A general method for the synthesis of sugar 2-C-sulfonic acids by 1 → 2 arylthio group migration in acid-sensitive thioglycosides. Direct transformation of thiotrityl ethers into C-sulfonic acids

Article abstract of DOI:10.1021/ol0353518

(Matrix presented) Fully protected triphenylmethyl 2-O-mesyl-1-thio-β- D-gluco- (14) and -α-D-mannopyranoside (28) were transformed by a stereoselective intramolecular 1 → 2 trans-arylthio migration into methyl 2-S-triphenylmethyl-α-D-manno- (15) and -β-D

Full text of DOI:10.1021/ol0353518

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3671-3674
A General Method for the Synthesis of
Sugar 2-C-Sulfonic Acids by 1
Arylthio Group Migration in
f 2
Acid-Sensitive Thioglycosides.1 Direct
Transformation of Thiotrityl Ethers into
C-Sulfonic Acids
Andra´s Lipta´k,*,† Ferenc Sajtos,† Lo´ra´nt Ja´nossy,‡ Diethmar Gehle,† and
La´szlo´ Szila´gyi§
Research Group for Carbohydrates of the Hungarian Academy of Sciences,
H-4010 Debrecen, P.O. Box 55, Hungary, Department of Biochemistry, UniVersity of
Debrecen, H-4010 Debrecen, P.O. Box 55, Hungary, and Department of Organic
Chemistry, UniVersity of Debrecen, H-4010 Debrecen, P.O.Box 20, Hungary
liptaka@tigris.klte.hu
Received July 21, 2003
ABSTRACT
Fully protected triphenylmethyl 2-O-mesyl-1-thio-
â
-D-gluco- (14) and -r-D-mannopyranoside (28) were transformed by a stereoselective
intramolecular 1 2 trans-arylthio migration into methyl 2-S-triphenylmethyl-
f
r
-D
-manno- (15) and - -glucopyranoside (29), respectively,
â-D
using NaOCH3 as nucleophile. The 2-S-triphenylmethyl ethers (15 and 29) were directly oxidized to sugar 2-C-sulfonic acids by using oxone
(2KHSO5, KHSO4, K2SO4). Compounds (21, 23, 32, and 35) are the first representatives of secondary sugar C-sulfonic acids.
The chloroplast membranes of all photosynthesizing plants
contain a glycolipid bearing a sugar component with a C-sul-
fonyl group.2 The most common representative of these sugar
sulfonic acids is 6-deoxy-6-sulfo-D-glucose (6-sulfoquino-
vose), which is one of the strongest acids occurring in nature.
The biosynthesis of 6-sulfoquinovose very probably follows
the reversed pathway of glycolysis, and the two starting
compounds are 3-sulfoglyceraldehyde and dihydroxyacetone
phosphate.3 Chemical syntheses of various 6-deoxy-6-sul-
fohexoses have been published.4
* Corresponding author.
† Research Group for Carbohydrates of the Hungarian Academy of
Sciences.
‡ Department of Biochemistry, University of Debrecen.
§ Department of Organic Chemistry, University of Debrecen.
(1) Lipta´k, A.; Sajtos, F.; Balla, E. Abstract, XXIst International
Carbohydrate Symposium, Cairns, Australia, July 7-12, 2002, PP146.
(2) (a) Benson, A. A.; Daniel, H.; Wiser, R. Proc. Natl. Acad. Sci.U.S.A.
1959, 45, 1582-1584. (b) Benson, A. A. AdV. Lipid Res. 1963, 1, 387-
394. (c) Harwood, J. L.; Nicholls, R. G. Biochem. Soc. Trans. 1979, 7,
440-447.
Pyranose C-sulfonates as mimics of charged ulosonic acid
species have been prepared using a nucleophilic addition
reaction.5 Quite recently, the preparation of anomeric R-D-
GlcpNAc 1-C-sulfonate has been also reported.6 To the best
10.1021/ol0353518 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/03/2003

