Selective synthesis of 1,2- cis -α-glycosides without directing groups. Application to iterative oligosaccharide synthesis

Article abstract of DOI:10.1021/ol401095k

A method for the highly selective synthesis of 1,2-cis-α-linked glycosides that does not require the use of the specialized protecting group patterns normally employed to control diastereoselectivity is described. Thioglycoside acceptors can be used, permitting iterative oligosaccharide synthesis. The approach eliminates the need for lengthy syntheses of monosaccharides possessing highly specialized and unconventional protecting group patterns.

Full text of DOI:10.1021/ol401095k

ORGANIC
LETTERS
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Vol. XX, No. XX
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Selective Synthesis of
1,2-cis-R-Glycosides without Directing
Groups. Application to Iterative
Oligosaccharide Synthesis
An-Hsiang Adam Chu, Son Hong Nguyen, Jordan A. Sisel,
Andrei Minciunescu, and Clay S. Bennett*
Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford,
Massachusetts 02145, United States
clay.bennett@tufts.edu
Received April 20, 2013
ABSTRACT
A method for the highly selective synthesis of 1,2-cis-R-linked glycosides that does not require the use of the specialized protecting group
patterns normally employed to control diastereoselectivity is described. Thioglycoside acceptors can be used, permitting iterative
oligosaccharide synthesis. The approach eliminates the need for lengthy syntheses of monosaccharides possessing highly specialized and
unconventional protecting group patterns.
Oligosaccharides found on the surface of pathogens and
malignant cells frequently possess 1,2-cis-R-linked glyco-
sides as a key structural element.1 The possibility of using
these structures in carbohydrate-based vaccine candidates
has promoted numerous investigations into the construc-
tion of these linkages.2 Despite these efforts, 1,2-cis-R-
glycosides remain one of the most difficult glycosidic
linkages to synthesize. Many of the approaches developed
to construct these linkages rely on the use of highly
specialized unconventional protecting group patterns,
which require multiple steps to install.3,4 Alternatively, it
is possible to obtain selectivity in the absence of directing
groups by using leaving groups that undergo SN2-like
displacement.5 For example, glycosyl iodides undergo
glycosylation in the presence of excess iodide ion to form
products with high R-selectivity.6,7 These species are
unstable, however, and must be generated under harsh
conditions. This limits their utility with both sensitive
substrates and technologies such as iterative and one-pot
oligosaccharide synthesis.8,9 Inprinciple, these issues could
(1) Astronomo, R. D.; Burton, D. R. Nat. Rev. Drug Disc. 2010, 9,
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r
10.1021/ol401095k
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be circumvented through rapid in situ conversion of a stable
donor, such as a thioglycoside, into a reactive glycosyl
iodide under mild conditions.10,11 Herein, we describe an
approach for highly selective glycosylation reactions that
uses stable thioglycoside donors and does not require the
use of directing groups to control selectivity. The applica-
tion of this technology to iterative oligosaccharide synthesis
is described.
in the presence of the non-nucleophilic base tri-tert-butyl-
pyrimidine (TTBP), followed by addition of 3 equiv
of tetrabutylammonium iodide (TBAI). After being stirred
at À78 °C for 10 min, the reaction was treated with
cholesterol (2) as an acceptor and allowed to warm to
room temperature. The presence of TBAI led to a reversal
of selectivity from that observed using Ph2SO/Tf2O alone
(Table 1, entries 2 vs 1). Addition of the nucleophile in
1,4-dioxane led to a modest increase in selectivity, accom-
panied by a loss in yield (Table 1, entry 4). Further
experiments revealed that both the yield and selectivity
Table 1. Preliminary Reaction Optimization
14
˚
could be improved through the use of 4 A MS (entry 5).
