Synthesis, Conformational Analysis, and Complexation Study of an Iminosugar-Aza-Crown, a Sweet Chiral Cyclam Analog

Article abstract of DOI:10.1021/acs.orglett.0c00503

A new family of chiral C₂ symmetric tetraazamacrocycles, coined ISAC for IminoSugar Aza-Crown, incorporating two iminosugars adopting a ⁴C₁ conformation is disclosed. Multinuclear NMR experiments on the corresponding Cd

Full text of DOI:10.1021/acs.orglett.0c00503

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Letter
Synthesis, Conformational Analysis, and Complexation Study of an
Iminosugar-Aza-Crown, a Sweet Chiral Cyclam Analog
́
Alexandra Bordes, Ana Poveda, Thibault Troadec, Antonio Franconetti, Ana Arda, Flavie Perrin,
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́
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̈
̈
Mickael Menand, Matthieu Sollogoub, Jerome Guillard, Jerome Desire, Raphael Tripier,
́
́
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Jesus Jimenez-Barbero,* and Yves Bleriot*
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ABSTRACT: A new family of chiral C2 symmetric tetraazamacrocycles, coined ISAC for IminoSugar Aza-Crown, incorporating two
4
iminosugars adopting a C1 conformation is disclosed. Multinuclear NMR experiments on the corresponding Cd2+ complex show
that the ISAC is a strong chelator in water and its tetramine cavity adopts a conformation similar to that of the parent Cd−cyclam
complex. Similar behavior is observed with Cu2+ in solution, with enhanced stability compared to the Cu−cyclam complex.
xygen- and nitrogen-based macrocycles, often referred to
as “crowns”, have been long known for their
O
coordinating abilities toward anions and cations. In this
context, sugar-based macrocyclic compounds are of high
interest and demonstrated biological, environmental, and
medical properties.1 Several advantages are associated with
their glycosidic nature including their availability from natural
sources and their polyhydroxylated pattern allowing the
modulation of their physicochemical properties. Furthermore,
their chirality combined with the geometric constraints
brought by the five- or six-membered sugar rings is useful for
the design of conformationally restricted chiral cavities. Thus,
the design of sugar-based macrocycles bearing a combination
of O- and N-donors is appealing and a vast array has been
reported,2 incorporating furanoses, pyranoses, and disacchar-
ides. Depending on the size of the macrocycle and/or the
number of oxygen and nitrogen donor atoms, different guests
can be accommodated. Large 15- to 19-membered rings
bearing up to three nitrogen atoms (1−3, Figure 1) have been
used as excellent ligands for large and/or hard (according to
HSAB theory) guests, such as amino acids3 or ammonium4−7
and alkali metal cations.8 Smaller 14-membered rings with two
oxygen and two nitrogen donors (4−5, Figure 1) have been
designed to accommodate softer or smaller transition metal
cations, such as cadmium(II), mercury(II), and copper-
(II).9−11
Figure 1. Structures and targeted guests of known and new polyaza
sugar-based macrocycles 1−6.
binding of transition metals, heavy metals, and lanthanides,
especially after their mono- or poly-N-functionalization. In
particular, cyclam is one of the azamacrocycles that has been
Received: February 11, 2020
Tetra-azamacrocycles, such as cyclam (1,4,8,11-tetraaza-
cyclotetradecane), constitute another specific class of ligands
that have been extensively studied for their complexation
properties.12,13 They have been exploited for the selective
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advantageously employed during these past decades in
extraction,14 catalysis,15−17 supramolecular,18 sensing,19 bio-
inorganic,20 and medicinal chemistry.21 Although they have
been decorated with appended carbohydrates on side chains,
for formulation or medical imaging purposes,22−24 sugar motifs
have never been, to the best of our knowledge, directly
included within the skeleton of such polyazamacrocycles. In
order to take the best of both worlds, we postulated that
incorporation of iminosugars, sugar analogues in which the
endocyclic oxygen has been replaced by nitrogen, could be of
interest to generate new “sweet” constrained cyclam
derivatives, which physicochemical properties could be tuned
thanks to their polyhydroxylated nature. Iminosugars have thus
far been almost exclusively developed as therapeutic
candidates25,26 targeting carbohydrate processing enzymes.
Herein, we report the synthesis, conformational analysis, and
preliminary ion-binding study of a new nitrogen-containing
sugar-based macrocycle coined iminosugar azacrown (ISAC) 6
(Figure 1).
