Chemoselective activation of ethyl: Vs. phenyl thioglycosides: One-pot synthesis of oligosaccharides

Article abstract of DOI:10.1039/d0ob01606c

Ethyl and phenyl thioglycosides are the two most common types of thioglycoside donors in carbohydrate chemistry. However, the chemoselective activation of ethyl vs. phenyl thioglycosides is very rare in the literature. In this work, ethyl thioglycosides c

Full text of DOI:10.1039/d0ob01606c

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Chemoselective Activation of Ethyl vs Phenyl Thioglycosides: One-pot Synthesis of
DOI: 10.1039/D0OB01606C
Oligosaccharides
Cian Mc Carthy and Xiangming Zhu*
Centre for Synthesis and Chemical Biology, UCD School of Chemistry, University College
Dublin, Belfield, Dublin 4, Ireland
Tel: +353 17162386; Fax: +353 17162501; e-mail: Xiangming.Zhu@ucd.ie
Electronic supplementary information (ESI) available. See DOI:
Abstract:
Ethyl and phenyl thioglycosides are the two most common types of thioglycoside donors in
carbohydragte chemistry, however, chemoselective activation of ethyl vs phenyl
thioglycosides is very rare in the literature. In this work, ethyl thioglycosides could be readily
activated with N-trifluoromethylthiosaccharin/TMSOTf system in the presence of phenyl
thioglycosides carrying the same or even more arming protecting group pattern. Both armed
and disarmed thioglycosides exhibited high chemoselectivity towards the promoter system.
The chemoselective glycosylation was subsequently applied to one-pot synthesis, thus
providing an efficient means to oligosaccharides.
Keywords: Thioglycoside; Chemoselective activation; N-trifluoromethylthiosaccharin;
Glycosidation reaction; one-pot synthesis
Introduction
The construction of glycosidic bonds is the focal point in carbohydrate syntheses, and often
requires exhaustive optimization of every parameter, such as leaving group, promoter and
reaction temperature, with the target to achieve high yield and stereoselectivity.1 A general
glycosylation procedure is highly desirable but has not appeared yet. Thus, the development of
new glycosylation methods and strategies are vital in carbohydrate chemistry in order to meet
the intrinsic structural diversity of carbohydrates.2 Unlike the glycosyl halide and glycosyl
trichloroacetimidate donors, thioglycosides can serve not only as glycosyl donors but also as
1

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glycosyl acceptors3 due to the anomeric thioether group possessing great stability under a wide
DOI: 10.1039/D0OB01606C
range of conditions for protecting group manipulation. As a result of their versatility,
thioglycosides have often been used as key building blocks in the assembly of various complex
oligosaccharides and have significantly improved synthetic efficiency. For example, a sulfated
trisaccharide repeating unit of fucosylated chondroitin sulfate was synthesised efficiently in a
one-pot manner with thioglycosides solely employed as the glycosyl donor.4 More recently,
thioglycosides were also used repeatedly as key building units in the synthesis of core
trisaccharides derived from Pseudomonas aeruginosa O11 and Staphylococcus aureus type 5,5
which are valuable structures for the development of carbohydrate vaccines and diagnostics.
Undoubtedly, thioglycosides have proven and will continue to be one of the most versatile and
frequently employed glycosyl donors.
Because of their inherent stability, reactivity tuning strategies to selectively activate one
thioglycosyl donor over another are very attractive as they can offer flexible oligosaccharide
sequencing. Such selective activation approaches of thioglycosides have been well documented
in the literature, as reported in Wong’s programmable one-pot synthesis6 and Demchenko7 and
Bol’s8 work on superarmed donors. Extensive work in this area has been focused on controlling
the reactivity of donors by choice of protecting group employed and induction of
conformational change on glycosides.
