Use of remote acyl groups for stereoselective 1,2-: Cis -glycosylation with fluorinated glucosazide thiodonors

Article abstract of DOI:10.1039/d0ob01065k

Fluorinated glycans are valuable probes for studying carbohydrate-protein interactions at the atomic level. Glucosamine is a ubiquitous component of glycans, and the stereoselective synthesis of α-linked fluorinated glucosamine is a challenge associated with the chemical synthesis of fluorinated glycans. We found that introducing a 6-O-acyl protecting group onto 3-fluoro and 4-fluoro glucosazide thiodonors endowed them with moderate α-selectivity in the glycosylation of carbohydrate acceptors, which was further improved by adjusting the acceptor reactivity via O-benzoylation. Excellent stereoselectivity was achieved for 3,6-di-O-acyl-4-fluoro analogues. The glycosylation of threonine-derived acceptors enabled the stereoselective synthesis of the protected fluorinated analogue of α-GlcNAc-O-Thr, a moiety abundant in cell-surface O-glycans of the protozoan parasite Trypanosoma cruzi. DFT calculations supported the involvement of transient cationic species which resulted from the stabilization of the oxocarbenium ion through O-6 acyl group participation. This journal is

Full text of DOI:10.1039/d0ob01065k

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ervenková Šastná, M. Kurfit, P. Curinova, M. Dracinsky and J. Karban, Org. Biomol. Chem., 2020, DOI:
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Oligonucleotide modifi cations enhance probe stability for
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01065K
Use of Remote Acyl Groups for Stereoselective 1,2-Cis-Glycosylation with
Fluorinated Glucosazide Thiodonors
1
,2
1
1,2
1
Vojtěch Hamala, Lucie Červenková Šťastná, Martin Kurfiřt, Petra Cuřínová, Martin
3
1,*
Dračínský, Jindřich Karban
1Institute of Chemical Process Fundamentals of the CAS, v. v. i., Rozvojová 135, 16502 Praha 6,
2
Czech Republic. University of Chemistry and Technology Prague, Technická 5, 16628 Praha 6,
3
Czech Republic. Institute of Organic Chemistry and Biochemistry of the CAS, v. v. i., Flemingovo
náměstí 542/2, 16000, Praha 6, Czech Republic
*
Email: karban@icpf.cas.cz.
Abstract. Fluorinated glycans are valuable probes for studying carbohydrate-protein interactions at the atomic
level. Glucosamine is a ubiquitous component of glycans, and the stereoselective synthesis of -linked
fluorinated glucosamine is a challenge associated with the chemical synthesis of fluorinated glycans. We found
that introducing a 6-O-acyl protecting group onto 3-fluoro and 4-fluoro glucosazide thiodonors endowed them
with moderate -selectivity in the glycosylation of carbohydrate acceptors, which was further improved by
adjusting the acceptor reactivity via O-benzoylation. Excellent stereoselectivity was achieved for 3,6-di-O-acyl-
4-fluoro analogues. The glycosylation of threonine-derived acceptors enabled the stereoselective synthesis of
the protected fluorinated analogue of -GlcNAc-O-Thr, a moiety abundant in cell-surface O-glycans of
protozoan parasite Trypanosoma cruzi. DFT calculations supported the involvement of transient cationic species
which resulted from the stabilization of the oxocarbenium ion through O-6 acyl group participation.
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Introduction.
