Orthogonally protected d-galactosamine thioglycoside building blocks via highly regioselective, double serial and double parallel inversions of β-d-thiomannoside

Article abstract of DOI:10.1039/c3ob40935j

An efficient route for the synthesis of orthogonally protected d-galactosamine thioglycosides via one-pot double serial and double parallel displacements of the d-mannosyl-2,4-bis-trifluoromethanesulfonates by azide and nitrite ions is described. These bu

Full text of DOI:10.1039/c3ob40935j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Orthogonally protected D-galactosamine thioglycoside
building blocks via highly regioselective, double serial
and double parallel inversions of β-D-thiomannoside†
Cite this: Org. Biomol. Chem., 2013, 11,
4825
Madhu Emmadi and Suvarn S. Kulkarni*
Received 3rd May 2013,
Accepted 28th May 2013
An efficient route for the synthesis of orthogonally protected D-galactosamine thioglycosides via one-pot
double serial and double parallel displacements of the D-mannosyl-2,4-bis-trifluoromethanesulfonates by
azide and nitrite ions is described. These building blocks were utilized to synthesize the rare disaccharide
moiety of the zwitterionic polysaccharide of Bacteroides fragilis and the selectively protected Tn antigen.
DOI: 10.1039/c3ob40935j
www.rsc.org/obc
and efficient strategy involving a highly regioselective, one-
pot double serial and double parallel displacement of the
Introduction
Cell-surface glycoconjugates and oligosaccharides participate D-mannosyl 2,4-bis-trifluoromethanesulfonates (OTf, triflate)
in a variety of important life processes such as, viral and bac- by azide, and nitrite ions as nucleophiles. The methodology is
terial infections, cell–cell interactions and immune response applied to the synthesis of the rare disaccharide moiety of the
and are thus implicated in various infectious diseases includ- zwitterionic polysaccharide of Bacteroides fragilis and the syn-
ing Tb, Flu, AIDS, meningitis, malaria and stomach thesis of the orthogonally protected Tn antigen.
infections.1–6 Several important glycoconjugates, including
mucin type O-glycoproteins, N-glycoproteins, globo-H, and
ganglioside cancer antigens, comprise α or β-linked N-acetyl
galactosamine (GalNAc) connected to various other sugars at
Results and discussion
Easily accessible β-D-thiomannoside 111 (Scheme 1) was
O3, O4 or O6 positions. However, due to their structural com-
plexity and micro-heterogeneity, they are not accessible in
acceptable purity and amounts by isolation from natural
sources. Thus, access to orthogonally protected D-galactos-
amine building blocks is essential for the chemical synthesis
of these glycoconjugates (glycolipids, lipooligosaccharides and
glycoproteins) and oligosaccharides. Owing to their biological
importance, various approaches have been developed for the
synthesis of D-galactosamine containing oligosaccharides and
glycoconjugates from a variety of carbohydrate precursors.7–10
Recently, we reported a straightforward transformation of
cheaply available D-mannose into orthogonally protected
D-galactosamine building blocks.10 Although this method was
a marked improvement over the existing ones, it still involved
multiple protection and deprotection steps. It was realized that
the number of steps could be cut down by employing regio-
selective and one-pot reactions. In this work, we report a short
selected as a suitable starting material due to its stereochemi-
cal resemblance with D-galactosamine; it has the same stereo-
chemistry at C3 and C5, and opposite stereochemistry at C2
and C4. It has been well-established that the presence of the
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai,
400076, India. E-mail: suvarn@chem.iitb.ac.in; Fax: (+)(91-22) 2576 7152;
Tel: (+)(91-22) 2576 7166
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data for all new compounds, and copies of 1H, 13C and
2D NMR spectra. See DOI: 10.1039/c3ob40935j
Scheme 1 A strategy for transformation of D-mannose into orthogonally pro-
tected D-galactosamine building blocks.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4825–4830 | 4825

View Article Online
Paper
Organic & Biomolecular Chemistry
β-linkage in D-mannoside10,12 and a neighbouring equatorial
acyl group10,13–16 are pivotal for achieving success in nucleo-
philic displacements using azide or nitrite ions, respectively.
