d-Glucose- and d-mannose-based antimetabolites. Part 2. Facile synthesis of 2-deoxy-2-halo-d-glucoses and -d-mannoses

Article abstract of DOI:10.1016/j.carres.2009.06.016

Modified d-glucose and d-mannose analogs are potentially clinically useful metabolic inhibitors. Biological evaluation of 2-deoxy-2-halo analogs has been impaired by limited availability and lack of efficient methods for their preparation. We have develop

Full text of DOI:10.1016/j.carres.2009.06.016

Carbohydrate Research 344 (2009) 1464–1473
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
D-Glucose- and D-mannose-based antimetabolites. Part 2. Facile synthesis
of 2-deoxy-2-halo-D-glucoses and -D-mannoses
*
Izabela Fokt, Slawomir Szymanski, Stanislaw Skora, Marcin Cybulski, Timothy Madden, Waldemar Priebe
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Modified
D
-glucose and
D
-mannose analogs are potentially clinically useful metabolic inhibitors. Biolog-
Received 17 March 2009
Received in revised form 29 May 2009
Accepted 12 June 2009
ical evaluation of 2-deoxy-2-halo analogs has been impaired by limited availability and lack of efficient
methods for their preparation. We have developed practical synthetic approaches to 2-deoxy-2-fluoro-,
2-chloro-2-deoxy-, 2-bromo-2-deoxy-, and 2-deoxy-2-iodo derivatives of
exploit electrophilic addition reactions to a commercially available 3,4,6-tri-O-acetyl-
Ó 2009 Elsevier Ltd. All rights reserved.
D-glucose and
D-mannose that
Available online 21 June 2009
D
-glucal.
Dedicated to Professor Hans Kamerling on
the occasion of his 65th birthday
Keywords:
2-Deoxy-2-halo-
2-Deoxy-2-halo-
D
D
-glucose
-mannose
Inhibitors of glycolysis
Synthesis
1. Introduction
glucose (3) and 2-bromo-2-deoxy-D-glucose (5) and noticed that
existing synthetic methodology needs improvement prior to
scale-up. Further in vitro evaluation in tumor cell lines indicated
Glycolysis is an energy-generating anaerobic metabolism of D-
glucose resulting in the net gain of two adenosine triphosphate
(ATP) molecules. Tumor cells can adopt this metabolic pathway
and use it to produce ATP without using oxygen even under nor-
moxia in a process known as the Warburg effect.1
that the antitumor activity of 2-chloro-2-deoxy-
2-bromo-2-deoxy- -glucose (5) was lower than that of 2-DG and
2-deoxy-2-fluoro-
-glucose (1).5
Because of the structural similarities (2-DG is also a 2-deoxy-
mannose), 2-DG can interfere with metabolism of either -glucose
or -mannose. Thus, it was important to evaluate biological prop-
erties of all C-2 halogen-substituted analogs of -glucose (1, 3, 5,
7) as well as -mannose (2, 4, 6, 8) (Chart 1). To achieve this goal
D-glucose (3) and
D
D
D
-
One of the most interesting and clinically explored properties of
D
2-deoxy-
to inhibit glycolysis.2 Lack of the hydroxyl group at C-2 in 2-DG
prevents its further metabolism to -fructose 6-phosphate and
D-arabino-hexose (2-deoxy-D-glucose, 2-DG) is its ability
D
D
D
D
leads to the accumulation of 2-DG 6-phosphate inside highly gly-
colytic tumor cells. High intracellular concentrations of 2-DG 6-
and make all these compounds available to other researchers, we
have focused on developing improved synthetic approaches allow-
ing for a preparation of multigram quantities of the desired
analogs.
phosphate block D-glucose metabolism and induce a unique form
of tumor cell death called autophagy.3
The same principle that leads to preferential accumulation of 2-
DG in tumor cells was exploited by 18F labeling of 2-deoxy-2-flu-
2. Results
oro-D-glucose (1), which is now widely used as cancer diagnostic
and imaging agent in positron emission tomography (PET).4
We have demonstrated in a paper (Part 1)5 preceding this work
2.1. Synthesis of 2-deoxy-2-fluoro-
D-glucose and 2-deoxy-2-
fluoro- -mannose
D
that 2-deoxy-2-fluoro-D-glucose (1) displays increased antitumor
activity when compared with 2-DG, and we have subsequently
showed that 1 is a potent inducer of autophagy in tumor cells.
We have also synthesized and isolated pure 2-chloro-2-deoxy-D-
Synthetic approaches to 2-deoxy-2-fluoro-
D-glucose (1) have
been the subject of intense studies since 18F isotopically labeled 2-
deoxy-2-fluoro-D-glucose is being widely used as cancer diagnostic
and imaging agent in positron emission tomography (PET).4 For
the last 50 years different fluorinating agents such as fluorine,6 acet-
yl hypofluorite,7–12 trifluoromethyl hypofluorite,13–15 or xenon
* Corresponding author. Tel.: +1 713 792 3777; fax: +1 713 745 4975.
E-mail address: wpriebe@mdanderson.org (W. Priebe).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.06.016

I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
1465
OH
O
OH
O
OH
O
OH
O
OH
OH F
OH
OH Cl
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
F
Cl
1
2
3
4
OH
O
OH
OH
O
OH
O
O
I
OH
OH Br
OH
OH
OH
Br
I
5
7
6
8
Chart 1. 2-Deoxy-2-halo-substituted D-glucose and D-mannose compounds.
difluoride16,17 in organic solvents or water18 have been used to
transform -glucal and its derivatives, or appropriately protected
The scale of our fluorination reactions with SelectfluorÒ ranged
from 30 g to 100 g of peracetylated -glucal (9) per batch. All reac-
tions gave a mixture (10) with 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-
,b- -mannose and 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro- ,b- -glu-
cose as the main products in a ratio of 42:48 with an overall yield
of ꢀ60%. The two additional minor products (3–5%) present in the
reaction mixture were isolated and determined to be a 3,4,6-tri-O-
D
D
methyl glucosides or mannosides, into 2-deoxy-2-fluoro deriva-
tives. Such fluorinating agents have limitations as they are poten-
tially hazardous, highly corrosive, or impractically expensive.
Preparation of selectively protected 2-O-trifluoromethanesulfonyl
esters of methyl glucosides or mannosides requires multistep syn-
theses, and although these processes allow the use of mild and safe
tetrabutylammonium fluoride as a fluoride source, this approach
can be quite costly for large-scale processes. Similarly, 1,3,4,6-tet-
a
D
a
D
acetyl-2-deoxy-2-fluoro-
a
-D
-glucosyl fluoride and 3,4,6-tri-O-
acetyl-2-deoxy-2-fluoro-b-
D
-mannosyl fluoride in a ratio of 1.4:1.
Separation of the gluco and manno isomers was not practical at this
stage of the process; therefore, the crude reaction mixture was
acetylated and subsequently subjected to low-pressure column
ra-O-acetyl-b-
lead to 2-deoxy-2-fluoro-
D
-mannose treated with DAST19 has been shown to
-mannose derivatives, but it is only con-
D
venient for small-scale reactions.
chromatography to give pure peracetylated 2-deoxy-2-fluoro-
glucose (11) in a 49% yield and peracetylated 2-deoxy-2-fluoro-
D
-
-
Our approach to large-scale fluorination has explored the reac-
D
tion of commercially available 3,4,6-tri-O-acetyl-
D
-glucal (9) with
mannose (12) in a 42% yield. Deacetylation of 11 and 12 under ba-
sic conditions in MeOH led to their respective methyl glycosides
instead of the desired fully unprotected 2-deoxy-2-fluorohexoses;
thus acidic conditions were used. 1,3,4,6-Tetra-O-acetyl-2-deoxy-
SelectfluorÒ, a relatively novel and convenient electrophilic N-flu-
orinating reagent20–22 (see Scheme 1). According to the procedure
described by Ortner et al.20 the reaction of
D
-glucal (9) using a 20%
excess of SelectfluorÒ in a mixture of 5:1 nitromethane–water
gives 2-deoxy-2-fluoro- -gluco- and 2-deoxy-2-fluoro- -manno
2-fluoro-
deoxy-2-fluoro-
70 °C to give fully deprotected 2-deoxy-2-fluoro-
and 2-deoxy-2-fluoro- ,b- -mannose (2), respectively (see Tables
D
-glucopyranose (11) and 1,3,4,6-tetra-O-acetyl-2-
-mannopyranose (12) were heated with N HCl at
,b- -glucose (1)
D
D
D
isomers in a ratio of 41:33 with an overall yield of 61% after sepa-
ration. Because our initial in vivo biological testing required over
100 g of the final product, we tested the applicability of Selectflu-
a
D
a
D
1 and 2). Deacetylation carried in the presence of N HCl was very
effective, and final products were isolated in 70% to >80% yields.
orÒ to a large-scale fluorination of
D
-glucal (9).
