Unexpected furanose/pyranose equilibration of N-glycosyl sulfonamides, sulfamides and sulfamates

Article abstract of DOI:10.1039/c5ob00851d

De-protected arabino N-glycosyl sulfamides, sulfonamides and sulfamates were found to mutarotate and convert from the furanose to the thermodynamically more stable pyranose form in aqueous solution. The presence of a strongly electron withdrawing group in

Full text of DOI:10.1039/c5ob00851d

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Unexpected furanose/pyranose equilibration of
N-glycosyl sulfonamides, sulfamides and sulfamates†
Cite this: DOI: 10.1039/c5ob00851d
Kajitha Suthagar,a Matthew I. J. Polsona and Antony J. Fairbanks*a,b
Received 28th April 2015,
Accepted 12th May 2015
De-protected arabino N-glycosyl sulfamides, sulfonamides and sulfamates were found to mutarotate and
convert from the furanose to the thermodynamically more stable pyranose form in aqueous solution. The
presence of a strongly electron withdrawing group in the alkyl chain stopped mutarotation and furanose/
pyranose equilibration, allowing the isolation of the first unprotected furanose N-glycosyl sulfonamide.
DOI: 10.1039/c5ob00851d
www.rsc.org/obc
and elaboration with suitable hydrophobic chains, would
produce mimics of DPA that may display useful anti-myco-
Introduction
The intermediacy of glycosyl phosphates in important biologi- bacterial activity.
cal processes, combined with their instability, has led to the
synthesis of a variety of glycomimetics in the search for new
bioactives for the treatment of a variety of disease states and
Results and discussion
infectious agents.1 As part of an on-going program2 into the
synthesis of mimics of decaprenolphosphoarabinose 1 (DPA,
Scheme 1) as novel anti-mycobacterial agents, suitable iso-
steric replacement for the labile glycosyl phosphate was
sought. DPA is the donor substrate used by arabinosyl trans-
ferases3 during the stepwise assembly of mycobacterial arabi-
A series of arabino furanose N-glycosyl sulfamides, sulfona-
mides, and sulfamates was synthesised starting from D-arabi-
nose 2 (Scheme 1), by conversion to methyl arabinofuranoside,
benzylation, and acid catalysed hydrolysis to give the furanose
hemiacetal 3.12 Although 3 has been previously described in
the literature, following the unexpected formation of pyranose
materials (vide infra) the structure of 3 was unambiguously
confirmed as the furanose form by X-ray crystallography
(Fig. 1).
nan,
a key component of the mycobacterial cell wall.
Metabolically stable analogues of DPA may inhibit arabinan
biosynthesis, and therefore compromise mycobacterial viabi-
lity.4 Previous studies have demonstrated biological activity of
configurationally stable S-glycosyl sulfonamides,5 and sulfen-
amides.6 By extrapolation one could envisage that N-glycosyl
sulfonamides,7 sulfamides,8 and sulfamates may also be
effective, and indeed may represent new classes of mimics of
glycosyl phosphates. Several synthetic approaches to N-glycosyl
sulfonamides,9 in which the sulfonamide nitrogen is attached
to the anomeric centre, have been reported,10 and some con-
formational studies of these materials have also been under-
taken.11 It was therefore envisaged that the synthesis of
sulfamides, sulfonamides and sulfamates of arabinofuranose,
TMS Triflate mediated glycosylation of 3 with decylsulf-
amide, methanesulfonamide and decyl sulfamate gave the
furanose sulfamide 4a, sulfonamide 4b and sulfamate 4c
respectively. In each case a mixture of anomers was produced
that could not be separated by chromatography. De-protection
of sulfamide 4a by catalytic hydrogenation in the presence of
Pd/C yielded a mixture of compounds, which were partially
separated by HPLC (see ESI†). NMR analysis of the individual
components by HMBC and HMQC was ambiguous, and so the
structure of the major component 5a was confirmed by X-ray
crystallography (Fig. 2). Surprisingly this revealed 5a to be the
α-pyranose isomer, in a 1C4 conformation in which the ano-
meric nitrogen occupies an equatorial position, and in which
the OH groups at positions 2 and 3 are also equatorial (OH-4 is
axial). Fig. 2 additionally shows that the pyranose sulfamide 5a
is stabilised by an exo-anomeric effect (n–σ* donation of the N
lone pair into the C1–O bond), a phenomenon that has been
observed previously in a variety of N-glycosides.13 The fact that
aDepartment of Chemistry, University of Canterbury, Private Bag 4800, Christchurch
8140, New Zealand. E-mail: antony.fairbanks@canterbury.ac.nz;
Fax: +64 3364 2110; Tel: +64 3364 3097
bBiomolecular Interaction Centre, University of Canterbury, Private Bag 4800,
Christchurch 8140, New Zealand
†Electronic supplementary information (ESI) available: Full experimental details
for the synthesis and characterisation of all compounds, including associated
spectra and X-ray crystal data of complexes (CIF), together with HPLC investi-
gations into furanose/pyranose equilibration. CCDC 1029228, 1058601 and
1029227. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5ob00851d
a
1C4 conformation is preferred, with the anomeric N equa-
torial, suggests that any endo-anomeric effect is relatively
unimportant in overall energetic terms. The other components
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 1 Synthesis of N-glycosyl sulfamides, sulfonamides and sulfamates. Reagents and conditions: (i) AcCl, MeOH rt, 6 h, 80%, α : β, 4 : 1; (ii)
NaH, BnBr, DMF, rt, 16 h, 87%; (iii) 80% aqueous AcOH, 115 °C, 48 h, 73%; (iv) NH2SO2NHC10H21, TMSOTf, CH2Cl2, 77%; (v) NH2SO2CH3, TMSOTf,
CH2Cl2, rt, 53%; (vi) NH2SO2OC10H21, TMSOTf, CH2Cl2, rt, 56%; (vii) H2, Pd/C, MeOH, rt; 5a, 46% from 4a, plus 28% other isomers; 5b, 33% from 4b,
plus 19% other isomers; 5c, 45% from 4c, plus 24% other isomers; (viii) NH2SO2CF3, TMSOTf, Et2O, rt, 44%; (ix) H2, Pd/C, MeOH, rt; 65%.
