Synthesis of thio-C-glycosides from 2′-carbonylalkyl C-glycosides by a tandem β-elimination and intramolecular hetero-Michael addition

Article abstract of DOI:10.1016/S0040-4039(03)01039-6

2′-Carbonyl 5-S-acetyl-C-glycofuranosides and 2′-carbonyl 4-S-acetyl-C-glycopyranosides were converted in good yields to respective 5-thio-C-glycopyranosides and 4-thio-C-glycofuranosides under base treatment. The transformation was resulted from β-elimin

Full text of DOI:10.1016/S0040-4039(03)01039-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4431–4433
Synthesis of thio-C-glycosides from 2%-carbonylalkyl
C-glycosides by a tandem b-elimination and intramolecular
hetero-Michael addition
Wei Zou,a,* Edith Lacroix,a Zerong Wanga and Shih-Hsiung Wub
aInstitute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada
bInstitute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
Received 10 April 2003; revised 22 April 2003; accepted 22 April 2003
Abstract—2%-Carbonyl 5-S-acetyl-C-glycofuranosides and 2%-carbonyl 4-S-acetyl-C-glycopyranosides were converted in good
yields to respective 5-thio-C-glycopyranosides and 4-thio-C-glycofuranosides under base treatment. The transformation was
resulted from b-elimination on 2%-carbonyl C-glycoside to form a,b-conjugated aldehyde (or ketone) and following intramolecular
hetero-Michael addition by the thiol group. Crown Copyright © 2003 Published by Elsevier Science Ltd. All rights reserved.
Thio-sugars, a class of sugar derivatives with sulfur in
the ring, have been used as glycosidase inhibitors1 and
precursors for the thionucleotides2 that have exhibited
potential antiviral and anticancer activities.3 In addi-
tion, thio-sugar have also been used to treat other
hetero-Michael addition then led to the formation of
stable b-C-glycopyranoside. Here, we describe
a
method based on the mechanism of this reaction, for
the synthesis of thio-C-glycosides using respective 4-S-
Ac and 5-S-Ac sugars as substrates. Under basic condi-
tions de-S-acetylation generates a thiol group, which, in
turn, reacts by an intramolecular 1,4-addition to an
a,b-conjugated aldehyde (ketone) intermediate to form
2%-carbonyl 5-thio-C-glycopyranosides and 4-thio-C-
glycofuranosides.
diseases; e.g. 1,5-dithio-b-D-xylopyranosides are orally
active against thrombosis by inhibition of glycosamino-
glycan biosynthesis;4 and natural products, Salacinol5
and Kotalanol,6 are potent a-glucosidase inhibitors and
could be useful for the treatment of diabetes. The
synthesis of thio-sugars has been reviewed by Fernan-
dez-Bolanos et al.7 However, few methods exist to
synthesize thio-C-glycosides, which may even be supe-
rior inhibitors because of their chemical and metabolic
stability. One synthesis reported by Praly et al. using
thio-xylopyranosyl trichloroacetamide as a donor and
heterocycles as receptors, afforded an anomeric mixture
(a/b 2:3–2:1) of thio-C-glycosides in moderate yields.8
Another was based on thio-glycosyl radical addition to
an enone derivative.9
Acetolysis of allyl C- -arabinofuranoside (1) with
L
0.05% H2SO4–Ac2O selectively removed the 5-O-benzyl
group to afford acetylated 2 in 70% yield. Removal of
5-O-Ac in 0.1% NaOMe followed by 5-O-mesylation
(MsCl/Py), converted 2 into 3 in 77% yield. An SN2
replacement by AcSK in DMF afforded allyl 5-S-ace-
tyl-C-furanoside 4, from which 2%-aldehyde 5 was then
derived by ozonolysis (O3 and Zn-HOAc) in good yield.
