Stereospecific synthesis of 1,2-cis glycosides by allyl-mediated intramolecular aglycon delivery. 2.The use of glycosyl fluorides.

Article abstract of DOI:10.1021/ol016175a

[reaction: see text] Stereospecific 1,2-cis glycosylation of 2-O-allyl-protected glucosyl and mannosyl fluorides via a sequence of allyl isomerization, N-iodosuccinimide-mediated tethering, and intramolecular aglycon delivery (IAD) is reported. The use of

Full text of DOI:10.1021/ol016175a

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2371-2374
Stereospecific Synthesis of 1,2-cis
Glycosides by Allyl-Mediated
Intramolecular Aglycon Delivery. 2. The
Use of Glycosyl Fluorides
,†
Ian Cumpstey,† Antony J. Fairbanks,* and Alison J. Redgrave‡
Dyson Perrins Laboratory, UniVersity of Oxford, South Parks Road,
Oxford, OX1 3QY, UK, and GlaxoSmithKline, Medicines Research Centre,
Gunnels Wood Road, SteVenage, SG1 2NY, UK
antony.fairbanks@chemistry.ox.ac.uk
Received May 25, 2001
ABSTRACT
Stereospecific 1,2-cis glycosylation of 2-O-allyl-protected glucosyl and mannosyl fluorides via a sequence of allyl isomerization, N-iodosuccinimide-
mediated tethering, and intramolecular aglycon delivery (IAD) is reported. The use of fluoride as anomeric leaving group is advantageous in
that tethering efficiencies can be increased for hindered aglycon alcohols by the use of extended reaction times without competitive anomeric
activation. Intramolecular glycosylation furnishes the desired r-glucosides and â-mannosides in an entirely stereoselective manner.
The efficient formation of 1,2-cis glycosidic linkages (e.g.,
R-gluco, â-manno) still represents a major challenge during
oligosaccharide synthesis. One of the most appealing ap-
proaches to find a generally applicable solution to this
problem is the technique of intramolecular aglycon delivery
(IAD), which was originally pioneered for the synthesis of
â-mannosides by Hindsgaul1 and Stork2 and more recently
to greater effect by Ogawa.3 As part of our ongoing interest
in the synthesis of oligosaccharides containing 1,2-cis
linkages, we originally reported4 a modification of the
Hindsgaul approach whereby N-iodosuccinimide (NIS) me-
diated tethering of an aglycon alcohol to a Tebbe-derived
2-O enol ether could be followed by in situ activation of a
thioglycoside donor to yield 1,2-cis glycosides in a one-pot
procedure. Subsequently we reported5 the development of
2-O-allyl protected thioglycosides as glycosyl donors for
IAD. Herein the enol ether at the 2 position of the glycosyl
donor is accessed in near quantitative yield from the
isomerization of a 2-O-allyl protecting group. However while
† Dyson Perrins Lab, Oxford.
‡ GlaxoSmithKline, Stevenage.
(1) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447. Barresi,
F.; Hindsgaul, O. Synlett 1992, 759-760. Barresi, F.; Hindsgaul, O. J. Am.
Chem. Soc. 1991, 113, 9377-9379.
(2) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088. Stork,
G.; La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248.
(3) Lergenmuller, M.; Nukada, T.; Kuramochi, K.; Dan, A.; Ogawa, T.;
Ito, Y. Eur. J. Org. Chem. 1999, 1367-1376. Dan, A.; Ito, Y.; Ogawa, T.
J. Org. Chem. 1995, 60, 4680-4681. Ito, Y.; Ogawa, T.; Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1765-1767.
Figure 1. Thioglycoside donors bearing 2-O-propenyl ethers.
10.1021/ol016175a CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/03/2001

