Stereocontrolled halofluorination of glycals with silicon tetrafluoride, leading to a facile synthesis of glycosyl fluorides

Article abstract of DOI:10.1016/S0022-1139(99)00026-3

Bromofluorination of glycals was carried out with SiF₄, 1,3-dibromo-5,5-dimethylhydantoin (DBH), and H₂O in 1,4-dioxane in the presence of HMPA to give bromofluoro sugars in good yields with good selectivities. Subsequent debrominati

Full text of DOI:10.1016/S0022-1139(99)00026-3

Journal of Fluorine Chemistry 97 (1999) 57±60
Short communication
Stereocontrolled halo¯uorination of glycals with silicon tetra¯uoride,
leading to a facile synthesis of glycosyl ¯uorides
Makoto Shimizua,*, Yuko Nakaharab, Hirosuke Yoshiokab
aDepartment of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
bRiken Institute of Physical and Chemical Research, Wako, Saitama 351-0198, Japan
Received 31 October 1998; received in revised form 12 December 1998; accepted 12 December 1998
Dedicated to Prof. Yoshiro Kobayashi on the occasion of his 75th birthday
Abstract
Bromo¯uorination of glycals was carried out with SiF4, 1,3-dibromo-5,5-dimethylhydantoin (DBH), and H2O in 1,4-dioxane in the
presence of HMPA to give bromo¯uoro sugars in good yields with good selectivities. Subsequent debromination with n-Bu3SnH gave 2-
deoxy sugars in good yields. Furthermore, hydroxy¯uorination of glycal was also successfully conducted using SiF4-PhI(OAc)2-H2O to
give ¯uoroglucose in 73% yield. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Bromo¯uorination; Fluorosugar; Glycal; Silicon tetra¯uoride
1. Introduction
2. Experimental
For the formation of glycoside bonds, glycosyl halides
play an important role as a glycosyl donor in terms of
stereoselectivity [1,2]. Among the glycosyl halides, the
¯uoride analogues have recently received considerable
attention due to their enhanced stability and the stereose-
lectivity on the glycoside synthesis [3,4]. There have been
several approaches to glycosyl ¯uorides, involving trans-
formations of glycals [5±7], lactols [3], glycosyl halides [8],
glycosyl acetate [9], and phenylthioglycosides [10]. How-
ever, there appears to be an important problem on their
preparations especially on the stereoselectivity. We have
already introduced a convenient method for the preparation
of bromo¯uorides from ole®ns using SiF4 and DBH [11±15].
The same reagent system was successfully used for the
preparation of glycosyl ¯uorides from glycals. This paper
describes a facile approach to 2-bromo- and 2-deoxyglyco-
syl ¯uorides.
Bromo¯uorination of glycals was carried out as follows:
Under an argon atmosphere, to DBH (1.1 mmol) placed in a
¯ask was added 1,4-dioxane (4 ml), H2O (1.0 mmol), and
HMPA (0±5.0 mmol) successively, and the mixture was
stirred at room temperature (for acetate) or at 508C (for
benzoate). A balloon ®lled with SiF4 gas was ®tted to the
¯ask, and a solution of glycal (1.0 mmol) in 1,4-dioxane
(1 ml) was added. After being stirred at room temperature
for 1 h, the reaction mixture was quenched by adding an aq.
solution of KF. The whole mixture was extracted with
AcOEt, and the organic layer was washed successively with
20% aq. Na2S2O3 and saturated aq. NaCl. After usual work-
up the crude oil was puri®ed by silica gel column chroma-
tography to give the 2-bromoglycosyl ¯uoride as a mixture
of isomers.
Debromination of the bromo¯uoride: A mixture of the
bromo¯uoride (1 mmol) and n-Bu3SnH (1.5 mmol) in
toluene (10 ml) was heated at 50±558C for 2 h. Usual
work-up followed by puri®cation on preparative TLC gave
the 2-deoxyglycosyl ¯uoride.
Hydroxy¯uorination of glycal: Under an argon atmo-
sphere, to PhI(OAc)2 (156 mg, 0.3 mmol) placed in a ¯ask
was added dichloromethane (8 ml), H2O (4.5 ml) and
HMPA (130 ml, 0.75 mmol), and the mixture was stirred
*Corresponding author. Tel.: +81-59-231-9414; fax: +81-59-231-9471;
e-mail: mshimizu@chem.mie-u.ac.jp
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 2 6 - 3

