An improved synthesis of 3,6-anhydro-d-glucal and a study of its unusual chemical reactivity

Article abstract of DOI:10.1016/j.carres.2014.03.005

6-O-Tosyl-d-glucal 1 upon treatment with excess LiAlH₄ unexpectedly gave 3,6-anhydro-d-glucal 2 as a major product in good yield. A crystal structure was obtained. Reaction of the anhydride 2 with N-iodosuccinimide (NIS) in excess methanol resulted in the formation of diastereomeric 2-deoxy-2-iodoglycosides. Addition of ceric (IV) ammonium nitrate and thiophenol to a solution of 2 in acetonitrile gave a mixture of 2-deoxy and 2,3-unsaturated thioglycosides. Reaction of 1,2:3,4-di-O-isopropylidine- α-d-galactopyranose with the anhydro sugar 2 in the presence of N-iodosuccinimide did not give the expected iodoglycoside mixture, but instead gave an unusual 1,4:3,6-dianhydride 7 as the major product.

Full text of DOI:10.1016/j.carres.2014.03.005

Carbohydrate Research 391 (2014) 106–111
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
An improved synthesis of 3,6-anhydro-D-glucal and a study
of its unusual chemical reactivity
⇑
Vikram Basava, Sergiu M. Gorun, Cecilia H. Marzabadi
Department of Chemistry & Biochemistry, Seton Hall University, 400 South Orange Ave, South Orange, NJ, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2014
Received in revised form 28 February 2014
Accepted 5 March 2014
Available online 13 March 2014
6-O-Tosyl-D-glucal 1 upon treatment with excess LiAlH4 unexpectedly gave 3,6-anhydro-D-glucal 2 as a
major product in good yield. A crystal structure was obtained. Reaction of the anhydride 2 with N-iodo-
succinimide (NIS) in excess methanol resulted in the formation of diastereomeric 2-deoxy-2-iodoglyco-
sides. Addition of ceric (IV) ammonium nitrate and thiophenol to a solution of 2 in acetonitrile gave a
mixture of 2-deoxy and 2,3-unsaturated thioglycosides. Reaction of 1,2:3,4-di-O-isopropylidine-a-D-
galactopyranose with the anhydro sugar 2 in the presence of N-iodosuccinimide did not give the expected
iodoglycoside mixture, but instead gave an unusual 1,4:3,6-dianhydride 7 as the major product.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
3, 6-Anhydro-
6-O-Tosyl- -glucal
D-glucal
D
Addition reactions
Dianhydride sugar
1. Introduction
H
H
O
O
OH
OH
Anhydro sugars have unique properties that allow them to
serve both as protecting groups and as reactive materials for the
formation of CAC and CAX bonds. Their advantage of easy removal
has led to the development of numerous methods for their prepa-
ration and their extensive utilization in carbohydrate chemistry.1–5
These derivatives have been used for the preparation of modified
carbohydrates6 (including C-glycosides),7 nucleosides,8 heterocy-
cles,9 and complex enantiomerically-pure products in which the
chirality of the parent sugar is transferred to the target.6
O
O
O
NHAc
O
H
NHAc
H
Furanodictine A
Furanodictine B
Figure 1. Examples of 3,6-anhydrofuranoses.
Anhydro sugars, as their name implies, are formed by the
removal of one or more molecules of water from the corresponding
parent sugar. The usual procedure for their synthesis is by activa-
tion of one of the hydroxyl groups of the diol or polyol into a leav-
ing group (such as tosylate, triflate, halogen, etc.) while a second
hydroxyl group acts as a nucleophile in basic medium. This results
in an intramolecular SN2 closure to form the anhydro ring.2,3
Milder conditions, such as activation of one of the hydroxyl groups
according either to Mitsunobu7 or Castro8 protocols, are also used
for the preparation of these molecules.
formed, with the larger tetrahydrofurans and tetrahydropyrans
being more stable.
