Chemical synthesis of a heparan sulfate glycopeptide: Syndecan-1

Article abstract of DOI:10.1002/anie.201205601

Finishing first: The highly complex structure of the title compound (see picture) was assembled. The protective groups utilized, as well as the sequences for formation of the glycosyl linkages and protecting group removal are critical to the success of the synthesis. This first preparation of a heparan sulfate glycopeptide lays the foundation for accessing other members of this class of molecules. Copyright

Full text of DOI:10.1002/anie.201205601

Angewandte
Chemie
DOI: 10.1002/anie.201205601
Total Synthesis
Chemical Synthesis of a Heparan Sulfate Glycopeptide: Syndecan-1**
Bo Yang, Keisuke Yoshida, Zhaojun Yin, Hang Dai, Herbert Kavunja, Mohammad H. El-
Dakdouki, Suttipun Sungsuwan, Steven B. Dulaney, and Xuefei Huang*
Heparan
sulfate
proteoglycans
(HSPGs), which are composed of
three parts: heparan sulfate (HS),
a
tetrasaccharide linker, and the
core protein, are ubiquitous compo-
nents of the mammalian cell surface
and the extracellular matrix.[1] This
family of molecules can serve as
receptors for many adhesion molecules and growth factors
such as fibroblast growth factor, integrin, Wnt proteins, and
herpes simplex virus glycoprotein D.[2] HSPGs play important
roles in a variety of biological processes including cancer
development, angiogenesis, viral infection, and wound
repair,[3] and thus renders them interesting targets for the
development of novel therapeutic interventions.[4] Although
the biological activities of HSPGs have been largely attrib-
uted to the HS chains, there is increasing evidence that both
the HS chain and the core protein can be important for
directing the biological functions.[3a,5] Naturally existing
HSPGs are highly heterogeneous mixtures, wherein a single
core protein contains diverse HS structures. This diversity
renders it extremely challenging to isolate HSPGs bearing
a homogeneous HS chain, thus hindering a thorough under-
standing of the structure–function relationship. Chemical
synthesis of HSPGs can reduce the structural heterogeneity
and provide sufficient quantities for biological evaluations.
Although much work has been done on the synthesis of HS[6,7]
and the tetrasaccharide linker,[8] no synthetic methods are
available to date for the preparation HSPGs. Herein, we
report our studies on the synthesis of HS glycopeptides
containing homogenous HS glycans.
and iduronic acid (IdoA), 2O sulfation, 6O sulfation, and
N acetylation. Successful synthesis of this molecule will lay
the groundwork for accessing other HS glycopeptides.
To prepare the octasaccharide of the glycopeptide 1, our
original strategy adapted a 2 + 5 + 1 glycosylation approach,
wherein the linkages between units B (GlcN) and C (IdoA),
and units G and H were to be formed by coupling the
disaccharide 2 with pentasaccharide 3 and the pentasacchar-
ide donor 4 with xyloside serine derivative 5, respectively.
Although the a-glycosyl linkage between GlcN and IdoA
was formed stereospecifically using monosaccharide building
blocks in our previous study,[10] the coupling between 2 and 3
failed to yield the desired heptasaccharide and donor
decomposition products were isolated as the major side
products. Varying the protective groups on 2 and 3 did not
improve the situation. The failure was attributed to the
reduced glycosylation power of these building blocks towards
unreactive acceptors compared to their monosaccharide
counterparts. This reduced reactivity was presumably
a result of their larger sizes and the electron-withdrawing
properties of the additional glycan units, which can reduce
their reactivity towards acceptors.[11] In addition to the
difficulty encountered in the 2 + 5 coupling, the 5 + 1
glycosylation of the pentasaccharide donor 4 with the xyloside
serine acceptor 5 was also not productive. These setbacks led
us to consider a new 3 + 2 + 3 synthetic route wherein the
difficult linkages between B and C, as well as G and H were to
be formed earlier in the synthesis.
