Synthesis, Resolution, and Absolute Configuration of Chiral Tris(2-pyridylmethyl)amine-Based Hemicryptophane Molecular Cages

Article abstract of DOI:10.1021/acs.joc.7b00559

The synthesis, characterization, and chiroptical properties of a new class of hemicryptophane cages combining a cyclotriveratrylene unit and a tris(2-pyridylmethyl)amine (TPA) moiety are reported. Changing the linkers between these two units allows for the modification of the size and shape of the cavity. The synthesis is straightforward and efficient, providing gram-scale of cage compounds. The racemic mixture of each hemicryptophane host can be readily resolved by chiral HPLC, giving an easy access to the enantiopure molecular cages of which absolute configurations have been assigned by ECD spectroscopy. These new hemicryptophanes are available chemical platforms ready to use for various purposes due to the versatile metal complexation properties of the TPA unit. A Zn(II)@hemicryptophane complex has been obtained and used as a heteroditopic host for the selective recognition of zwitterionic guests.

Full text of DOI:10.1021/acs.joc.7b00559

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Article
Synthesis, Resolution and Absolute Configuration of Chiral Tris(2-
pyridylmethyl)amine-Based Hemicryptophane Molecular Cages
Dawei Zhang, Benjamin Bousquet, Jean-Christophe Mulatier, Delphine Pitrat, Marion
Jean, Nicolas Vanthuyne, Laure Guy, Jean-Pierre Dutasta, and Alexandre Martinez
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 May 2017
Downloaded from http://pubs.acs.org on May 14, 2017
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Synthesis, Resolution and Absolute Configuration of Chiral Tris(2-
pyridylmethyl)amine-Based Hemicryptophane Molecular Cages
a
a
a
a
b
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Dawei Zhang, Benjamin Bousquet, Jean-Christophe Mulatier, Delphine Pitrat, Marion Jean,
b
a
a
b
Nicolas Vanthuyne, Laure Guy, Jean-Pierre Dutasta, Alexandre Martinez*
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a
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Laboratoire de Chimie, École Normale Supérieure de Lyon, CNRS, UCBL, 46 allée d’Italie, F-69364 Lyon,
France.
b
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France.
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ABSTRACT: The synthesis, characterization and chiroptical properties of a new class of
hemicryptophane cages combining a cyclotriveratrylene (CTV) unit and a tris(2-pyridylmethyl)amine
(TPA) moiety are reported. Changing the linkers between these two units allows for the modification
of the size and shape of the cavity. The synthesis is straightforward and efficient, providing gram-
scale of cage compounds. The racemic mixture of each hemicryptophane host can be readily resolved
by chiral HPLC, giving an easy access to the enantiopure molecular cages of which absolute
configurations have been assigned by ECD spectroscopy. These new hemicryptophanes are available
chemical platforms ready to use for various purposes due to the versatile metal complexation
properties of the TPA unit. A Zn(II)@hemicryptophane complex has been obtained and used as a
heteroditopic host for the selective recognition of zwitterionic guests.
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INTRODUCTION
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Molecular cages have attracted considerable attention in the last two decades, leading to
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important applications in recognition, catalysis, separation and reactive species stabilization. In
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particular, biomimetic chiral cages arouse a growing interest because of the important role of
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3
chirality in nature. One prominent example is substrate binding and transformation by enzymes,
3
displaying high chemoselectivity, regioselectivity and stereospecificity. Among the chiral cages,
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hemicryptophanes, which combine a cyclotriveratrylene (CTV) unit with another C
3
-symmetric
1a
2
5
moiety, exhibit remarkable properties in molecular recognition and supramolecular catalysis. The
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promising applications of hemicryptophanes benefit from the rigid bowl shape of the inherently
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chiral CTV unit as well as the feature of variability and easy functionalization of the other C -
symetrical moiety.
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To construct novel hemicryptophane scaffolds, tripodal building blocks, such as tris(2-aminoethyl)-
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amine (tren) and trialkanolamine units, have been attached to the CTV unit. The usefulness and
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easy availability should be considered when choosing this C -symmetric group. In this regard, tris(2-
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pyridylmethyl)amine (TPA) unit appears promising. Indeed, TPA ligand is widely used in coordination
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chemistry, and can bind with various metals, such as Fe, Cu, Zn, Co, Mn, Ru, Rh, Ni, and
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6-7,10b,11b,12
Ln. The resulting complexes have been extensively used in recognition, catalysis,
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chiroptical molecular switches, and enantiomeric excess (ee) determination.
