Efficient syntheses of a series of glycosphingolipids with 1,2-trans-glycosidic linkages

Article abstract of DOI:10.1080/07328300600859825

A series of glycosphingolipids with 1,2-trans-glycosidic linkages were synthesized in the presence of neighboring group participation using trichloroacetimidates as glycosyl donors and an azido-sphingosine as the glycosyl acceptor. During the preparation

Full text of DOI:10.1080/07328300600859825

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Efficient Syntheses of a Series of
Glycosphingolipids with 1,2‐trans‐Glycosidic
Linkages
Yunpeng Liu a , Ning Ding a , Hualing Xiao a & Yingxia Li a
a Key Laboratory of Marine Drugs , The Ministration of Education of China,
School of Pharmacy, Ocean University of China , Qingdao, China
Published online: 22 Sep 2006.
To cite this article: Yunpeng Liu , Ning Ding , Hualing Xiao & Yingxia Li (2006) Efficient Syntheses of a Series
of Glycosphingolipids with 1,2‐trans‐Glycosidic Linkages, Journal of Carbohydrate Chemistry, 25:6, 471-489,
DOI: 10.1080/07328300600859825
To link to this article: http://dx.doi.org/10.1080/07328300600859825
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Journal of Carbohydrate Chemistry, 25:471–489, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600859825
Efficient Syntheses of a
Series of Glycosphingolipids
with 1,2-trans-Glycosidic
Linkages
Yunpeng Liu, Ning Ding, Hualing Xiao, and Yingxia Li
Key Laboratory of Marine Drugs, The Ministration of Education of China, School of
Pharmacy, Ocean University of China, Qingdao, China
A series of glycosphingolipids with 1,2-trans-glycosidic linkages were synthesized in the
presence of neighboring group participation using trichloroacetimidates as glycosyl
donors and an azido-sphingosine as the glycosyl acceptor. During the preparation of
the target compounds, it was found that the a-L-arabinopyranosyl unit in target 7e
and intermediates 7b–7d existed in the 1C4 conformation and that the b-L-fucopyrano-
4
syl unit in 10e adopted the C1 conformation.
Keywords Glycosphingolipid with 1,2-trans-glycosidic linkage, Schmidt’s, glycosyl
trichloroacetimidate, Azido-sphingosine, Glycosylation, Conformation
INTRODUCTION
Glycosphingolipids (GSLs) are ubiquitous components of the cellular mem-
branes of all eukaryotic cells, and nearly 300 different structures have been
identified.[1] They are glycolipids composed of a long-chain amino alcohol,
known as a sphingoid base, with a fatty acid residue linked to its amino
group (the resulting amide is called ceramide, 1), and a carbohydrate chain
attached to the primary hydroxyl group of the ceramide.[2] The scientific
interest in GSLs has increased on account of their role in various cell-
surface-related processes, such as cell differentiation, transmembrane signal-
ing, cell recognition, and toxin binding.[3–5] Such events are common to
cancer, allergy, viral infection, inflammation, and autoimmune disease.[6,7]
Received March 29, 2006; accepted June 1, 2006.
Address correspondence to Yingxia Li, Key Laboratory of Marine Drugs, The Ministra-
tion of Education of China, School of Pharmacy, Ocean University of China, Qingdao
266003, China. E-mail: liyx417@ouc.edu.cn
471

Y. Liu et al.
472
Each of these events is mediated by a specific glycosphingolipid such as a
ganglioside, tumor antigen, or viral receptor.[7–9] This exquisite degree of
specificity suggests that glycosphingolipid analogs could be suitable candidates
for the development of new drugs.[6] Therefore, efficient synthetic routes to
pure glycosphingolipids and their derivatives are in demand.[10]
The functions of some glycosphingolipids with 1,2-trans-glycosidic linkages
have been studied extensively. For example, b-galactosyl ceramide (b-GalCer)
is known to act as a ligand for the HIV-1 viral glycoprotein gp120,[11] mediating
viral entry into epithelial cells. b-GalCer has also been suggested as a possible
ligand for the adhesion of Helicobacter pylori to cells in the gastric system.[12,13]
As another example, the simple monohexosyl sphingolipid glucosylceramide
has been reported to have mitogenic properties that stimulate cell growth,
differentiation, and DNA synthesis.[14,15]
Our interest in glycosphingolipids with 1,2-trans-glycosidic linkages stems
from our ongoing studies of glycosphingolipid carbohydrate-carbohydrate
interactions. As part of this work, we require a modular synthetic approach
to obtain some glycosphingolipids with 1,2-trans-glycosidic linkages as
shown in Figure 1, and the sugar portions in target molecules are D-lactopyr-
anosyl, D-galactopyranosyl, D-glucopyranosyl, D-mannopyranosyl, L-arabino-
pyranosyl, L-rhamnopyranosyl, and L-fucopyranosyl residue, respectively.
RESULTS AND DISCUSSION
Several syntheses of glycosphingolipids with 1,2-trans-glycosidic linkages have
been reported so far. The key step is the stereoselective and regioselective
coupling of the glycosyl acceptor with corresponding glycosyl donor. Among
these glycosylation methods, there are two main forms of glycosyl acceptors
used as shown in Figure 2, ceramide acceptor 2[16–20] and azido-sphingosine
acceptor 3.[21–25] For the glycosyl donor, Schmidt’s glycosyl trichloroacetimi-
dates with C-2 neighboring group participation are most successfully used
for the glycosphingolipids with 1,2-trans-glycosidic linkages. In 1986,
Schmidt and coworkers smoothly glycosylated a trisaccharide trichloroaceti-
midate with ceramide acceptor 2 in the presence of boron trifluoride etherate
Figure 1: Target compounds.

Syntheses of Series of Glycosphingolipids
473
Figure 2: Ceramide and glycosyl acceptors.
to obtain the protected GM3 ganglioside.[20] Recently, an a-series ganglioside
GM1a was efficiently synthesized by Takeda through the reaction of GM1a
oligosaccharide trichloroacetimidate with an azide-C20-sphingosine acceptor.[25]
Alternatively, glycosyl fluoride and glycosyl bromide donors were also used to
build up the corresponding glycosphingolipids with 1,2-trans-glycosidic
linkages.[16,17,19,23]
Taking into account the total efficiency to our target compounds and oper-
ational simpleness, we first selected Schmidt glycosyl donor and ceramide
acceptor 2,[26] and tried the glycosylation between benzoylated lactopyranosyl
trichloroacetimidate (4a) and ceramide acceptor 2 using 1.0 molar equiv
.
BF3 OEt2 as the catalyst at 2208C. As a result, the desired glycoside 4d was
obtained, however, only in 40% yield (Sch. 1). Having investigated a variety
of reaction conditions, including reaction solvent, promoters, reaction tempera-
ture, and the sequence of adding donor and acceptor, we found that it was very
difficult to further improve the glycosylation yield. The main reason might
result from the diminished nucleophilicity of the acceptor 2 due to the intra-
molecular hydrogen bond between the primary hydroxyl and the amide
group.[27,28] Protection of the 3-OH of ceramide 1 with an electron-donating
group (benzyl group) could enhance the nucleophilicity of the acceptor to
some extent; however, the glycosylation yield was still unsatisfactory.[28,29]
Next, the azido-sphingosine 3 was used as the glycosyl acceptor for further
investigation. Thus, perbenzoylated lactopyranosyl trichloroacetimidate (4a)
.
was glycosylated with 3 in the presence of BF3 OEt2 at 2208C, and the glyco-
side (4b) was smoothly produced in 90% yield. Glycosylation of the perbenzoy-
lated trichloroacetimidate donors (5a–10a) with acceptor 3 was undertaken
next. As shown in Table 1, all donors gave the corresponding glycosides
Scheme 1: Synthesis of protected glycosphingolipid with 1,2-trans-glycosidic linkage 4d.

