A facile synthesis of sialylated oligolactosamine glycans from lactose via the Lafont intermediate

Article abstract of DOI:10.1039/c4sc01013b

The 2-aminophosphonium iodide lactosamine glycoside (Lafont intermediate) readily obtained from lactose has been previously shown not to be amenable to derivatization for oligosaccharide synthesis, but has now been successfully converted via the salicylaldehyde imine into suitably protected lactosamine building blocks (13-16) for glycosylation. The titled strategy has enabled us to rapidly synthesize the Neu5Ac-α-2,3LacNAc-β-1,3LacNAc pentasaccharide and Neu5Ac-α-2,3LacNAc-β-1,3LacNAc-β-1,3LacNAc heptasaccharide. Furthermore, this strategy has been adopted for the synthesis of other 2-amino sugars (e.g., 23-27), which provides a useful method for the preparation of 2-amino sugar building blocks.

Full text of DOI:10.1039/c4sc01013b

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A facile synthesis of sialylated oligolactosamine
glycans from lactose via the Lafont intermediate†
Cite this: Chem. Sci., 2014, 5, 3634
a
a
a
b
acd
*
Peng Peng,‡ Han Liu,‡ Jianzhi Gong, John M. Nicholls and Xuechen Li
The 2-aminophosphonium iodide lactosamine glycoside (Lafont intermediate) readily obtained from
lactose has been previously shown not to be amenable to derivatization for oligosaccharide synthesis,
but has now been successfully converted via the salicylaldehyde imine into suitably protected
lactosamine building blocks (13–16) for glycosylation. The titled strategy has enabled us to rapidly
synthesize the Neu5Ac-a-2,3LacNAc-b-1,3LacNAc pentasaccharide and Neu5Ac-a-2,3LacNAc-b-
1,3LacNAc-b-1,3LacNAc heptasaccharide. Furthermore, this strategy has been adopted for the synthesis
of other 2-amino sugars (e.g., 23–27), which provides a useful method for the preparation of 2-amino
sugar building blocks.
Received 7th April 2014
Accepted 17th May 2014
DOI: 10.1039/c4sc01013b
www.rsc.org/chemicalscience
synthesis. Nevertheless, due to the intrinsic structural
complexity, the synthesis of these glycans in large amounts is
Introduction
challenging.
The pandemic of inuenza has posed a serious threat in the
public, such as was evidenced by the avian inuenza outbreak
of H5N1 in 1997 and 2003,1 the spread of H1N1 in 2011,2 and
the emergence of H7N9 in 2013.3 The viral surface glycoprotein,
hemagglutinin (HA), recognizes the sialylated glycans present
on the host cell, initiating the rst step of the viral entry.4 Sia-
lylated oligolactosamine glycan structures, including Neu5Ac-a-
2,3LacNAc (30SLN), Neu5Ac-a-2,3LacNAc-b-1,3LacNAc (30SLN-
LN), Neu5Ac-a-2,3LacNAc-b-1,3LacNAc-b-1,3LacNAc (30SLN-LN-
LN), Neu5Ac-a-2,6LacNAc (60SLN) and Neu5Ac-a-2,6LacNAc-b-
1,3LacNAc (60SLN-LN), serve as important determinants for
inuenza infection.5 Recent glycomic analysis of human respi-
ratory tract tissues has revealed the presence of N-glycans with
various length of sialylated a-2,3 oligoLacNAc extension in the
human lung.6 Regarding the novel H7N9 outbreaks, investiga-
tion of H7 receptor preference using biologically relevant
glycans found in the human respiratory tract will provide
important implications for the host adaptation of the H7N9
viruses. In a program aiming to investigate the receptor-binding
specicity of HAs from avian- and human-infecting H7N9
inuenza viruses using STD-NMR,7 the sialylated oligolactos-
amine glycans will be preferably provided by chemical
The past decades have witnessed great advances in the
construction of complex oligosaccharides, and thus it is fair to
state that almost any glycan could be synthesized now if given
enough time and resources.8 Future efforts are suggested to be
oriented to the development of high-throughput synthetic
strategies and methodologies to generate both small and large
quantities of complex glycans.9 In this regard, the identication
of universal building blocks and the rapid and inexpensive
access to the necessary building blocks will accelerate the
provision of glycans of biological interest.9
In the synthesis of the sialylated oligolactosamine glycans, a
bulk of the repeating unit, the lactosamine building block, is
required. The lactosamine structure is present in many bio-
logically relevant glycans, including the human milk glycan,10
Lewis X,11 a-Gal-pentasaccharide,12 and human glycan deter-
minants in N-linked glycoproteins, O-linked glycoproteins and
glycolipds13 (Fig. 1). Thus, a facile synthesis of the lactosamine
building block serving as a universal building block will be of
aDepartment of Chemistry, The University of Hong Kong, Hong Kong
bDepartment of Pathology, Li Ka-Shing Faculty of Medicine, The University of Hong
Kong, Hong Kong
cThe State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong
Kong
dShenzhen Institute of Research and Innovation of The University of Hong Kong,
Shenzhen, P.R. China. E-mail: xuechenl@hku.hk
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral and other characterization data. See DOI: 10.1039/c4sc01013b
‡ These authors contributed equally.
