Synthesis of α-S-galactosylceramides with a truncated sphingoid chain

Article abstract of DOI:10.1016/j.tetlet.2011.07.103

We present here a convenient synthesis of the truncated sphingoid iodide 15 from d-galactose, in which Mitsunobu reaction was utilized to retrieve successfully an unwanted intermediate, thereby increasing greatly the synthetic efficiency. Subsequent react

Full text of DOI:10.1016/j.tetlet.2011.07.103

Tetrahedron Letters 52 (2011) 4971–4974
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Synthesis of
a-S-galactosylceramides with a truncated sphingoid chain
Xiangming Zhu a,b, , Ravindra T. Dere b, Junyan Jiang a
⇑
a College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China
b Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here a convenient synthesis of the truncated sphingoid iodide 15 from D-galactose, in which
Received 15 June 2011
Revised 12 July 2011
Accepted 22 July 2011
Available online 29 July 2011
Mitsunobu reaction was utilized to retrieve successfully an unwanted intermediate, thereby increasing
greatly the synthetic efficiency. Subsequent reaction of 15 with the pre-prepared -galactosyl thiol 16
led smoothly to the desired thioglycoside 17 in good yield, from which the catabolically stable thiogly-
coside analogs of OCH 4 and 22 were synthesized.
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a-Galactosylceramide
Thioglycoside
Glycosyl thiol
Immunostimulant
The CD1 family of antigen-presenting proteins is monomorphic
major histocompatibility complex (MHC) class I like glycoproteins
that present lipid-based antigens recognized by T cells from differ-
ent individuals and even across species.1 Of all CD1 family mem-
bers, only CD1d seems to have specialized in the presentation of
a limited set of glycolipids2 for recognition by natural killer T
(NKT) cells,3 the unique lymphocytes defined by their co-expres-
sion of the surface marker associated with NK cells along with a
T cell antigen receptor (TCR). Extensive studies have shown that
NKT cells are implicated in a broad range of diseases and are potent
regulatory T cells that have the capacity to either initiate or shut
down a wide variety of immune responses.3 Hence there has been
intense interest in understanding how NKT cells are stimulated by
a CD1d-glycolipid complex and the extent to which NKT cell
responses can be controlled.
interferon-c (IFN-c) and interleukin-2 (IL-2), causes an inflamma-
tory response, termed as T helper 1 (TH1) response. In contrast,
other cytokines that can be released by NKT cells include IL-4
and IL-10, and these results in an immunomodulatory or TH2
response. Release of TH1 cytokines is believed to be responsible
for the antitumor, antiviral, and antibacterial effects of KRN7000.
However, autoimmune diseases, such as multiple sclerosis, lupus,
rheumatoid arthritis and type 1 diabetes, are TH1-mediated. TH2
cytokines can antagonize the immunostimulatory properties of
TH1 cytokines, consequently, production of TH2 cytokines can ame-
liorate autoimmune diseases.
KRN7000 has thus been utilized in studies for the treatment of
many diseases including cancer, diabetes, malaria, and hepatitis B,
and in most cases, impressive activities have been observed.7 Nev-
ertheless, the efficacy of KRN7000 has been limited because it
stimulates production of a mixture of TH1 and TH2 cytokines,8
and these two types of cytokines are antagonistic to each other
as described above. In addition, it has been shown that repeated
administration of KRN7000 induces long-term NKT unresponsive-
ness in mice,9 suggesting that there are also limitations to the
use of KRN7000 as a therapeutic option.
Hence, many efforts have been devoted to synthesize KRN7000
analogs with the hope of developing novel lead compounds with
better cytokine-inducing selectivities and appropriate potency as
immunostimulatory agents.10,11 In this context, a remarkable case
is the truncated analog of KRN7000, termed OCH12 which is the
first described TH2-biased agonist of NKT cells and has been the
most studied agonist after KRN7000.13 Stimulation of NKT cells
with OCH (3) results in release of primarily TH2 cytokines, as such,
OCH was more efficacious than KRN7000 in animal models of the
above-mentioned TH1-mediated autoimmune diseases,14 such as
To date, the best known class of agonist ligands for NKT cells is
agelasphins 1 (Fig. 1),4 first isolated from a marine sponge for their
antitumor attributes.5 An unusual feature of agelasphins is their
a-anomeric configuration, unlike the ubiquitous b-glycosidic link-
ages in nearly all known natural glycolipids of normal mammalian
cells. Later, a slightly simplified analog KRN7000 (2) was synthe-
sized in a structure–activity study on these marine glycolipids
and chosen as the lead compound for further development.6
KRN7000 in the context of CD1d can bind the TCR with high affin-
ity, stimulating NKT cells to release a variety of cytokines in vitro
and in vivo. These cytokines are recognized subsequently by other
cells of the immune system and may have a widespread influence
on immune responses. One group of cytokines, including
⇑
Corresponding author. Tel.: +86 57982284379; fax: +86 57982282269.
E-mail address: Xiangming.Zhu@ucd.ie (X. Zhu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.103