[Fe-(TPA)(MeCN) ](ClO
used as a readily accessible and efficient catalytic system for the visible-light-driven aerobic C-H bond
For instance, the
2
4 2
) complex combined with photocatalyst riboflavin tetraacetate has been
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oxidation of alkyl benzene to ketones and carboxylic acids. The copper complexes of TPA
derivatives have been widely used to catalyze the reactions of atom transfer radical cyclization
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a
7b
7c
(ATRC), atom transfer radical addition (ATRA), and atom transfer radical polymerization (ATRP).
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Moreover, Anslyn and Giulia et al. adopted Zn(II) or Cu(II) complexes of TPA derivatives for rapid
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a,8b,17
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determination of ee of alcohols, carboxylic acids, amines, and amino acids.
This application
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originates from the propeller-like arrangement of TPA ligands around the metal center. The
handedness of the helicity of the TPA analogues can also be controlled by the presence of a
stereogenic center in the ligand backbone, which realizes redox-triggered chiroptical switches, as
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reported by the group of Canary.
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In line with the versatile nature of TPA complexes and their potential applications, we hereby
report on the design and synthesis of a class of TPA-based hemicryptophanes (Figure 1). A
Zn(II)@hemicryptophane complex has also been obtained and used for the selective encapsulation of
zwitterionic guest. The racemic hemicryptophane ligand can be readily resolved by chiral HPLC to
give the enantiopure form in relatively large-scale. Electronic circular dichroism (ECD) spectroscopy
was used to determine the absolute configuration of each hemicryptophane enantiomer. To the best
of our knowledge, the synthesis of enantiopure TPA-based cage molecules is unprecedented and
these enantiopure hemicryptophanes are promising chemical platforms capable of complexation of
various metals for different purposes and applications.
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Figure 1. Structure of the new enantiopure TPA-based hemicryptophanes.
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RESULTS AND DISCUSSION
The structures of the enantiomeric hemicryptophanes M-1 and P-1 (Figure 1) present the following
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features: (i) Firstly, the bowl-shaped CTV unit allows the formation of a well-defined chiral cavity; (ii)
the naphthalene fluorophores, used as hydrophobic “walls” connecting the TPA and CTV units, confer
fluorescence properties to the host; (iii) as mentioned above, the TPA moiety is able to coordinate
with various metals giving rise to chemical platforms for further applications. Two synthesis routes
can be followed to obtain hemicryptophane compounds: i) the [1+1] coupling reaction between a
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CTV moiety and another C
3
symmetrical unit to afford the expected cage, or ii) the triple
1a
macrocylization reaction to build the CTV core in the last step of the synthesis. We anticipated that
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1
the protonation of the TPA unit in formic acid could lead to some preorganization of the precursor
1
a,1b,5a
for the cyclization, thus we decided to adopt the second strategy,
and we first prepared the
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TPA-trichloride 8 (Scheme 1).
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Scheme 1. Synthesis of TPA-trichloride 8.
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Starting from 2,6-pyridinedicarboxylic acid
prepared in two successive steps: chloroformylation with thionyl chloride under reflux followed by
esterification with MeOH at room temperature. The reduction of one ester group in by 1.0 equiv. of
NaBH in CH Cl /MeOH afforded alcohol in 56% yield. Bromide was then obtained quantitatively
by bromination of with PBr at r.t.. The addition of an ammonia solution to in the presence of
CO under reflux for 1 day, gave the TPA-triester in 34% yield. The synthesis of trichloride was
achieved by reduction of with an excess of NaBH followed by chlorination using thionyl chloride,
with an overall yield of 45% (Scheme 1).
2, 2,6-pyridinedicarboxylate 3 was quantitatively
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K
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In order to prepare the hemicryptophane precursor 13, the naphtol derivative 12 was synthesized
according to the pathway described in Scheme 2. Firstly, 2,6-dihydroxynaphthalene was mono-allyl-
protected via its reaction with 1.0 equiv. of allyl bromide in acetone in the presence of K
allyloxynaphtol in 29% yield. Then, reacted with compound 10, obtained in 3 steps as described
previously, in the presence of Cs CO
2 3
CO to give
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a
o
2
2
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2
3
in DMF at 80 C to give 11 in 78% yield. Compound 11 was
o
subsequently deprotected using Pd(II) complex in a H
2
O/THF mixture at 80 C to generate the
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naphtol derivative 12 in 88% Yield.
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Scheme 2. Synthesis of phenol derivative 12.
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Hemicryptophane precursor 13 was prepared in one step (98% yield) by heating a solution of 8 and
o
12 in DMF at 90 C for 3 days in the presence of Cs
2
CO
3
as a base (Scheme 3). The intramolecular
cyclization of 13, first performed in formic acid, led to low yields because of purification issues:
several side products were very difficult to separate from the cage compounds. Finally, the use of
o
stoichiometric amounts of Lewis acid Sc(OTf)
with a yield of 49%.
