winstein, S.; Allred, E.; Heck, R.; Glick, R. Tetrahe-
dron 1958, 1–13; (b) Brimacombe, J. S.; Ching, O. A. J.
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H2O); 1H NMR (400 MHz, CD3OD)
d
4.84 (d,
1H, J1;2 ¼ 3:8 Hz, H-1), 4.31 (t, 1H, J5;6a ¼ 6:0 Hz, H-5),
4.00 (d, 1H, J3;4 ¼ 3:1 Hz, H-4), 3.88 (dd, 1H, J2;3 ¼ 10:3,
H-3), 3.83 (dd, 1H, overlap, H-2), 3.22 (m, 2H, H-6a,
6b).
ꢀ
21. Mulard, L. A.; Kovaßc, P.; Glaudemans, C. P. J. Carbo-
hydr. Res. 1994, 259, 117–129.