Fig. 2 X-ray structure of α-pyranose sulfamide 5a.†
Fig. 1 X-ray structure of arabinofuranose hemiacetal 3.†
nitrogen is usually sufficient to render these materials config-
urationally stable, e.g. as in the case of glycosyl amides, the key
of the mixture produced during de-protection of 4a were stable linkages by which carbohydrates are attached to pep-
identified as the β-pyranose and the α- and β-furanose isomers tides in N-linked glycoproteins. The formation of the pyranose
(see ESI†).
isomers from these reactions was therefore surprising.
A similar outcome was observed upon de-protection of both
Colinas has previously undertaken the synthesis of a variety
sulfonamide 4b and sulfamate 4c; in each case the major of pyranose N-glycosyl sulfonamides, and reported in these
product of these reactions was the α-pyranose isomer. The cases that the β-anomers were the preferred reaction products,
structure of methyl sulfonamide 5b was also confirmed by again indicating the relative unimportance of the endo-ano-
single X-ray crystallography (Fig. 3). Sulfonamide 5b also meric effect for these materials. However no mention of the
adopts a 1C4 conformation with two of the three OH groups configurational lability of either these materials or β-glycosyl
equatorial, and the anomeric nitrogen also in an equatorial sulfamides was reported.10 Contrastingly the rapid conversion
position; the N lone pair is orientated anti to the C1–O bond of α-N-glycosyl sulfonamides to their thermodynamically more
(C2–O1 in the X-ray structure) demonstrating operation of the stable β-anomers has been reported by Petillo,9a in a reaction
exo-anomeric effect.
that was catalysed either by acid or water; the rate of this
The mutarotation, configurational lability, and high reactiv- interconversion was also dependent on protecting group
ity of glycosyl amines are all well documented.14 However the regimes. It is also notable that although there are multiple
addition of an electron-withdrawing group on the anomeric reports of N-glycosyl sulfonamides in the literature, there are
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
However, the measured MIC for this material was found to be
greater than 1 mM, indicating the importance of an extended
aliphatic chain for anti-mycobacterial activity.
Conclusions
N-Glycosyl sulfamides, sulfonamides and sulfamates of arabi-
nose were found to be configurationally labile in aqueous solu-
tion and underwent mutatoration and furanose-pyranose
equilibration; in the case of the arabino derivatives the α-pyra-
nose form is thermodynamically preferred. In contrast an
N-glycosyl trifluoromethylsulfonamide was shown to be config-
Fig. 3 X-ray structure of α-pyranose methyl sulfonamide 5b.†
no previous descriptions of any de-protected furanose urationally stable, allowing the synthesis and characterisation
materials.
of the first de-protected N-glycosyl sulfonamide of a furanose
In order to investigate the stability and inter-conversions of sugar.
these materials the isomers of sulfamide 5a were stirred in
water at pH 7 and analysed by HPLC after specific time inter-
vals (for full details see ESI†). The pure α-pyranose anomer 5a
only produced minimal amounts of the other isomers after
48 h. However in aqueous solution the other isomers (pure
Experimental
General methods
β-furanose and an α-furanose/β-pyranose mixture) all under- All reactions were carried out in oven-dried, nitrogen-purged
went interconversion to produce mixtures in which the α-pyra- glassware under an atmosphere of nitrogen. Melting points
nose isomer 5a was predominant (∼70%, see ESI†). Similar were recorded on an Electrothermal melting point apparatus
investigations into sulfonamide 5b and sulfamate 5c also indi- and are uncorrected. Optical rotations were measured on a
cated that in all cases mutarotation and interconversion of the Perkin-Elmer Polarimeter 341 with a path length of 1 dm. Con-
furanose and pyranose forms occurred, again with the α-pyra- centrations are given in g/100 mL. Infrared spectra were
nose isomer being the thermodynamically preferred form.
recorded on a Perkin-Elmer Spectrum One. Proton and carbon
The ring opening processes by which the furanose forms nuclear magnetic resonance (δH, δC) spectra were recorded on
are converted into the pyranose forms must involve the for- Agilent Technologies 400 MR (400 MHz) or Varian VNMR500
mation of N-sulfonyl imine/iminium ion intermediates. Anal- (500 MHz) spectrometers. All chemical shifts are quoted on
ogous glycosyl iminium ions have been demonstrated to be the δ-scale in ppm using residual solvent as an internal stan-
intermediates15 in the biosynthetic interconversion of UDP- dard. High-resolution mass spectra were recorded with a
galactopyranose and UDP-galactofuranose catalysed by the Bruker maXis 3G UHR-TOF mass spectrometer. Thin Layer
FAD dependent UDP-galactopyranose mutase (UGM) enzymes Chromatography (t.l.c.) was carried out on Merck silica gel
that are essential for many pathogenic species of bacteria.
