Stereoselective Electro-2-deoxyglycosylation from Glycals

Article abstract of DOI:10.1002/anie.202006115

We report a novel and highly stereoselective electro-2-deoxyglycosylation from glycals. This method features excellent stereoselectivity, scope, and functional-group tolerance. This process can also be applied to the modification of a wide range of natural products and drugs. Furthermore, a scalable synthesis of glycosylated podophyllotoxin and a one-pot trisaccharide synthesis through iterative electroglycosylations were achieved.

Full text of DOI:10.1002/anie.202006115

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Accepted Article
Title: Stereoselective Electro-2-Deoxyglycosylation from Glycals
Authors: Xinshan Ye, Miao Liu, Kai-Meng Liu, De-Cai Xiong, Hanyu
Zhang, Tian Li, Bohan Li, Xianjin Qin, and Jinhe Bai
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202006115
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Stereoselective Electro-2-Deoxyglycosylation from Glycals
Miao Liu,[+] Kai-Meng Liu,[+] De-Cai Xiong,* Hanyu Zhang, Tian Li, Bohan Li, Xianjin Qin, Jinhe Bai and
Xin-Shan Ye*
Dedicated to Professor Henry N. C. Wong on the occasion of his 70th birthday.
Abstract: We herein report a novel and highly stereoselective
electro-2-deoxyglycosylation from glycals. This method is featured
by the excellent stereoselectivity and scope as well as functional-
group tolerance. This process could also be amenable to the
modification of a wide range of natural products and drugs.
Furthermore, a scalable synthesis of glycosylated podophyllotoxin
and a one-pot trisaccharide synthesis through iterative electro-
glycosylations have also been achieved.
valuable addition to the synthetic community.[15] The application
of electrical current to catalyze glycosylation reactions could be
traced back to Noyori’s pioneer work in the late 1980s.[16] Later,
Yoshida and co-workers successfully identified that thio-/seleno-
/telluro- glycoside donors could also be activated and undergo
glycosylation under different electrochemical conditions.[17,18]
However, to the best of our knowledge, electro-2-
deoxyglycosylation remains elusive to date. In continuation of
our interest in the area of carbohydrate synthesis,[19] we
envisage the possibility of the generation of 2-deoxyglycosides
from glycals in an electro-induced fashion, and we report herein
the results of our studies on electro-2-deoxyglycosylation.
Glycosylation reaction is the central topic in modern
carbohydrate chemistry.[1] Due in large part to the fact that sugar
attachments are essential for the biological activities of naturally
occurring
glycosylated
natural
products.[2]
Moreover,
glycosylated modification of a drug could very often drastically
change its physical properties and thus significantly improve its
pharmacological activity.[3] Among them, 2-deoxyglycosides are
widely found as a single sugar motif or part of oligosaccharides,
in aureolic acid antibiotics, cardiac glycosides, anthracyclines,
avermectins, macrolides, pluramycins, angucyclines, enediynes
and other biologically active compounds and drugs (Figure 1A).[4]
Accordingly, the development of
a
highly effective 2-
deoxyglycosylation method has been in high demand over the
last decades. However, owing to the absence of any directing
group at C2 position, the stereoselective construction of the
labile 2-deoxyglycosidic bond has been
challenge.[5]
a long-standing
So far, many successful strategies have already been
developed to give access to 2-deoxyglycosides in a direct,
indirect, or de novo manner.[6-10] Of special note, 2-
deoxyglycosylation of glycals with glycosyl acceptors proves to
be one of the most atom-economic and straightforward
approaches.[5] Accordingly, numbers of elegant methods (Figure
1B), including metal-catalyzed glycosylation,[11] organo-catalyzed
glycosylation,[12] photo-catalyzed glycosylation,[13] have been
established in recent years. En route to stereoselective 2-
deoxyglycosylations, we gradually shift our focus to organic
electrochemistry, an old but potentially ideal pursuit since it is
green and sustainable.[14] Indeed, the beginning of this century
has witnessed the renaissance of organic electrosynthesis as a
Figure 1. Selected bioactive 2-deoxyglycosides and glycosylation methods
derived from glycals.
We commenced our investigation with a model reaction
using galactal 1 as the donor and the alcohol 2 as the acceptor
(Scheme
1 and Tables S1-S4). Upon extensive solvent
screening, CH2Cl2 and dimethoxyethane (DME) were initially
found to generate desired disaccharide 3 with exclusively α-
selectivity, albeit in a 5% yield. The combination of DME and
methyl nonafluorobutyl ether (MFE)[20] could slightly promoted
[a]
M. Liu,[+] K.-M. Liu,[+] Dr. D.-C. Xiong, H. Zhang, T. Li, B. Li, X. Qin,
J. Bai, Prof. X.-S. Ye.
the formation of desired disaccharide
3 along with less
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University,
Xue Yuan Road No. 38, Beijing 100191 (China)
E-mail: xinshan@bjmu.edu.cn, decai@bjmu.edu.cn
Dr. D.-C. Xiong
Shandong Key Laboratory of Carbohydrate Chemistry and
Glycobiology, Shandong University, 27 Shanda Nanlu, Jinan,
Shandong 250100 (China)
decomposition of the starting material 1 (Table S1). Later, the
additives proved to be essential to our reaction outcome.[15b]
After an extensive screening of numerous additives (entries 2-8,
Scheme 1 and Table S2), alkyl bromides were found to be
optimal, and saccharide 3 was obtained in 92% isolated yield
when using 60 mol% of 3-bromopropionitrile (entry 6, Scheme 1).
