Stereoselective β-mannosylation via anomeric O-alkylation: Formal synthesis of potent calcium signal modulator acremomannolipin A

Article abstract of DOI:10.1016/j.tetlet.2017.04.049

Stereoselective β-mannosylation has been investigated via cesium carbonate-mediated anomeric O-alkylation of D-mannose-derived lactol with various electrophiles. It was found that electrophiles bearing trifluoromethanesulfonate (triflate) as the leaving g

Full text of DOI:10.1016/j.tetlet.2017.04.049

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective b-mannosylation via anomeric O-alkylation: Formal
synthesis of potent calcium signal modulator acremomannolipin A
⇑
Xiaohua Li , Nader Berry, Kevin Saybolt, Uddin Ahmed, Yue Yuan
Department of Natural Sciences, University of Michigan-Dearborn, 4901 Evergreen Road, Dearborn, MI 48128, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective b-mannosylation has been investigated via cesium carbonate-mediated anomeric O-alky-
Received 20 March 2017
Revised 11 April 2017
Accepted 14 April 2017
Available online xxxx
lation of D-mannose-derived lactol with various electrophiles. It was found that electrophiles bearing tri-
fluoromethanesulfonate (triflate) as the leaving group are most reactive. In addition, a highly efficient
formal synthesis of potent calcium signal modulator acremomannolipin A has been achieved using this
b-mannosylation method.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
b-Mannosylation
Anomeric O-alkylation
Synthesis
Acremomannolipin A
The glycolipid acremomannolipin A (1) was isolated from a fil-
amentous fungus Acremonium strictum.1 Structurally, acremoman-
showed reduced activity.5 In 2015, the same group also prepared
five homologs of acremomannolipin A bearing alditols of different
length and found that the length of the alditol side chain was a cru-
cial determinant for the potent calcium signal modulating activ-
ity.6 Early 2015, Li and co-workers reported another total
synthesis of acremomannolipin A in which key intermediate
b-mannoside 7 was obtained via gold(I)-catalyzed glycosylation7
nolipin A contains a
and all the hydroxyls in the mannose are acylated with saturated
aliphatic acids (Fig. 1). Therefore, the -mannose moiety is made
hydrophobic, whereas the -mannitol portion is hydrophilic. The
D-mannopyranoside b-linked to a D-mannitol
D
D
structure of acremomannolipin A was elucidated on the basis of
intensive spectroscopic analyses as well as its degradation studies.
Biologically, acremomannolipin A showed the interesting activity
at 200 nM enabling calcineurin deletion mutant cells to grow in
the presence of Clꢀ, which would be caused by calcium signal mod-
ulating.1 As a potential calcium signal modulator, acremomanno-
lipin A is considered an attractive target for biologists as well as
synthetic chemists as acremomannolipin A and its synthetic ana-
logs may be of significance for therapeutic and biotechnological
purposes.
The structural features of acremomannolipin A have posed sig-
nificant difficulties for the total synthesis, mainly due to the pres-
ence of a b-mannoside which is known to be one of the most
synthetically challenging glycosidic linkages.2 Previously, acremo-
mannolipin A (1) was first synthesized by Muraoka and co-workers
in 2013 (Scheme 1).3 Based on Crich b-mannosylation protocol,4
key intermediate b-mannoside 4 was obtained from 4,6-O-benzyli-
between
ortho-alkynylbenzoate donor
(b/
4,6-O-benzylidene-protected
D
-mannose-derived
in 85% yield
5
and acceptor 6
a
= 13/1).8 In 2016, the Toshima group described the third total
synthesis of acremomannolipin A in which key intermediate
b-mannoside 10 was obtained via borinic acid-catalyzed glycosyla-
tion between 1,2-anhydromannose donor 8 and acceptor 9 in
99% yield (b only).9
Early in 2016 we disclosed a new method for stereoselective
construction of b-mannosides via cesium carbonate-mediated
anomeric O-alkylation of D
-mannose-derived lactols.10 In this Com-
munication, we would like to report our efforts in the synthesis of
acremomannolipin A in which the key intermediate b-mannoside
10 was prepared from known
D
-mannose-derived lactol 1111 and
D-mannitol-derived primary triflate 12 via cesium carbonate-medi-
ated anomeric O-alkylation.
In our previous report,10 only sugar-derived primary and sec-
dene-protected
a
D-mannose donor 2 and acceptor 3 in 71% yield (b/
ondary alkyl triflates, e.g. 14, were studied as electrophiles for
= 30/1). Later, Muraoka and co-workers also prepared 10-epi-
cesium carbonate-mediated anomeric O-alkylation with
D-man-
acremomannolipin A, the a-anomer of acremomannolipin A, which
nose-derived lactols. For example, when C6-primary triflate 14
was employed, b-D-mannoside 16 was obtained in 93% yield (b
only, entry 1).10 We wondered if other primary electrophiles bear-
ing different leaving groups other than triflates would also react
⇑
Corresponding author.
E-mail address: shannli@umich.edu (X. Li).
http://dx.doi.org/10.1016/j.tetlet.2017.04.049
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Li X., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.04.049