Scheme 1. Synthesis of the 2-O-Allyl Glycosyl Fluoridesa
a (i) DAST, DCM, 0 °C, 7 98%; (ii) nPrNH2, MeOH, THF, 45 °C, 9 99%; 10 91% from 6; (iii) allyl bromide, NaH, DMF, 0 °C, 3 96%;
4 93%.
good yields were obtained for NIS-mediated tethering of
ortho esters. Thus, DAST opening of 56 and 67 followed by
an n-propylamine-mediated de-acetylation of acetates 7 and
8 and finally reprotection of OH-2 by treatment with allyl
bromide and sodium hydride in DMF furnished the desired
donors 3 and 4 (Scheme 1).
thioglycoside donors 1 and 2 (Figure 1)with a variety of
simple aglycon alcohols, a limitation arose in the cases of
more hindered carbohydrate alcohols, where tethering oc-
curred more slowly.
The problem in particular was that in order to avoid
competitive activation of the anomeric leaving group, the
length of time that tethering could be left was limited. The
situation was exacerbated in the case of the more reactive
thioglycosides (such as SMe) wherein the differential in
reactivity between the vinyl ether and the thioglycoside was
small. Consequently in the case of hindered secondary
carbohydrate alcohols, only modest to poor tethering yields
were observed.
The utility of the approach was also somewhat limited by
competitive intermolecular reaction during the one-pot
procedure5 when the glycosyl acceptor was present in excess.
It was envisaged that the use of an orthogonal anomeric
leaving group, which would not be activated under the
tethering conditions, could provide a solution for the tethering
of secondary carbohydrate aglycons. We herein report our
findings using glycosyl fluorides as donors in the allyl-
derived IAD system.
We were pleased to find that the isomerization following
Boons’ 8 protocol proceeded as smoothly as in the thio-
glycoside case to furnish the enol ethers 11 and 12 in
excellent yields (Scheme 2). NIS-mediated tethering of the
manno vinyl ether 11 was carried out with a variety of
alcohols, 13a-h, under our established reaction condi-
tions,9,10 and the desired mixed acetals 14a-f,h were
obtained in good to excellent yields (Table 1). Notable are
the cases of the secondary carbohydrate alcohols 13e and
13f, and the steroid 13h, whereby longer reaction times were
now possible without activation of the glycosyl fluoride.
However, in the case of the more hindered alcohols 13d-
f,h an increasing amount of the succinimide-trapped material
18 was isolated (Figure 2).
In the gluco series, tethering of enol ether 12 with the
same series of alcohols 13a-h likewise proceeded to give
the mixed acetals 16a-e,g,h. While excellent yields were
obtained for alcohols 13a-c, slightly lower yields were
observed than in the manno series for some of the more bulky
carbohydrates 13d,e. Overall it is clear that tethering is
Both manno 3 and gluco 4 fluorides bearing allyl protec-
tion of the 2-hydroxyl were prepared from their respective
Scheme 2. Isomerization, Tethering, and IADa
a (i) Wilkinson’s catalyst, BuLi, THF, 70 °C, 96%; 3, 98%, 4; (ii) ROH 13a-h, NIS, DCE, -40 °C f rt, 4 Å; (iii) AgOTf, DTBMP,
SnCl2, DCE, or MeCN, 50 °C; then TFA, H2O or NIS, H2O.
2372
Org. Lett., Vol. 3, No. 15, 2001

of glycosyl fluorides were investigated, including Cp2HfCl2/
AgClO4/DTBMP,12 BF3.OEt2,13 and BF3.OEt2/DTBMP. While
some of the desired products were usually observed, in these
cases product formation was accompanied by hydrolysis of
the tether to various extents, the formation of R/â mixtures
of products (presumably arising from intermolecular
glycosylation following the hydrolysis of the tether), or
occasionally the formation of an intractable mixture of
products. However, optimum results were obtained using
tin(II) chloride, in combination with silver triflate and the
hindered base 2,6-di-tert-butyl-4-methylpyridine (DTBMP).
Heating to 50 °C ensured that the reaction proceeded at an
efficient rate. Thus, tethered materials treated under these
conditions14 furnished the desired â-mannosides 15a-f,h and
R-glucosides 17a-e,g,h stereospecifically as the pure 1,2-
cis anomers in all cases.
Table 1. Tethering and Glycosylation Yields
The efficiency of glycosylation was found to be solvent
dependent. For example, it was observed that while the
glycosylation of the manno mixed acetals 14c in acetonitrile
was sluggish, and occurred concomitantly with partial
hydrolysis of the tether, an otherwise identical experiment
employing dichloroethane (DCE) as solvent proceeded very
quickly (ca. 2 h), with no hydrolysis; subsequent glycosy-
lation reactions were therefore carried out in DCE.
Recently the question as to the possible fate of the
oxonium ion produced after intramolecular glycosylation has
arisen in the Ogawa/Ito PMB system.15 In our earlier work
on the thioglycosides,5 byproducts were observed after
glycosylation that were subsequently identified as mixed
acetals. These presumably arise from trapping out of the
oxonium ion produced after glycosylation reaction, by an
a Isolated yields. Reactions carried out in DCE except where otherwise
stated. b Reaction carried out in THF. c Isolated yields. Acid treatment with
TFA except where otherwise stated. d Reaction carried out in DCE.
f
e Reaction carried out in acetonitrile. No acid treatment. g Treatment with
(4) Ennis, S. C.; Fairbanks, A. J.; Tennant-Eyles, R. J.; Yeates, H. S.
Synlett 1999, 1387-1390. Ennis, S. C.; Fairbanks, A. J.; Slinn, C. A.;
Tennant-Eyles, R. J.; Yeates, H. S. Tetrahedron 2001, 57, 4221-4230.
(5) Seward, C. M. P.; Cumpstey, I.; Aloui, M.; Ennis, S. C.; Redgrave,
A. J.; Fairbanks A. J. J. Chem. Soc., Chem. Commun. 2000, 1409-1410.
(6) Zhang, Y. M.; Mallet, J.-M.; Sinay¨, P. Carbohydr. Res. 1992, 236,
73-88.
NIS, H2O.
slightly less efficient in the gluco series. In the case of the
steroid 13h, which was only partially soluble in DCE, a
change of solvent to THF for tethering was required in order
to obtain acceptable yields. Again some succinimide-trapped
material 19 was observed in the cases of the more hindered
alcohols.
Activation of glycosyl fluorides is generally carried out
by the use of some form of Lewis acid.11 However the mixed
acetal tether, which itself could be susceptible to Lewis acid
catalyzed cleavage, must remain intact for IAD to operate
and crucially ensure complete stereoselectivity. Several
different reaction conditions often employed for the activation
(7) Lichtentaler, F. W.; Schneider-Adams J. Org. Chem. 1994, 59, 6728-
6734.
(8) Boons, G.-J.; Isles, S. J. Org. Chem. 1996, 61, 4262-4271.
(9) Typical procedure for tethering: NIS (3 equiv) and powdered 4 Å
molecular sieves were stirred in 1 mL of dry DCE under argon at -40 °C.
The alcohol (1.5-3 equiv) was added by cannula under argon in 1.5 mL
of dry DCE. The vinyl ether (0.1 mmol) was added by cannula under argon
in 1.5 mL of dry DCE, and the mixture was allowed to warm slowly to
room temperature. After 1-24 h, the mixture was diluted with dichlo-
romethane, washed with aqueous sodium thiosulfate, dried, filtered, and
concentrated in vacuo. The resulting residue was purified by flash column
chromatography to give the mixed acetals as a colorless oil.
(10) Thieme, J.; Karl, H.; Schwenter, J. Synthesis 1978, 696-698.
(11) Toshima, K. Carbohydr. Res. 2000, 327, 15-26.
(12) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron
Lett. 1988, 29, 3567-3570.
(13) Nicolaou, K. C.; Chucholowski, A.; Dolle, R. E.; Randall, J. L. J.
Chem. Soc., Chem. Commun. 1984, 1155-1156.
(14) Typical procedure for glycosylation: 2,6-Di-tert-butyl-4-meth-
ylpyridine (DTBMP) (2 equiv), silver triflate (2 equiv), anhydrous tin(II)
chloride (2 equiv), and powdered 4 Å molecular sieves were stirred in 1
mL of dry DCE under argon at 50 °C. The mixed acetals (0.1 mmol) were
added by cannula under argon in 3 mL of dry DCE, and the reaction was
stirred at 50 °C until TLC indicated disappearance of starting material. TFA
(2 mL) and water (1 mL) were added, and the solution was stirred for a
further 30 min. Diethyl ether was added, and the mixture was filtered through
Celite, washed with saturated aqueous bicarbonate and brine, dried, filtered,
and concentrated in vacuo. The resulting residue was purified by flash
column chromatography to give the pure 1,2-cis glycoside.
(15) Ito, Y.; Ando, H.; Wada, M.; Kawai, T.; Ohnish, Y.; Nakahara, Y.
Tetrahedron 2001, 57, 4123-4132.
Figure 2. Succinimide-trapped species.
Org. Lett., Vol. 3, No. 15, 2001
2373