-Amino-2-deoxy-glucopyranoses (GlcN) linked as both 1,2-cis- and 1,2-trans-glycosides aVi
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1
structures found in various bioactive oligosaccharides. While 1,2-trans (β-)glucosaminyl linkage can be
reliably installed by taking advantage of neighbouring group participation by a C-2 amide or carbamate, there
is no general method for the synthesis of 1,2-cis (-)linked glucosamine. Several glycosylation strategies for
the construction of 1,2-cis-linked 2-aminoglucopyranosides have been developed,2-5 but glycosylation with 2-
6
azido-2-deoxy-glucopyranosyl (also known as glucosazide) donors, first investigated by Paulsen, is still
widely used.7-9 The presence of a non-participating C-2 azide does not guarantee α-selectivity, and a
8
substantial amount of 1,2-trans glycosides can be formed. Owing to the importance of fluorinated
carbohydrates as inhibitors and probes for carbohydrate-protein interactions,10-18 we have extended our initial
interest in the synthesis of fluorinated aminopyranoses19,20 to the systematic investigation of procedures for -
selective glucosaminylation with fluorinated GlcN donors. We have prepared O-benzylated deoxofluorinated
glucosazide thiodonors 1 and 2 (Fig. 1) and examined their stereoselectivity in preactivation-based
2
1
glycosylation with a Tf
2
O/Ph SO promoter system against a set of model carbohydrate acceptors. Both
2
thiodonors favoured formation of the corresponding 2-azido-2-deoxy-β-glucosides with reactive acceptors,
gradually loosing selectivity with decreasing acceptor reactivity. The stereoselective construction of 1,2-cis-
linkages could not be accomplished under these conditions. The overall tendency of compounds 1 and 2 to
form β-glycosides probably resulted from the destabilization of cationic intermediates by the combined
electron-withdrawing effects of azide and fluorine substituents.8,21
Figure 1. O-Benzylated 3-fluoro and 4-fluoro glucosazide thiodonors.
As thiodonors 1 and 2 were unsuitable for the stereoselective synthesis of 1,2-cis glycosidic linkages,
we searched for an alternative. The -stereodirecting effects of remote (non-vicinal) O-acyl protecting groups
are increasingly recognized and applied synthetically, 22-27 although the involvement of putative bicyclic
cationic intermediates shielding the trans-face of the donor has been questioned.28,29 However, the
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Organic & Biomolecular Chemistry
stereocontrol is reduced compared with participating functionalities at C-2, and empirical adjustment of the
protecting groups and reaction conditions typically precedes successful -glycosylation. For example
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showed that combining acetyl groups at the 3- and 6-positions in glucosazide thiodonor 3e (Scheme 1) gave
better -selectivity in the glycosylation of primary acceptor 4 compared with 6-O-acetyl donor 3c, while 3-O-
acetyl donor 3a was not selective, 4-O-acetyl donor 3b was moderately β-selective and 4,6-di-O-acetyl donor
30
3
d was marginally -selective. Ventura reported that good -stereoselectivity in the glycosylation of lactic
acid ester with 6-O-chloroacetyl thiodonor 5 (Scheme 1) was achieved in CH Cl /Et O 1:2 at −10 °C, while
the -selectivity was eroded by omitting Et
O, lower reaction temperatures, or using a 6-O-acetyl group.31
2
2
2
2
Scheme 1. Reported effects of remote acyl groups on stereoselectivity with glucosazide thiodonors.30,31
Inspired by these reports, we decided to evaluate the stereodirecting effects of remote O-acyl groups
in deoxofluorinated glucosazide thiodonors. Accordingly, we prepared a series of O-acyl protected 3- and 4-
deoxofluorinated phenyl 2-azido-2-deoxy-1-thioglucopyranosides and investigated the influence of protecting
groups on glycosylation stereoselectivity. We also prepared and tested donors carrying large 6-O-tert-
butyldimethylsilyl (TBS) and 6-O-tert-butyldiphenylsilyl (TBDPS) groups that were reported to increase -
32
selectivity by shielding the donor β-face. The N-iodosuccinimide (NIS)/triflic acid (TfOH) activation system
33
was selected because it is widely used, making comparison with the results obtained for nonfluorinated
glucosazide thiodonors possible.30,31 Herein, we present the results of this investigation. The versatility of 1,6-
anhydropyranose chemistry is demonstrated by the synthesis of orthogonally protected 3- and 4-
deoxofluorinated phenyl 2-azido-2-deoxy-1-thioglucopyranosides. We also show that installing remote 6-O-
acyl groups, combined with adjusting the acceptor reactivity, is a viable strategy for -glycosylation with
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fluorinated glucosazide thiodonors. The applicability of this glycosylation method is illustrated by the
synthesis of a fluorinated -GlcNAc-O-Thr moiety found in abundance in O-glycans of protozoan pa
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Trypanosoma cruzi.
