Glycosylated α-Azido Amino Acids: Versatile Intermediates in the Synthesis of Neoglycoconjugates

Article abstract of DOI:10.1055/s-0036-1591902

A series of glycosylated α-azido amino acids was synthesized as precursors for neoglycoconjugates, a class of important biomolecules for drug discovery, and sensor development. The synthetically challenging 1,2- cis α-galactosylated species described here

Full text of DOI:10.1055/s-0036-1591902

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
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R. O’Flaherty, T. Velasco-Torrijos
Letter
Synlett
Glycosylated α-Azido Amino Acids: Versatile Intermediates in the
Synthesis of Neoglycoconjugates
Róisín O’Flahertya,b
Trinidad Velasco-Torrijos*a
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a Department of Chemistry, Maynooth University, Maynooth,
Co. Kildare, Ireland
trinidad.velascotorrijos@mu.ie
b NIBRT GlycoScience Group, NIBRT - The National Institute for
Bioprocessing Research and Training, Fosters Avenue, Mount
Merrion, Blackrock, Co. Dublin, Ireland
Received: 05.11.2017
Accepted after revision: 21.12.2017
Published online: 06.02.2018
has not yet been explored. Thus the synthesis of glycosylat-
ed α-azido amino acid derivatives would allow the inclu-
sion of these intermediates in the tool box of glycoconjuga-
tion chemistry.
DOI: 10.1055/s-0036-1591902; Art ID: st-2017-d0817-l
Abstract A series of glycosylated α-azido amino acids was synthesized
as precursors for neoglycoconjugates, a class of important biomole-
cules for drug discovery, and sensor development. The synthetically
challenging 1,2-cis α-galactosylated species described herein were de-
signed as building blocks in the synthesis of analogues of α-galactosyl
ceramide, a potent immunomodulator. A benzyl-protected 1,2,3-tri-
azolyl α-galactosyl-L-serine derivative was prepared using copper azide
alkyne cycloaddition to showcase the potential of glycosylated α-azido
amino acids in neoglycoconjugate design.
This work describes the synthesis of α-azido-L-serine
glycosyl acceptors using different diazotransfer reagents
and their reactions with orthogonally protected galactosyl
donors to produce α- and β-galactosylated α-azido amino
acid building blocks. As proof of concept of their potential
in the preparation of neoglycoconjugates, the synthesis of
the novel benzyl-protected 1,2,3-triazolyl analogue 1 of the
immunostimulant glycosphingolipid α-galactosyl ceramide
18,19
Key words α-azido amino acid, glycosylation, neoglycoconjugates
1,2,3-triazolyl glycosides, CuAAC reaction
(α-GalCer)
was devised (Scheme 1). The remarkable
biological activity of α-GalCer as an adjuvant in immuno-
therapies has prompted the synthesis of numerous struc-
tural analogues.20,21 Some of these feature the 1,2,3-tri-
azolyl motif, a good surrogate for amide bonds, which may
improve physiological response.22–24 Thus, the preparation
of α-galactosyl glycolipid 1 was envisaged from α-galactosyl
The copper azide–alkyne cycloaddition (CuAAC) has
been used extensively in bioconjugation reactions of pro-
teins, peptides, and glycans.1–4 Thus, glycosyl azides have
become useful intermediates in synthetic carbohydrate
chemistry since they provide access to 1,2,3-triazole neo-
glycoconjugates via the CuAAC reaction.5,6 Neoglycoconju-
gates are synthetic molecules with largely unexplored
physiochemical properties and are finding interesting
applications in many fields of glycobiology.7,8 Many of the
1,2,3-triazole glycoconjugates reported are N-glycosides
prepared from anomeric azides;9 however, the azido group
can also be inserted at other positions in the sugar or as
part of the aglycone.10 O-Glycosylated amino acids are im-
portant building blocks for the synthesis of glycopeptides
and other glycoconjugates.11–13 Rather surprisingly, very
few examples of O-glycosylated α-azido amino acids have
been reported14–16 and even fewer of those refer to 1,2-cis
glycosidic linkages.17 In these reports the azido functional
group is often installed temporarily as a masked amine and
further functionalization by means of the CuAAC reaction
C13H27
OBn
OH
O
OBn
O
OH
O
N
C25H51
OH
N
HO
BnO
N
HN
H
BnO
HO
O
O
N
C14H29
C14H29
OH
O
α-GalCer
1,2,3-triazolyl-OBn-neoglycolipid 1
OBn
OBn
O
OBn
OBn
O
N3
BnO
N3
+
SPh
HO
BnO
BnO
CONHC14H29
O
OBn
CONHC14H29
2α
3c
4
Scheme 1 Synthetic precursors of 1,2,3-triazolyl analogue 1 of
immunostimulant glycoshingolipid α-galactosyl ceramide (α-GalCer)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
R. O’Flaherty, T. Velasco-Torrijos
Letter
Synlett
α-azido L-serine amide 2α, obtained from the reaction of
lipidic α-azido amide 3c and thiophenyl donor 4, in a highly
convergent approach as shown in Figure 1.
