Total synthesis of a glycoglycerolipid from Meiothermus taiwanensis through a one-pot glycosylation reaction and exploration of its immunological properties

Article abstract of DOI:10.1002/asia.201300933

The total synthesis of a glycoglycerolipid isolate of Meiothermus taiwanensis and its truncated structural analogues is reported. Our synthesis employed DMF-modulated and low-concentration glycosylation reactions for the construction of α- and β-glycosidic bonds in the absence of participating protecting groups. Further simplification of the synthesis was achieved by employing a low-concentration one-pot glycosylation procedure. Preliminary immunological studies showed that one of the truncated structural analogues suppressed the cytokine production of THP-1 monocytes. Copyright

Full text of DOI:10.1002/asia.201300933

FULL PAPER
DOI: 10.1002/asia.201300933
Total Synthesis of a Glycoglycerolipid from Meiothermus taiwanensis
through a One-Pot Glycosylation Reaction and Exploration of its
Immunological Properties
Bhaswati Ghosh,[a] Yen-Hsun Lai,[a] Yu-Yin Shih,[b] Tapan Kumar Pradhan,[a]
Chun-Hung Lin,*[b] and Kwok-Kong Tony Mong*[a]
Abstract: The total synthesis of a glycoglycerolipid isolate of Meiothermus taiwa-
nensis and its truncated structural analogues is reported. Our synthesis employed
DMF-modulated and low-concentration glycosylation reactions for the construc-
tion of a- and b-glycosidic bonds in the absence of participating protecting groups.
Further simplification of the synthesis was achieved by employing a low-concentra-
tion one-pot glycosylation procedure. Preliminary immunological studies showed
that one of the truncated structural analogues suppressed the cytokine production
of THP-1 monocytes.
Keywords: glycosylation
nology · lipids · natural products ·
total synthesis
· immu-
Introduction
vestigated in the induced production of proinflammatory cy-
tokines; however, little is known of the immunological prop-
erties of glycoglycerolipids. Consequently, it is highly desira-
ble to develop a practical synthetic route to glycoglyceroli-
pids from M. taiwanesis species, as well as their relevant
structural analogues, to pave the way for exploration of
their biological properties.
The general structure of the glycoglycerolipids from M.
taiwanensis comprises a a-d-Gal-(1!6)-b-d-Gal-(1!6)-b-d-
GalNacyl-(1!2)-d-Glc tetrasaccharide core that is connect-
ed to the 3-hydroxy function of a sn-glycerol through a 1,2-
cis a-glycosidic linkage (Scheme 1).[3] The remaining hy-
droxy functions of the glycerol and the amino group of the
galactosamine connect to fatty acids through ester and
amide bonds, respectively. The chain length of the fatty acid
varies from 14 to 18 carbon atoms. In addition to variation
in the chain length, different isomeric forms of the fatty
In nature, there is an inexhaustible pool of compounds for
exploration. Studies on the physiochemical and biological
properties of newly discovered compounds provide inspira-
tion for the design of new therapeutic agents and materials.
For example, investigations of natural cerebrosides that
were isolated from marine sponges led to the discovery of
synthetic glycolipid KRN7000, a potent immunostimulating
agent that has exhibited bioactivity against a range of patho-
gens.[1]
Meiothermus taiwanensis ATCC BAA-400 is a Gram-neg-
ative bacteria that was isolated in Taiwan.[2] Biochemical
studies revealed the presence of abundant phosphoglycoli-
pid (PGL) and glycoglycerolipid (GL) molecules in the cell
membrane of M. taiwanesis. Such amphiphobic molecules
play an important role in maintaining the thermal stability
of the bacterial membrane, in particular in harsh environ-
ments.[3,4]
A few examples of phosphoglycolipids from
M. taiwanensis[5] and other T. thermophilus[6] have been in-
[a] B. Ghosh, Y.-H. Lai, Dr. T. K. Pradhan, Prof. Dr. K.-K. T. Mong
Department of Applied Chemistry
National Chiao Tung University (NCTU)
SB 533, Science building II
1001, Ta Hsueh Road, Hsinchu (Taiwan)
Fax : (+886)3-5723764
E-mail: tmong@mail.nctu.edu.tw
[b] Y.-Y. Shih, Prof. Dr. C.-H. Lin
Institute of Biological Chemistry
Academia Sinica
Room 802, 128, Academia Road Sec. 2
Nankang, Taipei 115 (Taiwan)
E-mail: chunhung@gate.sinica.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300933.
Scheme 1. Structure of the glycoglycerolipid isolate from Meiothermus
taiwanensis ATCC BAA-400.
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acids are present. Owing to the high heterogeneity of the
lipids in the glycoglycerolipids, the isolation of homogene-
ous samples from the natural bacterial source is almost im-
possible. Accordingly, chemical synthesis provides a practical
entry to pure glycoglycerolipid samples for research studies.
Over the past decade, numerous publications concerning
the synthesis of glycolipids have been reported.[5–9] The
length of the synthetic route depended on the complexity of
the carbohydrate and algycone components. If an oligosac-
charide fragment was present, additional protecting-group
manipulations were required for stereochemical control of
the glycosidic-bond formation and post-glycosylation modifi-
cation, which affected the overall yields of the synthe-
ses.[7b,8,9] In 2007, Wu and co-workers reported a one-pot
synthesis of the fully protected tetrasaccharide core of the
glycoglycerolipids of M. taiwanensis,[10] although the stereo-
chemical control in this work was moderate and the total
synthesis of the complete glycoglycerolipid molecule was
not accomplished. Herein, we report the first total synthesis
of a glycoglycerolipid from M. taiwanensis, as well as its
truncated structural analogues. Furthermore, the immuno-
logical properties of these molecules will be discussed.
charide 3, were also prepared, which contained one and no
palmitic acid chains, respectively.