Results and Discussion.
The O-acylated thiodonors were prepared as described in Scheme 2. Protecting group patterns were
selected in which only the primary O-6 hydroxyl group or both the primary and secondary hydroxyl groups
(
O-3/O-4) were acylated. Selective acylation of a secondary hydroxyl group only was not attempted. The key
transformation was cleavage of the internal acetal in 2-azido-3- or 4-fluoro-1,6-anhydropyranoses by reaction
with phenyl trimethylsilyl sulfide (PhSTMS)/ZnI , followed by O-6 acylation or silylation. This approach
allowed independent protection of the primary and secondary hydroxyls. 3-Fluoro analogues were prepared
2
2
0
34
from known 2-azido-3-fluoro-1,6-anhydropyranoses 6 and 7. Reaction of compound 6 with PhSTMS gave
2
1
thioglycosides -8 and -8 as separable anomers that were converted to 6-O-benzyl derivative 1 and 6-O-
chloroacetyl derivatives - and -9 in parallel. Separation of the anomers of thioglycoside 8 was necessary
owing to an impurity that elutes between them during chromatography. For synthetic convenience, only the -
anomer (-8) was converted to 6-O-benzoyl and 6-O-TBS derivatives 10 and 11, respectively, using routine
35
procedures. Microwave-assisted fluorination of thioglycoside -8 yielded 3,6-difluoro analogue 12. The β-
36
anomer (-8) was not reacted with diethylaminosulfur trifluoride (DAST) owing to the risk of SPh migration.
2
0
4
,6-O-Benzylidene derivative 13 was obtained from compound 7 by trimethylsilylation, followed by reaction
with PhSTMS, removal of the trimethylsilyl groups during workup and conventional 4,6-O-benzylidenation.
O-Acetylation of compound 7, followed by cleavage of the internal acetal to give thioglycoside 15 and
subsequent acylation, furnished 16 and 17. The synthesis of 4-fluoro thiodonors followed a similar sequence,
commencing with known compounds 18 and 22.20,21 Therefore, 4-fluoro analogue 18 was transformed into
21
21
21
20
thioglycosides 2, 20, and 21 via compound 19, while compound 22 was converted into thioglycosides 25
and 26 via intermediates 23 and 24 (Scheme 2).
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Organic & Biomolecular Chemistry
Scheme 2. Synthesis of deoxofluorinated thiodonors (ClAc = chloroacetyl).
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Stereoselectivity in the glycosylation with 3-fluoro donors was evaluated against carbohydrate
3
7
38
38
39
40
acceptors A, B, C, D, and E (Table 1). A mixture of acceptor and thiodonor (1.2 equiv.) in
dichloromethane was treated with NIS (2.2 equiv.) and TfOH (0.4–1.1 equiv.) to afford the corresponding
glycosylation product. The anomeric configuration of the newly formed glycosidic bond was deduced from the
magnitude of the vicinal 3JH1,H2 coupling constants (3.5–3.9 Hz for 1,2-cis products and 7.5–8.5 Hz for 1,2-
1
9
trans products). The anomeric ratio was determined by integration of the F NMR signals of both anomers
after aqueous workup, but prior to chromatography.
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Table 1. Glycosylation of acceptors R-OH with 3-fluoro donors.
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entry Donor R1
R2 Acceptor R-OH
Product
/ Yield

1
2
3
4
5
6
7
-1 OBn OBn
-9 OClAc OBn
-9 OClAc OBn
10 OBz OBn
11 OTBS OBn
12 OBn
A1
A9
1.2:1 85%
4.5:1 83%
5.2:1 78%
5.2:1 82%
4.3:1 28%
A9
A10
A11
A12
A13
A
a
F
1.3:1 39%
b
13 PhCH<(O)O
1.8:1

8
9
-1 OBn OBn
-1 OBn OBn
-9 OClAc OBn
-9 OClAc OBn
-9 OClAc OBn
B1
B1
2.0:1 82%
c
1:1.2 86%
1
0
1
2
3
4
B9
7.3:1 83%
d
1
1
1
1
B
B9
9.6:1 75%
e
B9
9.7:1 70%
10
12
OBz OBn
OBn
B10
B12
6.6:1 71%
3.0:1 52%
F
1
1
5
6
-9 OClAc OBn
-9 OClAc OBn
8.7:1 68%
C9
D9
C
f
17.0:1 59%
D
1
1
7
8
16 OClAc OAc
E16
E9
4.6:1 49%
E
-9 OClAc OBn
7.6:1 67%
a
19
b
Yield of -anomer A12- only inseparable byproducts detected in -anomer by F NMR; partial
c
d
decomposition occurred during chromatography; Et O omitted from the reaction mixture; reaction conducted
2
e
f
at 0 °C; reaction conducted at 20 °C; 2 equiv of glycosyl donor used.
