An Air- and water-stable iodonium salt promoter for facile thioglycoside activation

Article abstract of DOI:10.1021/ol5004059

The air- and water-stable iodonium salt phenyl(trifluoroethyl)iodonium triflimide is shown to activate thioglycosides for glycosylation at room temperature. Both armed and disarmed thioglycosides rapidly undergo glycosylation in 68-97% yield. The reaction

Full text of DOI:10.1021/ol5004059

Letter
pubs.acs.org/OrgLett
An Air- and Water-Stable Iodonium Salt Promoter for Facile
Thioglycoside Activation
An-Hsiang Adam Chu, Andrei Minciunescu, Vittorio Montanari, Krishna Kumar, and Clay S. Bennett*
Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, Massachusetts 02155, United States
S
* Supporting Information
ABSTRACT: The air- and water-stable iodonium salt phenyl(trifluoroethyl)-
iodonium triflimide is shown to activate thioglycosides for glycosylation at
room temperature. Both armed and disarmed thioglycosides rapidly undergo
glycosylation in 68−97% yield. The reaction conditions are mild and do not
require strict exclusion of air and moisture. The operational simplicity of the
method should allow experimentalists with a limited synthetic background to
construct glycosidic linkages.
he recognition of the critical roles that oligosaccharides
and glycoconjugates play in an array of biological
shown to rapidly alkylate the thioether of methionine, even
during solid-phase peptide synthesis where nucleophiles display
reduced activity.9b Furthermore, we anticipated that using 1 to
activate thioglycosides would not result in the formation of
electrophilic byproducts that can sometimes complicate
glycosylations when using other thiophilic promoters (Scheme
1).10 Based on these observations we anticipated that 1 would
promote thioglycoside activation under particularly mild
conditions.
T
processes has led to significantly increased interest in
glycobiology over the past two decades.1,2 Despite this interest,
the field is still in its infancy compared to genomics and
proteomics. This is due in large part to the limited availability of
oligosaccharides to serve as standards for biological analysis. A
major reason for this is the difficulty associated with chemical
glycosylation reactions.3 In addition to the challenge of
controlling stereochemistry in oligosaccharide synthesis,4
many glycosylation reactions are extremely technically demand-
ing and require the use of water/air sensitive reagents. As a
consequence, extensive synthetic training is required to
successfully execute oligosaccharide synthesis, limiting its use
to highly specialized laboratories. We envisioned that if
carbohydrate synthesis is to be adopted by the broader
chemical biology community it will be necessary to develop
protocols that utilize shelf stable donors and promoters under
simple to use reaction conditions (room temperature, minimal
effort to exclude moisture). After surveying various donors for
oligosaccharide synthesis, we concluded that thioglycosides fit
this profile well and decided to examine mild and shelf-stable
thiophilic promoters for their activation. While many methods
for thioglycoside activation have been reported, most require
the use of toxic or unstable reagents, and/or extremely low
reaction temperatures.5 This has led to recent interest in
developing milder approaches to glycosylation reactions using
thioglycoside donors.6,7 A major part of our research program is
directed at developing facile yet highly efficient glycosylation
procedures. Here we report the use of phenyl(trifluoroethyl)-
iodonium triflimide (1) as a water- and air-stable thiophilic
glycosylation promoter.
Our preliminary study employed fully armed glucose
thioglycoside donor 211 and cholesterol (3) as coupling
partners (Table 1). Pleasingly, dropwise addition of a solution
Scheme 1. Phenyl(trifluoroethyl)iodonium Triflimide As a
Glycosylation Promoter
Table 1. Reaction Optimization
entry
time (h)
base
% yield
α:β
1
2
3
0.2
24
1
−
−
TTBP
63
0
1.9:1
N/A
1:1
The iodonium salt 1 is a remarkably air- and water-stable
crystalline solid that is readily synthesized in good yield in two
steps starting from 1,1,1-trifluoro-2-iodoethane.8 Not only does
the preparation of 1 involve a final crystallization from ice water
followed by drying under high vacuum, but it has also been
shown to selectively alkylate amine nucleophiles in aqueous
media.9 In addition, longer chain analogues of 1 have been
71
55
a
4
1
TTBP
1:1.2
a
Reaction was run open to air. TTBP = 2,4,6-tri-tert-butylpyrimidine.
Received: February 7, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Letter
Table 2. Reaction Scope with Fully Substituted Donors
Table 3. Reaction Scope with 2-Deoxy- and 6-Deoxy-sugar
Donors
various acceptors in consistently good yields (72% to 95%).
Importantly, both reactive and sterically hindered acceptors are
competent coupling partners in the reaction. The promoter
tolerates the presence of acetals, alkenes (e.g., cholesterol),
ethers, esters, azides, and carbamates. In most cases a 1:2
donor-to-acceptor ratio was sufficient to promote complete
glycosylation within 1 h.
of 1 (1.2 equiv) in dichloromethane to a premixed solution of
the donor and acceptor at room temperature led to rapid
