Stereoselective synthesis of β-arabino glycosyl sulfones as potential inhibitors of mycobacterial cell wall biosynthesis

Article abstract of DOI:10.1016/j.carres.2009.02.006

A series of β-arabino glycosyl sulfones with varying alkyl chain lengths were synthesised in a stereoselective fashion as putative mimics of decaprenolphosphoarabinose (DPA), and as potential inhibitors of mycobacterial cell wall biosynthesis. Biological

Full text of DOI:10.1016/j.carres.2009.02.006

Carbohydrate Research 344 (2009) 739–746
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Stereoselective synthesis of b-arabino glycosyl sulfones as potential inhibitors
of mycobacterial cell wall biosynthesis
Benjamin Ayers a, Hilary Long b, Edith Sim b, Iain A. Smellie a, Brendan L. Wilkinson a, Antony J. Fairbanks c,
*
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Department of Pharmacology, Oxford University, Mansfield Road, Oxford OX1 3QT, UK
c Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of b-arabino glycosyl sulfones with varying alkyl chain lengths were synthesised in a stereoselec-
tive fashion as putative mimics of decaprenolphosphoarabinose (DPA), and as potential inhibitors of
mycobacterial cell wall biosynthesis. Biological testing against Mycobacterium bovis BCG revealed low
to moderate anti-mycobacterial activity with marked dependence on alkyl chain length, which was max-
imal for a C-12 chain.
Received 28 October 2008
Received in revised form 16 January 2009
Accepted 3 February 2009
Available online 12 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
Thioglycosides
Glycosyl sulfones
Arabinose
Mycobacteria
Tuberculosis
1. Introduction
TB, and correspondingly has been a field of intense interest over re-
cent years.4 Approaches adopted have included the attempted
Mycobacterium tuberculosis, the bacterium responsible for
tuberculosis (TB), is probably the most prevalent of the pathogenic
strains of mycobacteria. Tuberculosis has once again emerged as a
major threat to human health; up to one third of the world’s pop-
ulation is currently estimated to have latent infection,1 whilst be-
tween two and three million people die annually from active
infection. Although a number of drug treatments for TB are cur-
rently available strains of these mycobacteria have already devel-
oped antibiotic resistance.2 Widespread recognition of the
pressing need to develop new therapeutic agents active against
TB has therefore led to the establishment of major global initiatives
to fund drug discovery programs and to facilitate screening of com-
pounds in the search for novel and useful anti-mycobacterial
bioactivity.3
The cell walls of mycobacteria are complex, and pertinently to
this study contain two polysaccharides, lipoarabinomannan
(LAM) and arabinogalactan (AG), the structures of which are un-
ique to mycobacteria and which are crucial to mycobacterial via-
bility. Inhibition of the biosynthesis of these carbohydrate
portions of the cell wall therefore represents an attractive thera-
peutic opportunity for the development of new drugs to combat
inhibition of various glycosyl transferases,5 and of the Galp/Galf
mutase enzyme responsible for a crucial pyranose/furanose isom-
erisation during assembly of the galactan cell wall component.6
Particular attention has focussed on attempted inhibition of the
biosynthesis of mycobacterial arabinan,7 which is assembled step-
wise by arabinosyl transferases that use decaprenolphophoarabi-
nose 1 (DPA, Fig. 1) as the glycosyl donor. Metabolically stable
analogues of DPA may inhibit these arabinosyl transferases, and
thus inhibit arabinan biosynthesis, which would correspondingly
be expected to have significantly deleterious effects on mycobacte-
rial growth and survival.
In order to design mimics of DPA which may be expected to dis-
play useful in vivo activity replacement of the labile and highly po-
lar glycosyl phosphate with a stable isostere could be considered
an essential first step. Additionally, it would not be unreasonable
O
O
O
P
O
HO
O
HO
OH
9
1
* Corresponding author. Tel.: +44 1865 275 647; fax: +44 1865 275 674.
E-mail address: antony.fairbanks@chem.ox.ac.uk (A.J. Fairbanks).
Figure 1. Decaprenolphophoarabinose 1 (DPA).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.02.006

740
B. Ayers et al. / Carbohydrate Research 344 (2009) 739–746
to expect that an alkyl chain, or other extended hydrophobic group
of a certain minimum length, would be required to mimic the large
decaprenyl moiety of DPA. Lowary, who has been one of the lead-
ing proponents in the field, has, amongst other approaches,7c–e re-
ported the synthesis of a variety of b-C-glycosyl sulfones8 and C-
phosphonates of arabinofuranose as mimics of DPA, and therefore
as putative anti-tubercular agents. In a somewhat related vein, von
Itzstein more recently reported the synthesis and bioactivity of a
variety of galactofuranosyl alkyl thioglycosides, glycosyl sulfones,
sulfenamides and sulfonamides9 which are presumed to act as
inhibitors of the biosynthesis of galactofuranose components of
the mycobacterial cell wall. Efforts from our laboratory have in-
cluded a recent report on the synthesis and anti-mycobacterial
activity of a series of glycosyl triazoles as putative mimics of DPA.10
In light of the greater bond length of C–S as compared to C–O,
and mindful of the ease with which thioglycosides may be synthes-
ised by direct nucleophilic substitution at the anomeric centre, it
was decided to access a variety of b-glycosyl sulfones of arabinof-
uranose, which were analogous to the C-glycosyl sulfones previ-
ously reported by Lowary,6b but which lacked the methylene unit
between the anomeric centre and the sulfur atom. Moreover, sys-
tematic variation of alkyl chain length as a mimic of the extended
polyprenyl side chain of DPA would facilitate further refinement of
the somewhat unclear structure–activity relationships which have
been observed in previous studies.
O
OH
OH
O
OMe
OBn
(i),(ii)
(vi)
BnO
BnO
HO
BnO
2
OH
1
(iii)
O
O
SR
R
BnO
BnO
OBn
4a-g
BnO
OBn
3a R = OH
3b R = OAc
3c R = Br
(iv)
(v)
(vii)
O
O
SO2R
SO2R
BnO
HO
(viii)
BnO
OBn
5a-g
HO
OH
6a-g
4a, 5a, 6a R = (CH2)3CH3
4b, 5b, 6b R = (CH2)5CH3
4c, 5c, 6c
4d, 5d, 6d
4e, 5e, 6e
R = (CH2)7CH3
R = (CH2)9CH3
R = (CH2)11CH3
R = (CH2)13CH3
4f, 5f, 6f
4g, 5g, 6g
R = (CH2)15CH3
This paper reports the stereoselective synthesis of a series of
b-arabinofuranose glycosyl sulfones as putative mimics of DPA, to-
gether with anti-bacterial activity observed in a variety of cell
growth assays against both Mycobacterium bovis BCG and E. coli.
Scheme 1. Reagents and conditions: (i) AcCl, MeOH rt, 6 h, 80%,
BnBr, DMF, rt, 16 h, 87%; (iii) 80% aqueous AcOH, 115 °C, 48 h, 73%; (iv) Ac2O,
pyridine, rt, 16 h, 94%, :b, 4:1; (vi)
RSH, TTBP, CH2Cl2, rt, 16–17 h; 4a, 94%, 4b, 85%, 4c, 83%, 4d, 80%, 4e, 63%, 4f, 97%,
4g, 80% (all over two steps); (vii) MCPBA, NaHCO3, CH2Cl2, 16 h; 5a, 83%, 5b, 78%, 5c,
84%, 5d, 88%, 5e, 87%, 5f, 83%, 5g, 86%; (viii) H2, 10% Pd on C, MeOH or MeOH:EtOAc,
1:1, or EtOAc, rt, 24 h; 6a, 72%, 6b, 82%, 6c, 80%, 6d, 75%, 6e, 94%, 6f, 88%, 6g, 81%.
a:b, 4:1; (ii) NaH,
a
:b, 1.7:1; (v) TMSBr, CH2Cl2, ꢁ40 °C to rt, 0.5 h, a
2. Results and discussion
2.1. Synthesis
on the stereoselectivity; in this case the desired b-anomer was pro-
duced as the sole reaction product.
