2-Nitro-thioglycosides: α-and β-selective generation and their potential as β-selective glycosyl donors

Article abstract of DOI:10.1021/acs.orglett.5b00295

Michael-type addition of thiolates to 2-nitro-d-glucal or to 2-nitro-d-galactal derivatives readily provides 2-deoxy-2-nitro-1-thioglycosides. Kinetic and thermodynamic reaction control permitted formation of either the α-or preferentially the β-anomers,

Full text of DOI:10.1021/acs.orglett.5b00295

Letter
pubs.acs.org/OrgLett
2‑Nitro-thioglycosides: α- and β‑Selective Generation and Their
Potential as β‑Selective Glycosyl Donors
Peng Peng, Yiqun Geng, Inigo Gottker-Schnetmann, and Richard R. Schmidt*
̈
Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany
S
* Supporting Information
ABSTRACT: Michael-type addition of thiolates to 2-nitro-D-glucal
or to 2-nitro-D-galactal derivatives readily provides 2-deoxy-2-nitro-1-
thioglycosides. Kinetic and thermodynamic reaction control
permitted formation of either the α- or preferentially the β-anomers,
respectively. Addition of achiral and chiral thiourea derivatives to the
reaction mixture increased the reaction rate; the outcome is
substrate-controlled. The 2-deoxy-2-nitro-1-thioglycosides are ex-
cellent glycosyl donors under arylsulfenyl chloride/silver triflate (ArSCl/AgOTf) activation, and they provide, anchimerically
assisted by the nitro group, mostly β-glycosides.
ase-catalyzed 2-nitrogalactal concatenation with nucleo-
philes is a very useful tool for forming α-glycosidic bonds
formation of the α-thioglucoside 2α which for stereoelectronic
reasons is due to fast Michael addition from the α-side and
following fast protonation from the β-side. The secondary
amines diisopropylamine and piperidine gave product mixtures.
In DCM as the solvent similar results were obtained: with
triethylamine as the base after 30 min, 1 was completely
transformed into 2α; extending the reaction time to 24 h led to
partial transformation into 3α. As DCM is more polar than
toluene, as expected, the reaction rate was slightly increased. 4-
Pyrrolidinopyridine and DMAP led, depending on reaction time
and base concentration, to an increase in the formation of 3α and
finally of 2β; thus, steric effects override the anomeric effect. The
reported exclusive formation of 2β could not be confirmed.3h
Also other solvents were studied, as for instance ether; however,
no advantages were visible. Therefore, the optimization studies
were performed in toluene as solvent with triethylamine as the
base (Table 1).
The variation of the base concentration showed that 0.01 equiv
of triethylamine led to complete formation of 2α within 30 min
(Table 1, entries 1, 2, and 6). Extension of the reaction time
(entries 3−5) or increasing the triethylamine concentration gave
in a slow reaction the α-thiomannoside 3α and, in an even slower
thermodynamically controlled reaction, the β-thioglucoside 2β
(entries 1−10) in up to ∼75% yield (entry 9). A very high base
concentration and long reaction time (entry 10) led to slow
degradation of 2α, 2β, and 3α resulting in the formation of
complex product mixtures.
B
with L-serine or L-threonine.1 This way, we synthesized all
members of the mucin family.1,2 This chemistry was successfully
employed for the synthesis of various O-, S-, P-, and C-
glycosides.2,3 Also nucleosides could be readily obtained; thus, it
was found that the base had a major influence on the α/β-
selectivity.4 This convenient and highly efficient glycosidation
method could be also extended to 2-nitroglucal. However,
anomeric stereocontrol in this base-catalyzed Michael-type
addition to the nitroolefin moiety was more complex.3d,5
As thiol addition to 2-nitroglycals is particularly efficient, the
derived 2-deoxy-2-nitro-1-thioglycosides are readily available.6
These thioglycosides can also be used as glycosyl donors.6b
Under NIS/TMSOTf activation in dichloromethane (DCM) at
0 °C or in propionitrile at −15 °C, respectively, with O-
nucleophiles, preferentially β-glycosides were obtained. These
studies were recently resumed, as we noticed that the base and
time dependence of thiol additions to 2-nitroglycals could be
used to generate either the α- or β-thioglycosides.
