Exclusive formation of α-anomers in NbCl5-promoted ferrier rearrangement for the synthesis of 2,3-unsaturated glycosides

Article abstract of DOI:10.3987/com-06-10812

NbCl₅-catalyzed reaction of primary and secondary alcohols with tri-O-lacetyl-d-glucal is described. Exclusive formation of α-anomers of eight 2,3-unsaturated glycosides (3a-h) in high yields has been observed. Among eight unsaturated glycosides (3a-h) prepared, two of them (3d,e) are new. A new mechanism of the formation of (3a-h) from tri- O-acetyl-d-glucal and an alcohol assisted by NbCl₅ as a catalyst has been suggested.{A figure is presented}. α-Unsaturated Glycoside NbCl₅ Tri-O-acetyl-D-glucal Ferrier Rearrangement.

Full text of DOI:10.3987/com-06-10812

HETEROCYCLES, Vol. 68, No. 12, 2006
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HETEROCYCLES, Vol. 68, No. 12, 2006, pp. 2607 - 2613. © The Japan Institute of Heterocyclic Chemistry
Received, 15th June, 2006, Accepted, 23rd October, 2006, Published online, 24th October, 2006. COM-06-10812
5
EXCLUSIVE FORMATION OF α-ANOMERS IN NbCl -PROMOTED FERRIER
REARRANGEMENT FOR THE SYNTHESIS OF 2,3-UNSATURATED
1
GLYCOSIDES
a
a
a
Ronaldo N. de Oliveira, Adriana C. N. de Melo, Rajendra M. Srivastava, *
b
and Denis Sinou
a
Departament of Fundamental Chemistry, Federal University of Pernambuco, University
City, 50740-540, Recife, PE, Brazil
b
Laboratory of Asymmetric Synthesis, UMR 5181, ESCPE Lyon, Claude Bernard
Lyon1University, 43 boulevard du 11 Novembre 1918, 69622, Villeurbanne Cedex, France
*
Tel. : +55-81-2126-8440. Fax : +55-2126-8442. E-mail: rms_indu@yahoo.com
Abstract – NbCl
tri-O-acetyl-D-glucal is described. Exclusive formation of α-anomers of eight
,3-unsaturated glycosides (3a-h) in high yields has been observed. Among
5
-catalyzed reaction of primary and secondary alcohols with
2
eight unsaturated glycosides (3a-h) prepared, two of them (3d,e) are new. A
new mechanism of the formation of (3a-h) from tri-O-acetyl-D-glucal and an
alcohol assisted by NbCl as a catalyst has been suggested.
5
INTRODUCTION
The initial discovery of BF
.
3
Et
2
O as a Lewis acid catalyst by Ferrier and Prasad for transforming a glycal to
2
a 2,3-unsaturated glycoside in the presence of an alcohol gave a big impetus to carbohydrate chemistry.
Since then many other acidic and oxidizing reagents have been employed for performing this reaction. A
3
recent publication by Hotha and Tripathi cites several references concerning this type of transformation.
The unsaturated glycosides are an important class of compounds which can be transformed to a variety of
4
other interesting and valuable carbohydrates.

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HETEROCYCLES, Vol. 68, No. 12, 2006
5
,6
Due to our interest in Ferrier’s rearrangement, we focused our attention on the use of niobium
pentachloride (NbCl ) as a catalyst for carrying out such a transformation. This catalyst has been receiving
5
7
,8
increasing attention in organic synthesis. Surprizingly, there is only one report in the literature on the use
3
of this catalyst for the synthesis of 2,3-unsaturated glycosides assisted by microwaves.
Generally, the Ferrier rearrangement is carried out in benzene or methylene chloride. Our aim was to see if
it was possible to obtain the desired glycoside quickly using NbCl
5
2 2
in CH Cl as solvent in a conventional
manner; NbCl
5
is effectively a powerful activating agent for various organic reactions and certainly a strong
8
Lewis acid. In this communication, we report the synthesis of 2,3-unsaturated glycosides (3a-h) from
5
tri-O-acetyl-D-glucal (1) and various alcohols (2a-h) (Scheme 1) in the presence of NbCl using methylene
chloride as well as THF as the solvent.
OAc
O
OAc
O
NbCl /solvent
5
OAc
ROH
OAc
2a-h
OAc
OR
1
3a-h
Scheme 1
RESULTS AND DISCUSSION
Initially, we expected that the reaction with tri-O-acetyl-D-glucal (1) and alcohols (2a-g) would go
smoothly employing a catalytic amount of NbCl (0.05 mole equiv.) in CH Cl . However, the reaction took
place only in the presence of a large quantity of the catalyst (0.40 mole equiv. of NbCl
noticed the precipitation of a solid arising probably from the complexation of NbCl
5
2
2
5
) in this solvent. We
and the unsaturated
5
carbohydrate. Therefore, more and more catalyst was needed to complete the reaction. Finally,
,4,6-tri-O-acetyl-D-glucal (1) reacted with various alcohols (2a-g) in the presence of 0.4 mole equiv. of
3
NbCl to afford only 2,3-unsaturated α-D-glycosides (3a-g) in quite good yields (70-81%) as shown in
5
Table 1 (Method A).
The anomeric configuration has been ascertained by obtaining the NOESY spectra of compounds (3d and 3e).
In both cases, H-1 showed a spatial interaction with H-4 proton, thus confirming the identity of these
compounds as α-anomers. Furthermore, no interaction between H-1 and H-5 has been observed.