Meanwhile, compound 2 was also subjected to ozonoly-
sis and the resultant 2%-aldehyde was reacted to
MeMgBr to furnish an alcohol 7 in 87%. Four
diastereomers of 7 were formed which were inseparable.
After protection of 5-OH with trityl group (Ph3CCl/Py)
the 2%-OH of 8 was oxidized to ketone by PCC and 9
was obtained in 31% yield. No attempt was made to
optimize the reaction conditions. The trityl group was
then removed by treatment of 9 with ZnBr2 to give 10
(71%). The 5-OH was mesylated and substituted by
AcS− by a procedure similar to that described in the
preparation of 4 to obtain 2%-ketone derivative 11 in
60%.
Recently, we found that 2%-carbonyl a-C-glycosides can
be epimerized to their b-anomers by base treatment, the
intermediate being an acyclic a,b-conjugated aldehyde
or ketone formed by b-elimination.10 An intramolecular
Keywords: synthesis; thio-glycoside; C-glycoside; b-elimination;
cycloaddition.
* Corresponding author. Tel.: 1-(613)-991-0855; fax: 1-(613)-952-
9092; e-mail: wei.zou@nrc.ca
0040-4039/03/$ - see front matter Crown Copyright © 2003 Published by Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01039-6

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W. Zou et al. / Tetrahedron Letters 44 (2003) 4431–4433
As a mixture of two anomers (a/b 1:1) compounds 5
and 11 were treated overnight with 4% NaOMe. Under
basic conditions de-S-acetylation was quickly achieved
explained because it is known that 2%-carbonyl C-fura-
noside formed by O-1,4-addition can be reversibly
opened by b-elimination to form more thermodynami-
cally stable C-pyranosides.10
1
releasing a thiol group as indicated by H NMR analy-
sis, while the enolation of the 2%-carbonyl group and
subsequent b-elimination resulted in an acyclic a,b-con-
jugated aldehyde (from 5) or ketone (from 11) (see
Scheme 1). Thus, there were two nucleophiles compet-
ing in the hetero-Michael cycloaddition, i.e. the 4-
hydroxy group and 5-thiol group, but the complete
We further attempted to prepare thio-C-furanoside
from respective C-pyranoside assuming that the C1ꢀS
bond in 2%-carbonyl thio-C-glycoside formed by
cycloaddition, would be stable under these conditions.
Thus, we prepared 18 from 13 in five steps (see Scheme
2). De-O-acetylation of 13 was followed by benzylide-
nation in acetonitrile to give compound 14, which was
readily crystallized from reaction mixture in excellent
yield. Compound 15 obtained after benzylation of 14
was also crystallized (EtOAc–hexanes) without using
column chromatography. Regioselective opening of
benzylidene gave 16 (NaCNBH3/H+) in 81% yield,
which was in turn treated with triflic anhydride. The
conversion of C-furanosides (5 and 11) to 5-thio-C-a-L-
arabinopyranosides (6 and 12, 60–80%) were
achieved.11 The same results were also obtained when
the reactions were performed in the presence of
Zn(OAc)2, which indicates, on the contrary to our
previous suggestion, that the additional Zn++ was not
essential to the stereoselectivity. The absence of fura-
nosides and the stereoselectivity in the product can be
Scheme 1. Reagents and conditions: (a) 0.05% H2SO4–Ac2O, rt, overnight, 70%; (b) i. 0.1% NaOMe, rt, 2 h; ii. MeSO2Cl/Py, 0°C
to rt, overnight, 77%; (c) AcSK/DMF, rt, overnight, 62%; (d) O3/CH2Cl2, −78°C 1 h; Zn/HOAc, rt, overnight, 67%; (e) 4%
NaOMe, rt, overnight, 76% for 6 and 70% for 12; (f) MeMgBr/Et2O, −78°C, 87%; (g) Ph3CCl/Py, rt, overnight; 45%; (h)
PCC/NaOAc/CH2Cl2, 31%; (i) ZnBr2/CH2Cl2, 71%; (j) i. MeSO2Cl/Py, 0°C to rt, overnight; ii. AcSK/DMF, rt, overnight, 60%.
