Stereoselective synthesis and properties of glycoazobenzene macrocycles through intramolecular glycosylation

Article abstract of DOI:10.1039/c9cc09853d

An intramolecular glycosylation strategy was used to synthesize a series of new glycoazobenzene macrocycles with high α-selectivity and interesting chiroptical properties. The photoisomerization of an azobenzene template influences mainly the efficiency of the glycosylation.

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Stereoselective synthesis and properties of glycoazo-
benzene macrocycles through intramolecular glycosyla-
tion
Cite this: DOI: 10.1039/x0xx00000x
Received,
Accepted
Chaoqi Lin, Jinbiao Jiao, Stéphane Maisonneuve, Julien Mallétroit and Juan Xie*
DOI: 10.1039/x0xx00000x
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Intramolecular glycosylation strategy was used to synthesize efficiency of the macrocyclization and enlarge the library of
a series of new glycoazobenzene macrocycles with high photoswitchable glycomacrocycles, we decided to employ the
selectivity and interesting chiroptical property. The pho- intramolecular glycosylation approach,12 by linking glycosyl

-
toisomerization of azobenzene template influences mainly the
efficiency of the glycosylation.
donor and acceptor together via non-reacting centre to a photo-
chromic template (Fig. 1). As molecular photoswitch, azoben-
zene has been chosen because of its small size, its excellent
photostability and the large changes in molecular size and
shape induced by the photoisomerization between the thermo-
Macrocycles represent an interesting class of molecules be-
cause of their unique structural, physicochemical and biologi-
cal properties as well as their potential applications in nano-
dynamically favoured
-isomer can thermally return to the more stable
isomer. It’s expected that photoisomerization of the photo-
E-isomer and the energetically higher Z-
1
technology, biology and medicine. Natural and synthetic gly-
isomer.13 The
Z
comacrocycles have attracted increasing interest in chemistry
E
2
and biology. Development of switchable glycomacrocycles is
chromic template would induce large concomitant geometrical
change and the disposition between the glycosyl donor and
glycosyl acceptor, and consequently influence the efficiency
and the stereoselectivity of the macrocyclization by stereoelec-
tronic and conformational effects.
appealing for controlling conformation, function and properties
of macrocycles by applying external stimuli. Light is an ex-
tremely attractive orthogonal stimulus for controlling chemical
and biological systems thanks to its non-invasibility and excel-
lent spatial and temporal precision.3-4 Photochromic molecules
have shown increasing applications not only for reversibly
photomodulating properties of molecules, but also for remote-
controlling chemical reactivity or catalytic activities as pho-
toswitchable catalysts.5,6 Several photoswitchable glycomacro-
cycles have been reported since 2017.7-10 These ‘smart’ gly-
comacrocycles displayed very interesting properties like chiral-
ity transfer and supramolecular chirality, photocontrolled mo-
lecular shape or solubility, as well as multistimuli-responsive
gelation ability in organic solvents.
Macrocycle synthesis remains a challenging task because of
competition between inter- and intra-molecular reactions, and
conformational restriction imposed by the cyclization. The
efficiency of the macrocyclization could be highly influenced
by the conformation of the substrate.11 For the synthesis of
Fig. 1. Photoswitchable glycomacrocycles through intramolecular glycosylation
approach.
7
azobenzene glycomacrocycles through thiourea formation or
9
We decided to use commercially available p- and o-
Glaser coupling, G. Despras and coll. reported that only
Z-
dihydroxy azobenzenes as photochromic templates for the
flowing reasons. First, the hydroxyl group allowed gathering
together the glycosyl donor and acceptor through cleavable
azobenzene-lined substrates underwent the macrocyclization.
To investigate the influence of the photoisomerization on the
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ester function. Second, the
Z
-isomers of
O
-substituted dihy- pling of azobenzene-functionalized glucosyl acceptors 24 or 25
10 and 13) or
droxy azobenzenes are stable at room temperature, permitting with the thioglucoside donors 16 or 17 (for 8,
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to realize the glycosylation without in situ thermal isomeriza- azobenzene-functionalized thioglucosides 18-20 with the gly-
DOI: 10.1039/C9CC09853D
-isomers. Phthaloyl (Phth) and/or cosyl acceptors 2312 or 2612 (for
8
9
,
11 and 12) according to
tion to the more stable
E
succinoyl (Suc) linkers were chosen to investigate the influence Scheme 1. The Phth and Suc linkers can be readily introduced
of relative rigidity/flexibility of the linkers on the intramolecu- into phenyl -thioglucoside 15 and methyl -glucoside 22

