Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity

Article abstract of DOI:10.1002/anie.201906297

Stereocontrolled chemical glycosylation remains a major challenge despite vast efforts reported over many decades and so far still mainly relies on trial and error. Now it is shown that the relative reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities according to four types of acceptors. Mechanistic studies show that the reaction is dominated by two distinct intermediates: glycosyl triflates and glycosyl halides from N-halosuccinimide (NXS)/TfOH. The formation of glycosyl halide is highly correlated with the production of α-glycoside. These findings enable glycosylation reactions to be foreseen by using RRVs as an α/β-selectivity indicator and guidelines and rules to be developed for stereocontrolled glycosylation.

Full text of DOI:10.1002/anie.201906297

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201906297
German Edition: DOI: 10.1002/ange.201906297
Glycosylation
Establishment of Guidelines for the Control of Glycosylation Reactions
and Intermediates by Quantitative Assessment of Reactivity
Chun-Wei Chang, Chia-Hui Wu, Mei-Huei Lin, Pin-Hsuan Liao, Chun-Chi Chang, Hsiao-
Han Chuang, Su-Ching Lin, Sarah Lam, Ved Prakash Verma, Chao-Ping Hsu,* and Cheng-
Chung Wang*
Abstract: Stereocontrolled chemical glycosylation remains
a major challenge despite vast efforts reported over many
decades and so far still mainly relies on trial and error. Now it is
shown that the relative reactivity value (RRV) of thioglycosides
is an indicator for revealing stereoselectivities according to four
types of acceptors. Mechanistic studies show that the reaction is
dominated by two distinct intermediates: glycosyl triflates and
glycosyl halides from N-halosuccinimide (NXS)/TfOH. The
formation of glycosyl halide is highly correlated with the
production of a-glycoside. These findings enable glycosylation
reactions to be foreseen by using RRVs as an a/b-selectivity
indicator and guidelines and rules to be developed for
stereocontrolled glycosylation.
Thioglycosides 1 (Figure 1) are the most commonly used
glycosyl donors and can be easily activated chemoselectively
by electrophilic promoter systems, among which N-iodosuc-
C
arbohydrates are essential biomolecules in living organ-
isms.[1] However, to access carbohydrate-based products in
large quantities with well-defined regio- and stereochemistry
is still challenging.[2] To date, no unifying strategy for
obtaining 1,2-cis glycosides exists as the glycosylation reaction
outcome is influenced by numerous factors and the detail
reaction mechanism is still unclear.[3] Therefore, an indicator
and a general guideline that predicts, foretells, and summa-
rizes the stereoselectivity would greatly simplify this indis-
pensible reaction and would facilitate advanced methods that
streamline oligosaccharide synthesis, such as solid-phase
automated oligosaccharide synthesis and one-pot glycosyla-
tion.[4]
Figure 1. RRV as a scale meter to define a/b stereoselectivity in
chemical glycosylation.
cinimide (NIS, 6-I)/TfOH is the most widely used.[5] Ye,
Huang, and Yoshida have developed a preactivation strategy
that allows iterative one-pot glycosylation.[3a,6] However,
similar to all other glycosylation reactions, the poorly
controlled stereoselectivity remains a long-standing prob-
lem.[3c,5a] The promotor systems are generally a combination
of a stoichiometric amount of an iodonium agent and
a catalytic amount of TfOH. The reactions are complicated
by the presence of various reactants, and glycosyl triflate 2 is
commonly believed as the main intermediate, which leads to
the mixture of products 5-a and 5-b.[3d,7]
[*] C.-W. Chang, Dr. C.-H. Wu, M.-H. Lin, P.-H. Liao, C.-C. Chang,
H.-H. Chuang, Dr. S.-C. Lin, Dr. S. Lam, Dr. V. P. Verma, Dr. C.-P. Hsu,
Dr. C.-C. Wang
Institute of Chemistry, Academia Sinica
Taipei 115 (Taiwan)
E-mail: cherri@chem.sinica.edu.tw
wangcc@chem.sinica.edu.tw
To predict glycosylation stereoselectivity and systemati-
cally analyze the factors that influence the outcome, an
objective comparison system is required. Ley was the first to
introduce deactivation factor (DF) to define the donor
reactivity.[8] Later, the relative reactivity value (RRV),
a comprehensive quantification system developed by Wong,
provides a quantitative assessment for programmable one-pot
oligosaccharide synthesis.[9] Herein, we show that RRVs serve
as a parameter/indicator to statistically predict stereoselec-
tivity in glycosidic bond formation and for the first time
chemical glycosylation reaction can be correlated with a gen-
eral statistical approach. Our mechanistic experiments
revealed that glycosylations proceeded via a glycosyl triflate
C.-W. Chang, Dr. C.-H. Wu, Dr. C.-C. Wang
Chemical Biology and Molecular Biophysics
Taiwan International Graduate Program, Academia Sinica
Taipei 115 (Taiwan)
C.-W. Chang, Dr. C.-H. Wu, H.-H. Chuang
Department of Chemistry, National Taiwan University
Taipei 106 (Taiwan)
H.-H. Chuang
Nanoscience and Technology Program, Taiwan International Grad-
uate Program, Academia Sinica and National Taiwan University
Taipei 115 (Taiwan)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201906297.