Whereas Bu4NOTf was identified as the suitable electrolyte
(entries 6, 12, Table S3), the carbon electrode and platinum
electrode were chosen as the optimal anode and cathode,
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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respectively (Table S4). Lastly, dichloromethane or DME alone
could also be applied as reaction solvent (entries 15-16,
Scheme 1), and we observed no conversion whatsoever in the
absence of electrical current (entry 17, Scheme 1). Of particular
note, all the reactions mentioned above were performed under
constant current conditions (2.0 mA) in an undivided cell at
ambient temperature.
excellent -selectivity for galactal and -selectivity for arabinal
were observed, respectively. Meanwhile, it is worth mentioning
that various functional groups including ketone (23), carboxylic
acid (24), uracil (25), enoate (26-27) and 1,3-diene (28-29)
moieties are all well tolerated during the reactions. And the
scalability of this protocol was further demonstrated by an
efficient synthesis of glycosylated podophyllotoxin 21 on a 934
mg scale in 75% isolated yield.
Scheme 1. Reaction Optimization.
With optimal conditions in hand, we next set out to
investigate the reaction scope. As shown in Figure 2A, to our
delight, under standard reaction conditions both secondary and
tertiary alcohols could all successfully react with galactal 1 to
deliver glycosides 4-7 in good yields with exclusive -selectivity.
Benzoyl and methyl protected galactals were also well-tolerated
to give glycosides 8 and 9 in moderate to good yields. TBS-
protected galactal proved to be sensitive under standard
reaction conditions and gave glycoside 10 in 41% yield.
Fortunately, the yield could be further improved to 75% upon
using CH2Cl2 as the solvent along with the addition of β-pinene
as a proton scavenger.[21] Moreover, glucal donor, which is
commonly believed to be more challenging,[12b] in our case
underwent 2-deoxyglycosylation smoothly and afforded
disaccharide 11 as a single -anomer in 72% yield. Arabinal was
also identified as a suitable substrate, providing disaccharide 12
as a single β-anomer in a 80% yield. Reaction with different
kinds of acceptors was also permissible and delivered the
desired glycosides 13 and 14 in satisfactory yields. Lastly,
thioglycosides were also well tolerated during the reaction,
which indicates the possibility of potential one-pot orthogonal
glycosylations.
Next, we applied our established protocol to the late-stage
modification of natural products and drugs.[22] As shown in
Figure 2B, late-stage glycosylated modification occurred
smoothly under standard reaction conditions, thus afforded the
desired products (16-29) in good to excellent yields. Of note,
owing to the solubility issue, CH2Cl2 was also applied as the
reaction solvent, as is the case for 26 and 27. In all cases,
Figure 2. Substrate scope. The yields were isolated yields, the α/β ratios were
determined by 1H NMR. (a) Standard conditions: glycal (0.30 mmol), acceptor
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(0.15 mmol), Bu4NOTf (2.0 equiv), BrCH2CH2CN (0.09 mmol), DME (2.0
mL)/MFE (1.0 mL), 2.0 mA, rt. (b) CH2Cl2 as the solvent. (c) -Pinene (0.15
mmol) was added.
Br with weak acidity is considered to be a good hydrogen source
in the hydrogen abstraction reaction.[27] Since enol radical
cations and related nucleophilic addition reactions are well-
evidenced,[26] anodic oxidation of glycal A affords radical cation
B.[26e] The attack of B by a glycosyl acceptor produces
Finally, to further extend the synthetic potential of this
method, we performed a one-pot trisaccharide synthesis via
iterative electro-glycosylations. As shown in Scheme 2, galactal
1 was first reacted with the acceptor 30 to furnish the
intermediate C.[26c] The combined effects of
a half-chair
conformer[28] and the orientation of 3-substituent in the glycal
radical cation might be responsible for the good stereoselectivity,
for instance, the -selectivity for disaccharide 11 and -
selectivity for disaccharide 12. Br- abstracts H+ from C to
produce HBr and radical D. Radical D abstracts hydrogen from
HBr to give the glycoside E and a Br radical at the anode. The
newly-formed C-H bond is mainly equatorial.[29] Two liberated Br
radicals combine to form Br2, which could diffuse back to the
cathode and react with two propionitrile radicals to regenerate
BrCH2CH2CN.
disaccharide 15 within
2 h under the standard reaction
conditions (2 mA in DME/MFE). Subsequent in-situ electro-
glycosylation with acceptor 2 following Yoshida’s18a,c protocol
delivered the trisaccharide 31 in low yield (<10%) at room
temperature. Fine-tuning Yoshida’s reaction conditions by
o
lowering the temperature to -50 C increased the yield to 22%.
