An Expeditious Synthesis of 1-Thiotrehalose

Article abstract of DOI:10.1055/s-0036-1591595

A two-step synthesis of 1-thiotrehalose is reported. In the key TMSOTf-mediated double thioglycosylation step, the tri- O -benzyl 1,6-anhydro-D-glucose reactant behaves both as a glycosyl donor and a glycosyl acceptor precursor. In this highly convergent process, two carbon-sulfur bonds are created at the anomeric positions with a high level of stereocontrol.

Full text of DOI:10.1055/s-0036-1591595

SYNTHESIS
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7
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1
1
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3
7
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2
1
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–D
paper
A
en
D. Tardieu et al.
Paper
Synthesis
An Expeditious Synthesis of 1-Thiotrehalose
Damien Tardieu
OH
O
Maria F. Céspedes Dávila
HO
HO
O
OTMS
O
OBn
O
Damien Hazelard
HO
TMS2S, TMSOTf
then deprotection
BnO
BnO
S
Philippe Compain*
OH
OH
BnO
OBn
OBn
O
STMS
HO
Laboratoire d’Innovation Moléculaire et Applications (LIMA),
Université de Strasbourg, Université de Haute-Alsace, CNRS
(UMR 7042). Equipe de Synthèse Organique et Molécules
Bioactives (SYBIO), Ecole Européenne de Chimie, Polymères et
Matériaux, 25 rue Becquerel, 67000 Strasbourg, France
philippe.compain@unistra.fr
glycosyl donor &
acceptor precursor
HO
1-thiotrehalose
Two-step synthesis
Highly stereoselective
Double thioglycosylation
Received: 19.04.2018
Accepted after revision: 24.05.2018
Published online: 12.07.2018
cobacterium tuberculosis. For this reason, trehalose metabo-
lism has recently been targeted for the treatment of several
infectious diseases such as tuberculosis.3,6 Considering the
biological interest in trehalose, several studies have been
reported on the synthesis of trehalose mimetics designed as
enzyme inhibitors or molecular probes.5,6a,7 Indeed, meta-
bolically stable analogues of trehalose may have interesting
applications as non-toxic insecticides and fungicides7a or as
antibacterial agents.3,6 In particular, due to the higher resis-
tance of its S-linked isostere to chemical and enzymatic hy-
drolysis, many efforts have been directed towards the syn-
thesis of 1-thiotrehalose analogues.8–15 Most methods in-
volve the coupling of a thioglucoside with an activated
sugar donor or a glycal.8–12 For example, Zhu and Xin re-
ported recently a four-step synthesis of a protected 1-
thiotrehalose derivative from 1,6-anhydro-D-glucose.8 The
key step was the diastereoselective glycosylation of an α-
glucosyl thiol acceptor16 with a glucosyl trichloroacetami-
date donor under typical Schmidt conditions. In connection
with our recent work on anhydrosugars,17 we have de-
signed a synthetic strategy in which the protected 1-
thiotrehalose 3 is obtained in one step from the commer-
cially available tri-O-benzyl-1,6-anhydro-D-glucose (1)
(Scheme 1).18 1,6-Anhydro sugars are stable glycosylating
agents with many synthetic advantages including dual pro-
tection of both C-1 and C-6, a bicyclic skeleton ensuring
high degree of steric-approach control, and the release of a
OH group at C-6 after the glycosylation step.19 In the highly
convergent approach designed, the preparation of the gly-
cosyl donor and its acceptor is not required. 1,6-Anhydro-D-
glucose 1 plays a double role as a glycosyl donor and a gly-
cosyl acceptor precursor in the key thioglycosylation step.
The thioglycoside acceptor 2 is indeed generated in situ
from 1 by TMSOTf-mediated nucleophilic ring-opening of
the anhydro bridge by following Zhu’s protocol16 and then
reacts with another molecule of 1 to provide 3.
DOI: 10.1055/s-0036-1591595; Art ID: ss-2018-z0270-op
Abstract A two-step synthesis of 1-thiotrehalose is reported. In the
key TMSOTf-mediated double thioglycosylation step, the tri-O-benzyl
1,6-anhydro-D-glucose reactant behaves both as a glycosyl donor and a
glycosyl acceptor precursor. In this highly convergent process, two car-
bon-sulfur bonds are created at the anomeric positions with a high level
of stereocontrol.
Key words glycomimetics, thio-sugars, anhydro sugars, domino reac-
tion, ring-opening
Trehalose is a non-reducing disaccharide consisting of
two D-glucose molecules linked by an α,α-1,1-linkage. This
naturally occurring disaccharide plays an important role in
plants, bacteria, invertebrates, fungi and microorganisms.1–5
For example, trehalose is involved in protection against ox-
ygen radicals, plant growth regulation, and development of
cells. Furthermore, this non-mammalian disaccharide is a
constituent of the cell wall of several bacteria including My-
6
OTMS
O
O
OBn
O
TMS2S
BnO
BnO
1
BnO
TMSOTf
STMS
OBn
OBn
2
1
glycosyl acceptor
glycosyl donor &
acceptor precursor
OH
O
BnO
BnO
BnO
S
OH
O
OBn
BnO
OBn
3
Scheme 1 One-step access to protected 1-thiotrehalose derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D

