Synthesis of S-glycosyl primary sulfonamides

Article abstract of DOI:10.1021/jo9000367

The synthesis of S-glycosyl sulfonamides wherein the primary sulfonamide functional group (-SO₂NH₂) is directly attached to the anomeric position of a carbohydrate moiety is reported. Our general approach consists of first introducing a thioacetate group at the anomeric center of a per-O-acetylated sugar derivative From this follows formation of a glycosyl sulfenamide (sugar-SNR₂), oxidation of the sulfenamide to give a glycosyl N-protected sulfonamide (sugar-SO₂NR₂), and removal of the sulfonamide protecting (R) group to yield a primary sulfonamide at the anomeric center (sugar-SO₂NH₂). A variety of monoand disaccharide derivatives were synthesized using this new methodology

Full text of DOI:10.1021/jo9000367

Synthesis of S-Glycosyl Primary Sulfonamides
Marie Lopez, Nicolas Drillaud, Laurent F. Bornaghi, and Sally-Ann Poulsen*
Eskitis Institute, Griffith UniVersity, Brisbane, Queensland 4111, Australia
s.poulsen@griffith.edu.au
ReceiVed January 8, 2009
The synthesis of S-glycosyl sulfonamides wherein the primary sulfonamide functional group (-SO2NH2)
is directly attached to the anomeric position of a carbohydrate moiety is reported. Our general approach
consists of first introducing a thioacetate group at the anomeric center of a per-O-acetylated sugar derivative.
From this follows formation of a glycosyl sulfenamide (sugar-SNR2), oxidation of the sulfenamide to
give a glycosyl N-protected sulfonamide (sugar-SO2NR2), and removal of the sulfonamide protecting
(R) group to yield a primary sulfonamide at the anomeric center (sugar-SO2NH2). A variety of mono-
and disaccharide derivatives were synthesized using this new methodology.
SCHEME 1. Proposed Strategy To Synthesize S-Glycosyl
Introduction
Sulfonamidesa
The sulfonamide group has been proven to have remarkable
utility in medicinal chemistry and features in the structure of a
number of clinically relevant small molecules.1 Almost all
therapeutically used sulfonamides are aromatic (Ar-SO2NH2 or
Ar-SO2NHR).2 To our knowledge, there are no reports of the
synthesis of S-glycosyl sulfonamides wherein the primary
sulfonamide functional group is linked directly to the anomeric
position of a carbohydrate.
The synthesis of primary sulfonamides is typically achieved
by the reaction of a substituted sulfonyl chloride with excess
ammonia. Anomeric sulfonyl chlorides, in principle, could serve
as precursors to anomeric sulfonamides. Recently, Knapp and
co-workers3 attempted the synthesis of anomeric sulfonyl
chlorides with this task in mind. All conditions evaluated in
this study resulted instead in the formation of anomeric chlorides
as product rather than the desired anomeric sulfonyl chloride.
It was proposed that although the anomeric sulfonyl chloride
was likely to have formed it proved unstable toward loss of
SO2, rapidly converting into the chloride. The lack of stability
of precursor anomeric sulfonyl chlorides eliminates this synthetic
methodology as an avenue to anomeric sulfonamides. We now
present a relatively simple procedure for the preparation of
S-glycosyl primary sulfonamides. We expect anomeric sulfona-
a R ) sulfonamide protecting group. This general strategy is illustrated
for a monosaccharide but is proposed to apply to a range of carbohydrate
substrates.
mides, as new chemical entities, will prove to be a valuable
species to investigate biological interactions and other param-
eters relevant to drug discovery.
Results and Discussion
Glycosyl sulfenamides (sugar-SNR2) have been prepared and
oxidized to glycosyl N,N-disubstituted sulfonamides (sugar-
SO2NR2) by others.4 We reasoned that this methodology may
be exploited to generate S-glycosyl primary sulfonamides (sugar-
SO2NH2) if an appropriate sulfonamide protecting group (R)
could be employed throughout the synthesis. Our general
approach, outlined in Scheme 1, consists of first introducing a
* Corresponding Author. Phone: +61 7 3735 7825. E-mail: s.poulsen@
griffith.edu.au.
(1) Njardarson, J. T. Cornell University; Outreach Web Page. http://
www.chem.cornell.edu/jn96/outreach.html (accessed November 2008).
(2) (a) Anand, N. Burger’s Medicinal Chemistry and Drug DiscoVery, 5th
ed.; Wollf, M. E., Ed.; John Wiley & Sons: New York, 1996; Vol. 2, p 527. (b)
Supuran, C. T. Nat. ReV. Drug DiscoVery 2008, 7, 168.
(4) (a) Owen, D. J.; von Itzstein, M. Carbohydr. Res. 2000, 328, 287. (b)
Owen, D. J.; Davis, C. B.; Hartnell, R. D.; Madge, P. D.; Thomson, R. J.; Chong,
A. K. J.; Coppel, R. L.; von Itzstein, M. Bioorg. Med. Chem. Lett. 2007, 17,
2274.
(3) Knapp, S.; Darout, E.; Amorelli, B. J. Org. Chem. 2006, 71, 1380.
10.1021/jo9000367 CCC: $40.75
Published on Web 03/10/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2811–2816 2811

Lopez et al.
a
SCHEME 2. Synthesis of Sulfonamides 4 and 5 from Per-O-acetylated D-Glucose
a Route a: R1 ) R2 ) DMB. Route b: R1 ) DMB, R2 ) H. Route c: R1 ) PMB, R2 ) H.
thioacetate group at the anomeric center of the per-O-acetylated
sugar derivative. From this follows formation of a glycosyl
sulfenamide (sugar-SNR2),4a oxidation of the sulfenamide to
give a glycosyl N-protected sulfonamide (sugar-SO2NR2), and
removal of the sulfonamide protecting (R) group to yield a
primary sulfonamide at the anomeric center (sugar-SO2NH2).