With an appropriate procedure in place that would allow ster-
eoselective access to the desired b-arabino thioglycosides from
the corresponding thiols, consideration was given to the range of
thioglycosides that should be synthesised. It was concluded that
appropriate mapping of hydrophobic space could be economically
achieved by only accessing alternate members of a homologous
series of n-alkyl thioglycosides, in which the alkyl chain contained
even numbers of carbon atoms. Glycosyl bromide 3c was therefore
reacted with the series of straight-chain alkyl thiols CH3(CH2)nSH,
(where n = an odd number from 3 to 15); in all cases reaction of
the thiol with 3c in the presence of TTBP in DCM produced the cor-
responding b-thioglycoside 4a–f as a single anomer in 60–97%
yields over two steps from acetate 3b. Subsequent oxidation by
treatment with metachloroperbenzoic acid (MCPBA, 3 equiv) in
DCM in the presence of NaHCO3 in fact produced mainly the glyco-
syl sulfoxide. However, omission of the base and the use of a larger
excess of MCPBA (5 equiv) led to exclusive formation of the desired
sulfone, and this procedure produced the glycosyl sulfones 5a–f in
78–86% yield, as the sole reaction products in each case. Finally, re-
moval of the benzyl protecting groups was achieved by catalytic
hydrogenation in the presence of 10% Pd on carbon, in a solvent
mixture of MeOH and 10% acetic acid by volume, producing the
de-protected glycosyl sulfones 6a–e. For reasons of compound sol-
ubility the solvent polarity was decreased for the de-protection of
the tetradecyl sulfone 6f and the hexadecyl sulfone 6g (solvents:
1:1 mixture of MeOH/EtOAc, and neat EtOAc, respectively, 10%
AcOH v/v was added in both cases).
Fischer glycosylation of arabinose 1 with 1 equiv of acetyl chlo-
ride in methanol provided methyl arabinofuranoside, which was
then immediately benzylated to give the fully protected furanoside
211
(a:b ratio, 1:2.3, Scheme 1). Acid-catalysed hydrolysis of the
methyl glycoside by prolonged heating in 80% aqueous acetic acid
provided hemiacetals 3a,12 which were then acetylated giving gly-
cosyl acetates 3b13
(
a
:b ratio, 1.7:1). Conversion to the glycosyl bro-
:b ratio, ꢀ6:1) was most conveniently achieved by
treatment with trimethylsilyl bromide (TMSBr) in dichloromethane
(DCM,
:b ratio, 7:1), and bromide 3c14 was used directly for subse-
mide 3c (
a
a
quent steps without extensive purification. Various methods were
then investigated for the synthesis of the required b-thioglycosides.
Attempts to access the dodecyl thioglycoside 4e directly from hemi-
acetals 3a by acid-catalysed reaction with dodecylthiol, using a pro-
cedure published by Wong15 for the synthesis of the corresponding
ethyl and phenyl b-thioglycosides, led to the formation of anomeric
mixtures of products and unsurprisingly to a considerable quantity
of open chain dithioacetal.16 Efforts therefore focused on substitu-
tion reactions of the glycosyl bromide. Reaction of 3c with dod-
ecylthiol alone in DCM did give the desired thioglycoside 4e, but
as an inseparable anomeric mixture in which the undesired
mer unexpectedly predominated ( :b ratio, 4:1). It is reasonable to
expect that direct SN2 substitution of 3c ( :b ratio, 7:1) would have
led to the formation of an anomeric mixture (1:7, :b) favouring the
a-ano-
a
a
a
desired product. It was therefore considered that either the reaction
had proceeded by a SN1-type pathway to a significant extent, or that
in situ epimerisation of 3c competed with substitution, or that HBr
produced during the reaction had caused undesired extensive epi-
merisation of the desired b-product. In order to both remove HBr
and increase the nucleophilicity of the thiol by de-protonation, the
hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP) was added to
the reaction mixture, and this had a significant and beneficial effect
2.2. Biological testing
Anti-mycobacterial testing of de-protected sulfones 6a–g was
initially performed using a spot test on M. bovis BCG; M. bovis

B. Ayers et al. / Carbohydrate Research 344 (2009) 739–746
741
Table 1
BCG cultures were spotted onto 6-well plates containing solid
Inhibitory effects of de-protected glycosyl sulfones 6a–g against M. bovis BCG
media and the test compounds were then added at various concen-
trations.17 These cultures were then grown in an incubator at 37 °C
for 7–14 days and any effect of the test compound on cell growth
was measured. In this manner, compounds 6a–g were tested for
biological activity, at concentrations of 0 (control), 2, 20, 200 and
Compound
R2
MICa
(
l
g/mL)
INH
6a
6b
6c
6d
6e
6f
—
0.1
–(CH2)3CH3
–(CH2)5CH3
–(CH2)7CH3
–(CH2)9CH3
–(CH2)11CH3
–(CH2)13CH3
–(CH2)15CH3
2000
500
250
125 > X > 62
62
2000
ity at the highest concentration (2 mg/mL), all the compounds
completely inhibited mycobacterial growth at the 200 g/mL level,
though none displayed activity at or below the 20 g/mL level. A
l
g mLꢁ1. Whilst the n-butyl sulfone 6a only displayed activ-
l
250 > X > 125
125
l
6g
second series of spot tests was performed on E. coli. (strain
JM109) in which none of the compounds 6a–g displayed any
anti-bacterial effects at the highest concentrations (2 mg/mL), indi-
cating a selective anti-mycobacterial mode of action. The mini-
mum inhibitory concentrations (MICs) of the anti-mycobacterial
activity of sulfones 6a–g were then measured somewhat more
accurately in a second series of tests on M. bovis BCG using the Ala-
mar Blue microplate assay, in which the Alamar Blue dye changes
from the oxidised indigo blue (and non-fluorescent) form to the re-
duced pink (and fluorescent) form in the presence of growing bac-
teria (Fig. 2)18 The results are shown in Table 1 and Figure 2.
The dependence of anti-mycobacterial activity upon alkyl chain
length is shown in Table 1 and Figure 2. For sulfones 6a–d biolog-
ical activity increases as side chain hydrophobicity is increased; a
reasonable expectation since the natural DPA substrate contains
an extended decaprenol side chain that is highly non-polar in nat-
ure.19 The n-butyl sulfone 6a is only active at extremely high con-
centrations (MIC ꢀ2 mg/mL), whereas the less polar n-decyl
sulfone 6d is at least 20 times more active (MIC between 62 and
a
MIC = minimum inhibitory concentration; the lowest concentration of the
compound which inhibited the growth of M. bovis BCG >90% from the Alamar Blue
assay. Isoniazid (INH) was used as a control (MIC 0.1 lg/mL).
C-15 chain that also incorporated an ether linkage. Direct compar-
ison of these studies with the related work on galactofuranose
mimics reported by von Itzstein9 is perhaps less appropriate. How-
ever, it is notable that the most active compounds identified in
those studies, which are more than an order of magnitude more
potent than the most active compounds reported by us, contain
branched side chains which comprised two n-octyl alkyl units. Fi-
nally, the fact that optimal bioactivity is reached for a C-12 chain
and that the longer chains result in lower bioactivity is also worthy
of comment. We concede20 that this is possibly an effect of the
physical properties of the longer chain sulfones, which may be
prone to aggregation in the testing medium, rather than being
due to an actual reduction in binding affinity. However, we cur-
rently lack any evidence to substantiate this hypothesis. It should
also be reiterated that in our previous study10 a triazole with a
C-15 side chain was found to be the most active.
In terms of arriving at more definite conclusions a certain de-
gree of caution must be exercised. Firstly, it should be borne in
mind that the optimal anti-mycobacterial activity observed herein
is rather modest; even the most potent compound 6e is at least
two orders of magnitude less active than isoniazid (INH). More-
over, the precise molecular target of these and analogous com-
pounds is still unclear at this juncture. Although the compounds
in this and the related study10 have been designed as mimics of
DPA, identification of their mode of action, for example, as inhibi-
tors of mycobacterial arabinosyl transferases, would require fur-
ther investigation. However, the low activity of these compounds
means that such further studies are likely to be of only limited va-
lue in the context of future anti-tubercular drug development.
125
length then reaches a maximum, which is observed for the C-12
sulfone 6e (MIC 62 g/mL). This result corroborates the earlier
lg/mL). However, this increase in activity with alkyl chain
l
findings of Lowary during his work on arabino C-glycosyl sulf-
ones8b with the caveat that their C-glycosides contain an extra
methylene unit between the sulfur atom and the anomeric centre.
Activity then subsequently decreases for sulfones 6f–g which pos-
sess more extended alkyl chains (MICs between 250 and 125 lg/
mL), indicating that there is not a simple correlation between in-
creased hydrophobicity and biological activity.
