Superbase-Catalyzed Stereo- And Regioselective Glycosylation with 2-Nitroglycals: Facile Access to 2-Amino-2-deoxy- O-glycosides

Article abstract of DOI:10.1021/acscatal.0c00753

An efficient superbase-catalyzed stereo- and regioselective glycosylation of 2-nitroglycals with high functional group compatibility is reported. The ion pair generated from alcohol and a catalytic amount of P4-t-Bu was vital for the successful implementa

Full text of DOI:10.1021/acscatal.0c00753

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Research Article
Superbase-Catalyzed Stereo- and Regioselective Glycosylation with
2‑Nitroglycals: Facile Access to 2‑Amino-2-deoxy‑O‑glycosides
́
́
Kumar Bhaskar Pal, Aoxin Guo, Mrinmoy Das, Gabor Bati, and Xue-Wei Liu*
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ABSTRACT: An efficient superbase-catalyzed stereo- and regio-
selective glycosylation of 2-nitroglycals with high functional group
compatibility is reported. The ion pair generated from alcohol and
a catalytic amount of P4-t-Bu was vital for the successful
implementation of this stereoselective glycosylation under mild
conditions, producing moderate to good yields. Under reported
reaction conditions, 2-nitrogalactals produce α-stereoisomers
exclusively, while 2-nitroglucal yielded more β-products. The
notable difference between the outcomes was investigated by the
density functional theory (DFT) study. In addition, we have
synthesized the key intermediate of a mucin-type core-6
glycoconjugate, thus illustrating the synthetic potency of this
method.
KEYWORDS: 2-nitroglycals, superbase, stereo- and regioselective glycosylation, ion pair, dipole−dipole interaction,
mucin-type core 6 glycan
haracterization, chemical preparation, and investigations
into the structure−function relationships of glycans and
reduction and acetylation step was easily performed by Galan’s
group.6d
In recent times, developing novel methodologies to prepare
C
glycoconjugates are of high practical interest and a discipline to
which continued scientific endeavors are devoted.1 2-Amino
sugars are one of the most significant classes of carbohydrates
that can be found in several natural products e.g., TMG-
chitotripmycin, tunicamycin V, ribostamicins, streptomycin,
gentamicins, and lividomycins.2 They contribute to extensive
diversity of biologically important functions including immune
and anti-inflammatory effects, antifungal and antibacterial
responses, surface-functionalized nanocarriers for the medi-
cation of numerous diseases.3 Alongside this, a certain number
of biologically important polysaccharides e.g., chitosan, heparan
sulfate, and peptidoglycans are there in which the 2-amino-2-
deoxy-O-glycoside structures are imparted. Thus, in the world of
carbohydrate chemistry, synthesis of 2-amino-2-deoxy-O-glyco-
side structures has been one of the most fascinating areas to
work on in recent days. Since most of the naturally occurring 2-
amino-2-deoxy sugars are N-acetylated, glycosylation with the
pristine 2-acetamido-2-deoxy glycosyl donor would be pref-
erable to simplify the protection strategy. However, the
traditional 1,2-trans-glycosylation of 2-acetamido glycosyl
donors turned out to be low yielding due to the formation of
a stable oxazoline intermediate.4 Besides that, 1,2-cis glyco-
sylation with 2-azido glycosyl is often accompanied by poor
stereoselectivity.5 As an alternative synthetic strategy, switching
the donor to 2-nitroglycals would afford us new prospects for
both 1,2-trans and 1,2-cis glycosides stereoselectively.6 To arrive
at the native 2-acetamido-2-deoxy glycosides, the subsequent
stereoselective O-glycosidic linkages gained interest in the
chemists’ society to a great extent.7−13 Over the past few years,
several alluring approaches have been ferreted out on
regioselective glycosylation and synchronously performing
both stereo- and regioselective glycosylation7,11b,14−18 providing
solutions for the daunting challenges associated with several
orthogonal protection and deprotection steps in oligosaccharide
synthesis. Despite the efforts that have been made toward
stereoselective glycosylation,4 we have identified an important
research gap to be filled, aiming to provide an alternative method
toward oligosaccharide and biologically salient natural product
synthesis.