Y. Liu et al.
474
Table 1: Synthesis of Glycosides 4b–10b.
Yield
(%)
Entry
Glycosyl donors
Products
1
90.0
95.0
100
2
3
4
94.5
5
6
98.4
98.2
7
97.1
(5b–10b) in excellent yields. Therefore, our synthetic route to the target sphin-
golipids was validated (Sch. 2).
Then, following the route shown in Scheme 2, reduction of azido groups in
4b–10b with triphenylphosphine was performed to produce amines (4c–10c),

Syntheses of Series of Glycosphingolipids
475
Scheme 2: The synthetic route to our target glycosphingolipids.
which were isolated without purification and immediately N-acylated with
.
palmitic acid in the presence of triethylamine, EDC HCl, and HOBt to
provide amides 4d–10d in good yields (Table 2).[10] Final removal of benzoyl
groups of 4d–10d with MeONa-MeOH readily yielded target glycosphingoli-
pids 4e–10e (Table 2). Overall yields for the four steps were high, ranging
from 43% to 67%.
1
The structures of all compounds were confirmed by H NMR, 13C NMR,
HMQC, HMBC, and MALDI-MS. Interestingly, the a-L-arabinopyranosyl
1
4
residue in 7b adopted a C4 chair conformation, instead of the C1 form. This
conformational assignment was supported by the proton coupling constants
observed for 7b (J1,2 ¼ J2,3 ¼ J3,4 ¼ 0 Hz) in the 1H NMR spectrum. The arabi-
nosyl C-10 signal at d 105.9 ppm in the 13C NMR spectrum and the coupling
0
0
constant JC1 -H1 (174.7 Hz) in the HMBC spectrum further confirmed the
axial linkage.[30] After reduction of the azido group of 7b, acylation of the
amino group of 7c, and removal of all protection to target 7e (J1,2 ¼ 1.4 Hz),
1
the C4 conformation of a-L-arabinopyranosyl residue did not reconvert into
4
the expected C1 form. What is more interesting is that the L-fucopyranosyl
1
ring, which adopted the expected C4 conformation in 10b and 10d, adopted
a
4C1 conformation in deprotected 10e. An apparent triplet for H-10 at
4.09 ppm [J1,2 ¼ 3.72 Hz, J1,3 ¼ 3.66 Hz (W coupling)] and three broad
singlet peaks at 3.26 (H-20), 3.28 (H-30), and 3.40 ppm (H-40) for the fucopyrano-
1
4
syl residue in the H NMR spectrum of 10e clearly indicated the C1 confor-
mation, instead of 1C4. The strong effect of ceramide aglycon on the chair
conformations of pentopyranose and 6-deoxy-hexopyranose rings was first
observed upon formation of glycosphingolipids bearing a 1,2-trans-diaxial
glycosidic linkage. However, such conformational changes were observed
previously in related series such as acetylated and benzoylated xylopyranosyl
derivatives[31–35] as well as in 6-deoxy-hexopyranosyl units including 6-deoxy-
L-talopyranosyl and L-rhamnopyranosyl analogs.[36]

Y. Liu et al.
476
Table 2: Synthesis of glycosphingolipids with 1,2-trans-glycosidic linkage 4e–10e.
Yield
(%)
Yield
(%)
Entry
Amides
4d
Products
1
68.4
76.2
2
5d
72.4
86.4
3
4
6d
7d
50.6
71.2
85.0
83.0
5
6
8d
9d
70.9
72.2
86.0
95.5
7
10d
61.6
85.1

Syntheses of Series of Glycosphingolipids
477
In conclusion, we have synthesized b-D-lactopyranosyl, b-D-glucopyrano-
syl, a-D-mannopyranosyl, b-D-galactopyranosyl, a-L-arabinopyranosyl, a-L-
rhamnopyranosyl, and b-L-fucopyranosyl ceramides with 1,2-trans-glycosidic
linkages. The results of the present investigation should be of value to
synthesize other structural analogs of glycosphingolipids.
EXPERIMENTAL
General methods. All reactions were conducted under a dried argon balloon.
.
.
CH2Cl2 was distilled from CaH2 BF3 OEt2 was distilled. All other solvents
and reagents were used without further purification. All reactions were moni-
tored by thin-layer chromatography (TLC) on aluminum sheets, Silica Gel 60
F254 (E. Merck). Flash column chromatography was performed on silica gel
(200-300 mesh, Qingdao, China). Optical rotations were determined with a
1
JACSO P-1020 digital polarimeter. H NMR, 13C NMR, HMQC, and HMBC
spectra were taken on a JEOL JNM-ECP 600 spectrometer with tetramethyl-
silane (TMS) as the internal standard, and chemical shifts are recorded in d
values. Mass spectra were measured using a HP5989A or VG Quattro
MALDITOF-MS with a-cyano-4-hydroxycinnamic acid (CCA) as the matrix.
General Procedure for Forming Glycosides 4b–10b
To a solution of perbenzoylated glycosyl trichloroacetimidate donor
(1.3 mmol) and acceptor 3 (1.0 mmol) in 20 mL of dry CH2Cl2 was added
˚
powdered molecular sieves (4 A, 1.2 g). The mixture was stirred for 30 min at
.
rt BF3 OEt2 (125.6 uL, 1.0 mmol) was added to the stirred mixture at 2208C.
The reaction mixture was stirred at 2208C until TLC revealed full conversion
of acceptor (30–45 min). The reaction was quenched with Et3N, and the solid
was then filtered off. The filtrate was concentrated under vacuum, and the
syrupy residue was purified by column chromatography on silica gel.
(2S,3R,4E)-[20,30,60-Tri-O-benzoyl-4-O-(200,300,400,600-Tetra-O-benzoyl-b-D-
galactopyranosyl)-b-D-glucopyranosyl]-(10 ! 1)-2-azido-3-benzoyl-4-
octadecene-1,3-diol (4b). Following the above-mentioned general procedure,
coupling of 3 (100 mg, 0.23 mmol) with 4a (368 mg, 0.30 mmol) afforded 4b
(310 mg, 90.0%) as a colorless oil. Rf 0.38 (3:1 petroleum ether-EtOAc);
[a]2D0 þ 22.18 (c 1.38, CHCl3); 1H NMR (CDCl3): d 7.15–8.01 (40 H, Ar-H),
5.82 (t, 1 H, J ¼ 9.1 Hz, H-300), 5.69–5.75 (m, 2 H, H-20, H-40), 5.69 (dt, 1 H,
J ¼ 15.2, 6.8 Hz, H-5), 5.49–5.53 (m, H-3, H-200), 5.39–5.44 (m, 2 H, H-4,
H-30), 4.89 (d, 1 H, J ¼ 7.8 Hz, H-10), 4.75 (d, 1 H, J ¼ 7.8 Hz, H-100), 4.58 (dd,
1 H, J ¼ 12.3, 1.8 Hz, H-6a00), 4.48 (dd, 1 H, J ¼ 12.3, 4.1 Hz, H-6b00), 4.29
(t, 1 H, J ¼ 9.7 Hz, H-400), 3.90–3.92 (m, 2 H, H-2, H-6a00), 3.85–3.87 (m, 2 H,
H-500, H-6b0), 3.70–3.75 (m, 2 H, H-1), 3.54–3.57 (m, 1 H, H-50), 1.87–1.90