60F254 aluminium-backed plates. Visualisation of the plates
These facile inter-conversions provide an explanation for was achieved using a UV lamp (λmax = 254 or 365 nm), and/or
the absence of de-protected furanose glycosyl sulfonamides 5% w/v ammonium molybdate in 2 M sulfuric acid. Flash
from the literature. However, DPA 1, the donor substrate used column chromatography was carried out using Sorbsil C60
by mycobacteria for cell wall assembly, is in the furanose form. 40/60 silica. Reverse phase high performance liquid chromato-
The question therefore arose as to what structural modification graphy (RP-HPLC) was performed on a Dionex P680 HPLC
could be made to an N-glycosyl sulfonamide so that pyranose/ instrument with a Phenomenex Luna C 18(2) 100 A column
furanose equilibration would not occur at an appreciable rate (5 µm, 10 × 250 mm) at 15 °C. The column was eluted with a
under physiological conditions? Since equilibration involves gradient of MeCN/H2O at a flow rate of 1 mL min−1. Unless
opening of the furanose ring with assistance from the nitrogen preparative details are provided, all reagents were commer-
lone pair, sulfonamides bearing a strongly electron withdraw- cially available or made following literature procedures.
ing group may show a reduced tendency to isomerise. The “Petrol” refers to the fraction of light petroleum ether boiling
N-glycosyl trifluoromethanesulfonamide 6 was therefore syn- in the range of 40–60 °C.
thesised using a route analogous to that employed above
Methyl 2,3,5-tri-O-benzyl-α,β-D-arabinofuranoside.17 Acetyl
(Scheme 1). De-protection of 6 by catalytic hydrogenation chloride (3.08 mL, 43 mmol) was added drop-wise to a solu-
yielded a single compound identified as the β-furanose isomer tion of D-arabinose 2 (5.0 g, 33 mmol) in methanol (100 mL)
7, which was demonstrated to be configurationally stable in under nitrogen. The reaction was stirred for 3 hours at room
aqueous solution (See ESI†). This compound therefore rep- temperature. After this time, t.l.c. (DCM : MeOH, 4 : 1) indi-
resents the first de-protected furanose N-glycosyl sulfonamide cated the formation of two products, a major product (methyl
to be reported. Sulfonamide 7 was then assayed for biological α,β-D-arabinofuranoside, Rf 0.5) and the complete consump-
activity against M. smegmatis using an Alamar Blue assay.16 tion of starting material (Rf 0.2). The reaction mixture was neu-
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
tralized by adding solid K2CO3 (∼7 g), filtered, concentrated sulfamide (0.27 g, 1 mmol) were stirred at room temperature
in vacuo, and the residue was co-evaporated with toluene in dry DCM (15 mL) under nitrogen. TMSOTf (0.17 mL) was
(3 × 50 mL) to afford a crude mixture of methyl α,β-D-arabino- added drop-wise, and the mixture stirred for 16 hours. After
furanoside and methyl α,β-D-arabinopyranoside as a brown oil this time, t.l.c (petrol: ethyl acetate, 2 : 1) indicated the for-
which was used in the next step without further purification. mation of a single product (Rf 0.5), and the complete con-
Sodium hydride (60% dispersion in mineral oil, 8.2 g, sumption of starting material (Rf 0.3). The reaction mixture
205 mmol) was added drop-wise to a solution of the mixture was then neutralized by the drop-wise addition of excess tri-
produced above (5.6 g, 34 mmol) in DMF (60 mL) under nitro- ethylamine (0.3 mL). The reaction mixture was filtered through
gen. The reaction was stirred for 1 hour and then cooled to Celite®, eluting with ethyl acetate, and concentrated in vacuo
0 °C. Benzyl bromide (24.3 mL, 205 mmol) was then added to give a residue which was purified by flash chromatography
drop-wise. The reaction mixture was warmed to room tempera- (petrol : ethyl acetate, 2 : 1) afford furanose sulfamide 4a
ture and then stirred for 16 hours. After this time, t.l.c. (0.47 g, 77%, α : β, 1 : 1) as a waxy yellow solid. νmax (neat) 3280
(petrol : ethyl acetate, 7 : 1) indicated the formation of a major (w, NH), 1350 (s, SvO), 1158 (s, SvO) cm−1; δH (400 MHz,
product (Rf 0.2), and the complete consumption of starting CDCl3) α anomer: 0.89 (3H, t, J 6.7 Hz, CH3), 1.24–1.29 (14H,
material (Rf 0.0). The reaction was cooled in an ice bath, m, 7 × CH2), 1.48–1.53 (2H, m, NHCH2CH2), 2.98–3.03 (2H, m,
quenched by the addition of methanol (90 mL), and then con- CH2NH), 3.46–3.50 (1H, m, H-5), 3.58 (1H, dd, J5,5′ 8.6 Hz, J4,5′
centrated in vacuo. The residue was dissolved in diethyl ether 6.7 Hz, H-5′), 3.95–3.97 (1H, m, H-3), 3.98–4.02 (1H, m, H-2),