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Organic & Biomolecular Chemistry
The results showed that the 1,2-cis stereoselectivity of the 3-fluoro glucosazide donors was improved
by 6-O-acyl protection. For example, the glycosylation of primary acceptor A with O-benzylated don
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showed almost no selectivity (entry 1), while introducing chloroacetyl (entries 2 and 3) and benzoyl (entry 4)
groups at O-6 improved the 1,2-cis stereoselectivity to 4.5–5.2:1. The nature of the tested acyl groups
(
chloroacetyl or benzoyl, entries 2–4, 10 and 13) and the anomeric configuration of the donor (entries 2 and 3)
only marginally influenced the stereoselectivity. 6-O-TBS donor 11 gave selectivity comparable to 6-O-acyl
donors, but a low yield (entry 5). Glycosylation with 4,6-O-benzylidene donor 13 resulted in low -selectivity
and decomposition during chromatographic purification (entry 7). Donors 11 and 13 were omitted from further
experiments. Glycosylation with 3,6-difluoro donor 12 showed lower stereoselectivity compared with 6-O-
acyl donors (entries 6 and 14), further indicating the -directing effect of O-acyl groups at the 6-position.
Decreased reactivity of the acceptor hydroxyl group due to its position and configuration in the hexopyranose
framework (primary hydroxyl → secondary equatorial → secondary axial) improved the 1,2-cis/1,2-trans ratio
4
1
(
entries 1 vs. 8, 2 and 3 vs. 10 and 15, 4 vs. 13). A significant improvement in -stereoselectivity resulted
4
2
from the glycosylation of secondary benzoyl protected (“disarmed”) acceptor D (entry 16). Using diethyl
ether in the reaction mixture as co-solvent (entries 8 vs. 9), and increasing the temperature from −20 to 0 °C
(
entries 10 and 11) also improved the -selectivity. Further increasing the temperature to 20 °C did not
promote selectivity (entry 12). Reducing the reactivity of the primary acceptor through O-benzoylation, as in
acceptor E, to compensate for the 4-O-acetyl β-directing effect in the glycosidation of 4,6-di-O-acyl donor 16
resulted in usable anomeric stereoselectivity (/β = 4.6:1, entry 17). Related non-fluorinated 4,6-di-O-acetyl-
3-O-benzyl D-glucosazide thiodonor 3d (Scheme 1) has been reported as only slightly -selective with the
30
same acceptor (/β = 1.8:1, Scheme 1), probably due to glycosylation being conducted at a low temperature
−78 °C). As expected, 4-O-benzyl analogue -9, which lacked the eroding influence of the 4-O-acetyl group,
(
gave higher -selectivity (/β = 7.6:1, entry 18) compared with 4-O-acetyl thiodonor 16.
Having established that an ester functionality at the 6-position improves the -selectivity of 3-fluoro-
D-glucosazide thiodonors, we further explored this concept with 4-fluoro-D-glucosazide thiodonors (Table 2).
