Stereoselective Epimerizations of Glycosyl Thiols

Article abstract of DOI:10.1021/acs.orglett.7b02760

Glycosyl thiols are widely used in stereoselective S-glycoside synthesis. Their epimerization from 1,2-trans to 1,2-cis thiols (e.g., equatorial to axial epimerization in thioglucopyranose) was attained using TiCl₄, while SnCl₄ promoted their axial-to-equatorial epimerization. The method included application for stereoselective β-d-manno- and β-l-rhamnopyranosyl thiol formation. Complex formation explains the equatorial preference when using SnCl₄, whereas TiCl₄ can shift the equilibrium toward the 1,2-cis thiol via 1,3-oxathiolane formation.

Full text of DOI:10.1021/acs.orglett.7b02760

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Stereoselective Epimerizations of Glycosyl Thiols
Lisa M. Doyle, Shane O’Sullivan, Claudia Di Salvo, Michelle McKinney, Patrick McArdle,
and Paul V. Murphy*
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland H91 TK33
S
* Supporting Information
ABSTRACT: Glycosyl thiols are widely used in stereo-
selective S-glycoside synthesis. Their epimerization from 1,2-
trans to 1,2-cis thiols (e.g., equatorial to axial epimerization in
thioglucopyranose) was attained using TiCl4, while SnCl4
promoted their axial-to-equatorial epimerization. The method
included application for stereoselective β-D-manno- and β-L-
rhamnopyranosyl thiol formation. Complex formation explains
the equatorial preference when using SnCl4, whereas TiCl4 can
shift the equilibrium toward the 1,2-cis thiol via 1,3-oxathiolane
formation.
Table 1. TiCl4 Promoted Epimerization of 2
lycoconjugates and their mimics/mimetics are being
1
2
Ginvestigated in drug discovery, vaccine development,
targeting,3 and as probes for molecular recognition.4 S-
Glycosides are less susceptible to acid and enzymatic
hydrolysis than O-glycosides, justifying their investigation as
glycomimetics.5 They have different conformational prefer-
ences to O-glycosides, which can influence their biological
properties.6 They have found application7 in reactivity based
oligosaccharide synthesis, which is influenced by anomeric
configuration.8 Glycolipids, glycopeptides, oligosaccharides,5,9
glycodendrimers,10 and glyconanoparticles11 containing S-
glycosidic linkages are studied, and glycosyl thiols (1-
thiosugars) are valuable building blocks in their synthesis.
Unlike saccharide hemiacetal groups (glycosyl alcohols),
glycosyl thiols often retain their anomeric configuration in
subsequent reactions, which makes stereoselective S-alkylation,
conjugate addition, and thiol−ene or thiol−yne coupling
reactions possible.12 Anomerization (epimerization of equato-
rial anomer to axial anomer) with Lewis acids has been
attained with glycosyl thiols derived from uronic acid, where
the rate of anomerization13,14 is generally faster than for other
pyranoses due to favorable chelation of the C-6 carbonyl
group.15,16 Here, we provide conditions for the successful
epimerization of 1,2-trans benzoylated glycosyl thiols, which
are not uronic acids, to the 1,2-cis thiols using TiCl4; the use
of benzoyl rather than acetyl groups compensate somewhat
for the absence of the C-6 carbonyl group. Notably, we also
report the axial to equatorial epimerization of glycosyl thiols
using SnCl4.