(50 mL), and washed with brine (3 × 50 mL). The combined 4.34 (1H, at, J 6.6 Hz, H-4), 4.38–4.63 (6H, m, Ph-CH2), 5.42
organic extracts were dried over anhydrous MgSO4, filtered, (1H, d, JNH,1 10.5 Hz, H-1), 5.54 (1H, d, JNH,1 11.0 Hz NH),
and concentrated in vacuo to afford a yellow oil, which was pur- 7.15–7.40 (15H, m, Ar–H); β anomer: 0.89 (3H, t, J 6.7 Hz,
ified by flash chromatography (petrol : ethyl acetate, 7 : 1) to CH3), 1.24–1.29 (14H, m, CH2), 1.48–1.53 (2H, m, NHCH2CH2),
afford methyl 2,3,5-tri-O-benzyl-α,β-D-arabinofuranoside (7.7 g, 2.98–3.03 (2H, m, CH2NH), 3.52–3.54 (1H, m, H-5, H-5′),
54%, α : β, 3 : 1) as a clear oil. δH (500 Hz, CDCl3) α-anomer: 3.95–3.97 (1H, m, H-3), 3.98–4.02 (1H, m, H-2), 4.05–4.06 (1H,
3.42 (3H, s, OCH3), 3.64 (2H, at, J 4.8 Hz, H-5, H-5′), 3.94 (1H, m, H-4), 4.38–4.63 (6H, m, Ph-CH2), 5.37 (1H, dd, JNH,1 10.2
dd, J3,4 6.2 Hz, J2,3 2.8 Hz, H-3), 4.03 (1H, m, H-2), 4.25 (1H, td, Hz, J1,2 4.3 Hz, H-1), 5.52 (1H, d, JNH,1 10.8 Hz NH), 7.15–7.40
J4,5 5.4 Hz, J4,5′ 5.4 Hz, J3,4 4.8 Hz, H-4), 4.56–4.59 (6H, m, (15H, m, Ar–H); δC (100 MHz, CDCl3) 14.1 (q, CH3), 22.6, 26.7,
PhCH2), 4.98 (1H, s, H-1), 7.26–7.39 (15H, m, Ar–H); β anomer: 29.2, 29.3, 29.4, 29.5, 29.5, 31.8, (8 × t, 8 × CH2), 43.4 (t,
3.35 (3H, s, OCH3), 3.56 (1H, dd, J5,5′ 8.9 Hz, J4,5 6.0 Hz, H-5), CH2NH), 70.1 (t, C-5α, C-5β), 71.7, 71.8, 71.9, 72.3, 73.3, 73.4 (6
3.61 (1H, d, J4,5′ 5.4 Hz, H-5′), 4.08–4.12 (1H, m, H-4), 4.13–4.14 × t, Ph-CH2), 80.8 (d, C-4β), 81.2, 81.8 (2 × d, C-2α, C-2β), 82.3
(1H, m, H-2), 4.15–4.17 (1H, m, H-3), 4.51 (5H, ABq, J 9.8 Hz, (d, C-3β), 83.3 (d, C-4α), 84.2 (d, C-1β), 84.8 (d, C-3α), 88.2 (d,
PhCH2) 4.62–4.66 (1H, m, PhCH2), 4.76 (1H, d, J 4.2 Hz, H-1), C-1α), 127.7, 127.8, 127.9, 128.5, 128.6 (5 × d, 5 × Ar–C), 136.7,
7.26–7.39 (15H, m, Ar–H); HRMS (ESI) calculated for 137.4, 137.9 (3 × s, 3 × Ar–C); HRMS (ESI) calculated for
C27H30NaO5 (M + Na+) 457.1991. Found 457.1984.
C36H50N2NaO6S (M + Na+) 661.3287. Found 661.3288.
N-(Decyl)-N′-(α-D-arabinopyranosyl)sulfamide 5a. 10% Acti-
2,3,5-Tri-O-benzyl-α,β-D-arabinofuranose 3.12 Methyl 2,3,5-
tri-O-benzyl-α,β-D-arabinofuranoside (7.7 g, 18 mmol) was dis- vated Pd/C (20 mg) was added to a solution of furanose sulf-
solved in a mixture of water and acetic acid (100 mL, 1 : 4, v/v), amide 4a (80 mg, 0.1 mmol) in methanol. The flask was
and then stirred at 115 °C for 2 days. After this time, t.l.c. evacuated and purged with nitrogen five times, before being
(petrol : ethyl acetate 3 : 1) indicated the formation of a single placed under an atmosphere of hydrogen. The solution was
product (Rf 0.2), and the complete consumption of starting then stirred for 16 hours at room temperature. After this time,
material (Rf 0.6). The reaction was quenched by the addition of t.l.c. (ethyl acetate) indicated the formation of a single product
ice water (100 mL), and extracted with diethyl ether (3 × (Rf 0.0), and the complete consumption of starting material (Rf
50 mL). The combined organic extracts were dried over anhy- 0.9). The reaction mixture was filtered through Celite® (eluting
drous MgSO4, filtered, and concentrated in vacuo to afford a with methanol, 20 mL), and concentrated in vacuo to give a
yellow oil, which was purified by flash chromatography residue which was purified by RP-HPLC (Luna C-18 column
(petrol : ethyl acetate, 3 : 1) to afford hemiacetals 3 (4.8 g, 64%, (Phenomenex); eluent: A (0.05% TFA in H2O) and B MeCN; gra-
α : β, 1 : 1) as a white crystalline solid. δH (500 MHz, CDCl3) α dient: the sample was run at 1 mL min−1 with a gradient of
anomer: 3.52–3.62 (2H, m, H-5, H-5′), 3.93–3.95 (1H, m, H-3), 50–85% B; column oven: 15 °C; detection: CAD) to afford α-pyr-
3.98–3.99 (1H, m, H-2), 4.46–4.48 (1H, m, H-4), 4.51–4.67 (6H, anose sulfamide 5a as the major product (21 mg, 45%) as
m, PhCH2), 5.40 (1H, s, H-1), 7.26–7.37 (15H, m, Ar–H); β white solid; [α]2D0 −14 (c, 0.5 in CH3OH); m.p. 103–105 °C
anomer: 3.52–3.62 (2H, m, H-5, H-5′), 4.02 (1H, d, J 4.5 Hz, (MeOH/diethyl ether); νmax (neat) 3288 (br s, OH), 1340 (s,
H-2), 4.09 (1H, aq, J 4.3 Hz, H-4), 4.17 (1H, t, J 4.5 Hz, H-3), SvO), 1157 (s, SvO) cm−1; δH (500 MHz, CD3CN) 0.90 (3H, t,
5.33 (1H, d, J1,2 3.2 Hz, H-1), 4.51–4.67 (6H, m, PhCH2), J 6.7 Hz, CH3), 1.29–1.36 (14H, m, 7 × CH2), 1.49–1.53 (2H, m,
7.26–7.37 (15H, m, Ar–H); HRMS (ESI) calculated for NHCH2CH2), 2.95–2.99 (2H, t, CH2NH), 3.44 (1H, at, J 7.3 Hz,
C26H28NaO5 (M + Na+) 443.1834. Found 443.1851.