B
D. Tardieu et al.
Paper
Synthesis
To explore the feasibility of the one-step double thiogly-
cosylation process, various experimental parameters were
evaluated (Table 1). The reaction of (TMS)2S with 2 equiv of
1 in the presence of 0.7 equiv of TMSOTf led to the forma-
tion of 3 in 18% yield (entry 1). Evaluation of the influence
of the amount of Lewis acid on the reaction outcome indi-
cated that the yields could be improved to 56% in the pres-
ence of 1.8 equiv of TMSOTf (entries 2–5). Further increase
of the amount of TMSOTf led to lower yields (entries 6–8).
Excess of 1 and the addition of 4Å molecular sieves17c in the
reaction medium did not improve the process (entries 8–
12). The one-pot double thioglycosylation is a remarkably
clean reaction occurring with high diastereoselectivity; no
other products apart from 3, the starting material 1 and the
thiol sugar resulting from the hydrolysis of unreacted inter-
mediate 2 were isolated during the optimization study. It is
noteworthy that the introduction of α,α-anomeric linkages
with high stereocontrol is considered to be particularly
challenging.8–15
advantage of our approach is that the primary hydroxyl
groups of compound 3 could be orthogonally functional-
ized to access therapeutically relevant diester derivatives. It
has been recently reported that thioglycosides analogues of
maradolipids, a family of trehalose derivatives with fatty
acid side chains at the 6- and 6′-positions, display promis-
ing immunological bioactivities (Scheme 2).21 The synthetic
feasibility of this approach was demonstrated with the di-
esterification of diol 3 in the presence of acetic anhydride,
which provided diacetate 5 in 80% yield.
OH
OAc
O
O
BnO
BnO
BnO
BnO
Ac2O, pyr.
BnO
BnO
S
S
80%
OH
OAc
OBn
O
O
OBn
BnO
BnO
OBn
OBn
5
3
O
H2, Pd/C
AcOEt, EtOH
( )7
O
( )7
O
HO
HO
95%
Table 1 Optimization of the One-Step Formation of 3
HO
O
S
OH
O
OH
( )11
O
OH
HO
HO
O
O
BnO
BnO
HO
O
HO
OH
S-maradolipid
OBn
O
S
BnO
TMSOTf
S
(TMS)2S
(1 equiv)
+
OH
OH
OH
O
CH2Cl2, Δ
HO
O
OBn
OBn
OBn
BnO
OH
1
3
4
OBn
Scheme 2 Synthesis of 1-thiotrehalose and derivatives
Entrya
1 (equiv)
TMSOTf (equiv) t (h)
Yield (%)b
1
2
2
0.7
0.6
1.4
1.6
1.8
2
40
20
6
18
27
33
49
56
42
44
17
18
31
17
31
In conclusion, we have reported the expeditious synthe-
sis of 1-thiotrehalose. The highly convergent strategy was
based on the original use of 1,6-anhydro-sugar which func-
tions both as a glycosyl donor and a glycosyl acceptor pre-
cursor in the key double thioglycosylation step. This is a
new application of 1,6-anhydro sugars that further high-
lights their synthetic potential for the preparation of bio-
logically relevant compounds.
2
3
2
4
2
6
5
2
6
6
2
6
7
2
1.9
3.6
1.4
1.8
1.8
1.4
6
8
2
2
9
3.5
3
3.5
Dichloromethane was distilled over CaH2 under argon. Flash column
chromatographies were carried out on silica gel 60 (230–400 mesh,
40–63 μm). 1H and 13C NMR experiments were carried out at 298 K
with a Bruker Advance III HD 400 MHz spectrometer. Assignments of
1H and 13C signals were based on the results of DEPT, COSY, HSQC and
HMBC experiments. Optical rotations were measured at 589 nm (so-
dium lamp) and at a temperature of 20 °C with an Anton Paar MCP
200 polarimeter. IR spectra were recorded neat with a Perkin–Elmer
Spectrum Two FT-IR spectrometer. High-resolution electrospray ion-
ization mass spectra were recorded with a Bruker microTOF® mass
spectrometer.
10
11c
12c
4.5
3.5
3.5
4
2
a The reactions are performed in sealed tubes.
b Isolated yield.
c Reaction performed in the presence of 4Å molecular sieves (50 mg).
Deprotection of benzyl groups with hydrogen in the
presence of palladium afforded 1-thiotrehalose (4) in 95%
yield (Scheme 2).20 Quite surprisingly, in the absence of
EtOAc, the reaction did not proceed and compound 3 was
recovered. Our approach is the shortest synthesis of 1-thio-
threalose reported to date, with an overall yield of 53% from
commercially available 1,6-anhydro-D-glucose 1. Another
2,3,4,2′,3′,4′-Hexa-O-benzyl-1-thio-α,α-D-trehalose (3)
In a tube, to a solution of anhydroglucose 1 (2 equiv, 200 mg, 0.462
mmol) in CH2Cl2 (1 mL) were added bis(trimethylsilyl)sulfide (1
equiv, 41.26 mg, 0.049 mL, 0.231 mmol) followed by TMSOTf (1.8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D

