Direct Glycosidation of 2-Azido-2-deoxyglycosyl Nitrates

Article abstract of DOI:10.1002/ejoc.201900748

Glycosyl nitrates are important synthetic intermediates which had never been glycosidated before our recent discovery that glycosyl nitrates can be glycosidated in the presence of lanthanides. Presented herein is our preliminary attempt to enhance the uti

Full text of DOI:10.1002/ejoc.201900748

DOI: 10.1002/ejoc.201900748
Communication
Carbohydrates
Direct Glycosidation of 2-Azido-2-deoxyglycosyl Nitrates
Yashapal Singh,[a] Tinghua Wang,[a] and Alexei V. Demchenko*[a]
Abstract: Glycosyl nitrates are important synthetic intermedi- ence of lanthanides. Presented herein is our preliminary at-
ates which had never been glycosidated before our recent dis- tempt to enhance the utility of glycosyl nitrates as donors for
covery that glycosyl nitrates can be glycosidated in the pres- O-glycosidation of 2-amino-2-deoxysugars.
Introduction
Lemieux and Ratcliffe.[9] Inspired by early studies by Trahanov-
sky and Robbins on the synthesis of α-azido-ꢀ-nitroalkanes,[10]
Lemieux and Ratcliffe anticipated that the azide radical-induced
addition to glycals would provide 2-azido-2-deoxyglycosyl
nitrates. This gave rise to the development of the azidonitration
of glycals with sodium azide in the presence of ceric ammon-
ium nitrate (CAN) in acetonitrile. Although this reaction may
proceed with high regioselectivity, achieving the subsequent
glycosidation is cumbersome because the anomeric nitrates
have to be converted to suitable leaving groups such as hemi-
acetal,[11] halide,[9,12] acetate,[13] trichloroacetimidate,[11d,14]
pentenyl,[15] phosphate,[16] thioglycoside,[17] xanthate,[13] etc.[3]
Amino sugars are commonly found as the components of more
complex molecules, mainly antibiotics, glycoproteins, lipopoly-
saccharides, or mucopolysaccharides.[1] Glycosides of 2-amino-
2-deoxysugars are present in many important classes of glyco-
conjugates and naturally occurring oligo-/polysaccharides such
as chitin.[2] Because of the natural abundance of 2-amino sugars
and their involvement in a variety of biological processes, the
development of chemical methods for the synthesis of oligosac-
charides containing these residues represents an important di-
rection of modern glycosciences.[3] Azides have been success-
fully and widely used as amine precursors/protecting groups in
the chemical synthesis of amino sugars. Beyond providing a
relatively simple way to create a C–N linkage, azides have many
advantages over other protecting groups used in synthesis.
These include lower steric hindrance, greater solubility in or-
ganic media, stability under many reaction conditions used in
other protecting group manipulations or during glycosylation
reaction, and the absence of the rotamer formation.[4] In addi-
tion, this protecting group provides excellent atom economy
and the absence of additional hydrogen or carbon nuclei that
could complicate NMR spectra.[4,5] Furthermore, azides can be
easily reduced to amines either concomitantly with other hyd-
rogenation-labile protecting groups or orthogonally by Staud-
inger reaction or thiol-mediated reduction.[6] In addition, azide
groups at C–2 position of glycosyl donors are especially valu-
able because of their non-participating effect during
glycosylation reactions, allowing for the synthesis of 1,2-cis
glycosidic linkages.[3] Until recent reports utilizing N-benzyl-
idene protected donors by Nguyen and co-workers,[7] practi-
cally all 1,2-cis glycosylations for the synthesis of glycosides of
2-amino sugars have employed glycosyl donors equipped with
the 2-azide moiety.[8]
Recently, we discovered that glycosyl nitrates of the
D-gluco,
D
-galacto- and -manno series can be used as effective glycosyl
D
donors for O-glycosylation.[18] Lanthanide triflates have been
found to be suitable promoters for the activation of nitrate leav-
ing groups of regular oxygenated sugars. This observation gave
us an idea that the reaction can also be used for the direct
glycosidation of glycosyl nitrates of the 2-azido-2-deoxy series.
Reported herein is our first attempt to study glycosyl nitrates
of 2-azido-2-deoxysugars as glycosyl donors in chemical
glycosylation reactions.
Results and Discussion
For our preliminary screening we synthesized 2-azido-3,4,6-tri-
O-benzoyl-2-deoxy-
protocol reported herein. According to our previous study, per-
benzylated and per-benzoylated glycosyl nitrates of the -gluc-
ose and -galactose series could be activated efficiently by us-
D
-galactopyranosyl nitrate 1 by a refined
D
D
ing a stoichiometric amount of ytterbium(III) trifluoromethane-
sulfonate [Yb(OTf)3] in Et2O/ClCH2CH2Cl (1,2-DCE, v/v, 1:1).[18]
However, the application of these reaction conditions to
glycosidation of 2-azido donor 1 with primary acceptor 2[19]
afforded the desired disaccharide 3 in only 33 % yield with poor
stereoselectivity (α/ꢀ = 1.6:1, Table 1, entry 1). This poor yield
was on a par with previous results achieved with other unreac-
tive nitrates of the disarmed mannosyl and superdisarmed gluc-
osyl donor series.[18] To improve the utility of this glycosylation
reaction, we endeavored to optimize the reaction conditions.