On the other hand, selective activation of similarly protected thioglycosides through the
exclusive use of leaving groups, remains relatively unexplored. There are a few reports of such
a strategy used to chemoselectively activate thioglycosides. Boons and co-workers realised the
effect of substituent size on the anomeric reactivity of thioglycoside donors by introducing a
bulky dicyclohexylmethylthio group onto the anomeric position which had an adverse effect
on its reactivity,9 and ultimately led to a chemoselective glycosylation. Modulating the
electronic properties of arylthio aglycons has also been explored. p-Acetamidophenyl
thioglycosides can be selectively activated in the presence of electronically deactivated p-
nitrophenyl thioglycosides, and the resulting disaccharide can subsequently be reduced and
acetylated to give another p-acetamidophenyl thioglycoside for chain elongation.10 Similarly,
a series of p-substituted phenyl thioglycosides differing only in the aglycon substituents were
also prepared and investigated towards donor differentiation,11 and ultimately led to the design
of a one-pot oligosaccharide synthesis.12 Another relevant investigation carried out by
Lahmann and co-workers focused on the reactivity of anomeric thioether groups, which led to
a successful chemoselective activation of an ethyl thioglucoside in the presence of a p-
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bromophenyl thioglucoside.13 Recently, orthogonal activation of glycosyl thioiDmOiI:d1a0.t1e03s9Vi/eaDwn0AOdrtBic0le1O60nl6inCe
ethyl thioglycosides was also achieved using different types of activation conditions and
applied successfully to an expeditious sequential synthesis of a hexasaccharide.14
Ethylthio and phenylthio groups are the most commonly employed leaving groups of choice
and thus are the most widely used thioglycoside donors.1a It is the commercial availability of
ethane thiol and thiophenol and the simplicity of preparation of such donors15 that has
popularized the use of ethyl and phenyl thioglycosides. Unfortunately, the selective activation
of ethyl over phenylthioglycosides bearing similar protecting group patterns is scarcely seen in
literature, even though it is strategically attractive and may add great value to the two most
common thioglycoside donors. To the best of our knowledge, there is only one report on
selective activation of anomeric ethylthio in the presence of phenylthio, in which an N+-
thiophilic reagent O-mesitylenesulfonylhydroxylamine was used to discriminate between an
armed ethyl and armed phenyl thioglucoside.16
Albeit high stability, thioglycosides can be activated effectively by numerous promoters,
but most of them, such as N-iodosuccinimide (NIS) plus a catalytic amount of protic acid or
Lewis acid, may be too robust to be employed for chemoselective activation of anomeric
ethylthio versus phenylthio groups. NIS in conjunction with TMSOTf was used recently to
selectively activate ethyl thioglycosides with the same protecting group patterns,17 in which a
great disparity in reactivity between the two anomeric ethylthio groups was mediated by
anomeric configuration and resulted in a successful chemoselective activation. However, the
reactivity difference between ethyl and phenyl thioglycosides with the same protecting group
patterns and anomeric configuration is subtle, and likely not sufficient to be discriminated by
most promoter systems.
Results and Discussion
Two effective thioglycoside activation systems, both involving electrophilic
trifluoromethylthiolating reagents18 (Figure 1) have been developed recently in our
laboratory.19,20 A thioperoxide reagent 1 in combination with TMSOTf was first found to be a
powerful thiophilic system, capable of activating different thioglycosides including armed and
disarmed phenyl thioglycosides.19 More recently, N-trifluoromethylthiosaccharin 2, a more
attractive reagent than 1 and most commonly used promoters in its ease of preparation and
shelf stability, was used to activate a range of ethyl thioglycosides in the presence of a catalytic
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amount of TMSOTf.20 Upon activation, these thioglycosides underwent glycosidation
DOI: 10.1039/D0OB01606C
reactions with various glycosyl acceptors in CH2Cl2 to give the desired disaccharides in good
to very high yields. All reactions proceeded cleanly as a result of saccharin precipitating out of
solution as a byproduct, thus minimising side product formation. In addition to CH2Cl2,
participating solvents CH3CN and Et2O were also employed as cosolvents in order to determine
their effect on the stereoselectivity of the glycosidation reactions (see Supporting Information).
Figure 1. Structures of thioperoxide 1 and N-trifluoromethylthiosaccharin 2.