A comparison of these results with those of other recent studies
is worthwhile. Our recent studies on glycosyl triazoles10 revealed
that for the n-alkyl derivatives, the compound possessing a C-8
chain was more active than the one that contained a C-10 chain;
the reverse of the situation is observed here. Moreover, in that
study the most active glycosyl triazole, which was approximately
twice as active as compound 6e, in fact contained a more extended
3. Experimental
3.1. General
Melting points were recorded on a Kofler hot block and are
uncorrected. Proton and carbon nuclear magnetic resonance (dH,
dC) spectra were recorded on Bruker AV 400 (400 MHz), or Bruker
AMX 500 (500 MHz) spectrometers. All chemical shifts are quoted
on the d-scale in ppm using residual solvent as an internal stan-
dard. Low resolution mass spectra were recorded on a Micromass
Platform 1 spectrometer using electrospray ionisation in either po-
sitive or negative polarity (ES+ or ES-), or using a VG Micromass
spectrometer. High-resolution mass spectra were recorded on a
Walters 2790-Micromass LCT electrospray ionisation mass spec-
trometer, using either electrospray ionisation (NH3, Cl) techniques
as stated. M/z values are reported in Daltons and are followed by
their percentage abundance in parentheses. Optical rotations were
measured on a Perkin–Elmer 241 polarimeter with a path length of
1 dm. Concentrations are given in g/100 mL. Microanalyses were
performed by the Inorganic Chemistry Laboratory Elemental Anal-
ysis service, Oxford University, UK. Thin Layer Chromatography
(TLC) was carried out on Merck Kieselgel 60F254 pre-coated
Figure 2. Alamar blue assay of M. bovis BCG with de-protected glycosyl sulfones
6a–g and control with isoniazid (INH).

742
B. Ayers et al. / Carbohydrate Research 344 (2009) 739–746
glass-backed plates. Visualisation of the plates was achieved using
a u.v. lamp (kmax = 254 or 365 nm), and/or ammonium molybdate
(5% in 2 M sulfuric acid), or sulfuric acid (5% in ethanol). Flash col-
umn chromatography was carried out using Sorbsil C60 40/60 sil-
ica. Alcohol-free dichloromethane was dried on an alumina
column. Anhydrous DMF, pyridine, methanol and toluene were
purchased from Sigma Aldrich. ‘Petrol’ refers to the fraction of light
petrol ether boiling in the range of 40–60 °C. TTBP was re-crystal-
lised from methanol. Compounds 2,11 3a,12 3b,13 and 3c,14 were
prepared using the route shown in Scheme 1, and exhibited spec-
troscopic data in agreement with those reported previously.
4.9 Hz, J2,3 3.8 Hz, H-2), 4.47–4.69 (6H, m, PhCH2), 5.40 (1H, d,
J1,2 4.9 Hz, H-1), 7.20–7.41 (15H, m, Ar-H); dC (125 MHz, CDCl3)
13.7 (q, CH3), 21.4, 30.6, 32.0 (3 ꢂ t, CH2), 71.4 (t, C-5), 71.9, 72.3,
73.3 (3 ꢂ t, PhCH2), 82.0, 83.8, 84.3, 87.1 (4 ꢂ d, C-4, C-3, C-2, C-
1), 125.3, 127.6, 127.7, 127.7, 127.8, 127.8, 127.9, 128.0, 128.1,
128.2, 128.3, 128.4, 128.7, 129.0, 129.8 (15 ꢂ d, Ar-H), 137.5,
137.8, 138.2 (3 ꢂ s, Ar-C); m/z (ESI)+ 515.2 (M+Na+, 16), 510.2
þ
(M þ NH4
,
100%). HRMS m/z calcd for C30H36O4S [M+Na]+:
515.2232. Found: 515.2214.
3.6. Hexyl 2,3,5-tri-O-benzyl-1-thio-b-D-arabinofuranoside (4b)
3.2. General procedure A: synthesis of thioglycosides
Procedure A: Method as described above afforded the hexyl thio-
glycoside 4b (480 mg, 85%) as a clear oil; ½a D25
ꢃ ꢁ43.3 (c, 1.1 in CHCl3);
To a solution of the crude glycosyl bromide 3c (1 equiv) and
TTBP (2.5 equiv) in dry DCM (15 mL) under argon, the correspond-
ing thiol (2 equiv) was added. After 18 h, TLC (toluene/ethyl ace-
tate, 30:1) indicated formation of a single product. The reaction
mixture was diluted in DCM (50 mL), washed with sodium bicar-
bonate (3 ꢂ 50 mL of a saturated solution) and brine (1 ꢂ 50 mL
of a saturated solution). The organic phase was dried (MgSO4), fil-
tered and concentrated in vacuo. The residue was purified by flash
column chromatography (toluene, until TTBP fully eluted, then tol-
uene/ethyl acetate, 30:1) to afford thioglycosides 4a–g.
dH (500 MHz, CDCl3) 0.90 (3H, t, J 7.0 Hz, CH3), 1.25–1.35 (4H, m,
CH2), 1.39 (2H, quin., J 7.2 Hz, CH2), 1.64 (2H, quin., J 7.5 Hz, CH2),
0
2.67 (2H, td, J 7.5 Hz, J 2.7 Hz, CH2), 3.66 (1H, dd, J4,5 6.5 Hz, J5,5
9.9 Hz, H-5), 3.74 (1H, dd, J4,5 6.5 Hz, J5,5 9.9 Hz, H-50), 4.06 (1H,
0
0
0
at, J 4.0 Hz, H-3), 4.16 (1H, td, J3,4 4.3 Hz, J4,5 6.5 Hz, J4,5 6.5 Hz, H-
4), 4.18 (1H, dd, J1,2 4.9 Hz, J2,3 4.9 Hz, H-2), 4.48–4.68 (6H, m,
PhCH2), 5.40 (1H, d, J1,2 4.9 Hz, H-1), 7.24–7.39 (15H, m, Ar-H); dC
(125 MHz, CDCl3) 14.0 (q, CH3), 21.5, 28.7, 29.9, 30.9, 31.4 (5 ꢂ t,
CH2), 71.4 (t, C-5), 71.9, 72.3, 73.3 (3 ꢂ t, PhCH2), 82.0, 83.8, 84.3,
87.1 (4 ꢂ d, C-4, C-3, C-2, C-1), 125.3, 127.6, 127.7, 127.8, 127.8,
127.9, 127.9, 128.0, 128.2, 128.2, 128.3, 128.3, 128.4, 128.4, 129.0
3.3. General procedure B: oxidation of thioglycosides
(15 ꢂ d, Ar-H), 137.5, 137.8, 138.2 (3 ꢂ s, Ar-C); m/z (ESI)+ 543.3
(M+Na+, 19), 538.3 (M þ NH4
, 100%). HRMS m/z calcd for
þ
The thioglycosides 4a–g (1 equiv) were dissolved in DCM
(10 mL) under argon. mCPBA (5 equiv) was added, and after 16 h
TLC (petrol/ethyl acetate, 5:1) indicated formation of a single prod-
uct. The reaction was quenched with sodium thiosulfate (30 mL of
a saturated solution) and was stirred vigorously for 30 min. The bi-
phasic solution was diluted with DCM (20 mL) and the phases were
separated. The aqueous phase was back-extracted with DCM
(3 ꢂ 20 mL), the organic phases were combined, washed with so-
dium bicarbonate (3 ꢂ 50 mL of a saturated solution) and brine
(1 ꢂ 50 mL of a saturated solution). The organic phase was dried
(MgSO4), filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (petrol/ethyl acetate, 5:1) to
afford glycosyl sulfones 5a–g.
C32H40O4S [M+Na]+: 543.2545. Found: 543.2535.
3.7. Octyl 2,3,5-tri-O-benzyl-1-thio-b-D-arabinofuranoside (4c)
Procedure A: Method as described above afforded the octyl thio-
glycoside 4c (395 mg, 83%) as a clear oil; ½a D25
ꢁ42.2 (c, 1.1 in
ꢃ
CHCl3); dH (500 MHz, CDCl3) 0.90 (3H, t, J 6.8 Hz, CH3), 1.23–1.34
(8H, m, CH2), 1.35–1.44 (2H, m, CH2), 1.64 (2H, quin., J 7.5 Hz,
CH2), 2.67 (2H, td, J 7.5 Hz, J 2.8 Hz, CH2), 3.66 (1H, dd, J4,5
0
0
0
6.5 Hz, J5,5 9.9 Hz, H-5), 3.74 (1H, dd, J4,5 6.5 Hz, J5,5 9.9 Hz, H-
50), 4.06 (1H, at, J 3.9 Hz, H-3), 4.16 (1H, td, J3,4 4.3 Hz, J4,5 6.5 Hz,
0
J4,5 6.5 Hz, H-4), 4.19 (1H, dd, J1,2 4.9 Hz, J2,3 3.8 Hz, H-2), 4.50–
4.68 (6H, m, PhCH2), 5.40 (1H, d, J1,2 4.9 Hz, H-1), 7.21–7.41
(15H, m, Ar-H); dC (125 MHz, CDCl3) 14.1 (q, CH3), 22.6, 29.0,
29.2, 29.7, 29.9, 30.9, 31.8 (7 ꢂ t, CH2), 71.4 (t, C-5), 71.9, 72.3,
73.3 (3 ꢂ t, PhCH2), 82.0, 83.8, 84.3, 87.1 (4 ꢂ d, C-4, C-3, C-2, C-
1), 127.6, 127.6, 127.7, 127.7, 127.8, 127.8, 127.8, 127.9, 127.9,
128.2, 128.3, 128.4, 128.4, 128.4, 128.7 (15 ꢂ d, Ar-H), 137.5,
3.4. General procedure C: de-protection of sulfone
The protected glycosyl sulfone (1 equiv) was dissolved in either
MeOH (5a–e), a 1:1 mixture of MeOH and EtOAc (5f), or EtOAc
(5g), before AcOH (10%, v/v) was added. 10% Pd–C was then added
(40% w/w of the starting material) and the reaction was stirred un-
der an atmosphere of hydrogen for 16 h. After this time, TLC (ethyl
acetate) indicated the formation of a single product. The reaction
mixture was filtered through CeliteÒ and was concentrated in va-
cuo. The residue was dissolved in ethyl acetate (50 mL), washed
with sodium bicarbonate (3 ꢂ 50 mL of a saturated solution) and
brine (1 ꢂ 50 mL of a saturated solution). The organic phase was
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (ethyl acetate) to
afford the de-protected glycosyl sulfones 6a–g.