-
D
-D
lar glycosylation reaction, while maintaining the chain length. by using phthalic or succinic anhydride; while the azobenzene-
We have firstly prepared photochromic glycosyl donor- functionalized glycosides were prepared by esterification with
acceptor compounds
8
-13 (Table 1) based on
p
- and o-
p
- or o-dihydroxy azobenzenes.
dihydroxy azobenzenes through a convergent strategy: cou-
We have firstly investigated the p-dihydroxy azobenzene
Scheme 1 Synthesis of azobenzene‐linked glycosyl donor‐acceptor pairs 8‐13.
functionalized substrates
intramolecular glycosylation was activated by NIS/TfOH. the H NMR signals after irradiation at 370 nm (Fig. S10). At
Compound with two Phth linkers led to the best yield of the PSS370, 84% of 13 has been converted to the corresponding
macrocyclization (entry 1). Interestingly, the macrocycle was -isomer. The conversion varied from 78 to 89% for
isolated in 60% yield with very good -selectivity ( : 9/1). compounds 13 (Table 1). The thermal stability of 13 has
The intramolecular glycosylation yield dropped to 20% with been followed by monitoring the absorption increase at room
the substrate bearing a Phth linker on the glycosyl donor and temperature in CH Cl , with the half-life (t1/2) estimated to be
a Suc linker on the acceptor side, with excellent -selectivity 114.2 h (Fig. S1,7). The t1/2 values for compounds to 13 are
entry 2). Inversion of the Phth/Suc linkers in 10 furnished between 27.7 h (for 11) to 127.7 h (for 12) (Fig. S2-6,
however the macrocycle as a mixture of isomers ( 1:1) Table S1). Consequently, all the -isomers should be stable
in 12% yield (entry 3). Glycosylation of the substrate 11 with during the glycosylation reaction (2-3 h at -78°C).
two flexible Suc linkers gave the corresponding macrocycle We then studied the photoisomerization effect on the intra-
in 15% yield with complete -selectivity (entry 4). The molecular glycosylation. Substrates to 11 were irradiated at
configuration was confirmed by the coupling constant 370 nm in CH Cl until the PSS to mostly convert into the
.6 Hz for the macrocycles and -isomers. Intramolecular glycosylation of
the formation of several intermolecular glycosylation products with two Phth linkers appeared to be much less efficient than
which remain difficult for separation and characterization. For the : many spots have been observed on TLC. After purifi-
o-dihydroxy azobenzene-linked substrates, intramolecular cation, 12% , 5% of and 16% have been iso-
glycosylation of 12 containing two Phth linkers led to 45% of lated, along with several unidentified oligomers. Consequently,
the macrocycle with complete -selectivity (entry 5), while the photoisomerization of the azobenzene template did not
with Suc and Phth linkers furnished the macrocycle in influence the stereoselectivity of the glycosylation, since main-
0% yield (entry 6). The -configuration was confirmed by the ly -isomers have been obtained. For compounds and 10
).14
with one Phth and one Suc linkers in inverted positions, the
In order to study the influence of photoisomerization on the glycomacrocycle with complete -selectivity has been
glycosylation, photochromic properties were firstly investigat- isolated in 15% yield from , along with 8% of recovered
ed. Compounds 13 can be readily converted into the corre- (entry 2); while reaction of 10 led to a complex mixture of
sponding -isomers under illumination at 370 nm in CH Cl compounds from which we have only isolated 8% of the start-
For example, compound 13 showed a relatively strong π π* ing material 10 without any desired macrocycle (entry
transition ( max = 328 nm) and a weaker forbidden n 11 with two flexible Suc
π* 3).15 Interestingly, the substrate
transition ( in 13% yield with
70 nm resulted in the decrease of the bands at 328, 454 nm complete -selectivity (entry 4). For o-substituted azobenzenes
and appearance of a new band at 440 nm, revealing the to Z 12 and 13, the 12 gave an inseparable mixture of - and
isomerization of 13 (Fig. 2b, orange line). Two isobestic points (ratio 3/1) in 30% yield, while the 13 led only to 6%
can be observed at 282 and 386 nm. The ratio at the photo- of (entry 6). The -azobenzene substrates seem to favour
8 to 11 in E-form (Table 1). The stationary state (PSS) can be determined by the integration of
1
8
E-
1
Z
EZ


/
8
-
Z-
9
2
2

Z-8
(
Z
-
Z-
3

/

Z
4


-
8
J
1’,2’
=
2
2
3
1
,
2
4
. We have also observed corresponding
Z
Z-8
E-8
Z
-
1
-
E
-
1
-
E-8
5

1
3
6-
3


Z
-9
Z-
coupling constant (JC1’,H1’ = 167 Hz for 5-
Z
-2

Z
-
9
E-
8
-
9
Z-
Z
2
2
.


