Enantio- A nd Substrate-Selective Recognition of Chiral Neurotransmitters with C3-Symmetric Switchable Receptors

Neurotransmitters with C ‑Symmetric Switchable Receptors

Letter

Enantio- and Substrate-Selective Recognition of Chiral

Jian Yang, Bastien Chatelet, Veronique Dufaud, Damien Herault, Marion Jean, Nicolas Vanthuyne,

́ ́

Jean-Christophe Mulatier, Delphine Pitrat, Laure Guy, Jean-Pierre Dutasta, and Alexandre Martinez*

Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04440

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sı Supporting Information

ABSTRACT: We report on the synthesis of C -symmetric enantiopure cage

molecules 1, which exhibit remarkable to exclusive enantioselective

recognition properties toward chiral ammonium neurotransmitters. Strong

changes in the substrate selectivity are also observed when diﬀerent

stereoisomers of 1 are used. Furthermore, protonation/deprotonation

induces a reversible modiﬁcation of the conformation of 1, which switches

from an imploded to an inﬂated form, leading to ejection and reuptake of the

guest initially encaged inside the cavity.

hiral recognition plays a crucial role in living systems and

is also a key issue for researchers dealing with chiral

Furthermore, as chiral ammoniums play a crucial role in

biological systems, for instance, as neurotransmitters, there is

also a challenge to build a receptor capable of displaying high

substrate selectivity in favor of one neurotransmitter, because

separations or asymmetric catalysis. If chiral receptors and

catalysts found in Nature display complex structures devoid of

symmetry, their synthetic counterparts present frequently

of its potential applications, in sensing or detection.

symmetry properties, like rotational axes. Besides the beauty

Moreover, if such a receptor is able to control the uptake

and release of the guest by switching between two strongly

diﬀerent states upon the action of an external stimulus, this

of symmetrical molecules, considerations of symmetry allow

simplifying both the synthesis and the analysis and may

improve the selectivity in enantioselective recognition or

catalysis by reducing the number of diastereomeric host−guest

could oﬀer new ways for drug delivery.

Here, we report on the synthesis of C -symmetric molecular

complexes or transition states. However, to perform chiral

cages that display unprecedented enantioselective recognition

properties for chiral ammoniums of biological interest. Binding

recognition, receptors or catalysts have to belong to the point

groups C (including C ) or D . Since the seminal work of

−1

constants up to 10 M can be reached by receptor M-(S,S,S)-

Kagan highlighting the advantages of C -symmetric ligands in

−1

, whereas low (100 M ) to no binding was observed with its

asymmetric catalysis, numerous chiral ligands and receptors

enantiomer P-(R,R,R)-1. Changing the stereochemistry of the

receptor also induced strong changes in the substrate

selectivity: receptor M-(S,S,S)-1 bound ephedrine more

strongly than adrenaline, whereas the opposite trend was

observed for its enantiomer P-(R,R,R)-1. Moreover, this cage

could be reversibly switched from an inﬂated form to an

imploded one upon protonation/deprotonation, allowing for

an easy control of the uptake and release of the enantiomeri-

cally pure neurotransmitters.

with 2-fold rotational symmetry have been reported. In

contrast, molecules with 3-fold rotational symmetry capable of

chiral recognition remain rare. The ability of C symmetric

hosts to discriminate enantiomers of ammoniums was even the

1a,6

subject of scientiﬁc controversy. However, the experimental

work of Ahn et al. and then the studies reported by

Hauberhauer et al. followed by the rationalization of Moberg

1a,7,8

put an end to this debate.

However, very few C₃-

symmetric hosts capable of chiral recognition of ammoniums

have been reported to date, and the best selectivity reached

only a modest value of 8.4 (87:13 ratio).

Therefore,

Received: December 11, 2019

experimental evidence that receptors with a 3-fold rotational

symmetry are able to recognize ammoniums with enantiose-

lectivity as high as those with 2-fold rotational symmetry

remains to be brought.

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

(protonated), Figure 2 )). This is consistent with the imploded

Letter

Scheme 1. Synthesis of the Four Enantiomerically Pure C -Symmetric Cages 1

Scheme 1 shows the synthetic route followed to obtain the

one signal of the NCH protons is strongly high-ﬁeld shifted

four C -symmetric stereoisomers of cage 1. Cyclotriveratrylene

when compared to the same protons in the deprotonated P-

(R,R,R)-1 cage (from 1.05 ppm (deprotonated) to −0.26 ppm

(

CTV) 2 was obtained enantiomerically pure according to our

11,12

previously reported procedure.

Racemic 2′-hydroxy-[1,1′-

binaphthalene]-2-carboxaldehyde derivative 3 was synthesized

using the methodology described by Xie et al., and a

subsequent resolution with a chiral HPLC a ﬀ orded the

enantiopure compound (S)-3 and (R)-3 (Figures S1 −S3 ).

Their absolute con ﬁ guration was then assigned using ECD

spectroscopy (Figures S4 and S5 ). Then, M-2 or P-2 was

reacted with (S)-3 or (R)-3 in DMF using CsCO as a base to

yield enantiomerically and diastereomerically pure P-(S,S,S)-4,

P-(R,R,R)-4, M-(S,S,S)-4, and M-(R,R,R)-4. Finally, a reductive

amination gave the expected hemicryptophane cages P-(S,S,S)-

, P-(R,R,R)-1, M-(S,S,S)-1, and M-(R,R,R)-1 in 27% yield as

single isomer in each case. The NMR spectra indicate that all

the stereoisomers of cage 1 display, on average, a C symmetry

in solution (Figures S14 and S19 ).