The most widely known compounds from the tetrahydrofuran
class of anhydro sugars are 3,6-anhydrofuranoses.6 Furanodictine
A and B (Fig. 1) are good examples of this class that show neuronal
differentiation activity.7 3,6-Anhydro-
D- and L-galactoses and their
partially methylated derivatives are typical constituents of
polysaccharides of red algae.8 3,6-Anhydro sugars forming bicyclic
nucleosides have shown antiviral activity.9 The puckering in the
bicyclic carbohydrate moiety is believed to cause the molecule to
be locked in the proper conformation for biological activity to be
observed.10,11
The anhydro sugars are conveniently classified, based on the
size of the anhydro ring formed intramolecularly, into sugar oxir-
anes, oxetanes, tetrahydrofurans and tetrahydropyrans. The stabil-
ity of the anhydro sugar is a reflection of the size of the cyclic ether
Among tetrahydropyran anhydro sugar derivatives, the most
common are 3,6-anhydro pyranoses. Methyl-3,6-anhydro-b-
coside has been synthesized by the treatment of methyl 2,3,4-tri-
O-acetyl-6-bromo-6-deoxy-b- -glucopyranoside with either sodium
methoxide or barium hydroxide (Fig. 2). 3,6-Anhydro- -galactose
and 3,6-anhydro-
-mannose were prepared in a similar fashion.12
D-glu-
D
D
⇑
Corresponding author. Tel.: +1 9737619032; fax: +1 9737619772.
E-mail address: cecilia.marzabadi@shu.edu (C.H. Marzabadi).
D
http://dx.doi.org/10.1016/j.carres.2014.03.005
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

V. Basava et al. / Carbohydrate Research 391 (2014) 106–111
107
3,6-Anhydro-
from 3,4-di-O-acetyl-6-O-tosyl-
resin in 66% yield.13 This paper describes the unexpected synthesis
of 3,6-anhydro- -glucal 2 from 6-O-tosyl- -glucal 1 using excess
LiAlH4 in THF as the reagent. With this combination of reagents,
an 82% yield of anhydro glycal was realized. Interestingly, the
3,6-anhydro-D-glucal 2 was previously reported as a byproduct
(40% yield) from the same reactants when an equimolar amount
of lithium aluminum hydride was used, though the structure of
D
-glucal 2 was earlier synthesized by Tucker et al.
this molecule was not fully characterized.16 The unusual chemical
reactivity of the resulting anhydro glycal 2 was also investigated.
There are only a handful of reports detailing the synthesis of
dianhydride sugars. They have most often been used in the con-
struction of polymers. The use of smaller anhydro rings, such as
oxiranes, gives the dianhydrides enhanced reactivity necessary
for the polymerization.14 Herein we also describe the synthesis of
an unusual 1,4:3,6-dianhydrosugar 7 via N-iodosuccinimide (NIS)
D
-glucal using deacidite FF IP (OH–)
D
D
addition to the 3,6-anhydro-
D-glucal 2.
R
O
O
O
O
O
Ba(OH)2
O
HO
O
HO
AcO
AcO
R = Br
OMe
OAc
HO
OMe
OH
or MeONa
OMe
HO
OMe
OH
Galacto
Manno
Gluco
R = Tos
Figure 2. Preparation of 3,6-anhydropyranoses.
OH
O
S
O
H
HO
HO
TsO
HO
HO
Cl
6eq LiAlH4 / THF
75oC overnight
O
O
O
HO
CH2Cl2
O
N
3
1
2
Scheme 1. Synthesis of 3,6-anhydro-
D-glucal.
VB_188_A_1H.esp
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
Chemical Shift (ppm)
Figure 3. 1H NMR (500 MHz, CDCl3) of compound 2.

108
V. Basava et al. / Carbohydrate Research 391 (2014) 106–111
yield. Treatment of 1 with three equivalents of LiAlH4 in THF did
not produce the anticipated 6-deoxy- -glycal, as previously
D
reported, but instead gave the 3,6-anhydro sugar 2 in 82% yield
(Scheme 1).16
Structural assignments for 2 were based on 1D and 2D 1H and 13
C
NMR experiments (Fig. 3). The proposed bridged structure was sup-
ported by the observationof long range couplingbetween the vinylic
proton at C2 and the bridgehead proton at C4 (W-coupling) in the
proton NMR. In the 1H–1H-COSY (Supporting materials), coupling
between H4 and H6 and H60 was also seen, while in the 1H NMR
the H6 and H60 peaks only appeared as broad doublets of doublets.