We envisioned that a 2,4-diol 2 obtained from 1, via a regio-
selective silylation at O6 followed by acylation at O3, could be
exploited by stereo-inversions and/or a double inversion at C2
and/or C4 positions to access D-galactosamine derivatives 4,
in an expedient manner. The corresponding 2,4-bis-triflate
derivatives 3 would offer an opportunity to carry our sequential
one-pot double parallel and double serial inversions using
azide (N3), and nitrite (NO2) anions as nucleophiles,
provided that the desired regioselectivity could be attained by
tuning the reaction conditions. Earlier, Sato and coworkers
successfully converted a β-D-galactosyl linked disaccharide into
a β-D-mannosyl one by a double parallel displacement of the
corresponding 2′,4′-bis triflates in excellent yields.17 Further,
Ramström and coworkers showed that such SN2 displacements
of methyl β-D-galactosyl and methyl β-D-glucosyl 2,4-bis-triflates
by nitrite or acetate anions proceed with exclusive C4 selecti-
vity.15 However, in the D-mannose case, we anticipated a rever-
sal of selectivity, based on the steric disposition of the axial
C2-OTf. Thus, selective azide displacement of C2-OTf followed
by nucleophilic displacement of C4-OTf by nitrite ion on
D-mannose scaffold seemed reasonable.
Table 1 Regioselective displacement of C2-triflyloxy group by azide ion
Yield (%)
Entry Azide (1 equiv.) Temp (°C) Time (h) Solvent 5a
6a
1
2
3
4
5
6
7
NaN3
NaN3
NaN3
TBAN3
TBAN3
TBAN3
TBAN3
RT
0
−78
RT
−78
−15
−30
2
2
6
DMF
DMF
DMF
CH3CN 44
CH3CN
CH3CN 35
CH3CN
41
36
40
—
—
—
—
36
22
60
2
48
10
20
5
—
As shown in Scheme 2, tetraol 1 was first regioselectively
silylated at O6 and subsequently acylated at O3 by using cat.
Me2SnCl2 with AcCl or BzCl to obtain the common inter-
Fig. 1 Steric effects in nucleophilic displacement of bis-triflate 3a and mono-
triflate 7a.
18
mediate 2,4-diols 2a and 2b, respectively. First, diol 2a was
used to systematically study the regioselectivity in the azide results, TBAN3 was employed in CH3CN as a solvent under
displacement of the corresponding 2,4-bis-triflate. The reac- high dilution conditions. Still, the reaction at RT gave similar
tion conditions and results are summarized in Table 1. Our results and offered the diazide 5a (entry 4). The temperature
general procedure involved the formation of the 2,4-bis-triflate effect was studied next. To our delight, when the reaction was
3 and its reaction with 1.0 equiv. of the azide, to find out if it conducted at −78 °C (entry 5), the desired galactosyl C2-mono-
proceeds selectively and if so, whether it displaces the C2-OTf azide 6a (36%) was generated very slowly, as a major product.
