Protecting group-free s-glycosylation towards

1. Protecting-group-free S-glycosylation towards thioglycosides and
thioglycopeptides in water

2. Abstract
• A facile and green S-glycosylation method has been
developed featuring protecting-group-free and
proceeding-in-water like enzymatic synthesis.
• Glycosylation of fluoride donors with thiol sugar
acceptors using Ca(OH)2 as a promoter afforded
various thioglycosides in good yields with exclusive
stereoselectivity.
• This method also enabled the successful production of
S-linked oligosaccharides and S linked glycopeptides.

3. Introduction
• In recent years, fluorine and sulfur groups have become crucial
components of pharmaceuticals in the medicinal industry.
• a Glycosyl fluorides have displayed relative stability in water and
have been widely applied in significant glycosylation reactions.
• A number of synthetic methods for obtaining glycosyl fluorides and
thiol-modified glycans15 have been developed.
• Herein, they report a facile and protecting-group-free method
towards thioglycosides using fluoride donors and thiol acceptors under
basic aqueous conditions.
• This chemical thioligation method provides an easier, more
practical, cleaner, and efficient alternative for the synthesis of
thioglycosides using renewable water and thereby eliminating organic
pollution.

4. Protecting-group-free synthesis of thioglycosides. (a) Enzymatic synthesis of β-
linked thioglycosides; (b) enzymatic synthesis of α-linked thioglycosides; and
(c) chemical synthesis of thioglycosides reported in this work. DNP = 2,4-
dinitrophenyl; pNP = para nitrophenyl.

5. Optimization of S-glycosylation
The fluoride-thiol coupling method was evaluated and optimized using coupling glucopyranosyl
fluoride 1 and 6-SH modified methyl glucopyranoside 2

6. basic aqueous conditions

7. basic aqueous conditions
• Firstly, they tested NaH as a base to promote the coupling reaction, given its standard implementation in the
glycosylation of glycosyl halides.16 Unfortunately, this reaction did not yield any product (entry 1).
• It was observed that as the reaction proceeded, thiol acceptor 2 was oxidized to a disulfide. In this context,
tris(2-carboxyethyl) phosphine (TCEP) was added to act as a reducing reagent in the reaction, but still no product
was formed (entry 2). Stronger bases like NaOH or KOH could not promote this coupling reaction as well
(entries 3 and 4).
• they then adopted the condition of Ca(OTf)2/45% aqueous NMe3, which was used to achieve the
regioselective O-glycosylation of unprotected sucrose or analogues with fluoride donors in an aqueous
medium.17 However, the coupling between 1 and 2 under this condition was unsuccessful (entry 5).
• Recently, Wadzinski and coworkers reported that fluoride donors could be efficiently coupled to phenols in
the presence of Ca(OH)2 in water.5 So, they tested Ca(OH)2 as a base to promote the coupling reaction between
fluoride donor 1 and thiol acceptor 2 in water (entry 6).
• Surprisingly, the S-linked disaccharide 3 was successfully afforded with nearly complete conversion within 0.5
h.
• The high yield and fast rate may be attributed to the strong nucleophilicity of thiol and the formation of CaF2
precipitation, which drive the reaction in the direction of product formation.

8. The impact of alkaline
earth metal hydroxides
• In addition to Ca(OH)2, other alkaline earth metal
hydroxides, including Sr(OH)2 (entry 7)
• and Ba(OH)2 (entry 8), were tested to promote this
coupling reaction as well.
• Only Sr(OH)2 was able to promote this coupling
reaction in a moderate yield.
• Although the lanthanide hydroxides, including
La(OH)3, Nd(OH)3, Sm(OH)3, Gd(OH)3, could also
drive fluoride precipitation, no corresponding
thioglycoside was generated (entries 9–12).
• Therefore, they reasoned that the basicity of these
hydroxides might not be strong enough to promote this
coupling reaction.

9. the impact of donor equivalents
• they then evaluated the impact of donor
equivalents where the use of 1.5 equiv. resulted in
a satisfactory yield of 79% (entry 13)
• 2 equiv. of the donor gave a high yield of 92%
(entry 14). When 1.5 equiv. of donor 1 was used,
• the thiol acceptor 2 could not be completely
consumed even when the reaction time was
extended to up to 3 h.

10. the concentration of the thiol acceptor
effect
• On the other hand, decreasing the
concentration of the thiol acceptor in the
system from 0.5 M (entry 6) to 0.1 M
(entry 15) had a minor influence on the
overall coupling yield (98% to 82%).
• Because the nature of the solvent is
known to influence the stereoselectivity
and the yield of glycosylation reactions,

11. Solvent Effect
• the nature of the solvent is known to influence the
stereoselectivity and the yield of glycosylation reactions, other
solvents were evaluated for the fluoride–thiol coupling,
including
• DMF,
• DMSO,
• DMF/H2O (1/1),
• CH3CN/H2O (1/1) (entries 17–20).
• It turned out that the reaction only proceeded well in the
CH3CN/H2O solvent system besides water.
• Moreover, a reaction of 5 mmol of 2 (1.05 g) with 15 mmol
of 1 (2.73 g) resulted in a 92% yield of 3 (1.71 g),
demonstrating the scalability of this reaction.

12. THANK YOU