To determine if the selectivity of the reaction was due
chiefly to the ethereal solvent,15 we ran the reaction with
1,4-dioxane in the absence of TBAI. Under these condi-
tions, the reaction was nonselective (1:1.2 R/β, Table 1,
entry 8), clearly indicating the importance of iodide for
the reaction. This last result supports the idea that the
conditions are promoting the in situ conversion of the
thioglycoside into the corresponding glycosyl iodide. Since
TTBP suppresses in situ anomerization of glycosylation
products,16 the R-selectivity observed in entry 5 is the result
of this glycosyl iodide reacting under halide ion conditions.7
Selectivity also appeared to depend on the nature of
the thiophilic promoter; 1-(benzenesulfinyl)piperidine
(BSP)/Tf2O17 led to a loss of selectivity (Table 1, entry 9).
While the reason for this diminished selectivity is not
known, we surmise that it may be due to the inability of
this latter promoter to completely convert the thioglycoside
toa glycosyl triflate at low temperature. If activation occurs
upon warming, the acceptor is already present in the reac-
tion and can react with the glycosyl triflate intermediate,
leading to a loss of selectivity.
Under the optimal conditions described above, the
reaction of 1 with sugar acceptor 4 led to the formation
of disaccharide 5 accompanied by what appeared to be
unreacted donor (Table 2, entry 1). This was surprising,
since we had observed that the thioglycoside 1 was rapidly
consumedupon activation with Ph2SO/Tf2O. Wereasoned
that the donor was somehow being regenerated under the
reaction conditions following activation. To determine
what was occurring, we examined the reaction in the
absence of an acceptor. Under these conditions we found
that 1 was quickly consumed upon activation with Ph2SO/
Tf2O; however, it slowly formed again after the addition
of TBAI. To confirm that TBAI was leading to regenera-
tion of the donor, we examined the effect of TBAI
a 1-(Benzenesulfinyl)piperidine used in place of Ph2SO.
We chose to examine thioglycosides as they are particu-
larly useful for iterative and one-pot synthesis. Many
methods for thioglycoside activation involve in situ genera-
tion of a glycosyl triflate.12 We reasoned that this inter-
mediate could be trapped by iodide ion, thereby providing
mild conditions for the in situ formation of a glycosyl iodide
for 1,2-cis-R-selective glycosylation reactions.
Preliminary studies involved activating thioglycoside 1
with Ph2SO/trifluoromethanesulfonic anhydride (Tf2O)13
(8) (a) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
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(14) Molecular sieves can impact the outcome of glycosylation reac-
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Nguyen, S. H.; Bennett, C. S. Org. Lett. 2011, 13, 2814–2817.
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Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Effect of TBAI and N-Methylmaleimide
Table 3. Reaction Scope
Scheme 1. Possible Mechanism of Thioglycoside Regeneration
a 3 equiv of N-methylmaleimide used.
the formation of 5 in 87% yield with excellent selectivity
(18:1 R/β, Table 2, entry 4). We therefore adopted these
conditions for the remainder of this study.
stoichiometry on the yield of the reaction with 4. To this
end, the addition of 2 equiv of TBAI led to an increase in
yield (89%) accompanied by a loss in selectivity, while the
addition of 5 equiv afforded the desired product as a single
anomer, albeit in reduced yield (Table 2, entries 2 and 3).
Based on these results, we concluded that TBAI was
reacting with the byproduct of thioglycoside activation
(6)13 to generate phenylthiolate7 (Scheme 1). Compound 7
then effectively competed with the acceptor to regenerate
the donor, which in the absence of additional promoter
was now inert under the reaction conditions. Rationalizing
thata thiol scavengercouldremove7 from the reaction and
thereby permit the use of the excess TBAI necessary for
selectivity, we chose to examine the effect of N-methylma-
leimide on the reaction.18 Toward this end, activation of 1
in the presence of N-methylmaleimide, followed first by
the addition of 5 equiv of TBAI, then 4 in dioxane, led to
The scope of the reaction was next examined with a
number of sugar acceptors (Table 3). Both glucose and
galactose donors reacted with a number of acceptors to
provide products with excellent selectivity. This included
a re-examination of cholesterol as a model small molecule
acceptor, which showed that these modifications led to a
dramatic increase in selectivity over our initial conditions
(Table 3, entries 1 and 2 vs Table 1, entry 5). In the case of
more hindered acceptors, it was necessary to use 3 equiv
of N-methylmaleimide to obtain good yields (Table 3,
entries 8 and 9). Even under these conditions, the use of
the hindered acceptor 11 provided the product in lower
yield than observed with other acceptors (Table 3, entry 10),
and the reaction was again accompanied by regeneration of
the donor.