Bis-H-bond donors, such as achiral or chiral thioureas greatly
effect Michael-type additions to nitroolefin moieties.7,8 Hence,
their influence on the reaction rate and α/β-selectivity of thiol
additions to 2-nitroglycals was of interest.
For thioglycoside activation efficient reagents have been
introduced in recent years.9 Hence, the potential of 2-deoxy-2-
nitro-thioglycosides as glycosyl donors and their usefulness for
the important glycosamine glycosidation is now displayed.
In studies of the base and solvent dependence of thiophenol
addition to the readily available 3,4,6-tri-O-benzyl-2-nitro-D-
glucal 1,3k the use of tert-BuOK as the base and toluene as the
solvent (see Scheme 1 and Table 1 in the Supporting
Information), led to a mixture of the α-thioglucoside 2α and
the α-thiomannoside 3α. An increase of the amount of base and
the reaction time shifted the equilibrium in favor of the β-
Addition of thiourea 9 to the reaction mixture (entries 11−
15), in order to raise the Michael-type properties of 1 via H-
bonding to the nitro group, led to fast equilibration (compare
entries 1 and 11, 4 and 13, 5 and 14, 9 and 15); however, the same
results were obtained. Combination of the base and thiourea
activation properties as in the chiral organocatalysts (R,R)-1010
thioglucoside 2β. Hunig’s base and N-methylmorpholine
furnished similar results; however, triethylamine led to clean
Received: January 29, 2015
Published: March 5, 2015
̈
© 2015 American Chemical Society
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Table 1. Optimization of the Reaction Conditions with
Triethylamine As Base and Toluene As Solvent
Table 2. Stability of 2α and 2β in the Presence of
Trethylamine As Base in Toluene As Solvent at Room
a
Temperature
a
b
All reactions were carried out with 1.0 equiv of 2. Yields were 90%−
100%; product ratio was obtained by NMR.
as readdition of thiophenol was faster than elimination to 1;
therefore, also no 3α (and 3β) was formed (entry 2). However,
with more base, after 30 min, appreciable amounts of 3α and 2β
were formed (entry 3) and after 18 h an ∼1:1:6 ratio of 2α, 3α,
and 2β was obtained (entry 4). Practically the same results were
found for 2β: no addition of thiophenol to the reaction mixture
led to equilibration with 1, 2α, and 3α (entry 5), whereas
addition of thiophenol suppressed the formation of 1 (entry 6).
Under all equilibrating conditions the same amount of 2β (∼70−
75%) was found. These results confirm the reaction course in
Scheme 1 with nitronates Aα and Aβ that lead via 1 to 2α, 3α,
and 2β. Protonation of Aβ from the α-side is for stereoelectronic
and thermodynamic reasons disfavored; hence, 3β is not found.
Isolation of 2β was performed by chromatography on silica gel
of equilibrated reaction mixtures (Table 1, entry 9). As 2α
decomposes under these conditions, 2β could be readily
obtained. Pure 2α was obtained by crystallization from solutions
that contained only 2α (Table 1, entries 2, 6). Hence,
chromatography of a mixture of 2α and 3α led to pure 3α.
The structures of these compounds were unequivocally assigned
with the help of NMR data (Table 3). The 1H NMR data clearly
a
Reactions 1−10 were carried out with 1.0 equiv of 1 and 2.0 equiv of
b
PhSH at rt. Reactions 11−17 were carried out by adding 0.3 equiv of
thiourea 9 or 0.05 equiv of (R,R)-10 and (S,S)-10, respectively. Yields
were 90%−100%; product ratio was determined by NMR.
c
and (S,S)-1011 showed only a slight rate difference, with (S,S)-10
being the more efficient catalyst (entries 16, 17). Site selectivity
in favor of α- or β-thiolate addition with (R,R)-10 and (S,S)-10,
respectively, was not observed. Hence, different from conforma-
tionally nonstrained nitro-olefins, thiolate addition to the
conformationally constrained 2-nitroglycal is essentially con-
trolled by the structure of the substrate and not by the
asymmetric induction of the chiral thiourea catalyst.