NaBH(OAc)3. Two solvents (THF, CHCl3) and three sources
o f p h o s p h i n e ( s u p p or t e d P P h 3 , P M e 3 , a n d
Ph2PCH2CH2PPh232) were screened, all leading to the
expected ISAC 13 albeit in poor yield (10−40%) that was
contaminated with traces of phosphine species in all cases
(Scheme 1). To gain insight into this unsatisfactory
dimerization, the reaction was monitored by H NMR in
CDCl3 at room temperature over a 4.5 h period using PPh3 as
the phosphine source (Figure 2). We observed the progressive
1
To build the tetraazamacrocyclic framework, we explored an
intermolecular macrocyclization, relying either on a reductive
amination or on a Staudinger-aza-Wittig (SAW) reaction, a
strategy successfully applied for the construction of sugar-aza-
crown (SAC) ethers.11,27 The required iminosugar-based
azidoaldehyde was prepared as follows. The known azidolactol
728 was submitted to a SAW reaction using PMe329 to provide
the corresponding bicyclic hemiaminal 830 that was directly
treated with AllMgBr and N-benzylated to afford the
hydroxyazepane 9. Mesylation of the free OH in 9 provided
the ring-contracted chlorinated piperidine 10. A subsequent
azide displacement yielded the azido-piperidine 11 in 74%
yield. Finally, oxidative cleavage of the allylic moiety with
OsO4/NaIO4 in the presence of 2,6-lutidine31 furnished the
target azidoaldehyde 12 (Scheme 1), the structure of which is
guided by the necessity to have relatively flexible arms
provided by the two carbon and three carbon appendages to
favor dimerization and disposed in a trans-relationship to avoid
intramolecular coupling. The dimerization of 12 was examined
next, the crude expected di-imine being further reduced with
Figure 2. Monitoring of the Staudinger−aza-Wittig reaction of
azidoaldehyde 12. Top: Proposed reaction pathway for the
Staudinger/Aza-Wittig reaction of azidoaldehyde 12. Bottom: selected
regions of the 1H NMR monitoring (CDCl3, 400 MHz, 300 K) of the
reaction of 12 with PPh3 and graph of the integrals intensity variation
during the reaction
consumption of the starting azidoaldehyde 12 (1H at 9.7 ppm)
affording the transient iminophosphorane A (1H at 9.6 ppm).
This latter converts to the bicyclic imine B (1H at 8.2 ppm)
that slowly equilibrates with the detrimental bicyclic enamine
C (1H at 6.3 ppm). The ESIMS analysis of the mixture after
195 min confirms the hypothesis, showing not only the
different intermediates but also the expected cyclic imine
dimer (see Supporting Information (SI)). These results forced
us to examine the alternative reductive amination route.
Azidoaldehyde 12 was reduced to the crude aminoaldehyde 14
that was directly engaged in a double reductive amination in
the presence of NaBH(OAc)3 identified as the reagent of
choice for imine reduction for such a motif.27 Satisfyingly, the
protected ISAC 13 was isolated in 60% yield after preparative
HPLC purification, its hydrogenolysis affording the target
ISAC 6 (Scheme 1).
Scheme 1. Synthesis of ISAC 6
The geometry in water of ISAC 6 was next studied through
extensive NMR analysis, supported by molecular modeling
1
protocols. The relative simplicity of its H NMR spectrum
associated with the presence of only one set of sugar protons
confirmed its C2 symmetry in the chemical shift NMR time
scale. Both iminosugar rings adopts a chair conformation with
the OH groups in the equatorial position as deduced from the
observed large coupling constants (J2,3 = J3,4 = J4,5 = 9.5 Hz)
(Figure 3A) and intraresidue NOEs (H1/H2, H2/H4, H3/
H5) (see SI). Analysis of the coupling constants of the
aminated arms connecting the iminosugar units suggested
some flexibility around the C6−C7−N moiety. In fact, larger
temperature coefficients were observed for the 1H NMR
1
signals at positions 7 and 8, while the rest of the H NMR
signals were barely altered (see SI). Moreover, medium size
B
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1
Figure 4. H NMR titration of the complexation of 113Cd2+ by ISAC
6 at 3.5 mM in Na2CO3/NaHCO3 buffer at pH = 11 in H2O/D2O
(9:1) at 298 K, with increasing amounts of CdCl2 (93.35% 113Cd2+)
solution in D2O.
Figure 3. Conformational study of ISAC 6 in D2O by NMR assisted
by molecular mechanics. (A) 1H NMR spectrum of ISAC 6 at 1 mM
in Na2CO3/NaHCO3 buffer at pH = 11 in D2O and 298 K. (B)
Possible conformations of ISAC 6 according to MM3* conforma-
tional search and NMR analysis.
coupling constants (between 6.5 and 8 Hz) were also deduced
(see SI). Indeed, molecular mechanics calculations showed an
ensemble of structures differing in the C6−C7 and C7−N
torsion angles that could be clustered into four different
families (conformers A−D), conformer A being the global
energy minimum (Figure 3B).