3
in CH
3
CN at 65 C provided rac-hemicryptophane
(
±)-
1
10
1
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Scheme 3. Synthesis of the racemic mixture of hemicryptophane (±)-1.
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Given the modular feature of this synthetic pathway, we decided to change the naphtyl linkers to
13
phenyl ones in order to prepare the hemicryptophane analogue
(
±)-16 presenting a smaller cavity
5a
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1
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(Scheme 4). Compound 14 was first obtained following the known procedure.
The
hemicryptophane precursor 15 was synthesized from 14, following a synthetic route similar to that
used to get 13 from 12. The macrocyclization of 15 in formic acid afforded the racemic mixture (±)-16
in 90% yield. Remarkably, hemicryptophane 16 was easily isolated by simple precipitation in
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2 2 2
CH Cl /Et O without the need of column chromatography purification. The preorganization of the
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precursor of cyclization in formic acid can account for the remarkable yield obtained. Moreover,
because the yields of the previous steps were relatively high, gram-scale synthesis of (±)-16 could be
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achieved. This constitutes an important step for the future development of this class of host
compounds as sensors or catalysts, considering the common limitation related to the difficulty of
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accessing cage compounds on a large scale.
THPO
(
±)
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OTHP
MeO
O
O
O
O
O
O
O
Cl
Cl
Cl
OMe
O
O
O
O
O
O
Cs2CO3
HCOOH
rt, 2 days
90%
O
N
+
N
N
DMF,90°C, 3 days
N
98%
O
O
N
O
8
N
N
N
OH
N
N
3
14
( ±)-16
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Scheme 4. Synthesis of the racemic mixture of hemicryptophane (±)-16.
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The H NMR spectra of (±)-1 and (±)-16 indicate that the molecules are, on average, of C symmetry
in solution (Figure 2). They display the usual features of the structure of the CTV unit, i.e. two singlets
for the aromatic protons, one singlet for the OCH groups, and the characteristic AB system for the
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a,1b
ArCH bridges.
The protons on aromatic TPA and linkers, and the multiplets for the OCH linkers in
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2
1
each cage were carefully assigned by 2D NMR experiments (see SI).
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Figure 2. H NMR spectra (500.1 MHz, CD
2
Cl
2
, 298 K) of hemicryptophanes (±)-1 (a) and (±)-16 (b) and their
= CHDCl = Et O.
protons assignment.
▼
2
;
▲
2
1
1
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To test the metal coordination ability of the TPA units of hemicryptophanes, we prepared the zinc
complex Zn(II)@16 by mixing the ligand 16 and Zn(ClO ) in a CHCl /CH OH mixture (1/1, v/v)
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16
(Scheme 5). The pure Zn(II)@16 complex gradually precipitates within four hours, and was fully
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characterized in DMSO-d
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by a series of NMR experiments (see SI) and HRMS spectroscopy. The H
NMR spectrum of Zn(II)@16 is consistent with that of the previously reported
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b
Zn(II)@hemicryptophane complex bearing tren unit, and exhibits complicated and broad signals
because of the conformational rigidification of the whole structure induced by the metal
complexation (Figure S11).
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(±)
(
±)
O
O
O
O
O
O
O
O
O
O
O
O
Zn(ClO
Triethylamine
Cl /CH OH = 1/1
7%
4 2 2 6
) (H O)
O
O
O
O
O
O
O
CH
2
2
3
5
O
O
O
O
O
N
N
N
Zn2+
N
N
N
ClO ꢀ
2
4
N
N
16
Zn(II)@16
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Scheme 5. Synthesis of hemicryptophane complex Zn(II)@16.
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Figure 3. Zwitterionic guests G1-G3 tested in this work and H NMR titration spectra (500.1 MHz, 298 K) of G1
1
0
with 1 mM hemicryptophane host Zn(II)@16 in DMSO-d /D O (80/20, v/v).
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The heteroditopic character of the new complex, prompted us to test its recognition properties
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toward zwitterionic guests. As shown in Figure 3, upon stepwise addition of zwitterionic G1 to a
1
13
DMSO-d
6
/D
2
O (80/20, v/v) solution of Zn(II)@16, several signals in the H NMR spectrum shifted
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1
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gradually, indicating that the host-guest complexation is fast on the NMR time-scale. Previously, our
group also reported three other heteroditopic hemicryptophanes which showed high selectivity
1
9a,b
19c
toward either taurine G2
or choline G3 (Figure 3). However, in the present case, no obvious
1
change of the H NMR spectra of Zn(II)@16 was observed after addition of G2 or G3, highlighting the
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selectivity of the new host and also the possibility to tune the structure of hemicryptophanes to
encapsulate selectively a targeted zwitterionic guest of biological interest.