Before laying out a synthetic plan, we considered some
potential issues in the synthesis of the target glycoglyceroli-
pids. The targets contain two 1,2-cis a-glycosidic linkages,
one connecting the non-reducing-end galactosyl residues
and the other connecting the reducing-end glucoside unit to
the sn-glycerol, and their formation is generally thought to
be challenging. Although several a-selective glycosylation
methods have been developed, most of them invoked the
use of specific protecting groups, which required additional
synthetic steps for their installation and removal.[11] Because
we aimed to develop a shorter synthetic scheme, we consid-
ered that DMF-modulated glycosylation may be useful for
the construction of the a-glycosidic bonds in this target com-
pound because this method employs DMF as a stereodirect-
ing agent.[12]
In general, racemization of the C2 chiral center of sn-glyc-
erol occurs frequently in the synthesis of glycoglycerolipids.
Such a side reaction is attributed to the migration of hy-
droxy protecting functions in sn-glycerol.[7a,10,13] We ad-
dressed this migration issue by protecting the sn-glycerol
moiety with a cyclohexylidene acetal group, which is known
to resist migration.[8a,14] The challenge facing the total syn-
thesis of glycoglycerolipids is the long synthetic route for
the assembly of the oligosaccharide component and post-
glycosylation modification. To simplify the assembly of the
tetrasaccharide core, the low-concentration one-pot glycosy-
lation method is employed.[15]
Results and Discussion
General Considerations
We chose glycoglycerolipid 1, which contained three palmit-
ic acid chains, as our target (Scheme 2). During the course
of the synthesis, two truncated structural analogues, namely
2’-palmitamido tetrasaccharide 2 and 2’-acetamido tetrasac-
Based on a consideration of these factors, a retrosynthetic
analysis of the glycoglycerolipid target was proposed
Scheme 2. Retrosynthetic analysis of a selected glycoglycerolipid of Meiothermus taiwanensis (1) and its truncated structural derivatives (2 and 3), build-
ing blocks (5–11), and fully protected tetrasaccharide core (4). Bn=benzyl, Tol=tolyl, Ac=acetyl.
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(Scheme 2). The target compounds (1–3) would be obtained
from a fully protected tetrasaccharide core (4). Disconnec-
tion of compound 4 at the b-glycosidic junctions would
afford three glycosyl building blocks, namely a-Gal-(1!6)-
Gal disaccharide thioglycoside 5, 2-azido-2-deoxy-thiogalac-
toside (GalN3) 6, and a-glucosyl glycerol building block 7.
Disaccharide building block 5 would be prepared from thio-
galactosides 8 and 9 and glucosyl building block 7 would be
prepared from thioglucoside 10 and sn-glycerol aglycon 11.
The GalN3 thioglycoside (6) was proposed to be synthesized
from known per-O-acetyl galactal.[16] Notably, no participat-
ing protecting groups would be present on these glycosyl
units, which would facilitate the post-glycosylation-modifica-
tion and global-deprotection steps.
Glycosyl building blocks 6 and 8–10 contained a thioacetal
anomeric leaving group, which is known to be stable under
a diverse range of reaction conditions.[17] Owing to the pres-
ence of an ester group in glycoglycerolipid 1, the thioglyco-
syl building blocks for the assembly of tetrasaccharide 4 did
not contain any ester-type protecting groups. If such func-
tions had been present, they would have had to be modified
before the introduction of the fatty acid component. To
avoid this redundant process, non-participation thioglycosyl
building blocks 5 and 6 were employed for the formation of
the 1,2-trans b-glycosidic bond through the low-concentra-
tion glycosylation (LCG) method.[15]
Preparation of Glycosyl Building Blocks 5–7
Our synthesis commenced with the preparation of the a-
Gal-(1!6)-Gal disaccharide building block (5). Two syn-
thetic routes were examined from thiogalactoside building
blocks 8, 9, and 13; these building blocks were readily pre-
pared from a known thiogalactoside (12) by employing liter-
ature procedures (Scheme 3a).[15b] In the first attempt, per-
O-benzyl-protected thiogalactoside donor 13 was coupled
with thiogalactoside 9 through a DMF-modulated glycosyla-
tion method.[12] The expected disaccharide (5) was obtained
in 72% yield, but only in a moderate 3:1 a/b anomeric ratio
(Scheme 3b). In the second attempt, 4,6-O-benzylidene-
acetal-protected thiogalactoside 8 was employed as the
donor because it has been used to give higher a-selectivities
for glycosylation reactions in a modulated-glycosylation con-
text. Pleasingly, the desired a-anomer of disaccharide 14
was produced in excellent (>20:1) a/b ratio and in 60%
yield (Scheme 3c). The a-configuration of compound 14 was
Scheme 3. a) Preparation of thiogalactoside building blocks 8, 9, and 13.
b) Preparation of disaccharide building block 5 from a glycosylation reac-
tion between compounds 9 and 13 by using a DMF-modulated glycosyla-
tion method. c) Preparation of disaccharide building block 5 from com-
pounds 9 and 8. d) Preparation of 2-azido-2-deoxy-thiogalactoside build-
ing block 6 from a known galactal. Bz=benzoyl, Nap=2-napthylmethyl.
confirmed by the chemical shift of the anomeric proton at
3
d=4.77 ppm and the J
N
The subsequent transformation of compound 14 into per-O-
benzyl-protected disaccharide 5 was readily accomplished by
1) removal of the acetal function under acidic conditions
and 2) standard benzylation.
