Niobium(V) chloride catalyzed microwave assisted synthesis of 2,3-unsaturated O-glycosides by the Ferrier reaction

Article abstract of DOI:10.1016/j.tetlet.2005.05.015

NbCl₅ catalyzes the Ferrier reaction of per-O-acetylated glycals with primary, secondary, allylic, benzylic and monosaccharide alcohols to give 2,3-unsaturated α-glycosides in short reaction times under microwave irradiation conditions.

Full text of DOI:10.1016/j.tetlet.2005.05.015

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4555–4558
Niobium(V) chloride catalyzed microwave assisted synthesis of
2,3-unsaturated O-glycosides by the Ferrier reaction
Srinivas Hotha* and Ashish Tripathi
Combi Chem-Bio Resource Center, Division of Organic Chemistry: Synthesis, National Chemical Laboratory, Pune 411 008, India
Received 7 February 2005; revised 27 April 2005; accepted 5 May 2005
Abstract—NbCl5 catalyzes the Ferrier reaction of per-O-acetylated glycals with primary, secondary, allylic, benzylic and mono-
saccharide alcohols to give 2,3-unsaturated a-glycosides in short reaction times under microwave irradiation conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
In the current era of chemical genetics, the importance
of diversity oriented synthesis (DOS) of small molecule
libraries with defined stereochemistry and interesting
chemical skeletons has increased.1 The starting template
in the diversity oriented synthesis occupies a predomi-
nant role in dictating the resulting skeletal and stereo-
chemical diversities.2 A recent survey indicated that a
large number of biologically active natural products
are oxygen-rich compared with the corresponding cong-
eners thus far synthesized from combinatorial libraries.3
In view of the above facts, we became interested in ini-
tiating a diversity oriented synthesis using glycals as
the starting template to enable oxygen-rich stereochemi-
cally pure scaffolds.
morillonite K10,10b SnCl4,10c BiCl3,10d FeCl3,10e
10i
Sc(OTf)3,10f ZnCl2,10g LiBF4,10h Dy(OTf)3
and
ZrCl4.10j In addition to these Lewis acids, oxidizing
agents such as 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ),11a N-iodosuccinimide (NIS),11b iodine,11c iodo-
nium dicollidine perchlorate (IDCP),11d ceric ammo-
nium nitrate11e and HClO4 on silica gel11f effect the
Ferrier reaction to yield 2,3-unsaturated glycopyrano-
sides. However, all these methods have drawbacks in
generality, varied yields and stereoselectivity, long reac-
tion times and practicality due to harsh reaction condi-
tions. In view of the above, there exists a need to develop
a practical stereoselective method that yields 2,3-dide-
oxy glycosides.
One of the important reactions to produce diversity in
glycal chemistry is the Ferrier reaction that gives access
to 2,3-unsaturated glycosides.4 Some of the syntheses
using 2,3-unsaturated glycosides as important interme-
diates comprise various natural products,5 glycopep-
tides,6 modified carbohydrate derivatives,7 nucleosides
and oligosaccharides.8 The 2,3-double bond in the pyran
ring can be subjected to stereoselective dihydroxylation,
hydrogenation, epoxidation and amino hydroxylation
reactions in order to achieve structural complexity and
diversity.9 The SN20 attack of alcohols or allylic rear-
rangement of per-O-acetylated glycals was discovered
by Ferrier using BF3ÆEt2O as the Lewis acid catalyst
and is known as the Ferrier reaction.4 Other reagents
that effect this transformation include InCl3,10a Mont-
Thus in our efforts to utilize glycal chemistry to achieve
diverse scaffolds, we focused on developing a practical,
low-cost, eco-friendly, procedure for synthesizing 2,3-
dideoxy glycopyranosides. The use of microwave reac-
tion conditions with carbohydrate templates is not yet
a mature subject, albeit various successful efforts in con-
ventional organic synthesis exist. The use of microwaves
in the Ferrier reaction were explored using Montmorillo-
nite K10 and InCl3. The microwave induced Montmo-
rillonite K1010b mediated Ferrier rearrangement of
per-O-acetylated glucal resulted in the formation of 2,3-
unsaturated glucosides; the corresponding InCl310a reac-
tion gave a-anomeric selectivity, however, 30 mol% of
InCl3 was required. Recently niobium(V) chloride has
emerged as a Lewis acid for a variety of reactions.12 In
particular NbCl5 has many advantages compared with
other Lewis acids such as ease of handling, moisture sta-
bility, long shelf-life and economic viability, all factors
that are required in DOS.13 In this article, we describe
*
Corresponding author. Tel.: +91 20 25893400x2401; fax: +91 20
25893153; e-mail: shotha@ems.ncl.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.015