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As enantiopure hosts are very helpful in chiral recognition, asymmetric catalysis, and chirality
2
sensing, we optically resolved the hemicryptophane racemates (±)-1 and (±)-16 using chiral HPLC
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(see SI). In the case of
mm) with an enantioselectivity of 1.52 and
heptane/ethanol/CH Cl /triethylamine (20/40/40/0.1) as the mobile phase. At preparative scale,
(
±)-1, the two enantiomers were separated on a Chiralpak IA column (250 × 4.6
6
a
resolution of 2.3, using
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2
2
8
after multiple injections on a Chiralpak IA column (250 × 10 mm), around 80 mg of each enantiomer
9
were obtained in 12 h with ee values of 99% and 90% for the first and second eluted compounds,
10
respectively. For (±)-16, the same eluent used with a Chiralpak ID column, gave the two enantiomers
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1
1
1
1
2
3
4
with an enantioselectivity of 1.51 and a resolution of 4.6 for the analytical separation. Preparative
scale separation afforded around 50 mg of each enantiomer with ee values > 99% in 3 h. The
absolute configuration of each enantiopure hemicryptophane was determined by ECD spectroscopy
20
2 2
recorded in CH Cl at 298 K by comparison with already assigned hemicryptophanes. As shown in
15
Figure 4, in both cases, the spectra of the first eluted enantiomers exhibit a characteristic positive-
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1
6
7
negative bisignate curve from 230-250 nm corresponding to the M-configuration. The second eluted
20
enantiomers show mirrored ECD signals allowing the assignment of the P-configuration.
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2
9
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Figure 4. Experimental ECD spectra in CH
2
Cl
2
at 298 K of: (a) (+)-(P)-1 (blue) and (–)-M-1 (green), and (b) (+)-(P)-
16 (blue) and (–)-M-16 (green).
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1
CONCLUSION
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In summary, we have described the synthesis of two hemicryptophanes (1 and 16) belonging to a
new class of TPA-based hemicryptophane cages. According to the metal binding abilities of the TPA
units, these hemicryptophanes are chemical platforms available for various purposes and
applications. This has been illustrated by the preparation of a Zn(II) complex and its subsequent use
for the selective recognition of zwitterionic guests. Despite the 14 steps involved in the synthesis of
each molecular cage, all the reactions are quite straightforward with relatively high yields. In
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particular, benefiting from a remarkable 90% yield for a triple macrocyclization reaction, gram-scale
synthesis of hemicryptophane 16 was achieved. The racemate of each hemicryptophane can be
readily resolved by chiral HPLC to give the enantiopure cages of which absolute configurations have
been assigned by ECD spectroscopy. Currently, the preparation of metal complexes for these new
cages, such as Cu(I) and Fe(II), and their applications in molecular recognition and supramolecular
catalysis are being investigated and will be reported in due course.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
EXPERIMENTAL SECTION
8
9
Methods and Materials. All reactions were carried out under argon by means of an inert gas/vacuum
double manifold and standard Schlenk techniques. Dichloromethane was dried and degassed on a
solvent station by passage through an activated alumina column followed by argon flush. Other
10
1
13
1
1
1
2
solvents were dried prior to use over molecular sieves. H and C NMR spectra were recorded at
500.1 and 125.7 MHz, respectively, and chemical shifts are reported relative to the residual solvent
δ
13
signal. The HRMS-ESI mass spectra were recorded in positive-ion mode (or negative) on a hybrid
quadrupole time-of-flight mass spectrometer with an electrospray ionization (ESI) ion source. Specific
1
1
4
5
2
-1
rotations (in deg cm g ) were measured in a 1 dm thermostated quartz cell on a Jasco-P1010
16
17
polarimeter. Circular dichroism spectra were recorded on a CD6 Jobin-Yvon dichrograph.
Synthesis of 8 and 9. Compound 8 was prepared starting from 2,6-pyridinedicarboxylic acid 2
1
8,21
1
1
8
9
according to the reported procedures.
Compound 9 was synthesized according to the published
2
2
procedure.
