Reagent controlled β-specific dehydrative glycosylation reactions with 2-deoxy-sugars

Article abstract of DOI:10.1021/ol4018547

N-Sulfonyl imidazoles activate 2-deoxy-sugar hemiacetals for glycosylation presumably by converting them into glycosyl sulfonates in situ. By matching the leaving group ability of the sulfonate with the reactivity of the donor, it is possible to obtain β-

Full text of DOI:10.1021/ol4018547

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Reagent Controlled β‑Specific
Dehydrative Glycosylation
Reactions with 2‑Deoxy-Sugars
John Paul Issa, Dina Lloyd, Emily Steliotes, and Clay S. Bennett*
Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
clay.bennett@tufts.edu
Received July 2, 2013
ABSTRACT
N-Sulfonyl imidazoles activate 2-deoxy-sugar hemiacetals for glycosylation presumably by converting them into glycosyl sulfonates in situ. By
matching the leaving group ability of the sulfonate with the reactivity of the donor, it is possible to obtain β-specific glycosylation reactions. The
reaction serves as proof of the principle that, by choosing promoters that can modulate the reactivity of active intermediates, it is possible to place
glycosylation reactions entirely under reagent control.
Despite numerous advances over the past several years,
the synthesis of stereodefined oligosaccharides remains a
nontrivial operation.1 This is due in large part to the fact
that most methods for diastereoselective chemical glycosyla-
tion rely on substrate control.2 In cases where neighboring
group participation or conformational locking cannot be
used to control selectivity, extensive optimization of both the
donor and acceptor is often necessary to obtain a “matched”
coupling pair.3 This is especially true when trying to synthe-
size “difficult” glycosidic linkages, such as β-linked 2-deoxy-
sugars. In principle, these challenges could be circumvented if
the stereoselectivity of the reaction was placed under reagent
control, where the stereochemical outcome of the glycosyla-
tion reaction is dictated entirely by the promoter. Here, we
describe such an approach for the stereospecific construction
of β-linked 2-deoxy-sugars (as opposed to stereoselective
construction, which still affords diastereomeric mixtures).
β-Linked 2-deoxy-sugars play an important role in
modulating the biological activity of many natural products,
such as landomycin,4 mithramycin,5 and digitoxin.6 This has
led to the realization that it is possible to dramatically alter
the pharmacokinetics of a natural product through changing
the composition of its glycosides.7 A significant hurdle to the
broader application of this technology to drug discovery is
the fact that β-linked 2-deoxy-sugars are generally considered
to be one of the most difficult glycosidic bonds to
synthesize.8,9 A number of methods for the direct synthesis
(5) (a) Crow, R. T.; Rosenbaum, B.; Smith, R., III; Guo, Y.; Ramos,
K. S.; Sulikowski, G. A. Bioorg. Med. Chem. Lett. 1999, 9, 1663–1666.
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r
10.1021/ol4018547
XXXX American Chemical Society