X-ray quality crystals were obtained and the structure of the
molecule was established unambiguously (Fig. 4).
Compound 2 was subjected to a series of different glycal addition
reactions. Treatment of compound 2 with NIS in the presence of
methanol led to the formation of a mixture of b-gluco-, b-manno-,
and
4c) in a ratio of 5.2:1.5:1 with an overall yield of 93% (Scheme 2).17
None of the -gluco diastereomer was detected in the mixture.
a-manno-2-deoxy-2-iodo-O-methylglycosides (4a, 4b, and
Figure 4. ORTEP representation of compound 2.
a
Treatment of 2 with thiophenol in the presence of a catalytic
amount of ceric (IV) ammonium nitrate (CAN) gave a mixture of
2. Results and discussion
a
- and b-2-deoxy sugars (5a and 5b) in a ratio 1.85:1 with a 65%
3,4,6-Tri-O-acetyl-
D
-glucal was deacetylated using Zemplen
-glucal
conditions to give
D
-glucal 3 in 98% yield.15 The resulting
D
yield. Also formed in the reaction was an -, b-mixture of the
a
Ferrier rearranged adducts (6a and 6b) with a 35% yield in a ratio
of 2.5:1, formed upon the breakdown of the anhydride ring
(Scheme 3).18
3 was selectively tosylated at the primary hydroxyl using p-tolu-
enesulfonyl chloride in a mixture of pyridine and dichlorometh-
ane.5 The 6-O-tosylated-
D-glucal 1 was obtained in 56% isolated
O
OH
O
H
O
N
I
O
O
I
O
I
O
O
O
O
HO
+
+
HO
HO
O
O
CH OH; CH CN
3
3
I
O
4b
4c
4a
2
Scheme 2. Synthesis of 2-deoxy-2-iodo-O-methylglycosides.
S
HO
HO
HO
HO
O
O
O
O
S
S
O
O
+
+
+
S
Ce(NH4)2(NO3)6
CH3CN
OH
OH
6a
6b
5a
5b
OH
O
H
SH
O
Ce(NH4)2(NO3)6
NaI
2
S
HO
HO
O
O
O
SH
CH3CN
S
O
O
+
+
OH
OH
S
6a
5a
5b
Scheme 3. Addition of thiophenol to 2 in the presence and absence of CAN.

V. Basava et al. / Carbohydrate Research 391 (2014) 106–111
109
O
OH
O
H
O
O
I
O
N
I
O
I
CH CN
3
O
O
O
O
HO
HO
HO
O
OH
OH
I
O
+
+
+
I
OH
O
O
O
OH
O
8b
2
7
8a
8c
O
O
Scheme 4. Synthesis of 1,4:3,6-dianhydride 7 from 2 in the presence of DIPG.
0
activated 4 ÅA molecular sieves were added, only the dianhydro
sugar 7 was obtained. Further reactions with 2 are ongoing.
O
OH
O
H
N
I
O
4. Experimental section
4.1. General methods
O
O
I
O
CH CN
3
O
4Ao sieves
2
7
Melting points (mp) were recorded on a Mel-Temp melting
point apparatus (Laboratory Devices, Inc., USA) and are uncor-
rected. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a Varian Inova (500 MHz) spectrometer. NMR sam-
ples were dissolved in CDCl3, and chemical shifts were reported
in ppm relative to the residual non-deuterated solvent (CHCl3 as
d = 7.26 ppm). 1H NMR data are reported as follows: chemical
shift, integration, multiplicity (s = singlet; d = doublet; dd = dou-
blet of doublets; ddd = doublet of doublet of doublets; m = multi-
plet), coupling constant, and assignment. 13C NMR spectra were
recorded on a Varian Inova (125 MHz) spectrometer. The samples
were dissolved in CDCl3, and chemical shifts are reported in ppm
relative to the solvent (CDCl3 as d = 77.0 ppm). 1H and 13C NMR
spectra were measured at room temperature and the chemical
shifts are reported in parts per million, unless otherwise noted.