137.8, 138.2 (3 ꢂ s, Ar-C); m/z (ESI)+ 571.3 (M+Na+, 17), 566.3
þ
(M þ NH4
,
100%). HRMS m/z calcd for C34H44O4S [M+Na]+:
571.2858. Found: 571.2836.
3.8. Decyl 2,3,5-tri-O-benzyl-1-thio-b-D-arabinofuranoside (4d)
Procedure A: Method as described above afforded the decyl thio-
glycoside 4d (500 mg, 80%) as a clear oil; ½a D25
ꢁ39.3 (c, 1.2 in
ꢃ
CHCl3); dH (500 MHz, CDCl3) 0.90 (3H, t, J 6.8 Hz, CH3), 1.23–1.35
(12H, m, CH2), 1.35–1.42 (2H, m, CH2), 1.64 (2H, quin., J 7.5 Hz,
CH2), 2.67 (2H, td, J 7.5 Hz, J 2.8 Hz, CH2), 3.66 (1H, dd, J4,5
0
0
0
6.5 Hz, J5,5 9.9 Hz, H-5), 3.74 (1H, dd, J4,5 6.5 Hz, J5,5 9.9 Hz, H-
0
3.5. Butyl 2,3,5-tri-O-benzyl-1-thio-b-
D-arabinofuranoside (4a)
5 ), 4.06 (1H, at, J 4.0 Hz, H-3), 4.16 (1H, td, J3,4 4.3 Hz, J4,5 6.5 Hz,
0
J4,5 6.5 Hz, H-4), 4.19 (1H, dd, J1,2 4.9 Hz, J2,3 3.8 Hz, H-2), 4.48–
Procedure A: Method as described above afforded the butyl thio-
4.68 (6H, m, PhCH2), 5.40 (1H, d, J1,2 4.9 Hz, H-1), 7.24–7.40
(15H, m, Ar-H); dC (125 MHz, CDCl3) 14.1 (q, CH3), 22.7, 29.0,
29.2, 29.3, 29.6, 29.6, 29.9, 30.3, 30.9 (9 ꢂ t, CH2), 71.4 (t, C-5),
71.9, 72.3, 73.3 (3 ꢂ t, PhCH2), 82.0, 83.8, 84.2, 87.1 (4 ꢂ d, C-4,
C-3, C-2, C-1), 127.6, 127.7, 127.8, 127.8, 127.9, 128.0, 128.1,
128.1, 128.2, 128.3, 128.4, 128.5, 128.7, 129.8, 130.9 (15 ꢂ d, Ar-
H), 137.5, 137.8, 138.2 (3 ꢂ s, 3 ꢂ Ar-C); m/z (ESI)+ 599.3 (M+Na+,
glycoside 4a (600 mg, 94%) as a clear oil; ½a D25
ꢁ48.7 (c, 1.0 in
ꢃ
CHCl3); dH (500 MHz, CDCl3) 0.93 (3H, t, J 7.41 Hz, CH3), 1.38–
1.46 (2H, m, CH2), 1.60–1.67 (2H, m, CH2), 2.68 (2H, td, J 7.5 Hz, J
0
2.5 Hz, CH2), 3.66 (1H, dd, J4,5 6.5 Hz, J5,5 9.8 Hz, H-5), 3.74 (1H,
dd, J4,5 6.5 Hz, J5,5 9.8 Hz, H-50), 4.06 (1H, at, J 4.0 Hz, H-3), 4.16
0
0
(1H, td, J3,4 4.3 Hz, J4,5 6.5 Hz, J4,5 6.5 Hz, H-4), 4.18 (1H, dd, J1,2

B. Ayers et al. / Carbohydrate Research 344 (2009) 739–746
743
18), 594.3 ((M þ NH4þ, 100%). HRMS m/z calcd for C36H48O4S
(KBr disc) 1317 (s, S@O, asymm. stretch), 1100 (s, S@O, symm.
stretch) cmꢁ1; dH (500 MHz, CDCl3) 0.90 (3H, t, J 7.4 Hz, CH3),
1.38 (2H, app. sext., J 7.4 Hz, CH2), 1.72–1.86 (2H, m, CH2), 2.99
(1H, ddd, J 13.8 Hz, J 10.4 Hz, J 5.8 Hz, CHH0), 3.12 (1H, ddd, J
[M+Na]+: 599.3171. Found: 599.3157.
3.9. Dodecyl b-
D-thio-2,3,5-tri-O-benzylarabinofuranoside (4e)
13.8 Hz, J 10.4 Hz, J 5.8 Hz, CHH0), 3.64 (1H, dd, J4,5 4.9 Hz, J5,5
0
0
0
0
Procedure A: Method as described above afforded the dodecyl
10.2 Hz, H-5), 3.75 (1H, dd, J4,5 6.3 Hz, J5,5 10.2 Hz, H-5 ), 4.24–
4.31 (2H, m, H-3, H-4), 4.48–4.60 (6H, m, H-2, 2 ꢂ PhCH2, PhCHH0),
4.81 (1H, d, JAB 11.5 Hz, PhCHH0), 4.98 (1H, d, J1,2 5.7 Hz, H-1), 7.19–
7.39 (15H, m, Ar-H); dC (125 MHz, CDCl3) 13.5 (q, CH3), 21.8, 22.9,
50.7 (3 ꢂ t, CH2), 81.7, 83.2, 83.5, 91.8 (4 ꢂ d, C-4, C-2, C-3, C-1),
127.7, 127.7, 127.8, 127.8, 128.0, 128.0, 128.1, 128.2, 128.3,
128.4, 128.4, 128.5, 128.5, 128.6, 128.6 (15 ꢂ d, Ar-H), 136.8,
23
thioglycoside 4e (190 mg, 63% over 2 steps; [
dH (400 MHz, CDCl3) 0.89 (3H, t, J 6.7 Hz, alkyl CH3), 1.25–1.41 (16H,
a
]
ꢁ70 (c 1.0 CHCl3);
m, alkyl CH2) 1.60–1.69 (2H, m, alkyl CH2), 2.64–4.71 (2H, m, alkyl
0
0
CH2), 3.66 (1H, dd, J4,5 6.6 Hz, J5,5 9.9 Hz, H-5), 3.75 (1H, dd, J4,5
6.3 Hz, J5,5 9.9 Hz, H-50), 4.06 (1H, at, J2,3 4.0 Hz, J3,4 4.0 Hz, H-3),
4.15–4.20 (2H, m, H-2, H-4), 4.51–4.66 (6H, m, 3 ꢂ OCH2C6H5),
5.41 (1H, d, J1,2 4.8 Hz H-1), 7.25–7.38 (15H, m, 3 ꢂ OCH2C6H5); dC
(100.6 MHz, CDCl3) 14.1 (alkyl CH3), 22.7, 29.0, 29.3, 29.4, 29.6,
29.6, 29.7, 29.7, 30.0, 30.9, 31.9 (11 ꢂ alkyl CH2), 71.4 (C-5), 71.9,
72.3, 73.3 (OCH2C6H5) 82.1 (C-4), 83.8, 84.3 (C-2, C-3), 87.1 (C-1),
127.6, 127.7, 127.8, 127.8, 127.9, 128.3, 128.4 (PhCH), 137.5, 137.8,
138.2 (Ar-C); m/z (ES+) 627 (M+Na+, 100%); HRMS (ES+) Calcd Na-
C38H52O4S 627.3479. Found: 627.3481).
0
137.3, 137.8 (3 ꢂ s, Ar-C); m/z (ESI)+ 547.3 (M+Na+, 14), 542.3
þ
((M þ NH4
,
100%). HRMS m/z calcd for C30H36O6S [M+Na]+:
547.2130. Found: 547.2117. (Found: C, 68.48; H, 7.11. C30H36O6S
requires C, 68.58; H, 6.92%).