OAc
OAc
O
OAc
OAc
O
b)
O
O
OAcF
OAc
a)
OAc
+
OAc
OH
OAc
OAc
AcO
AcO
AcO
9
AcO
F
F
10
11
12
c)
c)
OH
O
OH
O
H F
OH
1
OH
O
OH
HO
HO
F
2
Scheme 1. Synthesis of 2-deoxy-2-fluoro-D-glucose and -D
-mannose. Reagents and conditions: (a) SelectfluorÒ, MeNO2, H2O; (b) Ac2O–pyridine, CH2Cl2; (c) N HCl.

1466
I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
In the last step of such a deacetylation reaction, the strong inor-
deoxy-a,b-D-mannose (16). Column chromatography led to effi-
ganic acid must be neutralized, generally with barium or silver car-
bonates.23,24 To increase the practicality of the process, reduce the
cost, and avoid a prolonged filtration step, we successfully used so-
dium carbonate. Simple treatment of the reaction mixture with a
stoichiometric amount of Na2CO3, followed by evaporation of
water and column chromatography, gave us the pure deprotected
products 1 and 2.
cient separation of the gluco and manno isomers. Pure 15 and 16
were efficiently deacetylated using N HCl to produce fully depro-
tected 2-chloro-2-deoxy-
,b- -mannose (4) (see Tables 3 and 4).
Chemical characterization of the free 2-deoxy-2-halo hexopyra-
a,b-D-glucose (3) and 2-chloro-2-deoxy-
a
D
noses is rather limited or not reported. Data are available for their
derivatives rather than for the fully deprotected compounds. Be-
cause of the biological importance of these analogs, we have
undertaken efforts to characterize them in more detail. For exam-
ple, no analytical data have been reported for the 2-chloro-2-
2.2. Synthesis of 2-chloro-2-deoxy-a,b-D-glucose and 2-chloro-
2-deoxy- ,b- -mannose
a
D
deoxy-a,b-D
-mannose (4) except optical rotation.23 We have per-
2-Chloro-2-deoxy-
nose (4) were prepared on multigram scales according to method
in Scheme 2. Direct chlorination of 3,4,6-tri-O-acetyl- -glucal (9)
D
-glucose (3) and 2-chloro-2-deoxy-
D
-man-
formed detailed NMR analysis of compound 4 using 1D as well
as 2D NMR experiments (GRADCOSY, C13 HSQC, and ROESY) and
D
have assigned chemical shifts for the
a and b anomers of 2-
was first described by Fisher,25 and the effects of solvent on the
stereochemistry and yield of the addition reaction have also been
assessed by others.26–32 It has been shown by Igarashi that, using
dichloromethane (DCM) as a solvent in the reaction of the addition
of chloride to peracetylated glucal 9, the ratio of gluco:manno
dichlorides was 1.6:1.31 Since our goal was to obtain both gluco
and manno compounds, dichloromethane was our solvent of
choice. Previous experience with the synthesis of 2-deoxy-2-fluoro
derivatives 1 and 2 indicated that the most efficient way for sepa-
ration of gluco and manno isomers was through their peracetylated
derivatives 11 and 12.
chloro-2-deoxy- ,b- -mannose (4) (see Tables 3 and 4). Similar
a
D
studies have been performed for all final 2-deoxy-2-halo-hexopy-
ranoses. Our NMR data fully confirm the proposed structures and
were consistent with previously reported data (see Tables 1–4).
2.3. Synthesis of 2-bromo-2-deoxy-
2-deoxy- ,b- -mannose
a,b-D-glucose and 2-bromo-
a
D
The only method that allowed for direct synthesis of 2-bromo-
2-deoxy- ,b- -glucose and 2-bromo-2-deoxy- ,b- -mannose from
-glucal was reported by Liu and Wong.33 The authors used potas-
a
D
a
D
D
Thus
D
-glucal (9) was chlorinated in DCM to produce a mixture
sium bromide and chloroperoxidase in the presence of hydrogen
peroxide, which gave a 1:1 mixture of gluco and manno isomers
5 and 6, respectively. No separation of unprotected 2-bromo-2-
of dichloro derivatives 13 (see Scheme 2). The crude mixture of 13
was deprotected under acidic conditions and subsequently acety-
lated to produce a mixture of 1,3,4,6-tetra-O-acetyl-2-chloro-2-
deoxy-a,b-D-glucose (5) and 2-bromo-2-deoxy-a,b-D-mannose (6)
deoxy-a,b-
D-glucose (15) and 1,3,4,6-tetra-O-acetyl-2-chloro-2-
has been reported. The products were isolated and characterized
OAc
O
OAc
OH
O
OAc
O
OAc
b)
a)
OH
X
OH
HO
AcO
AcO
X
X
9
13 X = Cl
17 X = Br
14 X = Cl
18 X = Br
c)
OAc
O
OAc
O
X
OAc
OAc
OAc
+
OAc
AcO
AcO
X
15 X = Cl
16 X = Cl
20 X = Br
19 X = Br
b)
b)
OH
OH
O
X
O
OH
OH
OH
OH
HO
HO
X
3 X = Cl
4 X = Cl
6 X = Br
5 X = Br
Scheme 2. Synthesis of 2-chloro-2-deoxy and 2-bromo-2-deoxy derivatives of
D-glucose and D-mannose. Reagents and conditions: (a) Br2, CH2Cl2 or Cl2–CH2Cl2; (b) N HCl;
(c) Ac2O–pyridine.

I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
1467
Table 1
1H NMR data for
a
and b anomers of 2-deoxy-2-fluoro-D-glucose (1
a
, 1b) and 2-deoxy-2-fluoro-D-mannose (2
a
, 2b)a
Compound
H-1
J1,2
JF,1
H-2
J2,3
JF,2
H-3
J3,4
JF,3
H-4
J4,5
JF,4
H-5
J5,6
JF,5
H-6
J6a,6b
JF,6
1a
5.33
3.8 Hz
—
4.30
9.5 Hz
49.4 Hz
3.86
9.4 Hz
18.7 Hz
3.8–3.3
m
—
3.8–3.3
m
—
3.8–3.3
m
—
1b
4.79
4.00
3.8–3.3
3.8–3.3
3.8–3.3
3.8–3.3
7.8 Hz
2.2 Hz
9.0 Hz
51.4 Hz
m
—
m
—
m
—
m
—
2a
5.28
—
7.2 Hz
4.66
2.1 Hz
49.6 Hz
3.82
9.9 Hz
—
3.61
9.9 Hz
—
4.0–3.7
m
—
4.0–3.7
m
—
2b
4.91
—
20.3 Hz
4.70
—
51.6 Hz
4.0–3.7
m
—
3.53
9.7 Hz
—
3.35
—
—
4.0–3.7
m
—
a
All spectra recorded in D2O.
Table 2
13C NMR data for
a
and b anomers of 2-deoxy-2-fluoro-D-glucose (1
a
, 1b) and 2-deoxy-2-fluoro-D-mannose (2
a
, 2b)a
Compound
C-1
C-2
C-3
C-4
C-5
C-6
JF,1
JF,2
JF,3
JF,4
JF,5
JF,6
1a
89.62
18.0 Hz
92.26
105.8 Hz
71.15
13.5 Hz
69.16
4.8 Hz
71.25
—
60.56b
—
1b
93.5
13.9 Hz
92.79
94.5 Hz
74.03
10.3 Hz
69.28
4.9 Hz
76.02
—
60.37*
—
2a
91.27
29.5 Hz
90.32
172.2 Hz
69.4
17.5 Hz
66.82
—
72.25
—
60.55
—
2b
92.30
15.8 Hz
91.28
180.2 Hz
71.81
17.4 Hz
66.59
—
76.05
—
60.71
a
All spectra recorded in D2O.
b
Not assigned (either
a
or b).
*
Chemical shift value is either for
a
or b anomer.