Y. Liu et al.
478
(m, 2 H, CH255CH-CH2), 1.32–1.34 (m, 2 H, CH2-Alkyl), 1.20–1.25 (m, 20 H, 10
CH2-Alkyl), 0.88 (t, 3 H, J ¼ 6.8 Hz, CH3-Alkyl). 13C NMR (CDCl3): d 165.8,
165.5, 165.4, 165.3, 165.2, 165.0, 164.9, 164.8 (8 C55O), 138.9 (C-5), 133.5,
133.4 (2 C), 133.3, 133.2 (3 C), 133.0 (Ar-C), 128.2–129.9 (Ar-C), 122.3 (C-4),
100.9, 100.7, 75.8, 74.7, 73.0, 72.8, 71.7, 71.5, 71.3, 69.8, 68.2, 67.5, 63.3,
62.2, 61.0, 46.3 (C-6), 32.2 (C-7), 31.9 (C-8), 22.5–29.6 (C-9, C-10, C-11, C-12,
C-13, C-14, C-15, C-16), 22.6 (C-17), 14.1 (C-18). HRMS calcd. for
þ
C86H87N3O20 [M þ Na] 1504.6, found: 1504.8.
(2S,3R,4E)-20,30,40,60-Tetra-O-benzoyl-b-D-glucopyranosyl-(10 ! 1)-2-
azido-3-benzoyl-4-octadecene-1,3-diol (5b). Following the above-mentioned
general procedure, coupling of 3 (100 mg, 0.23 mmol) with 5a (222 mg,
0.30 mmol) afforded 5b (223 mg, 95.0%) as a colorless oil. Rf 0.36 (5:1 petroleum
ether-EtOAc); [a]2D0 27.398 (c 1.0, CHCl3); 1H NMR (CDCl3): d 7.26–8.02 (25 H,
Ar-H), 5.92 (t, 1 H, J ¼ 9.6 Hz, H-30), 5.73 (dt, 1 H, J ¼ 15.1, 6.9 Hz, H-5), 5.70
(t, 1 H, J ¼ 9.6 Hz, H-40), 5.57–5.60 (m, 2 H, H-3, H-20), 5.47 (dd, 1 H, J ¼ 15.1,
8.3 Hz, H-4), 4.90 (d, 1 H, J ¼ 7.7 Hz, H-10), 4.62 (dd, 1 H, J ¼ 12.1, 3.2 Hz,
H-6a0), 4.48 (dd, 1 H, J ¼ 12.1, 5.5 Hz, H-6b0), 4.16–4.19 (m, 1 H, H-50), 3.95–
3.98 (m, 2 H, H-2, H-1a), 3.66 (dd, 1 H, J ¼ 12.8, 8.7 Hz, H-1b), 1.90–1.94
(m, 2 H, CH255CH-CH2), 1.22–1.30 (m, 22 H, 11 CH2-Alkyl), 0.88 (t, 3 H,
J ¼ 6.9 Hz, CH3-Alkyl). 13C NMR (CDCl3): d 166.0, 165.7, 165.1, 164.9 (2 C)
(5 C55O), 139.0 (C-5), 133.4, 133.2 (2 C), 133.1, 133.0 (Ar-C), 128.2–129.9
(Ar-C), 122.4 (C-4), 100.9 (C-10), 74.7, 72.7, 72.4, 71.6, 69.5, 68.2, 63.4, 63.0,
46.8 (C-6), 32.2 (C-7), 31.9 (C-8), 28.6–29.6 (C-9, C-10, C-11, C-12, C-13,
C-14, C-15, C-16), 22.6 (C-17), 14.1 (C-18). HRMS calcd. for C58H65N3O12
[M þ Na] þ 1030.5, found: 1030.9.
(2S,3R,4E)-20, 30, 40, 60-Tetra-O-benzoyl-a-D-mannopyranosyl-(10 ! 1)-2-
azido-3-benzoyl-4-octadecene-1,3-diol (6b). Following the above-mentioned
general procedure, coupling of 3 (100 mg, 0.23 mmol) with 6a (222 mg,
0.3 mmol) afforded 6b (234 mg, 100.0%) as a colorless oil. Rf 0.38 (5:1 petroleum
1
ether-EtOAc); [a]2D0 243.58 (c 0.25, CHCl3); H NMR (CDCl3): d 7.25–8.10 (25
H, Ar-H), 6.13 (t, 1 H, J ¼ 10.1 Hz, H-40), 5.92–5.95 (m, 2 H, H-5, H-30), 5.76
(dd, 1 H, J ¼ 3.2, 1.8 Hz, H-20), 5.59–5.65 (m, 2 H, H-3, H-4), 5.17 (d, 1 H,
J ¼ 1.8, H-10), 4.70 (dd, 1 H, J ¼ 12.1, 2.3 Hz, H-6a0), 4.51 (dd, 1 H, J ¼ 12.1,
4.6 Hz, H-6b0), 4.44–4.47 (m, 1 H, H-50), 4.12–4.14 (m, 1 H, H-2), 3.99 (dd, 1
H, J ¼ 10.5, 3.7 Hz, H-1a), 3.64 (dd, 1 H, J ¼ 10.5, 8.2 Hz, H-1b), 2.05–2.08
(m, 2 H, CH255CH-CH2), 1.34–1.39 (m, 2 H, CH2-Alkyl), 1.21–1.30 (m, 20 H,
10 CH2-Alkyl), 0.87 (t, 3 H, J ¼ 7.4 Hz, CH3-Alkyl). 13C NMR (CDCl3): d
166.1, 165.5, 165.3 (3 C) (5 C55O), 139.2 (C-5), 133.5 (2 C), 133.3, 133.3, 133.1
(Ar-C), 128.3–130.0 (Ar-C), 122.8 (C-4), 98.5 (C-10), 74.8 (C-3), 70.2 (C-2),
69.7 (C-30), 69.3 (C-50), 68.2 (C-1), 66.8 (C-40), 63.9 (C-2), 62.7 (C-60), 47.0
(C-6), 32.4 (C-7), 31.9 (C-8), 28.7–29.7 (C-9, C-10, C-11, C-12, C-13, C-14,

Syntheses of Series of Glycosphingolipids
479
C-15, C-16), 22.7 (C-17), 14.1 (C-18). HRMS calcd. for C58H65N3O12 [M þ Na] þ
1030.5, found: 1030.6.
(2S,3R,4E)-20,30,40-Tri-O-benzoyl-a-L-arabinopyranosyl-(10 ! 1)-2-azido-
3-benzoyl-4-octadecene-1,3-diol (7b). Following the above-mentioned
general procedure, coupling of 3 (130 mg, 0.30 mmol) with 7a (291 mg,
0.39 mmol) afforded 7b (300 mg, 98.4%) as a colorless oil. Rf 0.34 (5:1 petroleum
ether-EtOAc); [a]2D0 211.38 (c 0.4, CHCl3); 1H NMR (CDCl3): d 7.26–8.13 (20 H,
Ar-H), 5.93 (dt, 1 H, J ¼ 15.6, 6.4 Hz, H-5), 5.69 (dd, 1 H, J ¼ 7.3, 5.0 Hz, H-3),
5.57–5.62 (m, 2 H, H-4, H-40), 5.55 (s, 1 H, H-30), 5.29 (s, 1 H, H-10), 4.81 (dd, 1
H, J ¼ 9.6, 3.6 Hz, H-5a0), 4.66 (s, 1 H, H-20), 4.65 (dd, 1 H, J ¼ 9.6, 3.2 Hz,
H-5b0), 3.99–4.02 (m, 1 H, H-2), 3.93 (dd, 1 H, J ¼ 9.6, 8.2 Hz, H-1a0), 3.70
(dd, 1 H, J ¼ 9.6, 4.1 Hz, H-1b0), 2.05–2.08 (m, 2 H, CH255CH-CH2), 1.35–
1.37 (m, 2 H, CH2-Alkyl), 1.23–1.29 (m, 20 H, 10 CH2-Alkyl), 0.87 (t, 3 H,
J ¼ 6.8 Hz, CH3-Alkyl). 13C NMR (CDCl3): d 166.2, 165.9, 165.4, 165.1 (4
C55O), 138.9 (C-5), 133.5 (2 C), 133.2, 133.0 (Ar-C), 128.3–130.0 (Ar-C), 122.9
(C-4), 105.9 (C-10), 82.1 (C-30), 81.4 (C-20), 77.6 (C-40), 74.5 (C-3), 66.7 (C-1),
63.5 (C-2, C-50), 32.4 (C-6), 31.9 (C-7), 28.7–29.6 (C-8, C-9, C-10, C-11, C-12,
C-13, C-14, C-15, C-16), 22.7 (C-17), 14.1 (C-18); HRMS calcd. for
C51H59N3O10 [M þ Na]þ 896.4, found: 896.8.
(2S,3R,4E)-20,30,40,60-Tetra-O-benzoyl-b-D-galactopyranosyl-(10 ! 1)-2-
azido-3-benzoyl-4-octadecene-1,3-diol (8b). Following the above-mentioned
general procedure, coupling of 3 (130 mg, 0.30 mmol) with 8a (291 mg,
0.39 mmol) afforded 8b (300 mg, 98.4%) as a colorless oil. Rf 0.34 (5:1 petroleum
1
ether-EtOAc); [a]2D0 þ 32.98 (c 0.52, CHCl3); H NMR (CDCl3): d 7.23–8.11 (25
H, Ar-H), 5.99 (d, 1 H, J ¼ 3.8, H-40), 5.83 (dd, 1 H, J ¼ 9.6, 7.8 Hz, H-20),
5.73 (dt, 1 H, J ¼ 15.1, 6.9 Hz, H-5), 5.62 (dd, 1 H, J ¼ 9.6, 3.7 Hz, H-30), 5.60
(dd, 1 H, J ¼ 7.3, 4.1 Hz, H-3), 5.49 (dd, 1 H, J ¼ 15.1, 8.3 Hz, H-4), 4.87 (d, 1
H, J ¼ 7.7 Hz, H-10), 4.63 (dd, 1 H, J ¼ 11.0, 6.4 Hz, H-6a0), 4.38 (dd, 1 H,
J ¼ 11.0, 6.8 Hz, H-6b0), 4.33 (dd, 1 H, J ¼ 6.8, 6.4 Hz, H-50), 4.03 (dd, 1 H,
J ¼ 9.6, 6.9 Hz, H-1a), 3.98–4.00 (m, 1 H, H-2), 3.69 (dd, 1 H, J ¼ 9.6, 5.5 Hz,
H-1b), 1.92–1.94 (m, 2 H, CH255CH-CH2), 1.21–1.30 (m, 22 H, 11 CH2-
Alkyl), 0.88 (t, 3 H, J ¼ 6.9 Hz, CH3-Alkyl). 13C NMR (CDCl3): d 166.0,
165.5(2 C), 165.0 (2 C) (5 C55O), 139.0 (H-5), 133.6, 133.3 (2 C), 133.2, 133.1
(Ar-C), 128.3–130.1 (Ar-C), 122.5 (H-4), 101.2 (C-10), 74.7, 71.6, 71.4, 69.6,
68.1, 67.9, 63.4, 61.8, 32.3 (C-6), 31.9 (C-7), 28.6–29.6 (C-8, C-9, C-10, C-11,
C-12, C-13, C-14, C-15, C-16), 22.7 (C-17), 14.1 (C-18). HRMS calcd. for
C58H65N3O12 [M þ Na]þ 1030.5, found: 1030.9.
(2S,3R,4E)-20,30,40-Tri-O-acetyl-a-L-rhamnopyranosyl-(10 ! 1)-2-azido-3-
benzoyl-4-octadecene-1,3-diol (9b). Following the above-mentioned general
procedure, coupling of 3 (100 mg, 0.23 mmol) with 9a (130 mg, 0.30 mmol)