HETEROCYCLES, Vol. 68, No. 12, 2006
2609
Table 1. Synthesis of 2,3-unsaturated O-glycosides (3a-h) from tri-O-acetyl-D-glucal (1)
Method A
Method B
c
(
0.4 equiv. NbCl
5
/CH
2
Cl
2
)
(0.1 equiv. NbCl
5
/THF)
Yield (%)
Time
Yield (%)a
Time
Yield (%)a
(Reference)
Alcohol
Product
(min.)
(min.)
OH
3
3
a
60
30
70
75
50
50
74
71
95 (11)
87 (6)
2
a
b
OH
2
2
b
c
OH
OH
3
c
30
30
81
74
50
50
87
73
64 (9)
-
b
3
d
2
d
OH
b
d
3
e
60
77
74
50
50
75
73
(10)
2
2
e
f
3
0
97 (2)
77 (6)
OH
3f
O
N
CH
2
OH
3g
60
-
78
-
50
50
80
2
2
g
O
d
7
2
(12)
h
3 2
CH CH OH
3
h
a
b
c
Yield of purified product; The spectral data are given in the experimental part; Yields reported are the ones
d
obtained by other procedures; Yield not reported.
We tried to improve the above-mentioned method by using other solvents. As described above, addition
of just 0.1 mol equivalent of NbCl
5
in CH
2
Cl
2
either failed to react or gave only a very poor yield of the
Cl
unsaturated glycosides at room temperature (Table 1). Addition of a few drops of acetonitrile to the CH
2
2
solution improved the yield to some extent, but not satisfactorily. The introduction of a couple drops of
DMF to the methylene chloride solution did not increase the yield as well. Finally, we found that
replacement of methylene chloride with dry tetrahydrofuran and using 0.1 equiv of NbCl
reaction in 50 min. at reflux temperature, the complex remained soluble in the THF solution. The yields in
this reaction are higher than those obtained when the condensation was performed in CH Cl , and ranged
5
gave a smooth
2
2
between 71-87% (Table 1, Method B), only the α-anomers have been formed. The use of THF as solvent
for affecting Ferrier rearrangement at reflux temperature has not yet been reported in the literature (Table 1,
Method B). Although, Ferrier´s rearrangement has recently been carried out in acetonitrile using

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HETEROCYCLES, Vol. 68, No. 12, 2006
3
microwave radiation, no report yet appeared about such reaction in solution employing conventional
heating. Therefore, our findings are the new ones.
The exclusive formation of α-anomer requires some comments. Niobium pentachloride could complex
with the carbonyl oxygen atom of the O-acetyl group at C-3 as shown in Scheme 2. Then one of the
chlorine atoms of niobium pentachloride could attack at C-1 via a 8-membered transition state to furnish
4
,6-di-O-acetyl-2,3-dideoxy-β-D-erythro-hex-2-enopyranosyl chloride (5) by a S 2′ mechanism. This
N
β-anomer could revert to α-anomer after some time, but as soon as 5 is formed, it reacts with the alcohol
instantaneously before anomerization of 5 to α-anomer. This leads to the privileged formation of the
α-unsaturated glycosides (3a-h).
In
order
to
get
more
perception
about
the
formation
of
4
,6-di-O-acetyl-2,3-dideoxy-β-D-hex-2-enopyranosyl chloride (5) as an intermediate, we conducted the
1
3
5
reaction between (1) and NbCl in refluxing THF without alcohol. After cooling the reaction contents and
1
evaporating the solvent, the H NMR spectrum of the crude mixture showed an absortion as a broad singlet
at δ 5.90 ppm indicating the presence of presumably (5). However, NOESY spectrum does not show any
spatial interaction between H-1 and H-5. Therefore, it is concluded that compound (5) forms first and
then
anomerizes
quickly
to
its
α-anomers.
A
closely
related
product,
viz.,
1
4
2
,4,6-tri-O-acetyl-3-deoxy-α-D-erythro-hex-2-enopyranosyl chloride has been reported in the literature.
This product showed H-1 proton at δ 6.28 ppm, which is close to the α-anomer of 5. This way, our
assumption for the proposed mechanism seems more appropriate.
3
Although the previous authors also reported the formation of α-anomers using NbCl
5
, but no insight was
given regarding the mechanism of formation. Therefore, we feel that this proposed mechanism is an
important literature addition in this rearrangement.
Me
OAc
OAc
OAc
O
AcO
O
Cl
O
O
O
NbCl4
S 2'
-HCl
NbCl5
N
O
OAc
OAc
Cl
R
-
NbCl OAc
4
O
OAc
OAc
OR
OAc
H
3
a-h
1
4
5
α
-anomers
Scheme 2. Mechanism of formation of α-anomers