or the C4-OTf, and subsequently add n-tetrabutylammonium In order to enhance the reactivity of the C2-OTf, the reaction
nitrite (TBANO2) under Lattrell–Dax conditions13–16,19,20 to was carried out at −15 °C (entry 6). However, the diazide 5a
complete the second displacement, followed by product was encountered again, as a major product. At this point, it
isolation and characterization. Accordingly, triflation of diol 2a became evident that under controlled conditions, the
using triflic anhydride (Tf2O) in dichloromethane (CH2Cl2), C2-monoazide 7a forms first via a regioselective displacement
evaporation of CH2Cl2 and one-pot nucleophilic displacement of C2-OTf in 3a (Fig. 1). However, in doing so, the configura-
using NaN3 (1 equiv.) in DMF was attempted first (Table 1, tion of the sugar changes from D-manno (3a) to D-gluco (7a),
entry 1). This reaction afforded the 2,4-diazide 5a (41%) relieving the steric congestion near C4 centre, thus imparting
without any selectivity. Further decreasing the temperature did higher reactivity to the C4-OTf and enabling a facile conversion
not have any effect on the selectivity (entries 2–3). In all the of glucosyl monoazide 7a to galactosyl diazide 5a. Importantly,
reactions, the corresponding 2,4-D-galactosyl diol (25–30%), the competing second azide displacement of C4-OTf can be
resulting from nitrite ion displacement of bis-triflate 3a, was arrested at −78 °C (entry 5). In an attempt to modulate the
obtained as a side product. Since NaN3 did not give good reactivity and selectivity still further, we conducted the reaction
at −30 °C (entry 7). Gratifyingly, this condition afforded the
desired galactosyl mono azide 6a as a single product in 60%
yield over three steps. Apparently, the C2-OTf of the β-isomer
3a is more accessible as compared to the sterically encum-
bered C4-OTf (Fig. 1). The axially oriented C2-triflate group
effectively shields the top face of D-mannoside allowing the
reaction to take place at C2 from the easily accessible bottom
face, preferentially. The selectivity is achieved by employing an
exact stoichiometric amount of a bulky TBA reagent, using low
Scheme 2 Preparation of common intermediate diols 2a/2b via regioselective
protection.
4826 | Org. Biomol. Chem., 2013, 11, 4825–4830
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
exclusively in 54% and 56% overall yields, respectively. Finally,
the 3-hydroxy GalN3 derivatives could be accessed by employ-
ing the acetate migration protocol. Accordingly, triflation of
2a, evaporation of CH2Cl2, and a successive low temperature
addition of TBAN3 in CH3CN cleanly generated the corres-
ponding 2-azido-4-OTf derivative as a single product, as evi-
denced by TLC. To this, addition of H2O and subsequent
heating at 65 °C for 90 min afforded the 3-hydroxy GalN3
derivative 9 (56%), in a one-pot manner. In this case, the 3-O-
acetyl group migrated from C-3 to C-4 along the top face of the
sugar to displace the C4-triflyloxy group with inversion at
C-4.14,22 The free 3-OH in 9 was capped by a chloroacetate
group to obtain orthogonally and fully protected D-galactos-
amine building block 10 (85%), which upon selective removal
of the TBDPS group using TBAF delivered the 6-OH galacto-
samine derivative 11 (82%). Thus a complete set of ortho-
gonally protected D-galactosamine building blocks could be
rapidly synthesized from D-mannose in a highly efficient
manner. All the monosaccharide building blocks are
thoroughly characterized by using H, 13C and 2D NMR spec-
1
Scheme 3 Synthesis of orthogonally protected D-galactosamine building
tral analyses (see ESI†). These valuable thioglycoside building
blocks can be utilized as stable glycosyl donors or acceptors to
stereoselectively assemble the biologically important glyco-
proteins and oligosaccharides as exemplified by the synthesis
of the disaccharide moiety of zwitterionic polysaccharide A1
and the synthesis of the Tn antigen.
blocks.
concentration of reagents and most importantly, conducting
the displacement at −30 °C. We believe that the steric hin-
drance of the C2-OTf is one of the major deciding factors in
governing the regioselectivity. The fact that the presence of the
bulky O6-TBDPS group is not significant is further confirmed
by conducting similar displacements in D-rhamnosides,
leading to rare sugars.21 Perhaps, the TBDPS group being
attached to the primary position has a much higher degree of
freedom and thus is able to get away from the incoming nitrite
nucleophile during the second displacement.
With these results in hand, we proceeded further to syn-
thesize various orthogonally protected D-galactosamine thiogly-
cosides (Scheme 3). Triflation of diols 2a and 2b, followed by
SN2 displacement of the formed bis-triflates, by using excess
NaN3 in DMF afforded the 2,4-diazido galactose derivatives 5a
and 5b, respectively, in 85% and 84% overall yields, in an
essentially one-pot manner. It was not necessary to work up
the reaction after triflation. CH2Cl2 was evaporated on a rotary
evaporator prior to the addition of sodium azide in DMF. The
double serial inversion also worked well on 2b under identical
conditions optimized earlier for 2a (Table 1, entry 7, 6a, 60%).