We are interested in human syndecan-1, an important
HSPG on the cell membrane.[4,9] Our synthetic target is the
HS glycopeptide 1 from the extracellular domain of synde-
can-1, which contains the binding sites for many receptors.[9d]
The octasaccharide in 1 incorporates typical structural
features of HSPGs, including the full tetrasaccharide linker,
glucosamine (GlcN) linked a to both glucuronic acid (GlcA)
[*] Dr. B. Yang, Dr. K. Yoshida, Dr. Z. Yin, H. Dai, H. Kavunja,
Dr. M. H. El-Dakdouki, S. Sungsuwan, S. B. Dulaney,
Prof. Dr. X. Huang
Department of Chemistry, Michigan State University
578 S. Shaw Lane, East Lansing, MI 48824 (USA)
E-mail: xuefei@chemistry.msu.edu
[**] This work was supported by the National Science Foundation (CHE
1111550) and the National Institute of General Medical Sciences,
and NIH (R01GM072667).
The 3 + 2 + 3 strategy called for the preparation of the
ABC trisaccharide 7, DE disaccharide 8, and FGH trisac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205601.
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ing the disaccharide acceptor 13. Coupling of the idosyl
thioglycoside 14 with 13 produced the ABC trisaccharide 7
(Scheme 1B).
The middle DE disaccharide 8 was formed in 75% yield
by reaction of the glucosamine donor 15 with glucoside
acceptor 16 under the preactivation reaction conditions
(Scheme 1C). Removal of the TBS moiety with subsequent
exchange of PMB with TBDPS produced 8.
With the ABC and DE modules in hand, we turned our
attention to the preparation of the FGH trisaccharide
acceptor 9. The TBS-protected xyloside donor 18 reacted
with 19 with subsequent TBS removal, thus leading to the
acceptor 5 (Scheme 2A). The formation of the challenging
GH linkage was then tested using the galactoside donor 20,
which successfully glycosylated 5 to give 21 in 81% yield
(Scheme 2B). This result suggested that the difficulty in the
glycosylation of 5 with the pentasaccharide 4 was indeed
a result of the additional glycans on the pentasaccharide
donor.
Figure 1. Retrosynthetic analysis of octasaccharide amino ester 6.
Bn=benzyl, Bz=benzoyl, Fmoc=9-fluorenylmethoxycarbonyl, Lev=le-
vulinoyl, PMB=para-methoxybenzyl, TBDPS=tert-butyldiphenylsilyl,
STol=thiotolyl.
charide 9 (Figure 1). The synthesis of 7 started from the
coupling of the donor 10 with acceptor 11 using the
preactivation protocol[12] with the promoter system of p-
TolSCl/AgOTf.[13] This procedure afforded the a-linked BC
disaccharide 12 in 80% yield with complete stereoselectivity
(Scheme 1A). All the preactivation-based glycosylation reac-
tions were performed with a slight excess (1.1 equiv) of the
glycosyl donor compared to the acceptor. Previously, when
the PMB group was used to mask the 6O-position of the
glycosyl donors, the electron-rich PMB moiety participated in
the reaction by forming a 1,6-anhydro sugar, thus shutting
down the desired glycosylation.[10] To avoid this side reaction,
the PMB group in 12 was replaced by a TBDPS group with
subsequent deprotection/protection sequences, thus generat-
Scheme 2. Reagents and conditions: a) 1. AgOTf, p-TolSCl, 4 ꢀ M.S.,
À788C, then 19, TTBP, À788C–08C; 2. Tf2O, THF, H2O; b) AgOTf,
p-TolSCl, 4 ꢀ M.S., À788C, then 5, TTBP, À788C–08C; c) 1. AcOH,
NH2NH2, CH2Cl2/MeOH (1:1); 2. 22, AgOTf, p-TolSCl, 4 ꢀ M.S., TTBP,
À788C-08C; d) AgOTf, p-TolSCl, MS 4 ꢀ, À788C, then 23, TTBP,
À788C–08C; e) AgOTf, p-TolSCl, 4 ꢀ M.S., À788C, then 5, TTBP,
À788C–08C; f) AcOH, NH2NH2, CH2Cl2/MeOH (1:1).