1H NMR assignments were done using gCOSY and 13C NMR
assignments were done using gHMQC. Elemental analysis was
performed at Robertson Microlit Laboratories Inc., Ledgewood,
NJ. High resolution and low resolution mass spectra (HRMS and
LRMS) were obtained at the Mass Spectrometry Lab, University
of Illinois, Champaign-Urbana, IL and are reported in m/z (electro-
spray ionization). X-ray crystallographic data for compound 2 was
deposited at the Cambridge Crystallographic Data Center (CCDC);
deposition number CCDC 988697.20 Reactions were monitored by
thin-layer chromatography (TLC) on 0.25 mm silica gel coated alu-
minum sheet 60 F254 (Analtech, # 157017). Silica gel (particle size
Scheme 5. Synthesis of 1,4:3,6-dianhydride 7 from 2 in the absence of DIPG.
When the anhydro sugar 2 was reacted with thiophenol and a
catalytic amount of ceric (IV) ammonium nitrate in the presence
of sodium iodide, a reagent known to enhance
ture of - and b-2-deoxy sugars (5a and 5b) was again obtained in
a-selectivity, a mix-
a
this reaction (34%), but only the a-adduct 6b from the Ferrier rear-
rangement was isolated (65%) (Scheme 3).19
Because of the success of the NIS addition with methanol,
attempts were made to synthesize disaccharides from the anhydro
sugar donor. Compound 2 was treated with an equimolar amount
of 1,2:3,4-di-O-isopropylidine-D-galactopyranose (DIPG) in the
presence of N-iodosuccinimide to give 2-deoxy-2-iodo-1,4:3,6-
dianhydride 7 as the major product (48%).8 An inseparable mixture
of 2-deoxy-2-iodo sugars (8a, 8b, and 8c) was also formed in low
yield, and residual starting materials were isolated (ꢀ20%)
(Scheme 4). When the same reaction was repeated in the absence
of 1,2:3,4-di-O-isopropylidine-D-galactopyranose and in the pres-
ence of 4 ÅA molecular sieves, 7 was obtained in a much higher yield
of 76% (Scheme 5).
0
3. Conclusion
In summary, good yields of 3,6-anhydro-
D
-glucal 2 have been
40–63
flash column chromatography. Preparative thin-layer chromato-
graphic separations were carried out on 2000 m silica gel coated
glass plate 60 F254 (Analtech). Rotary evaporation was performed
using a Buchi R-114 rotary evaporator. Unless otherwise noted,
non-aqueous reactions were carried out in oven-dried (125 °C)
glassware under nitrogen. Dry CH3CN, THF, and methanol were
purchased from Pharmco-Aaper products, Inc. All other commer-
cially available reagents were used as received.
lm, 230–400 mesh Silicycle Siliflash P60) was used for
obtained from 6-O-tosyl- -glucal 1 via reaction with excess lithium
D
aluminum hydride. The resulting anhydro glycal was studied
under a variety of reaction conditions. Iodoglycosylation of 2 with
methanol gave good yields of a mixture of 2-deoxy-2-iodomethyl-
glycosides 4a–c, but attempts to use the primary hydroxyl sugar
l
donor 1,2:3,4-diisopropylidine-D-galactopyranose gave the dian-