external alcohol acting as a nucleophile. Treatment of the
crude reaction mixture with TFA during workup resulted in
the hydrolysis of any such mixed acetals and an increased
the yield of the desired 1,2-cis glycoside.
Scheme 3a
Again, during the course of this work it was found that
byproducts (which were more prevalent in the gluco than
the manno series) were observed by TLC. Treatment of these
reaction byproducts with TFA yielded further 1,2-cis gly-
coside product. However it was noted that this byproduct
hydrolysis was faster than we had observed previously.
Therefore, in the case of alcohol 13e, which possesses an
acid-sensitive protecting group which may be cleaved by acid
treatment, rather than adopting this acid workup procedure
to optimize the yield of disaccharide product, we investigated
the identity of this so-called “trapped” material. Rather
surprisingly these minor byproducts were identified as the
enol ethers 20.16
a (i) NIS, THF, H2O then Et3N.
reaction times. However, although the method efficiently
provides â-mannosides, the use of 3-fold excesses of glycosyl
acceptor and NIS means that other methods are currently
more efficient for the synthesis of R-glucosides. Further
investigations into the use of allyl-derived IAD, with the aim
of increasing the efficiency of tethering and glycosylation
steps, are currently in progress and will be reported in due
course.
Treatment of these enol ethers 20 with NIS/H2O rapidly
resulted in the formation of the desired glycoside 17e, without
any cleavage of the acid-sensitive 4,6-benzylidene protection
(Scheme 3).
Acknowledgment. We gratefully acknowledge financial
support from the EPSRC and GlaxoSmithKline and the use
of the EPSRC National Mass Spectrometry Service at
Swansea and the Chemical Database Service at Daresbury.
In summary we have demonstrated that glycosyl fluorides
can be used as glycosyl donors for the allyl-mediated IAD
approach to 1,2-cis glycosides and that tethering and in-
tramolecular glycosylation may be achieved for a variety of
alcohols. The use of glycosyl fluorides is advantageous in
that tethering efficiency can be increased in the case of bulky
secondary carbohydrate alcohols by the use of extended
Supporting Information Available: Full characterization
and spectral data for compounds 3, 4, 7-12, 15a-f,h, and
17a-e,g,h. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) It is not yet entirely clear exactly how 20 (R ) H) is formed, since
this formally requires loss of I+ from the oxonium ion produced after
intramolecular glycosylation.
OL016175A
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Org. Lett., Vol. 3, No. 15, 2001