To prepare the trisaccharide 9, the diLev-protected
galactoside donor 22 glycosylated the acceptor 23, thus
forming the digalactoside 24 in 85% yield (Scheme 2C).
Compound 24 was then subjected to reaction with 5. The
desired trisaccharide 25 was obtained in 43% yield in addition
to the a-anomer 25a (45%). We tested various glycosylation
conditions (donor/acceptor ratio, solvent, temperature, etc.).
However, none of these trials improved the stereoselectivity.
Considering the high stereoselectivity in the formation of 21
and the disaccharide donor 24 bearing a 2O-Bz moiety (which
can function as a participating neighbouring group) at the
reducing end, the loss of stereoselectivity in reaction of 24
Scheme 1. Reagents and conditions: a) AgOTf, p-TolSCl, 4 ꢀ M.S.,
À788C, then 11, TTBP, À788C-08C; b) 1. Mg(OMe)2, CH2Cl2, À208C-
08C; 2. LevOH, EDC-HCl, DMAP, CH2Cl2; 3. DDQ, CH2Cl2/H2O (10:1);
4. HF/pyridine; 5. TBDPSCl, imidazole, CH2Cl2; c) AgOTf, p-TolSCl, 4 ꢀ
M.S., À788C, then 13, TTBP, À788C–08C; d) AgOTf, p-TolSCl, 4 ꢀ
M.S., À788C, then 16, TTBP, À788C-08C; e) 1. DDQ, CH2Cl2/H2O
(10:1); 2. HF/Pyridine; 3. TBDPSCl, imidazole, CH2Cl2. DMAP=4-
(dimethylamino)pyridine, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
M.S.=molecular sieves, TBS=tert-butyldimethylsilyl, Tf=trifuoro-
methanesulfonyl, TTBP=2,4,6-tri(tert-butyl)pyrimidine.
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with 5 was intriguing and the exact reason is unknown.
Several other groups have reported the loss of 1,2-trans
selectivities using 2O-acyl-protected galactosyl donors.[14] As
an alternative, the Lev group in 21 was removed and the
resulting acceptor was glycosylated with 22 to generate 25 in
62% yield (Scheme 2B). The two Lev groups in 25 were
removed by hydrazine acetate to afford the FGH trisacchar-
ide acceptor 9 (Scheme 2C).
Having prepared the three required modules, we inves-
tigated the union of these building blocks. The 3 + 2 coupling
between 7 and 8 proceeded smoothly to produce the
pentasaccharide 26 in an excellent 93% yield (Scheme 3).
Subsequent 5 + 3 coupling between 26 and 9 gave the
octasaccharide 27 in 83% yield, thus completing the oligo-
saccharide backbone of the glycopeptide. The octasaccharide
27 was treated with HF in pyridine to cleave the TBDPS
protective groups and expose three primary hydroxy groups,
which were oxidized[15] and subsequently converted into
methyl esters[16] to afford the octasaccharide amino ester 6
for peptide chain elongation.
Scheme 4. Reagents and conditions: a) 1. Ac2O, pyridine, 508C;
2. piperidine, CH2Cl2; b) HATU, DIPEA, DMF; c) Pd/C, H2, NH4OAc,
CH2Cl2/MeOH (1:1); d) multiple rounds of automated solid phase
peptide synthesis; e) TFA/H2O/Phenol/TIPS; f) 1. BnBr, DIPEA, DMF;
2. piperidine, DMF; g) HATU, DMF; h) 1. Zn, CuSO4 (sat.), Ac2O/THF/
HOAc; 2. NH2NH2-H2O, HOAc, CH2Cl2/MeOH (1:1); 3. SO3-Et3N,
DMF, 558C; 4. H2, Pd/C, CH2Cl2/MeOH (1:1); i) base-catalyzed hydrol-
ysis. DIPEA=diisopropylethylamine, HATU=O-(7-azabenzotriazol-1-
yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, TFA=tri-
fluoroacetic acid, TIPS=triisopropylsilane, THF=tetrahydrofuran.