NHBoc
COR
N3
i, ii
HO
HO
COR
61%
5a R = OBn
5b R = OMe
3a R = OBn
3b R = OMe
57%
5c R = NHC14H29
3c R = NHC14H29 75%
OBn
OBn
OAc
O
OBn
O
OBn
O
O
SPh
SPh
SPh
BnO
BnO
AcO
O
O
O
O
N
OBn
S
OBn
OBn
S
N3
HN
N3
HCl
4
8
9
HO
N
CONHC14H29
Figure 1 Galactosyl donors 4, 8, 9
6
7
Diazotransfer reaction
side product
Diazotransfer reagent
Firstly, the synthesis of L-serine α-azido glycosyl accep-
tors 3a–c using diazo-transfer methodologies was investi-
gated. Hence, benzyl and methyl α-azido esters 3a25 and
3b,16 respectively, were prepared from their corresponding
N-Boc-protected derivatives 5a26 and 5b as shown in
Scheme 1. The reactions were carried out as one-pot proce-
dures, initiated by the acidic removal of the carbamate pro-
tecting group followed by diazotransfer reaction with
either trifluoromethanesulfonyl (triflyl) azide27,28 or imida-
zole-1-sulfonyl azide 6 and Cu(II) catalysis in basic medi-
um.29 α-Azido esters 3a and 3b were obtained in 61% and
57% overall yields, respectively. In order to make the syn-
thesis of galactosyl α-azido L-serine amide 2 more conver-
gent, the direct conversion of lipidic amide 5c30 to the cor-
responding α-azido derivative 3c was attempted. The con-
version of amines into azides using diazotransfer
methodologies has been extensively studied in amino acid
esters28 and peptides,31 however, there is no literature prec-
edent for this reaction in lipidic amino acid derivatives. We
found that, if imidazole-1-sulfonyl azide 6 was used as the
diazotransfer reagent, the reaction yield decreased signifi-
cantly due to the formation of the side product 7, which
was isolated and identified (see Electronic Supporting
Information, ESI). The optimized conditions for the synthe-
sis of lipidic α-azido amide 3c involved treatment with tri-
fluoroacetic acid followed by diazotransfer reaction with
triflyl azide in a mixture of 3:10:3 of water/methanol/di-
chloromethane to give 3c in 75% yield (Scheme 2).
Scheme 2 Reagents and conditions: i) for 3a,b: 1 M HCl, CH2Cl2, 18 h;
for 3c: TFA, CH2Cl2, 0 °C to rt, 18 h; ii) for 3a: 6, K2CO3, CuSO4·5H2O,
t-BuOH, rt, 6 h; 61% over two steps; for 3b: TfN3, NEt3, CuSO4·5H2O,
CH2Cl2/MeOH/H2O (10:3:3), rt, 18 h; 57% over two steps; for 3c: TfN3,
NEt3, CuSO4·5H2O, CH2Cl2/MeOH/H2O (10:3:3), rt, 18 h; 75% over two
succinimide (NIS) and triflic acid in all cases (except in the
reaction for entry 5); however, the reaction temperature
and solvent were varied.
Perbenzylated galactosyl donor 4 was reacted with L-
serine α-azido benzyl ester 3a in dichloromethane at room
temperature, resulting in a mixture of α- and β-anomers
(10α and 10β) in a combined yield of 71% (Table 1, entry 1).