4972
X. Zhu et al. / Tetrahedron Letters 52 (2011) 4971–4974
O
4 and 22 containing the truncated sphingoid chain of OCH with a
OH
HO
HO
O
OH
OH
HO
HO
OH
O
lipid
lipid
view to developing therapeutic analogs with shorter lipid chains.
Based on our previous work,17 a truncated sphingoid derivative
needs to be prepared in order to construct the target molecules 4
and 22. For this purpose, Schmidt’s strategy21 for the synthesis of
phytosphingosine derivatives was again employed to synthesize
O
HN
(CH2)24CH3
OH
HN
HO
HO
O
O
(CH2)13CH3
OH
OH
O
KRN7000 (2)
agelasphins (1)
the desired truncated sphingoid chain. As shown in Scheme 1, D-
O
galactose was first converted into the aldehyde 5 in two steps
and 31% overall yield.22 Grignard reaction of 5 with pentylmagne-
sium bromide generated from 1-bromopentane and Mg was then
performed, affording the adducts 6 and 7 in 87% yield. Unfortu-
nately, as observed previously,17 the desired isomer 6 was pro-
duced as the minor product with a ratio of 6:7 = 1:1.4. We
presume that the observed selectivity, that is, the preferential for-
mation of 7, arises from substrate chelation to a magnesium cation
(through the aldehyde and b-hydroxy group) and pentyl addition
across the least hindered carbonyl si face, as depicted in Scheme
1. Attempts to reverse the selectivity to favor the formation of 6
were not made as previous studies indicated that lowering the
reaction temperature or adding chelating agents only increased
the formation of 7.21a Subsequent treatment of 6 with 1 equivalent
of methanesulfonyl chloride in the presence of pyridine led to the
selectively 2-mesylated compound 8 in 81% yield. As Schmidt
pointed out,21a the higher reactivity of the 2-OH group could be
attributed to its greater nucleophilicity caused by intramolecular
hydrogen bonding with the oxygen atoms of the dioxane ring.
Meanwhile, in order to make use of the major product 7 for the
synthesis of the target molecules, we inverted the configuration
of the 4-OH group via Mitsunobu reaction (Scheme 1). As with 6,
selective mesylation of 7 gave smoothly the 2-mesylated interme-
diate 9 in very high yield, which underwent Mitsunobu reaction
with p-nitrobenzoic acid to generate the 4-OH-inverted p-nitro-
benzoic ester 10 in 76% yield. Removal of the p-nitrobenzoyl group
was then effected by NaOMe in MeOH to give the desired 2-mesy-
lated intermediate 8 in high yields. Thus, by using Mitsunobu
reaction, both stereoisomers generated in the Grignard reaction
could be capitalized for the synthesis of the target structures. With
OH
HO
HO
OH
O
HO
HO
O
(CH2)22CH3
OH
HN
(CH2)22CH3
OH
HN
HO
HO
O
S
(CH2)4CH3
(CH2)4CH3
OH
OH
OCH (3)
Thioglycoside analogue of OCH (4)
Figure 1. Structures of
a
-galactosylceramides 1–4.
experimental autoimmune encephalomyelitis (EAE). Another
interesting case is the C-glycoside analog of KRN7000,15 which in-
duces a very TH1-biased response in vivo. It was thus significantly
more potent than KRN7000 in disease models where a TH1 re-
sponse would be expected to be beneficial, such as mouse models
of malaria and malignant tumors. Many other structural modifica-