Thus, triflation of 2b, followed by a regioselective SN2 displace-
ment of the C2-triflyloxy group at −30 °C by stoichiometric
TBAN3 and a tandem one-pot Lattrell–Dax inversion at C4
using TBANO2 (3.0 equiv.) afforded 4-hydroxy GalN3 derivative
6b, in 61% overall yield. In this transformation, we carried out
a brief aqueous work up after the triflation, so as to obtain the
exact weight of the crude triflate and accordingly add an exact
triflate equivalent of TBAN3 to obtain a single product. By
switching the course of addition of reagents, i.e. first adding
3.0 equivalents of TBANO2 at 0 °C, followed by 3.0 equivalents
of TBAN3 at 0 °C and allowing it to reach RT, the 4-azido,
2-hydroxy galactose derivatives 8a and 8b, could be obtained,
Zwitterionic polysaccharide A1 (ZPS A1) found in Bacter-
oides fragilis is responsible for the ability to form abdominal
abscesses in response to bacterial infections in humans. Due
to its unique zwitterionic structure, it is recognized by T-cells
and can modulate T-cell immune response in the absence of
proteins. It has been explored for the development of entirely
carbohydrate vaccines.23 Two routes for the chemical synthesis
of a ZPS A1 repeating unit have been recently reported.24,25
A facile synthesis of the disaccharide moiety of the ZPS A1
repeating unit using our building block 6a as a glycosyl accep-
tor is shown in Scheme 4. Treatment of thioglycoside 12 21
with bromine, generated the corresponding glycosyl bromide,
which was orthogonally glycosylated with the thioglycoside
acceptor 6a using AgOTf as a promoter to fashion the key dis-
accharide moiety of B. fragilis 13 (81%), with complete
α-selectivity (1H NMR δ 5.19, d, J1′,2′ = 4.0 Hz, H-1′). The
observed α-stereoselectivity in this case can be perhaps attribu-
ted to (1) the presence of non-participating azido group at the
C2 position of the glycosyl donor, and (2) the possible for-
mation of a more reactive β-glycosyl triflate using AgOTf and
its concomitant SN2 type displacement by the nucleophilic
acceptor 6a. The donor and acceptor are also ‘matched’ in
terms of reactivity.26 Disaccharide 13 is perfectly poised for
elaboration into the tetrasaccharide repeating unit; the C3-OAc
can be selectively removed to append the galactofuranoside
unit, the C1-SPh group could be activated to attach the galacto-
pyranoside unit, the C2-azido group would assist in the for-
mation of an α-glycosidic bond and can be selectively reduced
post glycosylation and converted to NHAc in the presence of
NPhth group.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4825–4830 | 4827

View Article Online
Paper
Organic & Biomolecular Chemistry
of thioglycoside 10 using a Ph2SO/Tf2O promoter system35 for
coupling with L-serine acceptor 14 at −60 °C proceeded
smoothly and with complete α-stereoselectivity to afford the
orthogonally protected Tn antigen 15. The O3 chloroacetate
groups in 15 could be smoothly removed using thiourea to
obtain 3-OH 16. Likewise the O6 TBDPS group was selectively
cleaved using TBAF in AcOH to generate 6-OH 17. Compounds
16 and 17 are valuable intermediates for the synthesis of
tumor associated cancer antigens such as STn and TF anti-
gens, respectively, which could be further elaborated into
various mucin type glycoproteins.
Conclusions
In conclusion, we have developed a convenient protocol for the
synthesis of various orthogonally protected D-galactosamine
thioglycoside building blocks from abundant and cheaply
available D-mannose. These stable thioglycosides36 can act as
flexible glycosyl donors or acceptors and can be coupled
together to access various biologically important glycoconju-
gates. The stable azido group not only assists the formation of
α-glycoside but also markedly enhances the reactivity of the
donors and acceptors in glycosylation.37 The inherent poten-
tial of the methodology can be gauged from the synthesis of
the disaccharide unit of the ZPS of B. fragilis and the Tn
antigen.
