A reagent-controlled SN2-glycosylation for the direct synthesis of β-linked 2-deoxy-sugars

Article abstract of DOI:10.1021/ja500410c

The efficient and stereoselective construction of glycosidic linkages remains one of the most formidable challenges in organic chemistry. This is especially true in cases such as β-linked deoxy-sugars, where the outcome of the reaction cannot be controlled using the stereochemical information intrinsic to the glycosyl donor. Here we show that p-toluenesulfonic anhydride activates 2-deoxy-sugar hemiacetals in situ as electrophilic species, which react stereoselectively with nucleophilic acceptors to produce β-anomers exclusively. NMR studies confirm that, under these conditions, the hemiacetal is quantitatively converted into an α-glycosyl tosylate, which is presumably the reactive species in the reaction. This approach demonstrates that use of promoters that activate hemiacetals as well-defined intermediates can be used to permit stereoselective glycosylation through an S_N2-pathway.

Full text of DOI:10.1021/ja500410c

Article
pubs.acs.org/JACS
A Reagent-Controlled SN2‑Glycosylation for the Direct Synthesis of
β‑Linked 2‑Deoxy-Sugars
John Paul Issa and Clay S. Bennett*
Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, Massachusetts 02155, United States
S
* Supporting Information
ABSTRACT: The efficient and stereoselective construction of
glycosidic linkages remains one of the most formidable
challenges in organic chemistry. This is especially true in
cases such as β-linked deoxy-sugars, where the outcome of the
reaction cannot be controlled using the stereochemical
information intrinsic to the glycosyl donor. Here we show
that p-toluenesulfonic anhydride activates 2-deoxy-sugar hemiacetals in situ as electrophilic species, which react stereoselectively
with nucleophilic acceptors to produce β-anomers exclusively. NMR studies confirm that, under these conditions, the hemiacetal
is quantitatively converted into an α-glycosyl tosylate, which is presumably the reactive species in the reaction. This approach
demonstrates that use of promoters that activate hemiacetals as well-defined intermediates can be used to permit stereoselective
glycosylation through an SN2-pathway.
directly, however, limiting the viability of such a task.5−7
Methods for the direct construction of β-linked phenolic
INTRODUCTION
■
β-Linked 2-deoxy-sugars are essential for the bioactivity of
glycosides and thioglycosides of 2-deoxy-sugars have been
many natural products (Figure 1A).1 Furthermore, oligosac-
described,8−12 but reports of the direct stereoselective synthesis
charides composed of deoxy-sugars have been shown to possess
of β-linked 2-deoxy-sugar disaccharides and oligosaccharides
potent biological activity.2 Altering the composition of these
sugars can modulate a natural product’s bioactivity, potentially
reducing undesirable side effects.3,4 These linkages are
considered to be among the most challenging to synthesize
are exceedingly rare.13−16 The mechanistic basis of selectivity in
most of these latter reactions has yet to be described, and
selectivity does not always translate well between systems.17,18
We reasoned that a glycosyl sulfonate generated in situ
would undergo an SN2-like reaction with nucleophiles if the
intrinsic reactivity of the glycosyl donor were matched to the
leaving group ability of the sulfonate. Aside from triflates,
however, glycosyl sulfonates have been largely overlooked by
the synthetic community since the 1970s.19 We recently
demonstrated that activating a hemiacetal with N-tosyl-4-
nitroimidazole under basic conditions led to the formation of a
species that reacted with strong nucleophiles to afford products
exclusively as β-anomers (Figure 1B, X = 4-nitroimidazole).10
The reaction presumably proceeds through the formation of an
α-linked glycosyl tosylate that reacts through an SN2 or SN2-like
manifold. Attempts to extend this method to less nucleophilic
carbohydrate acceptors were unsuccessful. Here we report that
the use of potassium hexamethyldisilazane (KHMDS)/p-
toluenesulfonic anhydride as a promoter system permits the
selective synthesis of β-linked 2-deoxy-sugar disaccharides from
hemiacetals donors (Figure 1B, X = OTs). Utilizing low-
temperature NMR, we demonstrate that the reaction
conditions quantitatively convert the hemiacetal into an α-
glycosyl tosylate, indicating that the stereoselectivity is the
result of an SN2-reaction. Together, these studies demonstrate
that, through proper selection of the promoter, it is possible to
Figure 1. Occurrence of β-linked deoxy-sugars and protocol for direct
glycosylation. (A) Representative biologically active natural products
containing β-glycosidic deoxy-sugar linkages. (B) Activation of 2-deoxy
and 2,6-dideoxy donors as glycosyl p-toluenesulfonates for β-specific
glycosylation.