The use of neat 1,2-DCE as the reaction solvent resulted in the
One of the significant methods used to introduce the 2-azido
moiety to glycals is the azidonitration protocol developed by
[a] Department of Chemistry and Biochemistry,
University of Missouri – St. Louis,
One University Boulevard, St. Louis, Missouri 63121, USA
E-mail: demchenkoa@umsl.edu
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900748.
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–
formation of disaccharide 3 in 19 % yield (α/ꢀ = 1.0:1, entry 2). methide (CTf3 ) is more reactive than Yb(OTf)3. This is because
When the same reaction was conducted in neat Et2O as the CTf3– is a more stable counteranion than OTf–, which makes the
reaction solvent, disaccharide 3 was produced in an enhanced lanthanide center more electrophilic for the “nitrate capture.”[22]
yield of 52 % yield. This reaction proceeded with enhanced α- Han et al. reported that a laborious preparation of the catalyst
–
stereoselectivity (α/ꢀ = 3.7:1, entry 3), which is an anticipated containing a CTf3 counterion is unnecessary for the purposes
outcome of reactions in ethereal solvents.[20] The use of 1,4- of enhancing its reactivity.[23] A similar effect can be achieved
dioxane as the reaction solvent gave disaccharide 3 in a re- by mixing commercial catalyst Yb(OTf)3 with potassium tris(tri-
spectable yield of 77 %. A commendable 1,2-cis stereoselecti- fluoromethanesulfonyl) methide (KCTf3) in situ. Unfortunately,
vity (α/ꢀ = 4.8:1, entry 4) was obtained due to a known effect the counteranion effect was proven insignificant in our glycosyl-
of 1,4-dioxane.[21] When neat CH3CN was used as the reaction ation reactions. Thus, when KCTf3 (0.15 equiv.) was used as an
solvent, disaccharide 3 was obtained in 70 % yield. This reaction additive, the reaction was not accelerated, and the yield did not
proceeded with preferential ꢀ-stereoselectivity (α/ꢀ = 1:3.6, en- increase.
try 5), which is an anticipated outcome of reactions in nitrilic
solvents.[20] Glycosylations performed in some other reaction
solvents, such as DMF or toluene, were sluggish and inefficient.
Since glycosylations in neat 1,4-dioxane provided the most ad-
vantageous combination of the reaction yield and stereoselecti-
vity subsequent studies of this glycosylation reaction were
based on 1,4-dioxane as the reaction solvent.
With the optimized reaction conditions, secondary acceptors
were also investigated with 3,4,6-tri-O-benzoyl galactosyl
nitrate donor 1. The reaction between donor 1 and 2-OH ac-
ceptor 4[19] led to disaccharide 5 in 65 % yield (α/ꢀ = 4.8:1,
Table 2, entry 1). The reaction between donor 1 and 3-OH ac-
ceptor 6[19] gave disaccharide 7 in 58 % yield (α/ꢀ = 10:1, entry
2). The reaction of donor 1 with the unreactive 4-OH acceptor
8[19] gave disaccharide 9 in only 26 % yield, but with exclusive
α-stereoselectivity (entry 3).
Table 1. Optimization of the reaction conditions for glycosidation of galact-
osyl nitrate donor 1.
With the general success of glycosylations with the fairly un-
reactive glycosyl donor 1, we switched to investigating known
3,4,6-tri-O-benzylated galactosyl nitrate donor 10[24] that was
expected to be more reactive (armed) due to the less deactivat-
ing nature of the remote ethereal substituents in comparison
to that of esters.[25] Indeed, glycosyl donor 10 showed much
greater reactivity than its tri-benzoylated counterpart 1. Thus,
glycosidation of donor 10 with the primary glycosyl acceptor 2
in the presence of Yb(OTf)3 (1.5 equiv.) in 1,4-dioxane at r.t.
produced disaccharide 11 in 1 h in 94 % yield (α/ꢀ = 1:2.2,
Table 2, entry 4). The reactions with secondary acceptors were
also quite swift, but generally provided somewhat lower yields,
which were still well within the preparative value. The declined
yields observed were due to competing hydrolysis of the donor.