Noticeably, in recent years, organic catalysts are making a
significant contribution in the stereoselective glycosylation of 2-
nitroglycals.6b−d In 2009, Yu and his co-workers demonstrated
the role of 4-dimethylaminopyridine (DMAP) and 2-phenyl-
pyridine (PPY) in the stereoselective β-glycosylation of 2-
nitroglycals.6b Schmidt’s group reported an exceptional method
Received: February 13, 2020
Revised: May 19, 2020
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© XXXX American Chemical Society
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Scheme 1. Optimized Reaction Conditions for Stereoselective O-Glycosylation of 3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-galactal
a
(2a) with Methyl-2,3-O-isopropylidene-D-ribofuranoside (3a)
a
Isolated yield.
Figure 1. Stereoselective α-O-glycosylation of 2a with a range of glycosyl acceptors (3b−3p). The reactions were carried out under a N2 atmosphere
using 0.075−0.15 mmol of 3,4,6-tri-O-benzyl-2-nitro-D-galactal (2a), 0.05−0.1 mmol of the acceptor, and 0.01−0.02 mmol of P4-t-Bu in hexane (10 or
20 mol %) in 2−4 mL of dry toluene for 24 h. Isolated yields.
to equip 2-nitrothioglycosides that act as mediators for the
formulation of 1,2-trans glycosidic linkages by utilizing chiral
thiourea catalysts.6c Recently, Galan and her team provided a
wonderful approach to furnish 2-nitrogalactosides with α-
stereoselectivity by employing a bifunctional chiral thiourea
catalyst,6d but certainly, the detailed mechanistic rationale
behind those stereoselective glycosylation reactions are awaiting
further empirical and theoretical investigations to be unraveled.
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Figure 2. Recent β-Selective O-glycosylation of 6a with a variety of glycosyl acceptors. a Stereoselectivity determined by 1H NMR. b Both anomers were
separated by flash column chromatography. Reaction conditions as in Figure 1. Isolated yields.
In the last 2 decades, P4-t-Bu has emerged as an exceedingly
valued tool in developing general and versatile synthetic
methods. It has received considerable attention for the
formation of carbon−carbon (C−C) and carbon−heteroatom
(C−X) bonds in several organic syntheses.19 Since the efficiency
of the phosphazene bases in carbohydrate chemistry has not
been assayed before, and thus, as a part of our ongoing research
interest in stereo and regioselective glycosylation,8b,11 we
envisioned that 2-nitroglycal, being an olefinic pyranose,
would react with the activated alkoxide ion pair derived from
glycosyl acceptors with a catalytic amount of P4-t-Bu to
eventually yield O-glycosides. On top of that, we assumed that
the large protonated P4-t-Bu ion pair could concede the
foundation for a stereoselective attack for the approaching
alkoxide toward 2-nitroglycal.
At the very outset to optimize the reaction condition, we
treated 3a with 3,4,6-tri-O-benzyl-2-deoxy-2-nitro-galactal
(2a)20 with an array of organic and inorganic bases both in
catalytic and stoichiometric amounts (Supporting Information,
Table S1). From these results, we have observed that P4-t-Bu
worked more efficiently starting the reaction at 0 °C and slowly
warming up to room temperature, yielding 89% (Scheme 1).
Throughout the catalyst screening, we found the loading crucial,
as the reaction provided lower yield when stoichiometric or 5
mol % of P4-t-Bu were introduced into the reaction. Moreover,
we have been fascinated by the exclusive α-selectivity when P4-t-
Bu was applied. Finally, it should be emphasized that we got a
decent yield even when we performed the reaction at 70 °C
(Supporting Information, Table S1).