Finally, the iterative electro-one-pot trisaccharide synthesis was
successfully accomplished by conducting the second electro-
glycosylation at -78 oC using CH2Cl2 as solvent, affording the
desired trisaccharide 31 in 75% isolated yield.
Scheme 2. Iterative Electro-Glycosylation. Conditions: (a) 1 (0.30 mmol), 30
(0.15 mmol), BrCH2CH2CN (0.09 mmol), CH2Cl2 (3.0 mL), 2.0 mA, rt. (b) 2
(0.08 mmol), 4.0 mA, -78 oC.
To shed light on the possible reaction mechanism (Figures
3A-C, Figures S1-5 and Tables S5-7), a series of mechanistic
experiments were carefully designed and executed. Firstly, two
deuterium labeling experiments proved a syn-addition of glycal
1
with alcohol (Figure 3A and Figures S1-2 ). H-NMR monitoring
the reaction between 1 and CH3OH in CD2Cl2 revealed just a
14% gradual loss of the mount of BrCH2CH2CN at the most
during the reaction (Figure S3 and Table S5). The CV of
-
BrCH2CH2CN was consistent with that of the full Br-/Br3 /Br2
reaction.[23] The CVs of the reactants depicted that the intensity
of both the oxidation peaks and the reduction peak increases,
especially a dramatic increase in the reduction peak current
(Figure 3B and Figure S4). Then, Bu4NBr, Bu4NBr3, Br2 or
ClCH2CH2CN were used as an alternative additive, respectively.
Only Br2 gave the disaccharide in 20% yield. ClCH2CH2CN alone
could not facilitate this reaction either (Figure 3C and entries 3-6
in Table S6). Interestingly, the combination of ClCH2CH2CN with
Br2 was able to generate the disaccharide in 52% yield (Table
S6, entries 9-10). TEMPO inhibition and trapping experiments
proved the presence of a propionitrile radical (entry 11 in Table
S6, and Figure S5). Thus, we speculate an involvement of
propionitrile radical, Br2, and Br- in this reaction.[24,25] Combining
these observations with enol ether radical cation work reported
previously,[26] a postulated mechanism is proposed in Figure 3D.
Cathodic reduction of BrCH2CH2CN generates propionitrile
radical and Br-, which could combine H+ to give HBr. Covalent H-
Figure 3. Mechanistic studies. (a) Standard conditions: glycal (0.30 mmol),
acceptor (9.0 mmol for CD3OD or 0.15 mmol for 2), Bu4NOTf (2.0 equiv),
BrCH2CH2CN (0.09 mmol), DME (2.0 mL)/MFE (1.0 mL), 2.0 mA, rt. (b) glycal
(0.30 mmol), 2 (0.15 mmol), Bu4NOTf (2.0 equiv), additive, DME (2.0 mL)/MFE
(1.0 mL), 2.0 mA, rt. Cyclic voltammogram at 50 mV/s of (I) glycal 1, (II)
BrCH2CH2CN and (III) 1+ 2 + BrCH2CH2CN in DME.
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To
conclude,
an
unprecedented
electro-2-
deoxyglycosylation from glycals has been established in an
undivided cell, using BrCH2CH2CN as an additive. Accordingly,
thirteen 2-deoxyglycosides covering a large set of challenging
linkages were prepared in good yields and with excellent
stereoselectivities. The glycosylation of fourteen natural
products and drugs further demonstrates its great potential in
carbohydrate-based drug discovery. A scalable synthesis of
glycosylated podophyllotoxin and an iterative one-pot
trisaccharide synthesis have also been achieved. Given the
large abundance of 2-deoxyglycosides in natural products, this
method might find wide applications in the field of
glycochemistry and glycomedicines.
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Acknowledgements
This work was financially supported by grants from the National
Natural Science Foundation of China (Grant No. 21572012), the
National Key R&D Program of China (2018YFA0507602), and
the Open Projects Fund of Shandong Key Laboratory of
Carbohydrate Chemistry and Glycobiology (No. 2019CCG01).
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Keywords: carbohydrate• electrosynthesis • 2-deoxyglycoside •
glycal • glycosylation
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[24] We thank a reviewer for calling our attention to the presence of trace
amount of bromide and control experiments by the addition of an
alternative bromide source.
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Angewandte Chemie International Edition
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Miao Liu,[+] Kai-Meng Liu,[+] De-Cai
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Stereoselective Electro-2-
Deoxyglycosylation from Glycals
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