Stereoselective cis glycosylation of 2-O-allyl protected glycosyl donors by intramolecular aglycon delivery (IAD)

Article abstract of DOI:10.1039/b004522p

2-O-Allyl protected glycosyl donors may be glycosylated stereoselectively via a three step sequence involving double bond isomerization, N-iodosuccinimide mediated tethering to a glycosyl acceptor and subsequent intramolecular glycosylation (intramolecula

Full text of DOI:10.1039/b004522p

Stereoselective cis glycosylation of 2-O-allyl protected glycosyl donors by
intramolecular aglycon delivery (IAD)
Christopher M. P. Seward,a Ian Cumpstey,a Mahmoud Aloui,a Seth C. Ennis,a Alison J. Redgraveb and
Antony J. Fairbanks*a
a Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, UK OX1 3QY.
Email: antony.fairbanks@chemistry.ox.ac.uk
b Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK
SG1 2NY
Received (in Liverpool, UK) 6th June 2000, Accepted 19th June 2000
Published on the Web 10th July 2000
2-O-Allyl protected glycosyl donors may be glycosylated
stereoselectively via a three step sequence involving double
bond isomerization, N-iodosuccinimide mediated tethering
to a glycosyl acceptor and subsequent intramolecular
glycosylation (intramolecular aglycon delivery, IAD).
extremely efficiently to yield the enol ethers 3 and 4
respectively in quantitative yield (Scheme 1). NIS mediated
tethering was then undertaken for both manno and gluco donors
3 and 4 with a series of alcohols (ROH, Table 1) in the presence
of 4 Å molecular sieves.‡ In all cases tethering proceeded
efficiently in either THF or 1,2-dichloroethane (DCE) as
solvent to yield mixed acetal intermediates 5a–e, 6a–d,f as
diastereomeric mixtures.§ Subsequent intramolecular glycosy-
lation proved more sluggish than we had previously experi-
enced.5 In the case of the less reactive anomeric thiophenyl
manno mixed acetals 5a–e, efficient reaction required the
addition of silver triflate and more protracted reaction times at
either room temperature or higher. However in all cases
intramolecular glycosylation occurred in a stereospecific fash-
ion to furnish the corresponding b-mannosides 7a–e. The more
reactive thiomethyl gluco mixed acetals 6a-d,f were efficiently
activated by the addition of methyl triflate, yielding a-
glucosides 8a–d,f again as single anomers following work-
up.¶∑
Attention then turned to the potential one-pot reaction,
whereby tethering and glycosylation are achieved in a single
reaction vessel. Unlike our previous results5 which were
obtained with the Hindsgaul mixed ketal system, attempted one-
pot glycosylation of donors 3 and 4 with an excess of
cyclohexanol (typically 3 equivalents) produced anomeric
mixtures, clearly indicating competitive intermolecular reaction
by the excess of acceptor in solution. In order to find a solution
to this problem, and also to overcome the sluggishness of the
thiophenyl manno glycosylation reaction, attention turned to the
use of the readily available thiomethyl substituted manno
glycosyl donor 9.† Isomerisation of 9 proceeded efficiently to
yield the enol ethers 10 which were subsequently examined as
Stereoselective intramolecular glycosylation of glycosyl accep-
tors temporarily tethered to the 2-hydroxy group of the glycosyl
donor is a synthetically useful technique allowing access to a
range of cis-1,2-glycosides which can otherwise be problematic
to synthesise. A number of methods have been developed for the
temporary linking of donor and acceptor prior to glycosyla-
tion.1–4 Modification of the donor 2-hydroxy protecting group
commonly provides a tethering site. Thus the Hindsgaul
approach involves Tebbe methylenation of a 2-O-acetate to
produce a vinyl ether which is then coupled with the acceptor
using acid catalysis to produce a mixed ketal.3 Alternative
methodology developed by Ogawa and co-workers employs
oxidation of a p-methoxybenzyl (PMB) protecting group, which
allows linking of donor and acceptor as a mixed acetal.4 We
would herein like to report the first use of the 2-O-allyl
protecting group as the means of tethering donor to acceptor. It
was envisaged that Wilkinson’s catalyst mediated isomerisation
of the double bond would efficiently produce a vinyl ether,
which could then be subjected to tethering with N-iodosuccini-
mide (NIS) and subsequent intramolecular glycosylation ac-
cording to our recently reported procedure.5
The 2-O-allyl protected glycosyl donors 1 and 2, which are
readily available through standard manipulations,† were iso-
merized using a combination of Wilkinson’s catalyst and n-
butyllithium according to a procedure recently reported by
Boons and Isles.6 This straightforward method proceeded
Scheme 1 Reagents and conditions: (i) (Ph3P)3RhCl, n-BuLi, THF, reflux, > 99%; (ii) ROH, N-iodosuccinimide, 4 Å molecular sieves, 1,2-dichloroethane,
240 °C to RT, 76–100%; (iii) N-iodosuccinimide, AgOTf, 2,6-di-tert-butyl-4-methylpyridine, 4 Å molecular sieves, 1,2-dichloroethane, RT (or 50 °C),
59–81%; (iv) ROH, N-iodosuccinimide, 4 Å molecular sieves, 1,2-dichloroethane, 240 °C to RT, 63–98%; (v) MeOTf, 2,6-di-tert-butyl-4-methylpyridine,
1,2-dichloroethane, RT, 65–77%.
DOI: 10.1039/b004522p
Chem. Commun., 2000, 1409–1410
This journal is © The Royal Society of Chemistry 2000
1409