With disaccharide building block 5 in hand, we prepared
2-azido-2-deoxy thiogalactoside building block 6. Previous
studies have shown that non-participating 2-azido-2-deoxy-
thioglycosides could be used for the formation of b-glyco-
sides under LCG conditions.[19] Thus, a known galactal was
converted into 2-azido-2-deoxy-thiogalactoside intermediate
15 according to literature procedures.[16,20] The treatment of
compound 15 with BH3·THF and TMSOTf at 08C furnished
the desired building block (6) in 85% yield (Scheme 3d).[21]
In addition, the C6 hydroxy group of compound 6 was pro-
tected with a benzoyl group to give fully protected 2-azido-
2-deoxy-thiogalactoside 16, which would be used as a model
donor for evaluation of the b-selectivity of the LCG
method.
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The synthesis of 3-O-(a-glucosyl)-sn-glycerol 7 began with
ACTHNGUTERNNUG
coupling constant (3J(H,H)=2.8 Hz).[18] With the desired
known thioglucoside 17. Thus, thioglucoside 17 underwent
deacetylation and alkylation with naphthylmethylene bro-
mide (NAP-Br) to furnish 2-O-NAP-protected thioglucoside
10 in 85% yield (Scheme 4). Subsequently the coupling of
anomer of compound 20 in hand, the final 3-O-(a-glucosyl)-
sn-glycerol acceptor (7) was produced by removal of the
NAP protecting group with 2,3-dichloro-5,6-dicyano-qui-
none (DDQ).[22]
Low-Concentration One-Pot Synthesis of the
Tetrasaccharide Core
With glycosyl building blocks 5–7 in hand, we attempted the
assembly of the protected tetrasaccharide (4). Because we
applied the one-pot glycosylation method under low-concen-
tration conditions, it was necessary to assess the selectivity
for each of the b-glycosidic-bond-formation steps.[15b]
For the formation of the reducing-end b-GalN3-(1!2)-
Glc disaccharide, model 2-azido-2-deoxy-thiogalactosyl
donor 16 and glucoside acceptor 19 were employed. Accept-
or 19 was obtained from protected glucoside 18, which, in
turn, was prepared from chlorohexanol and thioglucoside 17
(Scheme 5a). The glycosylation of glucoside acceptor 19
with thioglycoside donor 16 furnished the desired disacchar-
ide (21) in 69% yield with an excellent a/b anomeric ratio
(1:13, Scheme 5b).[15a] The b-configuration of the desired
anomer of compound 21 was supported by the chemical
Scheme 4. Preparation of the reducing-end a-glucosyl building block (7).
compound 10 with cyclohexylidene-protected glycerol 11
produced fully protected 3-O-(a-glucosyl)-sn-glycerol 20.
The construction of the a-glycosidic bond in compound 20
deserves some discussion. Previous glycosylation reactions
of the sn-glycerol acceptor resulted in 1:1 and 3.2:1 mixtures
of the a/b-glucosides.[8,10] Our initial attempts at preparing
glucoside 20 resulted in a modest (2:1) a/b anomeric mix-
ture, even under standard DMF-modulated glycosylation
conditions (Table 1, entry 1).[12] Thus, optimization of the re-
action conditions was required to improve the a-selectivity
of the reaction (Table 1).
shift of the anomeric carbon atom at d=101.3 ppm and by
1
the coupling constant of J
N
To assess the selectivity in the construction of the b-glyco-
sidic linkage in the b-Gal-(1!6)-GalN3 unit, model disac-
charide thioglycoside 14 was coupled with 2-azido-2-deoxy
b-thiogalactoside 6 under the LCG conditions. To our de-
light, the desired b-anomer of trisaccharide thioglycoside 22
was produced in a high yield (74%) with a >1:10 a/b ratio
(Scheme 5b).
Having confirmed the b-selectivity of the glycosylation re-
action under the LCG conditions, we attempted the one-pot
synthesis of tetrasaccharide 4 (Scheme 6). Thus, a-Gal-(1!
6)-Gal disaccharide thioglycoside 5 (0.092 mm) was coupled
with the 2-azido-2-deoxy-a-thiogalactoside 6 (0.082 mm) in
CH2Cl2/MeCN/EtCN (1:2:1v/v/v) at ꢀ608C to afford the de-
sired a-Gal-(1!6)-Gal-b-(1!6)-GalN3 trisaccharide thiogly-
coside. Without isolation, the trisaccharide thioglycoside was
activated by using NIS and TMSOTf and reacted with 3-O-
(a-glucosyl)-sn-glycerol 7 to furnish the desired tetrasacchar-
ide (4). After standard chromatographic purification, com-
pound 4 was isolated as a single anomer in high 62% yield.
To prepare sufficient material for post-glycosylation modifi-
cation and global deprotection, the one-pot synthesis of
compound 4 was repeated on the gram scale.
Notably, the b-anomer of 2-azido-2-deoxy thiogalactoside
6 was initially employed in the low-concentration one-pot
glycosylation reaction, but the second glycosylation step did
not go to completion, even after reacting overnight. Thus, it
appeared that the trisaccharide intermediate that was de-
rived from the b-anomer of compound 6 was less reactive
than that derived from its a-anomer counterpart. Accord-
ingly, we used the a-anomer of compound 6 for the one-pot
reaction.
Table 1. Optimization of the synthesis of a-glucosyl sn-glycerol (20).
