A divergent approach to the synthesis of simplexides and congeners via a late-stage olefin cross-metathesis reaction

Article abstract of DOI:10.1039/c3ob40552d

Simplexides constitute a unique group of immunosuppressive glycolipids that demonstrate antiproliferative activities against activated T-cell lymphocytes via a unique non-cytotoxic inhibition. To investigate the structure-activity relationship of the varied long-chain secondary alcohols on simplexides, we developed an efficient and divergent route to the synthesis of simplexides and congeners, taking advantage of a late-stage olefin cross-metathesis reaction.

Full text of DOI:10.1039/c3ob40552d

Organic &
Biomolecular Chemistry
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A divergent approach to the synthesis of simplexides
and congeners via a late-stage olefin cross-metathesis
reaction†
Cite this: Org. Biomol. Chem., 2013, 11,
4971
Jiakun Li,a,b Wei Li*b and Biao Yu*b
Simplexides constitute a unique group of immunosuppressive glycolipids that demonstrate antiprolifera-
tive activities against activated T-cell lymphocytes via a unique non-cytotoxic inhibition. To investigate the
structure–activity relationship of the varied long-chain secondary alcohols on simplexides, we developed
an efficient and divergent route to the synthesis of simplexides and congeners, taking advantage of a
late-stage olefin cross-metathesis reaction.
Received 20th March 2013,
Accepted 31st May 2013
DOI: 10.1039/c3ob40552d
www.rsc.org/obc
indicated that this potent inhibition was through a unique yet
unclear non-cytotoxic mechanism.1 Given the critical role of
Introduction
Simplexides, isolated as a mixture from the Caribbean sponge T-cell lymphocytes in the immune system,7 simplexides may
Plakortis simplex by Fattorusso et al.,1–3 represent a new serve as a promising lead for the development of novel
structural type of glycolipids that are composed of varied immunosuppressive drugs.8,9
long-chain secondary alcohols and a conserved disaccharide
Li et al. have reported the synthesis of several simplexide
consisting of glucose and galactose (Fig. 1). It was reported congeners byemploying thioglycosides as the donors.10 A fluore-
that simplexides strongly inhibited the proliferation of con- scent probe incorporated with a simplexide has also been
canavalin-A activated T-cell lymphocytes in vitro.1,4–6 A con- synthesized.11 However, there is little data about the structure–
centration of simplexides as low as 10 ng mL−1 could cause activity relationship of simplexides, apart from a couple of
43% antiproliferation of T-cells. In addition, an MTT assay simplified analogues.12 It has been revealed that immuno-
logical properties of glycolipids are usually modulated by the
length and branching of their lipid chains.13–15 Thus, it is
necessary to investigate the structure–activity relationship of
the long-chain secondary alcohols on simplexides to get a
better comprehension of their immunosuppressive activities.
Herein, we report the synthesis of simplexides and congeners
with varied long-chain secondary alcohols via a divergent late-
stage elaboration.16
As depicted in the retrosynthetic analysis (Scheme 1), we
envisioned the use of an olefin cross-metathesis (CM) reaction
as the key step to elaborate simplexides and congeners. In
recent years, olefin metathesis has been widely employed in
the synthesis of carbohydrate derivatives.17–21 Due to the mild
conditions and good tolerance to most of the functional
groups, olefin metathesis has been proved to be an excellent
and versatile tool in the diversity-oriented synthesis of
glycolipids.22–25 In our design, a variety of olefins 3 would be
attached to the homoallyl group in disaccharides 2a/2b via CM
reaction at a late stage in the synthesis, giving variation by
length and functionality of the long lipid chains. The acetyl
group was chosen as protecting group for 6-OH in the glucose
donor 4, anticipating a remote participation in glycosylation
Fig. 1 Structure of simplexides.
aDepartment of Chemistry, University of Science and Technology of China, 96 Jinzhai
Road, Hefei, Anhui 230026, China
bState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. E-mail: lmwave@mail.sioc.ac.cn, byu@mail.sioc.ac.cn
†Electronic supplementary information (ESI) available: Full experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra. See DOI: 10.1039/
c3ob40552d
with the galactose acceptor
5 to furnish the desired
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Scheme 3 Synthesis of homoallyl disaccharides 2a/2b.
this α-directing effect is still controversial. As expected, the
glycosylation of 4 and 5 catalyzed by TMSOTf proceeded
smoothly to give the desired α-linked disaccharide 9 in excel-
lent yield (91%), with no β-glycosidic product being obtained.
