Synthesis of 2,3-unsaturated O- and N-glycosides by HBF4· SiO2-catalyzed ferrier rearrangement of D-glycals

Article abstract of DOI:10.1055/s-0028-1088105

Fluoroboronic acid adsorbed on silica gel (HBF₄·SiO ₂) catalyzes the Ferrier rearrangement of per-O-acetylated glycals with alcohols and sulfonamides to give 2,3-unsaturated O- and N-glycosides in good to excellent yield and with high α-stereoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088105

1154
LETTER
Synthesis of 2,3-Unsaturated O- and N-Glycosides by HBF4·SiO2-Catalyzed
Ferrier Rearrangement of D-Glycals
S
ynthesis of 2,3-U
s
nsaturated
c
O
-
and
N
-
a
G
lycosidesr Mariano Rodríguez, Pedro Alfonso Colinas,* Rodolfo Daniel Bravo
LADECOR, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115 (1900) La Plata,
Argentina
Fax +54(221)4226947; E-mail: pcolinas@quimica.unlp.edu.ar
Received 1 January 2009
excellent yields with good a-stereoselectiviy.26 However,
Abstract: Fluoroboronic acid adsorbed on silica gel (HBF4·SiO2)
perchloric acid is known to be potentially explosive,
therefore, safety concerns limit the use of this reagent for
catalyzes the Ferrier rearrangement of per-O-acetylated glycals
with alcohols and sulfonamides to give 2,3-unsaturated O- and N-
large-scale preparations. Recent reports on the utilization
of fluoroboric acid inmobilized on silica in various organ-
ic reactions such as thia-Michael addition to a,b-unsatur-
ated carbonyl compounds,27 preparation of acetals and
ketals,28 synthesis of thiranes from oxiranes;29 acylation
of phenols, alcohol, and amines;30 prompted us to investi-
gate its use as an alternative catalyst to prepare 2,3-unsat-
urated glycosides. This Letter describes the synthesis of
2,3-unsaturated O- and N-glycosides by the Ferrier reac-
tion using a catalytic amount of HBF4·SiO2 (Scheme 1).
glycosides in good to excellent yield and with high a-stereoselectiv-
ity.
Key words: glycosylations, green chemistry, Ferrier rearrange-
ment, N-glycosylsulfonamides, O-glycosides
Glycals are amongst the most versatile chiral building
blocks that provide oxygen-rich stereochemically pure
scaffolds. One of the most important reactions to produce
diversity in glycal chemistry is the Ferrier rearrangement,
which is an allylic rearrangement of glycal esters in the
presence of nucleophiles leading to 2,3-unsaturated gly-
cosides.1 Some of the syntheses using 2,3-unsaturated
glycosides as important intermediates comprise various
glycopeptides,2 modified carbohydrate derivatives,3 and
oligosaccharides.4 In addition, very recently we have
shown that 2,3-unsaturated N-glycosylsulfonamides have
significant activities as human carbonic anhydrase inhibi-
tors.5
O
X
HX
O
AcO
AcO
AcO
AcO
HBF4⋅SiO2
MeCN
OAc
X = OR, HNSO2R
Scheme 1
The reaction of 3,4,6-tri-O-acetyl-D-glucal and allyl alco-
hol in acetonitrile was chosen as a model.31 To study the
effect of the catalyst, the reactions were carried out in the
presence of variable amounts of HBF4·SiO2.
The allylic rearrangement was discovered by Ferrier using
BF3·OEt2 as the Lewis catalyst.6,7 Other catalysts that ef-
fect this transformation include SnCl4,8 FeCl3,9
Sc(OTf)3,10 InCl3,11 Montmorillonite K-10,12 BiCl3,13
Dy(OTf)3,14 CeCl3·7H2O,15 ZnCl2,16 DDQ,17 NIS,18
Table 1 Reaction of 3,4,6-Tri-O-acetyl-D-glucal with Allyl Alco-
K5CoW12O40,19
I2,20
CAN,21
Bi(NO3)3·5H2O,22
hola
Fe(NO3)3·9H2O,23 NbCl5,24 and Fe2(SO4)3·xH2O.25 These
catalysts included Lewis acids and redox reagents. The
acid catalysts, usually employed in substoichiometric
amount, generally provide good anomeric selectivity un-
der mild conditions. However, some of them are moisture
sensitive and expensive. The oxidants are often required
in stoichiometric amount and generally demand either
longer reaction time or higher temperature. In addition,
they are known to offer low anomeric selectivity of the
product. Also, most of those methods entail the problems
of tedious workup procedures and expensive reagents and
equipment. It is worth noting that recently the use of per-
chloric acid inmobilized on silica has been reported to
provide access to 2,3-unsaturated-O-glucosides in good to
Entry Amount of
Temp Reaction time a/b
Yield (%)
catalyst (mg) (°C)
(min)
1
2
3
4
5
6
272
136
68
40
40
40
40
20
40
30
95:5
95:5
95:5
90:10
93:7
–
80
30
91
30
94
32
60
75
68
105
105
90
68b
no reaction
a All the reactions were performed using 0.5 mmol of the glycal and
2 equiv of the nucleophile in MeCN.
b Reaction performed with SiO2 (230–400 mesh) as catalyst.
SYNLETT 2009, No. 7, pp 1154–1156
Advanced online publication: 20.03.2009
DOI: 10.1055/s-0028-1088105; Art ID: S00309ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9
As can be seen in Table 1, use of 68 mg of HBF4·SiO2 per
mol of D-glucal, was enough for a fairly high yield. A