Thus the “R” protecting group must be readily introduced, be
stable to oxidation conditions, and readily removed following
oxidation so as to unmask the primary sulfonamide group. As
a final step, the deprotection of the hydroxyls of the glycosyl
moiety using standard Zemplen conditions5 should give the fully
deprotected target S-glycosyl sulfonamide.
Given the prominence of the sulfonamide group in medicinal
chemistry, there is a surprising paucity in the literature with
regard to protecting group strategies for primary sulfonamides.
A literature search revealed a small number of examples where
the 2,4-dimethoxybenzyl (DMB) substituent had been employed
as a protecting group for sulfonamides.6 We commenced
investigation of the DMB moiety as a protecting group with
the synthesis of the N,N-(DMB)2 glucosyl sulfenamide 2a.
Compound 2a was prepared with high anomeric stereoselectivity
from 1, diethyl bromomalonate, and bis(2,4-dimethoxybenzyl)-
amine as base (Scheme 2, route a).4a Oxidation of 2a with
m-CPBA led to a complex mixture of components, and we
postulated that the byproduct (m-chlorobenzoic acid) of the
reaction partially cleaves the acid-labile DMB groups.7 Misra
recently reported the rapid oxidation of thioglycosides to
glycosyl sulfones using a combination of KMnO4 and
CuSO4 ·5H2O in acetonitrile and water.8 These oxidative condi-
tions are neutral, and Misra confirmed compatibility with several
acid-labile hydroxyl protecting groups of sugar derivatives
including benzylidene acetal, isopropylidene acetal, and TB-
DMS.8 We were thus encouraged to investigate the capacity of
this mild oxidative protocol to effect the oxidation of sulfena-
mide 2a in the presence of our acid-labile protecting group.
Gratifyingly, the oxidation proceeded smoothly, leading to the
N,N-(DMB)2-protected glucosyl sulfonamide 3a (Scheme 2,
route a). Next, the DMB groups of 3a were removed using acidic
conditions (10% TFA in CH2Cl2), and this reaction was
complete after 2 h and delivered the target per-O-acetylated
glucosyl sulfonamide 4. Zemplen’s conditions5 were employed
to remove the acetate groups of 4 to prepare the fully deprotected
anomeric sulfonamide 5. Sulfonamides 4 and 5 were spectro-
scopically characterized using 1D and 2D NMR (1H, 13C,
gCOSY, gHSQC) and ESI HRMS. All characterization data
were consistent with the target structures. A characteristic signal
for the sulfonamide protons (SO2NH2) of 4 was observed at δ
5.01 ppm in CDCl3 and δ 7.22 ppm in DMSO-d6 and for 5 δ
6.69 ppm in DMSO-d6.
Although we had successfully synthesized the S-glucosyl
primary sulfonamides 4 and 5, we sought to further improve
our synthesis. The N,N-(DMB)2-protected compoundsssul-
fenamide 2a and sulfonamide 3asproved highly sensitive on
normal phase silica and were difficult to manipulate without
substantial degradation during standard purification protocols.
Even when the silica was preconditioned with 1% Et3N,
degradation occurred (including loss of the DMB group). Further
to this, bis(2,4-dimethoxybenzyl)amine is not commercially
available and required a two-step synthesis over 2 days using
hazardous reagents. We therefore decided to investigate the
utility of the primary amine derivatives 2,4-dimethoxybenzy-
lamine and 4-methoxybenzylamine in our synthesis as these
have the advantage of being readily available from commercial
suppliers. We had a concern that these reagents, as primary
amines, may cause undesirable O-deacetylation of the carbo-
hydrate moiety;4a however, this was not observed. As a
protecting group, the 4-methoxybenzyl substituent (PMB) should
have intermediate stability toward acid-promoted removal
compared to the more acid-labile DMB protecting group.
Sulfenamides 2b (NH-DMB) and 2c (NH-PMB) were syn-
thesized from 1 similarly to 2a (Scheme 2, routes b and c,
respectively). As observed for 2a, compound 2b was also
unstable on normal phase silica preconditioned with 1% Et3N
and so was instead semipurified on C18 reverse phase silica to
remove excess amine reagent. The PMB compound 2c was more
(5) Zemplen, G. Ber. Deutsch. Chem. Ges. 1926, 59, 1254.
(6) (a) Hill, B.; Liu, Y.; Taylor, S. D. Org. Lett. 2004, 6, 4285. (b) Hill, B.;
Ahmed, V.; Bates, D.; Taylor, S. D. J. Org. Chem. 2006, 71, 8190. (c) Navidpour,
L.; Lu, W.; Taylor, S. D. Org. Lett. 2006, 8, 5617. (d) Chen, L.; Gao, G.; Bonnac,
L.; Wilson, D. J.; Bennett, E. M.; Jayaram, H. N.; Pankiewicz, K. W. Bioorg.
Med. Chem. Lett. 2007, 17, 3152.
(7) Kocienski, P. J. Protecting Groups, 2nd ed.; Thieme: Stuttgart, 2000.
(8) Agnihotri, G.; Misra, A. K. Carbohydr. Res. 2006, 341, 275.