Because of the structural similarity between ISAC 6 and
cyclam, its ability to chelate divalent cations was scrutinized.
To gain insight into the metal binding event, we first
investigated cadmium(II) coordination as 113Cd is an NMR
active nucleus with the potential of providing structural
information through coupling constants and chemical shifts
analysis.17,33 ISAC 6 was titrated with a solution of 113Cd2+
enriched (93.35%) CdCl2 solution until the 1:1 complex was
formed. A slow exchange process in the NMR chemical shift
Figure 5. Superimposition of the 1H−15N HSQC (blue) and
1H−113Cd HSQC (red) spectra for the ISAC 6−Cd complex.
temperature experiments showed that the exposure of the NH
protons to the solvent is different. The measured temperature
coefficients indicated that NH(a) is more exposed to solvent
than NH(b) (see SI).
1
time scale was observed (Figure 4). Notably, the H NMR
signals of the NH groups were visible, but only when the ISAC
6−Cd complex was formed, strongly suggesting that the
exchange process with the water solvent is slowed down, the
typical nitrogen inversion is blocked, and the NH orientation
becomes fixed.
Additional NOE experiments showed strong NH(a)/H6-ax
and NH(a)/H4 cross peaks confirming the axial disposition of
the NH(a) further supported by the 3J coupling constants with
H5 (12.6 Hz, ax−ax) and H1 (3.4 Hz, ax−eq) (Figure 6). For
NH(b), the ax−ax coupling pattern is evident through H5−
H6ax−H7ax−NH(b), also assessing the axial orientation for
this NH. Thus, the N−H bonds point toward the same face of
the molecule as expected for a trans-I (R,S,R,S) type
conformation, which is in full agreement with all the
experimental NMR data (Figure 6 and SI).
We finally investigated copper(II) coordination by the ISAC
ligand. ISAC 6 with 1 equiv of Cu(ClO4)2·6H2O was placed in
water at pH 6.4, and the mixture was heated for 2 h at 50 °C
while adjusting the pH at 6.4. The dark blue solution suggested
rapid formation of the desired complex that was isolated by
precipitation in a water/acetone mixture. The targeted ISAC
Thus, H−15N and H−113Cd HSQC NMR experiments
were performed (Figure 5). The 1H−113Cd spectrum (Figure 5
red) showed only one signal for the 113Cd-containing complex
(δ(113Cd) = −387 ppm). Indeed, the chemical shift of this
signal did not change with the addition of more Cd2+
equivalents, strongly suggesting that only one type of complex
was generated. Moreover, strong heteronuclear correlations to
the 113Cd were found for the two NH’s and for only one
proton of each of the two CH2 groups 7 and 8, those close to
NH(b), indicating that these methylene protons display an anti
orientation with respect to the cation. Interestingly, variable
1
1
C
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mV when scanning from 50 to 1000 mV·s−1. This
demonstrates the enhanced stability of the ISAC 6−copper(I)
complex compared to its cyclam parent complex, for which an
irreversible reduction wave is described in the literature.36 To
further gain insight into this ISAC 6−copper(I) stability, a
pseudoelectrolysis was conducted by scanning from 0.3 to
−0.1 V and holding this potential for 30 s to trigger local
generation of the Cu+ complex (Figure 7D). When scanning
back to 0.3 V, the current jump and the intact oxidation wave
confirmed the stability of the Cu+ complex at the cyclic
voltammetry scale, which is very promising in this ligand
family. Another important factor in the characterization of
coordination complexes is the kinetic inertness of the complex
when placed in competitive media. As the nitrogen-based
macrocycles are highly basic (cyclam pKa’s = 11.29, 10.19,
1.61, 1.91),37 the kinetic inertness of their complexes can be
assessed by competition with protons in acidic solutions and
their degradation followed by UV−vis with the typical decrease
of the copper d−d transition band over time. ISAC 6−
copper(I) complex inertness was assessed at 20 °C in 1.5 M
HCl solution in distilled water. It proved very stable, as its UV
spectrum did not change after 15 days while a half-life of 42
min was recorded for the cyclam−Cu complex (see SI).
In conclusion, the synthesis of an iminosugar azacrown is
disclosed. In the resulting C2 symmetric macrocycle, some
flexibility around the aminated arms has been observed by
NMR, which disappears upon binding to Cd2+, suggesting an
interesting interplay between preorganization and flexibility.
Importantly, the ISAC 6−Cu2+complex adopts a geometry
comparable to that of the parent cyclam−Cu2+ complex, with
significantly enhanced coordination ability in solution. This
constitutes a first entry in the coordination chemistry of this
new class of azamacrocycles.