C
D. Tardieu et al.
Paper
Synthesis
equiv, 0.076 mL, 0.416 mmol). The tube was sealed and the solution
was stirred at 50 °C for 6 h. The mixture was allowed to cool to r.t. and
washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The organic layers were com-
bined and washed with brine (50 mL), dried over sodium sulfate and
concentrated under reduced pressure. The crude material was puri-
fied by flash column chromatography (petroleum ether/EtOAc, 8:2 to
7:3) to afford 3.
4.27 (dd, J = 12.0, 4.8 Hz, 2 H, H-6), 4.18 (dd, J = 12.0, 2.2 Hz, 2 H, H-6),
3.93 (dd, J = 9.6, 8.4 Hz, 2 H, H-3), 3.88 (dd, J = 9.6, 5.2 Hz, 2 H, H-2),
3.51 (dd, J = 10.0, 8.5 Hz, 2 H, H-4), 1.98 (s, 6 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 170.7 (C=0), 138.5 (Cq-Ar), 138.0 (Cq-
Ar), 137.5 (Cq-Ar), 128.7, 128.6, 128.55, 128.2, 128.15, 128.1, 128.0,
127.9 (Ph), 82.7 (C-3,), 80.5 (C-1), 79.0 (C-2), 77.4 (C-4), 76.0 (O-CH2-
Ph), 75.1 (O-CH2-Ph), 72.4 (O-CH2-Ph), 70.0 (C-5), 63.4 (C-6), 21.0
(CH3).
Yield: 116 mg (0.129 mmol, 56%); white solid; Rf = 0.27 (petroleum
ether/ EtOAc, 1:1); [α]D20+162.0 (c 0.8, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for [C58H63O12S]+: 983.403; found:
983.405.
IR (neat): 3473 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.40–7.30 (m, 30 H, Ph), 5.53 (d, J =
5.5 Hz, 2 H, H-1), 4.97 (d, J = 10.9 Hz, 2 H, O-CH2-Ph), 4.90 (d, J =
11.3 Hz, 2 H, O-CH2-Ph), 4.80 (d, J = 10.9 Hz, 2 H, O-CH2-Ph), 4.72 (d,
J = 12 Hz, 2 H, O-CH2-Ph), 4.64 (d, J = 10.5 Hz, 2 H, O-CH2-Ph), 4.62 (d,
J = 12.0 Hz, 2 H, O-CH2-Ph), 4.15 (m, 2 H, H-5), 3.94 (t, J = 9.4 Hz, 2 H,
H-3), 3.82 (dd, J = 9.5, 5.3 Hz, 2 H, H-2), 3.71 (m, 4 H, H-6,), 3.52 (dd,
J = 9.9, 8.9 Hz, 2 H, H-4), 1.70 (t, J = 6 Hz, 2 H, OH).
Funding Information
This work was supported by the CNRS, the University of Strasbourg