2812 J. Org. Chem. Vol. 74, No. 7, 2009

Synthesis of S-Glycosyl Primary Sulfonamides
TABLE 1. Synthesized S-Glycosyl Sulfonamides
a Yield (%) over three steps from thioacetate. b Yield (%) for Zemplen deprotection. c Yield (%) for deprotection using sodium hydroxide.
stable to chromatography on normal phase silica (conditioned
with 1% Et3N), consistent with the reduced lability of this
protecting group toward an acidic environment. Compounds 2b
and 2c were oxidized to the sulfonamides 3b and 3c, respec-
tively, applying our previously used neutral oxidation conditions
(KMnO4/CuSO4 ·5H2O). A small amount of protecting group
loss was observed during these reactions; however, oxidation
predominates, leading to a relatively clean reaction mixture that
required only an aqueous workup followed by purification on
reverse phase silica (C18). The deprotection of 3b and 3c to
remove the DMB and PMB groups was then achieved by stirring
with a solution of TFA in CH2Cl2 at room temperature to
generate the primary sulfonamide 4. Deprotection of 3b was
complete in 2 h (25% TFA, yield 10% over three steps from
thioacetate 1), while deprotection of 3c required 2 days (50%
TFA, yield 26% over three steps from thioacetate 1).
Each of the three sulfonamide protecting groups, (DMB)2,
DMB, and PMB, allowed the successful transformation of
thioacetate 1 to the primary sulfonamide 4 through the combina-
tion of neutral oxidizing conditions followed by acid-catalyzed
selective deprotection. The ready availability of the starting
amines for routes b and c is an advantage; however, the ease of
removal of the DMB group compared to the PMB group brings
us to conclude that DMB (route b) is the most practical
protecting group to facilitate the synthesis of anomeric sulfona-
mides for our substrates. Although not strictly a one-pot
synthesis, the use of intermediates 2b and 3b in a semipurified
form following rapid chromatography on reverse phase silica
(C18 SPE cartridges) proved highly effective and made the
overall transformation of glycosyl thioacetate to anomeric
sulfonamide a relatively succinct synthetic procedure.
Having the reaction conditions to form anomeric primary
sulfonamides established on the D-glucose moiety (to prepare
4 and 5), we then applied our methodology to a variety of
mono- (D-galactose, D-glucuronic acid) and disaccharide
(maltose, lactose) derivatives (Table 1). Glycosyl thioacetates
6-9 were synthesized from per-O-acetylated sugars using
thiourea and boron trifluoroetherate in yields ranging from
47 to 79%.9 The corresponding sulfenamides were prepared
from 2,4-dimethoxybenzyl amine similarly to 2b and were
used in the next step following semipurification on reverse
phase silica (C18). Oxidation of sulfenamides as before
(KMnO4/CuSO4 · 5H2O) followed by deprotection of the DMB
group with 25% TFA in CH2Cl2 for 2 h gave the target
anomeric primary sulfonamides 10-13 (18-45% yields over
three steps). Next, Zemplen’s conditions5 were applied to
remove the acetate groups of compounds 10, 12, and 13,
while NaOH (0.07 M) was used to deprotect both the
hydroxyl and carboxylic acid groups of the glucuronic acid
derivative 11. The fully deprotected anomeric sulfonamide
compounds 14-17 were obtained in good to high yields
(Table 1).
Conclusions
In conclusion, we have developed a relatively simple and
general procedure for the synthesis of S-glycosyl primary
sulfonamides starting from per-O-acetylated sugar derivatives.
Our approach has been to optimize reaction transformations
(9) Ibatullin, F. M.; Shabalin, K. A.; Ja¨nis, J. V.; Shavvac, A. G. Tetrahedron
Lett. 2003, 44, 7961.
J. Org. Chem. Vol. 74, No. 7, 2009 2813

Lopez et al.
N-(2,4-Dimethoxybenzyl)-1-S-(2,3,4,6-tetra-O-acetyl)-D-glu-
copyranosylsulfonamide (3b). The title compound was synthesized
from sulfenamide 2b (3.54 g, 6.68 mmol, 1.0 equiv) with the
procedure described for compound 3a. After washing, the crude
yellow oil obtained was used without purification: Rf ) 0.31 (1:1
EtOAc/hexane); LRMS (ESI+) m/z 584 [M + Na]+; HRMS (ESI)
calcd for C23H31N1O13SNa+ 584.1408, found 584.1411.
appropriate for the protecting group requirements leading to the
anomeric sulfonamide. We also propose that the DMB group
is a viable sulfonamide protecting group provided neutral
reaction conditions are employed.
Experimental Section
N-(4-Methoxybenzyl)-1-S-(2,3,4,6-tetra-O-acetyl)-D-glucopy-
ranosylsulfonamide (3c). To a solution of thioacetate derivative
1 (307 mg; 0.76 mmol, 1.0 equiv) in anhydrous MeOH (15 mL)
under argon was added diethyl bromomalonate (0.3 mL, 1.78 mmol,
2.3 equiv). The solution was stirred at rt for 20 min, and then
4-methoxybenzylamine (0.50 mL, 3.85 mmol, 5.1 equiv) was added.
The reaction mixture was stirred overnight at rt. The mixture was
concentrated, then purified by flash chromatography (2:3 EtOAc/
hexane, Rf ) 0.38). A yellow oil (313 mg, 0.63 mmol, 83%) was
obtained. Oxidation of the sulfenamide occurred as described for
the preparation of compound 3a using catalytic system (KMnO4/
CuSO4 · 5H2O; 1:1; w/w; 1.0 g, 4.2:2.6 equiv) in CH3CN/H2O
(5:1, 180 mL). The crude mixture was semipurified on reverse phase
silica (C-18 prepacked cartridge, 5 g sorbent) eluted with a gradient
of H2O/MeOH. Elution of sulfonamide 3c occurred over five
fractions (60-100% MeOH): Rf ) 0.37 (1:1 EtOAc/hexane); LRMS
(ESI+) m/z 554 [M + Na]+.