The anomeric ratio could not be determined from the crude
1
mixture due to overlapping of key signals in the H NMR
spectrum. Chromatographic separation only allowed the
isolation of the α-anomer 10α (26% yield). α-Azido methyl
ester 3b was reacted with galactosyl donor 4 using the
same conditions, to give a 2.2:1 mixture of products
(11α/11β) in 77% yield (Table 1, entry 2). Lowering the tem-
perature (Table 1, entry 3) improved the yield to 84%, how-
ever the α-selectivity was reduced to a 1.8:1 α/β anomeric
ratio. As anticipated, the stereoselective preference for the
α-anomer 11α was significantly increased when using THF
as solvent (Table 1, entry 4) to give a 4:1 mixture of prod-
ucts 11α/11β albeit in a moderate 53% yield. While the for-
mation of glycosides with galactosyl donor 8 have been re-
ported to occur with very high α-selectivity attributed to
the influence of the remote acetyl protecting groups at the
C-3 and C-4 positions,31 the reaction of α-azido methyl
ester 3b with galactosyl donor 8 was only moderately selec-
tive, yielding a 2:1 mixture of 12α/12β products in 63%
yield (Table 1, entry 5). The galactosylation of lipidic α-azido
amide 3c with galactosyl donors 4 (Table 1, entry 6) and 9
(Table 1, entry 7) gave the corresponding products 2α/2β
and 13α/13β in 63% and 80% yield, respectively, with a
slight preference for the α-anomeric product (2.7:1 and
2.3:1 α/β anomeric ratio, respectively).
Galactosyl thiophenyl ethers 4,32 8,33 and 934 were
selected as glycosyl donors suitable for 1,2-cis glycoside for-
mation (Figure 1, see ESI for optimized synthetic proce-
dures). Compounds 8 and 9 are functionalized with ortho-
gonal protecting groups35 and allow different reactivity re-
garding anomeric selectivity based on remote group
participation compared to perbenzylated thioglycoside 4.
Selective functionalisation can also occur with these glyco-
sides, leading to a greater variety of neoglyconjugate pre-
cursors. All donors feature a nonparticipating benzyl ether
at the C-2 position to allow for the formation of the α-glyco-
sylation product.
Glycosylated azido acid derivatives are biomolecules of
interest for the synthesis of structurally novel glycocon-
jugates.37 The galactosylated α-azido acid esters and amides
reported herein can be easily prepared and are valuable
synthetic intermediates in conjugation methodologies in-
The glycosylation reaction of α-azido amino acids 3a–c
was then explored under a range of conditions (Table 1).36
Thioglycoside activation was performed with N-iodo-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
R. O’Flaherty, T. Velasco-Torrijos
Letter
Synlett
Table 1 Galactosylation Reactions of L-Serine α-Azido Amino Acid Derivatives 3a–c
OP
OR'
O
N3
+
SPh
HO
PO
COR
OBn
4, 8 or 9
3a–c
NIS, TfOH
OP
PO
OR'
O
OP
OR'
N3
O
+
O
N3
PO
COR
BnO
O
OBn
COR
2, 10–13a
2, 10–13b
10 P = Bn, R' = Bn
11 P = Bn, R' = Bn
12 P = Ac, R' = Bn
R = OBn
R = OMe
R = OMe
2
P = Bn, R' = Bn
R = NHC14H29
13 P = Bn, R '= CH2CCH R = NHC14H29
Entry
Acceptor
Donor
Product
10
Temp
Solvent
Yield (%)
α/β ratioa
b
1
2
3
4
5c
6
7
3a
3b
3b
3b
3b
3c
3c
4
4
4
4
8
4
9
rt
CH2Cl2
CH2Cl2
CH2Cl2
THF
71
77
84
53
63
63
80
–
11
11
11
12
2
rt
2.2:1
1.8:1
4:1
–60 to –20 °C
rt
0 °C
rt
CH2Cl2
THF
2:1
2.7:1
2.3:1
13
rt
THF
a Anomeric ratio α/β of the product mixture was determined from the integration of key signals in the 1H NMR spectrum.
b Anomeric ratio of the α/β product mixture could not be determined from the product mixture due to overlapping of key signals in the 1H NMR spectrum.
c The promotor used in this reaction was TMSOTF in place of TfOH.
volving azido functionality, such as the CuAAC reaction.38
Lipidic derivatives such as 2α/2β serve as precursors to
novel 1,2,3-triazolyl neoglycoconjugates. To validate poten-
tial applications in this regard, the synthesis of the protect-
ed L-serinyl analogue 1 of the immunostimulant glyco-
sphingolipid α-GalCer was attempted as shown in Scheme
2. Thus, compound 2α was reacted with 1-pentadecyne and
copper(II) sulfate/sodium ascorbate catalysis to give per-
benzylated galactosyl glycolipid 1 in 71% yield (Scheme 3).