Table 3
1H NMR data for
a
and b anomers of 2-chloro-2-deoxy-D-glucose (3
a
, 3b), 2-chloro-2-deoxy-D-mannose (4
a, 4b), 2-bromo-2-deoxy-D-glucose (5
a
, 5b), 2-bromo-2-deoxy-D-
mannose (6
a, 6b), 2-deoxy-2-iodo-D-glucose (7
a
, 7b), and 2-deoxy-2-iodo-D-mannose (8a
, 8b)a
Compound
H-1
H-2
H-3
H-4
H-5
H-6
H-6
J1,2
J2,3
J3,4
J4,5
J5,6; J5,6
J6,6
J6,6
3a
5.06
—
3.7–3.6
m
3.54
10.0 Hz
3.13
9.6 Hz
3.7–3.6
m
3.7–3.6
m
3.6
11.8 Hz
3b
4.51
8.0 Hz
3.35
8.0 Hz
3.29
9.0 Hz
3.09
9.0 Hz
3.21–3.18
m
3.7–3.6
m
3.43
12.0 Hz
4a
5.29
1.5 Hz
4.27
3.6 Hz
4.06
9.3 Hz
3.83–3.62
m
3.83–3.62
m
3.83–3.62
m
3.83–3.62
m
4b
5.06
—
4.39
3.4 Hz
3.87
9.4 Hz
3.57
9.4 Hz
3.34
6.2 Hz; 1.9 Hz
3.83–3.62
m
3.83–3.62
m
5a
5.11
3.1 Hz
3.95
10.5 Hz
3.60
8.5 Hz
3.12
9.4 Hz
3.19
5.7 Hz; 1.8 Hz
3.48–3.41
m
3.48–3.41
m
5b
4.60
8.5 Hz
3.49
9.0 Hz
3.35
8.6 Hz
3.08
9.4 Hz
3.66
m
3.48–3.41
m
3.48–3.41
m
6a
3.23
—
4.33
3.8 Hz
3.89
9.1 Hz
3.84–3.53
m
3.84–3.53
m
3.84–3.53
m
3.84–3.53
m
6b
4.84
1.2 Hz
4.45
3.6 Hz
3.84–3.53
M
3.84–3.53
m
3.36
6.2 Hz; 2.3 Hz
3.36
m
3.84–3.53
m
7a
5.31
3.0 Hz
3.91
11.2 Hz
3.83–3.78
M
3.35
9.6 Hz
3.83–3.78
m
3.75–3.67
m
3.75–3.67
m
7b
4.90
8.7 Hz
3.71
9.3 Hz
3.75–3.67
M
3.29
9.3 Hz
3.43–3.37
m
3.83–3.78
m
3.83–3.78
m
8a
5.52
—
4.42
4.0 Hz
3.22
9.0 Hz
3.67–3.63
m
3.87–3.81
m
3.82–3.75
m
3.71
12.3 Hz
8b
4.16
—
4.55
3.9 Hz
3.15
9.1 Hz
3.58
9.4 Hz
3.43–3.37
m
3.82–3.75
m
3.67–3.63
m
a
Spectra recorded in D2O for compounds 4–7 and in DMSO-d6 + D2O for compounds 3.

1468
I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
Table 4
to mixture of 1-O-acetyl-2-deoxy-2-iodo-
D-gluco- and D-manno
13C NMR data for
a
and b anomers of 2-chloro-2-deoxy-D-glucose (3
, 4b), 2-bromo-2-deoxy-D-glucose (5 , 5b), 2-bromo-2-deoxy-
6b), 2-deoxy-2-iodo-D-glucose (7 7b), and 2-deoxy-2-iodo-D-
a
, 8b)a
a, 3b), 2-chloro-
isomers with a gluco to manno ratio of 9:1.
2-deoxy-D-mannose (4
D-mannose (6
mannose (8
a
a
This method was used by Morin36 for synthesis of 2-deoxy-2-
a
,
a,
iodo-a
,b-
D-glucose. The initial mixture of 1-O-acetyl-2-deoxy-2-
iodo-
D
-gluco and -
D
-manno isomers was separated by column chro-
Compound
C-1
C-2
C-3
C-4
C-5
C-6
matography, then the silyl ethers were removed by treatment with
the HFÁEt3N complex at 65 °C for 24 h. The last step, deacetylation
at the anomeric center, was completed by the method described by
Excoffier and co-workers37 using hydrazine acetate in MeOH.
Unfortunately the final product required chromatographic purifi-
cation twice in order to obtain pure 2-deoxy-2-iodo-
which was only partially characterized by NMR spectroscopy. In
the same report the synthesis of 2-deoxy-2-iodo- ,b- -mannose
was described using an iodohydration reaction previously de-
scribed by Liu and Wong33 for 2-deoxy-2-iodo-
-galactal. No infor-
3a
91.95
96.31
93.85
91.95
92.23
95.87
94.07
91.53
96.59
96.59
95.46
91.42
62.67
65.30
61.96
64.90
52.80
55.65
55.45
60.06
32.94
36.44
37.21
44.57
72.84
76.90
68.83
71.77
71.74
76.32
68.36
71.35
71.98
73.31
67.83
70.87
71.38
70.99
66.44
66.10
70.71
70.34
67.29
66.95
70.56
70.25
68.96
68.67
72.27
76.71
72.87
76.65
72.78
75.95
73.08
76.83
77.06
75.95
73.26
76.93
60.97
61.01
60.75*
60.61*
60.43
60.58
60.81*
60.66*
60.43
60.57
60.70
60.87
3b
4a
4b
5a
5b
a,b-D-glucose,
6a
6b
a
D
7a
7b
8a
D
8b
mation was provided concerning the separation, purity, or yield of
the product or its characterization. The structure was confirmed by
its peracetylated derivative.
a
Spectra recorded in D2O for compounds 4–7 and in DMSO-d6 + D2O for com-
pounds 3.
*
Chemical shift value is either for
a or b anomer.
In order to develop a practical method for the preparation of
both 2-deoxy-2-iodo-a,b-D-glucose (7) and 2-deoxy-2-iodo-a,b-D-
mannose (8), we have focused on the addition reaction using N-
only as their peracetylated derivatives. The only synthesis of fully
iodosuccinimide, in the presence of water, with commercially
deprotected 2-bromo-2-deoxy-
a
,b-
D
-mannose (6) was reported
available 3,4,6-tri-O-acetyl-D-glucal (9) (see Scheme 3). Pilot reac-
by David et al.34 in an elegant approach using N-bromophthalimide
tions were performed to test the effects of different solvents and
temperature on the proportion of gluco to manno isomers and on
the overall yield of the reaction. Under our preferred conditions
the addition reaction of N-iodosuccinimide in the presence of
as the source of bromine.
Based on our experience, the literature reports, and the need for
obtaining multigram amounts of both 2-bromo-2-deoxy-
cose (5) and 2-bromo-2-deoxy- ,b- -mannose (6), we used a
similar synthetic approach that permitted the efficient preparation
of both 2-deoxy-2-fluoro- and 2-chloro-2-deoxy- -glucoses and
a,b-D-glu-
a
D
water to 3,4,6-tri-O-acetyl-
3,4,6-tri-O-acetyl-2-deoxy-2-iodo-
acetyl-2-deoxy-2-iodo- ,b- -mannose in a ratio of 2:3. This crude
D-glucal (9) led to the formation of
a
,b- -glucose and 3,4,6-tri-O-
D
D
a
D
-mannoses in large, laboratory-scale reactions (i.e., >100 g, (see
Scheme 2). Thus, we selected the addition of bromine to commer-
cially available peracetylated glucal (9) as a preferred approach.
mixture was silylated with tert-butyldimethylsilyl chloride and
imidazole in dichloromethane. The silylation reaction was per-
formed in the smallest possible amount of solvent to achieve a high
concentration of reagents. Under such conditions the 1-O-silylated
b anomers, with manno and gluco configurations, were the main
The addition of bromine to 3,4,6-tri-O-acetyl-
mixture 17 of 3,4,6-tri-O-acetyl-1,2-dibromo-1,2-dideoxy-b-
cose and 3,4,6-tri-O-acetyl-1,2-dibromo-1,2-dideoxy- -mannose
D-glucal (9) led to a
D
-glu-
a-
D
products, accompanied by only a minor product having the a-man-
with ratio of isomers of 2.6:1. Such a combination was heated with
N HCl at 70 °C to produce a mixture 18 that was subsequently acet-
ylated. Peracetylated 2-bromo-2-deoxy derivatives were efficiently
separated by low-pressure chromatography. Acidic deacetylation
no configuration. Subsequent chromatography led to a separation
of pure isomers in high yield (96.5% total). Each compound was
then deacetylated using a catalytic amount of N sodium methoxide
in MeOH and then adjusted to neutral pH using a stoichiometric
amount of acetic acid. Evaporation of the solvents, followed by col-
umn chromatography, led to high yields (>95%) of 2-deoxy-2-iodo-
of either pure 1,3,4,6-tetra-O-acetyl-2-bromo-2-deoxy-
cose (19) or 1,3,4,6-tetra-O-acetyl-2-bromo-2-deoxy-
nose (20) gave, in excellent yields, the desired 2-bromo-2-deoxy-
,b- -glucose (5) and 2-bromo-2-deoxy- ,b- -mannose (6),
a
,b-
D-glu-
a
,b- -man-
D
1-O-tert-butyldimethylsilyl-b-
iodo-1-O-tert-butyldimethylsilyl-
deoxy-2-iodo-1-O-tert-butyldimethylsilyl-b-
D
-mannopyranose (26), 2-deoxy-2-
-mannopyranose (27) and 2-
-glucopyranose (25),
a
D
a
D
a-D
respectively. The structures of all compounds were confirmed by
D
1H and 13C NMR spectroscopies (see Tables 3 and 4).