N,N-Bis(2,4-dimethoxybenzyl)-1-S-(2,3,4,6-tetra-O-acetyl)-D-
glucopyranosylsulfenamide (2a). To a solution of thioacetate
derivative 1 (1.21 g, 2.98 mmol, 1.0 equiv) in anhydrous MeOH
(60 mL) under argon was added diethyl bromomalonate (1.2 mL,
7.13 mmol, 2.4 equiv). The solution was stirred at rt for 20 min,
and then bis(2,4-dimethoxybenzyl)amine (3.79 g, 11.9 mmol, 4.0
equiv) was added. The reaction mixture was stirred overnight at rt,
after which a precipitate was formed. The precipitate was collected
by filtration and washed with MeOH to afford the title compound
2a as a white solid (1.60 g, 2.35 mmol, 79%): Rf ) 0.47 (1:1 EtOAc/
hexane); mp ) 143-144 °C; 1H NMR (500 MHz, DMSO-d6) δ )
7.16 (d, J ) 8.5 Hz, 2H, Harom), 6.48 (m, 4H, Harom), 5.32 (t, J )
9.5 Hz, 1H, H-3), 5.21 (d, J ) 10.0 Hz, 1H, H-1), 4.86 (t, J ) 9.5
Hz, 1H, H-4), 4.65 (t, J ) 10.0 Hz, 1H, H-2), 4.14 (dd, J ) 6.0,
12.5 Hz, 1H, H-6a), 4.06 (m, 1H, H-5), 4.02 (m, 1H, H-6b), 3.99
(m, 4H, NCH2), 3.74, 3.70 (2 × s, 12H, OCH3), 2.01, 1.97, 1.94,
1.83 (4 × s, 12H, OCOCH3), assignments were confirmed by
1H-1H gCOSY; LRMS (ESI+) m/z ) 680 [M + H]+, 702 [M +
Na]+.
1-S-(2,3,4,6-Tetra-O-acetyl)-D-glucopyranosylsulfonamide (4).
The crude mixture of the protected sulfonamide 3b was dissolved
in a solution of 25% trifluoroacetic acid (TFA) in CH2Cl2 (24 mL)
and stirred 2 h at rt. Solvent and TFA were evaporated under
reduced pressure, and the remaining residue was diluted with
CH2Cl2 (150 mL) and washed with brine (×3). The aqueous extracts
were back extracted with CH2Cl2 (×2), and then all organic extracts
were combined, dried over MgSO4, filtered, and evaporated. The
residue was purified by flash chromatography with solid addition
(99:1 CH2Cl2/MeOH) to afford the title sulfonamide 4 as a colorless
solid (372 mg, 0.90 mmol, 14% over two steps from 2b): Rf )
N-(2,4-Dimethoxybenzyl)-1-S-(2,3,4,6-tetra-O-acetyl)-D-glu-
copyranosylsulfenamide (2b). The title compound was synthesized
from thioacetate 1 (300 mg, 0.74 mmol, 1.0 equiv), diethylbromo-
malonate (0.30 mL, 1.78 mmol, 2.4 equiv), and 2,4-dimethoxy-
benzylamine (0.42 mL, 2.80 mmol, 3.8 equiv) using the procedure
described for compound 2a. The crude product was semipurified
on reverse phase silica (C-18 prepacked cartridge, 5 g sorbent) with
a gradient of H2O/MeOH. The title compound eluted over four
fractions (40-70% MeOH) and was obtained as a yellow oil (265
0.26 (1:1 EtOAc/hexane); mp ) 210-211 °C; [R]25 ) -6 (c )
1
D
mg, 0.50 mmol, 68%): Rf ) 0.57 (1:1 EtOAc/hexane); H NMR
1
1.0, chloroform); H NMR (500 MHz, CDCl3) δ ) 5.36 (d, J )
(500 MHz, DMSO-d6) δ ) 7.13 (d, J ) 8.0 Hz, 1H, Harom), 6.53
(d, J ) 2.5 Hz, 1H, Harom), 6.46 (dd, J ) 2.5, 8.5 Hz, 1H, Harom),
5.35 (t, J ) 9.5 Hz, 1H, H-3), 5.00 (t, J ) 10.0 Hz, 1H, H-2), 4.89
(t, J ) 9.5 Hz, 1H, H-4), 4.69 (t, J ) 10.0 Hz, 1H, H-1), 4.06 (m,
4H, H-6a, H-6b, NCH2), 3.98 (m, 1H, H-5), 3.79, 3.75 (2 × s, 6H,
OCH3), 2.00, 1.99, 1.97, 1.96 (4 × s, 12H, OCOCH3), assignments
9.5 Hz, 1H, H-3), 5.33 (d, J ) 9.5 Hz, 1H, H-2), 5.14 (t, J ) 9.5
Hz, 1H, H-4), 4.96 (br s, 2H, NH2), 4.38 (d, J ) 9.0 Hz, 1H, H-1),
4.37 (dd, J ) 5.0, 12.5 Hz, 1H, H-6a), 4.18 (dd, J ) 2.5, 12.5 Hz,
1H, H-6b), 3.87 (ddd, J ) 2.5, 5.0, 10.5, 1H, H-5), 2.11, 2.10,
2.06, 2.04 (4 × s, 12H, OCOCH3), assignments were confirmed
by 1H-1H gCOSY; 13C NMR (125 MHz, CDCl3) δ ) 170.9, 170.6,
169.9, 169.4 (OCOCH3), 87.5 (C-1), 76.7 (C-5), 72.7 (C-3), 68.2
(C-2), 67.9 (C-4), 61.6 (C-6), 20.7, 20.6, 20.5 (2C) (OCOCH3),
assignments were confirmed by 1H-13C HSQC; LRMS (ESI+) m/z
) 434 [M + Na]+; LRMS (ESI-) m/z ) 410 [M - H]-; HRMS
(ESI) calcd for C14H21N1O11SNa+ 434.0728, found 434.0708.
1-S-D-Glucopyranosylsulfonamide (5). General Procedure 1.