Entry[a] Solvent t [h] DMF [equiv] T [8C]
Yield [%] a/b ratio[a]
1
2
3
4
5
6
CH2Cl2 24
CH2Cl2 42
CH2Cl2 24
CH2Cl2 48
CH2Cl2 36 16
Et2O 30
4
8
6
6
ꢀ10
75
65
58
68
63
60
2:1
3:1
5:1
7.3:1
8.2:1
4:1
ꢀ10
ꢀ30
ꢀ25/ꢀ20
ꢀ25/ꢀ20
ꢀ20
0
[a] The a/b ratio was determined by HPLC analysis of the crude product
mixture.
During the optimization process, different reaction condi-
tions were examined, including 1) various reaction tempera-
tures, 2) various solvents, and 3) employing a stoichiometric
amount of DMF (Table 1). The best result entailed the use
of 16 equivalents of DMF and a lower reaction temperature
of ꢀ25/ꢀ208C, thereby affording the target glycoside (20) as
an 8.2:1 a/b mixture. Notably, at low reaction temperatures
(<ꢀ208C), longer (1.5 to 2 days) reaction times were
needed (Table 1, entry 5). The a-configuration of the desired
anomer (20) was confirmed by the chemical shift of the
anomeric proton at d=4.94 ppm and by the corresponding
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Post-Glycosylation Modification
With sufficient quantities of protected tetrasaccharide 4 in
hand, the stage was set to conclude the synthesis of glycogly-
cerolipid 1. Thus, the treatment of compound 4 with tri-
fluoroacetic acid (TFA), followed by reduction with LiAlH4,
produced tetrasaccharide intermediate 23 (Scheme 7a). No-
Scheme 5. Evaluation of the low-concentration glycosylation method for
the construction of the b-glycosidic linkages in the target tetrasaccharide
(4).
Scheme 7. Post-glycosylation modification of protected tetrasaccharide
core 4 to afford target compounds 1–3.
tably, the removal of the acetal group in compound 4 with
TFA was carefully monitored to prevent cleavage of the gly-
cosidic linkage. Upon chromatographic purification, com-
pound 23 was functionalized by coupling with palmitic acid
by using ethyl-(dimethylaminopropyl) carbodiimide (EDC)
and dimethylaminopyridine (DMAP) to obtain fully protect-
ed glycoglycerolipid 24 in good yield (68%, Scheme 7b).[23]
Subsequent hydrogenolysis of compound 24 with 10%
Pd(OH)2 (Degussa-type) completed the total synthesis of
Scheme 6. One-pot synthesis of protected tetrasaccharide glycoside
under low-concentration glycosylation conditions.
4
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the target glycoglycerolipid (1). In summary, natural glyco-
glycerolipid 1 was prepared in ten linear steps from mono-
saccharide building blocks 6, 8, 9, and 10, sn-glycerol 11, and
palmitic acid in an overall 6% yield.
THP-1 cells that were treated with the individual tetrasac-
charide compounds (1, 2, or 3) did not induce any obvious
change in the secretion levels of IL-6, IL-1b, or TNF-a cyto-
kines, thus suggesting that these compounds had no immu-
nostimulation capacity (Figure 2a–c, left). In terms of the
suppression of LPS-induced cytokine production, 2’-palmita-
mido tetrasaccharide 2 exhibited a higher capacity for the
suppression of the production of IL-6, IL-1b, and TNF-a cy-
tokines, as compared to THP-1 cells that were treated with
LPS alone (Figure 2a–c, right).
The synthesis of truncated analogues 2’-palmitamido tet-
rasaccharide 2 and 2’-acetamido tetrasaccharide 3 required
the reduction of the azide group in protected tetrasaccharide
4 to afford an amine moiety, which was subsequently either
coupled with 1) palmitic acid to give protected 2’-palmitami-
do tetrasaccharide 25 or 2) acetic anhydride (Ac2O) to give
protected 2’-acetamido tetrasaccharide 26 (Scheme 7c). Re-
moval of the benzyl ether and cyclohexylidene acetal pro-
tecting groups in compounds 25 and 26 was achieved in one
pot by hydrogenolysis in formic-acid/MeOH (5% v/v) with
Pd(OH)2 as a catalyst. Truncated analogues 2 and 3 were
obtained in 69% and 72% yield, respectively.
Because the N-acetyl derivative of the natural glycogly-
cerolipid from M. taiwanensis had been reported, the
1H NMR spectrum of 2’-acetamido tetrasaccharide 3 was
compared with the literature data. The chemical shifts of the
anomeric protons of compound 3 at d=5.04 (H), 4.85 (H’’’),
4.46 (H’), and 4.33 ppm (H’’) fully matched with those re-
ported in the literature (Figure 1).[3] From the assignment of
the 1H NMR spectrum of compound 3, assignment of the
1
anomeric protons in the respective H NMR spectra of gly-
coglycerolipid 1 and 2’-palmitamido tetrasaccharide 2 was
performed.
1
Figure 1. Selected H NMR spectrum of 2’-acetamido tetrasaccharide 3.