Y. Liu et al.
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afforded (160 mg, 98.2%) as a colorless oil. Rf 0.24 (5:1 petroleum ether-EtOAc);
1
[a]2D0 245.98 (c 0.82, CHCl3); H NMR (CDCl3): d 8.05–8.06 (m, 2 H, Ar-H),
7.57–7.60 (m, 1 H, Ar-H), 7.45–7.48 (m, 2 H, Ar-H), 5.95 (dt, 1 H, J ¼ 14.6,
6.8 Hz, H-5), 5.54–5.60 (m, 2 H, H-3, H-4), 5.30 (dd, 1 H, J ¼ 10.1, 3.2 Hz,
H-30), 5.28 (dd, 1 H, J ¼ 3.2, 1.4 Hz, H-20), 5.08 (t, 1 H, J ¼ 10.1 Hz, H-40),
4.75 (d, 1 H, J ¼ 1.4 Hz, H-10), 3.95–3.98 (m, 1 H, H-2), 3.88–3.93 (m, 1 H,
H-50), 3.76 (dd, 1 H, J ¼ 10.1, 8.2 Hz, H-1a), 3.62 (dd, 1 H, J ¼ 10.1, 4.1 Hz,
H-1b), 2.15 (s, 3 H, CH3-Acetyl), 2.06–2.10 (m, 2 H, CH255CH-CH2), 2.06
(s, 3 H, CH3-Acetyl), 2.00 (s, 3 H, CH3-Acetyl), 1.37–1.39 (m, 2 H, CH2-
Alkyl), 1.24–1.30 (m, 20 H, 10 CH2-Alkyl), 1.18 (d, 3 H, J ¼ 5.9 Hz, H-60),
0.88 (t, 3 H, J ¼ 6.8 Hz, CH3-Alkyl). 13C NMR (CDCl3): d 170.1 (2 C), 169.8,
165.1 (4 C55O), 138.9 (C-5), 133.3, 129.7 (3 C), 128.5 (2 C) (Ar-C), 123.0 (C-4),
97.5 (C-10), 74.4, 70.7, 69.6, 68.9, 67.3, 66.8, 63.5, 32.3, 31.9, 28.6–29.6 (C-8,
C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16), 22.7 (C-17), 20.7, 20.8, 20.7,
17.3 (C-60), 14.1 (C-18). HRMS calcd. for C37H59N3O10 [M þ Na]þ 724.4,
found: 724.5.
(2S,3R,4E)-20,30,40-Tri-O-benzoyl-b-L-fucopyranosyl-(10 ! 1)-2-azido-3-
benzoyl-4-octadecene-1,3-diol (10b). Following the above-mentioned
general procedure, coupling of 3 (100 mg, 0.23 mmol) with 10a (186 mg,
0.30 mmol) afforded 10b (200 mg, 97.1%) as a colorless oil. Rf 0.13 (5:1 pet-
roleum ether-EtOAc); [a]D20 2108.88 (c 0.40, CHCl3); 1H NMR (CDCl3): d
7.23–8.10 (20 H, Ar-H), 5.84–5.88 (m, 1 H, H-5), 5.78 (dd, 1 H, J ¼ 10.6,
7.8 Hz, H-20), 5.72 (d, 1 H, J ¼ 3.5 Hz, H-40), 5.53 (dd, 1 H, J ¼ 10.6, 3.5 Hz,
H-30), 5.51–5.53 (m, 1 H, H-50), 5.51 (dd, 1 H, J ¼ 14.1, 7.7 Hz, H-4), 4.85
(d, 1 H, J ¼ 7.8 Hz, H-10), 4.08–4.12 (m, 2 H, H-2, H-1a), 3.95–3.98 (m, 1 H,
H-3), 3.59 (dd, 1 H, J ¼ 11.0, 8.3 Hz, H-1b), 2.01–2.05 (m, 2 H, CH255CH-
CH2), 1.35 (d, 3 H, J ¼ 6.4 Hz, H-60), 1.23–1.30 (m, 22 H, 11 CH2-Alkyl), 0.88
(t, 3 H, J ¼ 6.9 Hz, CH3-Alkyl). 13C NMR (CDCl3): d 166.0, 165.7, 165.3,
165.1 (4 C55O), 138.7 (C-5), 133.4, 133.2 (2 C), 133.1 (Ar-C), 128.2–130.0 (Ar-
C), 122.9 (C-4), 101.6 (C-10), 74.6, 72.1, 70.9, 69.9, 69.5, 68.9, 64.3, 32.3, 31.9,
28.6–29.2 (C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16), 22.7 (C-17),
16.3 (C-60), 14.1 (C-180). HRMS calcd. for C52H61N3O10 [M þ Na]þ 910.4,
found: 910.7.
General Procedure for the Syntheses of Amides 4d–10d
PPh3 (3.0 mol) and water (0.02 mol) were added to a stirred solution of
azide (1.0 mol) in THF (60 mL), and the mixture was heated at 458C until
TLC indicated the complete transformation of the starting azide into corre-
sponding amine (4c–10c, about 6 h). After rotary evaporation, the amine
residue was redissolved in dry CH2Cl2 (60 mL), and Et3N (1.5 mol),
.
EDC HCl (1.3 mol), HOBt (1.3 mol), and palmitic acid (1.0 mol) were added.