Received: January 14, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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products. While we had shown that this reagent readily
activates hemiacetals in THF for glycosylation using thiol
nucleophiles, the use of diglyme as a cosolvent was found
necessary to promote O-glycosylation. Under these conditions,
both electron-rich and electron-deficient phenolic nucleophiles
reacted smoothly with 1.5 equiv of the active donor to afford
the desired product exclusively as the β-anomer in moderate to
good yield (Table 1, entries 1−5). Attempts to extend this
result to carbohydrate acceptors appeared promising when the
glucose derivative 7 was used in the reaction (Table 1, entry 6).
The use of more hindered nucleophiles proved to be
problematic, however, affording the products in low yield
(Table 1, entries 7−8).
Table 1. Reaction Scope with N-Tosyl-4-Nitroimidazole
On the basis of these results, we concluded that a second
round of optimization would be necessary to achieve
synthetically useful yields with aliphatic acceptors. For our
model study, we chose to examine the reaction between 1 and
7. Attempts to improve this yield by increasing the donor and
acceptor stoichiometry, adjusting the reaction temperature, and
changing the sulfonylating agents employed proved to be
ineffective (Table 2, entries 1−5). Rationalizing that a more
potent sulfonylating agent would permit higher yields through
complete conversion of the hemiacetal to the glycosyl sulfonate
at low temperature, we turned our attention to p-
toluenesulfonic anhydride. Using this reagent in the presence
of the non-nucleophilic base tri-tert-butylpyrimidine (TTBP),21
we were able to obtain the product 16 in 83% yield as a single
anomer (Table 2, entry 6).
Having established the optimal reaction conditions, we
decided to survey the scope of the reaction. These new
conditions led to a dramatic increase in yield in the reactions
between 1 and hindered acceptors 8 and 9 without
compromising the selectivity (Table 3, entries 1−2 vs Table
Table 2. Reaction Optimization with Carbohydrate
Acceptors
donor
equiv
acceptor
equiv
sulfonylating
agent
temp
(°C)
yield
(%)
entry
α:β
1
2
3
4
5
6
3.0
1.5
3.0
1.5
1.5
1.5
1.0
3.0
1.0
1.0
1.0
1.0
A
A
A
B
C
D
−78
−78
−100
−78
−78
−78
45 β only
42 β only
55 β only
25 β only
trace
−
83 β only
obtain direct stereoselective glycosylation reactions with 2-
deoxy-sugar donors without recourse to prosthetic or directing
groups.
RESULTS AND DISCUSSION
■
Our initial studies focused on using N-tosyl-4-nitroimidazole20
to activate hemiacetal 1 for glycosylation. Preliminary studies
into O-glycosylations used phenolic nucleophiles, as aromatic 2-
deoxy-sugar glycosides are a common motif in many natural
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1, entries 7−8). The less nucleophilic acceptor 18 also reacted
with 1 in good yield and complete β-stereoselectivity. Acceptors
bearing acetonides afforded products 22 and 23 in lower yields,
despite the basic nature of the reaction conditions (Table 3,
entries 4−5). The basis of this reduction in yield is unknown at
this point; however, the reactions still afforded the product as
only the β-anomer, indicating that these groups do not interfere
with the selectivity of the reaction.
Table 3. Reaction Scope with 2-Deoxy-Sugars Promoted by
p-Toluenesulfonic Anhydride
We next chose to examine a more reactive 2,6-dideoxy-L-
arabino hexopyranose donor 24, which represents a common
motif in many bioactive natural products. These products were
of particular interest to us, as the lack of oxygenation at both
C2 and C6 makes these compounds somewhat unstable and
prone to elimination reactions to afford the corresponding
glycal.22 This did not prove to be a problem in our hands,
however, and we were again able to obtain β-linked products
stereoselectively (Table 4). The primary glucose-derived
alcoholic acceptor 7 reacted to afford 15 in 77% yield, while
the more hindered secondary acceptors 8 and 9 afforded
products 26 and 27 in 68% and 70% yield, respectively (Table
4, entries 1−3). Again, acetonide-protected acceptor 19 was
less effective in the reaction, providing disaccharide 28 in
moderate yield as a single isomer (Table 4, entry 4).