entry
additive
equiv TiCl4 equiv additive time (h)
α:β
1
2
no additive
MSA
2.5
2.5
2.5
2.5
2.5
3
−
17
16
16
16
16
16
72
72
72
16
79:21
84:16
93:7
0.3
0.3
0.3
0.3
−
3
Ph3P
4
pyridine
Et3N
93:7
5
92:8
6
no additive
no additive
pyridine
pyridine
pyridine
84:16
90:10
33:66
∼90:1
>90:1
7
3
−
8
0
0.5
0.3
0.5
9
3
10
3
generated, with mostly 1β remaining. Nevertheless, reaction of
a 1:2 mixture of benzoylated galactosyl thiols 2α and 2β with
TiCl4 (0.5 to 2 equiv) and MSA (0.3 equiv) gave 45−70% of
2α, with the main byproduct being glycosyl chloride, and 2β
was not detected. A wider study (Table 1, Table 2) was
conducted with 2α and 2β using TiCl4. For reaction with
TiCl4 alone (2.5 equiv), the α:β ratio was 79:21 after 17 h
(entry 1), increasing to 84:16 at higher concentration of TiCl4
(3 equiv) after 16 h (entry 8) with a further increase to ∼9:1
over 72 h (entry 9). In experiments with TiCl4 (2.5 equiv),
where additives triphenylphosphine, pyridine, and triethyl-
amine were added (entries 3−5) the α:β ratios exceeded 91:9
after 16 h. Carrying out the reactions at lower temperature
(e.g., 0 °C) led to lower selectivity after 16 h due to reduced
The rate of Lewis acid promoted anomerization of O-
glycosides is enhanced in the presence of acetic acid17 or a
Lewis acid18 additive. Preliminary experiments with an O-
glycoside showed that methanesulfonic acid (MSA) is superior
to acetic acid. Initially, when acetylated thiol 1β (Table 1) was
reacted with SnCl4 or TiCl4 (0.5 to 3 equiv) in the presence
of MSA (0.3 equiv), still only ∼30% of its α-anomer was
Received: September 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3α was treated with SnCl4 and again the β-thiol 3β was
preferred, with an 8:1 mixture generated after 36 h at 4 °C.
The reaction was found to be improved in 24 h if MSA was
added, and 3β was subsequently isolated in 78% yield
(Scheme 1).
Scheme 1. Axial to Equatorial Epimerization of 3α
Next SnCl4 was investigated for epimerization of
mannopyranosyl thiol 11α. For a range of reactions (Table
3) in the presence of SnCl4 in dichloromethane, epimerization
Table 3. Optimization of the Epimerization of 11α
Table 2. TiCl4 (3 equiv) Promoted Epimerization in
CH2Cl2 (room temp, 16 h)
equiv of
SnCl4
time
(h)
β:α
ratio
yield
11β
entry
additive (equiv)
T (°C)
1
2
3
4
5
6
7
no additive
no additive
no additive
no additive
no additive
PPh3 (0.5 equiv)
2.5
2.5
2.5
2.5
1.5
2.5
2.5
20
4
20
20
20
24
20
24
24
70:30
76:24
72:28
63:37
69:31
76:24
74:26
−
−
−
−
−
−
−
0
−30
4
4
sulfamic acid
(0.5 equiv)
4
8
9
MSA (2 equiv)
2.5
2.5
4
4
24
24
92:8
82%
79%
MSA (0.5 equiv)
89:11
of 11α to 11β was observed, with the β:α anomer selectivities
ranging from 63:37 to 76:24. The addition of MSA increased
the stereoselectivity to >9:1 in favor of the β-mannopyranosyl
thiol, and 11β was isolated in 82% yield from a 200 mg scale
reaction. A wider study of reactions of glycosyl thiols were
then conducted with SnCl4. Various glycosyl thiols (Table 4),
with the exception of 4α (not shown in Table 4), gave
mixtures that favored the equatorial product, irrespective of
whether the substituent at C-2 was axial, as is the case for
mannopyranose or rhamnopyranose, or equatorial at C-2.
Optimized conditions for various glycosyl thiols (each 100
mg scale) are shown in Table 4, and the isolated yields of
equatorial thiols varied from 34% (15α) to 90% (6β) with
glycosyl chloride formed to a minor extent in most cases. The
axial to equatorial epimerization with SnCl4 was also
successful for acetylated 12−16. In the case of the acetylated
rhamnopyranosyl thiol 13, the addition of MSA (0.5) led to a
reduction in amount of glycosyl chloride produced. The use
of lower reaction temperatures (−30 °C) led to a reduction in
chloride and unidentified product formation, particularly for
the L-thioarabinopyranose 15α,19 and L-thiofucopyranose 7β.
Next, we endeavored to gain an understanding of the origin
of stereoselectivity in these reactions. Hence, we first tested
the hypothesis that the glycosyl thiols coordinate to the Lewis
acids and that the relative stability of a complex formed in
dichloromethane ultimately contributes to defining the
anomer ratio of the glycosyl thiols generated after workup.
SnCl4 coordinates with heteroatoms such as O, N, and S, and
several crystal structures have been reported, as either SnCl4·L
or SnCl4·L2 complexes.19 We considered the possibility that
coordination would be reduced in an oxygen atom containing
solvent which would compete with the acylated pyranose for
coordination to the Lewis acid. Carbonyl groups are known to
coordinate to Lewis acids including SnCl4 in both the solid
state and in solution, and EtOAc was therefore investigated.