respectively. Subsequently, efficient desilylation at the C-1 position
using trifluoroacetic acid in acetonitrile and water, followed by the
evaporation of solvents and immediate chromatography, gave the
2.4. Synthesis of 2-deoxy-2-iodo-a,b-D-glucose and 2-deoxy-2-
iodo- ,b- -mannose
a
D
required 2-deoxy-2-iodo-
,b-
-mannose (8) in ꢀ70% overall yield of the process calculated
from 3,4,6-tri-O-acetyl- -glucal. Use of inexpensive and commer-
cially available substrates and reagents, combined with short reac-
tion times, simple workups and high yields, makes this the method
a,b-D-glucose (7) and 2-deoxy-2-iodo-
a
D
The first reported attempt to synthesize 2-deoxy-2-iodo-
a
,b-
-mannose used iodonolysis of C-
-glucose derivatives;35 however, no
D
-
D
glucose and 2-deoxy-2-iodo-
2-mercurated -mannose or
a
D
,b-D
D
supporting analytical data were presented. Other reports described
of choice for the preparation of 2-deoxy-2-iodo-
and 2-deoxy-2-iodo-a,b-D-mannose (8) on a large laboratory scale.
a
,b-
D-glucose (7)
this method as difficult to repeat.36
The most efficient method for the introduction of an iodine sub-
stituent at C-2 has been an addition reaction of N-iodosuccinimide
3. Experimental
to the double bond of
reaction to differentially protected
several groups, and the 2-deoxy-2-iodo-
to be the predominant product. It was also noted that the ratio of
manno and gluco isomers was affected by the nature of the -glucal
substituents and temperature, thus indicating that the preference
for the -manno isomer could be reversed. It has been shown that
addition of N-iodosuccinimide to 3,4,6-tri-O-(tert-butyldiphenylsi-
lyl)- -glucal in the presence of acetic acid in toluene at 100 °C led
D
-glucal. Stereochemistry of the addition
-glucal has been studied by
-manno isomer appeared
3.1. General methods
D
D
NMR spectra were recorded with Bruker Avanti 300 and 500
spectrometers. Chemical shifts are referenced to Me4Si as the inter-
nal reference. 1H and 13C signals were assigned based on 2D spec-
tra: proton–proton correlation (GRADCOSY), and proton–carbon
correlation (C13HSQC); in addition for
ton–carbon correlation (ROESY) experiments were also performed
D
D
D-mannose derivatives pro-
D

I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
1469
OAc
O
OAc
OAc
OAc
OTBMS
OAc
OTBMS
OAc
O
O
O
O
I
a)
b)
OAc
OAc
OAc
OAc I
+
+
OH
AcO
OTBMS
AcO
AcO
AcO
AcO
I
I
9
21
22
23
24
c)
c)
c)
OH
OH
OH
OTBMS
OTBMS
O
I
O
I
O
I
OH
OH
OH
HO
HO
HO
OTBMS
26
27
25
d)
d)
OH
O
OH
O
I
OH
7
OH
OH
OH
HO
HO
8
I
Scheme 3. Synthesis of 2-deoxy-2-iodo derivatives of D-glucose and D-mannose. Reagents and conditions: (a) NIS, H2O, toluene reflux; (b) TBDMSCl, imidazole, CH2Cl2; (c) N
NaOMe, MeOH; (d) CF3CO2H, H2O.
to confirm signal assignments. High-resolution mass spectra were
acquired using the Waters Quattro Ultima Q-TOF instrument. Opti-
cal rotations were determined on a Jasco DIP-370 digital polarim-
eter at room temperature. Melting points were measured with a
Buchi 530 apparatus and are not corrected. Thin-layer chromatog-
raphy (TLC) was carried on an aluminum sheet coated with Silica
Gel 60 F254 (EMD Chemicals, Inc.). Compounds were visualized
on TLC plates by spraying with 20% H2SO4 in EtOH and gently heat-
ing. Silica gel column chromatography was performed with a Com-
biFlash Companion purification system (Teledyne ISCO) and
Biotage SP1 purification system. SelectfluorÒ.is a product of Sig-
ma–Aldrich Chemical Co.
and the residual amount of pyridine was removed by co-evapora-
tion with toluene (3 Â 100 mL). The remaining residue containing
mixture of compounds 11 and 12 was separated using a low-
pressure liquid chromatography apparatus and hexanes–EtOAc
gradient (10–40% of EtOAc) as an eluent to give pure 1,3,4,6-tet-
ra-O-acetyl-2-deoxy-2-fluoro-
0.107 mol, 48.5%, :b ratio = 1:1.5); Rf 0.56 (1:1 hexanes–EtOAc).
Data for 11: 1H NMR (CDCl3): d 6.42 d 1Y, J1,2 = 4.0 Hz, H-1
),
5.78 (dd, 1H, J1,2 = 8.1 Hz, J1,F = 3.2 Hz, H-1b), 5.55 (ddd, 1H,
J3,F = 12.1 Hz, J3,2 = J3,4 = 9.5 Hz, H-3 ), 5.37 (ddd, 1H, J3,F
14.3 Hz, J3,2 = J3,4 = 9.2 Hz, H-3b), 5.09 (dd, 1H, J4,3 = J4,5 = 9.2 Hz,
a,b-D-glucopyranose (11) (37.4 g,
a
a
a
=
H-4
48.5 Hz, J2,3 = 9.6 Hz, J2,1 = 4.0 Hz, H-2
50.1 Hz, J2,3 = 9.2 Hz, J2.1 = 8.1 Hz, H-2b), 4.34–4.26 (m, 2H, H-6
H-6b), 4.1–4.02 (m, 3H, H-6 H-6b, H-5 ), 3.85 (ddd, 1H,
J5,4 = 10.0 Hz, J5,6 = 4.5 Hz, J5,6 = 3.2 Hz, H-5b), 2.20, 2.17, 2.08,
a
), 5.07 (dd, 1H, J4,3 = J4,5 = 9.6 Hz, H-4b), 4.74 (ddd, 1H, JH,F
=
a), 4.54 (ddd, 1H, JH,F
=
3.2. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-fluoro-
glucopyranose (11) and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-
,b- -mannopyranose (12)
a,b-
D
-
a,
a,
a
a
D
2.07, 2.04, 2.036, 2.033 (7s, 24H, OAc,
a, b); HRMS: calcd for
The solution of 3,4,6-tri-O-acetyl-
D
-glucal (9) (60 g, 0.22 mol) in
C14H19FNaO9 [M+Na]+ m/z 373.0911; found m/z 373.0843. The sec-
ond eluted compound was 1,3,4,6-tetra-O-acetyl-2-deoxy-2-flu-
a mixture of nitromethane (500 mL) and water (100 mL) was pre-
pared and cooled to 0 °C. SelectfluorÒ (100 g, 0.282 mol) was
added, and the reaction mixture was stirred overnight, while the
temperature was allowed to rise to ambient. The reaction mixture
was refluxed for 1 h, then the solvents were evaporated. CH2Cl2
(500 mL) was added, followed by a 5% NaHCO3 solution (200 mL).