Syntheses of Series of Glycosphingolipids
481
The reaction mixture was stirred at rt for 10 h. The solution was concentrated
under vacuum, and the syrupy residue was purified by column chromato-
graphy on silica gel.
(2S,3R,4E)-[20,30,60-Tri-O-benzoyl-4-O-(200,300,400,600-tetra-O-benzoyl-b-D-
galactopyanosyl)-b-D-glucopyranosyl]-(10 ! 1)-2-(hexadecanoylamido)-
3-benzoyl-4-octadecene-1,3-diol (4d). 4b (518 mg, 0.35 mmol) was treated
accordingly to the corresponding general procedure to afford 4d (405 mg,
68.4% for two steps) as a colorless oil. Rf 0.14 (5:1 petroleum ether-EtOAc);
1
[a]2D0 þ 27.88 (c 0.60, CHCl3); H NMR (CDCl3): d 7.16–8.00 (m, 40 H, Ar-H),
5.80 (t, 1 H, J ¼ 9.6 Hz, H-30), 5.78 (dt, 1 H, J ¼ 15.1, 6.9 Hz, H-5), 5.73
(d, 1H, J ¼ 3.5 Hz, H-400), 5.69 (dd, 1 H, J ¼ 10.1, 7.8 Hz, H-200), 5.63 (d, 1 H,
J ¼ 9.7 Hz, N-H), 5.49 (t, 1 H, J ¼ 7.8 Hz, H-3), 5.43 (dd, 1 H, J ¼ 9.6,
7.8 Hz, H-20), 5.41 (dd, 1 H, J ¼ 15.1, 7.3 Hz, H-4), 5.36 (dd, 1 H, J ¼ 10.1,
3.5 Hz, H-300), 4.83 (d, 1 H, J ¼ 7.8 Hz, H-100), 4.65 (d, 1 H, J ¼ 7.8 Hz, H-100),
4.39–4.21 (m, 2 H, H-1), 4.36–4.38 (m, 1 H, H-2), 4.21 (t, 1 H, J ¼ 9.6 Hz,
H-40), 4.09 (dd, 1 H, J ¼ 9.7, 2.8 Hz, H-6a0), 3.87 (t, 1 H, J ¼ 6.8 Hz, H-500),
3.74–3.78 (m, 2 H, H-50, H-6a00), 3.67 (dd, 1 H, J ¼ 11.5, 6.8 Hz, H-6b00), 3.57
(dd, 1 H, J ¼ 9.6, 3.7 Hz, H-6b0), 1.92–1.96 (m, 2 H, CH2-CO), 1.76–1.79
(m, 2 H, CH ¼ CH-CH2), 1.33–1.39 (m, 2 H, CH2-Alkyl), 1.16–1.26 (m, 44 H,
22 CH2-Alkyl), 1.08–1.11 (m, 2 H, CH2-Alkyl), 0.86–0.89 (m, 6 H, 2 CH3-
Alkyl). 13C NMR (CDCl3): d 172.6 (NC55O), 165.7, 165.5, 165.4, 165.3, 165.2
(2 C), 165.1, 164.8 (8 C55O), 137.3 (C-5), 133.5, 133.4 (2 C), 133.3 (2 C), 133.2
(2 C), 132.8 (Ar-C), 128.2–130.1 (Ar-C), 124.8 (C-4), 100.9 (2 C) (C-10, C-100),
75.7, 74.0, 73.0, 72.5, 72.1, 71.7, 71.3, 69.8, 67.6, 67.4, 65.9, 62.2, 61.0, 50.4,
36.4, 32.3, 31.9, 28.9–29.7 (21 C), 25.5, 22.7, 14.1. HRMS calcd. for
C
102H119NO21 [M þ Na]þ 1716.8, found: 1717.6.
(2S,3R,4E)-20,30,40,60-Tetra-O-benzoyl-b-D-glucopyranosyl-(10 ! 1)-2-
(hexadecanoylamido)-3- benzoyl-4-octadecene-1,3-diol (5d). 5b (182 mg,
0.18 mmol) was treated accordingly to the corresponding general procedure
to afford 5d (160 mg, 72.4% for two steps) as a white solid. Rf 0.15 (3:1 pet-
1
roleum ether-EtOAc); [a]2D0 þ 5.988 (c 0.31, CHCl3); H NMR (CDCl3): d 7.27–
8.01 (25 H, Ar-H), 5.92 (t, 1 H, J ¼ 9.6 Hz, H-30), 5.84 (dt, 1 H, J ¼ 15.1,
6.9 Hz, H-5), 5.74 (d, 1 H, J ¼ 9.1 Hz, N-H), 5.64 (t, 1 H, J ¼ 9.6 Hz, H-40),
5.56 (t, 1 H, J ¼ 7.3 Hz, H-3), 5.49 (dd, 1 H, J ¼ 9.6, 7.8 Hz, H-20), 5.46 (dd, 1
H, J ¼ 15.1, 7.8 Hz, H-4), 4.81 (d, 1 H, J ¼ 7.8 Hz, H-10), 4.44–4.48 (m, 2 H,
H-2, H6a0), 4.33 (dd, 1 H, J ¼ 12.4, 5.0 Hz, H-6b0), 4.18 (dd, 1 H, J ¼ 9.6,
3.2 Hz, H-1a), 4.09–4.11 (m, 1 H, H-50), 3.69 (dd, 1 H, J ¼ 9.6, 4.4 Hz, H-1b),
1.96–1.99 (m, 2 H, CH2-CO), 1.81–1.84 (m, 2 H, CH55CH-CH2), 1.38–1.42
(m, 2 H, CH2-Alkyl), 1.22–1.30 (m, 44 H, 22 CH2-Alkyl), 1.09–1.14 (2 H, m,
CH2-Alkyl), 0.86–0.89 (m, 6 H, 2 CH3-Alkyl). 13C NMR (CDCl3): d 172.7
(NC55O), 166.0, 165.7, 165.2 (2 C), 165.1 (C55O), 137.4 (C-5), 133.5, 133.4,

Y. Liu et al.
482
133.3, 133.1, 132.9 (Ar-C), 128.3–130.2 (25 C), 124.8 (C-4), 100.9 (C-10), 74.1,
72.5, 72.3, 72.2, 69.5, 67.5, 62.9, 50.5, 36.5, 32.3, 31.9, 28.9–29.7 (22 C), 25.5,
22.7, 14.1. HRMS S calcd. for C75H97NO13 [M þ Na]þ 1242.7, found: 1242.8.
(2S,3R,4E)-20,30,40,60-Tetra-O-benzoyl-a-D-mannopyranosyl-(10 ! 1)-2-
(hexadecanoylamido)-3-benzoyl-4-octadecene-1,3-diol (6d). 6b (217 mg,
0.22 mmol) was treated accordingly to the corresponding general procedure
to afford 6d (133 mg, 50.6% for two steps) as a colorless oil. Rf 0.15 (3:1 pet-
1
roleum ether-EtOAc); [a]2D0 223.28 (c 0.33, CHCl3); H NMR (CDCl3): d 7.26–
8.09 (25 H, Ar-H), 6.08 (t, 1 H, J ¼ 9.9 Hz, H-40), 6.00 (d, 1 H, J ¼ 9.2 Hz,
N-H), 5.95 (dt, 1 H, J ¼ 15.2, 6.6 Hz, H-5), 5.88 (dd, 1 H, J ¼ 9.9, 3.3 Hz,
H-30), 5.71 (dd, 1 H, J ¼ 3.3, 1.5 Hz, H-20), 5.68 (t, 1 H, J ¼ 6.8 Hz, H-3), 5.59
(dd, 1 H, J ¼ 15.2, 6.8 Hz, H-4), 5.08 (d, 1 H, J ¼ 1.5 Hz, H-10), 4.63–4.66
(m, 2 H, H-2, H-6a0), 4.42–4.48 (m, 2 H, H-50, H-6b0), 4.02 (dd, 1 H, J ¼ 10.4,
4.4 Hz, H-1a), 3.82 (dd, 1 H, J ¼ 10.4, 4.3 Hz, H-1b), 2.26–2.33 (m, 2 H,
CH2-CO), 2.06–2.09 (m, 2 H, CH55CH-CH2), 1.66–1.71 (m, 2 H, CH2-Alkyl),
1.32–1.38 (m, 2 H, CH2-Alkyl), 1.19–1.25 (m, 44 H, 22 CH2-Alkyl), 0.88 (t,
3 H, J ¼ 7.0 Hz, CH3-Alkyl), 0.87 (t, 3 H, J ¼ 7.3 Hz, CH3-Alkyl). 13C
NMR (CDCl3): d 173.0 (NC55O), 166.1, 165.5, 165.4 (2 C), 165.2 (C55O), 137.6
(C-5), 133.5 (2 C), 133.2 (2 C), 133.1, 128.3–129.9 (25 C), 124.5 (C-4), 98.4 (C-
1), 74.8, 70.1, 69.9, 69.2, 67.2, 66.8, 62.6, 51.3, 37.0, 32.4, 31.9, 28.9–29.7 (22
C), 25.8, 22.7, 14.1. HRMS calcd. for C75H97NO13 [M þ Na]þ 1242.7, found:
1242.9.
(2S,3R,4E)-20,30,40-Tri-O-benzoyl-a-L-arabinopyranosyl-(10 ! 1)-2-(hexa-
decanoylamido)-3-benzoyl-4-octadecene-1,3-diol (7d). 7b (133 mg,
0.15 mmol) was treated accordingly to the corresponding general procedure
to afford 7d (133 mg, 71.2% for two steps) as a yellow powder. Rf 0.35 (3:1
petroleum ether-EtOAc); [a]2D0 þ 7.328 (c 0.32, CHCl3); 1H NMR (CDCl3): d
7.26–8.18 (20 H, Ar-H), 6.00 (d, 1 H, J ¼ 9.6 Hz, N-H), 5.83 (dt, 1 H,
J ¼ 15.1, 6.9 Hz, H-5), 5.63 (t, 1 H, J ¼ 8.2 Hz, H-3), 5.60 (dd, 1 H, J ¼ 5.0,
1.4 Hz, H-30), 5.53 (dd, 1 H, J ¼ 15.1, 8.2 Hz, H-4), 5.51 (d, 1 H, J ¼ 1.4 Hz,
H-20), 5.20 (s, 1 H, H-10), 4.59–4.61 (m, 1 H, H-2), 4.58 (dd, 1 H, J ¼ 11.9,
3.7 Hz, H-5a0), 4.53 (dd, 1 H, J ¼ 8.7, 4.6 Hz, H-40), 4.49 (dd, 1 H, J ¼ 11.5,
4.6 Hz, H-5b0), 4.13 (dd, 1 H, J ¼ 10.1, 2.3 Hz, H-1a), 3.55 (dd, 1 H,
J ¼ 10.1, 3.2 Hz, H-1b), 2.15–2.24 (m, 2 H, CH2-CO), 1.98–2.02 (m, 2 H,
CH55CH-CH2), 1.58–1.64 (m, 2 H, CH2-Alkyl), 1.23–1.32 (m, 46 H, 23
CH2-Alkyl), 0.88 (t, 6 H, J ¼ 6.9 Hz, 2 CH3-Alkyl). 13C NMR (CDCl3): d
172.8 (NC55O), 166.1, 165.8, 165.7, 165.3 (C55O), 138.0 (C-5), 133.6, 133.5,
133.1, 133.0 (Ar-C), 128.3–130.2 (20 C, Ar-C), 125.2 (C-4), 106.2 (C-10),
82.5, 80.3, 77.4, 73.9, 66.3, 63.2, 50.4, 36.9, 32.3, 31.9, 28.9–29.7 (22 C),
25.8, 22.7, 14.1. HRMS calcd. for C67H91NO11 [M þ Na]þ 1108.7, found:
1109.0.

