Solvent incorporation during N-iodosaccharin mediated glycosylation:
facile synthesis of acetal linked disaccharides†
M. Aloui and A. J. Fairbanks*
Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, UK OX1 3QY.
E-mail: antony.fairbanks@chem.ox.ac.uk; Fax: +44 1865 275 674
Received (in Cambridge, UK) 14th May 2001, Accepted 15th June 2001
First published as an Advance Article on the web 12th July 2001
Solvent incorporation between glycosyl donor and acceptor
occurs during glycosylation reactions initiated by N-iodo-
saccharin (NISac) performed in acetone and cyclohexanone
solvents to stereoselectively produce acetal linked a-glyco-
sides.
Considerable work has been performed to understand the role of
solvent during the glycosylation process1,2 However the
situation is complicated by the identity of anomeric leaving
group, the activator and the protecting groups on the donor.
Therefore although there are several general ‘guiding princi-
ples’ as to how the choice of solvent may affect the
stereochemical outcome of glycosylation for donors with non-
participating OH-2 protecting groups, there is still requirement
for further mechanistic insight into each particular glycosyla-
Scheme 1 Reagents and conditions: (i) NISac 1, MeOH (3 equiv.), acetone,
278 to 0 °C, 2.5 h, 76%.
tion reaction.
One of the best-established examples of solvent participation
during the glycosylation process is the preferential formation of
b-glycoside products observed when using acetonitrile as
solvent.3 This b stereoselectivity has been ascribed to trapping
of the glycosyl cation formed during the glycosylation reaction
by solvent to produce an intermediate a-nitrilium ion, which
then undergoes SN2 type glycosylation, resulting in preferential
formation of the b-product.4 The isolation of a-nitrilium
trapped species has provided substantial supporting evidence
for this hypothesis.5 Reported herein are investigations into
glycosylation reactions performed in ketone solvents, in which
solvent incorporation invariably occurs to produce good yields
of mixed acetal linked a-glycosides and a-disaccharides, in an
entirely stereoselective manner.
We recently reported the use of N-iodosaccharin (NISac) 1
for the activation of thiophenyl glycosides under mild condi-
tions.6 During the course of these studies it became clear that
reduced yields of disaccharide products were obtained by
saccharin trapping of the glycosyl cation, which is probably
produced during the glycosylation reaction. In an attempt to
promote O-glycosylation, and in particular increase yields of
disaccharide products, studies turned to the use of more polar
solvents. Use of acetonitrile as solvent7 resulted in an increase
in the yield of disaccharides, but saccharin trapping was still
observed. For this reason acetone was also investigated as the
solvent for glycosylation. Although acetone has frequently been
employed as an organic co-solvent for enzyme catalysed
glycosylation, it has not been particularly widely used for
chemical glycosylation reactions.8
analogous to glycosylation in acetonitrile. Nucleophilic attack
on 4 by methanol then yields the mixed acetal. To the best of our
knowledge solvent participation by acetone during a glycosyla-
tion reaction has only been observed on two previous occa-
sions.9,10 Investigations then turned to the use of carbohydrates
as glycosyl acceptors to investigate if solvent trapping would
occur to produce disaccharides linked as mixed acetals.
Reaction of thioglycoside 2 with diacetonide galactose 5, in
acetone with NISac activation, produced acetal-linked disac-
charide 6 in an excellent 84%, as the pure a-anomer (Scheme
2).ठCarbohydrates with secondary hydroxy groups also
produced good yields of acetal-linked products. Thus reaction
of donor 2 with the manno acceptor 7 produced the mixed acetal
linked disaccharide 8, as the pure a-anomer, in 78% yield.
Investigation then turned to the use of other solvents to
determine the potential generality of the process. Initial
attempted reaction of 2 with methanol and NISac as activator in
butanal as an aldehyde solvent produced a complex mixture of
products and no appreciable amount of acetal glycoside.
However with cyclohexanone as solvent again good yields of
pure a-glycoside products were isolated. Thus reaction of donor
2 with methanol in cyclohexanone initiated by NISac produced
a good yield of the a-mixed acetal 9 (Scheme 3). Carbohydrate
acceptors also reacted well; diacetonide galactose 5 produced
the acetal linked a-disaccharide 10 in 73% yield.
In summary we have demonstrated that NISac11 activation of
thioglycosides in ketone solvents12 leads exclusively to the
formation of a-mixed acetal products, in which a solvent
molecule is incorporated between the anomeric centre of the
glycosyl donor and the hydroxy group of the glycosyl acceptor.
Formation of these mixed acetal products probably occurs by
trapping of an incipient a-acetonium ion 4 by the glycosyl
acceptor, and provides substantial evidence for the intermediacy
of such species during glycosylation reactions performed in
acetone as solvent. Furthermore this synthetic route to pure a-
acetal glycosides, which have been proposed as potential anti-
cancer prodrugs, compares favourably with the other published
routes.13,14
Glycosylation of perbenzylated thioglycoside 2 was under-
taken with methanol as glycosyl acceptor in acetone with N-
iodosaccharin (NISac, 1) as activator. Quite surprisingly none
of the desired methyl glycoside was observed, and the sole
reaction product was identified as the pure a-glycoside 3
(Scheme 1). Moreover, 3 was produced entirely as the a-
anomer. Formation of 3 can be explained by initial formation of
the a-acetonium ion 4, by solvent participation in a manner
† Electronic supplementary information (ESI) available: spectral data for
Further investigations into the generality of this novel
glycosylation reaction, and its development for the synthesis of
compounds 3,
b104196g/
1406
Chem. Commun., 2001, 1406–1407
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104196g
Aloui