Figure 6. DFT calculated structure for the ISAC 6−Cd2+ complex
according to the NMR data
6−Cu2+ complex was identified through ESI-MS spectrometry
(see SI) and compared to the cyclam−Cu2+ complex prepared
in parallel.34 Its EPR analysis shows the four expected lines at
low field and no superhyperfine splitting (Figure 7A) in
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00503.
Experimental procedures, characterization data for
1
compounds 7−13, copies of H and 13C NMR spectra
for compounds 6, 12, and 13; monitoring of the
Staudinger−aza-Wittig reaction with 12 by NMR and
MS; study of the ISAC 6−Cu2+ complex (stability,
analogy with cyclam−Cu2+ complex) by EPR, cyclic
voltammetry and UV−vis spectroscopy; NMR con-
formational study of ISAC 6 and its complex with Cd2+
(PDF)
Figure 7. Study of the Cu2+−ISAC 6 complex: (A) By EPR (X-band):
Overlap of Cu−ISAC and Cu−cyclam at 143 K in DMF/water (1:1);
(B−D) by cyclic voltammetry: (B) scan from 0.5 to −0.5 V at 100
mV·s−1; (C) overlap of different scan rates from 0.3 to −0.1 V; (D)
pseudoelectrolysis (30 s hold at −0.1 V).
agreement with a mononuclear copper(II) complex with a
square planar geometry (see SI). Comparison with the Cu−
cyclam spectrum showed high similarity in the electronic
parameters demonstrating a similar conformation in these
conditions. One of the main pathways in copper(II) complex
demetalation, and particularly in the case of in vivo use, is the
reduction to copper(I) and subsequent decoordination.35
Thus, to investigate the stability of the ISAC 6−Cu2+ complex
against reduction, electrochemical measurements were con-
ducted. A large scan showed the contribution of the other
oxidation states (Figure 7B); thus, the redox behavior of the
Cu2+/Cu+ couple was assigned upon scanning from 0.3 to
−0.180, with increasing scan rates (Figure 7C). Quasi-
reversible behavior of the redox couple was evidenced, with
AUTHOR INFORMATION
■
Corresponding Authors
́
́
̀
Yves Bleriot − Universite de Poitiers, Equipe “Synthese
Organique”, Groupe Glycochimie 4 rue Michel Brunet, 86073
Poitiers cedex 9, France; orcid.org/0000-0002-3209-9282;
Email: yves.bleriot@univ-poitiers.fr
́
́
Jesus Jimenez-Barbero − CIC bioGUNE, Parque Tecnologico
́
de Bizkaia, Derio-Bizkaia 48160, Spain; IKERBASQUE,
Basque Foundation for Science, 48009 Bilbao, Spain; Dept.
Organic Chemistry II, Faculty of Science and Technology,
University of the Basque Country, 48940 Leioa, Spain;
orcid.org/0000-0001-5421-8513; Email: jjbarbero@
cicbiogune.es
E
1/2 = 0.01 V (vs Ag/AgCl) and ΔEp ranging from 110 to 150
D
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Organic Letters
Authors
pubs.acs.org/OrgLett
Letter
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Ana Poveda − CIC bioGUNE, Parque Tecnologico de Bizkaia,
Derio-Bizkaia 48160, Spain; orcid.org/0000-0001-5060-
2307
Thibault Troadec − Universite de Brest, UMR-CNRS 6521
CEMCA, 29200 Brest, France
Antonio Franconetti − CIC bioGUNE, Parque Tecnologico de
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Mickael Menand − Sorbonne Universite, CNRS, Institut
́
Parisien de Chimie Moleculaire, 75005 Paris, France;
orcid.org/0000-0003-0174-9120
Matthieu Sollogoub − Sorbonne Universite, CNRS, Institut
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Jerome Desire − Universite de Poitiers, Equipe “Synthese
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CEMCA, 29200 Brest, France; orcid.org/0000-0001-9364-
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ACKNOWLEDGMENTS
■
YB acknowledges financial support from the European Union
(ERDF) and “Region Nouvelle Aquitaine”. J.J.B. thanks the
́
2
European Research Council for financial support (ERC-2017-
AdG, Project Number 788143-RECGLYC-ANMR). J.J.B. also
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Configurations and Fixation of CO2. Inorg. Chem. 2002, 41 (17),
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Polyammonium Macrocycle for Anion Naked-Eye Recognition. Org.
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thanks Agencia Estatal Investigacion of Spain, AEI (Grant
RTI2018-094751-B-C21, a Juan de la Cierva contract to A.F.,
and the Severo Ochoa Excellence Accreditation (SEV-2016-
0644). T.T. and R.T. thank the “Service Commun RMN-RPE”
́
from UBO for EPR measurements, and Dr. Noemie Lalaoui
(UMR CNRS 6521, Brest) for cyclic voltammetry studies.
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