Fig. 1 Glycans containing LacNAc.
3634 | Chem. Sci., 2014, 5, 3634–3639
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great importance in the assembly of the above-mentioned
glycans.
The conventional strategy for synthesis of the lactosamine
building block involves coupling a suitable galactopyranosyl
donor and a suitable glucosamine acceptor (commercially
available N-acetyl lactosamine, 100 mg, 765$, Aldrich).14 In
this regard, a lengthy and laborious synthetic route is neces-
sary to obtain the required specic linkage in terms of both
regioselectivity and anomeric stereoselectivity, and the
installation of orthogonal protecting groups (e.g., 5–6 steps for
the synthesis of each building block). Alternatively, to save
efforts in glycosylation, Danishefsky and co-workers have
obtained a lactosamine derivative through functionalizing the
lactal via iodosulfonamidation.15 Stutz and co-workers have
¨
Scheme
2
Synthesis of the Lafont intermediate from lactose.18
applied the Heyns rearrangement to convert lactulose into a
lactosamine.16
Reagents and conditions: (a) HBr, AcOH, CH2Cl2; (b) Zn, CuSO4$5H2O,
AcOH, H2O; (c) Cu(OAc)2, I2, AcOH, 80 ꢀC; (d) TMSN3, TMSOTf,
CH2Cl2, 78% over 4 steps; (e) EtSH, PPh3, CH2Cl2, 4 A˚ MS, 95%; (f) (1)
Dowex 2X8 (OHꢁ), column filtration; (2) NaOMe, MeOH; (3) Ac2O,
pyridine, 45% over 3 steps.
We wished to seek an alternative, robust and easy-handling
method to convert inexpensive lactose (1 kg, 147$, Aldrich)
into a suitably protected lactosamine building block (i.e. 3,
Scheme 1), which could serve effectively as both a glycosyl
donor and a glycosyl acceptor, thereby enabling one to prepare
sialylated oligolactosamine glycans, including 30SLN-LN and
30SLN-LN-LN. In our design, the properly protected thio-
lactosamine building block 3 is attractive, since thioglycosides
are convenient in the preparation and are stable during many
functional group transformations. Furthermore, in the pres-
ence of many thiophilic agents, they become reactive glycosyl
donors towards glycosylations.17 As the glycosyl acceptor, the
glycosylation will take place selectively at the equatorial OH.14c
Thus, the lactosamine building block 3 will allow for the
extension of the glycan chain from either the reducing end or
the non-reducing end.
the hexa-acylated lactal obtained from lactose in overall 3 steps,
followed by glycosylation with trimethylsilyl azide, afforded
compound 4. Next, the Staudinger reaction with triphenyl-
phosphine at the anomeric azide led in situ to an iminophos-
phorane, followed by rearrangement with the elimination of
iodine at C-2. The resultant aziridine intermediate reacted with
a suitable thiol (or alcohol) to afford the corresponding 2-ami-
nophosphonium iodide lactosamine b-glycoside 5. Indeed, the
Lafont intermediate 5 could be prepared easily on a multi-gram
scale.