LETTER
Synthesis of 2,3-Unsaturated O-and N-Glycosides
1155
fourfold increase in the catalyst concentration afforded a inhibitors5 and antiproliferative agents.33 We chose three
lower yield (entry 1). Meanwhile, we also tested the effect sulfonamides (entries 6, 7, and 8) as the glycosyl accep-
of temperature on the catalyzed reaction. When the reac- tors. As shown in Table 2, these reactions also gave high
tion was carried out at room temperature, the reaction was yields and a-selectivity. The sulfonamidoglycosylation
sluggish (entry 5). When it was carried out at 40 °C, the performed with sulfamide in the presence of HBF4·SiO2
highest yield was obtained in a short reaction time. In all was useful in the synthesis of a selective inhibitor of car-
cases the a-isomer was produced predominantly, and a/b bonic anhydrase IX (entry 8).5
ratios are not affected by the amount of catalyst or by the
temperature. The result incorporated in entry 6 shows that
the catalytic activity of HBF4·SiO2 is not contributed by
It is relevant to mention that not many methods are avail-
able for the Ferrier reaction of 3,4,6-tri-O-acetyl-D-galac-
tal, and the few synthetically viable methods are restricted
SiO2. To enhance the synthetic utility of our conditions,
by the use of Montmorillonite K-10 with the aid of micro-
we next tested the reaction of per-O-acetylated D-glucal
wave irradiation,12 NbCl5,24 Er(OTf)3,34 or HClO4.SiO2.26b
and D-galactal with a selected group of alcohols and sul-
Thus, we considered it pertinent to test our protocol on
this substrate. The glycosylations of D-galactal in the pres-
fonamides using HBF4·SiO2 as catalyst (Table 2).
In most cases we examined, 2,3-unsaturated glucosides ence of HBF4·SiO2 afforded the Ferrier products with
were obtained in good to excellent yield and with very good to high stereoselectivity and good yields. To our sur-
good a-stereoselectivity.32 The reaction only failed with prise, treatment of D-galactal with ethanesulfonamide
tert-butyl alcohol. Fluoroboronic acid adsorbed on silica gave the sulfonamidoglycoside in excellent yield (entry
gel was also found useful in the disaccharide synthesis us- 12). No formation of 2-deoxy-D-lyxo-hexopyranosides35
ing an acid sensitive acceptor (entry 5).
could be detected in the reaction mixtures.
Although, pure products could be obtained, in most cases,
by removal of the catalyst by simple filtration and evapo-
ration of solvent (with low-boiling-point nucleophiles),
analytical samples were prepared by passing the crude
reaction product through a short column of SiO2.
Table 2 Reaction of 3,4,6-Tri-O-acetyl-D-glucal (1) and 3,4,6-Tri-
O-acetyl-D-galactal (2) with Different Nucleophilesa
Entry D-Glycal Nucleophile
a/bb
85:15
95:5
83:17
–
Yield (%)
81
1c
2
glucal
MeOH
i-PrOH
BnOH
In view of green chemistry, recyclable catalysts are highly
preferred. In our process, HBF4·SiO2 was easily recovered
from the reaction by filtration and subsequently used di-
rectly for the next reaction cycle (Table 3). Using our con-
ditions for the glucosylation of allyl alcohol with the
recycled catalyst, this protocol was repeated three times,
the yields were always more than 90% and no change in
the anomeric selectivity was found.
85
3
91
4
t-BuOH
traces
OH
O
O
O
5
90:10
83
O
Table 3 The Reusability of HBF4·SiO2 as Catalyst for Ferrier Reac-
O
tion
6
ethanesulfonamide
p-toluenesulfonamide
sulfamide
85:15
85:15
95:5
98
88
97
75
70
74
97
Round
Nucleophile
allyl alcohol
allyl alcohol
allyl alcohol
Reaction time (min)
Yield (%)
7
1
2
3
30
30
30
91
94
92
8c
9
galactal allyl alcohol
i-PrOH
95:5
10
80:20
95:5
In conclusion, we have developed a mild an eco-friendly
approach for the synthesis of 2,3-dideoxy glycopyrano-
sides using a catalytic quantity of HBF4·SiO2. The very
good a-selectivity, inexpensive and reusable catalyst, and
its enviromentally benign character make this method an
attractive way to prepare 2,3-unsaturated-O- and N-glyco-
sides from D-glycals.
11
12
BnOH
ethanesulfonamide
90:10
a Reactions were performed using 0.5 mmol of the glycal, 2 equiv of
nucleophile and 68 mg of HBF4·SiO2 in MeCN.
b Anomeric ratios were determined by 1H NMR spectroscopy.
c Reaction performed with 4 equiv of nucleophile.
The scope of the glycosylation was further examined in
the context of N-glucosylsulfonamides synthesis. It has
been found that many sulfonamidoglycosides present in-
teresting biological activities as carbonic anhydrase
Acknowledgment
The authors are grateful to CONICET (PIP 5710), UNLP, CICPBA,
for financial help and Dr. Rubén S. Rimada for the NMR measure-
ments. P. A. C. is member of CIC of CONICET.
Synlett 2009, No. 7, 1154–1156 © Thieme Stuttgart · New York

1156
O. M. Rodríguez et al.
LETTER
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Synlett 2009, No. 7, 1154–1156 © Thieme Stuttgart · New York

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