Preliminary Immunological Studies
Tetrasaccharide compounds 1–3 contained different num-
bers of palmitic acids; thus, we were intrigued to investigate
how the number of the acyl chains affected the inflammato-
ry activity of immune cells.[24] To this end, a series of immu-
nological experiments were performed to examine the im-
munomodulating activities of these molecules. THP-1 cells
were treated with compound 1, 2, or 3 in the presence or ab-
sence of lipopolysaccharides (LPS, 1.0 mgmLꢀ1) and incubat-
ed for 24 h. The levels of IL-6, IL-1b, and TNF-a production
in the cell-free supernatant were measured by an enzyme-
linked immunosorbent assay (ELISA; R&D systems, Min-
neapolis, MN).[25,26]
Figure 2. Tetrasaccharides 1–3 exhibited negative regulation on the pro-
duction of inflammatory cytokines IL-6. THP-1 cells were stimulated
with or without LPS, followed by incubation with tripalmitoyl glycogly-
cerolipid 1, 2’-palmitamido tetrasaccharide 2, or 2’-acetamido tetrasac-
charide 3 (50 or 100 mgmLꢀ1) for 24 h. The culture media were collected
and subjected to an ELISA assay to detect the expression level of IL-6.
The level of IL 6 in the THP-1 cells without treatment of any compound
(control) is referred to as one aliquot of relative expression. Quantitative
results are presented as the mean ꢁ SEM of triplicate measurements
from three independent experiments and were analyzed by Student’s t-
tests.
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Chun-Hung Lin, Kwok-Kong Tony Mong et al.
1H), 3.95–3.87 (m, 3H), 3.83–3.77 (m, 2H), 3.69 (s, 1H), 3.65 (m, 1H),
3.59 (dd, J=9.2, 2 Hz, 1H), 3.34 (dd, J=12.0 Hz, 4.0 Hz, 1H), 2.25 ppm
(s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=139.2, 139.0, 138.8, 138.7,
138.6, 138.3, 137.1, 131.3, 131.0, 130.0, 129.2, 128.9, 128.79, 128.74, 128.70,
128.5, 128.4, 128.24, 128.23, 128.1, 127.9, 127.8, 126.7, 101.4 (benzylidene-
Some dose-dependence was observed for the suppression
of IL-6 and IL-1b production. In particular, treatment with
2’-palmitamido tetrasaccharide 2 (100 mgmLꢀ1) inhibited the
secretion of IL-6 to an almost-basal level. A similar suppres-
sion pattern of cytokine production was observed when
a second batch of the tetrasaccharide compound (2) was ex-
amined, thus validating the suppression capacity of com-
pound 2. In contrast, the treatment of THP-1 cells with
intact glycoglycerolipid 1 and 2’-acetamido tetrasaccharide 3
decreased the LPS-induced production of IL-6, but had no
observable effect on the secretions of IL-1b or TNF-a.
Taken together, these preliminary results suggest that the
tetrasaccharide with a single palmitoyl chain (2) produces
the best anti-inflammatory effect on LPS-induced cytokine
production.
CH), 98.5 (JACTHNUTRGENN(GU C,H)=171 Hz; C-1’), 87.4 (JACHUTNGTRENN(UNG C,H)=152 Hz; C-1), 84.6,
77.8, 77.6, 76.8, 76.1, 75.8, 74.8, 74.7, 74.4, 74.3, 73.5, 72.2, 69.9, 68.2, 62.9,
21.5 ppm (CH3); HRMS (ESI): m/z calcd for C61H62O10SNa: 1009.3956;
found: 1009.3928 [M+Na]+.
TFA (12 mL, 105 mmol) was added to a solution of disaccharide 14
(3.2 g, 3.2 mmol) in MeCN (10 mL) at 08C and the reaction was stirred
for 5 h at RT. After completion of the reaction (by TLC), the mixture
was quenched with NaHCO3, extracted with EtOAc (3ꢂ20 mL), and
washed with water (3ꢂ15 mL). The organic phase was concentrated as
a yellow oil (2.9 g, quantitative yield) and then treated with dry DMF
(30 mL) under a N2 atmosphere and NaH (60% in oil suspension,
439 mg, 10.9 mmol) was added cautiously under an ice bath. Subsequent-
ly, benzyl bromide (0.92 mL, 7.7 mmol) was added and the mixture was
stirred for 2 h. The desired product was extracted with EtOAc (3ꢂ
30 mL), washed with H2O (3ꢂ20 mL), dried (over MgSO4), filtered, and,
concentrated for flash chromatography on silica gel (n-hexane/EtOAc,
4:1). The desired product (5, 3.6 g) was isolated in 86% yield as a white
foam.
Conclusions
Rf =0.55 (n-hexane/EtOAc, 4:1); ½aꢂ2D0 =+22.6 (c=3.02, CHCl3);1H NMR
(400 MHz, CDCl3): d=7.48 (d, J=8.0 Hz, 2H; ArH), 7.42–7.25 (m, 35H;
ArH), 6.99–6.97 (d, J=8.0 Hz, 2H; ArH), 4.93 (dd, J=11.6, 4.8 Hz, 2H),
4.80–4.69 (m, 6H), 4.65–4.57 (m, 5H), 4.47 (d, J=12.0 Hz, 1H), 4.39 (d,
J=12.0 Hz, 1H), 4.04 (dd, J=8.0, 4.0 Hz, 1H), 3.99–3.84 (m, 7H), 3.67
(t, J=6 Hz, 1H), 3.60 (dd, J=9.2, 2.8 Hz, 1H), 3.58–3.54 (m, 3H),
2.26 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=138.79, 138.74,
138.69, 138.6, 138.6, 138.4, 138.3, 138.0, 137.1, 132.2, 130.1, 129.5, 128.36,
128.31, 128.2, 128.16, 128.13, 127.9, 127.8, 127.7, 127.67, 127.61, 127.59,
127.53, 127.5, 127.35, 127.31, 98.2 (C-1’), 87.7 (C-1), 84.1, 79.1, 77.2, 76.8,
76.4, 75.6, 74.8, 74.3, 73.9, 73.6, 73.5, 72.79, 72.75, 69.2, 68.7, 67.1,
21.1 ppm (CH3); HRMS (ESI): m/z calcd for C68H70O10SNa: 1101.4582;
found: 1101.4571 [M+Na]+.