However, a critical issue to prevent the potential applica-
tion of this strategy is that the aminophosphonium interme-
diate 5 (i.e., Lafont intermediate) appeared to be very stable
and could be isolated and puried by column chromatog-
raphy. The conversion of this compound to its free-amino
counterpart 7 was not successful at all, while the direct
conversion into the acetamido compound 6 was successful
but in only 45% yield.18 The acetamido is certainly not a
good N-protecting group for glycosylation, due to the forma-
tion of the stable 1,2-oxazoline intermediate under the
glycosylation conditions.19 However, the direct installation of
suitable N-protecting groups on the Lafont intermediate,
including Phth, Troc, and TFA, were fruitless. Thus, despite
the easy and efficient preparation of N-acetyl lactosamine
from lactose, the Lafont intermediate does not serve to
lead to a useful building block for usage in oligosaccharide
synthesis.
Results and discussion
Synthetic plan and conversion of the Lafont intermediate
We initiated our studies by noting an early report by Lafont and
co-workers.18 They have developed an interesting synthesis of N-
acetyl lactosamine 6 from lactose (Scheme 2). Iodoacetylation of
These results have indeed discouraged us. Instead of aban-
doning this route, we decided to seek the conditions enabling
the transformation of the Lafont intermediate into its free-
amino counterpart 7. In our initial efforts, various conditions,
including acidic20 and basic conditions, oxidation with H2O2,
and reduction with LiAlH4, failed to give any promising results
(Table 1, entry 1–5).
Interestingly, when the Lafont intermediate was treated with
KHCO3, the urea 8 was formed (Fig. 2). We have tried many
Scheme 1 Retrosynthesis of sialylated oligolactosamine glycans.
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Table 1 Our studies to convert the Lafont intermediate to a lactosamine derivative
Entry
Reagents
Temperature and time
Product (%)
1
0.2 M HCl
rt, 4 days
None
2
50% H2O2
rt, 2 days
None
3
KHCO3 (aq), EtOH
rt, 2 days
None
4
NEt3
rt, 2 days
None
5
6
LiAlH4
TrocCl, NEt3
Reux, 12 h
rt, 12 h
None
None
7
8
9
Boc2O, NEt3
KHCO3 (aq), THF
KHCO3 (aq), acetone
KHCO3 (aq), MeCN
rt, 12 h
9 (52)
8 (35)
8 (45)
8 (40)
None
10 (18)
10 (0)
10 (10)
10 (8)
10 (10)
10 (30)
11 (53)
11 (57)
11 (61)
11 (65)
11 (80)
40 ꢀC, 1 day
rt, 1 day
10
11
12
13
14
15
16
17
18
19
20
21
22
rt, 1 day
Anisaldehyde, Et3N, toluene
Anisaldehyde, Et3N, toluene
Anisaldehyde, Et3N, MeCN
Anisaldehyde, Et3N, xylene
Anisaldehyde, Et3N, xylene
Anisaldehyde, Et3N, xylene
Anisaldehyde, Et3N, chlorobenzene
Salicylaldehyde, Et3N, toluene
Salicylaldehyde, Et3N, chlorobenzene
Salicylaldehyde, Et3N, chlorobenzene
Salicylaldehyde, Et3N, chlorobenzene
Salicylaldehyde, Et3N, chlorobenzene (1 : 2 : 2)
rt, 3 days
80 ꢀC, 12 h
Reux, 12 h
Reux, 12 h
MW, 120 ꢀC, 30 min
MW, 140 ꢀC, 1 h
MW, 150 ꢀC, 30 min
Reux, 8 h
Reux, 4 h
MW, 130 ꢀC, 1 h
MW, 140 ꢀC, 30 min
MW, 140 ꢀC, 30 min
Next, we turned our attention to see whether the Lafont
intermediate could likely react with an aldehyde to form an
imine, which could then be converted easily to the free-amino
derivative. To our delight, anisaldehyde could react with
compound 5 affording compound 10, albeit in low yield (18%)
(Table 1, entry 12). Nevertheless, aer optimizing the reaction
conditions, the highest yield obtained was only 30% (entry 17).