4556
S. Hotha, A. Tripathi / Tetrahedron Letters 46 (2005) 4555–4558
quired 1 h to yield benzyl 4,6-di-O-acetyl-2,3-dideoxy-
OAc
O
OAc
O
R1
D-erythro-hex-2-eno a-D-glucopyranoside, whereas the
corresponding reaction under microwave conditions
was complete in two minutes (entry 6, Table 1), thereby
making this reaction a microwave oven-induced reac-
tion enhancement (MORE) technique.15 The generality
of this new reagent was shown by exposing per-O-acet-
ylated glucal to various alcohols including allylic, benz-
ylic, aliphatic, phenolic and monosaccharide donors.
We also tested our protocol on 3,4,6-tri-O-acetyl galac-
tal using various aglycones. It is pertinent to mention
that not many methods are available for the Ferrier
reaction of 3,4,6-tri-O-acetyl galactal. Treatment of
3,4,6-tri-O-acetyl galactal in the presence of an alcohol
with NbCl5 (cat.) in acetonitrile and irradiation with
microwaves for less than 3 min resulted in the forma-
tion of the Ferrier product 4,6-di-O-acetyl-2,3-
dideoxy-D-threo-hex-2-eno-a-D-galactopyranoside along
with a minor quantity of 2-deoxy-a-D-lyxo-hexopyrano-
side.16 In order to understand the scope of this reaction
we exposed different aglycones to 3,4,6-tri-O-acetyl
galactal (entries 11–20, Table 1). In almost all the reac-
tions, the ratio of the Ferrier product versus the 2-deoxy
R1
R2
NbCl5 (cat.)
+
R-OH
OAc
R2
R1 = OAc, R2 = H
1 = H, R2 = OAc
acetonitrile
MW
OR
R
Scheme 1. Synthesis of 2,3-dideoxy glycopyranosides using NbCl5.
a microwave assisted method for the synthesis of 2,3-
unsaturated O-glycosides by the Ferrier reaction using
a catalytic amount of niobium(V) chloride (Scheme 1).
In a typical experiment,14 per-O-acetylated glucal in the
presence of an alcohol was treated with one mole per-
cent of NbCl5 in acetonitrile and irradiated with micro-
waves in an open vessel for the specified time (Table 1)
in order to afford the corresponding 2,3-unsaturated
glycosides in good yields with a-stereoselectivity. All
the reactions were complete in less than 3 min. It is
interesting to note that the reaction of 3,4,6-tri-O-acetyl
glucal with benzyl alcohol at room temperature re-
Table 1. NbCl5 catalyzed microwave assisted synthesis of 2,3-unsaturated Ferrier rearranged products
Entry
Substrate
Alcohol
Product
Time (min)
2.0
Yield (% )
95
AcO
O
O
O
1
HO
AcO
O
AcO
AcO
O
AcO
OAc
2
2.5
92
HO
HO
AcO
AcO
O
O
3
4
5
6
7
8
2.0
1.5
2.0
2.0
3.0
2.0
80
85
93
97
84
87
AcO
AcO
O
O
O
O
O
S
HO
AcO
AcO
O
O
O
HO
AcO
AcO
O
HO
HO
AcO
AcO
O
AcO
AcO
O
HS
AcO
OMe
OBn
OH
O
AcO
O
O
O
BnO
BnO
9
3.0
3.0
90
87
BnO
OBn
OBn
AcO
OMe
OBn
O
OBn
AcO
O
O
HO
O
10
BnO
BnO
BnO
OMe
BnO
OMe
AcO

S. Hotha, A. Tripathi / Tetrahedron Letters 46 (2005) 4555–4558
4557
Table 1 (continued)
Entry
Substrate
Alcohol
Product
Time (min)
1.5
Yield (% )
AcO
O
O
11
79
HO
AcO
O
AcO
AcO
AcO
O
OAc
O
O
12
13
14
15
16
17
18
19
2.5
3.0
2.0
2.0
1.0
2.0
2.5
3.0
73
72
69
74
80
76
73
74
HO
HO
AcO
AcO
O
AcO
AcO
O
O
O
O
O
S
HO
AcO
AcO
O
O
O
HO
AcO
AcO
O
HO
HO
AcO
AcO
O
AcO
AcO
O
HS
AcO
OMe
OBn
OH
O
AcO
O
O
O
BnO
BnO
OBn
OBn
BnO
AcO
OMe
OBn
OBn
O
AcO
O
O
HO
O
20
3.0
68
BnO
BnO
BnO
OMe
BnO
OMe
AcO
compound was found to be 4:1 after isolation of the
respective compounds by conventional silica gel column
A.T. thanks the CSIR, New Delhi for a Junior Research
Fellowship.
1
chromatography. H and 13CNMR spectra of all the
compounds were in conformity with those reported
values.17
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Acknowledgements
We thank the Director, NCL for a Start-up grant and
DST, New Delhi for the financial support. We thank
Dr. K. N. Ganesh for support and encouragement.

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