Interestingly, no activation of a disarmed phenyl thioglycoside was observed in the
presence of 2/TMSOTf, as reported in our previous communication.20 Despite this low
reactivity, we felt that we could turn it into an advantage. Hence, two successful chemoselective
activations of disarmed ethyl thioglycoside donors in the presence of disarmed phenyl
thioglycoside acceptors were achieved under the new activation condition.20 Motivated by
these results, we decided to pursue approaches to chemoselective glycosylations, and wish to
report here N-trifluoromethylthiosaccharin 2 as an effective promoter for selective activation
of anomeric ethylthio in the presence of phenylthio leaving groups. Its differentiating ability
towards anomeric ethylthio vs phenylthio was also exploited in the design of an iterative one-
pot oligosaccharide assembly.
Our initial investigation was to gain an insight into the observed chemoselectivity of an
ethyl thioglycoside over a phenyl thioglycoside. As shown in Table 1, two sets of competition
experiments were carried out with a view to compare the reactivity of disarmed (3 vs 5) and
armed (4 vs 6) thioglucoside donors, respectively. The equimolar (1.1 eq.) mixture of ethyl and
phenyl thioglycosides were treated with the new promoter system, i.e. 2 and TMSOTf, in the
presence of one equivalent of glucosyl acceptor 7. Both reactions were quenched after 40
minutes. The unreacted donors were recovered and their relative reactivity was determined by
1
examination of the relative intensities of representative peaks on the H NMR spectra. As
displayed in Table 1, both thioglycoside pairs
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DOI: 10.1039/D0OB01606C
Table 1. Competitive glycosylation between ethyl and phenyl thioglucosides.
b
aCalculated from isolated product mass following column chromatography. Determined by
1
integration of representative signals in the H NMR; refers to the ratio of unreacted donors
(donor A : donor B) after quenching.
demonstrated a significant difference in reactivity towards the new activation conditions. Both
armed and disarmed ethyl thioglucoside donors could be preferentially activated with
2/TMSOTf in the presence of the corresponding phenylthioglucoside donors. Although the
recovery ratio for 3 and 5 may seem poor at first glance, this is a consequence of the lower
reactivity of disarmed donors and the sluggish nature of this competitive reaction leading to
incomplete conversion. Meanwhile, we were very pleased to observe the greater degree of
selectivity for the armed donor 4 over 6 (Table 1, entry 2). Despite being the more reactive pair
of the two, the armed donors showed a higher degree of selectivity under the present activation
condition. Apparently, the preferential activation of ethyl over phenyl thioglycosides exhibited
by the promoter stems from the higher nucleophilicity of the anomeric sulfur in the ethyl
thioglycosides, and it is the extent of this promoter’s influence that has made chemoselective
activation and one-pot synthesis feasible (vide infra). The competitive experimental results
indicated that N-trifluoromethylthiosaccharin-controlled selective activation could potentially
serve as an invaluable extension to reactivity-based oligosaccharide synthetic strategies.
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Encouraged by the above results, a series of thioglycoside donors and thioglycoside
DOI: 10.1039/D0OB01606C
acceptors were then prepared in order to further explore the scope and generality of the new
promoter system in selective activation of ethyl vs phenyl thioglycosides. Previous work20 has
shown disarmed ethyl thioglycosides donors could be effectively activated by promoter 2 in
the presence of catalytic amounts of TMSOTf, with disarmed phenyl thioglycoside donors
being relatively inert under the same activation conditions. This prompted us to test first the
chemoselective activation between disarmed ethyl thioglycoside 3 and phenyl thioglycoside 12
(Table 2, entry 1). To our delight, the reaction proceeded smoothly under the action of promoter
2 and a stoichiometric amount of TMSOTf at room temperature, and the desired disaccharide
17 was isolated in very high yield.