6-O-Chloroacetyl-4-fluoro thiodonor 20 exhibited somewhat inferior -selectivity compared with its 3-fluoro
counterpart 9. Thus, glycosylation of acceptor A with thiodonor 20 resulted in an anomeric (/β)
stereoselectivity of 2.9:1 (Table 2, entry 1) compared with values of 4.5:1 and 5.2:1 for thiodonors -9 and -
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9, respectively (Table 1, entries 2 and 3). The glycosylation of secondary acceptor B with thiodonor 20 gave a
disappointing /β selectivity of 3.3:1 (Table 2, entry 2), in contrast with the value of 7.3:1 obtained foVie
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thiodonor -9 (Table 1, entry 10). However, using disarmed O-benzoyl protected primary acceptor E
improved the /β stereoselectivity from 2.9:1 (Table 2, entry 1) to 5.6:1 (Table 2, entry 3). Thiodonor 21 with
3
0
a bulky TBDPS group gave comparable results (Table 2, entry 4). In agreement with the literature, the
combined effects of 3-O-acetyl and 6-O-choroacetyl substituents in donor 25 resulted in a marked
improvement in 1,2-cis selectivity (Table 2, entries 5 and 6). Unfortunately, product E25 was isolated in only
about 85% purity, owing to difficulties in chromatographic separation. Highly stereoselective glycosylation of
the acceptor D with donor 25 did not reach completion, probably owing to the low reactivity of both reactants
D and 25, leading to a diminished yield (46%) and recovery of unreacted acceptor D from the reaction mixture
(
Table 2, entry 6).
Table 2. Glycosylation of acceptors R-OH with 4-fluoro glucosazide thiodonors.
entry Donor
R1
R2 Acceptor R-OH
Product
/ Yield
1
2
20
20
ClAc Bn
ClAc Bn
2.9:1 63%
A20
A
B
3.3:1 69%
B20
3
4
5
20
21
25
ClAc Bn
TBDPS Bn
ClAc Ac
E20
E21
E25
5.6:1 72%
6.1:1 56%
a
C
>20:1 76%
b
6
25
ClAc Ac
 only 46%
D25
D
a
19
b
Isolated in approx. 85% purity ( F NMR); 36% unreacted acceptor isolated.
Altogether, the results for the glycosylation of carbohydrate acceptors with 3-fluoro and 4-fluoro
thiodonors indicated that, although O-6 acylation can reverse glycosylation diastereoselectivity in favour of
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Organic & Biomolecular Chemistry
the 1,2-cis-product, the /β ratio of the resulting diastereoisomers mostly achieved moderate values.
Significant improvement can be achieved by adjusting the acceptor reactivity by installing benzoate e
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instead of benzyl ethers, by increasing the reaction temperature to 0 °C, and by combining O-6 and O-3
acylation. The impact of acceptor reactivity on glycosylation stereoselectivity has recently been reviewed, and
4
1
our results are consistent with the general trends. Furthermore, the bulky O-6 TBS and TBDPS silyl
32
protecting groups also exhibited an -directing effect.
4
3
As experiments in this study were being completed, Zhang et al. reported glycosylation with 6-O-
benzoyl or 6-O-TBS derivatives of p-tolyl 2-azido-3,4-di-O-benzyl-2-deoxy-1-thio--D-glucopyranosides 26
4
4
and 27 (Fig. 2) using preactivation protocol with the TolSCl/AgOTf promoter system. Although moderate -
stereoselectivity comparable to our values was observed for some primary acceptors, excellent (/β ≥ 15:1) or
exclusive -selectivity was achieved in the glycosylation of various secondary acceptors and disarmed O-
benzoyl protected primary acceptors. The superior performance of 26 and 27 relative to the fluorinated
thiodonors in this study can probably be attributed to not only the fluorine electron-withdrawing effect, but
also differences in the reaction mechanism. Although anomeric -triflate is the dominant covalent
intermediate in preactivation-based glycosylation using the TolSCl/AgOTf promoter system, both anomers of
33
glycosyl iodide, anomeric -triflate, and potentially other covalent species can form and react with the
acceptor using the NIS/TfOH promoter system under pre-mix conditions.
4
3
Figure 2. -Stereoselective thiodonors used by Zhang et al.