Scheme 2. Reagents and conditions: (a) i. 0.1% NaOMe, rt, 2 h; ii. PhCH(OMe)2/MeCN/TsOH, rt, overnight, 87%; (b)
BnBr/NaH/DMF, rt, overnight, 73%; (c) NaCNBH3/HCl/THF, 0°C to rt, 3 h, 81%; (d) i. Tf2O/Py-CH2Cl2, 0°C to rt, 3 h; ii.
AcSK/DMF, rt, overnight, 61%; (e) O3/CH2Cl2, −78°C 1 h; Zn/HOAc, rt, overnight, 77%; (f) 4% NaOMe, rt, overnight, 70%.

W. Zou et al. / Tetrahedron Letters 44 (2003) 4431–4433
4433
introduction of 4-S-Ac by replacement of 4-O-triflate
to 17 (61%) was accompanied by the inversion of
configuration at C4. Ozonolysis of 17 afforded 2%-car-
bonyl C-glycopyranoside 18 in 60–80% yield. After
base treatment of 18 we were able to obtain 4-thio-C-
furanoside 19 in 70% yield.12 The anomeric mixture of
19 was inseparable by silica gel chromatography and
6. Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda,
H. Chem. Pharm. Bull. 1998, 46, 1339–1340.
7. Fernandez-Bolanos, J. G.; Al-Masoudi, N. A.; Maya, I.
Adv. Carbohydr. Chem. Biochem. 2001, 57, 21–98.
8. Baudry, M.; Barberousse, V.; Descotes, G.; Faure, R.;
Pires, J.; Praly, J.-P. Tetrahedron 1998, 54, 7431–7446.
9. (a) Tsuruta, O.; Yuasa, H.; Kurono, S.; Hashimoto, H.
Bioorg. Med. Chem. Lett. 1999, 9, 807–810; (b) Yuasa,
H.; Kurono, S.; Hashimoto, H. Tetrahedron 1993, 49,
8977–8998.
1
the a/b ratio was ca. 3:1 as determined by H NMR
analysis. Both anomers were characterized by various
2D NMR techniques and the stereochemistry of b-
anomer in 19 was confirmed by the observation of an
NOE between H-1 and H-3.
10. Shao, H.; Wang, Z.; Laroix, E.; Wu, S.-H.; Jennings, H.
J.; Zou, W. J. Am. Chem. Soc. 2002, 124, 2130–2131.
1
11. Selected data for 6 and 12. For 6: H NMR (CDCl3) lH
2.50–2.53 (m, 2H, H-5e, CHHCHO), 2.66 (dd, 1H,
CHHCHO, J=7.6, 17.6 Hz), 2.90 (dd, 1H, H-5a, J=
10.0, 12.8 Hz), 3.64 (m, 2H, H-1, 2), 3.89 (m, 1H, H-3),
4.12 (m, 1H, H-4), 4.45–4.70 (m, 4H, 2×CH2Ph), 9.51 (bs,
1H, CHO); 13C NMR (CDCl3) lC 29.5 (C-5), 34.6 (C-1),
43.7 (CH2CO), 67.5 (C-4), 73.1 (CH2Ph), 73.4 (CH2Ph),
75.7 (C-2), 76.9 (C-3), 199.5 (CꢁO); HRFABMS: Calcd
for C21H25O4S (M+H): 373.1474. Found: 373.1522. For
In conclusion we have described a new method for the
preparation of 2%-carbonylalkyl thio-C-glycosides by a
tandem b-elimination and intramolecular hetero-
Michael addition. Both yield and stereoselectivity are
excellent for pyranosides, but a mixture of anomers was
obtained from thio-C-furanosides. Derivatization of the
2%-carbonyl group and further modification of the sugar
moiety could lead to useful synthetic intermediates.