2
0
2 3
Synthesis of 11. A solution of 9 (100 mg, 0.500 mmol), 10 (172 mg, 0.500 mmol), and Cs CO (244 mg,
o
21
0.750 mmol) in DMF (4 mL) was stirred for 2 days at 80 C under argon. Then AcOEt (30 mL) and 10%
aqueous NaOH (30 mL) were added. The organic layer was separated, and the aqueous phase was
extracted with AcOEt (2 × 30 mL). The combined organic layers were washed with 10% aqueous
2
2
2
2
2
3
4
5
2 4
NaOH (2 × 30 mL) and dried over Na SO . After filtration, the organic solvent was removed under
vacuum. The crude product was purified by column chromatography on silica gel with a 400 : 3
26
mixture of CH Cl : MeOH as eluent to give compound 11 as a light yellow solid (180 mg, 0.39 mmol,
2
2
1
2
2
7
8
78% yield). H NMR (CDCl , 298K, 500.1 MHz): δ 7.65 (dd, J= 8.9, 1.9 Hz, 2H); 7.21-7.14 (m, 4H); 7.00-
3
6.93 (m, 3H); 6.19-6.11 (m, 1H); 5.50 (dd, J= 17.3, 1.4 Hz, 1H); 5.35 (dd, J = 10.5, 1.2 Hz, 1H); 4.76 (d, J
= 11.7 Hz, 1H); 4.72 (t, J = 3.6 Hz, 1H); 4.66 (d, J = 5.3 Hz, 1H); 4.50-4.47 (m, 5H); 3.98-3.91 (m, 1H);
29
1
3
3
3
3
3
0
1
2
3
3
3.90 (s, 3H); 3.60-3.56 (m, 1H); 1.93-1.62 (m, 6H) ppm. C NMR (CDCl , 298K, 125.7 MHz): δ 155.2(5),
155.1(9), 149.8, 147.7, 133.4, 131.9, 129.9, 129.8, 128.3, 128.2, 120.6, 119.3(1), 119.2(8), 117.7,
114.2, 112.1, 107.4, 107.3, 97.6, 69.0, 68.8, 68.0, 66.6, 62.4, 56.0, 30.7, 25.5, 19.5 ppm. HRMS (ESI-
+
o
TOF) m/z: [M + Na] Calcd for C28
H
32NaO
6
487.2091; Found 487.2077. M.p. = 99 C.
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0
Synthesis of 12. In a 25 mL round bottom flask, 11 (750 mg, 1.62 mmol), Pd(OAc) (7.3 mg, 0.033
2
mmol), PPh (28.5 mg, 0.110 mmol), NHEt (25.1 mmol), H O (2 mL) and THF (8 mL) were mixed and
3
2
2
o
stirred at 80 C under argon for 4 h. Then the mixture was cooled to r.t., and the solvents were
removed under vacuum. AcOEt (10 mL) was first added and then removed under vacuum twice.
AcOEt (200 mL) and H
separated, and the aqueous phase was extracted with AcOEt (2 × 30 mL). The combined organic
layers were dried over Na SO , and the organic solvent was removed under vacuum. The crude
2
O (100 mL) were then added. After thoroughly mixing, the organic layer was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
4
2 2
product was purified by column chromatography on silica gel with a 20 : 3 mixture of CH Cl : AcOEt
1
as eluent to give compound 12 as a light yellow solid (600 mg, 1.41 mmol, 88% yield). H NMR (CDCl
3
,
1
298K, 500.1 MHz): δ 7.60 (dd, J = 15.1, 8.3 Hz, 2H); 7.18-7.08 (m, 4H); 7.00-6.93 (m, 3H); 5.10 (s, 1H);
4.76 (d, J = 11.7 Hz, 1H); 4.72 (t, J = 3.7 Hz, 1H); 4.50-4.43 (m, 5H); 3.99-3.94 (m, 1H); 3.90 (s, 3H);
11
1
3
1
1
2
3
3
3.61-3.57 (m, 1H); 1.93-1.63 (m, 6H) ppm. C NMR (CDCl , 298K, 125.7 MHz): δ 155.1, 152.0, 149.7,
147.7, 131.8, 130.0, 129.6, 128.5, 127.8, 120.6, 119.6, 118.1, 114.1, 112.1, 109.7, 107.2, 97.7, 68.8,
+
14
67.9, 66.5, 62.4, 56.0, 30.7, 25.5, 19.5 ppm. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C25
H
28NaO
6
o
1
5
447.1778; Found 447.1763. M.p. > 70 C (decomp.).