E
-
Z-3

Z-

max = 454 nm) (Fig. 2b, black line). Irradiation at linkers furnished the desired macrocycle Z-4
3

E
Z
-
Z
E-5-

Z
/
E

Z-
Z
:
E
E
-
6
-
Z
2
| J. Name., 2012, 00, 1‐3
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Table 1 Intramolecular glycosylation outcome with azobenzene linked
glycosyl donor-acceptor pairs
Glycosylation from PSS370
Cyclization product
a
b
Glycosylation from E-isomer
Entry
1
E-Azobenzene-linked substrates
Cyclization product
yield, / ratio
Substrate at PSS370
yield, / ratio
2% Z-1
1
only 
+
6
0%
Z/E ≅ 80/20

/: 9/1
5% E-1, only 
+
1
6% E-8
1
5% Z-2
2
0%
only 
2
3
Z/E ≅ 86/14
Z/E ≅ 78/22
only 
+
8
% E-9
1
2%
-
8% E-10

/: 1:1
1
5%
13% Z-4
only 
4
Z/E ≅ 89/11
only 
3
0%
4
5%
5
6
Z/E ≅ 84/16
Z/E ≅ 84/16
Z/E ≅ 85/15
Z-5/E-5 : 3/1
only 
only 
3
0%
6% E-6
only 
E-6
only 
N
N
O
O
O
5
4%
30% E-7/Z-7
only 
O
O
O
7
O
OBn
O
only 
BnO
BnO
O
O
O
BnO
E-7
BnO
OMe
a
b
1
) CH
2 2 2 2
Cl , 4Å, Ar, 5h; 2) NIS (2 equiv.), TfOH (0.4 equiv.), -78 ℃, 2-3h. 1) CH Cl , 4Å, Ar, 5h; 2) irradiation at 370 nm until PSS; 3) NIS (2 equiv.), TfOH
(0.4 equiv.), -78 ℃, 2-3h.
intermolecular glycosylation, leading to complex reaction 12 with two Phth linkers gave better yields of cyclization prod-
products. The above studies demonstrate that the intramolecu- ucts. The photoisomerization influences mainly the efficiency
lar glycosylation outcome is influenced not only by the struc- of the macrocyclization reaction, without significant impact on
ture (
template (
p
- or
o
E
-substituted) and configuration of the photochromic the stereoselectivity with the tested substrates. Having estab-
or -azobenzene), but also by the nature and rela- lished that stereoselective -glucosylation can be achieved
Z

tive position of the used linkers (Phth or Suc). Substrates
8
and with azobenzene template bearing two Phth linkers, we have
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-
1
-1
then used the Phth linker for the mannosylation with the sub-
strate 14 (Table 1, entry 7). Reaction of 14 led to the corre- ty between E- and Z-macrocycles
sponding macrocycle with excellent -selectivity ( has been observed for , with slightly increased intensity (
67 Hz) in 54% yield. photoisomerization at 370 nm = -2.0 M cm at 403 nm), without inversion of helical chirali-
gave 85% of 14 which, after glycosylation, furnished in 30% ty (Fig. S24). It’s also interesting to notice that the correspond-
yield a mixture of E,Z . After thermal return, the mixture is ing maltose-constituted macrocycle did not show chiroptical
totally converted to , confirming the -stereoselectivity properties ( vs ).
for the -isomer. This result suggest that the change from the In conclusion, we have synthesized seven new pho-
gluco to manno glycosyl donor maintained the similar confor- toswitchable glycomacrocycles through intramolecular glyco-
mation favouring the -glycosylation. Finally, the photo- sylation, which enlarges the chiral cycloazobenzene library.
chromic template can be readily cleaved under Zemplen condi- Excellent -stereoselectivity can be achieved by using p- and
( = +5.6 M cm ), indicating an inversion of helical chirali-
E