hydro sugar 7 and iodohydrins 8a–c. These observed products
may result due to the steric hindrance present in the anhydroglycal
reactant or in the transition state for the reaction. Alternatively,
unfavorable dipole–dipole interactions in the transition state for
the sugar nucleophile approaching the glycal double bond may
be responsible for the observed products. b-Anomers were favored
4.2. 6-O-p-Toluenesulfonyl-D-arabino-hex-1-enitol (1)
To a solution of -glucal (7.6 g, 52.5 mmol) in anhydrous pyri-
D
over
a
-anomers by a ratio of ꢀ4:1. Furthermore, the formation of 7
dine was added dropwise a solution of p-toluenesulfonyl chloride
(15.02 g, 78.8 mmol) in anhydrous CH2Cl2 at 0 °C upon vigorous
stirring. The reaction was terminated after 3 h by the addition of
water, followed by washing with saturated CuSO4 (3 ꢁ 30 mL),
water (5 ꢁ 30 mL), and brine (1 ꢁ 30 mL). The organic extracts
were dried under anhydrous MgSO4 and concentrated in vacuo to
yield crude 1. Although the compound was synthesized earlier,13
is favored because the intramolecular attack by the bridgehead
hydroxyl group is anticipated to be faster entropically than is the
attack by the solvated nucleophiles. The small methanol nucleo-
phile and adventitious water can more easily access the double
bond and mixtures of product resulted from their attack. In those
cases where the DIPG was excluded and freshly powdered and

110
V. Basava et al. / Carbohydrate Research 391 (2014) 106–111
no spectroscopic data was reported. The product was purified by
flash chromatography using 3%, 4%, and 5% CH3OH in CHCl3 mix-
tures to give 8.18 g (56% yield) of 1 as a colorless oily mass which
crystallized upon freezing: Rf (1:20 CH3OH/CHCl3): 0.46; mp 50–
51 °C; 1H NMR (500 MHz, CDCl3) d 7.81 (d, 2H, J = 6.3 Hz, Ar),
7.35 (d, 2H, J = 7.9 Hz, Ar), 6.24 (d, 1H, J1,2 = 6.1, J1,3 = 1.8 Hz, H-1),
4.74 (dd, 1H, J2,1 = 6.3, J2,3 = 2.2 Hz, H-2), 4.47 (dd, 1H,
solvent was evaporated in vacuo and the residue was diluted with
excess CH2Cl2, washed with 10% NaOH, saturated NaHCO3 and sat-
urated NaCl and, dried over anhydrous Na2SO4. The organic solvent
was evaporated in vacuo and the crude (150 mg) obtained was
purified by preparatory TLC using 1:50 CH3OH/CHCl3 as the solvent
to give mixtures of compounds 5a, 5b (60 mg) and 6a, 6b (33 mg).
0
0
J6,6 = 11.25, J6,5 = 4 Hz, H-6), 4.28 (dd, 1H, J6,6 = 11.45,
0
4.5.1. Thiophenyl-3,6-anhydro-2-deoxy-
D-glucopyranoside (5a
J6 ,5 = 2.5 Hz, H-60), 4.26 (d, 1H, J3,4 = 6.8 Hz, H-3), 3.91 (ddd, 1H,
J5,4 = 9.75, J5,6 = 3.9, J5,6 = 2 Hz, H-5), 3.76 (dd, 1H, J4,3 = 8.3, J4,5
and 5b)
Data for a
-anomer (5b): Rf (1:50 CH3OH/CHCl3): 0.84; 1H NMR
0
=8.3 Hz, H-4), 3.09 (s, 1H, 4-OH), 2.45 (s, 3H, PhCH3), 2.23 (s, 1H,
3-OH); 13C NMR (125 MHz, CDCl3) d 145.19 (CH, Ar), 143.99
(C-1), 132.61, 129.93, 128.02 (CH, Ar), 103.04 (C-2), 75.7 (C-5),
69.57 (C-3), 69.35 (C-4), 67.92 (C-6), 21.66 (PhCH3).