Aer we took note of the unusually large rate and equilibrium
constant for the imine formation with salicylaldehyde resulting
from hydrogen bonding,23 we tried to use salicylaldehyde to
react with compound 5. Gratifyingly, this time compound 11
was obtained in 53% yield (entry 18). Further optimizations
Fig. 2 The resultant products from the reactions of the Lafont inter-
mediate under the conditions in Table 1.
conditions (entries 8–10), but compound 8 was always the major
product. Although the mechanism is not clear, it is very likely
that the iminophosphorane reacted with CO2 present in KHCO3
solution to generate an isocyanate derivative, which reacted
with the liberated amine to form the urea 8.21 We next pursued
the possibility of the direct protection of 5 with a Boc group
using Boc2O/NEt3 (Table 1, entry 7). Instead, a disaccharide
linked with a carbodiimide bond (9, Fig. 2) was obtained. It
seems likely that CO2 resulting from the decomposition of
Boc2O again reacted with the iminophosphorane to give the
isocyanate, which underwent an aza-Wittig-type reaction with a
Scheme 3 Synthesis of lactosamine glycan building blocks. Reagents
and conditions: (a) 3 M HCl (aq), acetone–CH2Cl2 (8 : 1), 76%; (b) for
second molecule of the iminophosphorane to afford the 13: phthalic anhydride, Et3N, pyridine, then, Ac2O, 95 ꢀC; for 14:
obtained carbodiimide compound.22 Although these efforts
TrocCl, CH2Cl2–H2O (1 : 1), Et3N, rt; for 15: tetrachlorophthalic
were not fruitful towards the desired product, the formation of
compounds 8 and 9 has indicated that the stable N–P bond of
the Lafont intermediate could still be amenable to oxidative
electrophilic attack.
anhydride, Et3N, pyridine, then, Ac2O, 95 ꢀC; for 16: imidazole-1-
sulfonyl azide hydrochloride, NaHCO3, CuSO4$5H2O, MeOH–H2O
(1 : 1); (c) (1) K2CO3, THF–MeOH (1 : 2), then H+ resin; (2) Me2C(OMe)2,
camphorsulfonic acid; (3) BnBr, NaH, 4 A˚ MS, dry DMF, 54% over 3
steps; (d) KHSO4$SiO2, MeOH–CH2Cl2 (1 : 1), 92%.
3636 | Chem. Sci., 2014, 5, 3634–3639
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revealed that the microwave condition can shorten the reaction oligolactosamine glycans. Compound 13 could be transformed
time dramatically (from 8 h to 30 min) with a much higher yield into 17 as a suitable glycosyl donor and 18 as a suitable glycosyl
(80%).
acceptor, through a series of protecting-group manipulations
Next, the conversion of the imine 11 into the free-amino sugar following the known protocol (Scheme 3).26
12 was uneventful with 3 M HCl aq. (Scheme 3) in 76% yield (72%
Compound 18 was then subjected to glycosylation with the
for the 7-g scale). Having obtained compound 12, we were poised sialyl donor 28 to form trisaccharide 29 as the only isomer in a
to synthesize a suitable lactosamine glycosyl donor. To further similar yield as that reported.26 Disaccharide glycosyl acceptor
exemplify the efficiency of this method, compound 12 was pro- 30 was synthesized from 25 through a similar strategy with
tected with the commonly-used Phth, Troc, TCP and azide. All the compound 18 and could be reacted with trisaccharide 29 to
conversions were in good yields using the common preparation obtain the pentasaccharide 31 in 75% yield (Scheme 5).
conditions (Scheme 3). These disaccharides could be further Among NIS/AgOTf,27 NIS/TfOH,28 and p-NO2C6H4SCl/AgOTf29
applied to form the b- or a-glycosides easily.
promoting systems, the latter gave the best yield. All the acetate
groups of compound 31 were removed by NaOMe in MeOH,
followed by the subsequent addition of water to the same ask
to convert the methyl ester of the sialic acid to a carboxylic acid.
Then the Phth protecting group was deprotected with hydrazine
hydrate and the liberated free amine group was selectively
protected with the acetate group. Aer removal of all the Bn
groups under hydrogenation with Pd(OH)2/C, compound 1 was
obtained with an overall yield of 47%.