Next, to validate the high selectivity observed above between armed thioglycosides 4 and
6, phenyl thioglycoside 13 bearing a highly reactive protecting group pattern was selected as
the acceptor to see if it could couple with ethyl thioglycoside 4 under similar reaction
conditions (Table 2, entry 2). Hence, a mixture of 13 and 4 was treated with 2 and catalytic
amount of TMSOTf at 0 °C, and as expected, the desired product 18 was formed in very good
yield. This is a very promising result as it highlights the opportunities of performing such
chemoselective glycosylation on other superarmed phenyl thioglycosides. Moreover, the
unreacted phenyl thioglycoside 13 could be easily recovered and the yield was much higher
based on the recovered material. It should be noted here that trace activation of 13 was also
detected by TLC if the reaction time was prolonged.
We subsequently investigated the use of phenyl thiogalactosides 14 and 15 as acceptors,
which represent typical equatorial and axial hydroxy groups, respectively (Table 2, entries 3
and 4). When a mixture of 4 and 14 was subjected to the above reaction conditions, the desired
disaccharide 19 was efficiently obtained as an α/β mixture in 82% yield. It is worth noting that
the α-stereoselectivity (α/β 5:1) observed in the formation of 19 was quite high for a normal
glycosidation reaction without neighbouring group participation and solvent assistance etc. We
speculated that the high stereoselectivity outcome could be attributed to the mildness of the
activation conditions plus the relatively weak nucleophilicity of the acceptor.21 Likewise,
chemoselective activation of ethyl thioglycoside 4 in the presence of phenyl thioglycoside 15
was also successfully achieved under the same conditions, and the disaccharide 20 was
produced again in very good yield (63%) and α-selectivity (α/β 3:1). Manα(12)Man
oligomers are interesting structures for constructing multivalent systems mimicking high
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DOI: 10.1039/D0OB01606C
Table 2. Chemoselective activation of ethyl vs phenyl thioglycosides using 2/TMSOTf.
b
c
a1.0 eq. of TMSOTf added to reaction. Temperature of reaction: 0 °C. Temperature of
reaction: -25 °C to -15 °C. d Determined by integration of representative signals in the 1H NMR.
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mannose interactions.22 For this reason, ethyl thiomannosyl donor 10 and phenyl thiomannosyl
DOI: 10.1039/D0OB01606C
acceptor 16 were also selected for the chemoselective activation with a view to construct
oligomannosides in a highly efficient way. As shown in entry 5 in Table 2, the coupling of 10
with 16 also met with success under the same conditions producing the desired disaccharide
21 in 59% yield. It should be mentioned here that the reaction time was critical to eliminate
unwanted activation of thioglycoside 16.
To demonstrate the compatibility of acid-sensitive protecting groups with this new
chemoselective glycosylation strategy, the 4,6-O-benzylidenated ethyl thioglycoside donor 11
was also prepared as the last example and reacted with phenyl thioglycoside 12, as shown in
entry 6 in Table 2. Again, upon treatment with promoter 2 and catalytic amounts of TMSOTf,
the reaction led to the formation of the desired disaccharide 22 in very high yield. Slow
dropwise addition of the solution of TMSOTf in CH2Cl2 at low temperature facilitated this
chemoselective glycosylation. Conceivably, all the above disaccharides 17 - 22 could be used
immediately as thioglycoside donors to construct more complex oligosaccharides, which, plus
the ready availability of ethyl and phenyl thioglycosides, suggests that the present
chemoselective glycosylation protocol may provide a convenient and efficient means to
oligosaccharides.
The high degree of chemoselectivity in the above reactions led us to explore this selective
glycosylation protocol further in the context of one-pot oligosaccharide chemistry. In addition,
we would like to probe the question whether the present promoter system would be compatible
with other commonly used promoters for thioglycoside activation, ideally those that can
sequentially activate anomeric phenylthio leaving group in the same pot reaction. Possessing
such compatibility would allow this new chemoselective glycosylation to be used as an
extension to reactivity based one-pot oligosaccharide synthesis, thereby expanding further
thioglycoside chemistry. For this purpose, ethyl thioglycoside 3, phenyl thioglycoside 12 and
methyl glycoside 7 were first chosen to undergo a sequential one-pot assembly, as illustrated
in Scheme 1. Following the above chemoselective activation procedure, a mixture of
thioglycosides 3 and 12 was first treated with thiosaccharin 2 in the presence of a stoichiometric
amount of TMSOTf. Upon the complete conversion of donor 3 and the formation of
disaccharide 17 as indicated by TLC, acceptor 7 and thioperoxide 1 were added successively
into the mixture. It should be noted that thioperoxide 1, belonging to the same family of
trifluoromethylthiolating reagents as 2,18 was reported earlier to be capable of activating phenyl
thioglycosides.19 As expected, the desired trisaccharide 23 was produced in very good yield
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over two glycosidation steps. To further demonstrate the compatibility of the tDhOioI:s10a.c10c3h9/aDr0iOnB01606C
system, NIS was also introduced instead of thioperoxide 1 into the above one-pot synthesis.