H-2), 3.53–3.56 (2H, m, H-3, H-5), 3.77–3.80 (1H, m, H-4), 3.84
N-(Decyl)-N′-(2,3,5-tri-O-benzyl-α,β-D-arabinofuranosyl)sulf- (1H, d, J4,5′ 4.0 Hz, H-5′), 4.27 (1H, d, J1,2 7.6 Hz, H-1), 5.03
amide 4a. Hemiacetals 3 (400 mg, 0.9 mmol), and N-(decyl)- (1H, t, JNH,CH 5.8 Hz, NHCH2) ; δC (100 MHz, CD3OD) 13.0 (q,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
CH3), 22.3, 26.5, 29.0, 29.3, 31.6 (5 × t, 8 × CH2), 42.6 (t, 66.9 (d, C-5), 68.3 (d, C-4), 69.8 (d, C-2), 73.4 (d, C-3), 85.2 (d,
CH2NH), 66.7 (t, C-5), 68.3 (d, C-4), 70.0 (d, C-2), 73.5 (d, C-3), C-1); HRMS (ESI) calculated for C6H13NNaO6S (M + Na+)
85.1 (d, C-1); HRMS (ESI) calculated for C15H32N2NaO6S (M + 250.0361. Found 250.0365.
Na+) 391.1879. Found 391.1881.
Decyl-N-(2,3,5-tri-O-benzyl-α,β-D-arabinofuranosyl)sulfamate
N-(2,3,5-Tri-O-benzyl-α,β-D-arabinofuranosyl)methanesulfon- 4c. Hemiacetals 3 (100 mg, 0.2 mmol), and decyl sulfamate
amide 4b. Hemiacetals 3 (100 mg), and methanesulfonamide (68 mg, 0.3 mmol) were stirred at room temperature in dry
(34 mg, 0.3 mmol) were stirred at room temperature in dry DCM (15 mL) under nitrogen. TMSOTf (40 µl) was added drop-
DCM (15 mL) under nitrogen. TMSOTf (40 µl) was added drop- wise, and the mixture stirred for 16 hours. After this time, t.l.c.
wise, and the mixture stirred for 16 hours. After this time, t.l.c (petrol : ethyl acetate, 3 : 1) indicated the formation of a single
(petrol : ethyl acetate, 2 : 1) indicated the formation of a product (Rf 0.5), and the complete consumption of starting
product (Rf 0.45), and the complete consumption of starting material (Rf 0.2). The reaction mixture was then neutralized by
material (Rf 0.3). The reaction was then neutralized by the the drop-wise addition of excess triethylamine (0.3 mL). The
drop-wise addition of excess triethylamine (0.1 mL). The reac- reaction mixture was filtered through Celite®, eluting with
tion mixture was filtered through Celite®, eluting with ethyl ethyl acetate, and concentrated in vacuo to give a residue
acetate, and concentrated in vacuo. Purification by flash which was purified by flash chromatography (petrol : ethyl
chromatography (petrol : ethyl acetate, 2 : 1) afforded furanose acetate, 2 : 1) to afford furanose sulfamate 4c (86 mg, 56%,
sulfonamide 4b (63 mg, 53%, α : β, 2 : 1) as a yellow waxy solid. α : β, 1 : 1) as a waxy yellow solid. νmax (neat) 3280 (w, NH), 1365
νmax (neat) 3267 (w, NH), 1328 (s, SvO), 1159 (s, SvO) cm−1
;
(s, SvO), 1181 (s, SvO) cm−1; δH (400 MHz, CDCl3) α anomer:
δH (400 MHz, CDCl3) α anomer: 3.07 (3H, s, CH3), 3.47 (1H, at, 0.90 (3H, t, J 6.7 Hz, CH3), 1.21–1.43 (14H, m, CH2), 1.64–1.74
J 9.2 Hz, H-5), 3.58 (1H, dd, J5,5′ 9.4 Hz, J4,5′ 5.9 Hz, H-5′), (2H, m, OCH2CH2), 3.44–3.46 (1H, m, H-5), 3.54–3.64 (1H, m,
3.94–3.97 (1H, m, H-3), 4.02–4.05 (1H, m, H-2), 4.34 (1H, at, H-5′), 4.04–4.09 (1H, m, H-3), 4.12 (2H, t, J 6.7 Hz, OCH2),
J 4.0 Hz, H-4) 4.42–4.46 (1H, m, Ph-CH2), 4.49–4.57 (5H, m, 4.16–4.22 (1H, m, H-2), 4.38 (1H, t, J 4.0 Hz, H-4), 4.43–4.48
PhCH2), 5.48 (1H, d, JNH,1 11.0 Hz, H-1), 5.63 (1H, d, J 11.2 Hz, (2H, m, Ph-CH2), 4.54 (4H, ABq, J 12.0 Hz, Ph-CH2), 5.44 (1H,
NH), 7.21–7.33 (15H, m, Ar–H); β anomer: 3.07 (3H, s, CH3), d, JNH,1 12.0 Hz, H-1), 5.73 (1H, d, J1,NH 10.6 Hz, NH),
3.52 (2H, at, J 4.1 Hz, H-5, H-5′), 3.94–3.97 (1H, m, H-3), 7.22–7.37 (15H, m, Ar–H); β anomer: 0.90 (3H, t, J 6.7 Hz,
4.02–4.05 (2H, m, H-2, H-4), 4.42–4.46 (1H, m, Ph-CH2), CH3), 1.21–1.43 (14H, m, CH2), 1.64–1.74 (2H, m, OCH2CH2),
4.49–4.57 (5H, m, PhCH2), 5.42 (1H, dd, J1,2 4.5 Hz, JNH,1 10.4 3.49–3.54 (2H, m, H-5, H-5′), 4.04–4.09 (1H, m, H-3), 4.12 (2H,