To further examine the synthetic utility of fluorinated thiodonors prepared in this study, we turned
our attention to the synthesis of fluorinated analogues of -glucosaminyl threonine (-GlcNAc-O-Thr) found
in Trypanosoma cruzi. The cell surface of this protozoan parasite responsible for Chagas disease is covered by
a dense coat of glycoproteins implicated in parasite entry and persistence in the cells of its mammalian host.45
Unlike mammalian mucin O-glycans, which commence with -GalNAc-O-Thr/Ser, O-glycans in these mucin-
like glycoproteins are attached to threonine residues via an -linked N-acetyl-glucosamine moiety. We
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investigated the glycosylation of protected threonine with O-acylated deoxofluorinated thiodonors, with the
results shown in Table 3.
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Table 3. Glycosylation of threonine.
entry Donor R1
R2
R3
Acceptor R-OH
Product
Yield
28%
a
/
1
2
3
4
16
16
17
25
ClAc OAc
ClAc OAc
Ac OAc
F
2.1:1
Fmoc-Thr-OBn
28
F
F
5.1:1
71%
29
Phth-Thr-OBn
b
7.4:1
6.6:1
68%
30
O
ClAcO
F
CO Bn
2
N3
O
c
AcO
ClAc
Ac
F
F
OAc
NHFmoc
Fmoc-Thr-OBn
Phth-Thr-OBn
31
b
5
26
OAc
18.0:1
49%
32
a
b
c
Isolated yield of -anomer; reaction conducted at 0 °C; 53% isolated yield containing approx. 17% inseparable
19
byproducts detected in F NMR.
The phthalimide protecting group on the threonine acceptor was superior to the N-
fluorenylmethoxycarbonyl group in terms of anomeric selectivity, product purity, and yield. This is consistent
with the results obtained for non-fluorinated galactosazide donors in the synthesis of the Thomsen-nouveau
46
antigen (-GalNAc-O-Thr/Ser). Coupling N-Fmoc threonine benzyl ester with 3-fluoro thiodonor 16 gave
anomeric /β ratio of 2.1:1 and a low yield (entry 1), whereas using N-phthaloyl threonine benzyl ester as
acceptor improved the diastereoselectivity to 5.1:1 (/β). A further increase in anomeric stereoselectivity was
attained with 4,6-di-O-acetyl thiodonor 17 at 0 °C (entry 3). Glycosylation of N-Fmoc threonine benzyl ester
with thiodonor 25 was accompanied by the formation of inseparable side products (entry 4). The coupling of
N-phthaloyl threonine benzyl ester with 3,6-O-diacetyl-4-fluoro thiodonor 26 resulted in excellent
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stereoselectivity (/β = 18.0:1; entry 5). Conventional azide reduction and acetylation converted threonine
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glycosides 30 and 32 into protected -GlcNAc-O-Thr 33 and 34 (Scheme 3).
Scheme 3. Azide reduction.
Activation of thioglycoside donors with the NIS/TfOH promoter system leads to the formation of
covalent intermediates, among which -glycosyl triflate, and - and -glycosyl iodides appear to be
3
3
dominant. These function as substrates for S 2-type stereospecific glycosylation and as a reservoir for the
N
formation of transient highly unstable covalent species (presumably β-triflate), contact ion pairs, and solvent-
separated oxocarbenium ions. To rationalize the stereodirecting effects of ester groups at C-6 and C-3, it has
been suggested that the oxocarbenium ion can be stabilized by forming bicyclic bridged dioxolenium-type
cations if suitable C-6 or C-3 positioned acyl groups are available, as shown in Scheme 4 for thiodonor 9.30
Stereospecific nucleophilic attack opposite to the acetoxonium-type bridge at C-1 then gives rise to anomeric

-stereoselectivity. The enhanced -selectivity observed for less nucleophilic benzoyl ester protected
acceptors supported this rationalization, because low-reactivity acceptors favour displacement of the more
reactive bicyclic cations over S 2-type displacement of anomeric -triflates leading to β-glycosides. The
N
increase in -selectivity with increasing temperature from −20 to 0 °C might be related to the increased
dissociation of covalent intermediates into ion pairs at higher temperatures.
Scheme 4. Examples of covalent and cationic intermediates formed upon NIS/TfOH activation of 9.