Syntheses of Series of Glycosphingolipids
483
(2S,3R,4E)-20,30,40,60-Tetra-O-benzoyl-b-D-galactopyranosyl-(10 ! 1)-2-
(hexadecanoylamido)-3-benzoyl-4-octadecene-1,3-diol (8d). 8b (270 mg,
0.27 mmol) was treated accordingly to the corresponding general procedure
to afford 8d (232 mg, 70.9% for two steps) as a colorless oil. Rf 0.29 (3:1 pet-
1
roleum ether-EtOAc); [a]2D0 þ 40.28 (c 0.72, CHCl3); H NMR (CDCl3): d 7.23–
8.13 (25 H, Ar-H), 5.94 (d, 1 H, J ¼ 3.5 Hz, H-40), 5.88 (dt, 1 H, J ¼ 15.1,
6.8 Hz, H-5), 5.74 (dd, 1 H, J ¼ 9.7, 7.8 Hz, H-20), 5.73 (d, 1 H, J ¼ 8.7 Hz,
N-H), 5.63 (dd, 1 H, J ¼ 9.7, 3.5 Hz, H-30), 5.59 (t, 1 H, J ¼ 7.5 Hz, H-3), 5.50
(dd, 1 H, J ¼ 15.1, 7.5 Hz, H-4), 4.79 (d, 1 H, J ¼ 7.8 Hz, H-10), 4.49–4.53
(m, 1 H, H-2), 4.34 (dd, 1 H, J ¼ 11.0, 6.4 Hz, H-6a0), 4.27 (dd, 1 H, J ¼ 9.1,
3.5 Hz, H-1a), 4.24 (t, 1 H, J ¼ 6.4 Hz, H-50), 4.18 (dd, 1 H, J ¼ 11.0, 6.4 Hz,
H-6b0), 3.69 (dd, 1 H, J ¼ 9.1, 3.5 Hz, H-1b), 1.99–2.02 (m, 2 H, CH2-CO),
1.80–1.83 (m, 2 H, CH55CH-CH2), 1.37–1.45 (m, 2 H, CH2-Alkyl), 1.23–1.32
(m, 46 H, 23 CH2-Alkyl), 0.88 (t, 6 H, J ¼ 6.8 Hz, 2 CH3-Alkyl). 13C NMR
(CDCl3): d 172.6 (NC55O), 165.8, 165.4 (2 C), 165.4, 165.1 (C55O), 137.4 (C-5),
133.6, 133.5, 133.3, 133.2, 132.9, 128.2–130.3 (25 C), 124.9 (C-4), 101.0 (C-
10), 74.0, 71.3, 71.2 (3 C), 67.8, 67.3, 61.6, 50.5, 36.5, 32.3, 31.9, 28.9–29.7 (21
C), 25.5, 22.7, 14.1. HRMS calcd. for C75H97NO13 [M þ Na]þ 1242.7, found:
1242.8.
(2S,3R,4E)-20,30,40-Tri-O-acetyl-a-L-rhamnopyranosyl-(10 ! 1)-2-(hexa-
decaneoylamido)-3-benzoyl-4-octadecene-1,3-diol (9d). 9b (140 mg,
0.20 mmol) was treated accordingly to the corresponding general procedure
to afford 9d (168 mg, 72.2% for two steps) as a colorless oil. Rf 0.40 (3:1 pet-
1
roleum ether-EtOAc); [a]2D0 215.38 (c 0.33, CHCl3); H NMR (CDCl3): d 8.03–
8.04 (m, 2 H, Ar-H), 7.55–7.58 (m, 1 H, Ar-H), 7.43–7.46 (m, 2 H, Ar-H),
5.94 (dt, 1 H, J ¼ 15.1, 7.3 Hz, H-5), 5.84 (d, 1 H, J ¼ 9.7 Hz, N-H), 5.48–
5.56 (m, 2 H, H-3, H-4), 5.33 (dd, 1 H, J ¼ 3.7, 1.8 Hz, H-20), 5.21 (dd, 1 H,
J ¼ 10.1, 3.7 Hz, H-30), 5.00 (t, 1 H, J ¼ 10.1 Hz, H-40), 4.67 (d, 1 H,
J ¼ 1.8 Hz, H-10), 4.56–4.59 (m, 1 H, H-2), 3.99 (dd, 1 H, J ¼ 10.1, 2.3 Hz,
H-1a), 3.61–3.65 (m, 1 H, H-50), 3.44 (dd, 1 H, J ¼ 10.1, 3.2 Hz, H-1b), 2.18–
2.26 (m, 2 H, CH2-CO), 2.13 (s, 3 H, CH3-Acetyl), 2.06 (s, 3 H, CH3-Acetyl),
2.01–2.05 (m, 2 H, CH55CH-CH2), 2.00 (s, 3 H, CH3-Acetyl), 1.62–1.65 (m, 2
H, CH2-Alkyl), 1.23–1.34 (m, 46 H, 23 CH2-Alkyl), 0.88 (t, 6 H, J ¼ 4.8 Hz, 2
CH3-Alkyl), 0.85 (d, 3 H, J ¼ 6.4 Hz, H-60). 13C NMR (CDCl3): d 172.9
(NC55O), 170.1, 170.0 (2 C), 165.1, 138.6 (C-5), 133.2, 129.6, 128.4, 124.9,
97.7 (C-10), 73.7, 70.4, 69.4, 69.3, 66.7, 66.6, 50.1, 36.9, 33.8, 32.3, 31.9, 28.9–
29.7 (17 C), 25.8, 24.7, 22.7, 20.8 (2 C), 20.7, 16.9 (C-60), 14.1.
(2S,3R,4E)-20,30,40-Tri-O-benzoyl-b-L-fucopyranosyl-(10 ! 1)-2-(hexadeca-
noylamido)-3-benzoyl-4-octadecene-1,3-diol (10d). 10b (400 mg, 0.45 mmol)
was treated accordingly to the corresponding general procedure to afford
10d (309 mg, 61.6% for two steps) as a white solid. Rf 0.40 (3:1 petroleum