Table 3. Selected NMR Data of Compounds 2α, β, 3α, 5α, β
In order to confirm the base catalyzed equilibration between
2α, 3α, and 2β (Schemes 1, 2), 2α was treated with triethylamine
Scheme 1. Base Catalyzed Thiophenol Addition to 2-
Nitroglucal 1
a
b
c
Solvent: CDCl3. Solvent: DMSO-d6. The NMR peaks overlap.
show that the compounds are preferentially in the 4C1-
conformation (J2,3 ≈ J3,4 ≈ 10 Hz for 2α and 2β and J3,4 = 7.6
Hz, J4,5 = 9.6 Hz for 3α). The J1,2 values confirmed the assigned
structures, and the 13C NMR shift of C-1 of 3α (δ = 83.97) and
the coupling constant of JC‑1, 1‑H 176 Hz is in accordance with the
expected value.12 Instead of the β-anomer 2β, the α-anomer 2α
was employed in the previously described glycosidation reactions
that led, as correctly assigned, mainly to β-glycosides.6b
Scheme 2. Thiophenol Addition to 2-Nitrogalactal 4
Thiophenol addition to 2-nitrogalactal 41b (Scheme 2)
furnished similar results as those found for 1. The α-anomer
5α was obtained in a very fast triethylamine catalyzed reaction. A
longer reaction time led to the formation of 5β that finally
became the main product. As equilibration was faster in this case,
for stereoelectronic reasons neither the α- nor the β-talo-product
was found. Hence, protonation of the C-2 carbanion
in toluene which led after 3 h to ∼25% of starting material 1
(Table 2, entry 1). Upon addition of thiophenol, 2α was retained,
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intermediate at the α-side is by far slower than protonation at the
β-side. As 5α is more stable than 2α, separation of 5α and 5β by
silica gel chromatography was possible. The structural assign-
ments are based on NMR data (Table 3). As the 1H NMR data of
5α and 5β were previously collected from CDCl3 solutions,
where the proton signals partly overlap, the anomeric assign-
ments were ambiguous. Solutions of 5α and 5β in DMSO-d6 led
to quite well separated 1H NMR shifts, and also the X-ray analysis
of 5β confirmed the C1-configuration (Figure 1, CCDC no.
1043491). Thus, the structures could be unequivocally assigned.
5). Diethyl ether as solvent did neither support the reaction nor
lead to preferential α-glycoside formation (entries 6, 7), and
THF as solvent led to a dramatic decrease in yield, as THF was
decomposed by the promoter system (entries 8−10). Hence, the
nitro group provides strong anchimeric assistance in these
glycosidations. A direct neighboring group participation of the 2-
nitro group at the anomeric center is for energetic reasons not
expected.14 A nitro group mediated stabilization of the H4-
3
conformer of the glycosyl cation together with a strong electronic
shielding of incoming nucleophiles on the α-side favor β-
anomeric attack. The β-directing effect of corresponding 2-fluoro
substituted glycosyl donors was also explained by the preference
15
3
for the H4-conformer. These effects cannot be overcome by
the ether solvent effect; the results in THF as the solvent are not
conclusive due to the unknown influence of the solvent
decomposition products on the anomeric selectivity. However,
H-bond formation of the acceptor to the donor nitro group could
overcome the shielding effect and thus favor α-product
formation. Hence, trifluoroethanol (6b) that is prone to H-
bond formation16 was selected as the acceptor and, indeed,
appreciable amounts of the α-products (7bα, 8bα) were formed
(entries 11−13). Thus, via increased H-bonding a strong dual-
directing effect of the nitro group can be envisaged.17,18
Figure 1. X-ray diffraction analysis of compound 5β (Ortep plot at 50%
probability ellipsoids).