tions on both the galactose residue and the lipid chains of the
galactosylceramide have also been conducted,10 and substantially
altered NKT responses were also reported in some cases.
Yet, it remains unclear how these a-galactosylceramide (a-Gal-
Cer) analogs elicit qualitatively different responses. Several related
X-ray crystal structures were recently elucidated,16 revealing that
the lipid chains of a-GalCer fit tightly into the CD1d binding groove
and the galactose ring is positioned above the groove for recogni-
tion by NKT TCR. A series of hydrogen bonds were identified and
are assumed to hold the complex together. However, from these
structures, it is still not immediately apparent how the lipid chain
length and the sugar moiety influence NKT cell responses although
the hydrogen bonds did answer theoretically some of the struc-
ture–activity data derived from
a
-GalCer analogs.16a It has been
postulated that the origin of cytokine polarization could relate to
the stability of the glycolipid-CD1d complex.8 Thus, the stability
is currently a focus point in the design of potent a-GalCer analogs.
_
R
Mg+
Br
Recently, we achieved the first total synthesis of a thioglycoside
analog of KRN7000 by using a nonconventional approach.17,18
Thioglycosides are very attractive substitutes for O-glycosides as
it is well known that they are much less susceptible to enzymatic
cleavage as well as chemical degradation.19 Moreover, unlike
C-glycosides, thioglycosides may possibly retain all hydrogen
bonding interactions with protein receptors. The subsequent bio-
assay demonstrated that this thioglycoside possessed similar
potency to KRN7000 in human NKT cell activation, and stimulated
cytokine release in a CD1d-dependent manner.20 As such, the thio-
glycoside analog may be superior to KRN7000 as a parent com-
pound for developing immune stimulants for humans in view of
its bioactivity, stability, ease of synthesis, and flexibility for making
other analogs. Thioglycosides usually have more flexibility around
the anomeric linkage compared with the corresponding O-glyco-
sides owing to the longer C–S bond and weaker stereoelectronic
OH
O
H
Ref. 22
C5H11Br, Mg
O
H
Ph
D-Galactose
O
O
_
2 steps, 31%
O
R
O
O
THF
87%
Mg+
H
Br
Ph
5
aq. NH4Cl
OH OH
C5H11
OH OH
C5H11
OMs OH
C5H11
MsCl, Py
81%
+
O
O
O
O
O
O
36%
Ph
51%
Ph
Ph
7
6
8
minor product
major product
NaOMe
MeOH
84%
MsCl, Py
86%
effects. We speculate that this increased flexibility may cause
a-
S-GalCer to sit differently in the CD1d binding groove, resulting
in an altered structure of the glycolipid/CD1d complex and a
change in its affinity with the TCR of NKT cells. Also, after binding
O
OMs OH
C5H11
OMs
O
NO2
p-nitrobenzoic acid
with CD1d, the sugar head of
a-S-GalCer may orientate at a differ-
C5H11
ent angle from that of -GalCer as the C–S–C bond angle is signif-
a
O
O
DIAD, PPh3
THF
76%
O
O
icantly smaller than the C–O–C angle, which could result in
Ph
differential recognition by the TCR of NKT cells.
Ph
10
9
Encouraged by the bioactivity of
the total synthesis of two other thioglycoside analogs of
a
-S-GalCer,20 we report here
a
-GalCer,
Scheme 1. Synthesis of intermediate 8.

