Halide effects on cyclopropenium cation promoted glycosylation with deoxy sugars: Highly α-selective glycosylations using a 3,3-dibromo-1,2- diphenylcyclopropene promoter

Article abstract of DOI:10.1002/ejoc.201200907

A mixture of 3,3-dibromocyclopropene and TBAI promotes highly α-selective glycosylation reactions (up to >20:1) by using deoxy sugar hemiacetal donors. The reaction provides a convenient method for generating highly reactive glycosyl donors in situ from s

Full text of DOI:10.1002/ejoc.201200907

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200907
Halide Effects on Cyclopropenium Cation Promoted Glycosylation with Deoxy
Sugars: Highly α-Selective Glycosylations Using a 3,3-Dibromo-1,2-
diphenylcyclopropene Promoter
Jason M. Nogueira,[a] John Paul Issa,[a] An-Hsiang Adam Chu,[a] Jordan A. Sisel,[a]
Ryan S. Schum,[a] and Clay S. Bennett*[a]
Dedicated to the memory of Professor David Y. Gin
Keywords: Carbohydrates / Diastereoselectivity / Glycosylation / Synthetic methods
A mixture of 3,3-dibromocyclopropene and TBAI promotes
highly α-selective glycosylation reactions (up to Ͼ20:1) by
using deoxy sugar hemiacetal donors. The reaction provides
a convenient method for generating highly reactive glycosyl
donors in situ from shelf-stable starting materials. Both
armed and disarmed sugars undergo the reaction, and selec-
tivity is independent of the configuration of the donor sugar.
glycosylations using deoxy sugar donors.[17,18] The reaction
proceeds through the formation of a glycosyl chloride,
which in the presence of an excess amount of iodide is a
competent donor, presumably through the in situ formation
of a reactive glycosyl iodide.[19] While the conditions toler-
ated a large number of functional groups, and yields were
generally good, the selectivity was only moderate (Table 1
entry 1). In addition, only armed deoxy sugar donors were
found to be effective in the reaction.[20] In this communica-
Introduction
Deoxy sugars constitute an important component of
many biologically active natural products such as vanco-
mycin, landomycin, mithramycin, and vineomycin B-2.[1–5]
While changing the composition of the sugar chains on
these molecules can have profound effects on their bio-
logical activity,[6] very few groups have taken advantage of
this approach for drug discovery.[7,8] This is due to the diffi-
culties associated with the stereoselective construction of
oligosaccharides, especially those possessing deoxy sugar
moieties.[9] In particular, the lack of oxygen at C-2 and C-6
in many deoxy sugars precludes the use of protecting group
strategies normally used to control the stereochemical out-
come of glycosylation reactions.[10–13] In addition, the insta-
bility of many activated deoxy sugars frequently limits their
direct use in synthesis.[14] As a consequence, there is a press-
ing need for stereoselective direct glycosylation reactions
using stable deoxy sugar donors.[15,16]
Table 1. Optimization of cyclopropenium cation promoted dehy-
drative glycosylation.
Results and Discussion
Our group has an interest in developing mild stereoselec-
tive glycosylation reactions using shelf-stable deoxy sugar
donors. Recently, we introduced a new promoter system,
based on cyclopropenium cation activation, for dehydrative
[a] Department of Chemistry, Tufts University
62 Talbot Ave. Medford, MA 02145, USA
Fax: +1-617-627-3443
[a] No TBAI added. [b] No TTBP added. [c] Oxalyl bromide and
TBAI used as a promoter. Chol = cholesterol, TBAI = tetra-
butylammonium iodide, TTBP = 2,4,6-tri-tert-butylpyrimidine,
TBME = tert-butyl methyl ether.
E-mail: clay.bennett@tufts.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200907.
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C. S. Bennett et al.
SHORT COMMUNICATION
tion we report a second-generation promoter for dehy- Table 2. Scope of reaction with 2-deoxy sugars.
drative glycosylations, which provides very high levels of α-
selectivity (up to Ͼ20:1) with both armed and disarmed
sugars.
