Convenient synthesis of glycosyl bromide from 1-O-acetyl sugars by photo-irradiative phase-vanishing reaction of molecular bromine

Article abstract of DOI:10.1016/j.tetlet.2013.10.088

The synthesis of glycosyl bromides from 1-O-acetyl sugars using a photo-irradiative phase-vanishing method involving molecular bromine was achieved. A bottom phase of molecular bromine was overlaid first with perfluorohexanes (FC-72), followed by overlaying with ethyl acetate containing a 1-O-acetyl sugar. Upon irradiation, the bromine layer gradually disappeared, leaving two phases. Glycosyl bromide was obtained in good yield from the ethyl acetate phase.

Full text of DOI:10.1016/j.tetlet.2013.10.088

Tetrahedron Letters 54 (2013) 7124–7126
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient synthesis of glycosyl bromide from 1-O-acetyl sugars by
photo-irradiative phase-vanishing reaction of molecular bromine
⇑
Mami Tojino, Yuriko Hirose, Mamoru Mizuno
Laboratory of Glyco-Organic Chemistry, The Noguchi Institute, 1-8-1, Kaga, Itabashi-ku, Tokyo 173-0003, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of glycosyl bromides from 1-O-acetyl sugars using a photo-irradiative phase-vanishing
method involving molecular bromine was achieved. A bottom phase of molecular bromine was overlaid
first with perfluorohexanes (FC-72), followed by overlaying with ethyl acetate containing a 1-O-acetyl
sugar. Upon irradiation, the bromine layer gradually disappeared, leaving two phases. Glycosyl bromide
was obtained in good yield from the ethyl acetate phase.
Received 5 September 2013
Revised 15 October 2013
Accepted 18 October 2013
Available online 26 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bromine
Carbohydrate
Radical reaction
Fluorous
The carbohydrate moiety can be important for the biological activ-
ity and recognition of the cellular targets.1 Therefore, complex carbo-
hydrate syntheses have been attempted, but have been challenging.2
Synthesis of the carbohydrate moiety often is conducted under the
reaction conditions using excess reagent. For example, the synthesis
of glycosyl bromide, which is a useful O-glycosyl donor3 and C-glyco-
syl precursor4 has been prepared from peracetylated saccharides and
an acetic acid solution of HBr5 or BiBr3–Me3SiBr6 or the free saccha-
rides with AcBr,7,8 AcBr–AcOH,9,10 or Ac2O–HBr–AcOH.11,12 Recently,
Hunsen and co-workers reported the one-pot preparation of glycosyl
bromide from acetyl bromide, MeOH, and excess acetic acid.13 How-
ever, environmentally friendly (‘green’) syntheses, which do not re-
quire heavy metals, are gaining favor for atom economy reactions.
Additionally, the removal of excess HBr and/or acetic acid is tedious.
Recently, Ryu’s group developed a method that controls the amount
of HBr generated, involving the treatment with molecular bromide
and isoocatane by a photo-irradiative phase-vanishing method
(Scheme1).14 Phase-vanishing methodis established in the fieldofflu-
orous chemistry15 and is employed in a fluorous triphasic system to
control exothermic reactions by diffusion-based transport of bottom
reagents via the middle fluorous phase to the top substrates.16 This
method was applied to the synthesis of the glycosyl bromides. In this
Letter, the synthesis of glycosyl bromides by a photo-irradiative
phase-vanishing method is described.
phases. Ultraviolet(UV)irradiation at 352 nmusinga15 Wblacklight
at room temperaturefor 7 h gave glycosyl bromide2a in22% yield, to-
gether with byproducts 3a (7%) and 4a (15%) (eq. 1). To determine the
resistance of glycosyl bromide to photodecomposition, the glycosyl
bromide 2a was exposed to UV irradiation at room temperature for
20 h (eq. 2). No degradation of 2a was occurred.