Fully deprotected compound 5 was prepared by treating a solution
of the per-O-acetylated compound 4 (191 mg, 0.46 mmol, 1.0 equiv)
in anhydrous MeOH (15 mL) at 0 °C with methanolic sodium
methoxide (25% w/v, 1 mL, 1.0 equiv), final pH ) 14. The reaction
was warmed to rt and left to stir until full deprotection was evident
by TLC (∼2 h). The solution was neutralized with Amberlite IR-
120 [H+], filtered, and the resin washed several times with methanol.
The solvent was evaporated under reduced pressure and lyophilized
to dryness to furnish the title sulfonamide 5 as a slightly yellow
hygroscopic solid (113 mg, 0.46 mmol, ∼100%) which was pure
1
were confirmed by H-1H gCOSY; LRMS (ESI+) m/z ) 530 [M
+ H]+, 552 [M + Na]+.
N,N-Bis(2,4-dimethoxybenzyl)-1-S-(2,3,4,6-tetra-O-acetyl)-D-
glucopyranosylsulfonamide (3a). A finely ground mixture of the
catalytic oxidative system (KMnO4/CuSO4 ·5H2O; 1:1; w/w; 2.4 g,
6.3:4.0 equiv) was dissolved in H2O (5 mL) and added to a solution
of sulfenamide 2a (825 mg, 1.21 mmol, 1.0 equiv) in acetonitrile
(15 mL). The reaction was stirred at rt for 1.5 h, after which the
acetonitrile was evaporated under reduced pressure and the remain-
ing aqueous residue extracted with EtOAc (×1). The organic phase
was washed with brine (×2), and aqueous extracts were back
extracted with EtOAc (×2). The organic extracts were combined,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (2:3 EtOAc/hexane, 1% Et3N)
affording the title compound as a yellow oil (150 mg, 0.21 mmol,
17%): Rf ) 0.32 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ ) 7.18 (m, 2H, Harom), 6.38 (dd, J ) 2.5, 8.0 Hz, 2H, Harom),
6.35 (d, J ) 2.5 Hz, 2H, Harom), 5.34 (t, J ) 9.5 Hz, 1H, H-2),
5.13 (t, J ) 9.5 Hz, 1H, H-3), 4.97 (t, J ) 10.0 Hz, 1H, H-4), 4.51
(d, J ) 16.0 Hz, 2H, NCH2), 4.29 (d, J ) 10.0 Hz, 1H, H-1), 4.20
(d, J ) 16.0 Hz, 2H, NCH2), 3.99 (dd, J ) 5.5, 10.0 Hz, 1H, H-6a),
3.94 (dd, J ) 2.5, 10.0 Hz, 1H, H-6b), 3.74, 3.69 (2 × s, 12H,
OCH3), 3.53 (m, 1H, H-5), 2.00, 1.95, 1.94, 1.93 (4 × s, 12H,
OCOCH3), assignments were confirmed by 1H-1H gCOSY; LRMS
(ESI+) m/z ) 734 [M + Na]+; HRMS (ESI) calcd for
C32H41N1O15SNa+ 734.2089, found 734.2085.
by 1H NMR: Rf ) 0.1 (9:1 CH3CN/H2O); mp ) 63-64 °C; [R]25
D
1
) + 5 (c ) 0.9, MeOH); H NMR (500 MHz, DMSO-d6) δ )
6.69 (br s, 2H, NH2), 5.11 (m, 1H, OH), 5.05 (d, J ) 5.0 Hz, 1H,
OH), 5.02 (d, J ) 5.5 Hz, 1H, OH), 4.47 (m, 1H, OH), 4.05 (d, J
) 9.5 Hz, H-1), 3.68 (m, 1H, H-6a), 3.45 (m, 2H, H-6b, H-2),
3.25 (m, 2H, H-5, H-3), 3.05 (m, 1H, H-4), assignments were
confirmed by 1H-1H gCOSY; 13C NMR (125 MHz, DMSO-d6) δ
) 90.5 (C-1), 81.3 (C-5), 77.3 (C-3), 70.6 (C-2), 69.6 (C-4), 61.2
(C-6) assignments were confirmed by 1H-13C HSQC; LRMS
2814 J. Org. Chem. Vol. 74, No. 7, 2009

Synthesis of S-Glycosyl Primary Sulfonamides
(ESI+) m/z ) 266 [M + Na]+; HRMS (ESI) calcd for
C6H13N1O7SNa+ 266.0305, found 266.0309.
assignments were confirmed by 1H-13C HSQC; LRMS (ESI+) m/z
) 722 [M + Na]+; LRMS (ESI-) m/z ) 697 [M - H]-; HRMS
(ESI) calcd for C26H37N1O19SNa+ 722.1573, found 722.1541.
(2,3,4,6-Tetra-O-acetyl-r-D-glucopyranosyl)-(1f4)-1,2,3,6-
tetra-O-acetyl-1-thio-ꢀ-D- glucopyranosylsulfonamide (13). The
title compound was obtained from thioacetate 9 (3.89 g, 5.60 mmol,
1.0 equiv) as described in general procedure 2 and obtained as a
light orange solid (1.76 g, 2.52 mmol, 45%): Rf ) 0.25 (3:2 EtOAc/
1-S-(2,3,4,6-Tetra-O-acetyl)-D-galactopyranosylsulfonamide
(10). General Procedure 2. The title compound was synthesized
over three steps from thioacetate derivative 6. First, the intermediate
sulfenamide was prepared from thioacetate 6 (4.00 g, 9.84 mmol,
1.0 equiv), diethyl bromomalonate (0.30 mL, 1.78 mmol, 2.4 equiv),
and 2,4-dimethoxybenzylamine (0.42 mL, 2.80 mmol, 3.8 equiv)
using the procedure described for the preparation of compound 2a.