1
12: H NMR (CDCl3) lH 1.96 (s, 3H, CH3), 2.33 (d, 1H,
4-OH, J=10 Hz), 2.45–2.51 (m, 2H, H-5ax, CHHCHO),
2.66 (dd, 1H, CH2CHO, J=8.4, 17.6 Hz), 2.90 (dd, 1H,
H-5eq, J=10.0, 13.2 Hz), 3.63–3.66 (m, 2H, H-1, 2), 3.97
(dd, 1H, H-3, J=2.8, 5.6 Hz), 4.11 (m, 1H, H-4), 4.43
and 4.62 (d and d, 1H each, CH2Ph, J=12.0 Hz), 4.50
and 4.72 (d and d, 1H each, CH2Ph, J=12.0 Hz), 7.28–
7.39 (m, 10H, 2×Ph); 13C NMR (CDCl3) lC 29.3 (C-5),
30.2 (CH3), 34.8 (C-1), 42.6 (CH2CO), 67.3 (C-4), 72.7
(CH2Ph), 72.8 (CH2Ph), 74.9 (C-2), 76.4 (C-3), 205.7
(CꢁO); HRFABMS: calcd for C22H27O4S (M+H):
387.1630. Found: 387.1664.
Acknowledgements
This work was supported in part by National Research
Council of Canada (to W.Z.) and National Science
Council of Taiwan (to S.-H.W.). We are grateful to Ms.
Lisa Morrison for mass spectroscopic analysis and Ms.
Suzon Laroque for her assistance in NMR analysis.
12. Selected data for 19 (a/b 3:1): HRFABMS: calcd for
C29H33O5S (M+H): 493.2049. Found: 493.1705. 19a: 1H
NMR (CDCl3) lH 2.62 (d, 1H, 5-OH, J=4.8 Hz), 2.79
(dd, 1H, CH2CHO, J=6.8, 18.8 Hz), 2.87 (dd, 1H,
CH2CHO, J=6.8, 18.8 Hz), 3.43 (dd, 1H, H-6a, J=6.4,
9.6 Hz), 3.60 (d, 1H, H-6b, J=2.8, 9.6 Hz), 3.74 (dd, 1H,
H-4, J=4.0, 10.0 Hz), 4.00 (m, 1H, H-2), 4.04 (m, 1H,
H-1), 4.13 (m, 1H, H-5), 4.29 (m, 1H, H-3), 4.48–4.64 (m,
6H, 3×CH2Ph), 7.19–3.38 (m, 15H, 3×Ph), 9.69 (s, 1H,
CHO); 13C NMR (CDCl3) lC 43.5 (C-1), 44.8
(CH2CHO), 51.4 (C-4), 70.0 (C-5), 73.8 (C-6), 82.5 (C-3),
83.4 (C-2), 200.5 (CꢁO). 19b: lH 2.78 (d, 1H, 5-OH,
J=4.8 Hz), 2.92 (dd, 1H, CHHCHO, J=6.8, 18.8 Hz),
2.98 (dd, 1H, CHHCHO, J=6.8, 18.8 Hz), 3.45 (dd, 1H,
H-6a, J=6.4, 9.6 Hz), 3.60 (d, 1H, H-6b, J=2.8, 9.6 Hz),
3.74 (dd, 1H, H-4, J=4.0, 10.0 Hz), 3.77 (m, 1H, H-1),
3.89 (m, 1H, H-2), 4.14 (m, 1H, H-5), 4.25 (m, 1H, H-3),
4.48–4.64 (m, 6H, 3×CH2Ph), 7.19–3.38 (m, 15H, 3×Ph),
9.64 (s, 1H, CHO); lC 45.0 (C-1), 50.2 (CH2CHO), 51.7
(C-4), 70.4 (C-5), 73.8 (C-6), 84.9 (C-3), 86.1 (C-2), 200.5
(CꢁO).
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