It is particularly noteworthy that poor α-selectivity was
observed in this glycosylation when replacing the acetyl group
in donor 4 with benzyl. Selective removal of the anomeric
p-methoxylphenyl (MP) group in 9 with CAN and subsequent
activation with ClC(CvNPh)CF3 provided PTFAI donor 10.42–46
Taking advantage of the neighboring group participation of
the 2-O-Ac, glycosylation of donor 10 and acceptor 6 in the
presence of a catalytic amount of TMSOTf gave fully the
desired β-glycosidic products 2a/2b in 85% yield. The resulting
2a/2b were a pair of separable diastereoisomers with the absol-
ute configuration at the alcoholic carbon uncharacterized.
Nevertheless, both of the diastereoisomers were applied to the
following transformations.
The next step was to examine the performance of CM reac-
tions on disaccharides 2a/2b (Table 1). Compared to that of
ring-closing and ring-opening olefin metathesis, the appli-
cation of CM reaction has been limited by its relatively poor
chemoselectivity because undesired self-metathesis is always
observed.47 Fortunately, the discovery of more active catalysts
helped to overcome this limitation and greatly extend the
application of CM reactions in total synthesis. An evaluation of
a relevant CM reaction with C-glycoamino acids as substrates
has been reported by McGarvey et al. in 2005.21 In the present
studies, after examining a number of potential conditions,48–51
we found that a catalytic amount of Grubbs’ 2nd generation
reagent at 40 °C in CH2Cl2 was highly efficient and universal
for the coupling of homoallyl disaccharides 2a/2b with an
excess amount (9 equiv.) of the terminal olefins 3a–3g. Thus,
the desired simplexide precursors 11a–11i, including two pairs
of diastereoisomers (11c/11d and 11e/11f) at the alcoholic
carbon, were prepared in high yields with the corresponding
self-metathesis products being well suppressed. It is note-
worthy that the E-olefins turned out to be the major products,
with only a few or even no Z-olefins being observed.
Scheme 1 Retrosynthesis of simplexides and congeners.
α-glycosidic linkage.26–30 The neighboring group participation
of 2-O-Ac in the galactose unit would secure a β-selective glyco-
sylation with homoallyl alcohol 6.27,31
Results and discussion
Our synthesis commenced with the preparation of the three
building blocks 4, 5 and 6. Treatment of commercially avail-
able alcohol 7 with PCC provided aldehyde 8,32 which was
then converted into the desired racemic olefin 6 in the pres-
ence of allyl bromide and Zn powder in good yield (Scheme 2).
In accordance with the literature, N-phenyltrifluoroacetimidate
(PTFAI) donor 4 was prepared from the commercially available
per-O-acetylated glucose (8 steps, 52%) in high yield.33–37
Acceptor 5 was efficiently prepared from per-O-acetylated galac-
tose via 5 steps in 49% overall yield.38
With the three building blocks in hand, we started the
assembly process (Scheme 3). The challenging step was to
create the α-glycosidic linkage with high selectivity between
glucose donor 4 and galactose acceptor 5. The formation of
1,2-cis glycosidic linkage remains a major subject of study in
carbohydrate chemistry, and the α-selectivity in the glyco-
sylation with glucose donors is still case-by-case.27,39,40 One
of those successful examples takes advantage of the acyl pro-
tecting group at 6-OH,26–30,41 although the mechanism of
Scheme 2 Synthesis of olefinic alcohol 6.
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Table 1 Synthesis of simplexides precursors via CM reaction
Conclusions
In summary, an efficient and concise route to the synthesis of
simplexides and congeners via a late-stage olefin cross-meta-
thesis reaction has been well established. A library of glyco-
lipids with structural alternation in the lipid moieties has
been successfully synthesized and characterized. The determi-
nation of the biological activities of these glycolipids is in pro-
gress and will be reported in due course.
Entry
Substrate
Olefins
Product (yield)
1
2
3
4
5
6
2a
2a
2a
2b
2a
2b
11a (86%)
11b (78%)
11c (80%)
11d (75%)
11e (76%)
11f (79%)
Acknowledgements
Thanks are due to the National Basic Research Program of
China (2010CB529706) and the National Natural Science
Foundation of China (20932009).
7
8
2a
2a
11g (99%)
11h (61%)
Notes and references
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R
Product (yield)
1
2
3
4
5
6
7
8
9
2a
C3H7
C7H15
C13H27
C17H35
C19H39
C19H39
C3H7Ph
C4H8OH
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1a (66%)
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1c (83%)
1d (91%)
1e (85%)
1f (90%)
1g (67%)
1h (32%)
1i (99%)
11a
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11e
11f
11g
11h
11i
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