X. Zhu et al. / Tetrahedron Letters 52 (2011) 4971–4974
4973
OMs OH
p-TsOH
N3
OH
C5H11
NaN3
DMF
HO
8
HO
C5H11
MeOH/CH2Cl2
(4:1)
76%
OH
11
OH
12
64%
Me2C(OMe)2
p-TsOH
71%
N3
C5H11
O
N3
N3
C5H11
O
C5H11
O
I
MsO
HO
MsCl, Py
72%
LiI, DMF
85%
O
O
O
15
14
13
Scheme 2. Synthesis of sphingoid building block 15.
OH
BnO
BnO
O
OH
O
BnO
BnO
OBn
15, aq. NaHCO3
TBAHS, EtOAc
Ref. 23
88%
O
N3
C5H11
O
BnO
BnO
S
BnO
65%
O
SH
OBn
17
16
O
1. Me3P/THF, 1 M NaOH
2. C23H47CO2H or C25H51CO2H
EDC, CH2Cl2
O
O
OH
BnO
BnO
OH
BnO
BnO
O
O
R
R
OH
HN
HN
HCl in 1,4-dioxane
C5H11
BnO
BnO
S
S
C5H11
O
O
OH
20 R = C23H47 (69%)
21 R = C25H51 (72%)
18 R = C23H47 (59%)
19 R = C25H51 (74%)
Na, NH3 (l)
O
OH
HO
HO
O
R
HN
OH
HO
S
C5H11
OH
4 R = C23H47 (86%)
22 R = C25H51 (83%)
Scheme 3. Synthesis of a-S-galactosylceramides 4 and 22.
sufficient amounts of 8 in hand, its transformation into the sphing-
oid building block was investigated. As expected, treatment of 8
with p-TsOH in a mixture of MeOH and CH2Cl2 gave rise to the
desired intermediate 11 in 64% yield (Scheme 2). Next, 11 was
treated with NaN3 under heating, leading smoothly to the azide
12 in 76% yield, which was subjected to standard isopropylidena-
tion conditions (2,2-dimethoxypropane/p-TsOH) to give the inter-
mediate 13 in 71% yield. Azide 13 was subsequently mesylated
with methanesulfonyl chloride in pyridine to generate compound
14 in 72% yield, which was converted into the iodide 15 in very
high yield by treatment with LiI in DMF.
under the action of NaHCO3 in biphasic conditions,24 providing
thioglycoside 17 in good yield (65%). It is noteworthy that the reac-
tion worked well regardless of the free hydroxy group present in
the sugar 16 due to extremely mild conditions.
Subsequently, 17 was exposed to Staudinger reduction condi-
tions to give smoothly the required free amine, which was used
directly in the subsequent acylation reaction. Coupling between
the amine and tetracosanoic acid or hexacosanoic acid was then
conducted in the presence of 1-ethyl-3-(dimethylaminopro-
pyl)carbodiimide hydrochloride (EDC) in CH2Cl2, and expectedly,
the corresponding amides 18 and 19 were produced in satisfactory
yields of 59% and 74%, respectively. Subsequent exposure of 18 and
19 to a solution of HCl in 1,4-dioxane led to the corresponding par-
tially protected glycolipids 20 and 21 in 69% and 72% yields. Final-
ly, these intermediates were debenzylated by Birch reduction to
give the desired target molecules 4 and 22 in 86% and 83% yields,
respectively.
To access the target molecules 4 and 22, the iodide 15 was gly-
cosylated with the pre-prepared a-galactosyl thiol 16 as shown in
Scheme 3. Thiol 16 could be readily prepared from the benzylated
1,6-anhydrogalactose following the stereospecific procedure for
the synthesis of
a
-glycosyl thiols developed in our laboratory.23
It is worth mentioning that this procedure is a significant advance
in glycosyl thiol chemistry because there have not been any reports
In summary, as a continuation of our previous project,17 in this
Letter, two thioglycoside analogs, 4 and 22 carrying the truncated
sphingoid chain of OCH were synthesized as potential immuno-
modulating agents. The synthetic efficiency was greatly increased
by employing Mitsunobu reaction to retrieve the unwanted
on direct stereoselective preparation of
our work. The desired galactosyl thiol was isolated exclusively as
the -anomer, which made purification very simple and straight-
forward. Thioglycosylation of 15 with 16 proceeded smoothly
a-glycosyl thiols prior to
a

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X. Zhu et al. / Tetrahedron Letters 52 (2011) 4971–4974
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the significant potency of the thioglycoside analog of KRN7000,
these two compounds may also exhibit interesting cytokine release
profiles. Bioassays on these compounds are currently underway
and the results will be reported elsewhere in due course.
Acknowledgments
This work was supported by the Research Frontier Program of
Science Foundation Ireland, the Program for Research in Third-Le-
vel Institution (PRTLI) Cycle 3, administered by the Higher Educa-
tion Authority (HEA) of Ireland and the Natural Science Foundation
of Zhejiang Province (R4110195).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.103.
14. Miyake, S.; Yamamura, T. Curr. Drug Target 2005, 5, 315.
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