We have reported the first total synthesis of a glyceroglycoli-
pid isolate from M. taiwanensis and its truncated structural
analogues. A short synthetic scheme was developed, which
included a low-concentration one-pot glycosylation reaction.
Our synthesis employed the “nitrile solvent effect” and the
modulating properties of DMF to control the stereochemis-
try in the formation of the b- and a-glycosidic bonds. Such
tactics simplified the post-glycosylation-modification and
global-deprotection steps because no specialized protecting
groups were involved. Preliminary immunological studies of
these compounds revealed that a truncated glyceroglycolipid
analogue with a single palmitoyl chain suppressed LPS-
stimulated cytokine production.
Synthesis of 3-O-[3,4,6-Tri-O-benzyl-2-O-(2-naphthylmethyl)-a-d-gluco
pyranosyl]-1,2-O-cyclohexylidene-sn-glycerol (20)
To a solution of thioglucoside donor 10 (100 mg, 0.14 mmol), DMF
(182 mL, 2.3 mmol), and 4 ꢁ molecular sieves (AW300, 300 mg) in
CH2Cl2 (2.6 mL) were added NIS (38 mg, 0.17 mmol) and TMSOTf
(30 mL, 1.13 mmol) and the mixture was stirred for 45 min, followed by
the addition of 1,2-O-cyclohexylidene-protected sn-glycerol 11 (36 mg,
0.21 mmol). The reaction mixture was stirred at ꢀ258C for 12 h and at
ꢀ208C for 24 h. After completion of the reaction, a few drops of Et3N,
a saturated aqueous solution of NaHCO3, and a few pieces of Na2S2O3(s)
were added to the mixture, followed by vigorous stirring at RT until the
color of the reacting solution turned pale yellow. Then, the mixture was
filtered (through celite) to obtain the organic fraction, which was concen-
trated for flash chromatography on silica gel (n-hexane/EtOAc, 4:1). The
a-anomer of glucoside 20 (80 mg, 0.08 mmol) was isolated as a colorless
syrup in 63% yield.
Rf =0.35 (n-hexane/EtOAc, 4:1); ½aꢂ2D0 =+33.10 (c=0.58, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.85–7.73 (m, 4H; ArH), 7.46–7.44 (m,
3H; ArH), 7.33–7.13 (m, 15H; ArH), 5.01 (d, J=10.8 Hz, 1H), 4.91–4.81
(m, 5H), 4.58 (d, J=12.4 Hz, 1H), 4.46 (t, J=10.8 Hz, 2H), 4.37 (t, J=
5.6 Hz, 1H), 4.06 (t, J=8.0 Hz, 1H), 3.98 (t, J=9.2 Hz, 1H), 3.77–3.58
(m, 8H), 1.62–1.58 (m, 8H; 4ꢂCH2), 1.26 ppm (br s, 2H; CH2);
13C NMR (100 MHz, CDCl3): d=139.3, 138.7, 138.4, 136.1, 133.6, 133.5,
128.81, 128.77, 128.70, 128.35, 128.31, 128.26, 128.1, 128.0, 127.3, 126.6,
126.41, 126.39, 110.5 (quaternary-C), 97.7 (C-1), 82.3, 80.3, 78.1, 76.1,
75.5, 74.8, 73.9, 73.5, 70.8, 69.5, 68.9, 67.1, 36.9 (CH2), 35.4 (CH2), 25.6
(CH2), 24.5 (CH2), 24.3 ppm (CH2); HRMS (ESI): m/z calcd for
C47H52O8Na: 767.3554; found: 767.3560 [M+Na]+.
Experimental Section
Synthesis of p-Methylphenyl 6-O-(2,3,4,6-tetra-O-benzyl-a-d-
galactopyranosyl)-2,3,4-tri-O-benzyl-1-thio-b-d-galactopyranoside (5)
from Compounds 8 and 9
A
solution of galactoside (Gal) thioglycosyl donor 8 (626 mg,
1.13 mmol), DMF (0.35 mL, 4.50 mmol), and 4 ꢁ molecular sieves
(AW300, 1.5 g) in CH2Cl2 (15 mL) was stirred at RT for 10 min, then
cooled to ꢀ108C for an additional 30 min. N-Iodosuccinimide (NIS,
250 mg, 1.13 mmol) and trimethylsilyl trifluoromethanesulfonate
(TMSOTf, 136 mL, 0.75 mmol) were added and the mixture was stirred
for 30 min. When the activation of compound 8 was complete (by TLC),
Gal acceptor 9 (417 mg, 0.75 mmol) was added and the mixture was
stirred for 2 h. After completion of the glycosylation reaction (by TLC),
the mixture was quenched with NEt3 (0.3 mL) at ꢀ108C. A small volume
of a saturated aqueous solution of NaHCO3 and a small lump of solid
Na2S2O3 were added and the mixture was stirred vigorously at RT until
the deep-red color of the solution changed to pale yellow. The resultant
mixture was dried over MgSO4, filtered, and concentrated for flash chro-
matography on silica gel (n-hexane/EtOAc, 5:1 to 4:1). The desired a-
anomer product (14, 420 mg, 0.36 mmol) was isolated in 60% yield as
a white foam.