In an effort to improve the reaction and understand the
basis of the selectivity, we used NMR spectroscopy to ident-
ify key intermediates.[17] Through these studies we found
that while 1a quickly converts hemiacetal donors to the cor-
responding glycosyl chlorides, these latter species react very
slowly with the excess amount of tetrabutylammonium iod-
ide (TBAI) to generate glycosyl iodides. Rationalizing that
a more reactive glycosyl halide would undergo faster ex-
change with the iodide,[21] we next examined the use of di-
bromocyclopropene 1b as a promoter. To this end, we
treated hemiacetal 2a with 1b in the presence of TBAI, fol-
lowed by the addition of cholesterol as an acceptor (Table 1,
entry 2). Under these conditions we observed a slight in-
crease in the selectivity of the reaction, accompanied by a
significant decrease in reaction time. Further studies
showed that both TBAI and base were essential for the effi-
cacy of the reaction (Table 1, entries 3 and 4). To further
enhance the selectivity of the reaction, we next examined
the effects of several solvents. Acetonitrile, which in certain
cases has been shown to promote β-selectivity,[22] led to a
modest increase in α-selectivity (Table 1, entry 5). Further
increases in selectivity were observed with ethereal solvents
(Table 1 entries 6–8), with 1,4-dioxane and diethyl ether af-
fording optimal selectivity.[23] Finally, to assess the necessity
of the dibromocyclopropene promoter, we examined the use
of oxalyl bromide and TBAI as a promoter system. Under
these conditions, the reaction afforded the desired product
dition, there was also a possibility that the selectivity of the
reaction would suffer, due to the higher reactivity of the
glycosyl bromide intermediate. Pleasingly, this proved not
to be the case, as 2,6-dideoxy donor 16 reacted under our
conditions to provide most products in good yield and ex-
cellent selectivity (Table 3). The one exception was with ac-
ceptor 8, which again led to lower selectivity than other
substrates (Table 3, entry 5).
with good selectivity; however, the yield was significantly
attenuated (Table 1 entry 9).
We next sought to examine the scope of the reaction. For
these studies, we chose to use 1,4-dioxane as a cosolvent,
owing to the limited solubility of many acceptors in diethyl
ether. Pleasingly, we found that in most cases both 2-deoxy-
glucose and 2-deoxygalactose donors provided the products
in good yield and excellent selectivity (Table 2). The excep-
tion was when diosgenin (8) was used as an acceptor
(Table 2, entry 4). In this case, both the yield and the selec-
tivity of product 12 were diminished. This was surprising,
considering that the structure of this acceptor closely re-
sembles cholesterol. While the lower yield may be due to
sensitivity of the spiroketal, we have yet to find a satisfying
rationale to explain the loss of selectivity. Importantly, both
glucose- and galactose-derived sugars afforded the product
with similar levels of yield and selectivity, indicating that
changing the configuration of the pyranose substituents did
not affect the outcome of the reaction.
Table 3. Dehydrative glycosylations of 2,6-dideoxy sugars pro-
moted by 1b.
We next turned our attention to 2,6-dideoxy sugars.