and a doctoral fellowship from the French Department of Research to
D.T.
)(
13C NMR (CDCl3, 100 MHz): δ = 138.7 (Cq-Ar), 138.3 (Cq-Ar), 137.7
(Cq-Ar), 128.7, 128.6, 128.5, 128.2, 128.1, 128.05, 128.0, 127.8 (Ph),
82.7 (C-3), 80.2 (C-1), 78.9 (C-2,), 75.9 (O-CH2-Ph), 77.3 (C-4), 75.1 (O-
CH2-Ph), 72.5 (O-CH2-Ph), 72.3 (C-5), 62.1 (C-6).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591595.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
HRMS (ESI): m/z [M + K]+ calcd for [C54H58O10SK]+: 937.338; found:
937.333.
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1-Thiotrehalose (4)
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1H NMR (D2O, 400 MHz): δ = 5.53 (d, J = 5.4 Hz, 2 H), 4.07 (ddd, J =
10.1, 5.6, 2.3 Hz, 2 H), 3.95–3.84 (m, 4 H), 3.80 (dd, J = 12.4, 5.5 Hz,
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To a solution of 3 (1 equiv, 75.4 mg, 0.084 mmol) in Ac2O (1 mL) was
added pyridine (1 mL). The solution was stirred at r.t. for 24 h, then
the mixture was then concentrated under reduced pressure. The
crude material was purified by flash column chromatography (pen-
tane/EtOAc, 7:3) to afford 5.
Yield: 65.8 mg (0.067 mmol, 80%); colorless oil; Rf = 0.83 (pen-
tane/EtOAc, 1:1); [α]D20+125.0 (c 1, CHCl3).
IR (neat): 1740 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.40–7.26 (m, 30 H, Ph), 5.61 (d, J =
5.2 Hz, 2 H, H-1), 4.98 (d, J = 10.8 Hz, 2 H, O-CH2-Ph), 4.90 (d, J =
11 Hz, 2 H, O-CH2-Ph), 4.79 (d, J = 10.7 Hz, 2 H, O-CH2-Ph), 4.74 (d, J =
11.7 Hz, 2 H, O-CH2-Ph), 4.60 (d, J = 11.6 Hz, 2 H, O-CH2-Ph), 4.58 (d,
J = 11.0 Hz, 2 H, O-CH2-Ph), 4.35 (ddd, J = 9.9, 4.8, 2.2 Hz, 2 H, H-5),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D

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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D