We also noted a general decline in stereoselectivity, which
could be explained by a well-established inverse correlation be-
tween the reactivity and stereoselectivity.[8] A reaction between
donor 10 and 2-OH acceptor 4 led to disaccharide 12 in 58 %
yield in 1 h (α/ꢀ = 1.4:1, entry 5). The reaction between donor
10 and 3-OH acceptor 6 gave disaccharide 13 in 78 % yield in
1 h (α/ꢀ = 1:1.6, entry 6). The reaction between donor 10 and
4-OH acceptor 8 gave disaccharide 14 in 63 % yield in 20 min
(α/ꢀ = 1:1.5, entry 7). The reaction between donor 10 and benz-
ylidene-protected 3-OH acceptor 15[26] gave disaccharide 16 in
57 % yield in 30 min (α/ꢀ = 1.3:1, entry 8). Finally, the reaction
of donor 10 with di-O-isopropylidene protected 6-OH acceptor
17 gave disaccharide 18 in 93 % yield in 15 min (α/ꢀ = 1:2.4,
entry 9).
Entry
Solvent
Time
Yield of 3
(ratio α/ꢀ)
1
2
3
4
5
6
7
Et2O/1,2-DCE (1:1, v/v), r.t.
1,2-DCE, r.t.
Et2O, r.t.
1,4-dioxane, r.t.
CH3CN, r.t.
1,4-dioxane, 50 °C
1,4-dioxane, 60 °C
18 h
18 h
18 h
18 h
18 h
5 h
33 % (1.6:1)
19 % (1.0:1)
52 % (3.7:1)
77 % (4.8:1)
70 % (1:3.6)
78 % (3.1:1)
71 % (2.8:1)
3 h
Having identified the most suitable reaction solvent, we
turned our attention to optimizing the reaction temperature.
As expected, the glycosidation of 2-azido donor 1 with acceptor
2 was accelerated at elevated temperatures. Thus, as shown in
Table 1, the reaction performed at 50 °C was completed within
5 h to give disaccharide 3 in 78 % yield (α/ꢀ = 3.1:1, entry 6).
Even faster reaction (3 h) was achieved at 60 °C, but both the
yield and stereoselectivity of disaccharide 3 declined (71 %
yield, α/ꢀ = 2.8:1, entry 7). Therefore, we concluded that room
temperature experiments offer the optimal outcome.
Having investigated 2-azido-2-deoxy galactosyl nitrate do-
nors, we switched our attention to 2-azido-2-deoxy glucosyl
nitrate donors. Azidonitration of 3,4,6-tri-O-benzylated glucal is
typically non-stereoselective and produces the C-2 epimers
2-azido-2-deoxy glucosyl and mannosyl nitrates.[27] When cyclic
Having refined the reaction solvent and temperature, we de- acetal protecting groups are used to conformationally constrain
cided to investigate the effect of promoters and additives. As the pyranose ring, 2-azido-2-deoxyglucosyl nitrates are pre-
reported previously, ytterbium(III) tris(trifluoromethanesulfonyl) ferred.[28] Therefore, we chose known 2-azido-4,6-O-benzyl-
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Table 2. Glycosylations with benzoylated and benzylated galactosyl nitrate
donors 1 and 10.
Table 3, entry 1). The reactions with secondary acceptors were
relatively sluggish, perhaps due to the known disarming effect
of the benzylidene acetal.[29] The glycosidation between donor
19 and 2-OH acceptor 4 gave disaccharide 21 in 55 % yield in
20 h (α/ꢀ = 1.6:1, entry 2). The reaction between donor 19 and
3-OH acceptor 6 gave disaccharide 22 in 42 % yield in 20 h
(α/ꢀ = 1.1:1, entry 3). The reaction between donor 19 and
4-OH acceptor 8 led to disaccharide 23 in 31 % yield in 20 h
(α/ꢀ = 2.2:1, entry 4). Finally, the reaction of donor 19 with di-
O-isopropylidene protected 6-OH acceptor 17 gave disacchar-
ide 24 in 78 % yield in 6 h (α/ꢀ = 1:1.8, entry 5).
Table 3. Glycosylations with 2-azidoglucosyl nitrate donor 19.
Conclusions
Presented herein is our preliminary attempt to employ 2-azido-
2-deoxyglycosyl nitrates as donors in O-glycosylation reactions.
Yb(OTf)3 was found to be an effective promoter and 1,4-diox-
ane was found to be the best reaction solvent for these glycos-
idene-2-deoxy-3-O-triisopropylsilyl-ꢀ-
-glucosyl nitrate 19[28] as ylations. The benzylated galactosyl azido nitrate donor showed
D
a more readily accessible substrate to be investigated as the high reactivity with both primary acceptors and secondary ac-
glycosyl donor. The reaction of donor 19 with primary acceptor ceptors in comparison to its acylated counterpart. 2-Azido-4,6-
2 in the presence of Yb(OTf)3 (1.5 equiv.) in 1,4-dioxane at O-benzylidene-2-deoxy-3-O-triisopropylsilyl-ꢀ-
D-glucosyl nitrate
r.t. produced disaccharide 20 in 76 % yield in 20 h (α/ꢀ = 2.5:1, donor showed high reactivity with primary acceptors. The reac-
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Acknowledgments
The authors thank the National Institute of General Medical
Sciences (GM120673) and the National Science Foundation
(CHE-1800350) for generous support of this work.
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Received: May 22, 2019
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