Donor-Reactivity-Controlled Sialylation Reactions

Article abstract of DOI:10.1002/ejoc.202100718

Although tremendous efforts have been made for the efficient preparation of sialosides, controlling the stereochemical outcome of sialylation reaction still remains one of the most challenging tasks due to the unique chemical structure of sialic acid. We developed a new strategy to statistically analyze the stereoselectivity of sialylation reactions on six types of p-tolyl thiosialosides in NIS/TfOH system using Relative Reactivity Value (RRV) as the indicator. Analysis of the reaction mechanism showed the formation of the relatively stable glycosyl bromide and glycosyl chloride intermediates from halide- and triflate-containing promotors in the absence of an acceptor. We found that the α/β-stereoselectivity, yields, and intermediate changes were associated with their donor reactivity. These findings enable to tailor the most suitable building blocks for stereo-controlled sialylation reactions.

Full text of DOI:10.1002/ejoc.202100718

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Donor-Reactivity-Controlled Sialylation Reactions
Kesatebrhan Haile Asressu,[a, b, c] Chun-Wei Chang,[a] Sarah Lam,[a] and
Cheng-Chung Wang*[a, b, c]
Although tremendous efforts have been made for the efficient
preparation of sialosides, controlling the stereochemical out-
come of sialylation reaction still remains one of the most
challenging tasks due to the unique chemical structure of sialic
acid. We developed a new strategy to statistically analyze the
stereoselectivity of sialylation reactions on six types of p-tolyl
thiosialosides in NIS/TfOH system using Relative Reactivity Value
(RRV) as the indicator. Analysis of the reaction mechanism
showed the formation of the relatively stable glycosyl bromide
and glycosyl chloride intermediates from halide- and triflate-
containing promotors in the absence of an acceptor. We found
that the α/β-stereoselectivity, yields, and intermediate changes
were associated with their donor reactivity. These findings
enable to tailor the most suitable building blocks for stereo-
controlled sialylation reactions.
Introduction
(PGs).[3,31,47] However, these approaches have limited generality,
depends on substrate-sensitivity and need systematic optimiza-
tions. Stereocontrolled α-sialylation still remains the most
challenging task because the stereoselectivity of sialylation is
unpredictable.[22,23,36,48] The participation of the solvent-sepa-
rated ion pair (SSIP) during sialylation reaction usually results in
poor α/β-selectivity.[19,49] Furthermore, the lack of stereo-direct-
ing neighboring group at position C-3 of sialyl donors also
contributes to the unsatisfactory stereochemistry outcome.
Among various glycosyl donors, thioglycosides are the most
widely used in chemical glycosylation.[4–6] This is because of
their simple preparation, high stability, and compatibility with
most functional group modifications. Thiosialosides 1 can be
activated by a number of electrophilic promotors-the most
common of which are N-halosuccinimide/triflic acid (NXS (X=
ClÀ , BrÀ , IÀ )/TfOH),[33,47] dimethyl(methylthio)sulfonium triflate
(DMTST),[21] para-toluenesulfenyl chloride/silver triflate (p-
TolSCl/AgOTf),[36,48] and diphenyl sulfoxide/trifluoromethanesul-
fonic anhydride (Ph2SO/Tf2O).[42,43]
Pre-activation-based stereoselective sialylation reactions of
thiosialoside donors 1 have been established to conduct
sequential glycosylation for oligosaccharide synthesis.[36,42,48]
Although several mechanism-based studies have been de-
scribed in the literature, the requirement of excess amount of
promotors on thioglycoside activation system makes the
reaction complicated as a stoichiometric amount of byproduct
was accompanied in-situ.[5,23,36,42,43,48] Previously, α-glycosides
were successfully synthesized by nitrile effect[19,26–28,35,38,41,46] via
SN2-type substitution reaction. However, the numerous combi-
nations of each sialyl donor 1 and acceptors (ROH 3) provide
their own α/β-selectivities depending on the nature of O- and
N-5 PGs,[40,49] side-chain conformations[50] and reaction
conditions.[28] Moreover, the stereochemistry of the reactive
intermediates and reagent dosage also undergoes the continual