Our observation that the thioglycoside that was regen-
erated upon addition of TBAI was not a competent donor
prompted us to examine thioglycoside acceptors in the
reaction. If thioglycoside acceptors could be used success-
fully, it would expand the reaction’s utility by permitting
(18) Brown, G. A.; Martel, S. R.; Wisedale, R.; Charmant, R. J. P.
H.; Hales, N. J.; Fishwick, C. W. G.; Gallagher, T. J. Chem. Soc., Perkin
Trans. 1 2001, 1281–1289.
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iodide intermediate reacting in the presence of excess
iodide ion. Specifically, at room temperature the glycosyl
donor exists as a mixture of R- and β-iodides, with the
β-iodide being significantly more reactive. At higher tem-
peratures, the R-iodide becomes a more competent donor,
leading to a slight erosion of selectivity. Despite this, at
higher temperatures the reaction still afforded the product
in synthetically useful selectivities. More importantly, the
results open up the exciting possibility that this approach
could ultimately be utilized for stereoselective one-pot
oligosaccharide synthesis using preactivation protocols.19
In conclusion, we have shown that activating thioglyco-
sides with Ph2SO/Tf2O followed by TBAI leads to the in
situ formation of a species that undergoes glycosylation
to afford 1,2-cis-R-glycosides in good yield and excellent
selectivity without the need for directing groups. The
dependence of selectivity on the quantity of TBAI in the
reaction indicates that the reaction may be proceeding
through a glycosyl iodide intermediate. Excess TBAI can
lead to regeneration of the starting donor; however, this
can be suppressed with the addition of N-methylmaleimide
as a thiol scavenger. The fact that the regenerated donor is
unreactive prompted us to examine thioglycoside accep-
tors in the reaction. These latter acceptors can be used
without detrimental effects, permitting iterative oligosac-
charide synthesis. We envision that this approach will
significantly facilitate oligosaccharide synthesis by elimi-
nating the need to use highly specialized protecting group
patterns on monosaccharide coupling partners, or very
unstable glycosyl donors in the construction of 1,2-cis-R-
glycosides. Studies directed at optimizing the reaction for
one-pot synthesis and examining the scope of the reaction
are under investigation in our laboratory.
Scheme 2. Iterative Oligosaccharide Synthesis
iterative and, potentially, one-pot oligosaccharide synth-
esis. As a preliminary study, we examined the reaction
between 1 and acceptor 21. Under our conditions, the
anomeric sulfide in acceptor 21 was not activated, and
we were able to obtain disaccharide 22 in good yield and
excellent selectivity (Scheme 2). This product was then
used directly as a donor in a reaction with acceptor 4 to
afford23. Interestingly, the stoichiometry ofthe donor and
acceptor did not appear to affect the reaction. Using either
the donor or acceptor in excess led to the formation of 23 in
excellent selectivity (>20:1 R/β). Heating the reaction after
it was warmed to room temperature resulted in an increase
in yield, with a slight decrease in selectivity (14:1 R/β). The
loss in selectivity could be explained by invoking a glycosyl
Acknowledgment. We thank Tufts University for finan-
cial support. J.A.S. was supported by a Robert R. Dewald
Summer Scholarship from donations provided by alumni.
We thank Professor Todd L. Lowary (U. Alberta) for
helpful comments on the manuscript.
Supporting Information Available. Experimental pro-
cedures, characterization of all new compounds, and
1H and 13C NMR. This material is available free of charge
via the Internet at http://pubs.acs.org.
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(19) (a) Codee, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.;
Overkleeft, H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003,
5, 1947–1950. (b) Huang, X.; Huang, L.; Wang, H.; Ye, X.-S. Angew.
Chem., Int. Ed. 2004, 43, 5221–5224. (c) Yang, L.; Qin, Q.; Ye, X.-S.
Asian J. Org. Chem. 2013, 2, 30–49.
The authors declare no competing financial interest
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