Having these optimized reaction conditions in hand, we then
explored the substrate scope of this stereoselective Michael-type
addition reaction of 2-nitrogalactals. As carbohydrate synthesis
often employs a wide range of protecting groups, we set out to
explore their tolerance in our transformation. Throughout our
studies, we have investigated the glycosylation of model 2-
nitrogalactal donor, 2a with a range of alcohols, ornamented by
electron-withdrawing, and electron-donating protecting-groups
(Figure 1). In each case, the reaction provided the
corresponding glycosylated products with entirely α-selectivity
in low to high yields. It must be mentioned that we pulled out
better yield when we have used 20 mol % P4-t-Bu while
conducting glycosylations with secondary alcohols (Figure 1).
Sterically hindered alcohols 3i and 3n (see the Supporting
Information) afforded lower yield (19% 4i and 27% 4n,
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Table 1. Reaction of Various 2-Nitroglycal 2b−2d and 6b−6d
a
Donors with Glycoside Acceptor 3a
b
entry donor
R1
Bn
Bn
Allyl
Bn
R2
Ac
Bn
Allyl
Ac
R3
Bn
Ac
Allyl
Bn
product yield (%)
α/β
1
2
3
4
5
6
2b
2c
2d
6b
6c
6d
4q
4r
60
64
76
42
51
63
1:0
1:0
1:0
0:1
0:1
1:8
4s
7l
Bn
Bn
Bn
Bn
Ac
TBDPS
7m
7n
a
The reactions were carried out under an inert atmosphere (N2)
using 0.15−0.3 mmol of 3,4,6-tri-O-benzyl-2-nitro-D-galactal (2a),
Figure 3. Calculated structures and relative energies of plausible 2-
nitroglycal-P4-t-Bu ion-pair intermediates.
0.1−0.2 mmol of the acceptor, and 0.01−0.02 mmol of P4-t-Bu in
b
hexane (10 mol %) in 2−4 mL of dry toluene for 24 h Isolated
yields.
position, while still maintaining a high yield (Figure 2). This
observation was later thoroughly investigated by density
functional theory (DFT) calculation with 6a donor and 3b
acceptor (Figure 3). Gratifyingly, this method proceeded with
moderate to excellent yields, which demonstrates that the
reaction condition tolerates a variety of common carbohydrate
protecting groups. This method performed exceptionally well on
primary alcohols, yielding a glycosidic product in favor of the β-
anomer (7a, 7b, 7c, and 7e, Figure 2). On the contrary, most of
the secondary alcohols brought forth corresponding glycosides
(7d, 7f, 7g, 7h, and 7i, Figure 2) with a 3:2 to 3:1 β/α
stereoselectivity. The reaction of cyclohexanol 3x with 6a also
proceeded to provide 7j in 75% yield with β-stereoselectivity
(Figure 2, >7:1 β/α). The use of the sterically hindered tertiary
alcohol 1-adamantol 3i led to the formation of 7k in 23% yield
with relatively weak β-selectivity when allowed to react with 6a
(Figure 2, 3:2 β/α).
DFT calculations were performed to explicate the mechanism
leading to the stereoselectivity of the glycosylation. The results
indicated that for glycosylation of both 3,4,6-tri-O-benzyl-2-
deoxy-2-nitro-galactal (2a) and 3,4,6-tri-O-benzyl-2-deoxy-2-
nitroglucal (6a), the α-glycoside product is thermodynamically
favored over the β-stereoisomer, with an energy difference
between α- and β-stereoisomers ΔEα−β = −2.3 kcal/mol for 2a
and ΔEα−β = −2.1 kcal/mol for 6a (Figure 3). Nevertheless, the
identification of transition states (TSs) arising from the reaction
routes of P4-t-Bu base-catalyzed glycosylation, leading to
different anomeric isomers (α- or β-face attack) revealed
disparate thermokinetics of glycosylation of 2a and 6a. For
glycosylation of 2a, the TS of the reaction route leading to α-
glycoside is lower in energy level by 3.9 kcal/mol with respect to
the TS of the reaction route leading to β-glycoside (Figure 3).