change under SN1- and SN2-like pathway which in turn
influences the stereochemical outcome of chemical
sialylation.[4,25,31,41] Therefore, such a complicated mechanism
results in unpredicted stereoselectivity, and glycosylation owing
to high stereoselectivity, besides, the yield meets the tremen-
Sialic acids are a large family of 2-keto-3-deoxy-nonulosonic
acids with a nine-carbon backbone. Due to their existence at
the terminal position of glycan chains, sialic acids play
significant roles in a large variety of biological processes such as
molecular recognition, polysaccharide digestion, tumor meta-
stasis, immune response and brain development.[1–3] Among the
50 naturally occurring derivatives of sialic acids, N-acetylneur-
aminic acid (Neu5Ac) is the most well-known and exists in a
myriad of glycosidic linkages, most commonly α(2!3) and
α(2!6) to galactose or galactosamine (or lactose), α(2!8),
α(2!9), α(2!4) to another Neu5Ac moiety, forming disialic
residues[4–10] and as C-2 linked to O-7 in 2,7-anhydroNeu5Ac.[9]
The structural diversity of sialic acid-containing oligosac-
charides, makes it difficult to obtain a pure and sufficient
amount of α-sialosides from a natural source and the process is
time consuming.[11–13] To improve the α/β-selectivity of sialyla-
tion reaction, numerous approaches have been explored
including changing anomeric leaving groups of C-2,[14,15,24–28,16–23]
modifications at C-1,[4,21,26,29,30] C-3,[20,31,32] C-4[22–24,33,34] and C-
5[14,17,39–41,22–25,35–38] positions, development of new activation
systems,[22,23,36,42,43] impact of acceptor reactivity,[9,36,44,45] use of
the solvent effect,[13,46] and employing new protecting groups
[a] Dr. K. H. Asressu, Dr. C.-W. Chang, Dr. S. Lam, Prof. C.-C. Wang
Institute of Chemistry, Academia Sinica,
Taipei 115, Taiwan
E-mail: wangcc@chem.sinica.edu.tw
[b] Dr. K. H. Asressu, Prof. C.-C. Wang
Taiwan International Graduate Program (TIGP),
Sustainable Chemical Science and Technology (SCST),
Academia Sinica,
Taipei 115, Taiwan
[c] Dr. K. H. Asressu, Prof. C.-C. Wang
Department of Applied Chemistry,
National Yang Ming Chiao Tung University,
Hsinchu 300, Taiwan
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100718
Part of the joint “Carbohydrate Chemistry” Special Collection with Chem-
CatChem.
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dous effort for the optimization. Thus, a general quantitative Results and Discussion
system to establish a guideline for both α- and β-selective
sialylation reactions and to identify the variability in chemical
glycosylation, may be the key to answer this question.[51,52]
According to our previous work, we have discovered that
Relative Reactivity Value (RRV), established by Wong et al., can
be used as a general indicator to define the stereoselectivity
change with numerous thioglycosides in NIS/TfOH promotor
system. Mechanistic studies also show that different ratios of
glycosyl triflate and glycosyl halide (ClÀ , BrÀ , IÀ ) intermediates
significantly change the stereoselectivity in different halogen-
containing promotor systems such as para-tolylsulfenyl halides
(p-TolSX, X=ClÀ , BrÀ , IÀ )/AgOTf.[51,52] However, the role of RRV of
thiosialoside donor 1 in stereoselectivity of sialylation remains
unclear. As a continuation of our RRV study, we describe herein
the pre-activation of diversified p-tolyl thiosialoside donors 1
with NXS (X=ClÀ , BrÀ , IÀ )/TfOH, p-TolSCl/AgOTf and BSP/Tf2O
promotors and identified their corresponding reactive inter-
mediates using low-temperature NMR spectroscopy to acquire
some information about the glycosylation reaction. Moreover,
RRV of various sialyl donors 1 were defined and correlated to
their corresponding reactive intermediate ratio, which in turn
controlled the stereochemical outcome of glycosylation
(Scheme 1).
Preparation of thiosialoside donors with defined RRV
To identify the correlation between the stereoselectivity of
sialylation and RRV of thiosialoside donors and acceptors, we
synthesized several C-5 modified thiosialoside donors 6–11
following earlier published procedures (Figure 1, see SI,
Scheme S1).[23,37–39,53–56] Four commonly used acceptors (primary
glycosyl alcohols 12 and 13, secondary glycosyl alcohols 14 and
tertiary alkyl alcohol 15) have been used for our investigation.