Hence 1β was converted by SnCl4 (2.5 equiv) to a 42:58
reaction progress. Pyridine was unable to promote the
anomerization reaction of 2 on its own (entry 10). Use of
TiCl4 (3 equiv) and pyridine (0.5 equiv) together led to only
2α being detected in the mixture after 16 h (entry 12) and
isolated in 56% yield. In the cases of the hexopyranoses 4
(>18:1 vs 11:1) and 10 (>20:1 vs 10:1) the addition of
pyridine led to improved stereoselectivity (Table 2). For 5−9
the use of pyridine showed no difference or a reduction in
selectivity (see Table S1). It was necessary to minimize the
quantity of silica gel used for chromatographic purification to
maximize the isolated yields of the thiols (reported in Table
2) as hydrolysis was occurring.
The TiCl4 promoted anomerization of the mixture of 2,3,4-
tri-O-benzoyl-thio-L-rhamnopyranosyl thiols 3α and 3β, which
contained mostly the axial or α-anomer (α:β = 2.5:1),
unexpectedly gave only the β-anomer 3β (40% isolated) and
glycosyl chloride 3-Cl. The structures of 3α/3β were
supported by NOESY and 13C NMR, and 3α was confirmed
by X-ray crystal structure determination. The pure α-anomer
B
DOI: 10.1021/acs.orglett.7b02760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dissolved in CDCl3 (0.75 mL) and 2 equiv of SnCl4 was
added (from a solution in CDCl3), which provided
information on the complex formed between 3β and SnCl4
(3β-SnCl4). The doublet (J = 10.0 Hz) at δ 2.61 ppm
corresponding to the thiol proton in uncomplexed 3β was no
longer visible as a sharp doublet in the spectrum. The signal
for the thiol proton of 3α broadened and decreased in
intensity as SnCl4 was added and a new broad signal appeared
downfield between δ 3.20−3.60 ppm for the SH. The
integration for this signal, assigned to the SH in 3β-SnCl4, was
equal to integration of other signals assigned to the
carbohydrate ring protons for 3β-SnCl4 in the spectrum,
with 3β-SnCl4 the most abundant species present. Compared
to 3β, the anomeric proton (Δδ = 0.42 ppm) and the
pyranose H-5 (Δδ = 0.41 ppm) in 3β-SnCl4 were most
shifted downfield, with the other pyranose signals shifted to a
lesser degree (Δδ < 0.2 ppm). The greatest shifts downfield
in the 13C NMR spectrum of 3β-SnCl4 were for the anomeric
carbon (δ 80.3 ppm vs δ 76.8 ppm; Δδ = 3.7 ppm) and for
the pyranose C-5 (δ 79.2 ppm vs δ 75.7 ppm; Δδ = 3.5
ppm). In contrast, the C-2 and C-4 signals were shifted
upfield (Δδ values = −3.3 and −3.1 ppm), respectively. No
shifts downfield or upfield of more than 0.3 ppm were
observed for the carbonyl peaks. This data supports
complexation involving the pyranose oxygen atom and the
thiol group of 3β coordinating to SnCl4 (Scheme 2). The
Table 4. SnCl4 (2.5 equiv) Promoted Epimerization in
CH2Cl2
Scheme 2. Mechanistic Investigations
1
pyranose ring maintains its C4 conformation on the basis of
coupling constants observed in the 1H NMR spectrum.
Workup of this mixture led to hydrolysis of the complex with
SnCl4 present and gave a product which contained mostly 3β.
An NMR spectroscopic study indicated that reaction of 3α
with TiCl4 established an equilibrium of 3α with 3β but that
TiCl4 also induced nucleophilic attack by the thiol of 3β at
the C-2 carbonyl group, cis to the thiol, which leads to
generation of the 2-phenyl-1,3-oxathiolan-2-ylium cation 17;21
this shifts the equilibrium (Scheme 2) toward species that give
3β after workup. This process may contribute to the preferred
formation of axial glycosyl thiols (Table 2), where the major
products isolated also have 1,2-cis configurations. Hence, the
1H and 13C NMR spectroscopic analysis, in one experiment,
of the mixture generated from treating 3α with TiCl4 (0.5
equiv) in CDCl3 showed signals consistent with the presence
of the thiols 3α (∼50%) and 3β (∼25%) as well as 17
(∼25%). The presence of the carbenium carbon atom was
supported by a diagnostic signal at δ 214.7 ppm in the 13C
NMR spectrum; the signals for C-2 (δ 96.5 ppm; Δδ = +23.8
ppm) and C-1 (δ 86.4 ppm; Δδ = +8.7 ppm) of the cationic
species are shifted significantly downfield compared to those
of free 3β and support the presence of the nearby positively
charged carbon. Workup of this mixture gave a 1:1 mixture of
a
This yield is from a reaction carried out with MSA (0.5 equiv) added.