Figure 4. Schematic representation of the proposed mechanism giving
rise to different stereoselectivities in P4-t-Bu base-catalyzed glyco-
sylation.
respectively, Figure 1) as expected. Furthermore, in cases of
alcohols 3j and 3o (see the Supporting Information), the yields
were moderate (45% 4j and 41% 4o, respectively, Figure 1), but
each case providing exclusive α-selectivity.
To investigate whether this method is extendable to 2-
nitroglucal derivatives, we turned our attention to exploring the
scope of P4-t-Bu catalyzed glycosylation on known donor O-
benzyl protected 2-nitroglucal (6a).20 Repeating the glyco-
sylation with an array of sugar acceptors, including a series of
common carbohydrate protecting building blocks, we were
surprised by the completely reversed selectivity at the anomeric
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c
Table 2. Regio- and Stereoselective Glycosylation of 2a with Various Glycoside Diol Acceptors (3s−3w)
a
b
c
All of the reactions afforded the α-stereoisomer. Isolated yields. Reaction conditions as in Table 1, and all of the reactions were carried out at 0
°C for 12 h.
Contrarily, for the glycosylation of 6a, TS of the reaction route
leading to α-glycoside is higher in energy level by 2.3 kcal/mol
with respect to the TS of the β-face reaction route (Figure 3).
Hence, while the formation of α-glycoside is both thermody-
namically and thermokinetically favored for 2a, the formation of
β-glycoside is thermokinetically favored for 6a. Presumably, the
contrast in the relative energy level of α- and β-TSs for 2a and 6a
can be ascribed to the steric repulsion between the alkyl groups
on the bulky phosphazenium cation (P4-t-BuH+) accompanying
the alkoxide nucleophile and the benzyl protecting groups on the
glycal substrate: In 2a, the C4 benzyl group sticks at the axial
position and pointing away from α-face, leaving the α-face of the
pyranose ring accessible, while repelling bulky nucleophiles
approaching from the β-face (Figure 4), whereas in 6a, the C4
substituent lies at the equatorial position and points away from
the β-face, leaving β-face exposed, while repelling bulky P4-t-
BuH+RO− approaching from the α-face (Figure 4).
catalyzed alcohol glycosylation reaction is virtually non-
reversible under the optimal conditions. The disparity in
reversibility can be explained by fact that the reaction outcome
of alcohol addition to aryl−alkene reaction is governed by
thermodynamics, while thermokinetics plays a more decisive
role in determining the outcome of the P4-t-Bu base-catalyzed
glycosylation reaction (see the Supporting Information for a
detailed discussion).
Inspections on the geometry of the TS species arising in
thermokinetically favored reaction routes reveal that the
distance between the P4-t-Bu quaternary ammonium nitrogen
and glycal 2-nitro group oxygen is 5.78 Å for the glucal-TS and
5.81 Å for the galactal-TS, both falling within the typical length
range of attractive dipole−dipole interactions. The computa-
tional results suggest that in TS species for both 2a and 6a,
attractive interactions between the permanent dipoles of the P4-
t-Bu quaternary ammonium group and the glycal nitro group
may be present. The plausible dipole−dipole interaction in the
TS species is expected to moderately shift the electron density
on the 2-nitroglycal substrate further toward the electron-
withdrawing nitro group, lowering the electron density on
adjacent carbons and enhancing the electrophilicity of the
It is worth mentioning that the P4-t-Bu base-catalyzed alcohol
addition to aryl alkenes reported by Bandar and his co-
workers,21 which closely resembles our glycosylation reaction, is
reversible under optimal conditions, while DFT computations
and experimental observations indicate that the P4-t-Bu base-
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Scheme 2. Synthesis of the Key Disaccharide Intermediate of Mucin-Type Core 6 Glycan and a Model Trisaccharide
anomeric center. This inference is further corroborated by the
computed Mulliken charges of C1 and C3 on the glycal ring
(Supporting Information, Table S8). In both 2-nitroglucal and
galactal, the Mulliken charges of C1 and C3 are slightly more
positive in the TS species with respect to the free 2-nitroglycal
substrates. The computational results agree with our observa-
catalyst, a few more reactions were attempted with a range of
diols. Galactoside diol 3t afforded the less-hindered 3-O-α-
glycosidic product (4u, 64%) alongside with other 4-O-
regioisomer in 5% (4u′), perhaps credited to the steric
hindrance around the axial hydroxyl groups (Table 2, entry
2).22 However, surprisingly, intrinsic site selectivity22,23 has
been reversed in the case of mannoside diol 3u (Table 2, entry
3), drafting a greater extent of axial the 2-O-glycosidic product
4v (66%) over the less-hindered 3-O-glycoside 4v′ (6%).