HETEROCYCLES, Vol. 68, No. 12, 2006
2611
One of the referees suggested to try the Ferrier’s rearrangement using tri-O-benzyl-D-glucal and an alcohol
in the presence of NbCl to clarify the mechanism. Initially, we tried to do the reaction with alcohols
2a,c,f) and 1, and verified on the tlc plates (10% EtOAc in CHCl ), where the products of the reaction and
tri-O-benzyl-D-glucal appeared to have the same R values, although it was a mixture. Finally, we
performed to do the same reaction using 1 and ethanol (2h), which showed a better separation of the
5
(
3
f
f
starting tri-O-benzyl-D-glucal and the allylic rearrangement products. Separation of the spots with R value
1
of 0.40 (dichloromethane) followed by the H NMR spectrum showed it to contain a mixture of ethyl
4
,6-di-O-benzyl-2,3-dideoxy-α,β-D-erythro-hex-2-enopyranosides in the ratio of (1:1) in 60% yield. The
.
literature search revealed that such reaction was done earlier in the presence of BF
3
Et
2
O where α:β ratio
1
5
was (2:1). In summary, the mechanism of the Ferrier rearrangement with C-3 O-acetyl group is different
that the one with C-3 O-benzyl function.
In conclusion, we have shown that the reaction of tri-O-acetyl-D-glucal with various alcohols does occur in
methylene chloride as solvent, but using a large amount of niobium pentachloride as a catalyst. However,
5
when the same reaction was carried out in THF, only 0.1 mol equivalent of NbCl could be used, the
unsaturated glycosides being obtained solely as α-anomers in quite good yields. It is worth mentioning that
proposal of eight-membered transition state in Ferrier’s rearrangement has not been encountered in the
literature. Also, the use of THF at reflux temperature is being reported for the first time.
EXPERIMENTAL
General experimental procedures
All commercially available reagents were used as received. All reactions were monitored by TLC analysis
(TLC plates GF254 Merck). Air- and moisture-sensitive reactions were performed under inert atmosphere
techniques. Column chromatography was performed on silica gel 60 (230-240 mesh, Merck). Optical
rotations were recorded using a Perkin-Elmer 241 polarimeter. NMR spectra were recorded with a Bruker
1
13
AMX 300 spectrometer and referenced as following: H (300 MHz), internal SiMe
4
at δ = 0.00 ppm, C
(
75 MHz), internal standard at δ = 77.23 ppm. Exact mass spectra were recorded on a Finnigan Mat 95 XL
spectrometer.
Method A: In a typical experiment, NbCl (40 mg, 0.15 mmol) was added to a stirred solution of
5
tri-O-acetyl-D-glucal (1) (100 mg, 0.37 mmol) dissolved in anhydrous methylene chloride (10 mL) at 0ºC
under a nitrogen atmosphere. After a few minutes, the appropriate alcohol (2) (3.0 mmol) was added into
the flask and the contents stirred at rt. In general, it took 30 min to an hour for the completion of the reaction
(
see Table 1). Then, the crude material was washed with a saturated aqueous solution of NaHCO and
3
extracted with AcOEt. Work-up, followed by chromatography, provided unsaturated glycoside (3).