Scheme 3. Reagents and conditions: a) AgOTf, p-TolSCl, 4 ꢀ M.S.,
À788C, then 8, TTBP, À788C–08C; b) AgOTf, p-TolSCl, 4 ꢀ M.S.,
À788C, then 9, TTBP, À788C–08C; c) 1. HF/pyridine; 2. TEMPO,
BAIB, CH2Cl2/H2O/tBuOH (4:1:4); 3. MeI, K2CO3, DMF. BAIB=[bis-
(acetoxy)iodo]benzene, DMF=N,N’-dimethylformamide,
TEMPO=2,2,6,6-tetramethyl-1-piperidinyl-oxyl.
generate the decapeptide 33 with a free amino terminal.
Coupling of the octasaccharide carboxylic acid 31 with 33
without any base additive[18] successfully produced the
glycopeptide 34 in 75% yield. It was important to omit the
base during this step to avoid the b elimination of the glycan
chain from the peptide backbone.
To avoid the undesired reaction at the 2-OH group of
unit F in 6 during O sulfation, we protected the 2-OH with an
acetyl (Ac) group, with subsequent treatment with piperidine
to expose the amino group (28; Scheme 4A). The free amine
28 was then subject to coupling with the dipeptide 29 to afford
the glycopeptide 30. Selective hydrogenation of 30 in the
presence of NH4OAc[17] generated the free carboxylic acid 31
without affecting the benzyl ethers in the molecule.
Parallel to oligosaccharide synthesis, solid-phase peptide
synthesis was performed to prepare the C-terminal peptide 33
(Scheme 4B). As the final product will contain acid sensitive
O sulfates, the traditional peptide deprotection promoted by
a strong acid needs to be avoided. Given this consideration,
the side chains of glutamic acid and threonine were protected
as the benzyl ester and benzyl ether, respectively. The peptide
was prepared on chlorotrityl resin and cleaved from the solid
phase by acid treatment (TFA/H2O/Phenol/TIPS). The free
carboxylic acid terminal was subsequently protected as the
benzyl ester and the N-terminal Fmoc was removed to
To accomplish the deprotection of the fully protected
glycopeptide 34, the right reaction sequence is critical.
Despite the fact that simultaneous hydrogenolysis of the
benzyl ethers and the azido groups in HS oligosaccharide
synthesis were reported before,[7i,10,19] treatment of 34 under
catalytic hydrogenation conditions led to a complex reaction
mixture. To overcome this, we resorted to selective reduction
of azide by zinc and copper sulfate with simultaneous
acetylation of the newly liberated free amines (Sche-
me 4C).[20] The acetylated glycopeptides were then subjected
to selective removal of the Lev groups by hydrazine acetate
with subsequent O sulfation of the free hydroxy groups and
hydrogenation, thus producing glycopeptide 35. Although
hydrolysis of the acetate and benzoate esters was the only step
remaining to the final glycopeptides, it proved to be extremely
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challenging. We investigated a variety of reagents including
LiOOH, NaOH, and LiOH with pH values ranging from 8 to
11. Unfortunately, with pH values around 8.5, Bz could not be
removed while at higher pH values, we observed a significant
degree of b-elimination of the glycan, which is a common
problem in glycopeptide synthesis.[21]
sequences for glycosyl linkage formation and protective
group removal are critical for the successful synthesis. We
believe the approach established and knowledge gained can
be applied to the synthesis of other HS glycopeptides. Work in
this regard as well as investigation of the exciting biological
functions of the prepared HSPG bearing homogenous HS
glycans is currently ongoing.