With this activation protocol for the glycosyl donors 2α, 2β,
5α, and 5β in hand, we studied the glycosidation of various
acceptors (Table 5). The reactions with isopropanol show
(entries 1, 2 and 8, 9) that, independent of the anomeric
configuration of the donor, exclusively the β-products 7aβ6b and
8aβ,6b respectively, were obtained. Hence, we used for the
following reactions the β-thioglycoside donors 2β and 5β.
Reaction with 6-O-, 2-O-, 3-O-, and 4-O-unprotected glucosides
6c−6f as acceptors furnished the β-products 7cβ3h and unknown
7dβ, 7eβ, and 7fβ in very good yields (entries 3−6). Also less
reactive 2,3,4-tri-O-benzoyl protected galactoside 6g gave with
2β exclusively the β-disaccharide 7gβ (entry 7). Similarly, with
the preactivation protocol,9a,19 from 5β as the donor and 6c and
6e as acceptors, almost exclusively the β-linked disaccharides
8cβ1b and 8eβ were generated (entries 10, 11).With the present
procedures, the thiogalactoside acceptor 6h could also be
glycosidated yielding practically exclusively β-linked disaccharide
8hβ, that is available for further chain extension with the same
promoter system (entry 12).9a Not unexpected for galactosyl
donors, some minor amounts of the α-linked glycosides were
detected that could be readily separated by chromatography. It is
noteworthy that β-1,4-linked disaccharides 7eβ and 8eβ could
not be obtained by direct Michael-type addition of the sterically
demanding acceptor 6e to 2-nitro-glycals.1b,3h
Improvements in glycosidation methodology are still in
demand.13 Hence, glycosyl donors with a nitro group in the 2-
position could provide a versatile alternative for the synthesis of
glycosamine glycosides, as the nitro group can be readily reduced
to the amino group.1c Thus, this approach is of importance, for
instance, for the synthesis of glycopeptide O- and N-glycans and
of glycosaminoglycans, respectively.
Previous glycosidation attempts with 2-nitro-1-thioglycosides
2α and 5α as glycosyl donors (not the β-anomers 2β and 5β but
the α-anomers were employed; see above) were performed with
NIS/TMSOTf as the promoter in DCM at 0 °C.6b The present
studies with 2β as the donor and 6d as the acceptor under varying
reaction conditions show (see Table 4, entries 1−5) that ArSCl/
AgOTf as the promoter system, in DCM as the solvent at −60
°C, leads to much better results in terms of product yield and
anomeric selectivity. Thus, from 2β and 6d the β-disaccharide
7dβ could be stereoselectively obtained in high yield (entries 4,
a
Table 4. Optimization of the Glycosidation Conditions
In conclusion, kinetic and thermodynamic reaction control of
thiolate addition to 2-nitroglycals permits the selective synthesis
of either α- or β-2-deoxy-2-nitro-1-thiogluco- and galatopyrano-
sides, respectively. The reaction rate is increased by the addition
of bis-H-bonding thioureas as the catalyst; with chiral derivatives
no influence on the α/β ratio was observed. The substrate
inherent strong stereoelectronic effect, favoring fast thiolate
addition from the α-side, overrides the anomeric diastereose-
lection control by a chiral thiourea.
The aryl 2-deoxy-2-nitro-thioglycosides obtained were
efficient glycosyl donors under arylsulfenyl chloride/silver triflate
activation. Moreover, due to anchimeric assistance by the nitro
group, they afford mainly the β-products. As the nitro group can
be readily transformed into the amino group, a competitive
alternative to the acylamino group assisted glycosidation of
glucosamine and galactosamine derivatives is available.
a
Reactions were carried out at −60 °C for 5 h except as otherwise
b
c
noted. NIS (2.0 equiv), TMSOTf (0.1 equiv) for 1 h. Reaction
temperature 0 °C. p-TolSCl (1.1 equiv), AgOTf (3.0 equiv). p-
O2NC6H5SCl (1.2 equiv), AgOTf (3.0 equiv) Preactivation.
d
e
f
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a
The reactions were performed in DCM at −60 °C with 1.2 equiv of
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data of new
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
■
S
Overkleeft, H. S.; Codee
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Richard.Schmidt@uni-konstanz.de.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful to University Konstanz for support of this work.
■
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