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a least reactive donor, tolyl tetra-O-acetylthiomannoside 23,
of which the RRV is defined as 1.0, as reported.[9a,b]
Next, donors 7–22 were pre-mixed with acceptors 24–27,
respectively. Secondary glycosyl alcohols 24 and 25, primary
glycosyl alcohol 26, and alkyl alcohol 27 are four types of
commonly used glycosyl acceptors in carbohydrate synthesis.
After testing the reactions from ꢀ78 to 08C, we found the
changes in stereoselectivity were very limited. Therefore, the
reaction condition was fixed at ꢀ408C in DCM to eliminate
the possible variables, and 1.0 equiv of NIS and 0.4 equiv of
TfOH were introduced to activate the donor in a traditional
(non-preactivated) manner. The reaction mixture was stirred
for 3 h, and the a/b ratio of the reaction was determined by
using HPLC.
After screening these combinations (Figure 3; Supporting
Information, Table S6), we interestingly found the a-selectiv-
ity is in roughly a linear correlation with log(RRV). For 4-OH
acceptor 24 (Figure 3A), the linear regression showed that
the slope is 16.6, in which R2 is 0.77 and Pearsonꢀs r is 0.89.
Consistent trends were observed with the other acceptors 25–
27, but in different slopes. For the other secondary alcohols,
namely, 3-OH acceptor 25 (Figure 3B), with the increasing
log(RRV) from 0–6, a-selectivity also rose linearly with
a steep slope of 15.7. For primary 6-OH acceptor 26 (Fig-
ure 3C), the linear regression showed that the slope was 13.3.
When using sterically least-hindered methanol (27) as
acceptor (Figure 3D), a-selectivity was enhanced the least.
These findings suggest that stereoselectivity is more
closely related to inductive effects on donors and the
Figure 2. Glycosyl donors with defined RRV.
2 and/or iodide 3-I, which we found is highly associated with
the formation of a-glycoside
5-a, as a function of RRV.
To understand the corre-
lation between the stereose-
lectivity and the identity of
glycosyl donors and accept-
ors, the reactivity of a series
of glycosyl donors were
quantified by their RRVs
and the stereoselectivity of
their reaction with a range
of glycosyl acceptors were
studied. In this study, the
RRVs of donors 7–22 on
different sugars without C2
participating
(Figure 2; Supporting Infor-
mation, Figures S1–S9),
group
including 1,2-trans thiotolyl
glucosides 7, 10, 11, 13,[9a] 16
and galactosides 17, 18,
19,[9a] mannosides 12[9a,10]
and 15,[9c] 2-azido-2-deoxy-
glucosides 8, 9, b-thiotolyl 2-
dexoygalactoside 20, 21, and
a-thiotolyl
2-deoxygluco-
side 14, 22,[11] were mea-
sured. These values were
determined by using compe-
Figure 3. a-Selectivity vs. donor reactivity (RRV). Using A) glucoside 4-OH 24; B) glucoside 3-OH 25;
tition experiments against C) glucoside 6-OH 26; D) MeOH (27) as the acceptors.
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reactivity of acceptors.[3c,12] For example, mannosides are
However, our NMR spectrum in turn showed the evidence of
commonly believed to produce a-major (1.2-trans) glycosides.