our knowledge, the synthesis of secondary sugar sulfonic
acids has not yet been disclosed, although such derivatives
might successfully mimic the building blocks of sulfated
polysaccharides which have very important biological prop-
erties.
Scheme 2. Preparation of Protected 2′-Methylnaphthyl
â-D-Thioglucopyranosides: Transformation of Compound 8 into
Protected Methyl 2-Thio(2′-methylnaphthyl)-
R-D-mannopyranosidea
Our approach to 2-sulfonic acid sugars is based upon
stereospecific 1,2-alkyl/arylthio group migration7-10 and the
use of an easily removable arylthio group to regenerate the
2-SH, followed by oxidation. Trityl, p-methoxybenzyl, and
2′-methylnaphthyl â-D-thioglycosides were prepared from
appropriate isothiouronium salts (111 and 1012) using trityl
chloride, p-methoxybenzyl bromide, and 2′-methylnaphthyl
bromide as arylation agents (Schemes 1-3).
a Key: (a) 3.5 equiv of Na2CO3, 1.8 equiv of Na2SO3, CH2Cl2,
H2O, rt, 1.5 h, 1.3 equiv of NAPBr, Hunig’s base, CH2Cl2, rt, 24
h; (b) NaOMe/MeOH, rt, overnight; (c) 1.3 equiv of MsCl, 0.15
equiv of DMAP, dry pyridine, rt, overnight; (d) 5 equiv of NaOMe,
MeOH, reflux, 4 h.
Scheme 1. Preparation of Protected p-methoxybenzyl
â-D-thioglucosides: Transformation of Compound 4 into
Protected Methyl 2-Thio(p-methoxybenzyl)-
R-D-mannopyranosidea
Scheme 3. Preparation of Protected Trityl
â-D-Thioglucopyranosides: Transformation of Compound 14
into Protected Methyl 2-Thiotrityl-R-D-mannopyranosidea
a Key: (a) 3.5 equiv of Na2CO3, 1.8 equiv of Na2SO3, CH2Cl2,
H2O, rt, 1.5 h, 1.3 equiv of PMBnBr, Hunig’s base, CH2Cl2, rt, 24
h; (b) NaOMe/MeOH, rt, overnight; (c) 1.3 equiv of MsCl, 0.15
equiv of DMAP, dry pyridine, rt, overnight; (d) 5 equiv of NaOMe,
MeOH, reflux, 4 h.
The partially acetylated thioglycosides 2, 6, and 11 were
deacetylated to furnish OH-2 compounds (3 and 7); 12 was
aKey: (a) 3.5 equiv of Na2CO3, 1.8 equiv of Na2SO3, CH2Cl2,
H2O, rt, 1.5 h, 1.3 equiv of TrCl, Hunig’s base, CH2Cl2, rt, 24 h;
(b) NaOMe/MeOH, rt, overnight; (c) 1.3 equiv of MsCl, 0.15 equiv
of DMAP, dry pyridine, rt, overnight; (d) 5 equiv of NaOMe,
MeOH, reflux, 4 h; (e) 1.5 equiv of R,R-dimethoxytoluene, 0.2
equiv of pTSA‚H2O, dry DMF 50 °C, vacuum 2 h.
(3) Lehmann, J. In Kohlenhydrate; Georg Thieme Verlag: Stuttgart,
1996; p 296.
(4) (a) Miyano, M.; Benson, A. A. J. Am. Chem. Soc. 1962, 84, 59-62.
(b) Johns, S. R.; Leslie, D. R.; Willing, R. I.; Bishop, D. G. Austral. J.
Chem. 1978, 31, 65-72. (c) Gigg, R.; Penglis, A. A.; Conant, R. J. Chem.
Soc., Perkin Trans. 1 1980, 2490-2493. (d) Fernandez-Bolanos, J.; Maya
Castilla, I.; Fernandez-Bolanos Guzman, J. Carbohydr. Res. 1986, 147,
325-329. (e) Ulgar, V.; Maya, I.; Fuentes, J.; Fernandez-Bolanos, J. G.
Tetrahedron 2002, 58, 7967-7973. (f) Hanashima, S.; Mizushina, Y.;
Yamazaki, T.; Ohta, K.; Takahashi, S.; Sahara, H.; Sakaguchi, K.; Sugawara,
F. Bioorg. Med. Chem. 2001, 9, 367-376.
(5) Borba´s, A.; Szabovik, G.; Antal, Z.; Fehe´r, K.; Csa´va´s, M.; Szila´gyi,
L.; Herczegh, P.; Lipta´k, A. Tetrahedron: Asymmetry 2000, 11, 549-566.
(6) Knapp, S.; Darout, E. Tetrahedron Lett. 2002, 43, 6075-6078.
(7) Ryan, K. J.; Acton, E. M.; Goodman, L. J. Org. Chem. 1971, 36,
2646-2657.
(8) (a) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski,
A. J. Am. Chem. Soc. 1986, 108, 2466-2467. (b) Nicolaou, K. C.; Mitchell,
H. J.; Fylaktakidou, K. C.; Rodriguez, R. M.; Suzuki, H. Chem. Eur. J.
2000, 6, 3116-3148. (c) Nicolaou, K. C.; Mitchell, H. J.; Rodriguez, R.
M.; Fylaktakidou, K. C.; Suzuki, H.; Conley, S. R. Chem. Eur. J. 2000, 6,
3149-3165. (d) Nicolaou, K. C.; Fylaktakidou, K. C.; Mitchell, H. J.; van
Delft, F. L.; Rodriguez, R. M.; Conley, S. R.; Jin, Z. Chem. Eur. J. 2000,
6, 3166-3185.
transformed into a 4,6-O-benzylidene derivative (13). The
OH-2 compounds (3, 7, and 13) were mesylated to give
mesyl compounds (4, 8, and 14) ready for transformation
via 1 f 2 thio migration (Schemes 1-3). These reactions
were performed in methanol in the presence of 5 equiv of
NaOCH3 at reflux temperature for 4 h. The products were
obtained in high yields and with complete stereoselectivity;
starting from thio â-D-glucopyranosides, methyl 2-thio-R-
D-mannopyranosides (5, 9, and 15) were formed.
The p-methoxybenzyl group is commonly used for the
protection of SH groups in peptide13 and in nucleoside
chemistry.7,14 It can be removed under mild acidic (TFA, in
(9) (a) Auzanneau, F.-I.; Bundle, D. R. Carbohydr. Res. 1991, 212, 13-
24. (b) Pozsgay, V. Carbohydr. Res. 1992, 235, 295-302.
(10) (a) Zuurmond, H. M.; van der Klein, P. A. M.; van der Marel, G.
A.; van Boom, J. H. Tetrahedron Lett. 1998, 33, 2063-2066. (b) Johnston,
B. D.; Pinto, B. M. J. Org. Chem. 2000, 65, 4607-4617. (c) Yu, B.; Yang,
Z. Tetrahedron Lett. 2000, 41, 2961-2964.
(11) Compound 1 was prepared from 2-O-acetyl-3,4,6-tri-O-benzyl-R-
glucopyranosyl bromide (Kochetkov, N. K.; Dmitriev, B. A.; Chizhov, O.
S.; Klimov, E. M.; Malysheva, N. K.; Chernyak, A. Ya.; Bayramova, N.
E.; Torgov, V. I. Carbohydr. Res. 1974, 33, C5-C7) by treating with
thiourea (4.7 equiv) in dry boiling acetone for 15 min.
3672
Org. Lett., Vol. 5, No. 20, 2003