hν
OAc
O
Br2 (1.5 equiv)
AcO
AcO
OAc
Galden HT-135* (4 mL)
isooctane (1.5 mL)
CH2Cl2 (1mL)
OAc
1a
(0.5 mmol)
r.t., 7 h
OAc
O
OAc
OAc
O
AcO
AcO
O
AcO
AcO
AcO
+
+
(eq.1)
AcO
OAc
Br
OAc OH
OAc
Br
2a
22%
3a
7%
4a
15%
*Galden HT-135: CF3[OCF(CF3)CF2)m(OCF2)n]OCF3
OAc
OAc
O
O
AcO
AcO
AcO
AcO
hν
(eq. 2)
CH2Cl2, r.t., 20 h
OAc
Br
OAc
Br
2a
2a
recovery ca. 100%
(determined by 1H NMR analysis)
Next, the synthesis of glycosy bromide using the phase-vanishing
method in various solvents was investigated (Table 1). The combina-
tionofAcOEtandperfluorohexanes(C6F14)assolventswaseffectivein
producing a high yield of 2a (run 10). Generally, perfluorohexane is
miscible with organic solvents, compared with Galden HT-135.17
Therefore, it would be expected that both bromine and AcOEt easily
diffused through the perfluorohexane phase to generate HBr
effectively. Consequently, this system was afforded the desired
First,thesynthesisofglycosylbromidewasconductedusingamix-
ture of CH2Cl2 and isooctane to dissolve the 1-O-acetyl sugar in the
organic phase, and the fluorous polyether, Galden HT-135 as fluorous
⇑
Corresponding author. Tel.: +81 3 5944 3215; fax: +81 3 3944 4071.
E-mail address: mmizuno@noguchi.or.jp (M. Mizuno).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.088

M. Tojino et al. / Tetrahedron Letters 54 (2013) 7124–7126
7125
ν
h
OAc
OAc
O
Br
AcO
AcO
O
hν
AcO
AcO
(eq.3)
OAc
94%
OAc
OAc
HBr
Br
Isooctane
(C8H18
57%
hν
)
+
Br2 C8H18
C8H17Br
FC-72
Br2
Hexyl
hν
hexanoate
Hexyl
hexanoate
FC-72
Scheme 1. Photo-irradiactive phase-vanishing generation of HBr and addition to 1-
Br2
FC-72
dodecence.5
O
O
O
hν
hν
Br2
+
OH
glycosyl bromide in good yield. Higher concentrations were the most
effective (runs 9, 10, and 12). Note that both the black light and
fluorousphaseareessentialforthesynthesisofglycosylbromidefrom
the 1-O-acetyl sugar and molecular bromide (run 13 and 14).
OAc
OAc
O
O
AcO
AcO
AcO
(eq.4)
OAc
AcO
Having the optimized reaction conditions, a series of carbohy-
drate derivatives were examined in the goal of obtaining the corre-
sponding glycosyl bromides (Table 2). Galactose derivative 1b gave
the corresponding glycosyl bromide 2b in excellent yield (run 1).
Mannose derivative 1c afforded the product 2c in moderate yield
along with 1-OH derivative 4c, which was hydrolyzed during isola-
tion on silica gel (run 2). 2-Azide-glucose derivative 1d gave the
corresponding glycosyl bromide 2d (84%). N-Troc glucosamine
derivative 1e gave the corresponding glycosyl bromide in moder-
ate yield. This reaction was complex, compared with other 1-O-
acetyl sugars from 1H NMR analysis of crude reaction mixture.
The minor products corresponding to 1e were not identified.
Glucuronate derivative 1f afforded the corresponding glycosyl
bromide 2f (run 5). These results can be explained by an ionic
mechanism with HBr generated in situ. A previous study reported
that the treatment of glucuronate derivative 1f under the favorable
radical conditions gave 5-bromo glucuronate derivative.18
OAc
OAc
Br
57%
n-Decyl
acetate
hν
n-Decyl
acetate
FC-72
Br2
FC-72
Br
O
hν
+
O
Br2
+
O
H
trace
Table 1
Optimization of solvents for synthesis of glycosyl bromide by phase-vanishing method
OAc
OAc
OAc
OAc
ν
h
O
O
AcO
AcO
AcO
O
O
Br2 (1.5 equiv)
AcO
+
AcO
AcO
+
AcO
solvent
OAc
AcO
OAc
Br
r.t.
OAc
(0.5 mmol)
OAc
OH
OAc
Br
1a
2a
3a
4a
Solvent
Yieldsa [%]
Run
Fluorous
Organic
Time
2a
1a
3a
4a
1
2
3
4
5
6
7
8
9
Galden HT-135
Galden HT-135
C6F14
Galden HT-135
Galden HT-135
Galden HT-135
Galden HT-135
Galden HT-135
C6F14
C6F14
C6F14
C6F14
C6F14
DMF
24
24
24
24
24
24
24
24
24
23
23
19
19
19
0
62
69
0
0
12
0
59
93
0
0
32
23
4
CH2Cl2
CH2Cl2
THF
CH3CN
22
Trace
27
7
1,4-Dioxane
Acetone
AcOEt
AcOEt
AcOEt
AcOEt/CH2Cl2 = 9/2
AcOEt
AcOEt
0
0
0
0
0
68 (
56 (
85 (82)b
93 (91)b
88 (85)b
90 (86)b
8b
10c
11c
12d
13e
14g
a
a
/b = 59/9)f
/b = 7/1)f
—
AcOEt
5
a
b
c
d
e
f
NMR yield.