Hz, H-1), 5.57 (1H, d, JNH,1 10.2 Hz, NH), 7.21–7.33 (15H, m, t, J 6.7 Hz, OCH2), 4.16–4.22 (2H, m, H-2, H-4), 4.54 (6H, m,
Ar–H); δC (100 MHz, CDCl3) 42.9 (q, CH3), 69.8, 70.1 (2 × t, Ph-CH2), 5.04 (1H, dd, J1,2 3.9 Hz, J1,NH 10.4 Hz, H-1), 5.79 (1H,
C-5α, C-5β), 71.7, 71.8, 71.9, 72.3, 73.3, 73.4 (6 × t, Ph-CH2), d, J1,NH 10.2 Hz, NH), 7.22–7.37 (15H, m, Ar–H); δC (100 MHz,
80.9 (d, C-4β), 81.1 (d, C-2β), 81.9 (C-3β), 82.3 (d, C-2α), 83.3 (d, CDCl3) 14.1 (q, CH3), 22.7, 25.5, 28.7, 29.1, 29.3, 29.4, 29.5,
C-4α), 83.9 (d, C-1β), 84.7 (d, C-3α), 87.9 (d, C-1α), 127.7, 127.9, 31.8 (8 × t, 8 × CH2), 69.7, 69.9 (2 × t, C-5α, C-5β), 71.2 (t,
128.4, 128.5, 128.7 (5 × d, 5 × Ar–C), 136.6, 136.8, 137.9 (3 × s, CH2O), 71.4, 71.7, 71.9, 72.3, 73.3, 73.6 (6 × t, Ph-CH2), 80.8,
3 × Ar–C); HRMS (ESI) calculated for C27H31NNaO6S (M + Na+) 80.8 (2 × d, C-2β, C-4β), 82.0 (d, C-3β), 82.1 (d, C-2α), 83.3 (d,
520.1770. Found 520.1767.
C-4α), 84.1 (d, C-1β), 84.7 (d, C-3α), 88.1 (d, C-1α), 127.6, 127.8,
N-(α-D-Arabinopyranosyl)methanesulfonamide
5b. 10% 127.9, 128.5, 128.6 (5 × d, 5 × Ar–C), 136.7, 137.4, 137.5 (3 × s,
Activated Pd/C (15 mg) was added to a solution of furanose sul- 3 × Ar–C); HRMS (ESI) calculated for C36H49NNaO7S (M + Na+)
fonamide 4b (60 mg, 0.1 mmol) in methanol. The flask was 662.3127. Found 662.3121.
evacuated and purged with nitrogen five times, before being
Decyl-N-(α-D-arabinopyranosyl)sulfamate 5c. 10% Activated
placed under an atmosphere of hydrogen. The solution was Pd/C (20 mg) was added to a solution of furanose sulfamate 4c
then stirred for 16 hours at room temperature. After this time, (80 mg, 0.1 mmol) in methanol. The flask was evacuated and
t.l.c. (ethyl acetate) indicated the formation of a single product purged with nitrogen five times, before being placed under an
(Rf 0.0), and the complete consumption of starting material atmosphere of hydrogen. The solution was then stirred for
(Rf 0.9). The reaction mixture was filtered through Celite® 16 hours at room temperature. After this time, t.l.c. (ethyl
(eluting with methanol, 20 mL), and concentrated in vacuo to acetate) indicated the formation of a single product (Rf 0.0),
give a residue which was purified by RP-HPLC (Luna C-18 and the complete consumption of starting material (Rf 0.9).
column (Phenomenex); eluent: A (0.05% TFA in H2O) and B The reaction mixture was filtered through Celite® (eluting with
MeCN; gradient: the sample was run at 1 mL min−1 with a iso- methanol, 20 mL), and concentrated in vacuo to give a residue
cratic flow of 20% B; column oven: 15 °C; detection: CAD) to which was purified by RP-HPLC (Luna C-18 column (Phenom-
afford α-pyranose sulfonamide 5b as the major product (9 mg, enex); eluent: A (0.05% TFA in H2O) and B MeCN; gradient:
33%) as white solid. α-anomer: m.p. 178–180 °C (MeOH/ the sample was run at 1 mL min−1 with a gradient of 50–85%
diethyl ether); [α]D20 −16 (c, 0.5 in CH3OH); νmax (neat) 3280 (br B; column oven 15 °C; detection: CAD) to afford α-pyranose
s, OH), 1328 (s, SvO), 1159 (s, SvO) cm−1; δH (400 MHz, sulfamate 5c as the major product (21 mg, 45%) as white
CD3CN) 3.01 (3H, s, CH3), 3.48 (1H, at, J1,2 7.9 Hz, H-2), solid. [α]2D0 −5.4 (c, 0.5 in CH3OH); m.p. 138–140 °C (MeOH/di-
3.53–3.59 (2H, m, H-3, H-5), 3.79–3.84 (1H, m, H-4, H-5′), 4.36 ethylether); νmax (neat) 3334 (br s, OH), 1344 (s, SvO), 1178 (s,
(1H, d, J1,2 7.6 Hz, H-1); δC (100 MHz, CD3OD) 42.0 (q, CH3), SvO) cm−1; δH (400 MHz, CD3CN) 0.91 (3H, t, J 6.5 Hz, CH3),
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
1.27–1.39 (14H, m, CH2), 1.66–1.74 (2H, m, OCH2CH2), 3.47 calculated for C6H10F3NNaO6S (M + Na+) 304.0079. Found
(1H, at, J 7.8 Hz, H-2), 3.52–3.58 (2H, m, H-3, H-5), 3.77–3.80 304.0090.