The failure to deprotect 35 prompted us to redesign our
deprotection sequence. Since b-elimination is presumably
caused by deprotonation of the a proton of the glycosylated
serine (marked Ha in 35), we envisioned that if the serine
carboxylic acid is kept in its free form, its deprotonation
should raise the pKa value of the a proton on the neighboring
carbon atom as a result of electrostatic repulsion, thus
reducing the potential for b-elimination. Furthermore, Kihl-
berg and co-workers reported that partially deprotected
glycopeptide was more stable against b-elimination compared
to the fully protected form.[21] Thus, an alternative route was
designed to first remove all the protecting groups on
compound 30 except the three methyl esters, and to couple
this partially deprotected glycopeptide to peptide 33. The
assembled glycopeptide could then be transformed into 1 by
hydrogenation and mild base treatment since methyl esters
are more sensitive to base hydrolysis. To test this, we
converted 30 into its partially protected form 36 (azide
reduction/acetylation, Lev removal, O sulfation, hydrogena-
tion, and transesterification; Scheme 5). For the transesteri-
fication step, the pH was carefully maintained at 9.5 to
minimize b-elimination while retaining the methyl esters by
NaOMe treatment. All Ac and Bz groups were cleaved under
these reaction conditions after 40 hours. With compound 36 in
hand, we tested its coupling with the peptide 33. It was shown
that sulfates did not affect peptide coupling reactions.[18]
Indeed, reaction of 36 with 33 produced the glycopeptide 37
in 60% yield. Subsequent hydrogenation and methyl ester
hydrolysis afforded the final glycopeptide 1.
Received: July 14, 2012
Published online: && &&, &&&&
Keywords: glycopeptides · glycosylation · sulfur ·
.
synthesis design · total synthesis
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Scheme 5. Reagents and conditions: a) 1. Zn, CuSO4 (sat.), Ac2O/
THF/HOAc (2:3:1); 2. NH2NH2-H2O, HOAc, CH2Cl2/MeOH (1:1);
3. SO3-Et3N, DMF, 558C; (4) H2, Pd/C, CH2Cl2/MeOH (1:1);
5. NaOMe, MeOH, pH=9.5; b) HATU, 2,4,6-collidine, DMF; c) 1. H2,
Pd/C, CH2Cl2/MeOH (1:1); 2. LiOH, CH3OH/H2O (1:1), pH=9.5.
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thesis, see: a) T.-Y. Huang, M. M. L. Zulueta, S.-C. Hung, Org.
Lett. 2011, 13, 1506 – 1509; b) J.-i. Tamura, T. Nakamura-
Yamamoto, Y. Nishimura, S. Mizumoto, J. Takahashi, K.
Sugahara, Carbohydr. Res. 2010, 345, 2115 – 2123; c) K. Shima-
waki, Y. Fujisawa, F. Sato, N. Fujitani, M. Kurogochi, H. Hoshi,
H. Hinou, S.-I. Nishimura, Angew. Chem. 2007, 119, 3134 – 3139;
Angew. Chem. Int. Ed. 2007, 46, 3074 – 3079; d) B. Thollas, J.-C.
Jacquinet, Org. Biomol. Chem. 2004, 2, 434 – 442; e) J. Tamura,
A. Yamaguchi, J. Tanaka, Bioorg. Med. Chem. Lett. 2002, 12,
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1999, 121, 468 – 469; g) T. Yasukochi, K. Fukase, Y. Suda, K.
Takagaki, M. Endo, S. Kusumoto, Bull. Chem. Soc. Jpn. 1997, 70,
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T. Ogawa, Bioorg. Med. Chem. 1995, 3, 1637 – 1650; j) S. Rio,
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Abildgaard, A. Waage, M. Børset, Blood 2000, 95, 388 – 392;
b) M. Kato, H. Wang, V. Kainulainen, M. L. Fitzgerald, S.
Ledbetter, D. M. Ornitz, M. Bernfield, Nat. Med. 1998, 4, 691 –
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[21] P. Sjçlin, J. Kihlberg, J. Org. Chem. 2001, 66, 2957 – 2965.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Total Synthesis
B. Yang, K. Yoshida, Z. Yin, H. Dai,
H. Kavunja, M. H. El-Dakdouki,
S. Sungsuwan, S. B. Dulaney,
X. Huang*
&&&& — &&&&
Chemical Synthesis of a Heparan Sulfate
Glycopeptide: Syndecan-1
Finishing first: The highly complex struc-
ture of the title compound (see picture)
was assembled. The protective groups
utilized, as well as the sequences for
formation of the glycosyl linkages and
protecting group removal are critical to
the success of the synthesis. This first
preparation of a heparan sulfate glyco-
peptide lays the foundation for accessing
other members of this class of molecules.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!