1
1
6
7
Synthesis of 13. In a 50 mL round bottom flask, 8 (100 mg, 0.230 mmol), 12 (321 mg, 0.757 mmol),
o
Cs CO (337 mg, 1.04 mmol), and DMF (10 mL) were mixed and stirred at 90 C for 3 days. Then the
2
3
18
mixture was cooled to r.t., and DMF was removed under vacuum. CH
were then added. After thoroughly mixing, the organic layer was separated, and the aqueous phase
was extracted with CH Cl (2 × 50 mL). The combined organic layers were dried over Na SO , and the
organic solvent was removed under vacuum. The crude product was purified by column
2 2 2
Cl (200 mL) and H O (200 mL)
1
2
2
2
9
0
1
2
2
2
2
4
chromatography on silica gel with a 18 : 1 mixture of CH
2
Cl
2
: MeOH as eluent to give
1
23
hemicryptophane precursor 13 as a yellow solid (330 mg, 0.207 mmol, 90% yield). H NMR (CDCl
3
,
2
2
4
5
298K, 500.1 MHz): δ 7.72-7.65 (m, 6H); 7.61-7.56 (m, 6H); 7.46 (d, J = 7.7 Hz, 3H); 7.26 (dd, J= 8.9, 2.5
Hz, 3H); 7.20-7.16 (m, 9H); 6.99-6.92 (m, 9H); 5.31 (s, 6H); 4.75 (d, J= 11.7 Hz, 3H); 4.72 (t, J= 3.5 Hz,
3H); 4.49-4.44 (m, 15H); 4.01(s, 6H); 3.98-3.93 (m, 3H); 3.89 (s, 9H); 3.59-3.56 (m, 3H); 1.90-1.54 (m,
26
1
3
2
2
2
3
7
8
9
0
3
18H) ppm. C NMR (CDCl , 298K, 125.7 MHz): δ 159.1, 156.7, 155.3, 155.0, 149.8, 147.7, 137.3, 131.9,
129.9, 129.8, 128.3, 121.8, 120.6, 119.6, 119.3, 119.1, 114.2, 112.1, 107.8, 107.3, 97.6, 70.8, 68.8,
+
67.9, 66.6, 62.4, 60.3, 56.0, 30.7, 25.5, 19.5 ppm. HRMS (ESI-TOF) m/z: [M + H] Calcd for C H N O
96 103
4
18
o
1599.7262; Found 1599.7249. M.p. > 64 C (decomp.).
3
3
3
3
1
2
3
4
Synthesis of hemicryptophane (±)-1. A solution of hemicryptophane precursor 13 (100 mg, 63.0
µmol) in CH CN (18 mL) was added dropwise (4 hours) under argon at 65 °C to a solution of Sc(OTf)
(44 mg, 88 µmol) in CH CN (46 mL). The mixture was stirred under argon at 65 °C for 24 hours. The
3
3
3
solvent was then evaporated. The crude product was purified by column chromatography on silica
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5
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1
2
3
gel with a 200 : 5 : 1 mixture of CHCl : MeOH : triethylamine as eluent to give hemicryptophane (±)-1
3
as a light yellow solid (40 mg, 88 µmol, 49% yield). The crude product could be also used directly for
the following resolution procedure.
-
1
4
5
6
Chiral HPLC analysis for (±)-1. On a Chiralpak IA column (250 × 4.6 mm), with 1 mL.min as flow-rate,
heptane/EtOH/CH Cl /TEA (20/40/40/0.1) as mobile phase, UV detection at 254 nm, Rt(M-1) = 4.7
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
min, Rt(P-1) = 5.6 min, k(M-1) = 0.59, k(P-1) = 0.90, α = 1.52 and Rs = 2.3.
7
8
9
0
Resolution of hemicryptophane (±)-1. The crude product of (±)-1 (320 mg) was dissolved in 25 mL of
-
1
CH
2 2
Cl . On a Chiralpak IA column (250 × 10 mm), with 5 mL min as flow-rate,
hexane/EtOH/CH
2
2
Cl /TEA (20/40/40/0.1) as mobile phase, UV detection at 254 nm, 210 injections of
1
120 µL were stacked every 3.5 minutes. Both enantiomers were collected and the solvent was then
11
evaporated. The first eluted enantiomer ((–), M-1, 84 mg) was obtained with 99% ee, and the second
ꢁꢂ
ꢁꢂ
1
1
2
3
one ((+), P-1, 73 mg) with 90% ee. P-1: [∝] : +38 (c = 0.114; CH Cl ); M-1: [∝] : -35 (c = 0.114;
ꢀ ꢀ
2
2
1
CH
2 2 2 2
Cl ). H NMR (CD Cl , 298K, 500.1 MHz): δ 7.48 (t, J = 7.7 Hz, 3H); 7.36-7.28 (m, 12H); 7.10-7.08 (m,
14
6H); 6.96 (s, 3H); 6.86 (s, 3H); 6.81 (d, J = 2.3 Hz, 3H); 6.76 (dd, J= 8.9, 2.5 Hz, 3H); 5.24 (s, 6H); 4.80
1
3
1
1
5
6
(d, J= 13.7 Hz, 3H); 4.30-4.19 (m, 12H); 4.01 (s, 6H); 3.62 (s, 9H); 3.58 (d, J = 13.7 Hz, 3H) ppm.
C
NMR (CD Cl , 298K, 125.7 MHz): δ 158.8, 156.6, 154.9, 154.6, 148.7, 146.9, 136.8, 133.1, 132.0, 129.7,
2
2
17
129.6, 128.1, 128.0, 122.2, 119.5, 119.2, 118.9, 118.7, 116.6, 113.9, 108.4, 107.4, 70.9, 68.2, 66.7,
+
1
8
60.6, 56.0, 36.2 ppm. For COSY, HSQC and HMBC, see SI. HRMS (ESI-TOF) m/z: [M + H] Calcd for
o
19
C
81
H
73
N
4
O
12 1293.5220; Found 1293.5202. M.p. > 250 C (decomp.).
