Synthetic studies on novel fucosylated glycosphingolipids from the millipede, Parafontaria laminata armigera

Article abstract of DOI:10.1016/S0040-4039(00)01603-8

A novel glycosphingolipid, β-D-Manp-(1→4)-[(α-L-Fucp-(1→3)]-β-D-Glcp-(1→1)-Cer, from the millipede, Parafontaria laminata armigera, was synthesized. A key reaction of this synthetic procedure is the formation of a spiro-orthoester and its reduction for β-selective mannosylation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01603-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9065–9068
Synthetic studies on novel fucosylated glycosphingolipids
from the millipede, Parafontaria laminata armigera
Noriyasu Hada,a Isao Ohtsuka,a Mutsumi Sugitab and Tadahiro Takedaa,*
aKyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
bDepartment of Chemistry, Faculty of Liberal Arts and Education, Shiga University, 2-5-1, Hiratsu, Otsu-shi,
Shiga 520-0862, Japan
Received 3 August 2000; revised 13 September 2000; accepted 14 September 2000
Abstract
A novel glycosphingolipid, b-
D
-Manp-(1“4)-[(a-
L
-Fucp-(1“3)]-b- -Glcp-(1“1)-Cer, from the milli-
D
pede, Parafontaria laminata armigera, was synthesized. A key reaction of this synthetic procedure is the
formation of a spiro-orthoester and its reduction for b-selective mannosylation. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: glycosphingolipids; Parafontaria laminata armigera; chemical synthesis.
We have been interested in the relationship between the structure and the biological functions
of glycolipids from invertebrate animal species and have so far synthesized oligosaccharides
from various protostomia phyla.1 In 1994, Sugita et al. found a novel glycolipid with b-
D
-Manp-
-Glcp linkage from the periodical millipede, Parafontaria laminata
armigera, which belongs to the class Diplopoda2 (Fig. 1). This compound has a novel
(1“4)-[(a-
L
-Fucp-(1“3)]-b-
D
fucosylated structure and also 1,2-cis-b- -mannopyranosidic linkage and it is one of the most
D
difficult glycosidic linkages to synthesize.3 There are two main reasons why the b-mannosidic
linkage is so difficult to synthesize: (1) The anomeric effect stereoelectronically favors the
a-mannosidic linkage both thermodynamically and kinetically. (2) Neighboring group participa-
Manβ(1→4)Glcβ(1-1)Cer
3
↑
Fucα1
1
Figure 1.
* Corresponding author. Tel: 03-5400-2696; fax: 03-5400-2556; e-mail: takeda-td@kyoritsu-ph.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01603-8

9066
tion via an ester gives a-mannopyranosides. Construction of a b-mannosidic linkage has been
developed by many carbohydrate chemists.3,4 Further application of these methods to the synthe-
sis of aspargine-linked oligosaccharide and the glycolipid from the fresh-water bivalve, Hyriopsis
schlegelii, is under current investigation.5
On the other hand, Ikegami et al. reported a highly stereoselective b-(1“4)-glycosidic bond
formation by reductive cleavage of cyclic orthoesters.6 This method is based on a two-step
glycosylation procedure; the first step is the formation of an orthoester from two sugar moieties
and the second step is the reductive cleavage of one CꢀO orthoester bond. We applied this
method to the synthesis of the glycolipid, and this is the first report on the total synthesis of the
natural products. Coupling of 2,3,4,6-tetra-O-benzyl-
-mannopyranolactone (1)6 with diol 2 in
D
toluene in the presence of trimethylsilyl trifrate and methoxy trimethylsilane for 3 h at room
temperature gave the 2-(trimethylsilyl)ethyl 4,6-O-(2,3,4,6-tetra-O-benzyl-mannopyranosylidene)-
2-O-benzyl-3-O-benzoyl-b-
-glucopyranoside (3)7 in 67% yield. The structure of 3 was deter-
D
mined by reference to Ohtake’s report.6a Next, the reduction of the orthoester 3 and removal of
the benzoyl ester of the glucose derivative with LiAlH4–AlCl3 smoothly occurred to produce the
glycoside 48 (56%) in completely regio- and stereoselective fashion. Selective 6-O-pivaloylation
of 4 gave compound 5 (57%), which was used as an acceptor. The glycosylation of compound
5 with phenyl 2,3,4-tri-O-benzyl-1-thio-b-
-fucopyranoside (6)9 in the presence of NIS and
L
,
TfOH as the glycosyl promoter and MS 4A in dichloromethane for 5 h at 0°C gave the desired
a-glycoside 7 in 65% yield. After depivaloylation and debenzylation, compound 8 was converted
to peracetylated trisaccharide 9 (Scheme 1). For the selective removal of the 2-(trimethyl-
silyl)ethyl group, compound 9 was treated10 with trifluoroacetic acid in dichloromethane for 1–2
h at 0°C to give the 1-hydroxy compounds which, on further treatment11 with trichloroacetoni-
trile in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane for 2 h at
0°C, gave the corresponding donor carbohydrate 10. Glycosylation12 of (2S,3R,4E)-2-azido-3-
O-benzoyl-4-octadecene-1,3-diol 1113 with the glycosyl donor 10, which was carried out in the
,
presence of TMSOTf and MS 4A for 2 h at 0°C, afforded the desired b-glycoside 12 (41%).
Selective reduction14 of the azido group in 12 with triphenylphosphine in 20:1 benzene–water
BnO
BnO
BnO
OBn
O
HO
HO
BzO
BnO
BnO
BnO
OBn
O
a
O
O
O
+
TMS
O
O
OBn
O
O
2
BzO
1
3
TMS
OBn
R1O
O
RO
HO
d
O
O
b
RO
RO
BnO
BnO
O
O
O
O
TMS
TMS
O
O
OBn
OR
OBn
RO
OR
Me
BnO
SPh
OBn
O
O
Me
OR
OBn
OBn
OR
OR
R
H
4
5
6
R
R1
c
7
8
9
Bn Piv
Piv
e
f
H
H
Ac
Ac
Scheme 1. Reagents: (a) TMSOTf, TMSOMe, toluene; (b) LiAlH4, AlCl3, CH2Cl2–Et2O; (c) PivCl, Pyr, 0°C; (d) NIS,
TfOH, CH2Cl2, 0°C; (e) (1) NaOMe, MeOH, (2) Pd–C/H2, MeOH; (f) Ac2O, Pyr