Glycoproteins, glycolipids and oligosaccharides are emer-
ging as potential glycoconjugate vaccine candidates. Ready
availability of such thioglycoside building blocks in conjunc-
tion with the programmable one-pot oligosaccharide syn-
thesis38 and automated solid phase synthesis39 would expedite
the glycan assembly.40
Scheme 4 Synthesis of the disaccharide moiety of the tetrasaccharide repeat-
ing unit of ZPS A1 from B. fragilis.
To this end, we extended our methodology to synthesize the
Tn antigen. Mucin type O-glycoproteins, in which the oligo-
saccharide moiety is linked via L-serine (Ser) or L-threonine
(Thr) of the proteins, are ubiquitously distributed on the cell
surface. Some of these O-glycosides are specifically over-
expressed on the surfaces of certain cancer cells. This differ-
ence, between the normal glycocalyx and the truncated one,
with the exposed tumor associated carbohydrate antigens
(TACAs), is exploited for the development of anti-cancer
vaccines.27–33 Of these abnormal glycosides, the Tn antigen
which has a simple structure, comprising a GalNAc residue
α-linked to Ser/Thr, is considered to be at the heart of it.34 An
application of building block 10 as a glycosyl donor to syn-
thesize the Tn antigen is shown in Scheme 5. Activation
Experimental
All reactions were conducted under a dry nitrogen atmosphere.
Solvents (CH2Cl2 >99%, THF 99.5%, acetonitrile 99.8%, DMF
99.5%) were purchased in capped bottles and dried under
sodium or CaH2. All other solvents and reagents were used
without further purification. All glassware was oven-dried
before use. TLC was performed on precoated aluminum plates
of silica gel 60 F254 (0.25 mm, E. Merck). Developed TLC
plates were visualized under a short-wave UV lamp and by
heating plates that were dipped in ammonium molybdate/
cerium(IV) sulfate solution. Silica gel column chromatography
was performed using silica gel (100–200 mesh) and employed
a solvent polarity correlated with TLC mobility. NMR experi-
ments were conducted on a Bruker 400 MHz instrument using
CDCl3 (D, 99.8%) or (CD3)2CO (D, 99.9% or CD3OD 99.8%) as
solvents. Chemical shifts are relative to the deuterated solvent
peaks and are in parts per million (ppm). 1H–1H COSY and
HSQC were used to confirm proton assignments. Mass spectra
were acquired in the ESI mode.
Scheme 5 Synthesis of orthogonally protected Tn antigen 15 and its selective
deprotection.
4828 | Org. Biomol. Chem., 2013, 11, 4825–4830
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Phenyl 3-O-acetyl-2-azido-2-deoxy-6-O-t-butyldiphenylsilyl-1-
thio-β-D-galactopyranoside (6a)
6 L. Morelli, L. Poletti and L. Lay, Eur. J. Org. Chem., 2011,
5723–5777.
7 J. Banoub, P. Boullanger and D. Lafont, Chem. Rev., 1992,
92, 1167–1195.
8 J. Debenham, R. Rodebaugh and B. Fraser-Reid, Liebigs
Ann./Recl., 1997, 791–802.
9 A. F. G. Bongat and A. V. Demchenko, Carbohydr. Res.,
2007, 342, 374–406.
10 M. Emmadi and S. S. Kulkarni, J. Org. Chem., 2011, 76,
4703–4709 and references therein.
11 V. Pedretti, A. Veyrières and P. Sinaÿ, Tetrahedron, 1990, 46,
77–88.
12 J. N. Vos, J. H. van Boom, C. A. A. van Boeckel and T. Beetz,
J. Carbohydr. Chem., 1984, 3, 117–124.
13 M. Hederos and P. Konradsson, J. Carbohydr. Chem., 2005,
24, 297–320.