Y. Liu et al.
484
ether-EtOAc); [a]2D0 264.98 (c 0.4, CHCl3); 1H NMR (CDCl3): d 7.23–8.19 (20 H,
Ar-H), 5.88 (d, 1 H, J ¼ 9.2 Hz, N-H), 5.75 (dd, 1 H, J ¼ 10.1, 7.8 Hz, H-20), 5.70
(d, 1 H, J ¼ 3.2 Hz, H-40), 5.59 (dd, 1 H, J ¼ 10.1, 3.2 Hz, H-30), 5.33–5.39 (m, 2
H, H-3, H-4), 5.19 (dt, 1 H, J ¼ 14.2, 6.9 Hz, H-5), 4.75 (d, 1 H, J ¼ 7.8 Hz, H-10),
4.40–4.44 (m, 1 H, H-2), 4.00–4.03 (m, 2 H, H-1a, H-50), 3.79 (dd, 1 H, J ¼ 10.5,
1.8 Hz, H-1b), 2.06–2.17 (m, 2 H, CH2-CO), 1.78–1.80 (m, 2 H, CH55CH-CH2),
1.55–1.57 (m, 2 H, CH2-Alkyl), 1.14–1.29 (m, 49 H, 23 CH2-Alkyl, H-60), 0.88
(t, 6 H, J ¼ 6.8 Hz, 2 CH3-Alkyl). 13C NMR (CDCl3): d 172.7 (NC55O), 165.9,
165.7, 165.5, 165.1 (C55O), 137.7 (C-5), 133.4, 133.3, 133.2, 133.0, 128.2–
130.2 (20 C), 124.8 (C-4), 101.7 (C-10), 73.9, 71.7, 71.0, 69.9, 69.8, 67.8, 50.5,
36.9, 32.1, 31.9, 28.7–29.7 (22 C), 25.7, 22.7, 16.2, 14.1. HRMS calcd. for
C68H93NO11 [M þ Na]þ 1122.7, found: 1123.2.
General Procedure for the Syntheses of Target
Glycolipids 4e–10e
The amide was dissolved in MeOH-CH2Cl2 (2:1, 6 mL), and then NaOMe in
MeOH was added until pH was 9. After stirring at rt for 12 h, the solution was
neutralized with ion-exchange resin (Hþ) and then filtered. To the filtrate was
added silica gel (100 mg), and the solvent was removed under vacuum. The
resulting silica powder was loaded into a column and purified.
(2S,3R,4E)-[4-O-(b-D-Galactopyanosyl)-b-D-glucopyranosyl]-(10 ! 1)-2-
(hexadecanoylamido)-4-octadecene-1,3-diol (4e). 4d (100 mg, 0.06 mmol)
was treated according to the general procedure for obtaining the target glyco-
lipid to provide 4e (39 mg, 76.2%) as a white solid. Rf 0.20 (5:1 CHCl3-MeOH);
[a]2D2 25.48 (c 1.0, Pyridine); 1H NMR (DMSO-d6, 21.98C): d 7.54 (d, 1 H,
J ¼ 9.2 Hz, N-H), 5.52 (dt, 1 H, J ¼ 15.1, 6.4 Hz, H-5), 5.35 (dd, 1 H,
J ¼ 15.1, 6.8 Hz, H-4), 5.16 (d, 1 H, J ¼ 2.3 Hz, 20-OH), 5.13 (d, 1 H,
J ¼ 2.2 Hz, 200-OH), 4.90 (d, 1 H, J ¼ 5.5 Hz, 3-OH), 4.84 (d, 1 H, J ¼ 3.2 Hz,
300-OH), 4.68–4.69 (m, 2 H, 30-OH, 600-OH), 4.60 (t, 1 H, J ¼ 5.0 Hz, 60-OH),
4.56 (d, 1 H, J ¼ 4.1 Hz, 400-OH), 4.20 (d, 1 H, J ¼ 6.4 Hz, H-100), 4.16 (d, 1 H,
J ¼ 7.8 Hz, H-10), 3.98–4.00 (m, 1 H, H-1), 3.86–3.88 (m, 1 H, H-3), 3.73–
3.78 (m, 2 H, H-2, H-6a0), 4.59–4.62 (m, 2 H, H-40, H-6b0), 3.52–3.54 (m, 1 H,
H-6a00), 3.48–3.50 (m, 1 H, H-6b00), 3.45–3.47 (m, 1 H, H-500), 3.39–3.41 (m, 2
H, H-1, H-400), 3.28–3.11 (m, 4 H, H-300, H-50, H-30, H-200), 3.03–3.05 (m, 1 H,
H-20), 2.01–2.03 (m, 2 H, CH2-CO), 1.92–1.94 (m, 2 H, CH55CH-CH2), 1.43–
1.45 (m, 2 H, CH2-Alkyl), 1.28–1.31 (m, 46 H, 23 CH2-Alkyl), 0.84–0.86 (m, 6
H, 2 CH3-Alkyl). 13C NMR (DMSO-d6, 21.98C): d 171.8, 131.4 (2 C), 103.8,
103.5, 80.7, 79.2, 75.5, 74.8, 74.6, 73.2, 70.8, 70.7, 70.5, 69.2, 68.1, 62.8, 60.4,
60.3, 53.0, 45.7, 40.4, 35.6, 31.7, 31.3, 28.7–29.1 (18 C), 25.4, 22.1, 13.9.
HRMS calcd. for C46H87NO13 [M þ Na]þ 884.6034, found: 884.6070.

Syntheses of Series of Glycosphingolipids
485
(2S,3R,4E)-b-D-Glucopyranosyl-(10 ! 1)-2-(hexadecanoylamido)-4-octa-
decene-1,3-diol (5e). 5d (50 mg, 0.04 mmol) was treated according to the
general procedure for obtaining the target glycolipid to provide 5e (25 mg,
86.4%) as a white solid. Rf 0.40 (3:1 CHCl3-MeOH); [a]2D2 29.18 (c 1, Pyridine),
1
fRef. [22] [a]2D2 29.58 (c 1.0, Pyridine)g; H NMR (DMSO-d6, 22.38C): d 7.50
(d, 1 H, J ¼ 9.2 Hz, N-H), 5.53 (dt, 1 H, J ¼ 15.1, 6.8 Hz, H-5), 5.35 (dd, 1 H,
J ¼ 15.1, 7.3 Hz, H-4), 5.04 (d, 1 H, J ¼ 1.9 Hz, 20-OH), 4.95 (d, 1 H,
J ¼ 3.2 Hz, 30-OH), 4.90 (d, 1 H, J ¼ 4.1 Hz, 40-OH), 4.88 (d, 1 H, J ¼ 5.0 Hz,
3-OH), 4.51 (t, 1 H, J ¼ 5.5 Hz, 60-OH), 4.07 (d, 1 H, J ¼ 7.8 Hz, H-10), 3.97 (dd,
1 H, J ¼ 10.5, 4.6 Hz, H-1a), 3.87 (d, 1 H, J ¼ 13.3, 7.3 Hz, H-3), 3.75–3.79
(m, 1 H, H-2), 3.66 (dd, 1 H, J ¼ 11.4, 5.0 Hz, H-6a0), 3.43 (dd, 1 H, J ¼ 11.4,
5.9 Hz, H-6b0), 3.40 (dd, 1 H, J ¼ 10.5, 3.7 Hz, H-1b), 3.13 (m, 1 H, H-30), 3.04–
3.09 (m, 2 H, H-40, H-50), 2.97 (m, 1 H, H-20), 2.00–2.03 (m, 2 H, CH2-CO),
1.90–1.95 (m, 2 H, CH55CH-CH2), 1.41–1.46 (m, 2 H, CH2-Alkyl), 1.22–1.28
(m, 46 H, 23 CH2-Alkyl), 0.83–0.86 (m, 6 H, 2 CH3-Alkyl). 13C NMR (DMSO-
d6, 22.38C): d 171.8 (NC55O), 131.5 (C-5), 131.4 (C-4), 103.8 (C-10), 76.9 (C-50),
76.3 (C-30), 73.5 (C-20), 70.7 (C-3), 70.0 (C-40), 69.1 (C-1), 61.0 (C-60), 53.0 (C-2),
35.6 (CH2-NCO), 31.8 (C-6), 31.3 (CH2-Alkyl), 28.7–29.1 (22 C) (CH2-Alkyl),
25.4 (CH2-Alkyl), 22.1 (CH3-Alkyl), 13.9 (CH3-Alkyl). HRMS calcd. for
C40H77NO8 [M þ Na]þ 722.5518, found: 722.5541. Physical data of compound
5e were in agreement with those reported in Ref. [37].
(2S,3R,4E)-a-D-Mannopyranosyl-(10 ! 1)-2-(hexadecanoylamido)-4-
octadecene-1,3-diol (6e). 6d (40 mg, 0.03 mmol) was treated according to the
general procedure for obtaining the target glycolipid to provide 6e (20 mg,
85.0%) as a white solid. Rf 0.19 (10:1 CHCl3-MeOH); [a]2D2 þ 10.58 (c 0.65,
1
Pyridine); H NMR (DMSO-d6, 22.38C): d 7.50 (d, 1 H, J ¼ 8.7 Hz, N-H), 5.53
(dt, 1 H, J ¼ 15.1, 6.4 Hz, H-5), 5.35 (dd, 1 H, J ¼ 15.1, 6.8 Hz, H-4), 4.86
(d, 1 H, J ¼ 6.4 Hz, 3-OH), 4.67 (brs, 2 H, 20-OH, 30-OH), 4.57 (brs, 1 H, H-10),
4.52 (brs, 1 H, 40-OH), 4.38 (m, 1 H, 60-OH), 3.83–3.86 (m, 1 H, H-3), 3.74–
3.79 (m, 1 H, H-2), 3.96 (dd, 1 H, J ¼ 10.1, 4.1 Hz, H-1a), 3.58–3.61 (m, 2 H,
H-20, H-6a0), 3.35–3.50 (m, 4 H, H-30, H-6b0, H-1b, H-40), 3.26–3.29 (m, 1 H,
H-50), 2.00–2.02 (m, 2 H, CH-CO), 1.90–1.94 (m, 2 H, CH55CH-CH2), 1.40–
1.46 (m, 2 H, CH2-Alkyl), 1.18–1.30 (m, 46 H, 23 CH2-Alkyl), 0.83–0.85 (m, 6
H, 2 CH3-Alkyl). 13C NMR (DMSO-d6, 22.38C): d 171.9 (NC55O), 131.2 (2 C),
100.6, 73.8, 71.0, 70.8, 70.3, 69.8, 66.9, 66.3, 61.1, 53.4, 35.5, 31.8, 31.3,
28.6–29.1 (19 C), 26.5, 25.4, 24.6, 22.1, 13.9. HRMS calcd. for C40H77NO8
[M þ Na]þ 722.5521, found: 722.5541.
(2S,3R,4E)-a-L-Arabinopyranosyl-(10 ! 1)-2-(hexadecanoylamido)-4-
octadecene-1, 3-diol (7e). 7d (60 mg, 0.06 mmol) was treated according to the
general procedure for obtaining the target glycolipid to provide 7e (31 mg,
83.0%) as a white solid. Rf 0.31 (15:1 CHCl3-MeOH); [a]2D2 26.98 (c 0.1,