2612
HETEROCYCLES, Vol. 68, No. 12, 2006
Method B: NbCl
5
(27 mg, 0.1 mmol) was added to a stirred solution of tri-O-acetyl-D-glucal (1) (272 mg, 1
mmol) dissolved in anhydrous THF (2.0 mL) at 0ºC under a nitrogen atmosphere. After a few minutes, the
appropriate alcohol (2) (1.5 mmol) was added and the mixture was refluxed for 50 min. The contents were
cooled, and the work-up, as described above, afforded the unsaturated glycoside (3). All products were
1
13
fully characterized by IR, H- and C- NMR spectra.
D
2
-Naphtalenoethyl 4,6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside (3d):oil; [α]20 = + 73 (c
1
0
.55, CH
2
Cl
2
). H NMR (300 MHz, CDCl
3
3 3
): δ 2.04 (s, 3H, CH CO), 2.06 (s, 3H, CH CO), 3.1 (t, 2H, J =7.0
Hz, CH
2
), 3.83 (dt, 2H, J =9.6, 7.0 Hz, OCH
2
), 3.96 (ddd, 1H, J =9.5, 5.4, 2.4 Hz, H-5), 4.03 (dd, 1H, J =2.4,
12.3 Hz, H-6), 4.13 (dd, 1H, J =5.4, 12.3 Hz, H-6’), 5.03 (brs, 1H, H-1), 5.28 (dd, 1H, J =9.6, 1.5 Hz, H-4),
5
.81 (ddd, 1H, J =10.2, 2.4, 1.8 Hz, H-2), 5.87 (brd, 1H, J =10.2 Hz, H-3), 7.36-7.49 (m, 3H, ar.), 7.68 (brs,
1
3
1
H, ar.), 7.77-7.83 (m, 3H, ar.). C NMR (75.5 MHz, CDCl
3
): δ 20.7, 20.9, 36.4, 62.8, 65.1, 66.8, 69.4,
9
4.4, 125.4, 126.0, 127.2, 127.4, 127.6, 127.7, 127.9, 129.1, 132.1, 133.5, 136.2, 170.2, and 170.7. Anal.
.
+
Calcd for C22H
24
O
6
, 1/4 H
2
O: C, 67.94; H, 6.35. Found: C, 67.80; H, 6.55. [M+Na] = Calcd. 407.1471.
Found: 407.1473.
D
(
1S,2R,5S)-Menthyl 4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside (3e): oil; [α]20 = + 46
1
(
c 0.75, CH
2
Cl
2
); H NMR (300 MHz, CDCl
3
): δ 0.78 (d, 3H, J =7.0 Hz, CH
, 3CH), 2.08 (s, 3H, CH CO), 2.11 (s, 3H, CH
.5 Hz, CHO), 4.16-4.23 (m, 3H, H-6, H-6’, H-5), 5.10 (brs, 1H, H-1), 5.29 (brd, 1H, J =10.5 Hz, H-4), 5.87
): δ 16.6, 21.1, 21.4, 21.5, 22.8, 23.5, 26.0, 32.1, 34.7,
3
), 0.91 (2d, 6H, J =7.0 Hz,
2
CH
3
), 0.77-2.05 (m, 9H, 3CH
2
3
3
CO), 3.42 (dt, 1H, J =10.6,
4
(
brs, 2H, H-2, H-3). 13C NMR (75.5 MHz, CDCl
3
4
8
3.7, 49.2, 63.7, 65.7, 67.1, 81.5, 96.5, 128.4, 129.0, 170.7, 171.2. Anal. Calcd for C20
.75. Found: C, 65.22; H, 8.81.
32 6
H O : C, 65.19; H,
ACKNOWLEDGEMENTS
We are indebted to the Brazilian National Research Council (CNPq) and CAPES/COFECUB for financial
support. One of us (R. N. de Oliveira) is grateful to CNPq for a fellowship.
REFERENCES AND NOTES
th
1
. R. N. de Oliveira, A. C. N. de Melo, and R. M. Srivastava, Presented in the 44 Annual Brazilian
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2
. a) R. J. Ferrier and N. Prasad, J. Chem. Soc., (C), 1969, 570. b) R. J. Ferrier and N. Prasad, J. Chem. Soc.,
(
C), 1969, 581.
3
4
. S. Hotha and A. Tripathi, Tetrahedron Lett., 2005, 46, 4555, and references cited therein.
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5
(
10%), and the mixture was refluxed for 10 min. Solvent evaporation after cooling followed by the
1
recording of H NMR spectrum in CDCl
3
presented a signal at δ 5.90 ppm indicative of H-1 proton of
4
,6-di-O-acetyl-2,3-dideoxy-α-D-hex-2-enopyranosyl chloride.
1
4.R. U. Lemieux and R. J. Bose, Can. J. Chem., 1966, 44, 1855.
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1