Rf =0.47 (n-hexane/EtOAc, 7:3); ½aꢂ2D7 =+42.6 (c=1.04, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.50–7.48 (m, 2H; ArH), 7.42–7.22 (m, 30H;
ArH), 6.97 (d, J=8.0 Hz, 2H; ArH), 5.41 (s, 1H; benzylidene-CH), 4.92
(d, J=11.6 Hz, 1H), 4.84 (d, J=11.6 Hz, 1H), 4.80–4.57 (m, 10H), 4.15
(d, J=12.8 Hz, 1H), 4.07 (d, J=2.8 Hz, 1H), 4.03 (dd, J=13.2, 2.8 Hz,
Chem. Asian J. 2013, 8, 3191 – 3199
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Chun-Hung Lin, Kwok-Kong Tony Mong et al.
Synthesis of 3-O-[2,3,4,6-Tetra-O-benzyl-a-d-galactopyranosyl-(1!6)-
2,3,4-tri-O-benzyl-b-d-galactopyranosyl-(1!6)-2-azido-3,4-di-O-benzyl-2-
deoxy-b-d-galactopyranosyl-(1!2)-3,4,6-tri-O-benzyl-a-d-
glucopyranosyl]-1,2-O-cyclohexylidene-sn-glycerol (4)
2H; C=OCH2, signal partly overlapped with residue H2O), 1.54 (br s>,
4H; 2ꢂCH2) 1.30–1.23 (m, 74H; 37ꢂCH2), 0.88 ppm (t, J=5.2 Hz, 9H;
3ꢂterminal CH3); 13C NMR (100 MHz, CDCl3): d=173.9 (C=O), 173.6
(C=O), 172.9 (C=O), 138.9, 138.78, 138.75, 138.6, 138.57, 138.4, 138.2,
138.13, 137.9, 137.8, 128.4, 128.3, 128.24, 128.20, 128.1, 128.0, 127.9,
127.85, 127.81, 127.78, 127.71, 127.6, 127.59, 127.53, 127.4, 127.37, 127.34,
127.28, 127.20, 103.4, 100.4, 99.6, 98.9, 82.1, 81.1, 79.1, 79.0, 77.7, 76.1,
74.9, 74.89, 74.84, 74.7, 74.5, 74.2, 73.5, 73.4, 72.9, 72.7, 72.6, 72.5, 72.1,
71.9, 70.4, 69.8, 69.5, 68.7, 68.5, 67.1, 66.9, 66.5, 62.9, 55.5, 36.6, 34.3, 34.1,
31.9, 29.7, 29.5, 29.5, 29.3, 29.1, 25.4, 24.9, 24.8, 22.7, 14.1 ppm. Global de-
protection of compound 24 was performed to give the target glycoglycer-
olipid (1) for mass spectrometry analysis.
A suspension of a-Gal-(1!6)-Gal disaccharide thioglycoside 5 (900 mg,
0.912 mmol), the a-anomer of GalN3 thioglycoside
6
(402 mg,
0.820 mmol), and 4 ꢁ molecular sieves (AW300, 12 g) in CH2Cl2/MeCN/
EtCN (44 mL, 1:2:1 v/v) was treated with NIS (206 mg, 0.912 mmol) and
TMSOTf (82 mL, 0.456 mmol). Then, the reaction mixture was stirred for
1.5 h. Glucoside acceptor
7 (445 mg, 0.912 mmol), NIS (206 mg,
0.912 mmol), and TMSOTf (82 mL, 0.456 mmol) were added to the reac-
tion mixture. After completion of the one-pot reactions, a few drops of
Et3N, a saturated aqueous solution of NaHCO3, and a few pieces of
Na2S2O3(s) were added to the mixture, followed by stirring at RT until
the color of the reaction mixture turned from red to pale yellow. The re-
sulting solution mixture was filtered (through celite) to obtain the organ-
ic fraction, which was concentrated and purified by flash chromatography
on silica gel (n-hexane/EtOAc, 17:3 to 4:1). Compound 4 (980 mg) was
afforded in 62% yield as a pale-yellow syrup.
Rf =0.3 (n-hexane/EtOAc, 2:1); ½aꢂ2D0 =+30.40 (c=0.28, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.22–6.94 (m, 60H; ArH), 4.92 (d, J=
10.4 Hz, 1H), 4.86–4.79 (m, 3H), 4.73–4.64 (m, 9H), 4.60–4.45 (m, 8H),
4.41–4.33 (m, 5H), 4.28–4.23 (m, 2H), 4.15 (dd, J=6, 4 Hz, 1H), 3.96–
3.88 (m, 5H), 3.83 (dd, J=10, 2.8 Hz, 2H), 3.78–3.72 (m, 4H), 3.70–3.59
(m, 5H), 3.57–3.39 (m, 9H), 3.23 (t, J=6.0 Hz, 1H), 3.08 (dd, J=10.4,
2.8 Hz, 1H), 1.57–1.46 ppm (m, 10H; 5ꢂCH2); 13C NMR (100 MHz,
CDCl3): d=139.35, 139.33, 139.2, 139.07, 139.05, 139.00, 138.9, 138.7,
138.4, 138.2, 138.0, 128.87, 128.84, 128.79, 128.76, 128.73, 128.70, 128.69,
128.66, 128.65, 128.60, 128.59, 128.57, 128.55, 128.4, 128.28, 128.23, 128.21,
128.18, 128.12, 128.06, 128.03, 128.0, 127.98, 127.94, 127.88, 127.85, 127.80,
127.7, 110.1 (quaternary-C), 104.0, 103.2, 99.4, 99.3, 82.5, 81.9, 81.1, 79.8,
79.5, 79.1, 78.7, 76.6, 75.8, 75.3,75.27, 75.21, 75.07, 75.05, 74.9, 74.1, 74.08,
74.04, 74.02, 73.8, 73.7, 73.1, 73.0, 72.6, 71.9, 70.7, 70.0, 69.2, 68.9, 68.8,
67.2, 67.0, 66.9, 63.6, 36.6 (CH2), 35.5 (CH2), 25.6 (CH2), 24.5 (CH2),
24.3 ppm (CH2); HRMS (ESI): m/z calcd for C117H127N3O22H: 1926.8984;
found: 1926.8937 [M+H]+.