-
6
. A blue shift of CD bands
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7
J
C1’,H1’
=
Z-7
DOI: 10.1039/C9CC09853D
-
1
-1
1
EZ
Z
-
-7-
E
-
7
-

5
-

7-
Z


tions and acetylated to the corresponding

-disaccharide in o-dihydroxy azobenzenes templates, demonstrating the proof-
8
3% yield from the macrocycle
The obtained excellent -stereoselectivity with both
-substrates might be explained by a relatively favouring con- tion influenced mainly the efficiency of the intramolecular
-face of the interme- glycosylation. Chiroptical property has been observed for two
diate oxocarbenium ion, or by the steric hindrance on the β- of the o-substituted azobenzene macrocycles with inversion of
face. DFT calculations showed that all the macrocycles are helical chirality upon photoisomerization for one of
more stable than the Z- isomers, with the macrocycles bearing them. These newly synthesized photoswitchable glycomacro-
two Phth linkers more stable ( vs ) (Fig. S15-21, cycles with chiroptical property should find interesting applica-
Table S2). The are also more stable than the corre- tions in light-driven materials.
sponding
5
(Scheme S2).
of-concept of using photoswitchable template to achieve the

E EZ photoisomeriza-
and challenging 1,2-cis glycosylation.16 The
Z
formation for the 4-OH attack from the

E
-

EZ

1
,
5
,
7
2-4, 6
E-1,7-
E
-
1
,
7
-
macrocycles (Fig. S22-23).
C. Lin and J. Jiao gratefully acknowledge China Scholarship
Council (CSC) for a doctoral scholarship.
Notes and references
Université Paris-Saclay, ENS Paris-Saclay, CNRS, PPSM, 61 av. du
Président Wilson, 94235 Cachan, France. Email: joanne.xie@ens-
paris-saclay.fr (J. Xie)
Electronic Supplementary Information (ESI) available: [Experimental
section, additional figures and original spectral copies]. See
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Fig. 2. Absorption spectra of
after irradiation at 370 (orange line) and 433 nm (grey line). Normalized absorp‐
tion (c) and circular dichroism spectra (d) of
line) or at PSS370 (orange line) in MeCN.
2 2
6 (a) and 13 (b) in CH Cl before (black line) and
6 (C = 11.4 µM) in E‐isomer (black
4
1
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vestigated their photochromic properties. All macrocycles can
be reversibly photoswitched between E- and Z-isomers under
8
C. Lin, S. Maisonneuve, R. Métivier, J. Xie, Chem. Eur. J. 2017, 23,
UV and visible illumination (see Fig. 2c for the macrocycle
), and high fatigue resistance (Fig. S11-14). Furthermore, we
have found that among the compounds 14, only the
showed chiroptical prop-
E-
1
4996-15001.
6
9
J. Hain, G. Despras, Chem. Commun. 2018, 54, 8563-8566.
1
-
o
-
10 C. Lin, S. Maisonneuve, C. Theulier, J. Xie, Eur. J. Org. Chem. 2019,
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substituted cycloazobenzenes
6 and 7
erties as previously reported glycomacrocycles.7-10 On the CD
spectra, a negative band at 457 nm ( = -2.6 M-1 cm ) and a
-1
1
2
P. Pornsuriyasak, X. G. Jia, S. Kaeothip, A. V. Demchenko, Org. Lett.
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positive band at 323 nm corresponding respectively to n
and π π* transitions of E-azobenzene in acetonitrile have
been observed for (Fig. 2d, black line). The macrocycle
showed also a negative band at 416 nm ( = -1.7 M-1 cm-1)
Fig. S24). Consequently, there are chirality transfers from the
disaccharide to the azobenzene moiety. Irradiation at 370 nm
led to and which induced the inversion of the Cotton
effect in the case of : from negative to positive at 410 nm
π*
2

1
1
3
4
H. M. D. Bandara, S. C. Burdette, Chem. Soc. Rev. 2012, 41, 1809-1825.
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6
7
15 As in the case of Z-8, the recovered E-9 and E-10 might come from the
remaining E-isomers at PSS and/or conversion from the Z-isomers after
the workup.
(
1
6
R. A. Mensink, T. J. Boltje, Chem. Eur. J. 2017, 23, 17637-17653.
Z
-6
Z-7
Z-6
4
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