3.13. 2,3,5-Tri-O-benzyl-b-D-arabinofuranosyl hexyl sulfone
(5b)
3.10. Tetradecyl 2,3,5-tri-O-benzyl-1-thio-b-
arabinofuranoside (4f)
D
-
Procedure B: Method as described above afforded the hexyl sul-
fone 5b (332 mg, 78%) as a clear oil; ½a D25
ꢁ7.4 (c, 1.1 in CHCl3);
ꢃ
m
max (KBr disc) 1317 (s, S@O, asymm. stretch), 1102 (s, S@O, symm.
Procedure A: Method as described above afforded the tetradecyl
stretch) cmꢁ1; dH (500 MHz, CDCl3) 0.88 (3H, t, J 7.0 Hz, CH3), 1.20–
1.39 (6H, m, CH2), 1.72–1.89 (2H, m, CH2), 2.98 (1H, ddd, J 13.7 Hz, J
10.6 Hz, J 5.6 Hz, CHH0), 3.12 (1H, ddd, J 13.7 Hz, J 10.6 Hz, J 5.6 Hz,
thioglycoside 4f (802 mg, 97%) as a clear oil; ½a D25
ꢁ38.2 (c, 1.1 in
ꢃ
CHCl3); dH (500 MHz, CDCl3) 0.90 (3H, t, J 6.8 Hz, CH3), 1.25–1.34
CHH0), 3.64 (1H, dd, J4,5 5.0 Hz, J5,5 10.3 Hz, H-5), 3.75 (1H, dd, J4,5
0
0
(20H, m, CH2), 1.35–1.44 (2H, m, CH2), 1.61–1.68 (2H, m, CH2),
0
0
0
2.67 (2H, td, J 7.1 Hz, J 2.8 Hz, CH2), 3.66 (1H, dd, J4,5 6.5 Hz, J5,5
6.3 Hz, J5,5 10.3 Hz, H-5 ), 4.24–4.31 (2H, m, H-3, H-4), 4.49–4.60
(6H, m, H-2, 2 ꢂ PhCH2, PhCHH0), 4.81 (1H, d, JAB 11.5 Hz, PhCHH0),
4.98 (1H, d, J1,2 5.5 Hz, H-1), 7.19–7.39 (15H, m, 15 ꢂ Ar-H); dC
(125 MHz, CDCl3) 13.9 (q, CH2), 20.9, 22.3, 28.2, 31.2, 50.9 (5 ꢂ t,
CH2), 70.2 (t, C-5), 72.7, 73.6, 73.8 (3 ꢂ t, PhCH2), 81.7, 83.1, 83.5,
91.1 (4 ꢂ d, C-4, C-2, C-3, C-1), 127.7, 127.7, 127.8, 128.0, 128.1,
128.3, 128.3, 128.4, 128.4, 128.5, 128.5, 128.5, 128.6, 128.6, 129.0
(11 ꢂ d, Ar-H), 136.8, 137.3, 137.8 (3 ꢂ s, 3 ꢂ Ar-C); m/z (ESI)+
575.3 (M+Na+, 29), 570.3 ((M þ NH4þ, 100%). HRMS m/z calcd for
C32H40O6S [M+Na]+: 575.2443. Found: 575.2433.
9.9 Hz, H-5), 3.74 (1H, dd, J4,5 6.5 Hz, J5,5 9.9 Hz, H-50), 4.06 (1H,
at, J 4.0 Hz, H-3), 4.16 (1H, td, J3,4 4.3 Hz, J4,5 6.5 Hz, J4,5 6.5 Hz,
0
0
0
H-4), 4.19 (1H, dd, J1,2 4.9 Hz, J2,3 3.8 Hz, H-2), 4.48–4.69 (6H, m,
PhCH2), 5.40 (1H, d, J1,2 4.9 Hz, H-1), 7.24–7.39 (15H, m, Ar-H);
dC (125 MHz, CDCl3) 14.1 (q, CH3), 29.0, 29.3, 29.4, 29.6, 29.6,
29.7, 29.7, 29.9, 30.4, 30.9, 31.8, 31.9, 32.1 (13 ꢂ t, CH2), 71.9 (t,
C-5), 72.1, 72.3, 73.3 (3 ꢂ t, PhCH2), 82.0, 83.8, 84.3, 87.1 (4 ꢂ d,
C-4, C-3, C-2, C-1), 127.5, 127.6, 127.7, 127.8, 127.8, 127.9, 128.0,
128.1, 128.2, 128.2, 128.3, 128.4, 128.7, 128.8, 130.9 (15 ꢂ d, Ar-
H), 137.8, 138.2, 138.4 (3 ꢂ s, Ar-C); m/z (ESI)+ 655.4 (M+Na+, 21),
þ
650.4 ((M þ NH4
,
100%). HRMS m/z calcd for C40H56O4S
3.14. 2,3,5-Tri-O-benzyl-b-D-arabinofuranosyl octyl sulfone (5c)
[M+Na]+: 655.3797. Found: 655.3768.
Procedure B: Method as described above afforded the octyl sul-
3.11. Hexadecyl 2,3,5-tri-O-benzyl-1-thio-b-
arabinofuranoside (4g)
D
-
fone 5c (320 mg, 84%) as a clear oil; ½a D25
ꢁ18.8 (c, 1.0 in CHCl3);
ꢃ
mmax (KBr disc) 1317 (s, S@O, asymm. stretch), 1100 (s, S@O, symm.
stretch) cmꢁ1; dH (500 MHz, CDCl3) 0.89 (3H, t, J 7.0 Hz, CH3), 1.19–
1.39 (10H, m, CH2), 1.69–1.88 (2H, m, CH2), 2.98 (1H, ddd, J
13.7 Hz, J 10.6 Hz, J 5.6 Hz, CHH0), 3.12 (1H, ddd, J 13.7 Hz, J
Procedure A: Method as described above afforded the hexadecyl
thioglycoside 4f (692 mg, 80%) as a white waxy solid, mp 33 °C;
a 2D5
ꢃ
ꢁ37.0 (c, 1.0 in CHCl3); dH (500 MHz, CDCl3) 0.90 (3H, t, J
10.3 Hz, J 5.8 Hz, CHH0), 3.64 (1H, dd, J4,5 4.9 Hz, J5,5 10.1 Hz, H-
0
½
0
0
6.8 Hz, CH3), 1.20–1.35 (24H, m, CH2), 1.35–1.43 (2H, m, CH2), 1.64
5), 3.75 (1H, dd, J4,5 6.3 Hz, J5,5’ 10.1 Hz, H-5 ), 4.23–4.36 (2H, m,
H-3, H-4), 4.49–4.61 (6H, m, H-2, 2 ꢂ PhCH2, PhCHH0), 4.81 (1H,
d, JAB 11.5 Hz, PhCHH0), 4.98 (1H, d, J1,2 5.8 Hz, H-1), 7.15–7.42
(15H, m, Ar-H); dC (125 MHz, CDCl3) 14.1 (q, CH3), 20.9, 22.6,
28.6, 28.9, 29.0, 31.7, 51.0 (7 ꢂ t, CH2), 70.2 (t, C-5), 72.3, 73.3,
73.6 (3 ꢂ t, PhCH2), 81.8, 83.2, 83.5, 91.8 (4 ꢂ d, C-4, C-2, C-3, C-
1), 127.7, 127.7, 127.8, 127.8, 128.0, 128.0, 128.1, 128.2, 128.3,
128.3, 128.4, 128.5, 128.5, 128.6, 128.6 (15 ꢂ d, Ar-H), 136.8,
(2H, quin., J 7.5 Hz, CH2), 2.67 (2H, td, J 7.1 Hz, J 2.8 Hz, CH2), 3.66
0
0
0
(1H, dd, J4,5 6.5 Hz, J5,5 9.9 Hz, H-5), 3.74 (1H, dd, J4,5 6.5 Hz, J5,5
9.9 Hz, H-50), 4.06 (1H, at, J 3.9 Hz, H-3), 4.16 (1H, td, J3,4 4.3 Hz, J4,5
0
6.5 Hz, J4,5 6.5 Hz, H-4), 4.18 (1H, dd, J1,2 4.9 Hz, J2,3 3.8 Hz, H-2),
4.49–4.68 (6H, m, PhCH2), 5.40 (1H, d, J1,2 4.9 Hz, H-1), 7.22–7.39
(15H, m, Ar-H); dC (125 MHz, CDCl3) 14.2 (q, CH3), 28.4, 29.0, 29.1,
29.2, 29.3, 29.4, 29.6, 29.6, 29.7, 29.7, 29.9, 30.4, 30.7, 30.9, 31.3
(15 ꢂ t, CH2), 71.4 (t, C-5), 71.9, 72.3, 73.3 (3 ꢂ t, PhCH2), 82.0,
83.8, 84.3, 87.1 (4 ꢂ d, C-4. C-3, C-2, C-1), 127.6, 127.6, 127.7,
127.8, 127.8, 127.8, 127.9, 128.0, 128.1, 128.2, 128.2, 128.3, 128.4,
129.0, 129.8 (15 ꢂ d, Ar-H), 137.5, 137.8, 138.2 (3 ꢂ s, Ar-C); m/z
(ESI)+ 683.4 (M+Na+, 18), 678.4 ((M þ NH4þ, 100%). HRMS m/z calcd
for C42H60O4S [M+Na]+: 683.4110. Found: 683.4084.