2
X. Li et al. / Tetrahedron Letters xxx (2017) xxx–xxx
1.
2,2-dimethoxypropane,
O
O
OH OH
CSA, DMF, 70 o 88%
C,
O
O
HO
HO
OH
HO
22
OH OH
2. H2SO4/silica, MeOH, 91%
21
D-mannitol
(
)
,
1. Bu2SnO BnBr
toluene, 73%
2. TBSCl, imidazole,
DMF, 85%
Figure 1. The structure of acremomannolipin A (1).
O
with lactol 11 in this type of b-mannosylation. As shown in Table 1,
it was found that only the use of excess 1-iodopentane and Cs2CO3
afforded desired b-D-mannoside 17 in 21% yield (b only, entry 2),
while there was no detectable product when 1-bromopentane,
n-pentyl mesylate or tosylate was employed (entries 3–5).
Elevation of the reaction temperature to 50 °C or use of other
solvents did not improve the reaction outcome. Use of methyl
O
O
O
O
HO
O
,
BnO
Pd/C, H2 MeOH
23
TBSO
83%
TBSO
O
O
24
,
Tf2
CH Cl
O,
C,
pyridine,
2
2
iodide gave methyl b-
D
-mannoside 18 in 71% yield (b only, entry
0 o 96%
6). Over-methylation at O2 could be seen if the reaction was
allowed to proceed longer. When activated alkyl halides, such as
allyl bromide and benzyl bromide, were used, corresponding
O
OH
O
BnO
BnO
BnO
O
O
O
O
11
12
eq.),
eq.),
eq.),
h
TfO
(1.0
Cs2CO
(1.5
O
O
desired b-D-mannoside 19 and 20 were produced in 94% and 64%
3 (2.0
TBSO
yields, respectively (b only, entries 7 and 8). These studies
indicated that non-activated primary alkyl triflates are required
to react with mannose-derived lactols in the presence of cesium
carbonate for efficient synthesis of b-mannosides.
,
ClCH2CH2Cl 40 o 24
87%,
TBSO
10
O
C,
O
only
β
12
ref
9
Next, we aimed at the synthesis of acremomannolipin A. Start-
ing from
steps by adopting the known procedures.9,12 As shown in Scheme 2,
conversion of commercially available -mannitol 21 into its
D-mannitol, the triflate acceptor 12 can be prepared in six
acremomannolipin
A (1)
D
Scheme 2. Synthesis of acremomannolipin A.
corresponding tri-acetonide (88%) followed by regioselective
1. Muraoka
OTBS
,
OPMB
O
OTBS
O
O
OPMB
O
Tf
DTMBP,
Ph
2O
HO
O
O
Ph
-78 o
BnO
O
O
O
O
C,
+
acremomannolipin
1)
A (
BnO
O
O
SPh
O
=
30/1
71%,
O
β/α
4
2
O
3
O
2. Li
Ph
ODEIPS
PAuCl,
CH2Cl2
OBn
O
(4-MeOPh)3
O
,
,
O
ODEIPS
F5 4
HO
OBn
OBn
AgB(C6
)
OBn
O
NapO
Ph
0 oC to RT,
O
O
+
O
OBn
OBn
NapO
acremomannolipin A (1)
O
BnO
85%yield, β/α = 13/1
O
5
OBn
BnO
7
OBn
O
6
3. Toshima
BnO
Bu
F
F
OH
BnO
BnO
BnO
O
O
O
O
O
O
O
B
OH
HO
O
0.2 eq.
O
BnO
+
acremomannolipin A (1)
BnO
TBSO
TBSO
,
CH3CN 0 o
8
eq.)
(2
C, 99%, β only
O
O
9
10
4. This work
BnO
OH
O
BnO
BnO
BnO
O
O
O
OH
O
β-mannosylation
via anomeric O-alkylation
O
O
+
O
TfO
BnO
BnO
acremomannolipin A (1)
OH
TBSO
TBSO
O
O
11
O
10
12
Scheme 1. Previous synthesis of acremomannolipin A and our strategy.
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X. Li et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 1
Studies of stereoselective b-mannosylation via anomeric O-alkylation involving various
electrophiles.a
OH
O
OH
O
BnO
BnO
BnO
BnO
X
electrophile R
Cs2CO3
BnO
O
BnO
R
OH
11
13
OTf
O
=
15a X
I
=
=
=
BnO
X
X
15b
Br
14
BnO
15c X
15d X
OMs
OTs
BnO
OMe
electrophile/condition
product, yield,b
α
entry
110
2
ratio
/
β
OH
BnO
BnO
BnO
O
O
O
14
/ condition A
BnO
BnO
OMe
BnO
only
only
16
OH
O
93%,
β
BnO
BnO
BnO
15a condition B
/
O
17
21%,
β
15b
B
/ condition
/
17
17
17
3
4
5
0%
0%
0%
15c condition B
15d / condition B
OH
O
BnO
I
CH3 / condition B
6
7
8
BnO
O
CH3
only
BnO
18
19
20
71%,
β
OH
O
BnO
Br
/
condition B
BnO
O
BnO
only
94%,
β
OH
O
BnO
BnO
BnO
BnBr
/ condition B
OBn
only
64%,
β
aCondition A: 11 (1.0 eq.), 14 (1.5 eq.), Cs2CO3 (2.0 eq.), ClCH2CH2Cl, 40 °C, 24 h;
Condition B: 11 (1.0 eq.), electrophile (2.5 eq.), Cs2CO3 (3.0 eq.), ClCH2CH2Cl, 40 °C, 24 h.
bIsolated yield.
deprotection of one of the terminal acetonides afforded diol 22
Acknowledgments
(91%).12 Regioselective benzylation11 of the primary alcohol of 22
(73%) followed by silylation9 of the secondary alcohol gave rise
to 23 (85%). Next, removal of the benzyl ether of 23 via palla-
dium-catalyzed hydrogenolysis furnished the known primary alco-
hol 24 in 83% yield.9 This primary alcohol 24 was then subjected to
standard triflation (triflic anhydride, pyridine, dichloromethane,
0 °C) to afford desired triflate 12 in 96% yield.13 Under our recently
We are grateful to National Science Foundation (CHE-1464787)
and University of Michigan-Dearborn for supporting this research.
We would also like to thank Professor Jianglong Zhu (Department
of Chemistry and Biochemistry, University of Toledo) for helpful
discussions.
developed optimal b-mannosylation condition,10 known
D-man-
nose-derived lactol 1111 reacted with triflate acceptor 12 in
dichloroethane in the presence of cesium carbonate at 40 °C for
24 h afforded the desired key b-mannoside 10 in 87% yield
(b only).14 The Rf, 1H and 13C NMR, optical rotation, and HRMS data
of our synthesized b-mannoside 10 were found to be identical to
those reported in the literature.9 For the synthesis of acremoman-
nolipin A (1), b-mannoside 10 would just need to undergo standard
acylations and deprotections.9 Thus, our efforts constitute a highly
efficient formal synthesis of acremomannolipin A (1).
References
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mannose-derived lactol with various electrophiles. It was found
that electrophiles bearing triflate as the leaving group are most
reactive and efficient for this type of b-mannosylation. In addition,
a highly efficient formal synthesis of potent calcium signal modu-
lator acremomannolipin A has been achieved using this b-manno-
sylation method.
Please cite this article in press as: Li X., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.04.049