Thiomannosides 12 (RRV= 315, log(RRV) = 2.50) and 15
(RRV= 5000, log(RRV) = 3.70), having moderate RRVs, in
fact gave considerable amounts of b-products (1.2-cis) with
the a/b ratio predictable by the 4 linear fits in Figure 3, For
O6-actylated glucose donor 7 (dots in dash box), the
selectivity deviated from the trends for secondary acceptors
24 and 25 as observed in previous reports;[13] but not for
primary acceptors 26 and 27. Based on Figure 3, we herein
provide a reliable guideline to design glycosyl donors for both
a- and b-selective glycosylation reactions by using RRVs as
indicators (Supporting Information, Figure S29). Moreover,
stereoselectivity showed no significant change between
preactivation and the traditional approach (non-preactiva-
tion).[14]
We then tried to identify the intermediates before the
addition of glycosyl acceptor by using low-temperature NMR
experiments at ꢀ408C (Figure 4). Donors 7–22 were treated
with 1.0 equiv of NIS and 0.4 equiv of TfOH in CD2Cl2 at
ꢀ408C for 15 min individually. We initially expected to
observe the signals of glycosyl triflate 2, which was the most
common believed intermediate from previous reports.[3b,15]
glycosyl iodide 3-I intermediate formation for the first time in
the TfOH promoted system (Supporting Information,
Table S1, Figures S10–24). Furthermore, the existence of 3-I
1
in the reaction was confirmed by comparing the H NMR
spectrum obtained with that of the suspected intermediates
synthesized independently through relevant procedures
under TMSI conditions (Supporting Information, Fig-
ures S10–S24, Table S1).[16] Moreover, 3-I can be further
identified by high-resolution ESI-MASS (Supporting Infor-
mation, Figure S11).
The intermediate distribution of 3-I (Figure 4A) is also
inductive-effect-dependent and was highly correlated with a-
selectivity (Figure 3). RRV provides a universal system to
predict the intermediate change in the scaffold of log(RRV)
between 1.27 and 2.50 (or RRV between 18.6 and 315).
Consistent results of the intermediate change were also
observed in other halide-containing promotor systems such as
NBS/TfOH (Figure 4B), NCS/TfOH (Figure 4C), and
TolSCl/AgOTf (Figure 4D) with their glycosyl bromide 3-Br
and chloride 3-Cl being observed as well (Supporting
Information, Figures S10–S24, Table S1).
To further clarify the intermediate transformation, we
performed a theoretical computational study. The transition
states TS consisted of an oxocarbenium cation with a certain
degree of association with both triflate anion (OTfꢀ) and
halide anion (Xꢀ). The conversion mechanism is most
accurately described as an SN2-like process. Computational
experiments all yielded consistent results in each NXS/TfOH
system (Supporting Information, Figures S25–S28, Tables S2–
S5). The relatively low free-energy barriers were 4.17 and
5.48 kcalmolꢀ1, respectively, when calculated with the tem-
perature set at ꢀ408C (Supporting Information, Figure S25).
These address the fact that facile intermediate transformation
could happen to produce the glycosyl halide intermediate
in situ.
Although the relevance between glycosyl intermediates
and stereoselectivity is hard to define owing to the partic-
ipation of solvent-separated ion pairs (SSIPs),[3d,17] and
clearly, the electronic nature of the protecting groups bound
to the glycosyl donors play a key role in shifting the SN1–SN2
reaction paradigm.[17] We have found the correlation between
donor reactivity (RRV) and the intermediate glycosyl halide/
triflate ratio, which in turn influences the a/b selectivity upon
the addition of an acceptor. This is important, because the
reaction stereoselectivity is highly dependent on the identity
of the reactive intermediate as reported by Gervay-Hague,
Field, and Codee.[12,16,17b,c,18] The glycosyl iodide 3-I can lead
to distinct a-selectivity, and 3-I can then be converted into an
even more reactive b-counterpart 3-I-b via a Lemieux
anomerization pathway,[19] which undergoes an SN2-like
reaction with a nucleophilic acceptor from the bottom side
for selective a-glycosyl bond formation.[16,18] In contrast, the
a-triflate intermediate 2 favors the SN2 reaction and b-
selective reaction with the acceptor in the cases of the
unreactive donors.[12,17b,c] Since both preactivation and non-
preactivation showed very similar stereoselectivity (Figure 3),
it implied that glycosides formation occurs through glycosyl
Figure 4. Intermediate distribution vs. donor reactivity (RRV). Using
A) NIS/TfOH; B) NBS/TfOH; C) NCS/TfOH; D) TolSCl/AgOTf as the
promotor.
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iodide 3-I after facile intermediate transformation at a low
temperature within the donor activation timeframe.
We targeted numerous disaccharides or glycoconjugates
(Scheme 1; Supporting Information, Table S6). The coupling
between glycan and linkers 34 and 35 is useful and common in
studies on glycosciences.[4a] Clearly indicated by our RRV
Finally, we aimed at an a-Gal-(1!4)-b-GlcNA disacchar-
ide motif 48 (Scheme 1C), equipped with a b-pentyl linker at
the reducing end. First, a semi-protected glucosamine donor
44 with a low RRV of 151 was designed for b-selective
glycosylation. Predicted well by our system (a selectivity =
21% in Figures 3D), a majority of b-glycoside 46 (a-
selectivity = 22%) was furnished in 81%. Next, a Gal donor
47 with higher RRV of 9153 gave a high a-selectivity and
produced 48 in 70%.