mixture of 1α and 1β in EtOAc−CH2Cl2 (3:2), which had
lower selectivity than in dichloromethane alone (α:β = 20:80,
Table 4). Thus, EtOAc competes with the pyranosyl thiols for
coordination to SnCl4 but does not inhibit the epimerization.
The reaction in the presence of EtOAc reflects the
equilibrium ratio of anomers of the glycosyl thiols in the
absence of significant chelation to the Lewis acid, whereas
stereoselectivity in dichloromethane is influenced by a more
stable complex being formed between SnCl4 and the glycosyl
thiol.
The use of 119Sn NMR spectroscopy proved diagnostic for
probing the interaction of SnCl4 with 3β in dichloromethane.
There was a peak at δ −149 ppm in the proton decoupled
119Sn NMR spectrum for free SnCl4 (0.9 M solution in
CDCl3), whereas on addition of 3β the colorless solution
became a brick red color and the 119Sn peak shifted to −188.9
ppm, consistent with formation of a hexavalent tin complex in
solution.20 This proposal was supported by H and 13C NMR
1
analysis of the mixture generated after 3α (0.068 mmol) was
C
DOI: 10.1021/acs.orglett.7b02760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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(6) Montero, E.; García-Herrero, A.; Asensio, J. L.; Hirai, K.;
the thiols. The cation 17 was trapped in the presence of
sodium cyanoborohydride to give 18.
Further support for this proposal in Scheme 2 was obtained
by isolation of the stable dihydrothiazole 20 from the reaction
of GlcNAc derivative 19β with TiCl4, which was subsequently
hydrolyzed to give thiol 19α (Scheme 3).
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thioacetates,23 or thiophosphates24 followed by release of the
free thiol or reaction of glycosyl alcohols with Lawesson’s
reagent, with moderate to good stereoselectivity observed.25
Reactions with carbon disulfide have been used, to give α-26
or β-thiols.27 Axially oriented glycosyl thiols can be selectively
prepared via equatorial glycosyl chlorides,28 or by treating 1,2-
anhydro or 1,6-anhydro sugars or glycosyl trichloroacetimi-
dates with bis-trimethylsilyl sulfide.29 The complementary
strategy developed herein provides the opportunity to
epimerize acylated glycosyl thiols, contributing to stereo-
selective synthesis of S-glycosides.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02760.
■
S
(21) For related cations, see: (a) Pittman, C. U., Jr.; McManus, S.
P.; Larsen, J. W. Chem. Rev. 1972, 72, 357. (b) Godage, H. Y.; Riley,
A. M.; Woodman, T. J.; Potter, B. V. L Chem. Commun. 2006, 2989.
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X-ray crystal structure of 3α (CIF)
Schemes S1−S3, Table S1, Experimental Section (PDF)
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.v.murphy@nuigalway.ie.
ORCID
́ ̂
(26) Ane, A.; Josse, S.; Naud, S.; Lacone, V.; Vidot, S.; Fournial, A.;
Paul V. Murphy: 0000-0002-1529-6540
Notes
Kar, A.; Pipelier, M.; Dubreuil, D. Tetrahedron 2006, 62, 4784.
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The authors declare no competing financial interest.
(29) (a) Dere, R. T.; Wang, Y.; Zhu, X. Org. Biomol. Chem. 2008, 6,
2061. (b) Zhu, X.; Dere, R. T.; Jiang, J.; Zhang, L.; Wang, X. J. Org.
Chem. 2011, 76, 10187. (c) Dere, R. T.; Kumar, A.; Kumar, V.; Zhu,
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ACKNOWLEDGMENTS
■
The authors thank Science Foundation Ireland for an IvP
award (Grant Number 12/IA/1398) cofunded by the
European Regional Development Fund (Grant Number 14/
SP/2710). The Irish Research Council can also be thanked
for a scholarship award to M. McKinney.
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D
DOI: 10.1021/acs.orglett.7b02760
Org. Lett. XXXX, XXX, XXX−XXX