14 H. Dong, Z. Pei and O. Ramström, J. Org. Chem., 2006, 71,
3306–3309.
15 H. Dong, Z. Pei, M. Angelin, S. Byström and O. Ramström,
J. Org. Chem., 2007, 72, 3694–3701.
16 H. Dong, M. Rahm, N. Thota, L. Deng, T. Brinck
and O. Ramström, Org. Biomol. Chem., 2013, 11, 648–
653.
17 K. Sato, S. Akai, A. Yoshitomo and Y. Takai, Tetrahedron
Lett., 2004, 45, 8199–8201.
18 Y. Demizu, Y. Kubo, H. Miyoshi, T. Maki, Y. Matsumura,
N. Moriyama and O. Onomura, Org. Lett., 2008, 10, 5075–
5077.
19 R. Lattrell and G. Lohaus, Justus Liebigs Ann. Chem., 1974,
901–920.
20 R. Albert, K. Dax, R. W. Link and A. E. Stütz, Carbohydr.
Res., 1983, 118, C5–C6.
21 M. Emmadi and S. S. Kulkarni, Org. Biomol. Chem., 2013,
11, 3098–3102.
22 Y. Cai, C.-C. Ling and D. R. Bundle, J. Org. Chem., 2009, 74,
580–589.
Trifluoromethanesulfonic anhydride (2.97 mL, 17.5 mmol)
and pyridine (2.97 mL, 37.6 mmol) were added sequentially at
−10 °C to a stirred solution of 2a (1.58 g, 2.90 mmol) in
CH2Cl2 (60 mL). Then the reaction mixture was gradually
warmed to 10 °C. After 2 h, the reaction mixture was diluted
with CH2Cl2 and washed successively with 1 M HCl, aq.
NaHCO3 and brine. The separated organic layer was dried over
Na2SO4 and concentrated.
The crude product so obtained was dissolved in acetonitrile
(60 mL) and to this, TBAN3 (0.74 g, 2.64 mmol) was added at
−30 °C and this reaction was stirred at the same temperature
for 20 h. After 20 h, TBANO2 (2.4 g, 8.6 mmol) was added and
the reaction mixture was stirred at RT for 1 h. The reaction
mixture was diluted with EtOAc and washed with water. The
separated organic layer was dried over Na2SO4 and concen-
trated in vacuo. The crude product was purified by column
chromatography on silica gel (1 : 9 ethyl acetate–pet ether) to
obtain 6a as a pale yellowish viscous liquid (1.0 g, 60%): [α]D25
+11.4 (c 0.12, CHCl3); IR (CHCl3) ν 3455, 3019, 2932, 2115,
1748, 1523, 1427, 1364, 1217, 928, 770, 669, 623 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.76–7.74 (m, 2H, ArH), 7.69–7.66
(m, 2H, ArH), 7.64–7.61 (m, 2H, ArH), 7.46–7.37 (m, 6H, ArH),
7.30–7.24 (m, 3H, ArH), 4.77 (dd, J = 10.0, 2.8 Hz, 1H, H-3),
4.47 (d, J = 10.0 Hz, 1H, H-1), 4.28 (d, J = 2.8 Hz, 1H, H-4), 4.02
(dd, J = 11.2, 4.0 Hz, 1H, H-6a), 3.92 (dd, J = 11.2, 4.0 Hz, 1H,
H-6b), 3.85 (t, J = 10.0 Hz, 1H, H-2), 3.61 (bs, 1H, OH), 3.51 (t,
J = 4.0 Hz, 1H, H-5), 2.17 (s, 3H, CH3), 1.07 (s, 9H, (CH3)3CSi);
13C NMR (100 MHz, CDCl3) δ 170.3, 135.8, 135.7, 133.6, 132.4,
132.0, 131.2, 130.27, 130.23, 129.24, 128.5, 128.1, 128.0, 86.5,
76.7, 75.8, 68.4, 65.2, 59.2, 26.8, 21.2, 19.2; HR-ESI-MS (m/z):
[M
+
Na]+ calcd. for C30H35N3O5NaSSi 600.1964, found
600.1980.