This intermediate was semipurified on reverse phase silica (C-18
prepacked cartridge, 5 g sorbent) using a gradient of H2O/MeOH
and eluted over three fractions (60-80% MeOH) to give a yellow
oil. This sulfenamide intermediate was immediately submitted to
oxidation using the procedure described for preparation of com-
pound 3a to afford the N-protected sulfonamide intermediate which
was used without purification: Rf ) 0.29 (1:1 EtOAc/hexane).
Removal of the DMB protecting group was achieved as described
for compound 4. The yellow oil obtained was purified by flash
chromatography (1:1 EtOAc/hexane) to afford the title sulfonamide
10 (980 mg, 2.38 mmol, 24% over three steps): Rf ) 0.22 (1:1
EtOAc/hexane); [R]25D ) + 5 (c ) 1.1, chloroform); 1H NMR (500
MHz, CDCl3) δ ) 5.50 (t, J ) 9.5 Hz, 1H, H-2), 5.49 (t, J ) 9.5
Hz, 1H, H-3), 5.19 (dd, J ) 3.0, 10.0 Hz, 1H, H-4), 5.03 (br s, 2H,
NH2), 4.39 (d, J ) 10.0 Hz, 1H, H-1), 4.24 (m, 1H, H-6a), 4.16
(m, 1H, H-5), 4.11 (m, 1H, H-6b), 2.19, 2.11, 2.07, 2.02 (4 × s,
12H, OCOCH3), assignments were confirmed by 1H-1H gCOSY;
13C NMR (125 MHz, CDCl3) δ ) 171.3, 170.5, 170.1, 169.9
(OCOCH3), 88.1 (C-1), 75.6 (C-5), 70.8 (C-4), 67.1 (C-3), 65.6
(C-2), 61.1 (C-6), 20.7, 20.5 (2C), 20.4 (OCOCH3), assignments
hexane); mp ) 96-98 °C; [R]25 ) + 57 (c ) 1.3, chloroform);
D
1H NMR (500 MHz, CDCl3) δ ) 5.41 (t, J ) 9.0 Hz, 1H, H-3),
5.41 (d, J ) 3.5 Hz, 1H, H-1′), 5.37 (t, J ) 10.0 Hz, 1H, H-3′),
5.19 (t, J ) 9.5 Hz, 1H, H-2), 5.07 (t, J ) 10.0 Hz, 1H, H-4′),
4.95 (br s, 2H, NH2), 4.87 (dd, J ) 4.0, 10.5 Hz, 1H, H-2′), 4.55
(dd, J ) 2.5, 12.5 Hz, 1H, H-6a), 4.43 (d, J ) 9.5 Hz, 1H, H-1),
4.32 (dd, J ) 4.5, 12.5 Hz, 1H, H-6b), 4.24 (dd, J ) 4.0, 12.5 Hz,
1H, H-6a′), 4.08 (dd, J ) 2.5, 12.5 Hz, 1H, H-6b′), 4.044 (t, J )
9.0 Hz, 1H, H-4), 3.96 (m, 1H, H-5′), 3.85 (m, 1H, H-5), 2.16,
2.11, 2.07, 2.06, 2.05, 2.04, 2.02 (7 × s, 21H, OCOCH3),
1
assignments were confirmed by H-1H gCOSY; 13C NMR (125
MHz, CDCl3) δ ) 170.7 (3C), 170.6, 170.0, 169.9, 169.5
(OCOCH3), 96.0 (C-1′), 87.3 (C-1), 77.1 (C-5), 75.0 (C-3), 72.6
(C-4), 70.2 (C-2′), 69.3 (C-3′), 68.9 (C-5′), 68.8 (C-2), 68.2 (C-
4′), 62.4 (C-6), 61.7 (C-6′), 20.9 (2C), 20.7 (3C), 20.6 (2C)
(OCOCH3), assignments were confirmed by 1H-13C HSQC; LRMS
(ESI+) m/z ) 722 [M + Na]+; LRMS (ESI-) m/z ) 697 [M -
H]-; HRMS (ESI) calcd for C26H37N1O19SNa+ 722.1573, found
722.1541.
1-S-D-Galactopyranosylsulfonamide (14). The title compound
was prepared from 10 (295 mg, 0.72 mmol) as described in general
procedure 1 (except the reaction was maintained overnight at 50
°C). The lyophilized compound was obtained as an orange
hygroscopic solid (174 mg, 0.72 mmol, ∼100%): Rf ) 0.46 (8:2
CH3CN/H2O); mp ) 58-59 °C; [R]25D ) + 11 (c ) 1.2, MeOH);
1H NMR (400 MHz, D2O) δ ) 4.49 (d, J ) 9.6 Hz, H-1), 4.06 (d,
J ) 3.2 Hz, 1H, H-4), 4.04 (t, J ) 9.2 Hz, 1H, H-2), 3.72-3.64
(m, 3H, H-5, H-6a, H-6b), 3.62 (dd, J ) 3.6, 9.6 Hz, 1H, H-3),
1
were confirmed by H-13C HSQC; LRMS (ESI+) m/z ) 434 [M
+ Na]+; LRMS (ESI-) m/z ) 410 [M - H]+; HRMS (ESI) calcd
for C14H21N1O11SNa+ 434.0728, found 434.0706.