(500 MHz, CDCl3) d 7.54–7.50 (m, 2H, Ar), 7.33–7.24 (m, 3H, Ar),
0
5.73 (dd, 1H, J1,2 = 8.0, J1,2 = 3.2 Hz, H-1), 4.69–4.67 (m, 1H, H-5),
4.59 (dd, 1H, J2,3 = 5.4, J3,4 = 1.2 Hz, H-3), 4.29–4.26 (m, 1H, H-4),
0
0
3.99 (dd, 1H, J6,6 = 9.7, J5,6 = 4.4 Hz, H-6), 3.84 (dd, 1H, J6,6 = 9,
J5,6 = 5.5 Hz, H-60), 3.06 (d, 1H, J4,–OH = 10.7 Hz, 4-OH), 2.63 (ddd,
0
0
4.3. 3,6-Anhydro-2-deoxy-
D
-arabino-hex-1-enitol (2)
1H, J2,2 = 14.15, J1,2 = 8.55, J2,3 = 6.3 Hz, H-2), 2.35 (ddd, 1H,
J2,2 = 14.1, J1,2 = 3.15, J2 ,3 = 1.3 Hz, H-20); 13C NMR (125 MHz,
CDCl3) d 132.3, 130.8, 129.1 (CH, Ar), 89.8 (C-1), 85.17 (C-5), 82.9
(C-3), 74.86 (C-6), 71.83 (C-4), 40.6 (C-2); HRMS (ESI): Calcd
0
0
0
To a solution of 1 (200 mg, 0.33 mmol) in 20 mL of tetrahydro-
furan (THF) was added dropwise 0.83 mL of 2.4 M LiAlH4 in THF
(2 mmol) at 0 °C. The mixture was refluxed at 73 °C for two days.
It was then cooled to 0 °C and neutralized with 15% w/v NaOH
and water, and filtered through a Celite@ bed upon dilution with
ethyl acetate (EtOAc). The mixture was concentrated in vacuo
and the product was purified by flash chromatography using 1:1
C
12H14O3NaS for (M+Na)+: 261.0570. Found: 261.0561. Data for
b-anomer (5a): Rf (1:50 CH3OH/CHCl3): 0.76; 1H NMR (500 MHz,
CDCl3) d 7.54–7.50 (m, 2H, Ar), 7.33–7.24 (m, 3H, Ar), 5.66 (dd,
0
1H, J1,2 = 6.8, J1,2 = 1.3 Hz, H-1), 4.69–4.67 (m, 1H, H-5), 4.64
(dd, 1H, J3,4 = 5.4, J2,3 = 1.2 Hz, H-3), 4.26–4.25 (m, 1H, H-4), 3.82
(dd, 1H, J6,6 = 9.55, J5,6 = 5.7 Hz, H-60), 3.63 (dd, 1H, J6,6 = 9.5,
J5,6 = 6.2 Hz, H-6), 2.58 (d, 1H, J4,–OH = 7.4 Hz, 4-OH), 2.5 (ddd, 1H,
0
0
0
mixture of EtOAc/hexanes to give 73 mg (84%) of 2 as a white solid:
22
Rf (1:20 CH3OH/CHCl3): 0.42; ½aD
ꢂ
ꢃ24.17 (c 0.58, CHCl3); 1H NMR
J2,2 = 14.1, J1,2 = 6.35, J2,3 = 2 Hz, H-2), 2.17–2.22 (m, 1H, H-20);
0
(500 MHz, CDCl3) d 6.54 (d, 1H, J1,2 = 5.0 Hz, H-1), 5.02 (ddd, 1H,
J2,1 = 5.25, J2,3 = 5.5, J2,4 = 1.5 Hz, H-2), 4.36 (br dd, 1H, J5,6 = 3.65,
13C NMR (125 MHz, CDCl3) d 129, 127.78, 127.35 (CH, Ar), 88.41
(C-1), 82.52 (C-5), 82.39 (C-3), 73.16 (C-6), 72.12 (C-4), 40.77
(C-2); HRMS (ESI): Calcd C12H14O3NaS for (M+Na)+: 261.0570.
Found: 261.0561.
J5,6 = 3.65 Hz, H-5), 4.27 (d, 1H, J6 ,6 =11.2 Hz, H-60), 4.23–4.2 (m,
0
0
0
1H, H-4), 4.18 (dd, 1H, J6,6 = 11.3, J5,6 = 4.5 Hz, H-6), 4.03 (br dd,
1H, J3,4 = 4.5, J3,2 = 5.5 Hz, H-3), 2.09 (d, 1H, J4,–OH = 10.7 Hz,
4-OH); 13C NMR (125 MHz, CDCl3) d 146.53 (C-1), 100.41 (C-2),
76.56 (C-5), 74.71 (C-6), 68.76 (C-3), 66.26 (C-4); Anal. Calcd for
C6H8O3: C, 56.24; H, 6.29. Found: C, 56.15; H, 6.42.