4
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8.4 Hz, 1H), 3.92–3.89 (J = 7.2, 15.0 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.37 (s,
3H), 1.36 (s, 3H), 0.94 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H). 13C NMR (100 MHz,
CDCl3) d 112.3, 109.9, 109.0, 82.7, 81.0, 80.3, 73.2, 73.1, 70.2, 67.7, 66.8, 26.8,
26.4, 25.9, 25.7, 25.2, 24.7, 24.5.
13. Preparation of triflate 12: To known alcohol 249 (50.0 mg, 0.13 mmol) in 1.0 mL
anhydrous CH2Cl2 cooled at 0 °C was added anhydrous pyridine (0.39 mmol,
0.03 mL) followed by the addition of triflic anhydride (0.2 mmol, 0.03 mL). The
mixture was stirred at 0 °C for 30 min before being quenched with water. The
crude reaction mixture was diluted with CH2Cl2 and washed sequentially with
saturated CuSO4 aqueous solution, water, and brine. The organic solution was
dried over sodium sulfate, filtered, and concentrated in vacuo to afford 64 mg
of the desired triflate 12 (96% yield) which was sufficiently pure for the next
step. 1H NMR (400 MHz, CDCl3) d 4.65–4.62 (dd, J = 3.7, 10.3 Hz, 1H), 4.56–4.51
(dd, J = 7.0, 10.3 Hz, 1H), 4.26–4.23 (m, 1H), 4.19–4.15 (dd, J = 6.2, 8.4 Hz, 1H),
4.09–4.04 (m, 1H), 4.02–3.99 (dd, J = 3.2, 7.0 Hz, 1H), 3.97–3.93 (dd, J = 5.9,
14. Synthesis of key b-mannoside 10: To a mixture of known D-mannose-derived
lactol 1111 (45 mg, 0.1 mmol), sugar-derived triflate 12 (76 mg, 0.15 mmol),
and cesium carbonate (65 mg, 0.2 mmol) was added 1,2-dichloroethane
(1.0 mL). The reaction mixture was stirred at 40 °C for 24 h under Argon. The
crude reaction mixture was diluted with 1 mL dichloromethane and directly
purified by preparative thin layer chromatography (hexanes:EtOAc = 1:1) to
furnish 70 mg of b-mannoside 7 (87% yield). The Rf, 1H and 13C NMR, optical
rotation, and HRMS data of our synthetic b-mannoside 10 were found to be
identical to those reported in the literature.9
Please cite this article in press as: Li X., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.04.049