of various 2-deoxy-sugars have been described.10 However,
with the exception of Gervay-Hague’s glycosyl iodides and
Zhu’s umpolung approach,10d,f little attempt has been made
to elucidate the origins of the stereoselectivity in these
reactions. In addition, this selectivity does not always trans-
late well between different systems,11 and many activated
2-deoxy-sugars are extremely unstable, requiring specialized
media for their purification.10e As a result, many groups have
developed indirect approaches to the construction of
2-deoxy-sugars through the use of either temporary directing
groups12 or de novo synthesis.13 These latter approaches
necessarily introduce additional steps, decreasing the overall
efficiency of the synthesis.
reactivity of different sulfonates has been reported to span
several orders of magnitude,18 little work has been done on
glycosyl sulfonates other than triflates since the seminal
studies of the Schuerch and Koto groups over three decades
ago.19 This is due to the fact that many of these procedures
required the isolation of highly unstable species. Addition-
ally, those procedures for in situ generation of sulfonates
often led to nonselective reactions. The lack of selectivity is
presumably due to the presence of several other nucleophilic
ions in solution, which could scramble the stereochemistry of
the anomeric leaving group.20
As part of an ongoing program aimed at developing
selective methods for 2-deoxy-sugar synthesis,14 we chose
to examine the in situ generation of different glycosyl
sulfonates for β-selective glycosylations. While glycosyl
triflates can undergo SN2-like reactions to afford β-linked
products with certain substrates,15 Crich has shown that
2-deoxy glycosyl triflates are generally very unstable.16
Furthermore, Woerpel has demonstrated that, even in
examples where 2-deoxy-sugar triflates are not subject to
decomposition, they only undergo β-selective reactions when
strong carbon nucleophiles are employed as acceptors.17 In
principle, a more stable sulfonate should possess greater
covalent character, permitting direct SN2 displacement to
afford the product as a single diastereomer. While the
Scheme 1. N-Sulfonylimidazoles for β-Selective Glycosylations
To address these issues we chose to examine the use of
N-sulfonyl imidazoles as reagents for converting hemiacetals
into glycosyl sulfonates in situ (Scheme 1). These species
have been shown to promote sulfonate ester formation21
and nucleotide coupling22 without the generation of nucleo-
philic byproducts. Importantly, the synthesis of N-sulfonyl
imidazoles is trivial,23 which would permit the rapid synth-
esis of a large library of compounds to tune reactivity.
Our initial investigations focused on thiol nucleophiles
owing to both their increased reactivity and the fact that thio-
glycoside linkages are useful, nonhydrolyzable carbohydrate
mimetics.24 To this end, deprotonation of 1 with KHMDS
in THF at low temperature25 was followed first by addition
of N-tosylimidazole (TsIm) and then the nucleophile. The
selectivity in the reaction was dependent on the amount
of time 1 was allowed to react with the TsIm (Table 1,
entries 1ꢀ3). Longer reaction times generally led to higher
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Tetrahedron Lett. 1987, 28, 2723–2726. (d) Preuss, R.; Schmidt, R. R.
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James, R. A. Tetrahedron 1997, 53, 8837–8852. (n) Franck, R. W.;
Marzabadi, C. H. J. Org. Chem. 1998, 63, 2197–2208. (o) Roush, W. R.;
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(f) Zhou, M.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–2493.
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2011, 13, 2814–2817. (b) Nogueira, J. M.; Issa, J. P.; Chu, A.-H. A.; Sisel,
J. A.; Schum, R. S.; Bennett, C. S. Eur. J. Org. Chem. 2012, 4927–4930.
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T. J.; Wheat, P. E.; Schuerch, C. Carbohydr. Res. 1978, 60, 85–96. (e)
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S.; Sato, T.; Morishima, N.; Zen, S. Bull. Chem. Soc. Jpn. 1980, 53, 1761–
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Org. Lett., Vol. XX, No. XX, XXXX