Scheme 4. Transformation of 2-Arylthioethers into
2-C-Sulfonic Acid Salts (Na and NHEt3) of
R-D-Mannopyranosidesa
Scheme 5. Preparation of Trityl 1-Thio-R-D-mannopyranoside
Derivatives and Transformation of the 2-O-Mesyl Compound
into 2-Thiotrityl Ether of Methyl â-D-Glucopyranoside: Its
Oxidation by Oxone into 2-C-Sulfonic Acid Salts (Na and
NHEt3) of Methyl â-D-Glucopyranosidea
a Key: (f) 1.2 equiv of mercuric trifluoroacetate, 80% AcOH,
rt, 4 h; (g) 8 equiv of DDQ, CH2Cl2, rt, 3 h; Ac2O, pyridine, rt, 3
h; (h) 1 equiv of AgNO3, 1 equiv of pyridine, dry CH2Cl2/dry EtOH
(1/1), reflux, 1.5 h; 4 equiv of dithiothreitol, dry EtOAc, rt,
overnight; (i) 18 equiv of m-CPBA, 2.5 equiv of NaOAc, CH2Cl2,
rt, 4 h; (j) 2.5 equiv of Oxone, 30 equiv of KOAc, concd AcOH,
rt, 5 h; (k) H2/Pd-C, AcOH, EtOH, rt, 24 h.
a Key: (l) 1.5 equiv of TrSH, 2 equiv of BF3‚Et2O, nitromethane,
rt, overnight; (m) 2 equiv of 2-methoxypropene, 0.2 equiv of pTSA,
dry DMF, 0 °C, 1 h; (n) 1.1 equiv of Bu2SnO, reflux, overnight,
1.1 equiv of BnBr, dry DMF, rt, overnight; (o) 10 equiv of NaOMe,
CH2Cl2/MeOH (1/1), reflux, 24 h; (p) TFA, CH2Cl2, H2O, rt, 3 h.
the presence of anisole or phenol) or reductive7 (sodium/
liquid ammonia) conditions to regenerate SH functionality.
When compound 5 was treated with AcOH in the
presence15 of mercuric trifluoroacetate, disulfide formation
occurred, and the product could be directly oxidized into
the desired C2-sulfonic acid derivative (17) by m-CPBA.
The 2-SNAP congener (9) was stable in the presence of
AcOH; it could be oxidatively cleaved using DDQ, although
a benzyl group was also removed during the reaction. The
product obtained after acetylation proved to be methyl 4-O-
acetyl-2-S-acetyl-3,6-di-O-benzyl-R-D-mannopyranoside (18).
The most promising results were obtained with the 2-S-
trityl derivative (15). Its hydrolysis resulted in the SH-2
compound (19) which was oxidized into a 2-SO3Na product
(20) using Oxone (2KHSO5, KHSO4, K2SO4) as the oxidation
agent in the presence of potassium acetate in glacial acetic
acid. Hydrolysis and oxidation can be performed in one step;
treatment of compound 15 with Oxone provided directly the
C2-sulfonic acid derivative (20) in good yield (Scheme 4).
Compounds 17 and 20 were hydrogenolyzed in ethanol in
the presence of 10% Pd-C catalyst to give compound 21.16
(12) Compound 10 was obtained from 2,4,6-tri-O-acetyl-3-O-benzyl-R-
D-glucopyranosyl bromide (Finan, P. A.; Warren, C. D. J. Chem. Soc. 1962,
3089) as in ref 11.
(13) (a) Sakakibara, S.; Nobuhara, Y.; Shimonishi, Y.; Kiyoi, R. Bull.
Chem. Soc. Jpn. 1965, 38, 120-123. (b) Martin, L.; Cornille, F.; Turcaud,
S.; Meudal, H.; Roques, B. P.; Fournie´-Zaluski, M.-C. J. Med. Chem. 1999,
42, 515-525.
(14) Divakar, K. J.; Mottoh, A.; Reese, C. B.; Sanghvi, Y. S. J. Chem.
Soc., Perkin Trans. 1 1990, 969-974.
(15) Zervas, L.; Photaki, I. J. Am. Chem. Soc. 1962, 84, 3887-3897.
Org. Lett., Vol. 5, No. 20, 2003
3673

