The first total synthesis of acremomannolipin A, the potential Ca 2+ signal modulator with a characteristic glycolipid structure, isolated from the filamentous fungus Acremonium strictum

Article abstract of DOI:10.1016/j.tetlet.2012.10.128

The first total synthesis of acremomannolipin A, the potential Ca ²⁺ signal modulator isolated from Acremonium strictum, was achieved by employing the characteristic stereoselective β-mannosylation of 4,6-O-benzylidene-protected mannosyl sulfox

Full text of DOI:10.1016/j.tetlet.2012.10.128

Tetrahedron Letters 54 (2013) 451–453
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Tetrahedron Letters
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The first total synthesis of acremomannolipin A, the potential Ca2+ signal
modulator with a characteristic glycolipid structure, isolated from
the filamentous fungus Acremonium strictum
Nozomi Tsutsui a, Genzoh Tanabe a, Ayako Kita b, Reiko Sugiura b, , Osamu Muraoka a,
⇑
⇑
a Laboratory of Pharmaceutical Organic Chemistry, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
b Laboratory of Molecular Pharmacogenomics, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
a r t i c l e i n f o
a b s t r a c t
The first total synthesis of acremomannolipin A, the potential Ca2+ signal modulator isolated from
Article history:
Received 23 August 2012
Revised 27 October 2012
Accepted 31 October 2012
Available online 19 November 2012
Acremonium strictum, was achieved by employing the characteristic stereoselective b-mannosylation of
4,6-O-benzylidene-protected mannosyl sulfoxide with a
D-mannitol derivative in the presence of
trifluoromethanesulfonic anhydride as the key reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acremomannolipin A
Glycolipid
Calcium signal modulator
Selective b-mannosylation
Acremonium strictum
Acremonium Link et Fries 1821 belongs to a very large group of
white or pink moulds with wet heads of conidia produced one-
by-one from the tips of straight hyphae or lateral nipples. They
are extremely common in man’s environment, are found in soil,
decaying vegetation and food stuffs.1 It is not commonly associated
with human diseases, but has been identified as a pathogen in
cases of mycetoma, keratomycosis, postoperative endophthalmitis,
onychomycosis and meningitis.2 The genus is well known for pro-
ducing numerous important enzymes including alkaline protease,3
isopenicillin N synthetase,4 glucooligosaccharide oxidase,5 prote-
ase,6 ascorbate oxidase,7 phenol oxidase8 and b-glucanases.9
Xenovulene A, a novel GABA-benzodiazepine receptor binding
compound;10 acremonol and acremodiol, two new fungal bislac-
tones;11 acremostatins A, B and C, three new lipoaminopeptides;12
UCS 1025 A and B, new antitumor antibiotics;13 polyketide-derived
organisms18 using a newly developed chemical-genetic method.19
The structure elucidated on the basis of various spectroscopic anal-
yses as well as its degradation studies was quite unique, in which
the
D-mannopyranose is connected to a D-mannitol through a
b-glycoside linkage. All the hydroxyls in the mannose are highly
masked as peresters with aliphatic acids, and thus the moiety is
hydrophobic, whereas the mannitol part exhibits the highly hydro-
philic property (Fig. 1).
In this work, we report the first total synthesis of this novel gly-
colipid (1) by employing the characteristic stereoselective b-man-
nosylation of 4,6-O-benzylidene-protected mannosyl sulfoxide
with D-mannitol in the presence of trifluoromethanesulfonic anhy-
dride (Tf2O).
The b-mannopyranosidic bond had long been considered as one
of the most difficult classes of glycosidic linkage to be prepared un-
til 1996 when Crich and Sun developed the innovative approach to
the highly selective and effective b-mannosylation.20 In the present
study, to establish the characteristic b-mannopyranosidic linkage,
the protocol developed by them was applied. In the synthetic
antibiotics;14 Acremostrictin,
a
new antibacterial tricyclic
lactone;15 and Acremolin16 are some new secondary metabolites
isolated from the genus belonging to Acremonium.
Recently, we also identified a novel glycolipid, acremomannoli-
pin A (1),17 from a species of the same genus, Acremonium strictum,
as a potential calcium signal modulator which might be involved in
the MAPK-related and/or calcineurin-mediated processes in higher
OCO(CH2)6CH3
CH3(CH2)4COO
OH
R
OH
O
CH3(CH2)4COO
O
R
CH3(CH2)4COO
R
R
OH
⇑
Corresponding authors. Tel.: +81 6 6721 2332x5570 (O.M.); tel.: +81 6 6721
2332x3850 (R.S.).
OH
OH
E-mail addresses: sugiurar@phar.kindai.ac.jp (R. Sugiura), muraoka@phar.kindai.
ac.jp (O. Muraoka).