selectivity. We attribute the change in selectivity to the rapid
formation of a mixture of glycosyl tosylates followed by
equilibration to the more stable R-anomer. In order to
improve the yield of the reaction, we next examined the
more reactive leaving group found in tosyl 4-nitroimidazole
(TsImNO2). Not only did this reagent improve the yield of
the reaction, but we observed a dramatic increase in selec-
tivity from 5:1 β:R to all β (Table 1, entry 4). Finally, the use
of a slight excess of the activated donor led to a further
increase in yield without compromising selectivity (88%,
β only, Table 1, entry 5).
Table 2. Scope with Thiol Acceptors
Table 1. Reaction Optimization with Sulfur Nucleophiles
PhSH
time
yield
(%)
entry
(equiv)
Y
(min)
R:β
1:1
1
1
H
0
30
65
60
60
60
40
40
40
62
88
77
2
1
H
1:2
3
1
H
1:5
4
1
NO2
NO2
NO2
β only
β only
β only
5
6a
0.67
0.67
a An equivalent of potassium imidazolide was added to the reaction.
To determine if the lower selectivity observed with TsIm
was due to the presence of imidazole interfering with the
reaction, we repeated the reaction using TsImNO2 in the
presence of an equivalent of potassium imidazolide
(Table 1, entry 6). No change in selectivity was observed,
indicating that imidazole was only acting as a leaving
group. While the origins of the change in selectivity are
unclear at this point, we attribute the lower selectivity with
TsIm to incomplete conversion of the donor to the glycosyl
sulfonate prior to the addition of the acceptor. If the
acceptor is present before the sulfonate can equilibrate to
the more stable R configuration,19 β-sulfonates will be
present and react to reduce selectivity.
The scopeof the reactionwas nextexaminedwith several
thiol acceptors (Table 2).24e For aliphatic thiol acceptors
we found it necessary to use the potassium salt to obtain
useful yields. Yields were generally moderate-to-good,
with the secondary galactose derived thiol 4 providing
the highest yield. In the case of primary thiol 6 the reaction
was accompanied by significant amounts of disulfide bond
formation, despite efforts to rigorously exclude oxygen
from the reaction. In every single case, however, the
reaction provided the product as a single β-anomer, as
determined by 1H NMR.
since aryloxy glycosides are important structural motifs in
many natural products.7 The reaction of 1 with TsImNO2,
followed by the addition of the potassium salt of 2-naphthol
(prepared by treating the acceptor with KHMDS), provided
the desired product as a single anomer as determined by 1H
NMR (Table 3, entry 1).26 Rationalizing that a solvent
which could better coordinate the counterion could provide
the product in enhanced yield, we next examined the use of
diglyme as an additive. Pleasingly, this led to an increase in
the yield, affording the product in 76% yield as a single
β-anomer (Table 3, entry 2). Under these conditions we did
not observe any glycal formation, indicating that elimination
of the active leaving group was not a competitive pathway.
Other phenolic acceptors reacted in moderate-to-good yield,
with electron-rich phenols providing the best yields.
We next turned our attention to the more reactive 2,6-
dideoxy-L-arabino hexopyranose donor 11 (Table 4).
Again no glycal formation was observed. Interestingly,
electron-rich phenols were less effective than electron-poor
phenols with this substrate, representing a reversal of the
trend observed in Table 3. While we can attribute the lower
Having established that the reaction was effective with
thiolates, we turned our attention to phenoxide nucleophiles,
(26) No reaction was observed with neutral acceptors.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Scope with Aryloxy Acceptors
Table 4. Reactions with 2,6-Dideoxy-donors
ArOꢀKþ
product
yield (%)
R:β
entry
ArOꢀKþ
solvent
product yield (%)
R:β
entry
1
2
3
4
5
6
7
2-naphthol
2-naphthol
1-naphthol
PhOK
THF
11
11
12
13
14
15
16
43
76
70
67
62
74
45
β only
β only
β only
β only
β only
β only
β only
1
2
3
4
5
6
2-naphthol
1-naphthol
PhOK
18
19
20
21
22
23
41
53
73
56
63
71
β only
β only
β only
β only
β only
β only
diglyme
diglyme
diglyme
diglyme
o-cresol
o-cresol
p-MeO-PhOK
p-CF3-PhOK
p-MeO-PhOK diglyme
p-CF3-PhOK diglyme
with our cyclopropenium cation promoted R-selective
glycosylation methodology,14 these studies also demon-
strate that it is possible to obtain either anomer of a
glycoside starting from the same donor, simply by placing
the reaction under reagent control. While it is unlikely that
the tosylate leaving group will be effective with all classes
of glycosyl donors (such as mannose, rhamnose, etc.), the
range of reactivities of different sulfonates is such that it
should be possible to match each class of donor to a proper
leaving group for β-specific glycosylation reactions. Stu-
dies aimed at doing this and confirming our proposed
reaction mechanism are currently under investigation in
our laboratory.
yields to be due in part to the decreased stability of the 2,6-
dideoxy-sugar products, the origin of this reversal in
reactivity trend is unclear at this point. Importantly how-
ever, the reactions again afforded the products exclusively
as β-anomers, despite the fact that the absolute configura-
tion of the donor had been switched from D- to L-. These
observations support our hypothesis that that the TsIm-
NO2 activates the hemiacetal donors as R-glycosyl tosy-
lates, which react through an SN2-like manifold to afford
β-linked products.
In conclusion, we have found that treating 2-deoxy-
sugar hemiacetals with TsImNO2 results in the in situ
formation of a species that reacts with S- and O-nucleo-
philestoformglycoside productsexclusivelyasβ-anomers.
The reaction presumably proceeds through the formation
of a glycosyl tosylate, which reacts through an SN2 or SN2-
like manifold. This is supported by the fact that no
R-anomer was observed with either D- or L-sugar donors.
These studies provide proof of the principle that it is
possible to obtain stereospecific glycosylation reactions
by matching sulfonate leaving group ability with the
intrinsic reactivity of the glycosyl donor. Taken together
Acknowledgment. We thank the National Science
Foundation (NSF 1300334) and Tufts University for
supporting this work.
Supporting Information Available. Experimental de-
tails and 1H and 13C NMR, and additional characteriza-
tion data. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest
D
Org. Lett., Vol. XX, No. XX, XXXX