The layers were separated, and the organic layer was washed with
brine, dried over Na2SO4, and evaporated to dryness. The crude
product was dissolved in CH2Cl2 (500 mL) and pyridine (32 mL,
0.4 mol), followed by Ac2O (25 mL, 0.264 mol), and the reaction
mixture was stirred overnight. The mixture was washed with a
solution of satd NaHCO3 (150 mL), then washed with water until
a neutral pH was achieved. The organic solution was dried over an-
hyd Na2SO4. The solvent was evaporated under reduced pressure,
oro-a,b-D-mannopyranose (12) (32.4 g, 0.092 mol, 42%, a:b
ratio = 0.9:10); Rf 0.44 (1:1 hexanes–EtOAc). 1H NMR (CDCl3): d
6.28 dd, 1Y, J1,F = 6.5 Hz, J1,2 = 2.0 Hz, H-1b), 5.80 dd, 1Y,
J1,F = 18.8 Hz, H-1
H-4 ), 5.44–5.36 (m, 1H, H-4
10.1 Hz, J3,2 = 2.5 Hz, H-3b), 5.06 (ddd, 1H, J3,F = 27.0 Hz,
J3,4 = 10.0 Hz, J3,2 = 2.3 Hz, H-3 ), 4.88 (dd, 1H, J2,F = 51.2 Hz, J2,3
2.3 Hz, H-2 ), 4.75 (ddd, 1H, J2,F = 48.7 Hz, J2,1 = J2,3 = 2.5 Hz,
H-2b), 4.28 (dd, 1H, J6,6 = 12.4 Hz, J6,5 = 4.4 Hz, H-6 ), 4.11
(dd, 1H, J6,6 = 12.4 Hz, J6,5 = 2.3 Hz, H-6 ), 4.05 (ddd, 1H, J5,4
9.9 Hz, J5.6 = 4.4 Hz, J5,6 = 2.3 Hz, H-5 ), 2.19, 2.18, 2.12, 2.09,
2.06, 2.04 (6s, 24H, OAc, , b); HRMS: calcd for C14H19FNaO9
[M+Na]+ m/z 373.0911; found m/z 373.0927.
a), 5.43 (ddd, 1H, J4,3 = J4,5 = 10.1 Hz, J4,F = 1.0 Hz,
a
a), 5.27 (ddd, 1H, J3,F = 27.6 Hz, J3,4 =
a
=
a
a
a
=
a
a

1470
I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
3.3. Preparation of 2-deoxy-2-fluoro-
a
,b-
D
-glucopyranose (1)
,b- -glu-
tion was washed with a solution of satd Na2CO3 until neutral, then
with brine, and then dried over anhyd Na2SO4. The drying agent
was filtered off, and solvents were evaporated to dryness. Remain-
ing pyridine was removed by co-evaporation with toluene
(3 Â 100 mL). Products were then separated by low-pressure col-
umn chromatography using a hexanes–EtOAc gradient (10–40%
A mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-
a
D
copyranose (11) (37.4 g, 0.107 mol) and N HCl (370 mL) was pre-
pared and heated with vigorous stirring at 70 °C. The progress of
the reaction was monitored by TLC, and after completion, the reac-
tion mixture was cooled to room temperature, and Na2CO3 (19.6 g,
0.185 mol) was added. The solution was evaporated to dryness,
and MeOH (100 mL) was added to the residue. The resulting mix-
ture was stirred for 15 min, then the solid was filtered off. The
MeOH was evaporated, and the product was then purified by col-
umn chromatography using a CHCl3–MeOH gradient increasing
from 10% to 30%. Fractions containing the product were pooled to-
gether and evaporated to dryness. The residual solvents were re-
EtOAc) to give 1,3,4,6-tetra-O-acetyl-2-chloro-2-deoxy-
copyranose (15) (13.2 g, 36 mmol, 49.6%, :b ratio 1:2.4); Rf 0.58
(1:1 hexanes–EtOAc), 1H NMR (CDCl3): d 6.36 d, 1Y, J1,2 = 3.5 Hz,
H-1 ), 5.76 (d, 1H, J1,2 = 8.8 Hz, H-1b), 5.48 (dd, 1H, J4,5 = 10.5 Hz,
J4,3 = 9.5 Hz, H-4 ), 5.30 (dd, 1H, J4,5 = 10.3 Hz, J4,3 = 9.4 Hz, H-4b),
5.10 (dd, 1H, J3,2 = 10.1 Hz, J3,4 = 9.5 Hz, H–3 ), 5.07 (dd, 1H,
J3,2 = 10.0 Hz, J3,4 = 9.4 Hz, H-3b), 4.33 (dd, 1H, J6,6 = 12.5 Hz,
J6,5 = 4.5 Hz, H-6b), 4.31 (dd, 1H, J6,6 = 12.3 Hz, J6,5 = 4.2 Hz, H-6 ),
4.18–4.05 (m, 4H, H-2 H-6 H-6b, H-5 ), 3.89 (dd, 1H,
a,b-D-glu-
a
a
a
a
a
moved using a vacuum pump to give 2-deoxy-2-fluoro-
(1) (13.6 g, 75 mmol, 70%) as a white powder: mp 163–167 °C,
lit. 160–165 °C,13 +63.6 (c, 1.2 H2O), lit.3 +56. Anal. Calcd for
C6H11FO5: C, 39.56; H, 6.09. Found: C, 39.06; H, 6.06.
D-glucose
a
,
a,
a
J2,1 = 8.8 Hz, J2.3 = 10.3 Hz, H-2b), 3.88 (ddd, 1H, J5,4 = 10.0 Hz,
[a]
D
J5,6 = 4.5 Hz, J5,6 = 2.3 Hz, H-5b), 2.22, 2.16, 2.11, 2.09, 2.06, 2.05
(6s, 24 H, OAc,
389.0615; found, m/z 389.0412. The second eluted isomer
was 1,3,4,6-tetra-O-acetyl-2-chloro-2-deoxy- ,b- -mannopyranose
(16)38 (3.6 g, 9.8 mmol, 13.5%,
:b ratio 3.3:1); Rf 0.58 (1:1 hex-
anes–EtOAc), 1H NMR (CDCl3): d 6.26 s, 1Y, Y-1
, 5.95 d, 1Y,
J1,2 = 1.1 Hz, H-1b), 5.50 (dd, 1H, J4,3 = J4,5 = 9.8 Hz, H-4 ), 5.43 (dd,
1H, J4,3 = J4,5 = 9.6 Hz, H-4b), 5.38 (dd, 1H, J3,4 = 9.8 Hz, J3,2 = 3.7 Hz,
H-3 ), 5.15 (dd, 1H, J3,4 = 9.7 Hz, J3,2 = 3.6 Hz, H-3b), 4.57 (d, 1H,
J2,1 = 3.2 Hz, H-2b), 4.4 (dd, 1H, J2,1 = 1.1 Hz, J2,3 = 3.7 Hz, H-2 ),
4.29 (dd, 1H, J6,6 = 12.5 Hz, J6,5 = 5.1 Hz, H-6b), 4.27 (dd, 1H,
J6,6 = 12.5 Hz, J6,5 = 4.5 Hz, H-6 ), 4.19 (dd, 1H, J6,6 = 12.5 Hz,
J6,5 = 2.2 Hz, H-6b), 4.16 (dd, 1H, J6,6 = 12.5 Hz, J6,5 = 2.3 Hz, H-6 ),
4.11 (ddd, 1H, J5,6 = 2.2 Hz, J5,6 = 4.5 Hz, J5,4 = 10.0 Hz, H-5 ), 3.82
(ddd, 1H, J5,6 = 2.2 Hz, J5,6 = 5.1 Hz, J5,4 = 9.5 Hz, H-5b), 2.20, 2.14,
2.13, 2.12, 2.11, 2.09 (6s, 24 H, OAc, , b); HRMS: calcd for
C14H19ClNaO9 [M+Na]+ m/z 389.0615; found 389.0625.
a
, b); HRMS: calcd for C14H19ClNaO9 [M+Na]+ m/z
3.4. Preparation of 2-deoxy-2-fluoro-
a
,b-D
-mannopyranose (2)
,b-
a
D
a
A
mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-
a
D
-
a
mannopyranose (12) (32.4 g, 0.092 mol) and N HCl (300 mL) was
prepared and heated with vigorous stirring at 70 °C. Progress of
the reaction was monitored by TLC, and after the reaction was
completed the mixture was cooled to room temperature and
Na2CO3 (15.9 g, 0.15 mol) was added. Water was then evaporated,
and MeOH (50 mL) was added to the residue. The resultant mixture
was stirred for 15 min, the solid was filtered off, MeOH was evap-
orated, and the product was purified by column chromatography
using a CHCl3–MeOH gradient increasing from 10% to 30%. Frac-
tions containing the product were pooled and evaporated to dry-
ness. The residual solvents were removed using a vacuum pump
a
a
a
a
a
a
a
to give 2-deoxy-2-fluoro-a,b-D-mannopyranose (2) (14.6 g,
80 mmol, 87%): mp 136–137 °C lit.13 131–132 °C, [
a] + 27.3 (c,
D
3.6. Preparation of 2-chloro-2-deoxy-a,b-D-glucopyranose (3)
1.18 H2O), lit. +19 °C;13 HRMS calcd for C6H11FNaO5 [M+Na]+ m/z
205.0488; found, m/z 205.0430.