Isolated yield by chromatography on SiO2.
1 mmol of 1 was used.
0.8 mmol of 1 was used.
The reaction was carried out in the dark.
Determined by 1H NMR.
g
Bromine was directly added to a solution of 1 in AcOEt.

7126
M. Tojino et al. / Tetrahedron Letters 54 (2013) 7124–7126
forming hydrolyzed ethyl acetate, to give HBr.21 The HBr generated
in situ reacted with the 1-O-acetyl sugar to give the corresponding
glycosyl bromide.
Table 2
Synthesis of glycosyl bromides by phase-vanishing method
hν
O
O
Br2 (1.5 equiv)
In summary, a synthesis of glycosyl bromides by photo-irradia-
tive phase-vanishing method was developed. Fluorous phase is
essential to be reacted with molecular bromine and AcOEt predom-
inantly. In this reaction, HBr generated from molecular bromine
and ethyl acetate under UV irradiation at 352 nm reacted with a
monosaccharide to give glycosyl bromide in high yield. This
method is simple and environmentally friendly, limiting the
amount of HBr generated.
C6F14 (4 mL)/AcOEt (2 mL)
30 °C, 19 h
OP
OP
OAc
Br
1
2
Run
1
Substrate
Product yielda(NMR yield)b
OAc
AcO
OAc
OAc
O
O
OAc
OAc
AcO
AcO
OAc
1b
OAc
Br
2b 91%(quant)
AcO
AcO
AcO
AcO
AcO
AcO
OAc
O
OAc
O
AcO
AcO
AcO
OAc
O
Acknowledgement
2
3
4
5
We thank Professor Ilhyong Ryu and Professor Hiroshi Matsu-
bara of Osaka Prefecture University for useful discussions.
OH
Br
4c
28%
2c
67%(86%)
1c
OAc
OAc
O
O
AcO
AcO
AcO
AcO
Supplementary data
N3
N3
OAc
1d (α/β =69/31)c
Br
2d 84%(85%)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.088.
OAc
OAc
O
O
AcO
AcO
AcO
OAc
NHTroc
AcO
TrocHN
Br
2e 60%(63%)
1e
Reference and notes
MeOOC
AcO
AcO
MeOOC
1. (a) Wong, C.-H. Carbohydrate-based Drug Discovery In ; Wiley-VCH: Weinheim,
2003; Vol. 1–2,; (b) Weymouth-Wilson, A C. Nat. Prod. Rep. 1997, 14, 99–100.
2. (a) Ernst; Hart, G. W.; Sinay, P. Carbohydrates in Chemistry and Biology In ;
O
O
AcO
AcO
OAc
OAc
OAc
2f 89%(90%)
Br
Wiley-VCH: Weinheim, 2000; Vols.
1 and 2, For recent reviews of
1f
oligosaccharide, synthesis, see:; (b) Davis, B. G. J. Chem. Soc., Perkin Trans. 1
2000, 2137; (c) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40,
1576; (d) Sears, P.; Wong, C.-H. Science 2001, 291, 2344; (e)Handbook of
Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance;
Demchenko, A. V., Ed.; Wiley-VCH: Weinheim, Germany, 2008.
3. Koenigs, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957.
4. (a) Renaud, P.; Bjorup, P.; Carrupt, P. A.; Schenk, K.; Schuber, S. Synlett 1992,
211–213; (b) Manabe, S.; Aihara, Y.; Ito, Y. Chem. Commun. 2011, 47, 9720.
5. (a) Fischer, E. Ber. Dtsch. Chem. Ges. 1910, 43, 1898; (b) Redemann, C. E.;
Niemann, C. Org. Synth. 1955, 3, 11.
a
b
c
Isolated yield by chromatography on SiO2.
Determined by 1H NMR of crude reaction mixture.
Determined by 1H NMR.
Path (1)
Br
HBr
6. Montero, J. L.; Winum, J. Y.; Leydet, A.; Kamal, M.; Pavia, A. A.; Roque, J. P.
Carbohydr. Res. 1997, 297, 175.