2
2
2
0
1
2
Synthesis of 15. In a 100 mL round bottom flask, 8 (225 mg, 0.516 mmol), 14 (638 mg, 1.70 mmol),
o
Cs
2
CO
3
(757 mg, 2.32 mmol), and DMF (22 mL) were mixed and stirred at 90 C for 3 days. Then the
mixture was cooled to r.t., and DMF was removed under vacuum. 300 mL CH
were then added. After thoroughly mixing, the organic layer was separated, and the aqueous phase
was extracted with CH Cl (2 × 100 mL). The combined organic layers were dried over Na SO , and
2 2 2
Cl and 300 mL H O
23
2
2
4
5
2
2
2
4
the organic solvent was removed under vacuum. The crude product was purified by column
chromatography on silica gel with a 25 : 1 mixture of CH Cl : MeOH as eluent to give
26
2
2
1
2
2
2
3
7
8
9
0
3
hemicryptophane precursor 15 as a white solid (728 mg, 0.504 mmol, 98% yield). H NMR (CDCl ,
298K, 500.1 MHz): δ 7.70 (t, J = 7.8 Hz, 3H); 7.55 (d, J = 7.7 Hz, 3H); 7.40 (d, J= 7.7 Hz, 3H); 6.96-6.88
(m, 21H); 5.15 (s, 6H); 4.75 (d, J= 11.8 Hz, 3H); 4.71 (t, J= 3.5 Hz, 3H); 4.47 (d, J = 11.8 Hz, 3H); 4.36 (t,
J= 5.0 Hz, 6H); 4.30 (t, J = 5.0 Hz, 6H); 3.98-3.89 (m, 9H); 3.88 (s, 9H); 3.60-3.55 (m, 3H); 1.91-1.54 (m,
1
3
31
3
18H) ppm. C NMR (CDCl , 298K, 125.7 MHz): δ 159.0, 156.9, 153.1, 152.9, 149.8, 147.7, 137.2, 131.8,
3
3
2
3
121.6, 120.6, 119.5, 116.1, 116.0, 115.8, 115.7, 114.1, 112.1, 97.6, 71.3, 68.8, 68.0, 67.2, 62.3, 56.0,
+
30.7, 25.5, 19.5 ppm. HRMS (ESI-TOF) m/z: [M + H] Calcd for C84
H
97
N
4
O18 1449.6792; Found
o
34
1449.6768. M.p. > 70 C (decomp.).
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4
4
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5
5
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5
5
5
5
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5
6
1
Synthesis of hemicryptophane (±)-16. In a 2 L round bottom flask, the hemicryptophane precursor
15 (1.45 g, 1.00 mmol), HCOOH (1 L) and CH Cl (10 mL) were added. The mixture was stirred at r.t.
2
3
4
5
6
7
2
2
for 2 days. Then HCOOH was removed under vacuum and yellow oil was obtained. CH Cl (100 mL)
2
2
and TEA (5 mL) were added and then evaporated. Finally CH
the crude product followed by the addition of Et O (300 mL) to precipitate the product. After
O, the pure (±)-16 was obtained as a white solid (1.03 g, 0.900 mmol,
2 2
Cl (3 mL) was added to fully solubilize
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
filtration and washing with Et
90% yield).
2
-
1
8
9
Chiral HPLC analysis for (±)-16. On Chiralpak ID column (250 × 4.6 mm), with 1 mL min as flow-rate,
heptane/EtOH/CH Cl /TEA (20/40/40/0.1) as mobile phase, UV detection at 254 nm, Rt(M-16) = 8.7
2
2
10
min, Rt(P-16) = 11.7 min, k(M-16) = 1.92, k(P-16) = 2.90, α = 1.51 and Rs = 4.6.