Y. Liu et al.
486
1
Pyridine); H NMR (DMSO-d6-D2O, 608C): d 5.55 (dt, 1 H, J ¼ 15.5, 6.4 Hz,
H-5), 5.38 (dd, 1 H, J ¼ 15.6, 6.8 Hz, H-4), 4.71 (d, 1 H, J ¼ 1.4 Hz, H-10),
3.89 (t, 1 H, J ¼ 6.8 Hz, H-3), 3.76–3.84 (m, 3 H, H-2, H-20, H-40), 3.65–3.68
(m, 2 H, H-1a, H-30), 3.54 (dd, 1 H, J ¼ 11.5, 3.7 Hz, H-5a0), 3.42–3.46 (m, 2
H, H-1b, H-5b0), 2.03–2.06 (m, 2 H, CH2-CO), 1.92–1.96 (m, 2 H, CH ¼ CH-
CH2), 1.44–1.49 (m, 2 H, CH2-Alkyl), 1.19–1.31 (m, 46 H, 23 CH2-Alkyl),
0.84–0.86 (m, 6 H, 2 CH3-Alkyl). 13C NMR (DMSO-d6, 608C): d 171.8
(NC55O), 131.1 (C-5), 130.9 (C-4), 107.7 (C-10), 84.0 (C-40), 81.5 (C-20), 76.9 (C-
30), 71.2 (C-3), 66.2 (C-1), 61.3 (C-50), 52.9 (C-2), 35.5, 31.6, 31.2, 28.6–30.0
(22 C), 25.2, 21.9, 13.7. HRMS calcd. for C39H75NO7 [M þ Na]þ 692.5418,
found: 692.5436.
(2S,3R,4E)-b-D-Galactopyranosyl-(10 ! 1)-2-(hexadecanoylamido)-4-
octadecene-1, 3-diol (8e). 8d (40 mg, 0.03 mmol) was treated according to
the general procedure for obtaining the target glycolipid to provide 8e
(20 mg, 85.0%) as a white solid. Rf 0.31 (5:1 CHCl3-MeOH); [a]2D2 24.48 (c 1.0,
1
Pyridine), Ref. [22] [a]2D2 25.28 (c 1.0, Pyridine)g; H NMR (DMSO-d6-D2O,
508C): d5.55 (1 H, dt, J ¼ 15.1, 6.9 Hz, H-5), 5.38 (dd, 1 H, J ¼ 15.1, 7.3 Hz,
H-4), 4.05 (d, 1 H, J ¼ 7.3 Hz, H-10), 3.91–3.95 (m, 2 H, H-1a, H-3), 3.77–
3.80 (m, 1 H, H-2), 3.65 (d, 1 H, J ¼ 3.2 Hz, H-40), 3.55 (dd, 1 H, J ¼ 11.0,
5.9 Hz, H-6a0), 3.49 (dd, 1 H, J ¼ 11.0, 6.0 Hz, H-6b0), 3.44 (dd, 1 H, J ¼ 10.1,
4.1 Hz, H-1b), 3.31–3.34 (m, 2 H, H-20, H-50), 3.28 (dd, 1 H, J ¼ 9.2, 3.2 Hz,
H-30), 2.02–2.04 (m, 2 H, CH2-CO), 1.92–1.96 (m, 2 H, CH55CH-CH2), 1.45–
1.48 (m, 2 H, CH2-Alkyl), 1.20–1.30 (m, 46 H, 23 CH2-Alkyl), 0.86 (t, 6 H,
J ¼ 6.9 Hz, 2 CH3-Alkyl). 13C NMR (DMSO-d6, 508C): d 171.7 (NC55O),
131.4, 131.3, 104.4, 75.2, 72.9, 70.6 (2 C), 70.5, 68.9, 68.0, 67.9, 60.3, 60.2,
52.9 (2 C), 35.5, 31.7, 31.2,þ28.7–29.0 (18 C), 25.3, 22.1, 13.8. HRMS calcd.
for C40H77NO8 [M þ Na]
722.5551, found: 722.5541. Physical data of
compound 8e were in agreement with those reported in Ref. 23.
(2S,3R,4E)-a-L-Rhamnopyranosyl-(10 ! 1)-2-(hexadecanoylamido)-4-
octadecene-1, 3-diol (9e). 9d (42 mg, 0.05 mmol) was treated according to the
general procedure for obtaining the target glycolipid to provide 9e (30 mg,
95.5%) as a white solid. Rf 0.13 (15:1 CHCl3-MeOH); [a]2D2 22.18 (c 0.25,
1
Pyridine); H NMR (DMSO-d6, 26.38C): d 7.47 (d, 1 H, J ¼ 8.3 Hz, N-H), 5.52
(dt, 1 H, J ¼ 15.1, 6.9 Hz, H-5), 5.35 (dd, 1 H, J ¼ 15.1, 6.4 Hz, H-4), 4.81 (dd,
1 H, J ¼ 5.0 Hz, 3-OH), 4.67 (d, 1 H, J ¼ 4.6 Hz, 20-OH), 4.64 (d, 1 H,
J ¼ 2.8 Hz, 40-OH), 4.48 (d, 1 H, J , 1 Hz, H-10), 4.43 (d, 1 H, J ¼ 4.6 Hz, 30-
OH), 3.79–3.82 (m, 2 H, H-2, H-3), 3.59–3.63 (m, 2 H, H-1a, H-20), 3.43–3.45
(m, 1 H, H-1b), 3.38–3.40 (m, 1 H, H-50), 3.37–3.38 (m, 1 H, H-30), 3.15–3.18
(m, 1 H, H-40), 1.99–2.04 (m, 2 H, CH2-CO), 1.89–1.94 (m, 2 H, CH55CH-
CH2), 1.22–1.30 (m, 48 H, 24 CH2-Alkyl), 1.11 (d, 3 H, J ¼ 6.4 Hz, H-60),
0.83–0.86 (m, 6 H, 2 CH3-Alkyl). 13C NMR (DMSO-d6, 26.38C): d 171.7

Syntheses of Series of Glycosphingolipids
487
(NC55O), 131.4, 131.1, 99.5, 72.0, 71.2, 70.7, 68.2, 65.7, 52.5, 52.4, 35.5 (2 C),
31.7, 31.3, 28.7–29.1 (20 C), 25.4, 22.1, 17.9, 13.9. HRMS calcd. for
C40H77NO7 [M þ Na]þ 706.5571, found: 706.5592.
(2S,3R,4E)-b-L-Fucopyranosyl-(10 ! 1)-2-(hexadecanoylamido)-4-octa-
decene-1,3- diol (10e). 10d (75 mg, 0.07 mmol) was treated according to the
general procedure for obtaining the target glycolipid to provide 10e (40 mg,
85.1%) as a white solid. Rf 0.36 (10:1 CHCl3-MeOH); [a]2D2 27.48 (c 0.1,
1
Pyridine); H NMR (DMSO-d6, 408C): d 7.30 (d, 1 H, J ¼ 8.7 Hz, N-H), 5.54
(dt, 1 H, J ¼ 15.1, 6.4 Hz, H-5), 5.36 (dd, 1 H, J ¼ 15.5, 6.9 Hz, H-4), 4.77
(d, 1 H, J ¼ 5.0 Hz, 3-OH), 4.60 (brs, 1 H, 30-OH), 4.55 (brs, 1 H, 20-OH), 4.30
(brs, 1 H, 40-OH), 4.09 (apparent t, 1 H, J ¼ 3.7 Hz, H-10), 3.96 (dd, 1 H,
J ¼ 12.4, 6.4 Hz, H-3), 3.72–3.74 (m, 1 H, H-2), 3.66–2.68 (m, 2 H, H-1), 3.50
(q, 1 H, J ¼ 6.4 Hz, H-50), 3.40 (brs, 1 H, H-40), 3.28 (brs, 1 H, H-30), 3.26 (brs,
1 H, H-20), 2.02–2.04 (m, 2 H, CH2-CO), 1.91–1.94 (m, 2 H, CH55CH-CH2),
1.20–1.30 (m, 48 H, 24 CH2-Alkyl), 1.13 (d, 3 H, J ¼ 6.4 Hz, H-6), 0.85 (t, 6
H, J ¼ 6.4 Hz, 2 CH3-Alkyl). 13C NMR (DMSO-d6, 408C): d 171.6 (NC55O),
131.1, 130.9, 103.8, 73.3, 70.9, 70.6, 70.3, 69.9, 67.9, 53.3, 31.6, 31.2, 28.5–
28.9 (22 C), 25.2, 21.9, 16.4, 13.7. HRMS calcd. for C40H77NO7 [M þ Na]þ
706.5564, found: 706.5592.
ACKNOWLEDGMENTS
This work is supported by the National Basic Research Program of China
(2003CB716400).
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