ZrCl4-catalyzed efficient ferrier glycosylation: A facile synthesis of pseudoglycals

Article abstract of DOI:10.1055/s-2004-815974

The reaction of tri-O-acetyl-D-glucal with silyl nucleophiles, alcohols and thiols was effectively promoted by a catalytic amount of zirconium(IV) chloride to produce the corresponding pseudoglycals via Ferrier rearrangement.

Full text of DOI:10.1055/s-2004-815974

834
SHORT PAPER
ZrCl4-Catalyzed Efficient Ferrier Glycosylation: A Facile Synthesis of
Pseudoglycals
Z
rCl -Catalyze
d
E
.
fficient Ferri
S
er
G
lycosylati
mon itha, Ch. Sanjeeva Reddy*
4
Department of Chemistry, Kakatiya University, Warangal-506 009, India
E-mail: chsrkuc@yahoo.co.in
Received 28 November 2003; revised 21 January 2004
(Scheme 1). The reaction proceeds smoothly at room tem-
perature and the products are obtained in good yields and
in short reaction times.
Abstract: The reaction of tri-O-acetyl-D-glucal with silyl nucleo-
philes, alcohols and thiols was effectively promoted by a catalytic
amount of zirconium(IV) chloride to produce the corresponding
pseudoglycals via Ferrier rearrangement.
O
O
Nu
ZrCl4 (10 mol%)
CH3CN, r. t.
Key words: zirconium(IV) chloride, Ferrier glycosylation,
pseudoglycals
AcO
AcO
AcO
AcO
+
Nu-X
OAc
Nu = H, R, OR, SR; X = H, SiMe3
R = alkyl, aryl
The acid-catalyzed allylic rearrangement of glycals in the
presence of nucleophiles is known as Ferrier rearrange-
ment,1 which is widely employed to obtain 2,3-unsaturat-
ed glycosides (pseudoglycals). Pseudoglycals are
valuable intermediates in the synthesis of glycopeptides,
uronic acids, nucleosides and oligosaccharides2 and also
constitute the structural units of several antibiotics.3 These
are very important class of compounds due to the presence
of double bond between C(2) and C(3), which may be eas-
ily modified, for instance, by hydroxylation, hydrogena-
tion, epoxidation and aminohydroxylation. A variety of
acid catalysts are employed to promote the Ferrier glyco-
sylation which include strong acids such as BF3·Et2O,4
SnCl4,5 DDQ,6 TMSOTf,7 NIS,8 LiBF4,9 trichloroacetim-
idate,10 montmorillonite K-10,11 FeCl3,12 InCl3,13 InBr3,14
Sc(OTf)3,15 Yb(OTf)3,16 Dy(OTf)3,17 I2,18 CAN,19 BiCl3,20
ZnCl221 and others.22 All of these while offering some ad-
vantages, also suffer from disadvantages in terms of yield,
reaction time, temperature, selectivity, cost of the reagent
and use of a large amount of reagent or catalyst. Further-
more, some of these catalysts are used for either C-glyco-
sylation with silyl nucleophiles or O- and S-glycosylation
with alcohols and thiols respectively and a few of them are
utilized for C-, O- and S-glycosylation in their individual
reports. However, the wider acceptability of these re-
agents has not been demonstrated so far. Hence, the devel-
opment of new reagents that leads to a potentially general
and convenient procedures for this transformation is still
of interest.
Scheme 1
The results are summarized in Table 1, which reveal the
scope and generality of this reagent system with respect to
various nucleophiles. Initially, we examined the reaction
of glucal with silyl nucleophiles to get the C-glycosylation
products. In the first case, the treatment of 3,4,6-tri-O-
acetyl-D-glucal with allyl trimethylsilane in the presence
of 10 mol% ZrCl4 at room temperature led to the forma-
tion of 2,3-unsaturated allyl glycoside in 94% yield with
high a-selectivity (entry 1). Similarly, the reaction of the
same glycal with trimethylsilyl azide and trimethylsilyl
cyanide gave the corresponding glycosyl azide and cya-
nide in 86% and 85% yields, respectively (entry 2 and 3).
The present protocol also behaved well with Et3SiH to
give the corresponding pseudoglycal in 93% yield within
5 minutes (entry 4). Interestingly, phenyl (trimethylsi-
lyl)acetylene reacted smoothly to afford the correspond-
ing alkynyl C-glycoside as a-anomer in 88% yield (entry
5). This success encouraged us to extend the generality of
the reaction to other nucleophiles. The glycosylation of
tri-O-acetyl-D-glucal with primary, secondary, allyl, ben-
zyl and propargyl alcohols under the present reaction con-
ditions furnished the corresponding 2,3-unsaturated
glycopyranosides in high yields with a-anomer as the ma-
jor product (entries 6–10). The versatility of this protocol
was furthermore illustrated by making thioglycosides
In continuation of our interest in exploring the utility of with thiophenol and ethane thiol (entries 11 and 12). The
zirconium(IV) chloride (ZrCl4) as a Lewis acid catalyst,23 a-anomer was obtained as a major product in each reac-
herein we wish to report a mild and efficient general meth- tion, the structure of which was characterized by spectro-
od for the glycosylation of tri-O-acetyl-D-glucal with silyl scopic data.
nucleophiles, alcohols and thiols in CH3CN using a cata-
lytic amount of ZrCl4 (10 mol%) for the first time
cosylation has been developed to produce structurally di-
In conclusion, an efficient and stereoselective Ferrier gly-
verse C-, O- and S-glycopyranosides in the presence of a
catalytic amount of ZrCl4. The advantages of this protocol
such as mild reaction conditions, shorter reaction times,
simple experimental workup procedure and high yields of
SYNTHESIS 2004, No. 6, pp 0834–0836
Advanced online publication: 12.02.2004
DOI: 10.1055/s-2004-815974; Art ID: Z16703SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