58
M. Shimizu et al. / Journal of Fluorine Chemistry 97 (1999) 57±60
Table 1
Bromofluorination of glycal 1a
Entry
R
HMPA (eq)
Yield of 2b (%)
2a(a): 2b(a); 2c(b)c
1
2
3
4
5
6
7
Bz
Bz
Bz
Bz
Bz
Ac
Ac
None
1.0
70
79
80
84
78
82
85
47:27:26
66:14:20
71:10:19
70:22:8
2.0
3.0
5.0
None
3.0
73:19:8
36:28:36
59:17:24
a The reaction was carried out according to the typical experimental procedure.
b Isolated yield.
c Ratio determined by HPLC and/or 19F NMR.
at 08C. A balloon ®lled with SiF4 gas was ®tted to the
¯ask, and a solution of glycal-tribenzoate 1 (RˆBz)
(111 mg, 0.25 mmol) in dichloromethane (2 ml) was
added. After being stirred at room temperature for 2 h,
the reaction mixture was quenched by adding an aq.
solution of KF. The whole mixture was extracted with
AcOEt, and the organic layer was washed with saturated
aq. NaCl. After usual work-up the crude oil was puri-
®ed on silica gel TLC to give the ¯uoroglucose 11
(88 mg, 73%).
Other glycals derived from galactose, rhamnose, fucose,
xylose, and arabinose were also subjected to the present
bromo¯uorination, and the results are summarized in
Table 2.
3. Results and discussion
Bromo¯uorination of the glycals derived from glucose
was carried out according to the typical experimental pro-
cedure, and the results are shown in Table 1.
As shown in Table 2, the added HMPA effected the
predominant formation of a-¯uorides in particular in the
cases of entries 1±10, where the glycals possess C-6 car-
bons. In contrast, the glycals derived from xylose and
arabinose did not undergo stereoselective bromo¯uorination
even in the presence of HMPA (entries 11±14).
The high a-stereoselectivity of addition of the ¯uoride
anion in the present bromo¯uorination may be explained as
‡
Stereoselectivity of the present bromo¯uorination was
highly in¯uenced by the solvent polarity. In the absence
of HMPA, formation of the a-¯uorides predominated with
the ratio of 74:26, and the addition of HMPA improved
the selectivity in favour of the a-isomers. The best selec-
tivity was obtained when the bromo¯uorination was
carried out in the presence of 3.0 eq. of HMPA, in which
the a- vs. b-isomer ratio was 92:8. The chemoselective
reduction of the bromine atom of the bromo¯uoride 2
derived from the entry 4 in Table 1 was readily carried
out with n-Bu3SnH in toluene at 558C in good yield without
affecting the stereochemistry at the C-1 carbon as shown
below [16].
follows: The activation of the ole®nic bond with Br species
is effected from the pseudo-axial position to form epibro-
monium species which is attacked by the ¯uoride anion
from the axial position due to the stereoelectronic reason to
give trans-bromo¯uorides 5a and 5c as depicted in the
transition states I and II. When HMPA is added, the inter-
mediary oxonium ions are more stabilized, and hence the
initial oxonium species IV and V may isomerize to III and
VI, respectively. If there is R4 group, the intermediate V
isomerizes to the energetically more stable conformer VI to
give cis-bromo¯uoride 5b as an adduct (entries 2, 4, 6, 8,
and 10). In the cases with the glycals where R4 is H, the
energetic differences among four species III, IV, V, and VI

M. Shimizu et al. / Journal of Fluorine Chemistry 97 (1999) 57±60
59
Table 2
Bromofluorination of glycal 4a
Entry
R1
R2
R3
R4
HMPA
(eq)
5 (%)b
5a(a): 5b(a);
5c(b); 5d(b)2c
1
2
AcO
AcO
BzO
BzO
AcO
AcO
BzO
BzO
BzO
BzO
BzO
BzO
BzO
BzO
H
AcO
AcO
BzO
BzO
H
AcOCH2
AcOCH2
BzOCH2
BzOCH2
CH3
None
3.0
79
69
88
90
64
69
83
90
76
73
75
83
75
75
27:31:42:0
43:57:0:0
H
3
H
None
3.0
41:20:39:0
54:41:5:0
4
H
5
AcO
AcO
BzO
BzO
H
None
3.0
36:20:44:0
65:35:0:0
6
H
CH3
7
H
CH3
CH3
None
3.0
43:24:33:0
56:44:0:0
8
H
9
BzO
BzO
H
CH3
None
3.0
24:45:31:0
42:53:5:0
10
11
12
13
14
H
CH3
BzO
BzO
H
H
None
3.0
47:5:37:11
32:30:25:13
20:24:54:2
23:52:12:13
H
H
BzO
BzO
H
None
3.0
H
H
a The reaction was carried out according to the typical experimental procedure.
b Isolated yield.
c Ratio determined by HPLC and/or 19F NMR.
are not large, resulting in the formation of four possible
adducts 5a±5d (entries 11±14).
from entry 4 in Table 2), 7 (from entry 8), 8 (from entry 10), 9
(fromentry12),and10(fromentry14)ingoodyields,inwhich
The debromination was carried out as described above
using n-Bu3SnH to give 2-deoxy sugars 6 (using the products
thestereochemicalintegritiesattheC-1carbonsofthestarting
bromo¯uoro sugars were not affected in every case.

60
M. Shimizu et al. / Journal of Fluorine Chemistry 97 (1999) 57±60
Forthepreparationof¯uoroglucosehydroxy¯uorinationof
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4. Conclusions
The bromo¯uorination studied here provides a rapid
access to this important class of compounds in a stereo-
selective manner. Since a variety of glycals are readily
available, this method offers a convenient procedure for
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