4.5.2. Thiophenyl-2,3-dideoxy-
D-glucopyranoside (6a and 6b)
Data for
a
-anomer (6a): Rf (1:50 CH3OH/CHCl3): 0.19; 1H NMR
(500 MHz, CDCl3) d 7.51–7.53 (m, 2H, Ar), 7.26–7.33 (m, 3H, Ar),
6.0 (dd, 1H, J1,2 = 10.2 Hz, J2,3 = 2 Hz, H-2), 5.98 (d, 1H,
J1,2 = 10.2 Hz, H-1), 5.74 (dd, 1H, J3,4 = 1.2 Hz, J2,3 = 2.7 Hz, H-3),
4.32 (dd, 1H, J3,4 = 2 Hz, J4,5 = 8.75 Hz, H-4), 4.03–4.07 (m, 1H,
H-5), 3.86–3.92 (m, 2H, H-6,60), 1.85 (d, 1H, J4,–OH = 7.3 Hz, 4-OH),
4.4. General procedure for the synthesis of 3,6-anhydro-O-glyc
osides
To a solution of 50 mg (0.39 mmol) of 2 in 5 mL of anhydrous
CH3CN at 0 °C was added 105.5 mg (0.47 mmol) of N-iodosuccini-
mide. To the solution was then added 1.2 equiv of the desired
nucleophile and the reaction mixture was stirred at rt overnight.
The solvent was evaporated in vacuo and the crude product was
purified by preparatory thin-layer chromatography (TLC) using
1:50 CH3OH/CHCl3 as the solvent.
1.82 (dd, 1H, J6,–OH = 6.35 Hz, J6 ,–OH = 6.4 Hz, 6-OH); 13C NMR
0
(125 MHz, CDCl3) d 131.77, 129.03, 127.32 (CH, Ar), 131.72 (C-1),
127.12 (C-2), 83.61 (C-3), 71.88 (C-5), 64.29 (C-4), 62.91 (C-6);
HRMS (ESI): Calcd C12H14O3NaS for (M+Na)+: 261.0561. Found:
261.0561. Data for b-anomer (6b): Rf (1:50 CH3OH/CHCl3): 0.19;
1H NMR (500 MHz, CDCl3) d 7.51–7.53 (m, 2H, Ar), 7.26–7.33 (m,
3H, Ar), 5.88 (dd, 1H, J1,2 = 2 Hz, J2,3 = 1.9 Hz, H-2), 5.86 (dd, 1H,
J1,2 = 1.5 Hz, J2,3 = 1.4 Hz, H-1), 4.72–4.78 (m, 1H, H-4), 4.54–4.60
(m, 1H, H-5), 4.11–4.16 (m, 2H, H-6,60), 2.18–2.24 (m, 4-OH, 6-
OH); 13C NMR (125 MHz, CDCl3) d 135.10, 132.5, 131.69 (CH, Ar),
131.62 (C-1), 128.84 (C-2), 81.74 (C-3), 79.74 (C-5), 63.40 (C-4),
4.4.1. Methyl-3,6-anhydro-2-deoxy-2-iodo-gluco- and manno-
pyranosides (4a, 4b, and 4c)
Data for the mixture of diastereomers: 1H NMR (500 MHz,
CDCl3) d 5.31 (s, 1H), 5.03 (d, 1H, J = 7.8 Hz), 4.72 (s, 1H), 4.47
(dd, 1H, J = 4.4 Hz, J = 3.4 Hz), 4.42–4.44 (m, 1H), 4.39–4.36 (m,
2H), 4.28–4.32 (m, 2H), 4.24 (d, 2H, J = 10.7 Hz), 4.15–4.12 (m,
1H), 4.09–4.06 (m, 3H), 3.96 (dd, 1H, J = 10 Hz, J = 5 Hz), 3.91 (dd,
1H, J = 5 Hz, J = 10 Hz), 3.54 (s, 1H), 3.48 (s, 1H), 3.46 (s, 1H), 2.64
(d, 1H, J = 8.8 Hz), 2.44 (d, 1H, J = 5 Hz), 2.41 (d, 1H, J = 8.8 Hz),
2.04 (d, 1H, J = 5.3 Hz); 13C NMR (125 MHz, CDCl3) d 80.43, 72.81,
69.06, 29.57, 26.60, 20.28; HRMS (ESI): Calcd C7H11O4NaI for
(M+Na)+: 308.9611. Found: 308.9600.