Figure 1. Acremomannolipin A (1).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.128

452
N. Tsutsui et al. / Tetrahedron Letters 54 (2013) 451–453
OCO(CH2)6CH3
Firstly, phenyl 3-O-benzyl-4,6-O-benzylidene-1-thio-a-D-man-
6'
3'
OH
nopyranoside (4), prepared from D-mannose in 5 steps according
CH3(CH2)4COO
CH3(CH2)4COO
CH3(CH2)4COO
O
to the literature,21 was treated with PMBCl, and the resulting
6
4'
O
OH
OH
2'
1'
1
perprotected mannose derivative, phenyl 3-O-benzyl-4,6-O-ben-
zylidene-2-O-p-methoxybenzyl-1-thio-a-D-mannopyranoside (5)
was oxidized with metachloroperbenzoic acid (mCPBA) to give
exclusively the corresponding mannosyl sulfoxide 2 with R config-
uration22 at the sulfur in good yield. On the other hand, the
HO
1
OH
OTBS
6
D
-mannitol derivative (3) as an acceptor was prepared by adding
slowly an equimolar amount of tert-butyldimethylsilyl (TBS) chlo-
ride to bisacetonide, 2,3:4,5-di-O-isopropylidene- -mannitol
(6),23 in the presence of sodium hydride in 88% yield.
OPMB
O
6
HO
O
O
O
Ph
1
a
D
4
O
+
1
BnO
2
3
O
When the sulfoxide 2 was subjected to the coupling reaction
with the alcohol 3 at ꢀ78 °C in the presence of Tf2O, the desired
b-isomer, 6-O-(tert-butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
S
O
Ph
2
O
3
D
-mannitol-1-yl 3-O-benzyl-4,6-O-benzylidene-2-O-p-methoxy-
Scheme 1. Retrosynthetic analysis of acremomannolipin A (1).
benzyl-b- -mannopyranoside (7), was obtained in 71% isolated
D
yield.24 The FAB MS spectrum run in a positive ion mode showed
a peak at m/z 859 corresponding to the quasimolecular ion
[M+Na]+ of the desired coupled product. The b-stereochemistry
of the mannitol side chain was confirmed by the NOE correlations
between a signal at d 4.58 due to the anomeric proton at C10 and
signals at d 3.56 and d 3.31 due to C30–H and C50–H, respectively.
methodology especially for the sugar related molecules, selection
of the protecting groups is the most important step. Therefore, pro-
tective groups for the ten hydroxyls in the intermediates (2 and 3)
designed in the retrosynthetic studies were carefully chosen in this
study (Scheme 1).
The formation of a trace amount of the undesirable
a-isomer was
Crich and Sun reported that the introduction of a cyclic acetal
moiety to the positions C4 and C6 of the mannose was essential
for the b-selective mannosylation. Thus, the hydroxyls at these
two positions in the mannose were protected as the benzylidene
acetal. To discriminate the C20 hydroxyl, which composes an
octanoate in 1, from other three hydroxyls composing hexano-
ates, the C2 hydroxyl was protected by the p-methoxybenzyl
(PMB) moiety, which is exclusively removable under the oxida-
tive conditions. The protection of the C3 hydroxyl was with
the benzyl (Bn) group, which is removable simultaneously with
the benzylidene acetal moiety by the hydrogenolysis. Thus,
detected by the careful inspection of the 1H NMR spectrum of
the crude products (b:a ratio, ca. 30:1) (Supplementary data S5).
The selective removal of the PMB group at C20 in 7 was
successively conducted by DDQ to give 6-O-(tert-butyldimethylsi-
lyl)-2,3:4,5-di-O-isopropylidene-
D
-mannitol-1-yl
3-O-benzyl-4,
6-O-benzylidene-b- -mannopyranoside (8) in 91% yield, which
D
was then treated with octanoyl chloride to afford the correspond-
ing octanoyl ester, 6-O-(tert-butyldimethylsilyl)-2,3:4,5-di-O-
isopropylidene-D-mannitol-1-yl 3-O-benzyl-4,6-O-benzylidene-2-
O-octanoyl-b- -mannopyranoside (9) in good yield. Simultaneous
D
hydrogenolysis of both the benzyl and benzylidene moieties of 9
over palladium on carbon gave the desired trisalcohol, 6-O-(tert-
phenyl
1-thio-
3-O-benzyl-4,6-O-benzylidene-2-O-p-methoxybenzyl-
-D-mannopyranoside S-oxide (2) was designed as the do-
a
butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
O-octanoyl-b- -mannopyranoside (10), which was then derived
to the corresponding tetraester, 6-O-(tert-butyldimethylsilyl)-2,3:
D-mannitol-1-yl 2-
nor for the selective mannosylation reaction as shown in Scheme
1. As an acceptor, a pentasubstituted primary alcohol, 6-O-
(tert-butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
D
D-mannitol (3),
4,5-di-O-isopropylidene-
D
-mannitol-1-yl 3,4,6-tri-O-hexanoyl-2-
was employed.