The RRV of donors 6–11 bearing different anomeric stereo-
chemistry including NHAc, N-Ac2- and N3-protected α-p-tolyl
thiosialosides 6–8,[21,41] and 5-N,4-O-oxazolidinone-based β-p-
tolyl thiosialosides 9–11, were measured by competitive HPLC
experiment and showed poor and narrow ranges (Figure 1).[41,51]
NIS/TfOH-promoted stereoselective sialylation
After obtaining RRV, we set out to determine the glycosylation
stereoselectivity of these thiosialosides. Our work began by
premixing donor 6–11 and acceptor 12–15 individually, using a
°
3 Å molecular sieve in dichloromethane (CH2Cl2) at À 40 C. The
combined promotors, 1 equiv. of NIS and 0.4 equiv. of TfOH,
were then treated in the next step to facilitate the reaction. The
reaction completed over 2 h, and the α/β ratio of the sialylated
1
disaccharides 16–19 was determined by H NMR analysis of the
crude reaction mixtures.
The percentage of α-sialoside formed was calculated
relative to the β-isomers. The anomeric configuration of the
disaccharides 16–19 was determined by following the empirical
rules of chemical shift, distinctive three-bond coupling constant
of C1-C2-C3-H-3ax (3JC-1,H-3ax) and by comparing with the NMR
data of known compounds[21,31,47,57] The anomeric configurations
can also be identified by considering the chemical shift position
1
of H-3eq and H-3ax in their H NMR spectra. Accordingly, α-
sialosides show a close pattern relationship; however, β-
configured sialosides have very far apart patterns in their H-3eq
and H-3ax chemical shift.[57]
Scheme 1. Reactivity-controlled stereoselective sialylation.
Prediction of sialylation stereoselectivity and yields by sugar
reactivity
After we studied a range of NIS/TfOH-promoted stereoselective
sialylations (see SI, Scheme S2), we examined the correlation of
the stereoselectivity with donor reactivity. As revealed in the
summary of glycosylation results in Figures 2A–D, the stereo-
selectivity of sialylation is dependent on donor reactivity and
can be defined based on the RRV of sialyl donors. Interestingly,
we observed a higher α-selectivity in the medium RRV (2.2 to
7.2) of donors, and the β-selectivity was gradually performed
outward from the center. For primary sugar acceptor galacto-
side HO-6 12 (Figure 2A), the α-selectivity initially increased as
the donor RRV increased from 2.2 to 7.2. Consistent trends were
also witnessed with acceptors 13–15 with the exception of a
Figure 1. Thiosialoside donors 6–11 with defined RRV (in parentheses) and
acceptors 12–15.
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Figure 3. Effect of donor RRV on sialylation yield.
Figure 2. Effect of donor RRV on α-selectivity. Using A) galactoside HO-6 12;
B) glucoside HO-6 13; C) galactoside HO-3 14; D) 1-admantanol 15 as the
acceptors.
selectivity due to its high reactivity which tends to the
elimination side reactions.
slight decline in the percentage of α-sialoside formation
(Figures 2B–D). As the donor RRV increased from 7.2 to 12.2, the
α-selectivity of these acceptors decreased.
Identification of glycosyl intermediates
With sterically hindered acceptor 14 (Figure 2C), as the RRV
increased from 2.2 to 6.2, the α-selectivity did not show a
significant change but the β-selectivity increased when the RRV
become greater than 7.2 like that of acceptors 12, 13, and 15.