62.75 (C-6); HRMS (ESI): Calcd
261.0561. Found: 261.0561.
C
12H14O3NaS for (M+Na)+:
4.6. General procedure for the preparation of the
dianhydrosugar
To 100 mg (0.78 mmol) of 2 in 10 mL of CH3CN was added
0
210 mg (0.94 mmol) of N-iodosuccinimide in the presence of 4 ÅA
molecular sieves, and allowed to stir overnight at rt. The solvent
was removed in vacuo and the residue was diluted with excess
CH2Cl2, washed with 10% Na2S2O3, saturated NaCl and dried over
anhydrous Na2SO4. The organic filtrate was evaporated in vacuo
and the crude product (170 mg) was purified by flash chromatog-
raphy using 2:3 EtOAc/hexanes to give 150 mg (0.61 mmol, 76%)
of 7. In the absence of activated sieves, a mixture of 2-deoxy-2-
iodo-hexopyranoses (8a–c) was also obtained (30%).
4.5. General procedure for the synthesis of 2-
deoxythioglycosides
To a stirred solution of 50 mg (0.39 mmol) of 2 and 21 mg
(0.039 mmol) of Ce(NH4)2(NO3)6 in anhydrous CH3CN (5 mL) was
added a solution of 0.2 mL (1.95 mmol) of PhSH in anhydrous
CH3CN (5 mL) at 0 °C and allowed to stir overnight at rt. The

V. Basava et al. / Carbohydrate Research 391 (2014) 106–111
111
4.6.1. 1,4:3,6-Dianhydro-2-deoxy-2-iodo-
Data for the dianhydrosugar: Rf (1:50 CH3OH/CHCl3): 0.9; 1H
NMR (500 MHz, CDCl3) d 5.51 (br s, 1H, H-1), 5.09 (dd, 1H, J4,3
D-glucopyranose (7)
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4.25, J4,5 = 4.5 Hz, H-4), 4.27 (dd, 1H, J5,4 = 3.5, J5,6 = 3.25 Hz, H-5),
4.18 (dd, 1H, J3,2 = 7.0, J3,4 = 5.0 Hz, H-3), 4.15 (d, 1H,
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Data for mixture of diastereomers: Rf 1:50 CH3OH/CHCl3): 0.12;
1H NMR (500 MHz, CDCl3) d 5.76 (s, 1H), 5.68 (d, 1H, J = 5 Hz), 5.38
(s, 1H), 5.02 (dd, 1H, J = 5.4 Hz, J = 4.9 Hz), 4.89 (d, 1H, J = 5 Hz),
4.83 (ddd, 1H, J = 15 Hz, J = 5 Hz, J = 5 Hz), 4.73–4.70 (m, 2H),
4.48 (d, 1H, J = 1.4 Hz), 4.44 (d, 1H, J = 4.9 Hz), 4.40–4.37 (m, 2H),
4.19 (dd, 1H, J = 4.9 Hz, J = 4.4 Hz), 4.14 (d, 1H, J = 5 Hz), 4.09–
4.06 (m, 2H), 4.04–3.98 (m, 2H), 3.79–3.76 (m, 2H), 3.62 (dd, 1H,
J = 9.5 Hz, J = 6.6 Hz); 13C NMR (125 MHz, CDCl3) d 107.69, 99.48,
96.06, 90.68, 84.04, 83.32, 82.26, 76.37, 75.55, 71.75, 70.55,
46.57, 46.56, 26.66, 25.12, 23.61, 8.72, 8.71; LRMS (ESI): Calcd
C6H9IO4: 271.9. Found for (M+Na)+: 294.8.
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Supplementary data
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20. CCDC 988697 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.carres.
2014.03.005.