OR
O
OPMB
O
O
O
Ph
Ph
ii
O
O
BnO
OR
O
BnO
OTBS
O
S+
Ph
5'
SPh
4 : R = H
5 : R = PMB
OH
Ph
2
O
1'
O
O
O
O-
2'
BnO
3'
i
iv
H
H
H
O
NOE
O
HO
O
O
iii
3
7 : R = PMB
8 : R = H
9 : R = CO(CH2)6CH3
v
O
vi
O
OCO(CH2)6CH3
6
OTBS
RO
O
RO
O
vii
O
ix
RO
1
O
O
10 : R = H
11 : R = CO(CH2)4CH3
O
viii
Scheme 2. Reagents and conditions: (i) PMBCl, NaH, DMF, rt (78%); (ii) mCPBA, CH2Cl2, 0 °C (83%); (iii) TBSCl, NaH, DMF, 0 °C (88%); (iv) Tf2O, DTBMP, CH2Cl2, ꢀ78 °C (71%);
(v) DDQ, CH2Cl2, H2O, rt (91%); (vi) CH3(CH2)6COCl, Py, DMAP, CH2Cl2, rt (93%); (vii) H2, Pd-C, AcOEt, rt (88%); (viii) [CH3(CH2)4CO]2O, Py, DMAP, CH2Cl2, rt (93%); (ix) 90% TFA
aq., 0 °C (94%).

N. Tsutsui et al. / Tetrahedron Letters 54 (2013) 451–453
453
9. Jayus, M.; Dougall, B. M.; Seviour, R. J. FEMS Microbiol. Lett. 2004, 230, 259.
O-octanoyl-b-D-mannopyranoside (11), by treating with hexanoic
10. Ainsworth, A. M.; Chicarelli-Robinson, M. I.; Copp, B. R.; Fauth, U.; Hylands, P.
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53, 2885.
17. Sugiura, R.; Kita, A.; Tsutsui, N.; Muraoka, O.; Hagihara, K.; Umeda, N.; Kunoh,
T.; Takada, H.; Hirose, D. Bioorg. Med. Chem. Lett. 2012, 22, 6735.
18. (a) Sugiura, R.; Toda, T.; Shuntoh, H.; Yanagida, M.; Kuno, T. EMBO J. 1998, 17,
140; (b) Takada, H.; Nishimura, M.; Asayama, Y.; Mannse, Y.; Ishiwata, S.; Kita,
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Sugiura, R. Mol. Biol. Cell 2007, 18, 4794; (c) Sugiura, R.; Kita, A.; Shimizu, Y.;
Shuntoh, H.; Sio, S. O.; Kuno, T. Nature 2003, 424, 961; (d) Ma, Y.; Kuno, T.; Kita,
A.; Asayama, Y.; Sugiura, R. Mol. Biol. Cell 2006, 17, 5028.
anhydride, in 82% yields in two steps. The suspected migration of
the octanoyl group from the 20-oxygen to the 30-hydroxyl group
was not observed in both reactions. Finally, the two acetonide moi-
eties and the TBS group in 11 were selectively removed without
affecting ester moieties under acidic conditions to afford the target
acremomannolipin A (1) in 94% yield. The physical and spectro-
scopic properties of the synthesized specimen were completely
in accord with those of natural acremomannolipin A17 (Scheme 2).
Thus, the first total synthesis of 1 has been accomplished by the
stereoselective b-mannosylation of a mannitol to the appropriately
protected mannose derivative (2), which were prepared starting
from a readily available mannose derivative (4), in 24% overall
yields in 8 steps. A plausible mechanism of action of 1 to modulate
Ca2+ signal transduction could be derived from our previous find-
ings that the Pmk1 MAPK and calcineurin pathways antagonisti-
cally regulate cytosolic Ca2+ concentration.18,25
Intensive structure–activity relationship studies including its a-
19. Ishiwata, S.; Kuno, T.; Takada, H.; Koike, A.; Sugiura, R. In Source-book of Models
for Biomedical Research; Conn, P. M., Ed.; Humana Press: New Jersey, 2008; pp
439–443.
20. (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506; (b) Crich, D.; Sun, S.
Tetrahedron 1998, 54, 8321.
isomer and analogues with a various type of ester moieties and/or
those with different alditol moieties for more potent analogues are
in progress.
21. (a) Crich, D.; Jayalath, P.; Hutton, T. J. Org. Chem. 2006, 71, 3064; (b) Ekholm, F.
S.; Poláková, M.; Pawłowicz, A. J.; Leino, R. Synthesis 2009, 4, 567.