23 R. A. De Silva, Q. Wang, T. Chidley, D. K. Appulage
and P. R. Andreana, J. Am. Chem. Soc., 2009, 131,
9622–9623.
24 L. J. van den Bos, T. J. Boltje, T. Provoost, J. Mazurek,
H. S. Overkleeft and G. A. van der Marel, Tetrahedron Lett.,
2007, 48, 2697–2700.
Acknowledgements
This work was supported by the Department of Science and
Technology (Grant No. SR/S1/OC-40/2009) and the Council of
Scientific and Industrial Research (Grant No. 01(2376)/10/
EMR-II). ME thanks CSIR-New Delhi for a fellowship.
25 R. Pragani and P. H. Seeberger, J. Am. Chem.Soc., 2011, 133,
102–107.
26 T. Buskas and P. Konradson, J. Carbohydr. Chem., 2000, 19,
25–51.
Notes and references
1 A. Varki, Glycobiology, 1993, 3, 97–130.
2 C. R. Bertozzi and L. L. Kiessling, Science, 2001, 291, 2357–
2364.
3 L. Schofield, M. C. Hewitt, K. Evans, M. A. Siomos and
P. H. Seeberger, Nature, 2002, 418, 785–789.
4 C.-C. Wang, J.-C. Lee, S.-Y. Luo, S. S. Kulkarni,
27 S. J. Danishefsky and J. R. Allen, Angew. Chem., Int. Ed.,
2000, 39, 836–863.
28 C. Brocke and H. Kunz, Bioorg. Med. Chem., 2002, 10, 3085–
3112.
29 T. Buskas, S. Ingale and G.-J. Boons, Angew. Chem., Int. Ed.,
2005, 44, 5985–5988.
Y.-W. Huang, C.-C. Lee, K.-L. Chang and S.-C. Hung, 30 S. Dziadek, A. Hobel, E. Schmitt and H. Kunz, Angew.
Nature, 2007, 446, 896–899. Chem., Int. Ed., 2005, 44, 7630–7635.
5 T. J. Boltje, T. Buskas and G.-J. Boons, Nat. Chem., 2009, 1, 31 D. Lee and S. J. Danishefsky, Tetrahedron Lett., 2009, 50,
611–622.
2167–2170 and references therein.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4825–4830 | 4829

View Article Online
Paper
Organic & Biomolecular Chemistry
32 A. Kaiser, N. Gaidzik, T. Becker, C. Menge, K. Groh, H. Cai, 36 J. D. C. Codée, R. E. J. N. Litjens, L. J. van den Bos,
Y.-M. Li, B. Gerlitzki, E. Schmitt and H. Kunz, Angew.
Chem., Int. Ed., 2010, 49, 3688–3692.
H. S. Overkleeft and G. A. van der Marel, Chem. Soc. Rev.,
2005, 34, 769–782.
33 Z. Yin and X. J. Huang, J. Carbohydr. Chem., 2012, 31, 143– 37 D. Crich and V. Dudkin, J. Am. Chem. Soc., 2001, 123, 6819–6825.
186.
38 Z. Zhang, I. R. Ollmann, X.-S. Ye, R. Wischnat, T. Baasov
and C.-H. Wong, J. Am. Chem. Soc., 1999, 121, 734–753.
39 P. H. Seeberger, Chem. Soc. Rev., 2008, 37, 19–28.
34 T. Ju, V. I. Otto and R. D. Cummings, Angew. Chem., Int.
Ed., 2011, 50, 1770–1791.
35 D. Cato, T. Buskas and G.-J. Boons, J. Carbohydr. Chem., 40 C.-H. Hsu, S.-C. Hung, C.-Y. Wu and C.-H. Wong, Angew.
2005, 24, 503–516.
Chem., Int. Ed., 2011, 50, 11872–11923.
4830 | Org. Biomol. Chem., 2013, 11, 4825–4830
This journal is © The Royal Society of Chemistry 2013