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The proposed bicyclic cations are short-lived and, therefore, difficult to characterize
spectroscopically. However, the bridging cations resulting from O-4 acetyl participation in D-manno-Vi
a
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d
rti
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DOI: 10.1039/D0OB01065K
gluco-configured 3,6-uronic acid lactones have been generated in the gas phase by collision-induced
2
6
dissociation after electrospray ionization, and characterized by infrared ion spectroscopy. Recently, bicyclic
cations resulting from O-4 acetyl participation in D-galacto donors were characterized by cryogenic
47
vibrational spectroscopy. To the best of our knowledge, spectroscopic characterization of D-gluco-configured
bicyclic dioxolenium-type cations has not yet been reported.
The hypothesis of oxocarbenium ion stabilization through formation of bicyclic bridged
dioxolenium-type cations leading to increased 1,2-cis-selectivity was supported by computational optimization
of 2-azido-3-fluoro-D-gluco-configured (3F) and 2-azido-4-fluoro-D-gluco-configured (4F) 6-O-acyl-
substituted oxocarbenium ions using density functional theory (DFT; see SI for details). To simplify these
calculations, OBn and OCOCH Cl groups were substituted with OMe and OAc groups, respectively, in the
2
model oxocarbenium ions (Fig. 3). Calculations were performed to identify possible conformers of the model
solvent-separated oxocarbenium ions and compare their energies with the corresponding bridged dioxolenium-
type ions.48
Figure 3. Conformations and relative energies of the most stable 3F and 4F geometry-optimized bridged
dioxolenium-type and oxocarbenium ions calculated by DFT (see Experimental in SI); implicit Et O solvation
2
was considered.
On the basis of the QM calculations, conformations B3,O/1S
and C
1
of bridged dioxolenium-type 3F
3
4
and 4F ions were identified as significantly more stable than the corresponding oxocarbenium ions. Therefore,
bridged dioxolenium-type ions formed by the participation of the 6-O-acyl group in 3F and 4F oxocarbenium
12

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Organic & Biomolecular Chemistry
ions are presumably important glycosylation reaction intermediates that give rise to enhanced -selectivity.
Energies of the optimized geometries of oxocarbenium ions were strongly affected by the C5–C6 conf
V
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Ar
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used as input geometry in calculations (stable conformers defined by dihedral angles O5–C5–C6–O6 and C4–
49
C5–C6–O6 as gg, gt, and tg). In our calculations, using the gg conformation as input geometry led to the most
5
2
5
2
stable conformers close to H
). In contrast, when the gt and tg conformers were used as input geometries, the optimization converged at
energetically much higher conformers (see SI).
4
and H
3
for 3F oxocarbenium ion, and H
4
and H for 4F oxocarbenium ions (Fig.
O
3
In conclusion, we have synthesized a series of acyl protected fluorinated glucosazide thiodonors that
exhibit moderate to excellent 1,2-cis stereoselectivity using NIS/TfOH-promoted glycosylation. Consistent with
recent investigations,41–44,46 our results underscore the importance of acceptor protecting groups for manipulation
of glycosylation stereoselectivity. We have also demonstrated the versatility of 1,6-anhydrohexopyranose
chemistry for the synthesis of orthogonally protected fluorinated glucosazide thiodonors.
Conflicts of Interest
There are no conflicts of interest to declare.
Acknowledgements
We thank the Czech Science Foundation for supporting our research (grant no. 17-18203S).
Computational resources were supplied by the project "e-Infrastruktura CZ" (e-INFRA LM2018140) provided
within the program Projects of Large Research, Development, and Innovations Infrastructures.
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View Article Online
DOI: 10.1039/D0OB01065K
Introducing remote O-acyl protecting groups enabled 1,2-cis stereoselective glycosylation with
fluorinated glucosazide glycosyl donors.
OClAc
OClAc
O
BnO
NIS/TfOH
OH
stereoselective
O
F
OBz
O
BnO
F
SPh
R
N3
O
N3
BzO
BzO
1
,2-cis glycosylation
NIS/TfOH
OH
OAc
OMe
OAc
O
F
AcO
F
AcO
O
N3
R
O
CO2Bn
NPhth
N3SPh