137.3, 137.8 (3 ꢂ s, Ar-C); m/z (ESI)+ 603.3 (M+Na+, 23), 598.3
þ
((M þ NH4
,
100%). HRMS m/z calcd for C34H44O6S [M+Na]+:
603.2756. Found: 603.2738. (Found: C, 70.13; H, 7.56. C34H44O6S
requires C, 70.31; H, 7.64%).
3.15. 2,3,5-Tri-O-benzyl-b-D-arabinofuranosyl decyl sulfone (5d)
3.12. 2,3,5-Tri-O-benzyl-b-
D
-arabinofuranosyl butyl sulfone (5a)
Procedure B: Method as described above afforded the decyl sul-
fone 5d (250 mg, 88%) as a clear oil; ½a D25
ꢁ35.0 (c, 1.0 in CHCl3);
ꢃ
Procedure B: Method as described above afforded the butyl sul-
mmax (KBr disc) 1317 (s, S@O, asymm. stretch), 1099 (s, S@O, symm.
fone 5a (425 mg, 83%) as a clear oil; ½a D25
ꢃ
ꢁ4.2 (c, 1.1 in CHCl3); mmax
stretch) cmꢁ1; dH (500 MHz, CDCl3) 0.89 (3H, t, J 6.9 Hz, CH3),

744
B. Ayers et al. / Carbohydrate Research 344 (2009) 739–746
1.20–1.37 (14H, m, CH2), 1.73–1.88 (2H, m, CH2), 2.98 (1H, ddd, J
13.7 Hz, J 10.6 Hz, J 5.6 Hz, CHH0), 3.11 (1H, ddd, J 13.7 Hz, J
3.12 (1H, ddd, J 13.7 Hz, J 10.4 Hz, J 5.6 Hz, CHH0), 3.64 (1H, dd,
0
0
0
J4,5 4.9 Hz, J5,5 10.2 Hz, H-5), 3.76 (1H, dd, J4,5 6.3 Hz, J5,5
10.6 Hz, J 5.7 Hz, CHH0), 3.64 (1H, dd, J4,5 4.9 Hz, J5,5 10.2 Hz, H-
10.2 Hz, H-5 ), 4.24–4.32 (2H, m, H-3, H-4), 4.46–4.60 (6H, m, H-
2, 2 ꢂ PhCH2, PhCHH0), 4.82 (1H, d, JAB 11.5 Hz, PhCHH0), 4.98
(1H, d, J1,2 5.5 Hz, H-1), 7.19–7.41 (15H, m, Ar-H); dC (125 MHz,
CDCl3) 14.1 (q, CH3), 20.9, 22.7, 28.6, 29.1, 29.3, 29.4, 29.5, 29.6,
29.7, 29.7, 31.9, 51.0 (12 ꢂ t, CH2), 70.3 (t, C-5), 72.3, 73.3, 73.6
(3 ꢂ t, PhCH2), 81.8, 83.2, 83.5, 91.8 (4 ꢂ d, C-4, C-2, C-3, C-1),
127.7, 127.7, 127.7, 127.8, 128.0, 128.0, 128.1, 128.2, 128.2,
128.3, 128.4, 128.5, 128.5, 129.0, 129.7 (15 ꢂ d, Ar-H), 136.8,
0
0
0
0
0
5), 3.75 (1H, dd, J4,5 6.5 Hz, J5,5 10.2 Hz, H-5 ), 4.24–4.31 (2H, m,
H-3, H-4), 4.47–4.59 (6H, m, H-2, 2 ꢂ PhCH2, PhCHH0), 4.81 (1H,
d, JAB 11.5 Hz, PhCHH0), 4.98 (1H, d, J1,2 5.7 Hz, H-1), 7.19–7.38
(15H, m, Ar-H); dC (125 MHz, CDCl3) 14.1 (q, CH3), 20.9, 22.7,
28.6, 29.1, 29.2, 29.3, 29.4, 31.8, 51.0 (9 ꢂ t, CH2), 70.2 (t, C-5),
72.3, 73.3, 73.6 (3 ꢂ t, PhCH2), 81.8, 83.2, 83.5, 91.8 (4 ꢂ d, C-4,
C-2, C-3, C-1), 127.7, 127.7, 127.8, 127.8, 128.0, 128.0, 128.1,
128.2, 128.3, 128.4, 128.5, 128.5, 128.6, 129.0, 129.7 (15 ꢂ d, Ar-
137.4, 137.8 (3 ꢂ s, Ar-C); m/z (ESI)+ 715.4 (M+Na+, 22), 710.4
H), 136.8, 137.3, 137.8 (3 ꢂ s, Ar-C); m/z (ESI)+ 631.3 (M+Na+, 68),
((M þ NH4
,
100%). HRMS m/z calcd for C42H60O6S [M+Na]+:
þ
þ
626.3 ((M þ NH4
,
100%). HRMS m/z calcd for C36H48O6S
715.4008. Found: 715.3980. (Found: C, 72.79; H, 8.76. C42H60O6S
requires C, 72.79; H, 8.73%).
[M+Na]+: 599.3171. Found: 599.3157. (Found: C, 70.64; H, 7.69.
C36H48O6S requires C, 71.02; H, 7.95%).
3.19. b-D-Arabinofuranosyl butyl sulfone (6a)
3.16. 2,3,5-Tri-O-benzyl-b-D-arabinofuranosyl dodecyl sulfone
(5e)
Procedure C: Method as described above afforded de-protected
butyl sulfone 6a (128 mg, 0.533 mmol) as a clear oil; ½a D25
ꢃ
+221
Procedure B: Method as described above afforded the dodecyl
(c, 1.0 in acetone); dH (500 MHz, acetone-d6) 0.93 (3H, t, J 7.3 Hz,
CH3), 1.40–1.51 (2H, app. sext., J 7.4 Hz, CH2), 1.77 (2H, quin., J
sulfone 5e (160 mg, 87%); ½a D25
ꢁ49.2 (c, 0.85 in CHCl3); dH
ꢃ
(400 MHz, CDCl3) 0.91 (3H, t, J 6.6 Hz, alkyl CH3), 1.24–1.39 (16H,
m, alkyl CH2) 1.73–1.88 (2H, m, alkyl CH2), 2.95–3.17 (2H, m, alkyl
7.7 Hz, CH2), 3.10 (1H, dt, J 8.0 Hz, J 13.7 Hz, CHH0), 3.26 (1H, dt, J
0
0
8.0 Hz, J 13.9 Hz, CHH ), 3.76–3.85 (2H, m, H-5, H-5 ), 4.06 (1H,
0
0
CH2), 3.65 (1H, dd, J4,5 6.3 Hz, J5,5 10.4 Hz, H-5), 3.77 (1H, dd, J4,5
aq, J 3.6 Hz, H-4), 4.28 (1H, aq, J 3.6 Hz, H-3), 4.39–4.46 (2H, m,
5-OH, H-2), 4.73 (1H, d, J3,3-OH 4.1 Hz, 3-OH), 4.83 (1H, d, J1,2
4.7 Hz, H-1), 5.08 (1H, d, J2,2-OH 7.3 Hz, 2-OH); dC (125 MHz,
acetone-d6) 13.9 (q, CH3), 22.5, 23.5, 51.5 (3 ꢂ t, CH2), 63.0 (t, C-5),
77.6, 78.2, 88.8, 94.7 (4 ꢂ d, C-3, C-2, C-4, C-1); mmax (KBr disc)
3450–3500 (br s, OH), 1304 (s, S@O, asymm. stretch), 1134 (s,
S@O, symm. stretch) cmꢁ1; m/z (ESI)+ 785.2 (3M+Na+, 17), 780.3
((3M þ NH4þ, 9), 531.2 (2M+Na+, 96), 526.2 (2M þ NH4þ, 100),
277.1 (M+Na+, 29), 272.1 (M þ NH4þ, 77%). HRMS m/z calcd for
C9H18O6S [M+Na]+: 277.0722. Found: 277.0716.