A suspension of 1,3,4,6-tetra-O-acetyl-2-chloro-2-deoxy-
a,b-D-
glucopyranose (15) (13.0 g, 35.4 mmol) in HCl (130 mL,
N
3.5. 1,3,4,6-Tetra-O-acetyl-2-chloro-2-deoxy-
nose (15) and 1,3,4,6-tetra-O-acetyl-2-chloro-2-deoxy-
b- -mannopyranose (16)
a,b-D-glucopyra-
0.13 mol) was prepared and heated with vigorous stirring at
70 °C. Progress of the reaction was monitored by TLC. After com-
pletion, the reaction mixture was cooled to room temperature
and Na2CO3 (6.9 g, 0.065 mol) was added in portions. Water was
evaporated and MeOH (25 mL) was added to the residue. The mix-
ture thus obtained was stirred for 15 min, and the solid was fil-
tered off. MeOH was then evaporated, and the product was
purified by column chromatography using a CHCl3–MeOH gradient
increasing from 10% to 30%. Fractions containing the product were
pooled together and evaporated to give pure 2-chloro-2-deoxy-
a
,
D
Chlorine was passed through a solution of 3,4,6-tri-O-acetyl-D-
glucal (9) (20 g, 74.3 mmol) in CH2Cl2 (200 mL) until the solution
became a pale yellow-green in color. The reaction mixture was
stirred vigorously for 15 min., then the solvent was evaporated to
dryness, and the remaining residue was subjected to separation
by low-pressure column chromatography, using a hexane–EtOAc
gradient (0–10% of EtOAc). Fractions containing the product were
pooled and evaporated to give a mixture 13 (19.2 g, 56 mmol,
75.3%). A suspension of the mixture 13 (19.2 g, 56 mmol) in N
HCl (192 mL, 0.192 mol) was prepared and heated with vigorous
stirring at 70 °C. Progress of the reaction was monitored by TLC,
and at completion, the reaction mixture was cooled to room tem-
perature, and Na2CO3 (10.2 g, 0.096 mol) was added. Water was
evaporated and MeOH (25 mL) was added to the residue. The
resulting mixture was stirred for 15 min, and the solid was then fil-
tered off. MeOH was then evaporated and the product was purified
by column chromatography using a CHCl3–MeOH gradient increas-
ing from 10% to 30%. Fractions that contained the product were
pooled together and evaporated to give 14 (14.4 g, 42 mmol,
74.9%). A solution of 14 (14.4 g, 72.5 mmol) in pyridine (144 mL)
was prepared and cooled to 0 °C. Ac2O (32 mL, 336 mmol) was
added, and the reaction mixture was stirred overnight, while the
temperature was allowed to rise to ambient. The reaction mixture
was diluted with EtOAc (250 mL), and the resulting organic solu-
a
,b-
D
-glucopyranose (3) (5.1 g, 25.9 mmol, 75%): mp 135–136 °C,
lit. 149 °C,26
[a]
D
+70 (c, 1.1 H2O), lit.26 +71. Anal. Calcd for
C6H11ClO5: C, 36.29; H, 5.58; Cl, 17.85. Found: C, 36.41; H, 5.82;
Cl, 17.49.
3.7. Preparation of 2-chloro-2-deoxy-
a
,b-
D
-mannopyranose (4)
,b-D-
A suspension of 1,3,4,6-tetra-O-acetyl-2-chloro-2-deoxy-
a
mannopyranose (14) (3.5 g, 9.5 mmol) in N HCl (35 mL, 35 mmol)
was prepared and heated with vigorous stirring at 70 °C. Progress
of the reaction was monitored by TLC. After completion, the reac-
tion mixture was cooled to room temperature, and Na2CO3 (1.9 g,
17.5 mmol) was added in portions. Water was then evaporated,
and MeOH (15 mL) was added to the residue. The resultant mix-
ture was stirred for 15 min, then the solid was filtered off. The
MeOH was evaporated, and the crude product was purified by col-
umn chromatography using a CHCl3–MeOH gradient (0–10% of

I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
1471
MeOH). Fractions were pooled together and evaporated to
3.9. 2-Bromo-2-deoxy-a,b-D-glucose (5)
give pure 2-chloro-2-deoxy-a,b-D-mannopyranose (4) (1.4 g,
7.13 mmol, 75%): mp 128–129 °C, [
a]
D
À4 (c, 1.0, H2O), lit.23 À6;
A suspension of 1,3,4,6-tetra-O-acetyl-2-bromo-2-deoxy-
a,b-D-
HRMS: calcd for C6H11ClNaO5 [M+Na]+ m/z 221.0193; found m/z
glucopyranose (19) (8.7 g, 21.2 mmol) in HCl (87 mL,
N
221.0134.
0.087 mmol) was prepared and heated with vigorous stirring at
70 °C. The progress of the reaction was monitored by TLC. After
the reaction was completed, the mixture was cooled to room tem-
perature and Na2CO3 (4.6 g, 0.044 mol) was added. Water was
evaporated, and MeOH (15 mL) was added to the residue. The
resulting mixture was stirred for 15 min, the solid was filtered
off, the MeOH was evaporated, and the product was purified by
column chromatography using a CHCl–MeOH gradient (0% to 10%
of MeOH). Fractions that contained the product were pooled to-
3.8. 1,3,4,6-Tetra-O-acetyl-2-bromo-2-deoxy-
glucopyranose (19) and 1,3,4,6-tetra-O-acetyl-2-bromo-2-
deoxy- ,b- -mannopyranose (20)
a,b-D-
a
D
Bromine (3.9 mL, 75 mmol) was added to a solution of 3,4,6-tri-
O-acetyl- -glucal (9) (20 g, 74.3 mmol) in CH2Cl2 (200 mL). The
D
mixture was stirred at room temperature for 15 min, and the sol-
vent was evaporated to dryness. The crude product was purified
by low-pressure column chromatography to give a mixture 17
(25.7 g, 59.4 mmol) that contained only 3,4,6-tri-O-acetyl-2-bro-
gether and evaporated to give pure 2-deoxy-2-bromo-
a,b-D-glu-
cose (5) (3.8 g, 15.7 mmol, 74%): mp 74–77 °C, [ +70 (c, 1.1,
a]
D
H2O). Anal. Calcd for C6H11BrO5: C, 29.65; H, 4.56, Br, 32.88. Found:
mo-2-deoxy-b-
D-glucopyranosyl bromide and 3,4,6-tetra-O-acet-
C, 39.53; H, 4.75; Br, 32.60.
yl-2-bromo-2-deoxy-
a-D
-mannopyranosyl bromide (gluco:manno
ratio = 2.6:1). A suspension of 17 (25.7 g, 59.4 mmol) in N HCl
(275 mL, 0.275 mol) was prepared and heated with vigorous stir-
ring at 70 °C. Progress of the reaction was monitored by TLC. After
the reaction was completed, the mixture was cooled to room tem-
perature, and Na2CO3 (14.6 g, 0.138 mol) was added. Water was
evaporated and MeOH (50 mL) was added to the residue. The mix-
ture thus obtained was stirred for 15 min, the solid was filtered off,
the MeOH was evaporated, and the crude product was purified by
column chromatography using a CHCl3–MeOH gradient (0–10%
MeOH). Fractions containing the product were pooled together
and evaporated to give 18 (10.8 g, 44.5 mmol). A solution of 18
(10.8 g, 44.5 mmol) in pyridine (75 mL) was prepared and cooled
to 0 °C. Ac2O (28 mL, 0.296 mol) was added, and the reaction mix-
ture was stirred overnight, while the temperature was allowed to
rise to ambient. The reaction mixture was diluted with EtOAc
(250 mL), and the solution thus obtained was washed with a satd
solution of Na2CO3. The organic extract was washed with water un-
til neutral, followed by brine, and the extract was then dried over
anhyd Na2SO4. The drying agent was filtered off, and the solvents
were evaporated. The remaining pyridine was removed by co-
evaporation with toluene (3 Â 100 mL), and the products were sep-
arated by low-pressure column chromatography to give 1,3,4,
3.10. 2-Bromo-2-deoxy-a,b-D-mannose (6)
A suspension of 1,3,4,6-tetra-O-acetyl-2-bromo-2-deoxy-
mannopyranose (20) (6.3 g, 15.3 mmol) in HCl (63 mL,
a,b-D-
N
0.063 mmol) was prepared and heated with vigorous stirring at
70 °C. Progress of the reaction was monitored by TLC. After the
reaction was completed, the reaction mixture was cooled to room
temperature, and Na2CO3 (3.4 g, 0.032 mol) was added. Water was
evaporated, and MeOH (15 mL) was added to the residue. The mix-
ture thus obtained was stirred for 15 min, and the solid was fil-
tered off. MeOH was evaporated, and the crude product was
purified by column chromatography using a CHCl3–MeOH gradient
(0–10% of MeOH). Fractions that contained the product were
pooled together and evaporated to give pure 2-deoxy-2-bromo-
a
,b-D-mannose (6) (2.8 g, 11.5 mmol, 74%): mp 64–65 °C, [a]
D
+5.4 (c, 1.28, H2O); HRMS: calcd for C6H11BrNaO5 [M+Na]+ m/z
264.9688; found, m/z 264.9599.