Methyl 1-S-(2,3,4,6-Tetra-O-acetyl)-D-glucopyranuronylsul-
fonamide (11). The title compound was obtained from thioacetate
7 (2.94 g, 7.49 mmol, 1.0 equiv) as described in general procedure
2 and obtained as a light yellow solid (542 mg, 1.36 mmol, 18%
over 3 steps): Rf ) 0.41 (2:1 EtOAc/hexane); mp ) 200-202 °C;
[R]25D ) -13 (c ) 0.8, chloroform); 1H NMR (500 MHz, CDCl3)
δ ) 5.41 (t, J ) 9.5 Hz, 1H, H-3), 5.35 (t, J ) 9.5 Hz, 1H, H-2),
5.24 (t, J ) 9.5 Hz, 1H, H-4), 5.13 (br s, 2H, NH2), 4.41 (d, J )
10.0 Hz, 1H, H-1), 4.18 (d, J ) 9.5 Hz, 1H, H-5), 3.77 (s, 3H,
OCH3), 2.10, 2.05 (2 × s, 9H, OCOCH3), assignments were
1
assignments were confirmed by H-1H gCOSY; 13C NMR (125
MHz, DMSO-d6) δ ) 91.3 (C-1), 79.8 (C-5), 73.9 (C-3), 68.1 (C-
4), 67.5 (C-2), 60.5 (C-6), assignments were confirmed by 1H-13C
HSQC; LRMS (ESI+) m/z ) 266 [M + Na]+; LRMS (ESI-) m/z
) 242 [M - H]-; HRMS (ESI) calcd for C6H13N1O7SNa+
266.0305, found 266.0310.
1
confirmed by H-1H gCOSY; 13C NMR (125 MHz, CDCl3) δ )
Methyl 1-S-D-Glucopyranuronylsulfonamide (15). To a solu-
tion of 11 (173 mg, 0.44 mmol, 1 equiv) in MeOH/H2O (1:4, 7.5
mL) was added NaOH (20 mg, 0.50 mmol, 1.1 equiv). The reaction
was stirred for 5 h at 0 °C then neutralized with Amberlite resin
IR-120 H+, filtered, evaporated, and the residue purified by flash
chromatography with solid addition (8:2 CH3CN/H2O). Acetonitrile
was evaporated from fractions containing the title compound, and
the remaining aqueous solution was filtered (0.42 µm syringe filter)
and lyophilized to dryness to furnish the title sulfonamide 15 as a
171.1, 169.8, 169.5, 166.7 (OCOCH3), 87.1 (C-1), 76.2 (C-5), 72.0
(C-3), 69.3 (C-4), 68.1 (C-2), 53.4 (CO2CH3), 20.9, 20.7, 20.6
(OCOCH3), assignments were confirmed by 1H-13C HSQC; LRMS
(ESI+) m/z ) 420 [M + Na]+; LRMS (ESI-) m/z ) 396 [M -
H]+; HRMS (ESI) calcd for C13H19N1O11SNa+ 420.0571, found
420.0580.
(2,3,4,6-Tetra-O-acetyl-ꢀ-D-galactopyranosyl)-(1f4)-1,2,3,6-
tetra-O-acetyl-1-thio-ꢀ-D- glucopyranosylsulfonamide (12). The
title compound was obtained from thioacetate 8 (4.36 g, 6.28 mmol,
1.0 equiv) as described in general procedure 2 and obtained as a
light orange solid (1.35 g, 1.93 mmol, 31%): Rf ) 0.23 (3:2 EtOAc/
hexane); mp ) 103-105 °C; [R]25D ) -12 (c ) 1.1, chloroform);
1H NMR (500 MHz, CDCl3) δ ) 5.37 (d, J ) 3.0 Hz, 1H, H-4′),
5.32 (t, J ) 9.0 Hz, 1H, H-3), 5.27 (t, J ) 9.5 Hz, 1H, H-2), 5.12
(dd, J ) 8.0, 10.5 Hz, 1H, H-2′), 4.98 (dd, J ) 3.5, 10.5 Hz, 1H,
H-3′), 4.96 (br s, 2H, NH2), 4.54 (dd, J ) 1.5, 12.5 Hz, 1H, H-6a),
4.51 (d, J ) 7.5 Hz, 1H, H-1′), 4.37 (d, J ) 10.0 Hz, 1H, H-1),
4.20 (dd, J ) 4.0, 12.5 Hz, 1H, H-6b), 4.16 (dd, J ) 6.5, 11.5 Hz,
1H, H-6a′), 4.09 (dd, J ) 7.5, 11.0 Hz, 1H, H-6b′), 3.89 (m, 1H,
H-5′), 3.86 (t, J ) 9.5 Hz, 1H, H-4), 3.79 (m, 1H, H-5), 2.17, 2.14,
2.08 (6H), 2.07, 2.06, 1.98 (6 × s, 21H, OCOCH3), assignments
were confirmed by 1H-1H gCOSY; 13C NMR (125 MHz, CDCl3)
δ ) 170.9, 170.7, 170.6, 170.3, 170.2, 169.7, 169.2 (OCOCH3),
101.2 (C-1′), 87.6 (C-1), 77.6 (C-5), 75.7 (C-4), 72.8 (C-3), 71.1
(C-3′), 71.1 (C-5′), 69.3 (C-2′), 68.5 (C-2), 66.8 (C-4′), 61.7
(C-6), 61.0 (C-6′), 21.0, 20.9 (2C), 20.8 (2C), 20.7 (2C) (OCOCH3),
white solid (66 mg, 0.26 mmol, 59%): mp ) 109-111 °C; [R]25
D
) -18 (c ) 1.1, MeOH); 1H NMR (400 MHz, D2O) δ ) 4.59 (d,
J ) 9.6 Hz, H-1), 4.07 (d, J ) 9.2 Hz, 1H, H-5), 3.87 (t, J ) 9.2
Hz, 1H, H-2), 3.71 (t, J ) 9.2 Hz, 1H, H-3), 3.66 (t, J ) 9.2 Hz,
1
1H, H-4), assignments were confirmed by H-1H gCOSY; 13C
NMR (125 MHz, DMSO-d6) δ ) 170.2 (CO2H), 90.6 (C-1), 78.7,
76.8, 71.2, 70.6 (C-5, C-2, C-3, C-4); LRMS (ESI+) m/z ) 280
[M + Na]+; HRMS (ESI) calcd for C6H11N1O8SNa+ 280.0098,
found 280.0112.