0
0
5.1 Hz, J5,5 10.4 Hz, H-5 ), 4.27–4.32 (2H, m, H-3, H-4), 4.51–4.60
(6H, m, H-2, 2 ꢂ OCH2C6H5, OCHHC6H5), 4.83 (1H, d, J 11.4
OCHHC6H5), 5.00 (1H, d, J1,2 5.6 Hz H-1), 7.23–7.38 (15H, m,
3 ꢂ OCH2C6H5); dC (100.6 MHz, CDCl3) 14.1 (alkyl CH3), 21.0,
22.7, 28.6, 28.61, 29.1, 29.3, 29.5, 29.6, 31.9, 51.0 (11 ꢂ alkyl
CH2), 70.3 (C-5), 70.3, 72.3, 73.7 (OCH2C6H5) 81.8, 83.2, 83.5 (C-2,
C-3, C-4), 91.8 (C-1), 127.7, 127.8, 127.8, 128.2, 128.3, 128.4,
128.5, 128.5 (PhCH), 136.9, 137.4, 137.8 (Ar-C); m/z (ES+) 659
(M+Na+, 100%); HRMS (ES+) Calcd NaC38H52O6S 659.3377. Found:
659.3377).
3.20. b-D-Arabinofuranosyl hexyl sulfone (6b)
3.17. 2,3,5-Tri-O-benzyl-b-D-arabinofuranosyl tetradecyl
sulfone (5f)
Procedure C: Method as described above afforded de-protected
hexyl sulfone 6b (105 mg, 82%) as a waxy white solid, mp
Procedure B: Method as described above afforded the tetradecyl
66–67 °C; ½a 2D5
ꢃ
+216 (c, 1.0 in acetone); dH (500 MHz, acetone-d6)
sulfone 5f (607 mg, 83%) as a clear oil; ½a D25
ꢃ
ꢁ47.0 (c, 1.3 in CHCl3);
0.89 (3H, t, J 7.1 Hz, CH3), 1.28–1.37 (4H, m, CH2), 1.45 (2H, quin.,
J 7.3 Hz, CH2), 1.79 (2H, quin., J 7.8 Hz, CH2), 3.10 (1H, dt, J 8.0 Hz, J
13.7 Hz, CHH0), 3.26 (1H, dt, J 7.8 Hz, J 13.7 Hz, CHH0), 3.76–3.86
m
max (KBr disc) 1322 (s, S@O, asymm. stretch), 1103 (s, S@O, symm.
stretch) cmꢁ1; dH (500 MHz, CDCl3) 0.90 (3H, t, J 6.8 Hz, CH3), 1.18–
1.44 (22H, m, CH2), 1.71–1.89 (2H, m, CH2), 2.98 (1H, ddd, J
13.7 Hz, J 10.5 Hz, J 5.6 Hz, CHH0), 3.12 (1H, ddd, J 13.7 Hz, J
0
(2H, m, H-5, H-5 ), 4.06 (1H, aq, J 3.8 Hz, H-4), 4.29 (1H, aq, J
0
3.7 Hz, H-3), 4.41 (1H, t, J5,5-OH 5.4 Hz, J5 ,5-OH 5.4 Hz, 5-OH), 4.44
10.5 Hz, J 5.6 Hz, CHH0), 3.64 (1H, dd, J4,5 5.0 Hz, J5,5 10.2 Hz, H-
(1H, app. quin., J 3.5 Hz, H-2), 4.72 (1H, d, J3,3-OH 4.1 Hz, 3-OH),
4.83 (1H, d, J1,2 4.6 Hz, H-1), 5.07 (1H, d, J2,2-OH 7.4 Hz, 2-OH); dC
(125 MHz, acetone-d6) 14.2 (q, CH3), 21.5, 23.1, 29.1, 32.1, 51.8
(5 ꢂ t, CH2), 63.0 (t, C-5), 77.6, 78.2, 88.8, 94.7 (4 ꢂ d, C-3, C-2, C-
0
0
0
0
5), 3.76 (1H, dd, J4,5 6.5 Hz, J5,5 10.2 Hz, H-5 ), 4.20–4.33 (2H, m,
H-3, H-4), 4.45–4.62 (6H, m, H-2, 2 ꢂ PhCH2, PhCHH0), 4.82 (1H,
d, JAB 11.5 Hz, PhCHH0), 4.99 (1H, d, J1,2 5.7 Hz, H-1), 7.18–7.39
(15H, m, Ar-H); dC (125 MHz, CDCl3) 14.1 (q, CH3), 21.0, 28.2,
28.6, 29.1, 29.3, 29.3, 29.5, 29.6, 29.6, 29.7, 31.9, 51.0 (12 ꢂ t,
CH2), 70.3 (t, C-5), 72.3, 73.3, 73.6 (3 ꢂ t, PhCH2), 81.8, 83.2, 83.5,
91.8 (4 ꢂ d, C-4, C-2, C-3, C-1), 127.7, 127.7, 127.8, 127.8, 128.0,
128.1, 128.2, 128.3, 128.3, 128.4, 128.5, 128.5, 128.5, 128.6, 128.6
4, C-1); mmax (KBr disc) 3450–3500 (br s, OH), 1306 (s, S@O, asymm.
stretch), 1135 (s, S@O, symm. stretch) cmꢁ1; m/z (ESI)+ 869.3
(3M+Na+, 17), 537.2 (2M+Na+, 100), 532.2 (2M þ NH4þ, 53), 305.1
(M+Na+, 68), 300.1 (M þ NH4
, 77%). HRMS m/z calcd for
þ
C11H22O6S [M+Na]+: 305.1035. Found: 305.1031.
(15 ꢂ d, Ar-H), 136.8, 137.3, 137.8 (3 ꢂ s, Ar-C); m/z (ESI)+ 687.4
(M+Na+, 14), 682.4 ((M þ NH4
,
100%). HRMS m/z calcd for
3.21. b-D-Arabinofuranosyl octyl sulfone (6c)
þ
C40H56O6S [M+Na]+: 687.3695. Found: 687.3685.
Procedure C: Method as described above afforded de-protected
octyl sulfone 6c (137 mg, 80%) as a waxy white solid; mp
3.18. 2,3,5-Tri-O-benzyl-b-D-arabinofuranosyl hexadecyl
sulfone (5g)
80–81 °C; ½a 2D5
ꢃ
+207 (c, 1.0 in acetone); dH (500 MHz, acetone-d6)
0.88 (3H, t, J 7.1 Hz, CH3), 1.24–1.38 (8H, m, CH2), 1.44 (2H, quin.,
J 7.4 Hz, CH2), 1.79 (2H, quin., J 7.8 Hz, CH2), 3.10 (1H, dt, J 8.0 Hz, J
13.7 Hz, CHH0), 3.25 (1H, dt, J 7.9 Hz, J 13.7 Hz, CHH0), 3.75–3.86
Procedure B: Method as described above afforded the hexadecyl
sulfone 5g (543 mg, 86%) as a white, waxy solid, mp 47–48 °C; ½a D25
ꢃ
0
ꢁ55.1 (c, 1.3 in CHCl3); mmax (KBr disc) 1322 (s, S@O, asymm.
stretch), 1103 (s, S@O, symm. stretch) cmꢁ1; dH (500 MHz, CDCl3)
0.90 (3H, t, J 6.8 Hz, CH3), 1.20–1.45 (26H, m, CH2), 1.71–1.89
(2H, m, CH2), 2.98 (1H, ddd, J 13.7 Hz, J 10.6 Hz, J 5.6 Hz, CHH0),
(2H, m, H-5, H-5 ), 4.06 (1H, aq, J 3.8 Hz, H-4), 4.28 (1H, aq, J
0
3.7 Hz, H-3), 4.39 (1H, t, J5,5-OH 5.4 Hz, J5 ,5-OH 5.4 Hz, 5-OH), 4.44
(1H, ddd, J1,2 4.6 Hz, J2-OH,2 7.4 Hz, J2,3 3.7 Hz, H-2), 4.71 (1H, d,
J3,3-OH 4.1 Hz, 3-OH), 4.83 (1H, d, J1,2 4.6 Hz, H-1), 5.06 (1H, d,

B. Ayers et al. / Carbohydrate Research 344 (2009) 739–746
745
J2,2-OH 7.4 Hz, 2-OH); dC (125 MHz, Acetone-d6) 14.4 (q, CH3), 21.5,
23.3, 29.4, 29.8, 30.1, 32.5, 51.8 (7 ꢂ t, CH2), 63.0 (t, C-5), 77.7, 78.2,
(2M þ NH4þ, 95), 417.2 (M+Na+, 31), 412.3 (M þ NH4þ, 86%). HRMS
m/z calcd for C19H38O6S [M+Na]+: 417.2287. Found: 417.2282.
(Found: C, 57.83; H, 9.74. C19H38O6S requires C, 57.84; H, 9.71).