Next, we continued to synthesize 30SLN-LN-LN. Firstly,
the glycosylation between donor 17 and acceptor 30 using
the p-NO2C6H4SCl/AgOTf-promoting system afforded the
tetrasaccharide in 70% yield. Aer deprotecting the iso-
propylidene group of the obtained tetrasaccharide,
compound 32 was obtained in 91% yield, which was subjected
to the glycosylation with trisaccharide 29. Under the p-
NO2C6H4SCl/AgOTf-promoted glycosylation conditions, the
fully protected heptasaccharide 33 was isolated in 72%
yield. Following the same deprotection procedure as that of
pentasaccharide 31, compound 2 was obtained in 41% yield
over 5 steps (Scheme 6).
Extension of the strategy to other sugars to synthesize 2-
aminosaccharides
Thus, we have developed a two-step strategy to transform the
Lafont intermediate into a derivatizable compound 12 (7 steps
from lactose). Having established the validity of this approach,
we continued to extend the principle of this strategy to prepare
other types of 2-amino sugars from the corresponding
compounds 19–22, which were readily obtained from glycals. To
our delight, various saccharides with different protecting
groups could also proceed smoothly using this protocol to form
the corresponding 2-aminosaccharides (23–27) in 44–60%
overall yields (Scheme 4).
Synthesis of Neu5Ac-a-2,3LacNAc-b-1,3LacNAc (30SLN-LN)
and Neu5Ac-a-2,3LacNAc-b-1,3LacNAc-b-1,3LacNAc (30SLN-
LN-LN)
We selected the Phth-protected compound (i.e., 13) as our key
intermediate to advance towards the targeted sialylated
Scheme 5 Synthesis of 3S0LN–LN. Reagents and conditions: (a) (1)
TMSOTf, 4 A˚ MS, ꢁ40 ꢀC to rt; (2) Ac2O, pyridine, DMAP, 39% over 2
steps; (b) p-NO2C6H4SCl/AgOTf, CH2Cl2, AW 300 MS, 75%; (c) (1)
NaOMe, MeOH; (2) H2O, Dowex 50; (3) NH2NH2$H2O, PhMe, n-BuOH,
90 ꢀC; (4) Ac2O, Et3N, MeOH; (5) Pd(OH)2/C, H2, 3 days, 47% over 5
steps.
Scheme 4 Extension of the strategy to other types of sugars. Reagents
and conditions: (a) EtSH, PPh3, dry CH2Cl2, 4 A˚ MS; (b) salicylaldehyde,
Et3N, chlorobenzene; (c) 3 M HCl (aq.), acetone–CH2Cl2 (8 : 1); (d)
BnOH, PPh3, dry CH2Cl2, 4 A˚ MS. Compounds 19–22 were obtained
according to the literature.18,24,25
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Excellence Scheme of the University Grants Committee (AoE/M-
12/06).
Notes and references
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Scheme 6 Synthesis of 3S0LN-LN-LN. Reagents and conditions: (a) p-
NO2C6H4SCl/AgOTf, CH2Cl2, AW 300 MS, 70%; (b) KHSO4$SiO2,
MeOH/DCM, 91%; (c) p-NO2C6H4SCl/AgOTf, CH2Cl2, AW 300 MS,
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In summary, we have developed a facile synthesis of the sialy-
lated oligolactosamine glycans, including Neu5Ac-a-2,3LacNAc-
b-1,3LacNAc (30SLN-LN) and Neu5Ac-a-2,3LacNAc-b-1,3LacNAc-
b-1,3LacNAc (30SLN-LN-LN). The key feature of the current study
includes a rapid and robust synthesis of a suitably protected
lactosamine building block (i.e., 3) from inexpensive lactose via
the Lafont intermediate. The stable 2-aminophosphonium
iodide lactosamine glycoside has previously been shown not to
be amenable to transformation into a useful glycosyl building
block; however, we found herein that it could react with sali-
cylaldehyde under microwave conditions, affording an imine
derivative, which upon mild acidolysis gave rise to the 2-amino
lactosamine. This strategy could be extended to convert other
types of sugars to form the corresponding 2-aminosaccharides
(23–27). The whole process can be completed in a multi-gram
scale over a short time (ꢂ2 weeks), which provides rapid access
to the necessary building blocking used in automated glycan
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