7. Ditmar, R. Monatsh. Chem. 1902, 23, 865.
O
H
O
H
O
β-fission
+
O
O
O
8. Fischer, E.; Fischer, H. Ber. Dtsch. Chem. Ges. 1910, 43, 2521.
9. Koto, S.; Morishima, N.; Irisawa, T.; Hashimoto, Y.; Yamazaki, M.; Zen, S. Nippon
Kakgaku Kaishi 1982, 1651.
10. Koto, S.; Morishima, N.; Shichi, S.; Haigoh, H.; Hirooka, M.; Okamoto, M.;
Higuchi, T.; Shimizu, K.; Yamazaki, M.; Mori, Y.; Kudo, K.; Ikegaki, T.; Suzuki, S.;
Aen, S. Bull. Chem. Soc. Jpn. 1992, 65, 3257.
Br2
O
O
H2O
Br
OH
Path (2)
11. Kartha, C. P. R.; Jennings, H. J. J. Carbohydr. Chem. 1990, 9, 777.
12. Larsen, K.; Olsen, C. E.; Motwia, M. S. Carbohydr. Res. 1997, 297, 175.
13. Hunsen, M.; Long, A. D.; D’Ardenne, C. R.; Smith, A. L. Carbohydr. Res. 2005, 340,
2670.
14. Matsubara, H.; Tsukida, M.; Ishihara, D.; Kuniyoshi, K.; Ryu, I. Synlett 2010,
2014.
Br2
OH
HBr
O
O
hydrolysis
OBr
UV
H2O
HBr
15. (a) Horváth, I. T.; Rabái, J. Science 1994, 266, 72; (b) Horváth, I. T. Acc. Chem. Res.
1998, 31, 641; (c) Gladysz, J. A.; Curran, D. P.; Horváth, I. T. (Ed.) Handbook of
Fluorous Chemistry, Wiley-VCH, Weinheim, Germany, 2004.
16. (a) Ryu, I.; Matsubara, H.; Yasuda, S.; Nakamura, H.; Curran, D. P. J. Am. Chem.
Soc. 2002, 124, 12946; (b) Matsubara, H.; Yasuda, S.; Ryu, I. Synlett 2003, 247;
(c) Nakamura, H.; Usui, T.; Ryu, I.; Matusbara, H.; Yasuda, S.; Curran, D. P. Org.
Lett. 2003, 5, 1167; (d) Curran, D. P.; Werner, S. Org. Lett. 2004, 1021, 6. Recent
reviews;; (e) Ryu, I.; Matsubara, H.; Nakamura, H.; Curran, D. P. Chem. Rec.
2008, 8, 351; (f) Iskra, J.; Stavber, S.; Zupan, M. Chem. Commun. 2003, 2496; (g)
Jana, N. K.; Verkade, J. G. Org. Lett. 2003, 5, 3787.
Br
Scheme 2. Two possible processes of HBr generation.
The generation of HBr also was investigated. The use of hexyl hex-
anoate as a solvent resulted in the partial formation of hexanoic
acid (eq. 3). Unfortunately, we could not detect another part of hex-
yl hexanoate. To pursue another part of ester, n-decyl acetate was
used as a solvent, which was partially converted into n-decyl bro-
mide and a trace amount of n-decyl aldehyde (eq. 4).19 These results
suggest that HBr was generated through two paths (Scheme 2): (1)
a bromide radical generated from molecular bromine under irradi-
ative homolysis abstracted a hydrogen from ethyl acetate to give
HBr20 or (2) a bromine radical abstracted a hydrogen from ethanol,
17. Matsuda, H.; Hirota, Y.; Kurihara, K.; Tochigi, K.; Ochi, K. Fluid Phase Equilibria
2013, 357, 71.
18. (a) Czifrák, K.; Somsák, L. Tetrahedron Lett. 2002, 43, 8849; (b) Ferrier, R. J.;
Furneaux, R. H. J. Chem. Soc., Perkin Trans. 1 1980, 1535.
19. Moon, D. W. Arch. Pharm. Res. 1983, 6, 1.
20. Solly, R. K.; Benson, S. W. J. Phys. Chem. 1970, 74, 4071.
21. (a) Jackson, E. L. J. Am. Chem. Soc. 1926, 48, 2166; (b) Walling, C.; Padwa, A. J.
Org. Chem. 1962, 27, 2976.