88.8, 94.7 (4 ꢂ d, C-3, C-2, C-4, C-1);
mmax (KBr disc) 3450–3500 (br.
s, OH), 1301 (s, S@O, asymm. stretch), 1135 (s, S@O, symm. stretch)
cm-1; m/z (ESI)+ 953.4 (3M+Na+, 29), 948.5 (3M+NH4+, 7), 643.3
3.25. b-D-Arabinofuranosyl hexadecyl sulfone (6g)
(2M+Na+, 94), 638.3 (2M+NH4+, 85), 333.1 (M+Na+, 58), 328.2
+
(M+NH4
,
100%). HRMS m/z calcd for C13H26O6S [M+Na]+:
Procedure C: Method as described above, except reaction solvent
(EtOAc) and flash column chromatography (chloroform/isopropyl
alcohol, 9:1) afforded de-protected sulfone 6g (200 mg, 81%) as a
333.1348. Found: 333.1340.
waxy white solid, mp 110–111 °C; ½a D25
ꢃ
+149 (c, 1.1 in acetone);
mmax (KBr disc) 3450–3500 (br s, OH), 1301 (s, S@O, asymm.
3.22. b- -Arabinofuranosyl decyl sulfone (6d)
D
stretch), 1135 (s, S@O, symm. stretch) cmꢁ1
; dH (500 MHz,
Procedure C: Method as described above, except flash column
chromatography (chloroform/isopropyl alcohol, 9:1) afforded de-
protected decyl sulfone 6c (103 mg, 75%) as a waxy white solid,
acetone-d6) 0.88 (3H, t, J 6.7 Hz, alkyl CH3), 1.22–1.39 (24H, m,
alkyl CH2), 1.45 (2H, quin., J 7.1 Hz, CH2), 1.80 (2H, quin.,
a 2D5
+183 (c, 1.1 in acetone); dH (500 MHz,
ꢃ
J 7.7 Hz, CH2), 3.10 (1H, dt, J 8.0 Hz, J 13.7 Hz, CHH0), 3.26 (1H, dt,
mp 92–93 °C;
½
0
acetone-d6) 0.88 (3H, t, J 6.8 Hz, CH3), 1.25–1.37 (12H, m, CH2),
0
J 7.4 Hz, J 13.7 Hz, CHH ), 3.77–3.86 (2H, m, H-5, H-5 ), 4.06
1.44 (2H, quin., J 7.2 Hz, CH2), 1.79 (2H, quin., J 7.8 Hz, CH2), 3.10
(1H, aq, J 3.9 Hz, H-4), 4.29 (1H, aq, J 3.5 Hz, H-3), 4.39 (1H, t,
(1H, dt, J 8.0 Hz, J 14.1 Hz, CHH0), 3.25 (1H, dt, J 7.9 Hz, J 14.1 Hz,
0
J5,5-OH 5.4 Hz, J5 ,5-OH 5.4 Hz, 5-OH), 4.44 (1H, app. quin., J 3.6 Hz,
0
0
CHH ), 3.76–3.86 (2H, m, H-5, H-5 ), 4.06 (1H, aq, J 3.8 Hz, H-4),
H-2), 4.71 (1H, d, J3,3-OH 4.1 Hz, 3-OH), 4.83 (1H, d, J1,2 4.7 Hz,
H-1), 5.05 (1H, d, J2,2-OH 7.3 Hz, 2-OH); dC (125 MHz, acetone-d6)
14.4 (q, CH3), 21.5, 23.3, 25.5, 30.0, 30.1, 30.1, 30.2, 30.3, 30.3,
30.4, 30.4, 30.4, 30.5, 32.7, 51.8 (15 ꢂ t, CH2), 63.0 (t, C-5), 77.6,
78.8, 88.8, 94.6 (4 ꢂ d, C-3, C-2, C-4, C-1); m/z (ESI)+ 867.5
0
4.28 (1H, aq, J 3.4 Hz, H-3), 4.39 (1H, t, J5,5-OH 5.3 Hz, J5 ,5-OH 5.3
Hz, 5-OH), 4.44 (1H, app. quin., J 3.3 Hz, H-2), 4.71 (1H, d, J3,3-OH
3.9 Hz, 3-OH), 4.83 (1H, d, J1,2 4.6 Hz, H-1), 5.06 (1H, d, J2,2-OH
7.3 Hz, 2-OH); dC (125 MHz, acetone-d6) 14.4 (q, CH3), 21.6, 23.4,
29.4, 30.0, 30.1, 30.3, 31.6, 32.7, 51.8 (9 ꢂ t, CH2), 63.0 (t, C-5),
77.7, 78.2, 88.8, 94.7 (4 ꢂ d, C-3, C-2, C-4, C-1); mmax (KBr disc)
3450–3500 (br s, OH), 1303 (s, S@O, asymm. stretch), 1135 (s,
S@O, symm. stretch) cmꢁ1; m/z (ESI)+ 699.3 (2M+Na+, 77), 694.4
(2M þ NH4þ, 100), 361.2 (M+Na+, 56), 356.2 (M þ NH4þ, 92%).
HRMS m/z calcd for C15H30O6S [M+Na]+: 316.1661. Found:
316.1653. (Found: C, 52.97; H, 8.78. C15H30O6S requires C, 53.23;
H, 8.93%).
(2M+Na+, 44), 862.5 (2M þ NH4þ, 100), 445.3 (M+Na+, 39), 440.3
þ
(M þ NH4
,
95%). HRMS m/z calcd for C21H42O6S [M+Na]+:
445.2600. Found 445.2593. (Found: C, 59.70; H, 10.07. C21H42O6S
requires C, 59.68; H, 10.02).
3.26. Spot culture method for testing of anti-mycobacterial
activity
Purified test compounds 6a–g were prepared in DMSO at a
range of concentrations up to 100 mg/mL. These stock solutions
3.23. b-
D-Arabinofuranosyl dodecyl sulfone (6e)
were added into different wells of 6-well plates, with 5 lL DMSO
Procedure C: Method as described above afforded de-protected
alone added to control wells (0.1% v/v). Molten MB agar (5 mL)
containing OADC (Oleic acid-Albumin-Dextrose-Catalase, Difco)
was poured immediately into the wells of the 6-well plates con-
taining the extracts with thorough mixing. Once solidified, the
MB agar containing test reagents and controls was inoculated with
23
dodecyl sulfone 6e (87 mg, 94%) as a waxy solid; [
1.0 CH3OH); dH (400 MHz, DMSO-d6) 0.85 (3H, t, J 6.6 Hz, alkyl
CH3), 1.22–1.38 (16H, m, alkyl CH2) 1.62–1.69 (2H, m, alkyl CH2),
a
]
ꢁ15 (c,
0
3.01–3.22 (2H, m, alkyl CH2), 3.52 (1H, dd, J4,5 6.6 Hz, J5,5
11.4 Hz, H-5), 3.58 (1H, dd, J4,5 4.3 Hz, J5,5 11.4 Hz, H-50), 3.77–
3.81 (1H, m, H-4), 3.99 (1H, at, J3–4 5.1, H-3), 4.29 (1H, at, J2–3
5.3, H-2), 4.80 (1H, d, J1,2 5.6 Hz H-1); dC (100.6 MHz, CDCl3) 14.8
(alkyl CH3), 21.1, 23.0, 28.9, 29.4, 29.6, 29.6, 29.8, 29.9, 30.0, 32.2,
51.0 (11 ꢂ alkyl CH2), 62.7 (C-5), 76.0 (C-3), 77.5 (C-2), 87.6
(C-4), 93.9 (C-1); m/z (ES+) 389 (M+Na+, 100%); HRMS (ES+)
Calculated NaC17H34O6S 389.1968. Found: 389.1973).
5 l
L of a 105 dilution of a mid-log phase culture (OD 1.0) of M. bovis
0
0
BCG Pasteur containing approximately 500 cells. The cells were al-
lowed to soak onto MB agar before the plates were covered, sealed
with parafilm, inverted and incubated at 37 °C for 7–14 days. The
resulting circular spot cultures were photographed using a BioRad
Gel-Doc 2000 system.
Acknowledgements
3.24. b-D-Arabinofuranosyl tetradecyl sulfone (6f)
We gratefully acknowledge financial support from the EPSRC
(Project Grant D051495/1) and the Leverhulme Trust (Project
Grant F/08 341/E).
Procedure C: Method as described above, except reaction solvent
(MeOH/EtOAc, 1:1, v/v) and flash column chromatography (chloro-
form/isopropyl alcohol, 9:1) afforded de-protected tetradecyl sul-
fone 6f (250 mg, 88%) as a waxy white solid, m.p. 103–104 °C;
½
a 2D5
+175 (c, 1.1 in acetone); mmax (KBr disc) 3450–3500 (br s,
ꢃ
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20. We thank referees for pointing out this possibility to us.