3.11. 3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-
butyldimethylsilyl-
2-deoxy-2-iodo-1-O-tert-butyldimethylsilyl-b-
mannopyranose (23), and 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-1-
O-tert-butyldimethylsilyl-b- -glucopyranose (22)
a-D-mannopyranose (24), 3,4,6-tri-O-acetyl-
D
-
6-tetra-O-acetyl-2-bromo-2-deoxy-
(8.7 g, 21.2 mmol, 47.6%, :b ratio 10:7); Rf 0.58 (1:1 hexanes–
EtOAc); 1H NMR (CDCl3): d 6.36 (d, 1Y, J1,2 = 3.3 Hz, H-1b), 5.82 d
1Y, J1,2 = 9.1 Hz, H-1 ), 5.51 (dd, 1H, J3,2 = 11.8 Hz, J3,4 = 9.3 Hz, H-
), 5.35 (dd, 1H, J3,2 = 10.6 Hz, J3,4 = 9.3 Hz, H-3b), 5.09 (dd, 1H,
J4,3 = J4,5 = 9.5 Hz, H-4 ), 5.03 (dd, 1H, J4,3 = J4,5 = 9.5 Hz, H-4b),
4.32 (dd, 1H, J6,6 = 13.5 Hz J6,5 = 4.5 Hz, H-6 ), 4.29 (dd, 1H,
J6,6 = 12.3 Hz J6,5 = 4.1 Hz, H-6b, 4.15 (ddd, 1H, J5,4 = 9.5 Hz, J5,6
4.5 Hz, J5,6 = 2.0 Hz, H-5 ), 4.11–4.06 (m, 3H, H-2 , H-6 , H-6b),
3.91 (dd, 1H, J2,3 = 10.6 Hz J2,1 = 9.1 Hz, H-2b), 3.94–3.88 (m, 1H,
a,b-
D-glucopyranose
(19)33
D
a
The mixture of 3,4,6-tri-O-acetyl-D-glucal (27.2 g, 0.1 mol) and
a
NIS (33.75 g, 0.15 mol) in toluene (270 mL) was prepared and
heated until reflux, then water (3.6 mL, 0.2 mol) was added, and re-
flux was continued. After 10 min the reaction was completed, and
the toluene was evaporated to dryness. The crude mixture was dis-
solved in CH2Cl2 (300 mL). The resulting organic solution was
washed with a 10% Na2S2O5 solution, then with water until neutral,
followed with brine. The crude product, after drying over Na2SO4
and solvent evaporation, was dissolved in CH2Cl2 (30 mL). tert-
Butyldimethylsilyl chloride (18 g, 0.12 mol), followed by imidazole
(10.2 g, 0.15 mol), was then added, and the reaction mixture was
stirred at room temperature. After 1 h the reaction was completed.
The reaction mixture was then diluted with CH2Cl2 (250 mL) and
washed with water (3 Â 100 mL), followed by drying over Na2SO4.
The drying agent and solvent were removed, and the products
were separated using low-pressure liquid chromatography with a
hexane–EtOAc gradient (0–20% of EtOAc) for elution. The following
products were obtained.
3a
a
a
=
a
a
a
H-5b), 2.21, 2.18, 2.10, 2.08, 2.04, 2.03 (6s, 24 H, OAc a,b); HRMS:
calcd for C14H19BrNaO9 [M+Na]+ m/z 433.0110; found, m/z
433.0118. The second eluted compound was 1,3,4,6-tetra-O-
acetyl-2-bromo-2-deoxy-
15.3 mmol, 34.4.%, :b ratio 10:7); Rf 0.45 (hexanes/EtOAc 1:1),
1H NMR (CDCl3): d 6.30 (s, 1H, H-1
), 5.74 (s, 1H, Y-1b, 5.48 dd,
1Y, J4,3 = J4,5 = 9.8 Hz, H-4 ), 5.42 (dd, 1Y, J4,3 = J4,5 = 9.7 Hz, H-4b),
5.20 (dd, 1Y, J3,4 = 9.6 Hz, J3,2 = 3.9 Hz, H-3 ), 5.00 (dd, 1Y,
J3,4 = 9.6 Hz, J3,2 = 3.8 Hz, H-3b), 4.59 (bd, 1Y, J3,1 = 3.8 Hz, H-2b),
4.43 (dd, 1Y, J2,3 = 3.8 Hz, J2,1 = 1.5 Hz, H-2 ), 4.23 (dd, 1Y,
J6,6 = 12.4 Hz, J6,5 = 4.5 Hz, H-6 ), 4.14 (dd, 1Y, J6,6 = 12.4 Hz, J6,5
2.3 Hz, H-6 ), 4.10 (ddd, 1Y, J5,4 = 9.9 Hz, J5,6 = 4.5 Hz, J5,6 = 2.3 Hz,
H-5 ), 3.83 (ddd, 1H, J5,6 = 9.7 Hz, J5,6 = 4.9 Hz, J5,6 = 2.4 Hz, H-5b)
a,b-D
-mannopyranose
(20)33
(6.3 g,
a
a
a
a
a
a
=
a
3.11.1. 3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-butyldimeth-
a
ylsilyl-a-D-mannopyranose (24) (3 g, 6.5 mmol, 6.5%)
2.19, 2.18, 2.13, 2.125, 2,122, 2.11, 2.08, 2.06 (8s, 24 H, OAc
a
, b);
Rf 0.59 (2:1 hexanes–EtOAc), 1H NMR (CDCl3): d 5.47 (bs, 1H, H-
1), 5.38 (dd, 1H, J4,3 = J4,5 = 9.3 Hz, H-4), 4.72 (dd, 1H J3,4 = 9.3 Hz,
J3,2 = 4.2 Hz, H-3), 4.49 (dd, 1H, J2,1 = 1.3 Hz, J2,3 = 4.2 Hz, H-2),
HRMS calcd for C14H19BrNaO9 [M+Na]+ m/z 433.0110; found, m/z
433.0091.

1472
I. Fokt et al. / Carbohydrate Research 344 (2009) 1464–1473
4.22 (dd, 1H, J6,6 = 11.3 Hz, J6,5 = 4.7 Hz, H-6), 4.16 (ddd, 1H,
J5,4 = 9.3 Hz, J5,6 = 4.7 Hz, J5,6 = 1.7 Hz, H-5), 4.10 (dd, 1H,
J6,6 = 11.3 Hz, J6,5 = 1.7 Hz, H-6), 2.14, 2.08, 2.06 (3s, 3H ea, OAc),
0.93 (s, 9H, t-Bu), 0.13, 0.12 (2s, 3H ea, Me); HRMS:calcd for
C18H31INaO8Si [M+Na]+ m/z 553.0731; found, m/z 553.0753.
H-3), 0.87 (s, 9H, t-Bu), 0.08 (s, 6H, Me); HRMS: calcd for C12H25I-
NaO5Si [M+Na]+ m/z 427.0414; found, m/z 427.0414.
3.14. 2-Deoxy-2-iodo-1-O-tert-butyldimethylsilyl-b-D-glucopy-
ranose (25)
3.11.2. 3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-butyldimeth-
3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-butyldimethylsilyl-
-glucopyranose (22) (19 g, 41 mmol) was deacetylated accord-
ing to method described for 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-1-
O-tert-butyldimethylsilyl-b- -mannopyranose (24). 2-Deoxy-2-
iodo-1-O-tert-butyldimethylsilyl-b- -glucopyranose (25) (12.7 g,
ylsilyl-b-D-mannopyranose (23) (23 g, 50 mmol, 50%)
b-D
Rf 0.46 (2:1 hexanes–EtOAc), 1H NMR (CDCl3): d 5.33 (dd, 1H,
J4,3 = J4,5 = 9.5 Hz, H-4), 4.65 (dd, 1H, J2,3 = 4.2 Hz, J2,1 = 1.4 Hz, H-
2), 4.47 (dd, 1H, J3,4 = 9.5 Hz, J3,2 = 4.2 Hz, H-3), 4.20 (dd, 1H,
J6,6 = 12.0 Hz, J6,5 = 3.2 Hz, H-6), 4.15 (dd, 1H, J6,6 = 12.0 Hz,
J6,5 = 5.8 Hz, H-6), 4.02 (d, 1H, J1,2 = 1.4 Hz, H-1), 3.68 (ddd, 1H,
J5,4 = 9.5 Hz, J5,6 = 5.8 Hz, J5,6 = 3.2 Hz, H-5), 2.11, 2.09, 2.08 (3s,
3H ea, OAc), 0.93 (s, (H, 9H, t-Bu), 0.17, 0.13 (2s, 3H ea, Me); HRMS:
calcd for C18H31INaO8Si [M+Na]+ m/z 553.0731; found, m/z
553.0684.