Together, these studies help shed light on the mechanism of
the reaction. If the reaction were proceeding through an SN1-
manifold, changing the absolute configuration of one of the
coupling partners would be expected to alter the stereochemical
outcome. Since both D- and L-configured deoxy-donors react to
form β-linked products, this study demonstrates that the
reaction is not subject to stereochemical “match” and
“mismatch” between donors and acceptors of different
configurations.23 The studies point to the reaction proceeding
through the intermediacy of an α-linked electrophilic species
that reacts through an SN2-manifold. Furthermore, the data
support our hypothesis that the stereochemical outcome of the
reaction is entirely under control of the promoter.
To establish the identity of this species, we examined its low-
1
temperature H−13C heteronuclear single-quantum correlation
(HSQC) NMR spectrum. To this end, we treated a THF-d8
solution of the potassium alkoxide of hemiacetal 1 with p-
toluenesulfonic anhydride in an airtight NMR tube at −78 °C.
This experiment revealed a correlation between a broad singlet
ments establish that the reaction proceeds through the
intermediacy of an α-glycosyl tosylate, which presumably reacts
through an SN2-manifold. These studies demonstrate that using
a promoter system designed to convert a hemiacetal into
glycosyl sulfonate where the donor reactivity is matched to the
sulfonate leaving-group ability allows for the stereoselective
construction of glycosidic linkages. Taken together with our
previously reported TBAI/cyclopropenium cation-promoted α-
selective dehydrative glycosylation reaction,24 these results
show that it is possible to obtain either anomer of a glycosidic
linkage starting from the same coupling partners, simply by
changing the promoter.
While it is unlikely that a single sulfonic anhydride can be
used to activate all classes of glycosyl donors to effect β-
selective glycosylations, the reactivity of sulfonates spans several
orders of magnitude.18 Therefore, we anticipate that this
approach will be amenable to other classes of glycosyl donors.
This concept of reagent control and, more specifically, using a
promoter to activate hemiacetals as predefined electrophiles in
situ for SN2-glycosylation reactions will provide a particularly
effective and direct approach to stereocontrolled oligosacchar-
ide and glycoconjugate synthesis.
1
in the H NMR spectrum with a chemical shift of δ 6.11 ppm
and a 13C NMR signal at δ 102.3 ppm, both of which are
consistent with a glycosyl sulfonate (see Supporting Informa-
tion[SI]). The presence of a single anomeric carbon peak
clearly demonstrates that only one anomer is formed at low
temperature. This intermediate 2-deoxy-α-glucosyl tosylate
persisted for nearly 2 h at −78 °C with no indication of
decomposition or anomerization. The tosylate was stable at
temperatures up to −5 °C, but appeared to eliminate rapidly to
form the corresponding glucal above this threshold. These
experiments further corroborate our working hypothesis that
the reaction proceeds through the intermediacy of an α-glycosyl
tosylate that reacts via an SN2-reaction to form β-linked
products specifically.
CONCLUSION
■
In conclusion, we have demonstrated that p-toluenesulfonic
anhydride can activate 2-deoxy-sugar hemiacetals for β-selective
glycosylation reactions. The approach works with a wide range
of acceptors, and the reaction is not sensitive to the absolute
configuration of the donor. Low-temperature NMR experi-
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for 30 min, transferred by syringe to a precooled 5-mm low-
pressure/vacuum valve NMR tube, and promptly inserted into
the NMR instrument probe precooled to −78 °C for 1H NMR,
13C NMR, and 2D-gradient HSQC data acquisition. The
temperature was maintained for 2 h, then warmed by 10 °C
Table 4. Reaction Scope with 2,6-Dideoxy-Sugars
1
every 10 min. At each 10-min interval, the H NMR spectrum
was recorded.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization of all new
compounds. Full VT NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
clay.bennett@tufts.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the National
Science Foundation (NSF 1300334). J.P.I. is supported by a
GAANN graduate fellowship from the U.S. Department of
Education.We thank Dr. David Wilbur (Tufts University) for
assistance with low-temperature NMR experiments.
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EXPERIMENTAL SECTION
■
General Experimental Procedure. A solution of donor
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