Again, TLC indicated a clean reaction and the target trisaccharide 23 was produced smoothly
in high overall yield. Here it is worth mentioning that the precipitation of saccharin in the first
glycosidation step may be crucial to the success of the one-pot chemistry as insoluble saccharin
could not interfere with the subsequent glycosidation step, thereby reducing the occurrence of
side reactions. This sequential assembly involving chemoselective activation of ethyl vs phenyl
thioglycosides thereby provides an attractive alternative in the synthesis of oligosaccharides.
Scheme 1. One-pot synthesis of trisaccharide 23.
To further demonstrate the effectiveness of the chemoselective glycosylation and the power
of the one-pot synthesis, we proceeded to use 4, 14, 11 and 12 as thioglycosides in the one-pot
synthesis of oligosaccharides. As shown in Scheme 2, coupling of thioglycosides 4 and 14 was
first conducted under the above chemoselective activation conditions to generate disaccharide
19, which was then activated by thioperoxide 1 in the presence of acceptor 7, to give the desired
trisaccharide 24 in 56% overall yield. Similarly, glycosylation of phenyl thioglycoside 12 with
ethyl thioglycoside 11 was also carried out as part of the one-pot synthesis of trisaccharide 26.
Upon the formation of disaccharide 22 under thiosaccharin activation conditions, benzylidene-
protected acceptor 25 and NIS were added successively into the reaction mixture. Fortunately,
both benzylidene protecting groups survived under the current conditions containing catalytic
amounts of TMSOTf and trisaccharide 26 was isolated in 41% overall yield.
Scheme 2. One-pot synthesis of trisaccharides 24 and 26.
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DOI: 10.1039/D0OB01606C
In conclusion, this investigation has demonstrated the power of N-
trifluoromethylthiosaccharin 2 in the chemoselective activation of ethyl thioglycosides over
phenyl thioglycosides in glycosylation reactions. The source of this differentiation stems from
the higher nucleophilicity of the anomeric sulfur in the ethyl thioglycosides, and the extent of
this preferential activation was applicable to both armed and disarmed ethyl thioglycosides.
This reagent controlled chemoselective glycosylation was demonstrated through coupling of
various ethyl thioglycoside donors and phenyl thioglycoside acceptors to give their
corresponding disaccharides in good to high yields. Finally, the chemoselective glycosylation
protocol was explored in the context of one-pot oligosaccharide chemistry with thiosaccharin
2 and thioperoxide 1 or NIS as promoters. Not only did we demonstrate the simplicity of the
design and success of these oligosaccharide assemblies, but also the potential flexibility and
future of thiosaccharin 2 with other common promoters. We believe that this straightforward
chemoselective system will expand greatly thioglycoside chemistry and serve as an extension
to reactivity-based one-pot oligosaccharide strategies.
Conflicts of interest
The authors state that there are no conflicts to declare.
Acknowledgments
The authors thank University College Dublin for financial support. C. Mc C. is grateful for a
demonstratorship from the UCD School of Chemistry.
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DOI: 10.1039/D0OB01606C
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Ethyl thioglycosides could be selectively activated in the presence of phenyl thioglycosides carrying
the same or even more arming protecting group pattern.
O O
S
N SCF3
OH
O
O
O
O
O
PGO
O
SEt
SPh
+
PGO
PGO
SPh
PGO
TMSOTf