D
D
38 mmol, 92.7%) was obtained. 1H NMR (DMSO-d6 + D2O): d 4.78
(d, 1H, J1,2 = 8.6 Hz, H-1), 3.64 (bd, 1H, J6,6 = 10.7 Hz, H-6), 3.56
(dd, 1H, J2,1 = 8.6 Hz, J2,3 = 10.4 Hz, H-2), 3.47–3.40 (m, 2H, H-6),
3.36 (dd, 1H, J3,2 = 10.4 Hz, J3,4 = 9.6 Hz, H-3), 3.19 (dd, 1H,
J5,4 = 9.0 Hz, J5,6 = 5.8 Hz, H-5), 3.09 (dd, 1H, J4,3 = 9.6 Hz,
J4,5 = 9.0 Hz, H-4), 0.88 (s, 9H, t-Bu), 0.12, 0.09 (2s, 3H ea, Me);
HRMS: calcd for C12H25INaO5Si [M+Na]+ m/z 427.0414; found,
m/z 427.0489.
3.11.3. 3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-butyldimeth-
ylsilyl-b-D-glucopyranose (22) (19 g, 41 mmol, 41%)
3.15. 2-Deoxy-2-iodo-D-mannose (8)
Rf 0.54 (2:1 hexanes–EtOAc), 1H NMR (CDCl3): d 5.30 (dd, 1H,
J3,4 = 9.0 Hz, J3,2 = 11.2 Hz, H-3), 4.91 (dd, 1H, J4,3 = 9.0 Hz,
J4,5 = 10.0 Hz, H-4), 4.89 (d, 1H, J1,2 = 8.6 Hz, H-1), 4.21 (dd, 1H,
J6,6 = 12.0 Hz, J6,5 = 6.0 Hz, H-6), 4.12 (dd, 1H, J6,6 = 12.0 Hz,
J6,5 = 2.5 Hz, H-6), 3.89 (dd, 1H, J2,1 = 8.6 Hz, J2,3 = 11.2 Hz H-2),
3.75 (ddd, 1H, J5,4 = 10.0 Hz, J5,6 = 6.0 Hz, J5,6 = 2.5 Hz, H-5), 2.08,
2.07, 2.01 (3s, 3H ea, OAc), 0.93 (s, 9H, t-Bu), 0.17, 0.15 (2s, 3H
ea, Me); HRMS calcd for C18H31INaO8Si [M+Na]+ m/z 553.0731;
found, m/z 553.0674.
A suspension of combined 2-deoxy-2-iodo-1-O-tert-butyldi-
methylsilyl- -mannopyranose (27) and 2-deoxy-2-iodo-1-O-
tert-butyldimethylsilyl-b- -mannopyranose (26) (18 g, 53.7 mmol)
a
-D
D
was prepared in acetonitrile (60 mL) and water (120 mL). Trifluo-
roacetic acid (8.25 mL, 12.31 g, 107 mmol) was added, and the
reaction mixture was stirred at room temperature. After the reac-
tion was completed, the solvents were evaporated to dryness, and
the product was purified by column chromatography using a
CHCl3–MeOH gradient (0–10% MeOH) for elution. Fractions con-
taining the product were pooled and evaporated to dryness. Resid-
ual solvents were removed by additional drying under low
3.12. 2-Deoxy-2-iodo-1-O-tert-butyldimethylsilyl-b-D-mannopy-
ranose (26)
pressure. (13.2 g, 45.6 mmol, 85%) of pure 2-deoxy-2-iodo-
a
,b-
D-
3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-butyldimethylsilyl-
D-mannopyranose (23) (23 g, 50 mmol) was dissolved in MeOH
mannose (8) was obtained: mp 88–89 °C (dec); [a]
À22.16 (c,
D
1.23 H2O); HRMS: calcd for C6H11INaO5 [M+Na]+ m/z 312.9549;
found, m/z 312.9592.
b-
(230 mL). N MeONa in MeOH (5 mL, 5 mmol) was added, and the
reaction mixture was stirred at room temperature. After the reac-
tion was completed (TLC) the reaction was quenched by addition of
HOAc (0.3 mL, 5 mmol). The solvent was evaporated to dryness,
and the crude product was purified by column chromatography
using a CHCl3–MeOH gradient (0–10% of MeOH) for elution. Frac-
3.16. 2-Deoxy-2-iodo-a,b-D-glucose (7)
A suspension of 2-deoxy-2-iodo-1-O-tert-butyldimethylsilyl-b-
-glucopyranose (25) (12.7 g, 38 mmol) was prepared in acetoni-
D
tions containing 2-deoxy-2-iodo-1-O-tert-butyldimethylsilyl-a-D-
trile (40 mL) and water (80 mL). Trifluoroacetic acid (5.85 mL,
8.74 g, 76 mmol) was added, and the reaction mixture was stirred
at room temperature. After the reaction was completed the sol-
vents were evaporated to dryness, and the resulting product was
purified by column chromatography using a CHCl3–MeOH gradient
(0–10% MeOH) for elution. Fractions containing the product were
pooled and evaporated to dryness. Residual solvents were removed
by additional drying under low pressure, and pure 2-deoxy-2-iodo-
mannopyranose (26) were pooled together and evaporated to dry-
ness. Traces of solvents were removed by additional drying under
high vacuum. Compound 26 (16.1 g, 48 mmol, 96%) was obtained.
1H NMR (DMSO-d6 + D2O): d 4.38 (dd, 1H, J2,1 = 3.9 Hz, J2,3 = 2.5 Hz,
H-2), 4.06 (d, 1H, J1,2 = 2.5 Hz, H-1), 3.66 (dd, 1H, J6,6 = 11.5 Hz,
J6,5 = 1.8 Hz, H-6), 3.40 (dd, 1H, J6,6 = 11.5 Hz, J6,5 = 6.3 Hz, H-6),
3.27 (dd, 1H, J4,3 = 9.4 Hz, J4,5 = 9.5 Hz, H-4), 3.20 (ddd, 1H,
J5,4 = 9.5 Hz, J5,6 = 1.8 Hz, J5,6 = 6.3 Hz, H-5), 2.94 (dd, 1H,
J3,4 = 9.4 Hz, J3,2 = 3.9 Hz, H-3), 0.88 (s, 9H, t-Bu), 0.12, 0.10 (2s,
3H ea, Me); HRMS: calcd for C12H25INaO5Si [M+Na]+ m/z
427.0414; found, m/z 427.0459.
a,b-D-glucose (7) (9.6 g, 33.1 mmol, 87%) was obtained: mp 79–
80 °C (dec); [a] +57.1 (c, 1.04 H2O); HRMS: calcd for C6H11INaO5
D
[M+Na]+ m/z 312.9549; found, m/z 312.9539.
Acknowledgments
3.13. 2-Deoxy-2-iodo-1-O-tert-butyldimethylsilyl-a-D-mannopy-
ranose (27)
This work was supported in part by NCI SPORE in a Pancreatic
Cancer P20 CA101936 grant (WP) and The Morton and Angela Top-
fer Pancreatic Cancer Research Fund (WP). We also acknowledge
the NCI Cancer Center Support Grant CA016672 for the support
of NMR facility at UT M. D. Anderson Cancer Center.
3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-1-O-tert-butyldimethylsilyl-
-mannopyranose (24) (3 g, 6.5 mmol) was deacetylated using
method described for its b isomer. 2-Deoxy-2-iodo-1-O-tert-butyl-
a-D
dimethylsilyl-a-D-mannopyranose (27) (2.07 g, 6.17 mmol, 95%)
was obtained. 1H NMR (DMSO-d6 + D2O): d 5.35 (s, 1H, H-1), 4.25
(dd, 1H, J2,1 = 1.3 Hz, J2,3 = 4.0 Hz, H-2), 3.62–3.55 (m, 2H, H-5, H-
6), 3.45 (dd, 1H, J6,6 = 12.1 Hz, J6,5 = 6.3 Hz, H-6), 3.34 (dd, 1H,
J4,3 = J4,5 = 9.5 Hz, H-4), 3.02 (dd, 1H, J3,4 = 9.5 Hz, J3,2 = 4.0 Hz,
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