Table 1 Yields for tethering and glycosylation
intermediates. Further investigations into the use of allyl
derived enol ethers for cis glycosylation procedures, partic-
ularly employing hindered secondary carbohydrate glycosyl
acceptors are currently in progress, and the results will be
reported in due course.
We gratefully acknowledge financial support from the
Leverhulme Trust (Postdoctoral Fellowship to M. A.), the
EPSRC (Quota award to C. M. P. S.) and Glaxo Wellcome
(CASE award to I. C.), and also the use of the Chemical
Database Service (CDS) at Daresbury, UK and the EPSRC
National Mass Spectrometry Service at Swansea.
Notes and references
† 2-O-Allyl protected donor 1 was prepared from the corresponding 2-O-
acetate5 via deprotection with sodium methoxide in methanol and allylation
with sodium hydride and allyl bromide in DMF. 2-O-Allyl protected donors
2 and 9 were prepared from the corresponding 2-O-acetyl-1-bromo and
2-O-acetyl-1-chloro glycosides respectively by reaction with dimethyl
disulfide and butyllithium in THF followed by allylation as above.8 Full
experimental details will be published in due course.
‡ Typical procedure for manno/S-phenyl tethering: the vinyl ether (0.15
mmol), the alcohol (3 equiv.) and powdered 4 Å molecular sieves (ca. 500
mg) were stirred in 3.5 ml dry DCE under argon at 240 °C. NIS (2.5 equiv.)
was added and the mixture was allowed to warm slowly to room
temperature. After 16 h, dichloromethane was added, the mixture was
filtered through Celite®, washed with aqueous sodium thiosulfate, dried,
filtered and concentrated in vacuo. The resulting residue was purified by
flash column chromatography to give the mixed acetal as a clear oil.
§ No attempt was made at separation, and the mixtures were used as such for
subsequent glycosylation.
¶ In line with our previous observations, the oxonium ion produced after
aglycon delivery may be trapped, either by any available alcohol in solution
or alternatively by succinimide. Simple treatment of the crude reaction
mixture with either aqueous TFA or aqueous lithium hydroxide respectively
efficiently hydrolyses these trapped products, typically increasing the yield
of glycosylated product by 10–15%.
∑ Typical procedure for manno/S-phenyl glycosylation: the mixed acetals
(0.1 mmol), NIS (5 equiv.), silver triflate (1 equiv.), 2,6-di-tert-butyl-
4-methyl pyridine (DTBMP) (5 equiv.) and powdered 4 Å molecular sieves
(ca. 250 mg) were dissolved in dry DCE under argon. The solution was then
stirred at room temperature (or 50 °C) until TLC indicated disappearance of
the starting material. TFA (10 ml), methanol (4 ml) and water (2 ml) were
added and the solution was stirred for a further 1–4 h. Dichloromethane was
added, the mixture filtered through Celite®, washed with saturated aqueous
sodium bicarbonate and the aqueous layers were re-extracted with
dichloromethane. The combined organic extracts were washed with
aqueous sodium thiosulfate, dried (MgSO4), filtered and concentrated in
vacuo. The resulting residue was purified by flash column chromatography
to give the pure b-mannoside.
Scheme 2 Reagents and conditions: (i) (Ph3P)3RhCl, n-BuLi, THF, reflux,
> 99%; (ii) diacetone galactose, N-iodosuccinimide, 4 Å molecular sieves,
CH3CN, 240 °C to RT, then MeOTf, 72%; (iii) cyclohexanol, N-
iodosuccinimide, 4 Å molecular sieves, 1,2-dichloroethane, 240 °C to RT,
then MeOTf, 67%.
substrates for tethering and glycosylation. Conditions initially
employed for the one-pot reactions of 10, involving NIS
mediated tethering with cyclohexanol and subsequent glycosy-
lation by the addition of methyl triflate to the reaction mixture,
again resulted in the formation of anomeric mixtures. The b+a
ratio could be increased from 2+1 to a respectable 5+1 by simple
dilution of the reaction mixture once tethering was complete
before the addition of the methyl triflate, but a products could
not be entirely eliminated. However by the use of an excess of
glycosyl donor any competing intermolecular reaction could be
avoided. Thus reaction of the donor 10 (2.0 equivalents) with
either diacetone galactose or cyclohexanol (in acetonitrile and
1,2-dichloroethane respectively) produced the corresponding b-
mannosides 7b and 7c as single anomers in 72% and 67% yield
respectively (Scheme 2).
In summary we have demonstrated that 2-O-allyl protected
glycosyl donors may be employed for the synthesis of a variety
of cis-1,2-glycosides. Of particular note is that isomerization of
the allyl group is a very efficient process, and is superior to the
often troublesome and messy Tebbe methylenation reaction. In
addition the use of an excess of glycosyl donor allows both
tethering and glycosylation to be performed in a single reaction
vessel, obviating the need for handling of sensitive mixed acetal
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7 Data for b-mannosides 7a–d and a-glucosides 8a–d was consistent with
that reported by us previously.5 Selected data for 7e: a white solid, mp
22
25
105–108 °C (Et2O–petrol), [a]D +22.2 (c, 0.91, CHCl3), [lit.1b [a]D
+24.0 (c, 1.0, CHCl3); 8f: a colourless oil, [a]D22 +65.5 (c, 1.1, CHCl3),
(HRMS+H+: 897.4229. C55H61O11 requires: 897.4214).
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1990, 201, 31; Y. Ito, O. Kanie and T. Ogawa, Angew. Chem., Int. Ed.
Engl., 1996, 35, 2510; F. W. Lichtentaler and T. Schneider-Adams,
J. Org. Chem., 1994, 59, 6728.
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Chem. Commun., 2000, 1409–1410