These molecules are important components in many natu-
ral products; however, glycosidic linkages between 2,6-dide-
oxy sugars are extremely labile due to the lack of two stabi-
lizing oxygen atoms. While dichlorocyclopropene activation
was compatible with these species, we were concerned that
the 2,6-dideoxyglycosyl bromides that we were generating
Having established that this new promoter was indeed
in situ could decompose in the presence of base. In ad- superior to our previously reported one, we turned out at-
2
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Cyclopropenium Cation Promoted Glycosylation with Deoxy Sugars
tention to disarmed donors.[24] When dichlorocyclopropene with no appreciable loss in selectivity. To the best of our
1a was used as a promoter, disarmed donors did not un- knowledge this is the first example of a dehydrative glyc-
dergo glycosylation reactions. We attributed this to the dis- osylation between a disarmed 2-deoxy sugar donor and a
armed 2-deoxyglycosyl chloride intermediate being too complex aliphatic acceptor.[28–30] In addition, it demon-
stable to undergo exchange with iodide to generate a reac- strates that the diastereoselectivity of these glycosylations
tive species. Reasoning that the more reactive species gener- can be enhanced through fine-tuning of the cyclopropenium
ated by 1b could potentially undergo glycosylation, we cation promoter. In principle, this promoter system should
chose to examine the reaction between 22 and 4 (Scheme 1). be applicable to glycosylation reactions using other classes
Using 1b as a promoter, glycosylation between these two of monosaccharides, perhaps with further tuning of the cy-
species proceeded efficiently to afford 23 with good selectiv- clopropene. This avenue of investigation and studies di-
ity. While the yield of this reaction was somewhat lower rected at determining the exact mechanism of the reaction
than that observed with armed 2a, this result indicates that are currently under investigation in our laboratory.
other classes of glycosyl donors could be amenable to dehy-
drative glycosylation using cyclopropenium cation pro-
moters.
Experimental Section
Typical Glycosylation Procedure: A solution of diphenylcycloprop-
enone (0.75 mmol) and TBAI (0.75 mmol) in CH2Cl2 (5 mL) was
treated dropwise with a solution of oxalyl bromide (2.0 m in
CH2Cl2, 0.375 mL) and allowed to stir at room temperature for
5 min. Once gas evolution ceased, the resulting dark-brown solu-
tion was treated with the hemiacetal donor (0.75 mmol) and TTBP
(1.5 mmol) in CH2Cl2 (4 mL). After stirring for 15 min, the ac-
ceptor (0.25 mmol) in 1,4-dioxane (4 mL) was added to the reac-
tion. Following consumption of the acceptor, the reaction was con-
centrated in vacuo. Flash column chromatography afforded the de-
sired product.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the NMR spectra.
Scheme 1. Glycosylation with disarmed donor 22.
Acknowledgments
Our working hypothesis for the mechanism of the reac-
tion involves conversion of the hemiacetal into the corre-
sponding glycosyl bromide. The α and β anomers are ex-
pected to be in equilibrium, and the β anomer is anticipated
to react at a faster rate leading to the preferential formation
of the α-product.[19,21,25] In the presence of an excess
We thank Tufts University for financial support. J. M. N. is sup-
ported by a GAANN graduate fellowship from the U.S. Depart-
ment of Education.
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In conclusion we have demonstrated that a combination
of 3,3-dibromo-1,2-diphenylcyclopropene and TBAI is a
highly efficient promoter of dehydrative glycosylations with
deoxy sugars. The reaction tolerates a broad range of func-
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nation can promote glycosylations using disarmed donors
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SHORT COMMUNICATION
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Received: July 9, 2012
Published Online: ᭿
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Cyclopropenium Cation Promoted Glycosylation with Deoxy Sugars
Glycosylation
J. M. Nogueira, J. P. Issa, A.-H. A. Chu,
J. A. Sisel, R. S. Schum,
C. S. Bennett* ................................... 1–5
α-Selective dehydrative glycosylations are
achieved by using a cyclopropenium cation
promoter system. The conditions permit
glycosylations using 2-deoxy sugar donors
without the need to isolate highly reactive
intermediates. Yields and selectivity (up to
Ͼ20:1) are good, and the reaction tolerates
a range of substrates, including disarmed
donors.
Halide Effects on Cyclopropenium Cation
Promoted Glycosylation with Deoxy Su-
gars: Highly α-Selective Glycosylations
Using
a 3,3-Dibromo-1,2-diphenylcyclo-
propene Promoter
Keywords: Carbohydrates / Diastereoselec-
tivity / Glycosylation / Synthetic methods
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