Furthermore, glycosides in which azides and alkynes are
present simultaneously are becoming interesting molecular
scaffolds that can lead to macrocyclic derivatives via intra-
molecular CuAAC reactions.39–41 The possibility of applying
such approach in the synthesis of macrocyclic neoglyco-
lipids is presently being explored in our research group
with galactosylated azido amides like 13α/13β, which fea-
ture a propargyl ether at the C-6 position. Optimisation of
the macrocyclization conditions is currently ongoing.
In summary, this work aims to highlight the potential of
glycosylated α-azido acid derivatives as versatile inter-
mediates in the synthesis of novel neoglycoconjugates. α-
Azido L-serine glycosyl acceptors, including the novel lipidic
amide 3c, were prepared by diazotransfer reactions. The
reactivity of these compounds in glycosylation reactions
was demonstrated with a range of orthogonally protected
galactosyl thiophenyl donors. As proof of concept for the
suitability of these novel building blocks in glycoconjugate
synthesis, galactosyl 1,2,3-triazolyl protected neoglycolipid
1 was readily prepared from 1,2-cis-galactosylated lipidic
α-azido amide 2α. Further investigations into the applica-
tion of the glycosylated α-azido acid derivatives described
herein are currently under way.
C13H27
BnO
BnO
BnO
BnO
OBn
O
OBn
O
N
C13H27
N
i
N3
N
BnO
BnO
O
O
CONHC14H29
CONHC14H29
Funding Information
12a
1
Scheme 3 Reagents and conditions: i) CuSO4·5H2O, sodium ascorbate,
The authors want to thank the Irish Research Council (IRC-IRCSET) for
THF/MeOH/H2O (2:2:1), rt, 18 h, 71%.
the award of a Postgraduate Scholarship to Róisín O’Flaherty.
)(
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
R. O’Flaherty, T. Velasco-Torrijos
Letter
Synlett
Acknowledgment
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S
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Amino Acid Derivatives
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2,3,4,6-tetra-O-benzyl-β-D-galactopyranoside (4, 388 mg, 0.61
mmol) and α-azido-L-serine tetradecyl amide (3c, 200 mg, 0.61
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20 h. MeOH was added, and the solvent was removed in the
rotary evaporator. The residue was diluted with CH2Cl2 (20 mL)
and washed with 1 M aq Na2S2O4 (20 mL) followed by brine (20
mL). The organic layer was dried (Na2SO4), filtered, and concen-
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estimated from integration of 1H NMR spectrum signals). The
crude product was purified by flash column chromatography
(PE to PE/EtOAc 5:1). Fractions containing glycosylated products
2α/2β were recovered in a combined yield of 328 mg, 63%. The
α-anomer product 2α could be isolated as a white solid (81 mg,
25
35%): Rf = 0.13 (PE/EtOAc/toluene = 3:1:6); [α]D +34.3 (c, 0.35
in CH2Cl2). IR (NaCl plate, CH2Cl2): νmax = 3350.5, 2924.3, 2858.2,
2108.2, 1726.4, 1452.2, 1261.4 cm–1 1H NMR (300 MHz): δ =
.
0.87 (t, J = 7.3 Hz, 3 H, CH3), 1.25 (br s, 20 H, (CH2)10CH3), 1.37–
1.44 (m, 2 H, NHCH2CH2(CH2)10CH3), 2.95–3.07 (m, 1 H, NHCH),
3.16–3.23 (m, 1 H, NHCH), 3.52–3.54 (m,2 H, H-6, H-6′), 3.68–
3.76 (m, 1 H, H-β′), 3.90–3.96 (m, 3 H, H-3, H-4, H-5), 4.04–4.13
(m, 3 H, H-α, H-β, H-2), 4.38–4.95 (m, 8 H, CH2Ph × 4), 4.87 (d,
J = 3.1 Hz, 1 H, H-1), 6.59 (t, J = 5.0 Hz, 1 H, NH), 7.26–7.36 (m,
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39.5 (NHCH2(CH2)12CH3), 63.0 (C-α), 68.8 (C-6), 69.1 (C-β), 70.0
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128.39, 128.4, 137.9, 138.4, 138.5, 138.6 (aromatics), 166.9
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D