Glycosylation with the glucoside diol 3v afforded 6-O-glycoside
4w (84%) with an absolute α-stereoselectivity, explicitly proving
that 6-O-glycosylation advances much quicker than 4-O-
glycosylation (Table 2, entry 4). However, it is worth noting
that the glucoside diol 3w solely furnished 3-O-α-glycoside (4x,
63%) with complete regioselectivity (Table 2, entry 5).
DFT computations of the relative stability of ion pairs formed
at different positions of the sugar acceptor have been performed
to rationalize the experimentally observed regioselectivity of the
reaction. The results from the optimized alkoxide-phosphaze-
nium ion pair structures (Supporting Information, Table S6 and
Figure S6) suggest that, for the fused ring glucose acceptor 3s, 2-
position ion pair is favored over the 3-position ion pair by ∼11.9
kcal/mol, probably resulting from a stronger steric interaction
between the bulky phosphazenium and the silyl-di-tert-butyl
group on the fused ring in 3-position ion pair (Supporting
Information, Table S6 and Figure S6). For the mannose
acceptor 3u, 2-position ion pair is favored over its 3-position
counterpart by ∼7.4 kcal/mol, presumably stabilized by the
hydrogen bond between the pyranose ring oxygen and the
protonated phosphazenium cation (Supporting Information,
Table S6 and Figure S6). For the 2-phthalimido glucose
acceptor 3w, the 3-position ion pair is favored over its 4-position
counterpart by ∼9.8 kcal/mol, presumably stabilized by the
hydrogen bond between the protonated phosphazenium cation
1
tions from H NMR experiments (Supporting Information,
Figures S3 and S4). The H1 and H3 peaks of 2-nitrogalactal (2a)
endured a weak yet appreciable downfield shift (7.643−7.649
ppm for H1 and 4.569−4.580 ppm for H3, Figure S4) when P4-t-
Bu and alcohol were added to 2-nitrogalactal (2a). Lower
electron density is experienced by C1 and C3 carbons when the
phosphazenium-alkoxide ion pair forms.
Afterward, we attempted to explore the donor scope with both
2-nitrogalactal and glucal derivatives having varying protecting
groups. Pleasingly, this glycosylation method proceeded
smoothly with a range of 2-nitrogalactal (α selective, 4q−4s,
Table 1, entries 1, 2, and 3) and 2-nitroglucal donors (β
selective, 7l−7n, Table 1, entries 4, 5 and 6). Having established
the stereoselective transformation, we turned our attention to
regioselective glycosylation (Table 2, entry 1). We began our
studies with the known diol 3s and O-benzyl-protected 2-
nitrogalactal, 2a (Table 2, entry 1). To our satisfaction, we
obtained 66% α-anomer of 2-O-glycoside (4t) and 6% of 3-O-α-
glycosidic product (4t′). It is worth mentioning that when we
have performed the reaction at 0 °C and slowly warming up to
room temperature we obtained a trace amount (9%) of β
anomer of the 2-O-glycosidic product (4tβ). Therefore, we
maintained the temperature at 0 °C throughout the reaction,
omitting the formation of the β-anomer of the 2-O-glycosylated
product. Furthermore, we obtained improved yield for 2-O-α-
glycoside 4t (71%) over 3-O-α-glycoside 4t′ (8%) when we
carried out the reaction at 0 °C (Table 2, entry 1). Encouraged
by the regioselective glycosidic bond formation using P4-t-Bu
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and the C2-phthalimide group, which stabilizes the 3-position
ion pair (Supporting Information, Table S6 and Figure S6).