(1H, m, H-4), 3.83 (1H, d, J4,5′ 2.7 Hz, H-5′), 4.15 (2H, t, J 6.5
Hz, CH2O), 4.31 (1H, d, J1,2 7.8 Hz, H-1); δC (100 MHz, CD3OD)
13.0 (q, CH3), 22.3, 25.2, 28.4, 29.2, 31.8 (5 × t, 8 × CH2), 67.1
(t, C-5), 68.4 (d, C-4), 69.9 (d, C-2), 70.3 (t, CH2O), 73.5 (d, C-3),
Acknowledgements
85.3 (d, C-1); HRMS (ESI) calculated for C15H31NNaO7S We thank the New Zealand synchrotron group for funding
(M + Na+) 392.1719. Found 392.1707.
(RA8769) and the Australian Synchrotron for the use of the
1,1,1-Trifluoro-N-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)- Mx1 beamline.
methanesulfonamide 6. Hemiacetals 3 (100 mg, 0.2 mmol),
and trifluoromethanesulfonamide (71 mg, 0.3 mmol) were
stirred at room temperature in dry diethyl ether (15 mL) under
Notes and references
nitrogen. TMSOTf (40 µl) was added drop-wise, and the
mixture stirred for 16 hours. After this time, t.l.c. (petrol : ethyl
acetate, 3 : 1) indicated the formation of a single product
(Rf 0.4), and complete consumption of starting material
(Rf 0.2). The reaction mixture was then neutralized by the drop-
wise addition of excess triethylamine (0.1 mL), filtered through
Celite®, eluting with ethyl acetate, and concentrated in vacuo
to give a residue which was purified by flash chromatography
(petrol: ethyl acetate, 3 : 1) afford β-furanose sulfonamide 6
(58 mg, 44%) as a white solid. m.p. 110–113 °C (DCM/petrol);
[α]2D0 +9.0 (c, 0.35 in CH3OH); νmax (neat) 3386 (w, NH), 1382 (s,
SvO), 1188 (s, SvO) cm−1; δH (400 MHz, CD3OD) 3.59–3.62
(2H, m, H-5, H-5′), 3.90 (1H, dd, J3,4 6.3 Hz, J2,32.3 Hz, H-3),
4.04–4.05 (1H, m, H-2), 4.14 (1H, aq, J 5.5 Hz, H-4), 4.43–4.58
(6H, m, Ph-CH2), 5.38 (1H, s, H-1), 7.24–7.33 (15H, m, Ar–H);
δC (100 MHz, CD3OD) 69.6 (t, C-5), 71.5, 71.7, 72.9 (3 × t, Ph-
CH2), 81.5 (d, C-4), 83.6 (d, C-3), 87.4 (d, C-2), 101.9 (d, C-1),
119.8 (q, JC,F 334.1 HZ, CF3), 127.3, 127.5, 127.6, 127.9, 128.0
(5 × d, 5 × Ar–C), 137.4, 137.8, 137.9 (3 × s, 3 × Ar–C); δF
(376.6 MHz, CD3OD) −81.59; HRMS (ESI) calculated for
C27H28F3NNaO6S (M + Na+) 574.1487. Found 574.1478.
1,1,1-Trifluoro-N-(β-D-arabinofuranosyl)methanesulfonamide
7. 10% Activated Pd/C (10 mg) was added to a solution of pro-
tected furanose sulfonamide 6 (40 mg, 0.1 mmol) in methanol.
The flask was evacuated and purged with nitrogen five times,
before being placed under an atmosphere of hydrogen. The
solution was stirred for 16 hours at room temperature. After
this time, t.l.c. (ethyl acetate) indicated the formation of a
single product (Rf 0.0), and the complete consumption of start-
ing material (Rf 0.9). The reaction mixture was filtered through
Celite® (eluting with methanol, 20 mL), and concentrated in
vacuo to give a residue which was purified by RP-HPLC (Luna
C-18 column (Phenomenex); eluent: A (0.05% TFA in H2O) and
B MeCN; gradient: the sample was run at 1 mL min−1 with a
gradient of 50–80% B; column oven 15 °C; detection: CAD) to
afford β-furanose sulfonamide 7 (13 mg, 65%) as waxy yellow
1 For some recent syntheses of stable analogues of glycosyl
phosphates see: (a) C. A. Centrone and T. L. Lowary, Bioorg.
Med. Chem., 2004, 12, 5495–5503; (b) C. A. Centrone and
T. L. Lowary, J. Org. Chem., 2002, 67, 8862–8870;
(c) T. Kannan, S. Vinodhkumar, B. Vargheseb and
D. Loganathan, Bioorg. Med. Chem. Lett., 2001, 11, 2433–
2435; (d) F. Casero, L. Cipolla, L. Lay, F. Nicotra, L. Panza
and G. Russo, J. Org. Chem., 1996, 61, 3428–3432.