SHORT PAPER
ZrCl4-Catalyzed Efficient Ferrier Glycosylation
835
sponding pseudoglycal, which was purified by column
chromatography.
the desired products are worthy of mention and make this
method an attractive and useful addition to the present
known methods.
Spectral data (Entry 6)
[a]D +77.6 (c = 1, CHCl3).
IR (neat): 2949, 1740, 1368, 1229, 1037, 698 cm–1.
Reaction of Tri-O-acetyl-D-glucal with C, O and S-Nucleophiles;
General Procedure
1H NMR (400 MHz, CDCl3): d = 7.3–7.26 (m, 2 H), 7.2–7.18 (m, 3
H), 5.87 (dd, J = 20.8, 10.3 Hz, 2 H,), 5.3 (d, J = 8.4 Hz, 1 H), 5.02
(br s, 1 H), 4.26–4.22 (m, 1 H), 4.16–4.09 (m, 2 H), 3.83–3.77 (m,
1 H), 3.55–3.49 (m, 1 H), 2.71 (t, J = 7.2 Hz, 2 H), 2.09 (s, 3 H),
2.04 (s, 3 H), 1.98–1.93 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.7, 170.2, 141.7, 129.0, 128.4
(4 C), 127.9, 125.9, 94.5, 68.2, 66.9, 65.3, 63.2, 32.4, 31.3, 21.0,
20.7.
To a stirred solution of the 3,4,6-tri-O-acetyl-D-glucal (0.272 g, 1
mmol) in CH3CN (10 mL), were added nucleophile (1.1 mmol) fol-
lowed by ZrCl4 (10 mol%) and the reaction mixture was stirred at
r.t. for the given time (see Table 1). After completion of the reac-
tion, the solvent was evaporated in vacuo, extracted with EtOAc,
washed with 10% aq NaHCO3 and brine solution. The combined or-
ganic layers were dried (Na2SO4) and evaporated to give the corre-
HRMS (ESI): m/z calcd for C19H24O6: 348.1573; found: 348.1640.
Table 1 ZrCl4-Catalyzed Glycosylation of Tri-O-acetyl-D-glucal
Entry
1
Nu-X
Time (min)
3
Pseudoglycal
Yield (%)a
9414a
Ratio (a/b)b
20:1
2
3
4
5
Me3SiN3
Me3SiCN
Et3SiH
8
8614a
8514a
9313c
8814b
6:1
4:1
–
10
5
8
a
6
7
5
8
5
6
6
92
12:1
9:1
8921
9013d
9413d
9120
8
12:1
10:1
8:1
9
10
11
12
PhSH
EtSH
4
5
8620
7:1
6:1
8715c
a Isolated yield are as pure anomeric mixtures after purification. The literature references are given for known products.
b The a:b ratio was determined by integration of the anomeric protons in 1H NMR spectra.
Synthesis 2004, No. 6, 834–836 © Thieme Stuttgart · New York

836
G. Smitha, Ch. S. Reddy
SHORT PAPER
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Synthesis 2004, No. 6, 834–836 © Thieme Stuttgart · New York