Our finding is consistent with Wong’s work who observed β-
selective sialylation with several primary and secondary alcohols
coupled with a highly armed sialyl donor having a protected
hydroxymethyl group at C-2 (RRV=4.0×104).[21] Compared with
the primary sugar acceptors 12 and 13, the bulky 1-adamanta-
nol 15 acceptor gave moderate α-selectivity in the range RRV of
3.0 to 7.2 (Figure 2D)
Next, we identified the corresponding intermediates in the
absence of glycosyl acceptor using low-temperature NMR
°
experiments at À 70 C. The treatment of donors 6–11 with 1.0
°
equiv. of NIS and 0.4 equiv. of TfOH at À 70 C in the presence
of 3 Å molecular sieve in deuterated dichloromethane (CD2Cl2)
showed no activation. However, these donors were completely
°
activated after the temperature raised to À 40 C. We initially
estimated to detect glycosyl triflate 2-OTf, which is the
dominant intermediate in sialylation reactions promoted under
this system.[31,41,43,60] However, our low-temperature NMR
°
We also investigated the relation between sialylation yields
of NIS/TfOH promotion system and sugar reactivity and found
that the sialylation yields were dependent on the donor RRV
(Figure 3) like the α/β-selectivity. High sialylation yields were
obtained with primary sugar acceptors 12 and 13 in the range
of donor RRV from 2.2 to 11.5. However, the glycosylation yields
were generally lower with the hindered acceptors 14 and 15.
The chemical yields and the selectivity of the oxazolidinone-
protected compounds 9–11 (RRV 3.0 to 7.2) is significantly
higher than the other compounds tested. This may be due to
the stabilizing ability of the trans-fused oxazolidinone ring of
these donors to the equatorial glycosides over their axial
counterparts, reducing the anomeric effect and glycal
formation.[58,59] On the other hand, the highest RRV of com-
pound 7 gives the lowest chemical yield and lowest α-stereo-
(À 70 C) and high-resolution ESI-mass experiments revealed
that only glycal 3-G was formed as a side product (see SI,
Table S2). We surmised that these labile intermediates (2-OTf/2-
I) undergo a rapid decomposition to generate the 2,3-dehydro
glycal 3-G in the absence of acceptors. These results were also
supported by our modulating experiment using 1 equiv. of BSP/
°
Tf2O at À 70 C (see Supporting Information, Table S2). Instanta-
neous degradation of unstable intermediates (2-OTf and 2-I)
into 3-G through the 2,3-elimination reaction have also been
observed at low-temperature NMR spectroscopy by Gervay-
Hague’s,[25] Crich’s,[43,49] and De Meo’s[60] groups.
Consequently, we identified the corresponding reactive
intermediates in the alternative halonium promoter system
such as NBS/TfOH and NCS/TfOH, as the bromide (2-Br) and
chloride (2-Cl) intermediate are relatively stable to determine.
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Accordingly, donors 6–11 were activated by 1 equiv. of N-
Effect of donor reactivity on intermediate distribution
halosuccinimide (NXS, X=ClÀ , BrÀ )/TfOH as promotors in the
°
presence of 3 Å molecular sieve in CD2Cl2 at À 70 C. As
RRV can be used as a tool to guide the intermediate change
with promoters.[51,52] We observed nearly consistent results of
intermediate change under the activation of other halogen and
triflate-containing promotors, namely 1 equiv. of p-TolSCl and
3 equiv. of AgOTf (Figure 4C, see SI, Tables S1 and S2). The
activation of the oxazolidinone-based donors 9–11 which have
moderate RRV (3.0 to 7.2), gave a high percentage of 2-Cl,
especially under the p-TolSCl/AgOTf activation system.
expected, the corresponding relatively stable halide intermedi-
ate, glycosyl bromide 2-Br and chloride 2-Cl were generated
cleanly within 5 minutes (Figure 4A and Figure 4B, see SI,
Table S1 and Table S2). The selectivity of halides (2-Cl and 2-Br)
and triflate 2-OTf intermediates did not vary significantly with
different amounts of TfOH. Compared with 2-Br, the distribution
of the relatively stable 2-Cl showed a high correlation with the
donor reactivity and the α-selectivity of sialylation (Figure 2).
The formation 2-Cl and 2-Br were confirmed by low-temper-
Due to the involvement of the SSIP,[19,49,62] it is difficult to
describe the significant connection between the reactive
intermediates and stereoselectivity. The SN1- and SN2-like
mechanisms are highly dependent on the types of the PGs
installed to the thiosialoside donors.[25,49] Our finding showed
the correlation between donor RRV and the sialyl intermediates
(halide/triflate ratio). This kind of association affects the ano-
meric stereoselectivity of sialylation in the presence of acceptor.