ꢀ-D-Galactopyranosyl-(1f4)-1-thio-ꢀ-D-glucopyranosylsul-
fonamide (16). The title compound was prepared from 12 (462
mg, 0.66 mmol) as described in general procedure 1 and obtained
as an orange solid following purification by flash chromatography
with solid addition (85:15 CH3CN/H2O). Acetonitrile was evapo-
rated from fractions containing the title compound, and the
remaining aqueous solution was filtered (0.42 µm syringe filter)
and lyophilized to dryness to furnish the title sulfonamide 16 as a
white solid (144 mg, 0.36 mmol, 55%): Rf ) 0.32 (8:2 CH3CN/
J. Org. Chem. Vol. 74, No. 7, 2009 2815

Lopez et al.
1
H2O); mp ) 138-139 °C; [R]25 ) + 13 (c ) 1.0, MeOH); H
OH), 5.04 (d, J ) 4.0 Hz, 1H, OH), 4.88 (d, J ) 5.5 Hz, 1H, OH),
4.85 (d, J ) 4.5 Hz, 1H, OH), 4.52-4.46 (m, 2H, OH, H-1′), 4.12
(d, J ) 9.0 Hz, 1H, H-1), 3.74 (m, 1H), 4.63-3.34 (m, 9H, H-2,
H-2′, H-3, H-3′, H-4, H-4′, H-6a, H-6a′, H-6b, H-6b′), 3.23 (m,
1H, H-5), 3.23 (m, 1H, H-5′), assignments were confirmed by
1H-1H gCOSY; 13C NMR (125 MHz, DMSO-d6) δ ) 100.7 (C-
1′), 90.2 (C-1, C-1′), 79.9 (C-4), 78.9 (C-3′), 75.5, 75.4 (C-5, C-5′),
73.2 (C-3), 70.5 (2C) (C-2, C-2′), 68.1 (C-4′), 60.5, 60.4 (C-6, C-6′),
assignments were confirmed by 1H-13C HSQC; LRMS (ESI+) m/z
) 423 [M + NH4]+, 428 [M + Na]+; LRMS (ESI-) m/z ) 404
D
NMR (500 MHz, DMSO-d6) δ ) 6.71 (br s, 2H, NH2), 5.21 (m,
1H, OH), 5.06 (d, J ) 4.0 Hz, 1H, OH), 4.79 (d, J ) 1.0 Hz, 1H,
OH), 4.76 (m, 1H, OH), 4.63 (t, J ) 5.0 Hz, 1H, OH), 4.52 (t, J
) 6.5 Hz, OH), 4.48 (d, J ) 4.5 Hz, 1H, OH), 4.20 (d, J ) 7.5 Hz,
1H, H-1′), 4.13 (d, J ) 9.5 Hz, 1H, H-1), 3.80 (m, 1H), 3.62-3.43
(m, 11H, H-2, H-2′, H-3, H-3′, H-4, H-4′, H-5, H-5′, H-6a, H-6a′,
H-6b, H-6b′), assignments were confirmed by 1H-1H gCOSY; 13
C
NMR (125 MHz, DMSO-d6) δ ) 103.7 (C-1′), 90.0 (C-1), 79.9
(C-4), 78.9 (C-3′), 75.5, 75.4 (C-5, C-5′), 73.2 (C-3), 70.5 (2C)
(C-2, C-2′), 68.1 (C-4′), 60.5, 60.4 (C-6, C-6′), assignments were
confirmed by 1H-13C HSQC; LRMS (ESI+) m/z ) 428 [M + Na]+,
833 [2 M + Na]+; HRMS (ESI) calcd for C12H23N1O12SNa+
428.0833, found 428.0836.
[M
- +
H]-, 440 [M Cl]-; HRMS (ESI) calcd for
C12H23N1O12SNa+ 428.0833, found 428.0823.
Acknowledgment. This work was financed by the Australian
Research Council (Grant No. DP0877554); the Eskitis Institute
for Cell and Molecular Therapies (Griffith University). We thank
A/Prof Scott Taylor for the provision of synthetic details for
bis(2,4-dimethoxybenzyl)amine.
r-D-Glucopyranosyl-(1f4)-1-thio-ꢀ-D-glucopyranosylsulfona-
mide (17). The title compound was prepared from 13 (605 mg,
0.86 mmol) as described in general procedure 1 and obtained as
an orange solid following purification by flash chromatography with
solid addition (85:15 CH3CN/H2O). Acetonitrile was evaporated
from fractions containing the title compound, and the remaining
aqueous solution was filtered (0.42 µm syringe filter) and lyoph-
ilized to dryness to furnish the title sulfonamide 17 as a white solid
Supporting Information Available: Detailed experimental
1
procedures, characterization data, and copies of H and 13C
(207 mg, 0.51 mmol, 59%): Rf ) 0.34 (8:2 CH3CN/H2O); mp )
spectra of new compounds 4, 5, and 10-17. This material is
available free of charge via the Internet at http://pubs.acs.org.
127-128 °C; [R]25 ) + 79 (c ) 0.9, MeOH); H NMR (500
1
D
MHz, DMSO-d6) δ ) 6.74 (br s, 2H, NH2), 5.63 (d, J ) 3.0 Hz,
1H, OH), 5.40 (d, J ) 6.0 Hz, 1H, OH), 5.13 (d, J ) 5.5 Hz, 1H,
JO9000367
2816 J. Org. Chem. Vol. 74, No. 7, 2009