22. The exclusive formation of a diastereomer with R configuration at the sulfur
was reported (a) Crich, D.; Mataka, J.; Zakharov, L. N.; Rheingold, A. L.; Wink, D.
J. J. Am. Chem. Soc. 2002, 124, 6028; (b) Crich, D.; de la Mora, M. A.; Cruz, R.
Tetrahedron 2002, 58, 35.
Acknowledgments
Financial support for this study was provided by Grant-in-Aid
for Scientific Research on Innovative Areas, and research grants
from the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan (to RS). This work was also financially supported by
‘Antiaging Center Project’ (to RS) and ‘High-Tech Research Center
Project’ (to OM) for Private Universities from the Ministry of Edu-
cation, Culture, Sports, Science and Technology.
23. Gawronska, K. Carbohydr. Res. 1988, 176, 79.
24. Preparation of 7: under an argon atomosphere, to a solution of 2 (1.00 g,
1.70 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 700 mg,
3.41 mmol) in dichloromethane (17 mL) was added trifluoromethanesulfonic
anhydride (Tf2O, 0.30 mL, 1.87 mmol) at ꢀ78 °C. After 10 min, a solution of 3
(770 mg, 2.05 mmol) in dichloromethane (17 mL) was added, and the reaction
mixture was stirred for 1 h at ꢀ78 °C. After the reaction was quenched with
aqueous sodium hydrogen carbonate, the resulting mixture was extracted with
dichloromethane. The extract was washed with brine and dried over
anhydrous Na2SO4. The filtrate was concentrated in vacuo and the crude
products were purified by column chromatography over silica gel with n-
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
128.
hexane–EtOAc (10:1) to give 7 (1.01 g, 71% yield) as a colorless oil. ½a D24
ꢀ35.6
ꢁ
(c 1.08, CHCl3); IR (neat) cmꢀ1: 1250, 1092; 1H NMR (500 MHz, CDCl3) d: 0.07/
0.08 [each s, 3H, Si(CH3)2], 0.90 [s, 9H, SiC(CH3)3], 1.36/1.39/1.46/1.50 [each s,
3H, C(CH3)2], 3.31 (ddd, J = 10.4, 9.8, 4.6 Hz, 1H, H-50), 3.56 (dd, J = 9.8, 2.9 Hz,
1H, H-30), 3.60 (dd, J = 10.3, 3.7 Hz, 1H, H-6a), 3.65 (dd, J = 10.3, 6.6 Hz, 1H, H-
1a), 3.76 (dd, J = 10.3, 7.8 Hz, 1H, H-6b), 3.80 (s, 3H, OMe), 3.90 (dd, J = 10.4,
10.4 Hz, 1H, H-60a), 3.97 (d, J = 2.9 Hz, 1H, H-20), 4.00 (dd, J = 10.3, 4.3 Hz, 1H,
H-1b), 4.17 (dd, J = 9.8, 9.8 Hz, 1H, H-40), 4.24 (ddd, J = 7.8, 6.0, 3.7 Hz, 1H, H-5),
4.26 (dd, J = 6.0, 5.8 Hz, 1H, H-4), 4.31 (dd, J = 10.4, 4.6 Hz, 1H, H-60b), 4.44 (dd,
J = 6.0, 5.8 Hz, 1H, H-3), 4.45 (ddd, J = 6.6, 6.0, 4.3 Hz, 1H, H-2), 4.54/4.64 (each
d, J = 12.6 Hz, 1H, OCH2Ph), 4.58 (s, 1H, H-10), 4.79/4.87 (each d, J = 11.8 Hz, 1H,
OCH2PMP), 5.61 (s, 1H, CHPh), 6.84 (d, J = 8.6 Hz, 2H, arom.), 7.25–7.39 (m,
10H, arom.), 7.49 (dd, J = 8.0, 1.7 Hz, 2H, arom.); 13C NMR (125 MHz, CDCl3) d:
ꢀ5.5/ꢀ5.4 [Si(CH3)2], 18.3 [SiC(CH3)3], 25.46/25.51/27.6/27.8 [C(CH3)2], 25.9
[SiC(CH3)3], 55.2 (OCH3), 62.2 (C6), 67.6 (C50), 68.6 (C60), 68.7 (C1), 72.2
(OCH2Ph), 74.4 (OCH2PMP), 74.9 (C3), 75.1 (C4), 75.4 (C20), 76.2 (C2), 76.9 (C5),
77.8 (C30), 78.6 (C40), 101.4 (CHPh), 102.1 (C10), 108.5/108.8 [C(CH3)2], 113.5/
126.0/127.46/128.16/128.24/127.49/128.8/130.1 (d, arom.), 130.5/137.5/
138.3/159.1 (s, arom.); FABMS m/z (%): 859 [(M+Na)+, 10], 73 (100);
FABHRMS 859.4042 (C46H64O12SiNa requires 859.4065).
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