Previous reports have also shown the stereochemical outcome
of glycosylation is highly related to the types of glycosyl
intermediate.[3,25,41,51]
°
ature (À 70 C) NMR spectroscopy and ESI-mass (see SI).
However, the highly unstable 2-OTf intermediate which was
obtained mainly from least and relatively reactive donors 6–8
(RRV=2.2, 11.5 and 12.2) under NBS/TfOH activation system
decomposed rapidly into sialyl glycal 3-G (Figure 4A, see SI,
Table S1 and Table S2). In our previous work,[51] we found that
the activation of thioglycoside donors by p-TolSX (X=ClÀ , BrÀ ,
IÀ )/AgOTf resulted in the in situ generation of glycosyl halides
(ClÀ , BrÀ , IÀ ), which provided a consistent α-stereoselectivity of
glycosylation through these common intermediates. Addition-
ally, stereoselectivity showed no significant change in both
preactivation and non-preactivation systems. Accordingly, there
is a high possibility for the formation of 2-halo intermediates
during the sialylation reaction. The reaction mechanism for the
formation of 2-Cl and 2-Br derivatives from NCS and NBS
treatment, respectively, can likely follow similar pathway as
discovered in our previous works.[51,61]
Guideline for sialylation stereoselectivity by sugar reactivity
Using of RRV as an indicator (Figure 2), we described a
convenient guideline to identify sialyl donors for both α-and β-
selective sialylation reactions (Figure 5). To get 2,6-linked sialo-
sides 16 and 17, the RRV of the donor should be greater than
2.2 but less than 11.5 for α-sialylation (α-selectivity >75%, red
bar) (Figure 5A and Figure 5B). With HO-3 galactosyl acceptor
14, the sialylation reaction with donor RRV less than 11 yielded
α/β-mixture for 2,3-linked sialylated disaccharide 18. Attaining
highly α-selective sialylation was difficult with acceptor 14, but
relatively easier to carryout β-selective reactions (β-selectivity
>75% for β-sialosides 18, blue bar) with the RRV higher than
11 (Figure 5C). Enzymatically stable unnatural oligosaccharides
having β-sialosides may have important biological roles.[21] For
alkyl sialoside 19, attaining α-selective sialylation reaction was
difficult with the sterically hindered tertiary alkyl alcohol 15.
Coupling of this acceptor with any thiosialoside donor gave the
α/β-mixture (Figure 5D, gray color). These results indicate that
RRV of donors can be used as an indicator to predict the
stereochemical outcome of sialylation reactions based on the
type of acceptor used. As a result, the tedious trial-and-error
method to get the optimal conditions can be circumvented.
Conclusion
RRV defined the stereoselectivity and yield of sialylation on six
thiosialoside donors under the NIS/TfOH activation system
without solvent participation. To attain stereoselective sialyla-
tion, the intermediate ratio was controlled using RRV, pro-
moters, and varying reaction temperatures. Based on the
donors considered in our investigation, the stereoselectivity
outcome, glycosylation yield and intermediate distribution have
Figure 4. Intermediate distribution vs. donor reactivity. Using A) NBS/TfOH;
B) NCS/TfOH and C) p-TolSCl/AgOTf as the promoter.
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Acknowledgements
This work was supported by the Ministry of Science and
Technology of Taiwan (MOST 108-2113-M-001-019-; MOST 106-
2113-M-001-009-MY2) and Academia Sinica (MOST 108-3114-Y-
001-002; AS-SUMMIT-109). We also thank Dr. Su-Ching Lin, Ms. Yi-
Ping Huang, and Ms. Mei-Man Chen for their help with NMR
experiments, and Ms. Ping-Yu Lin for conducting mass spectrom-
etry experiments.
Conflict of Interest
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Manuscript received: June 18, 2021
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FULL PAPERS
Dr. K. H. Asressu, Dr. C.-W. Chang,
Dr. S. Lam, Prof. C.-C. Wang*
1 – 7
Donor-Reactivity-Controlled Sialy-
lation Reactions
°
The relative reactivity value was found
to provide a guideline to control the
stereoselectivity of sialylation
system at À 40 C, resulting α-selectiv-
ity >75% for α(2!6)-linked disac-
charides and β-selectivity >75% for
β(2!3)-linked disaccharides.
reactions under NIS/TfOH promotion