2 (a) B. Ayers, H. Long, E. Sim, I. A. Smellie, B. L. Wilkinson
and A. J. Fairbanks, Carbohydr. Res., 2009, 344, 739–746;
(b) B. L. Wilkinson, H. Long, E. Sim and A. J. Fairbanks,
Bioorg. Med. Chem. Lett., 2008, 18, 6265–6267.
3 L. J. Alderwick, G. S. Lloyd, H. Ghadbane, J. W. May,
A. Bhatt, L. Eggeling, K. Fuetterer and G. S. Besra, PLoS
Pathog., 2011, 7, e1001299.
4 T. L. Lowary, Mini-Rev. Med. Chem., 2003, 3, 689–702.
5 P. A. Colinas, Curr. Org. Chem., 2012, 16, 1670–1679.
6 D. J. Owen, C. B. Davis, R. D. Hartnell, P. D. Madge,
R. J. Thomson, A. K. J. Chong, R. L. Coppel and M. von Itz-
stein, Bioorg. Med. Chem. Lett., 2007, 17, 2274–2277.
7 (a) S. Knapp, E. Darout and B. Amorelli, J. Org. Chem.,
2006, 71, 1380–1389; (b) K. Czifrák and L. Somsák, Carbo-
hydr. Res., 2009, 344, 269–277; (c) M. Lopez, N. Drillaud,
L. Bornaghi and S.-A. Poulsen, J. Org. Chem., 2009, 74,
2811–2816; (d) M. Lopez, B. Paul, A. Hofmann, J. Morizzi,
Q. K. Wu, S. A. Charman, A. Innocenti, D. Vullo,
C. T. Supuran and S.-A. Poulsen, J. Med. Chem., 2009, 52,
6421–6432.
8 O. M. Rodríguez, A. Maresca, C. A. Témpera, R. D. Bravo,
P. A. Colinas and C. T. Supuran, Bioorg. Med. Chem. Lett.,
2011, 21, 4447–4450.
9 (a) J. M. Owens, B. K. S. Yeung, D. C. Hill and P. A. Petillo,
J. Org. Chem., 2001, 66, 1484–1486; (b) A. Srivastava,
B. Varghese and D. Loganathan, Chem. – Eur. J., 2013, 19,
17720–17732.
solid. [α]2D0 +36.4 (c, 0.5 in CH3OH); νmax (neat) 3288 (br s, OH), 10 (a) P. A. Colinas and R. D. Bravo, Org. Lett., 2003, 5, 4509–
1316 (s, SvO), 1150 (s, SvO) cm−1; δH (400 MHz, CD3OD) 3.64
(1H, dd, J4,5 5.8 Hz, J5,5′ 11.7 Hz, H-5), 3.74 (1H, dd, J4,5′ 4.3 Hz,
J5.5′ 12.5 Hz, H-5′), 3.84–3.86 (1H, dd, J3,4 5.7 Hz, J2,3 3.3 Hz,
H-3), 3.97–4.00 (1H, aq, J 5.1 Hz, H-4), 4.02 (1H, m, H-2), 5.17
(1H, s, H-1); δC (100 MHz, CD3OD) 61.7 (t, C-5), 77.4 (d, C-3),
81.9 (d, C-2), 84.8 (d, C-4), 103.9 (d, C-1), 118.3 (q, JC,F
324.2 HZ, CF3); δF (376.6 MHz, CD3OD) −81.59; HRMS (ESI)
4511; (b) P. A. Colinas and R. D. Bravo, Tetrahedron Lett.,
2005, 46, 1687–1689; (c) P. A. Colinas and R. D. Bravo, Car-
bohydr. Res., 2007, 342, 2297–2302; (d) P. A. Colinas,
C. A. Témpera, O. M. Rodríguez and R. D. Bravo, Synthesis,
2009, 4143–4148; (e) R. Crespo, M. G. de Bravo,
P. A. Colinas and R. D. Bravo, Bioorg. Med. Chem. Lett.,
2010, 20, 6469–6471.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
11 M. Lavecchia, O. Rodríguez, G. Echeverría, R. P. Diez and 14 H. S. Isbell and H. L. Frush, J. Org. Chem., 1958, 23, 1309–
P. A. Colinas, Carbohydr. Res., 2012, 361, 182–188. 1319.
12 H. B. Mereyala and S. R. Lingannagaru, Tetrahedron, 1997, 15 (a) M. Soltero-Higgin, E. E. Carlson, T. D. Gruber and
53, 17501–17512.
L. L. Kiessling, Nat. Struct. Mol. Biol., 2004, 11, 539–543;
(b) H. G. Sun, M. W. Ruszczycky, W. C. Chang,
C. J. Thibodeaux and H. W. Liu, J. Biol. Chem., 2012, 287,
4602–4608.
13 (a) B. Kranke and H. Kunz, Org. Biomol. Chem., 2007, 5,
349–354; (b) R. J. Batchelor, D. F. Green, B. D. Johnston,
B. O. Patrick and B. M. Pinto, Carbohydr. Res., 2001, 330,
421–426; (c) V. Bertolasi, V. Ferretti, G. Gilli, P. Marchetti 16 L. A. Collins and S. G. Franzblau, Antimicrob. Agents Chemo-
and F. D’Angeli, J. Chem. Soc., Perkin Trans. 2, 1990, 2135– ther., 1997, 41, 1004–1009.
2136; (d) H. Booth, J. M. Dixon, K. A. Khedhair and 17 P. A. M. van der Klein, A. E. J. de Nooy, G. A. van der Marel
S. A. Readshaw, Tetrahedron, 1990, 46, 1625–1652.
and J. H. van Boom, Synthesis, 1991, 347–349.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.