Synthesis of 3-O-[a-d-galactopyranosyl-(1!6)-b-d-galactopyranosyl-(1!
6)-2-palmitamido-2-deoxy-b-d-galactopyranosyl-(1!2)-a-d-
glucopyranosyl]-1,2-di-O-palmitoyl-sn-glycerol (1)
Fully protected tetrasaccharide 24 (180 mg, 0.07 mmol) was dissolved in
EtOAc/MeOH (8 mL, 1:1 v/v) at RT. Pd/C (68 mg, Degussa type) was
added to the solution, followed by stirring at RT for 12 h under a H2 at-
mosphere (1 atm). Then, the reaction mixture was filtered (through
celite) and the filtrate was concentrated for chromatography on silica gel
(CH2Cl2/MeOH, 9:1 to 1:1) to afford target glycoglycerolipid 1 (70 mg,
76% yield) as a white amorphous powder.
Rf =0.17 (CH2Cl2/MeOH, 2:1); ½aꢂ2D0 =+20.57 (c=0.15, CHCl3); 1H NMR
(400 MHz, CDCl3/CD3OD 10:1): d=5.16 (d, J=5.2 Hz, 1H; NHC=O),
4.90 (d, J=2.4 Hz, 1H; H-1), 4.83 (d, J=2.4 Hz, 1H; H-1’’’), 4.58 (d, J=
8.4 Hz, 1H; H-1’), 4.36 (br s, 1H; H-1’’, signal partly covered by residual
H2O), 4.25 (br s, 1H), 4.12 (dd, J=12.0, 6.8 Hz, 1H), 3.91–3.36 (m, 25H),
3.26 (s, 2H), 2.23 (t, J=7.6 Hz, 4H; 2ꢂCH2), 2.17 (t, J=8 Hz, 2H; CH2),
1.59–1.46 (m, 6H; 3ꢂCH2), 1.33–1.18 (m, 72H; 36ꢂCH2), 0.81–0.77 ppm
(m, 9H; 3ꢂCH3); HRMS (ESI): m/z calcd for C75H140NO25: 1454.9709;
found: 1454.9695 [M+H]+. The assignment of the anomeric protons of
compound 1 was based on NMR data that were obtained for the N-
acetyl derivative of the natural glycoglycerolipid isolate of M. taiwanen-
sis.[3]
Synthesis of 3-O-[2,3,4,6-Tetra-O-benzyl-a-d-galactopyranosyl-(1!6)-
2,3,4-tri-O-benzyl-b-d-galactopyranosyl-(1!6)-2-palmitamido-3,4-di-O-
benzyl-2-deoxy-b-d-galactopyranosyl-(1!2)-3,4,6-tri-O-benzyl-a-d-
glucopyranosyl]-1,2-di-O-palmitoyl-sn-glycerol (24)
Acknowledgements
We thank the National Science Council of Taiwan (NSC 99-2113M-009-
009) and the Center for Interdisciplinary Science of National Chiao Tung
University for financial support. We also express our thanks to Mr. Sha-
heen Mulani for the revision of the Supporting Information.
A solution of fully protected tetrasaccharide 4 (580 mg, 0.290 mmol) in
CH2Cl2/MeOH (14 mL, 5:1 v/v) was treated with TFA (6.0 mL). The mix-
ture was stirred from 08C to RT for 3 h and quenched with a saturated
aqueous solution of NaHCO3 and CH2Cl2. The organic phase was collect-
ed, washed with water, dried (MgSO4), and concentrated for chromato-
graphic purification on silica gel (n-hexane/EtOAc, 3:2) to give the crude
product (about 90% yield) for azide reduction. Then, the crude product
(485 mg, 0.262 mmol) was dissolved in THF (10 mL) and lithium alumi-
num hydride (LAH, 100 mg, 2.62 mmol) was added at 08C under a N2 at-
mosphere. After stirring for 3 h, equal volumes of EtOAc and H2O were
sequentially added to the mixture to quench any excess LAH. The organ-
ic phase was separated and concentrated for chromatographic purifica-
tion on silica gel (n-hexane/EtOAc 3:7, with 1% Et3N) to afford the ex-
pected product (450 mg, >90% yield). Then, the product from the pre-
ceding step (250 mg, 0.981 mmol) was dissolved in CH2Cl2 (10 mL) and
DMAP (11 mg, 0.09 mmol), EDC (112 mg, 0.588 mmol), and palmitic
acid (112 mg, 0.441 mmol) were added. The resulting mixture was stirred
for 12 h and diluted with CH2Cl2. The resulting organic phase was
washed with a saturated aqueous solution of NaHCO3, H2O, and brine,
dried over MgSO4, filtered, and concentrated for flash chromatography
on silica gel (n-hexane/EtOAc, 4:1) to afford fully protected glycoglycer-
olipid 24 (224 mg, 68% yield).
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Received: July 15, 2013
Published online: September 12, 2013
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