11
Resolution of hemicryptophane (±)-16. The pure product of (±)-16 (100 mg) was dissolved in 5.2 mL
-
1
1
1
2
3
of CH
2
Cl
2
. On a Chiralpak ID column (250 × 10 mm), with 5 mL min as flow-rate,
hexane/EtOH/CH
2
2
Cl /TEA (20/40/40/0.1) as mobile phase, UV detection at 300 nm, 26 injections of
14
200 µL were stacked every 7.2 minutes. Both enantiomers were collected and the solvent was then
1
1
5
6
evaporated. The first eluted enantiomer ((–), M-16, 46 mg) and the second one ((+), P-16, 48 mg)
ꢁꢂ
ꢁꢂ
were obtained with both ee values > 99%. P-16: [∝] : +52 (c = 0.27; CH
2
Cl
2
); M-16: [∝] : -52 (c =
ꢀ
ꢀ
1
17
0.25; CH
2
Cl
2
). H NMR (CD
2
Cl
2
, 298K, 500.1 MHz): δ 7.56 (t, J = 7.7 Hz, 3H); 7.34 (d, J= 7.4 Hz, 3H); 7.22
1
8
(d, J = 7.7 Hz, 3H); 6.90 (s, 3H); 6.82 (s, 3H); 6.70 (d, J = 9.0 Hz, 6H); 6.56 (d, J= 9.0 Hz, 6H); 5.08 (s, 6H);
4.75 (d, J= 13.7 Hz, 3H); 4.27-4.23 (m, 3H); 4.19-4.15 (m, 3H); 4.09-4.03 (m, 6H); 3.97-3.90 (m, 6H);
19
1
3
2
2
0
1
3.66 (s, 9H); 3.54 (d, J = 13.7 Hz, 3H) ppm. C NMR (CD
2 2
Cl , 298K, 125.7 MHz): δ 158.7, 156.8, 152.6,
148.8, 146.7, 136.8, 133.1, 131.9, 122.2, 119.4, 116.7, 115.7, 115.6, 113.8, 71.2, 68.2, 67.2, 60.5, 56.0,
2
+
22
68 4 12
36.1 ppm. For COSY, HSQC and HMBC, see SI. HRMS (ESI-TOF) m/z: [M + 2H] Calcd for C69H N O
o
2
3
572.2411; Found 572.2398. M.p. = 260 C.
2
2
4
5
Synthesis of the racemic hemicryptophane complex Zn(II)@16. To a solution of (±)-16 (47 mg, 0.041
mmol) in 4 mL CHCl , 12 µL triethylamine was added under argon followed by addition of the
2
26
solution of Zn(ClO ) (H O) (15 mg, 0.041 mmol, 1 equivalent) in 2.5 mL CH OH. After stirring the
4
2
2
6
3
2
2
2
3
7
8
9
0
reaction mixture at room temperature for 4 hours, a large amount of precipitate appeared. The
precipitate was collected, washed thoroughly with Et
2
O and dried under vacuum to give the pure
1
complex as a white solid (33 mg, 0.023 mmol, 57% yield). The H NMR spectrum of Zn(II)@16 exhibits
complex and broad signals because of the conformational rigidification of the whole structure
induced by the metal complexation that gives different isomers, which is similar as the previously
31
4
b
1
13
3
3
2
3
reported Zn(II)@Hemicryptophane complex. For the detailed spectra of H NMR, C NMR, COSY,
+
HSQC and HMBC, see SI. HRMS (ESI-TOF) m/z: [M + HCOO] Calcd for C70
H
67
N
4
O14Zn 1251.3940;
+
o
34
Found 1251.3930; [M + Cl] Calcd for C69
H
66ClN
4
O
12Zn 1241.3652; Found 1241.3640. M.p. > 220 C
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6
1
(decomp.).
2
3
SUPPORTING INFORMATION
1
13
H, C, and 2D NMR spectra, chiral HPLC reports for resolution of (±)-1 and (±)-16.
0
1
2
3
4
5
6
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AUTHOR INFORMATION
E-mail: alexandre.martinez@centrale-marseille.fr
6
ACKNOWLEDGEMENT
7
8
9
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D.Z. acknowledges grants from the China Scholarship Council, the Région Auvergne-Rhône-
Alpes, France, for an Accueil Doc Bursary, and ENS-Lyon for an Attractiveness Fellowship
for PhD studies. A.M. would like to thank ANR OH-risque for funding, grant number: ANR-
14-OHRI-0015-01.
1
1
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REFERENCES
(1) (a) Zhang, D.; Martinez, A.; Dutasta, J. P. Chem. Rev. 2017, 117, 4900. (b) Ajami, D.; Liu, L. J.;
Rebek, J. Chem. Soc. Rev. 2015, 44, 490. (c) Zarra, S.; Wood, D. M.; Roberts, D. A.; Nitschke, J. R. Chem.
Soc. Rev. 2015, 44, 419. (d) Brown, C. J.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Chem. Rev.
2015, 115, 3012. (e) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Chem. Soc.
Rev. 2014, 43, 1660. (f) Blanco, V.; Leigh, D. A.; Marcos V. Chem. Soc. Rev., 2015, 44, 5341.
(2) Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. Rev. 2008, 108, 1.
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1
1
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(3) (a) Wiester, M. J.; Ulmann, P. A.; Mirkin, C. A. Angew. Chem., Int. Ed. 2011, 50, 114. (b) Jaeger,
K. E.; Eggert, T. Curr. Opin. Biotech. 2004, 15, 305. (c) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van
Leeuwen, P. W. N. M. Chem. Soc. Rev. 2014, 43, 1734.
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