To showcase the applicability of our method, we then turned
our focus to synthesize the precursor for the disaccharide core of
mucin-type Core 6 glycan (Scheme 2).6c,24,25 Therefore, we
started with selective nitration at the C2 position of 7eβ, which
afforded our desired disaccharide donor 8 in 74% yield.
Glycosylation of Boc-functionalized serine (3k) employing 10
mol % of P4-t-Bu proceeded smoothly to give the corresponding
glycoconjugate 9 as a sole isolated product with absolute α-
stereoselectivity (Scheme 2). Thereafter, we applied this
method effectively to furnish trisaccharide 10 with a complete
α-selectivity from disaccharide donor 8, which demonstrates
that we can certainly employ this method to prepare higher
analogues of N-glycans and 2-amino-2-deoxy sugar-containing
oligosaccharides (Scheme 2).
To summarize, a highly stereo- and regioselective O-
glycosylation of 2-nitroglycals with various types of alcohols
has been accomplished in the presence of a catalytic amount of
organic superbase P4-t-Bu. A wide range of 2-nitrogalactals and
2-nitroglucals underwent O-glycosylation and provided syn-
thetically useful 2-deoxy-2-nitro-O-glycosides in good to
excellent yields. Throughout our studies, we observed that 2-
nitrogalactals produce α-stereoisomers as the sole isolated
product, whereas 2-nitroglucals furnished more β-products. We
have investigated the reason behind these varying results with
the aid of DFT studies. Mechanistically, the reaction proceeds
via the formation of an ion pair (P4-t-BuH+RO−) between the
P4-t-Bu and alcohol (ROH), which activates the alcohol for the
nucleophilic addition with 2-nitroglycals. From these results, we
suggest a probable dipole−dipole interaction amongst the nitro
group of the 2-nitroglycals and the P4-t-BuH+ (cationic part of
the ion pair), which triggers the catalytic reaction process by
enhancing the electrophilicity of the anomeric carbon. Apart
from that, we profited from our method to regioselectively
perform glycosylation as well. This method has been effectively
used to synthesize the disaccharide precursor of mucin-type
Core 6 glycan that demonstrates the applicability of this
procedure. In the end, to illustrate the efficacy of our method, we
have synthesized a trisaccharide which shows that our method
can be applied to furnish higher analogues of N-glycans and 2-
amino-2-deoxy glycoside-containing oligosaccharides. We
would like to emphasize that a simple step of reduction of the
2-deoxy-2-nitro-glycosides provides facile access to the corre-
sponding 2-deoxy-2-amino-glycosides,6c which further can be
transformed into 2-acetamido-, 2-N-phthalimido-, 2-N-trichlor-
oethoxycarbamido-, or 2-azido-functionalized glycosides as
required.26 Hence, our methodology provides a more efficient
alternative for the chemical synthesis of this family of
biologically important oligosaccharides. With this straightfor-
ward method toward various 2-nitro-2-deoxy-O-glycosides, we
hope to provide a handy tool for carbohydrate synthesis.
AUTHOR INFORMATION
■
Corresponding Author
Xue-Wei Liu − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371; orcid.org/
0000-0002-8327-6664; Email: xuewei@ntu.edu.sg
Authors
Kumar Bhaskar Pal − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371;
orcid.org/0000-0002-1892-1890
Aoxin Guo − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371; orcid.org/
0000-0002-7072-4106
Mrinmoy Das − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371; orcid.org/
0000-0002-9955-9044
́
́
Gabor Bati − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c00753
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Nanyang Technological University (RG120/18),
the Ministry of Education (MOE 2013-T3-1-002), and the
National Research Foundation (NRF2016NRF-NSFC002-
005), Singapore, for their financial support. This work is
dedicated to Professor Charles E. Mckenna on his 75th birthday.
ABBREVIATIONS USED
■
DMAP, 4-dimethylaminopyridine; PPY, 2-phenylpyridine
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c00753.
Experimental procedures and full characterization of all
compounds (PDF)
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