When compound 20 was purified by column chomatog-
raphy in dichloromethane-methanol 65:35 (containing 1%
TEA), the TEA salt (22) was formed. Hydrogenolysis of 22
gave the TEA salt (23).
The easy transformation of the sugar thiotrityl ethers into
sugar C-sulfonic acid prompted us to prepare suitably
protected trityl 1-thio-R-D-mannopyranoside to be used for
the synthesis of 2-C-sulfonic acid of D-glucose.
Penta-O-acetyl-R-D-mannopyranose (24) was treated with
triphenylmethanethiol in the presence of BF3‚Et2O. The
syrupy product was isolated after column chromatography
and its deacetylation resulted in the crystalline triphenyl-
methyl 1-thio-R-D-mannopyranoside (25). The OH-4,6 were
protected by isopropylidenation (25 f 26), and the OH-3
of compound 26 was selectively activated by dibutyltin acetal
followed by treatment with benzyl bromide in DMF to give
27. The OH-2 of 27 was mesylated, and the fully protected
compound 28 was treated with 10 equiv of NaOMe in
dichloromethane-methanol (1:1) at reflux for 24 h. The
intramolecular thiotrityl migration proceeded with excellent
stereoselectivity and methyl 3-O-benzyl-4,6-O-isopropyli-
dene-2-S-trityl-â-D-glucopyranoside (29) was isolated. The
3J1,2) 5.9 Hz coupling constant confirmed the â-gluco-
configuration. Oxidation of the thiotrityl ether into C-sulfonic
acid proceeded smoothly without the hydrolysis of the
isopropylidene group. The sodium salt of the oxidized
product (30) could be isolated by organic solvent extraction.
Converting the Na salt into triethylamine salt (33) increased
the product solubility in organic solvents. The isopropylidene
groups of the salts (30 and 33) were hydrolyzed with diluted
TFA in dichloromethane at rt to give compounds 31 and
34. The purification was easy in these forms and the benzyl
group could be removed by catalytic hydrogenolysis (Pd on
Carbon) using ethanol containing traces of acetic acid
(Scheme 5).
The end products with gluco configuration (32 and 35)
1
were characterized by H- and 13C NMR spectra.
In summary, the 1,2-trans-thiotrityl glycosides are excel-
lent starting compounds for the preparation of 1,2-trans-2-
C-sulfonic acid salts of methyl glycosides. Compounds 21,
23, 32, and 35 are, to the best of our knowledge, the first
secondary C-sulfonic acids described in the literature. Their
biological investigation is in progress.
Acknowledgment. This work was supported by the
Hungarian Scientific Research Fund (OTKA: T 38066) and
by the Hungarian Academy of Sciences.
(16) All of the synthesized compounds exhibited spectral (1H NMR, 13
C
NMR) and analytical (MS) data were fully consistent with the assigned
structures.
OL0353518
3674
Org. Lett., Vol. 5, No. 20, 2003