Stereocontrolled glycosylation was the main challenge in
carbohydrate chemistry owning to the lack of a clear mech-
anism and too many control variables.[3c] We herein first
demonstrated that stereoselectivity can be predicted using
reactivity of donors (RRVs) on different acceptors in a NIS/
TfOH system. Our studies also revealed that the reaction was
dominated by two distinct intermediates, including glycosyl
triflate and iodide. A further understanding of mechanistic
pathways is in progress. We believe the behavior of donors
can be further clarified, and our indicator and guideline can
provide a new solution for chemists to simplify glycosylation
reaction and design building blocks in a quantifiable manner.
This discovery gives new insight to stereocontrolled glyco-
sylation for carbohydrate/organic chemistry and presents
a multidisciplinary direction that combines statistics. Since
anomeric selectivity is simultaneously influenced by remote
functional group participation,[3a,20] acceptor nucleophilicity,
solvent polarity, temperature, and activation sys-
tem,[3b,11,12,17b,c,21] we are studying these permanent and
environmental variables by using RRV as the analytic tools.
Similar trends can also be observed when using TolSCl/
AgOTf and BSP/Tf2O combinations as the promoters. More
types of building blocks, such as l-6-deoxy sugars and
glycuronic acids, will be included in our future studies. The
incorporation of this system into artificial intelligence for
carbohydrate synthesis is now undergoing.[22]
Scheme 1. Stereoselectivity-predictable glycosylation using RRV as the
indicator.
Acknowledgements
indicating system to synthesize alkyl glycoside 31 (Fig-
ures 3D), for 18 (RRV of 7180, log(RRV) = 3.86), product
36 was obtained only with poor a/b selectivity (a-selectivity =
33%) when the linker acceptor 35 was treated. According to
Figures 3D, we then adopted a partially protected donor 33
with lower RRV of 104 (log(RRV) = 2.02) (Scheme 1A).
Without the electron-donating effect on C2 and C3, the
unreactive 33 resulted in high b-selectivity with linkers 34 and
35 individually, in which 37 (a-selectivity = 15%) and 38 (a-
selectivity = 0%) were isolated.
We thank Dr. Tsyr-Yan Yu, Dr. Shang-Te Danny Hsu
(Academia Sinica), Prof. Yasuhiro Kajihara, and Yuta Maki
(Osaka University) for helpful discussion and Ping-Yu Lin
(Academia Sinica) for Mass measurement; This work was
supported by the Ministry of Science and Technology, Taiwan
(MOST 108-2133-M-001-019-; 106–2113-M-001-009-MY2)
and Academia Sinica (MOST 108-3114-Y-001-002; AS-
SUMMIT-108).
A prediction based on secondary alcohols in Figures 3B
was noted for donors 22, 13, and 39 with the secondary
threonine 40 as the acceptor (Scheme 1B). As pinpointed by
the linear fit, 80% a-selectivity was observed on 2-deoxy-
glucosyl donor 22 (log(RRV) = 6). Next, for tetra-O-benzy-
lated thioglucoside 13 (log(RRV) = 3.42), the selectivity of 42
decreased to 66% a-selectivity. Eventually, for 2-azido-2-
deoxy thioglucoside 39 (log(RRV) = 2.44, RRV= 270),[9e]
product 43 was obtained with the poorest selectivity (50%
a-selectivity) in 75%.
Conflict of interest
The authors declare no conflict of interest.
Keywords: carbohydrates · diastereoselectivity · glycosylation
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Manuscript received: May 21, 2019
Revised manuscript received: August 23, 2019
Accepted manuscript online: September 13, 2019
Version of record online: && &&, &&&&
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Communications
Glycosylation
Selectivity rev-counter: The relative reac-
tivity value (RRV) of thioglycosides is an
indicator for revealing stereoselectivities
for chemical glycosylation.
C.-W. Chang, C.-H. Wu, M.-H. Lin,
P.-H. Liao, C.-C. Chang, H.-H. Chuang,
S.-C. Lin, S. Lam, V. P. Verma, C.-P. Hsu,*
C.-C. Wang*
&&&& — &&&&
Establishment of Guidelines for the
Control of Glycosylation Reactions and
Intermediates by Quantitative
Assessment of Reactivity
6
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ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!