9067
gave the amine, which on condensation with stearic acid using 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (WSC) in dichloromethane, gave the fully protected derivative
13 (74%). Finally, removal of the acyl groups in 13 under basic conditions and column
chromatography on Sephadex LH-20 furnished the target glycolipid 1 (Scheme 2). The structure
1
and purity of 1 were demonstrated by the H NMR and TOFMS data.15 In conclusion, a highly
efficient synthesis of a novel fucosylated glycosphingolipid from the millipede, Parafontaria
laminata armigera, has been achieved for the first time.
AcO
O
AcO
O
O
O
N3
AcO
AcO
AcO
AcO
O
O
O
C13H27
g
h
O
O
OAc
AcO
9
AcO
OAc
Me
OBz
AcO
OAc
Me
O
CCl3
HO
O
O
OAc
12
OAc
N3
NH
OAc
OAc
OAc
OAc
C13H27
10
OBz
11
O
RO
O
C
17H35
O
HN
RO
RO
O
O
C13H27
i
O
OR
Me
OR
RO
OR'
O
OR
OR
OR
R
R'
13 Ac Bz
j
1
H
H
Scheme 2. Reagents: (g) (1) CF3COOH–CH2Cl2, 0°C, (2) CCl3CN, DBU, CH2Cl2, 0°C; (h) TMSOTf, CH2Cl2, 0°C;
(i) (1) Ph3P, benzene–H2O, (2) WSC, C17H35COOH, CH2Cl2; (j) NaOMe, 1,4-dioxane–MeOH
Acknowledgements
This work was supported by the Uehara Memorial Foundation and also supported by a
Grant-in-Aid for Encouragement of Young Scientists, No. 70296531, from the Ministry of
Education, Science, Sports and Culture of Japan. The authors thank Dr. H. Ohtake (Faculty of
Pharmaceutical Sciences, Teikyo University) for valuable discussions.
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1
7. [h]2D3=+0.32° (c=l.0, CHCl3); H NMR (CDCl3) l: 7.89–7.01 (m, 55H, 11×Ph), 5.50 (t, 1H, J2,3=J3,4=9.8 Hz,
H-3), 4.86–4.47 (m, 10H, 5×benzyl methylene), 4.62 (d, 1H, J1,2=8.0 Hz, H-1), 4.23 (t, 1H, H-4), 4.02–3.98 (m,
1H, -OCH
6
2CH2-), 3.89–3.82 (m, 4H, H-3%, 4%, 6a, 6b), 3.75 (dd, 1H, J2%,3%=3.0 Hz, H-2%), 3.72–3.63 (m, 3H, H-6%a,
6%b, -OCH
6
2CH2-), 3.58–3.53 (m, 2H, H-2, 5%), 3.48 (dt, 1H, H-5). 13C NMR l: 110.7 (C-1%), 104.0 (C-1), 80.5
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(C-6%), 68.1 (C-C
C59H66O12Si: m/z 994. Found: m/z 1017 (M+Na)+.
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6 H2CH2Si), 66.1 (C-5), 60.4 (C-6), 18.6 (C-CH2C6 H2Si), −1.4 (SiMe3). MALDI-TOFMS: calcd for
1
J
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TOFMS: calcd for C52H64O11Si: m/z 892. Found: m/z 915 (M+Na)+.
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1
(d, 1H, J1,2=3.7 Hz, H-1 of Fuc), 4.60 (s, 1H, H-1 of Man), 4.34 (d, 1H, J1,2=7.9 Hz, H-1 of Glc).
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.