formation (<20 min) of the desired glycosylation product in
63% yield (Table 1, entry 1). Importantly, additives normally
used in glycosylation reactions to remove excess water, such as
molecular sieves, were not necessary. Attempts to improve the
yield through longer reaction times led to complete product
decomposition (Table 1, entry 2). We reasoned that this was
promoted by acidic trifluoromethanesulfonimide byproducts
generated during the course of the reaction. Consistent with
this rationale, adding the non-nucleophilic base 2,4,6-tri-tert-
butylpyrimidine (TTBP) to the reaction prevented any
unwanted side reactions, thereby allowing for longer reaction
times and an increase in yield (Table 1, entry 3). Finally,
intrigued by the stability of the promoter and ease of setup we
decided to assess the robustness of the reaction. To this end, we
ran it exposed to open air (Table 1, entry 4). Under these
conditions the product was obtained in slightly decreased yield
(55%), indicating that strict exclusion of moisture is not
entirely necessary to conduct this chemistry. This yield was less
than optimal, however, due to competitive reaction of the
activated thioglycoside with water to afford the corresponding
hemiacetal. We therefore used an argon atmosphere for the rest
of this study.
When disarmed donors were used the reaction was slower,
and both donor decomposition and byproduct formation again
became a problem. In order to address this problem we decided
to use the acceptor as the limiting reagent. Under these
modified conditions, the reactions still took slightly longer to
proceed (2 to 3 h). Despite this, the reaction now proceeded in
synthetically useful yields (91−95%, products 13 and 14).
Having established that the promoter could rapidly activate
thioglycosides for glycosylation, we turned our attention to
deoxy-sugar donors (Table 3). These sugars are an important
component of many biological systems, including human
glycoproteins,12 bacterial polysaccharides,13 and natural prod-
ucts.14 The lack of oxygenation in these molecules, either at C2
or C6, destabilizes these glycosidic linkages relative to other
sugars. As a result, product decomposition during the course of
the reaction can be a problem if reaction conditions are too
acidic.15 Pleasingly, we found that 1 could promote
glycosylations with both 2-deoxy- and 6-deoxy-sugar donors
in good to excellent yield (68%−97%). As with the fully
substituted sugars in Table 2, these studies used a 1:2 donor-to-
acceptor ratio for thioglycosides possessing arming protecting
Having established optimal reaction conditions, we turned
our attention to the scope of the reaction. As shown in Table 2,
fully substituted thioglycoside donors all reacted smoothly with
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Letter
1334. (f) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015−
groups. Once again, however, the presence of disarming
protecting groups was problematic when the donor was used
as the limiting reagent. As with our above study, this problem
could be dealt with by modifying conditions so that the donor
was used in excess. In all cases examined, under the optimal
conditions product decomposition was not observed, even with
highly reactive 2-deoxy-sugar donors.16 The fact that we were
able to use this promoter to make relatively unstable products
such as 22 to 24 without incident or modification to the
reaction conditions further demonstrates the effectiveness of
this new promoter.
In conclusion, we have described the use of phenyl(tri-
fluoroethyl)iodonium triflimide (1) as a representative of a new
class of single-component thiophilic promoters. As a water- and
air-stable white crystalline solid, the iodonium salt offers an
advantage over other glycosylation promoters through its
particular ease of handling. The salt is stable for 5 days at room
temperature and will keep for more than 6 months if stored in
the refrigerator in the dark. Furthermore, low temperatures or
additives used to remove water from the reaction, such as
molecular sieves, are not necessary to run this chemistry. The
reaction is robust, and a wide array of thioglycoside donors
were shown to cleanly and rapidly undergo glycosylations in
high yields at room temperature. Due to the mildness of the
reaction conditions, the procedure permits the construction of
sensitive glycosides, such as 2-deoxy- and 6-deoxy-sugars. We
envision that this approach will significantly facilitate
oligosaccharide synthesis and ultimately lay the foundation
for chemistries that will permit experimentalists with a limited
synthetic background to construct their own oligosaccharide
standards.
́
9020. (g) Codee, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.;
Overkleeft, H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett.
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thioglycosides, see: Goswami, M.; Ellern, A.; Pohl, N. L. B. Angew.
Chem., Int. Ed. 2013, 52, 8441−8445.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: clay.bennett@tufts.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Tufts University and the National Institutes of
Health (CA125033 to K.K.) for support of this work.
■
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