Crystals of P-(R,R,R)-1 suitable for X-ray diﬀraction analysis

were obtained by slow evaporation from a concentrated

solution of the cage in CHCl /CH OH. Because of traces of

Figure 2. H NMR (CDCl

(

, 400 MHz, 298 K) spectra of (a) P-

R,R,R)-1 and (b) P-(R,R,R)-1·3H . The black and blue ◆ represent

acetone and grease, respectively.

HCl in CHCl , the P-(R,R,R)-1 compound crystallized as its

protonated counterpart P-(R,R,R)-1-3H with protonation on

each secondary amine (Figure 1 ). Interestingly, this triproto-

conformation of the protonated compound observed in the

solid state, where one of the diastereotopic protons of the

NCH units appears in the shielding area of the CTV moiety.

Furthermore, cross-peaks between the protons of the NCH of

the tren moiety and those of the aromatic rings of the CTV

core were evidenced on the NOESY map (Figure S30)

indicating short distances between the two units. On the

contrary, when the similar NOESY experiment was performed

on the deprotonated cage, no NOE correlation between the

tren moiety and the CTV unit was shown, suggesting a well-

deﬁned cavity in the cage compound P-(R,R,R)-1 (Figure S23).

More insight into this strong diﬀerence in the conformation of

P-(R,R,R)-1 and P-(R,R,R)-1·3H is further given by the ability

Figure 1. X-ray structure of P-(RRR)-1·3H : (a) side view and (b)

of P-(R,R,R)-1 to complex tetramethylammonium (Me N )

−

top view.

with a binding constant of 373 M , whereas no complexation

could be detected with its protonated counterpart P-(R,R,R)-1·

nated structure exhibits a C symmetry but with an unexpected

3H . All these NMR experiments strongly support that the

imploded conformation: the tren (tris(2-aminoethyl)amine)

moiety appears fully collapsed inward the CTV unit, leading to

a compound devoid of cavity. C−H···O and C−H···π

interactions between the NCH CH protons of the tren unit

imploded conformation of P-(R,R,R)-1·3H is maintained in

solution whereas its basic partner P-(R,R,R)-1 presents a

hollow core. As pH switch can be used as a speciﬁc stimulus to

perform reversible nanomechanical processes at molecular

and both the oxygen atoms and aromatic rings of the CTV

level, we then investigated whether the protonation/

deprotonation of cage 1 could enable the control of the

dynamic motion from an inﬂated state to a fully imploded one.

We were pleased to note that the alternating use of HCl (aq)

and NaOH (aq) resulted in a reversible switch from a fully

inﬂated form to a collapsed one and that at least ﬁ ve cycles

could be performed between these two states (Figure S7).

could account for the stability of this imploded state (C−H···O

and C−H···π distances of 2.94 and 3.03 Å, respectively). The

H NMR spectrum of this protonated form was obtained either

by dissolution of these crystals in CDCl or by addition of 3

equiv of picric acid to compound P-(R,R,R)-1 (Figures S6 and

S25 ). One can see that, despite the protonation of the amines,

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Thus, the pH acts as an eﬀective and simple stimulus to switch

contrast, the two other enantiomeric cages M-(S,S,S)-1 and

P-(R,R,R)-1 exhibited unprecedented enantioselectivity as C₃-

symmetric receptors: with the primary ammonium norephe-

drine, an enantioselectivity value (K_M_‑₍_S_,_S_,_S₎_‑₁/K_P_‑₍_R_,_R_,_R₎_‑₁) of 445

was measured and with the secondary ammonium ephedrine

an exclusive enantioselectivity was observed with a binding

reversibly from a collapsed state to a reinﬂated cage.

Once the conformational issues of the deprotonated and

protonated cages 1 were solved, we examined the ability of the

four inﬂated C -symmetric receptors P-(S,S,S)-1, P-(R,R,R)-1,

M-(S,S,S)-1, and M-(R,R,R)-1 to complex chiral ammonium

neurotransmitters: (1R,2S)-(−)-ephedrine, (1R,2S)-(−)-nor-

−

constant close to 19 000 M for the M-(S,S,S)-1 host, while

no binding occurred with its enantiomer counterpart P-

(R,R,R)-1.

ephedrine, (1S,2S)-(+)-pseudoephedrine, and L-adrenaline. H

NMR titration experiments were performed, and the modeling

of the resulting titration curves gives rise to the binding

constants given in Table 1. In most of the cases, the best ﬁt was

The H NMR titration curves shown in Figure 3 clearly

evidence the diﬀerence in the binding properties of these two

Table 1. Association Constants of the Enantiopure

Receptors 1 with Ammonium Guests in CDCl /CD OD 95/

at 298 K

Figure 3. Titration curves of hosts M-(S,S,S)-1 (blue) and P-(R,R,R)-

(orange) with (1R,2S)-(−)-ephedrine. The complexation-induced

) of the guest’s proton at 5.18 ppm

shifts (Δδ = δ

− δ

uncomplex

complex

were recorded and plotted as a function of the ratio [G]/[H] (dots).

Curves were ﬁtted with the Bindﬁt program (solid lines).

enantiomers toward ephedrine. Changing only one stereogenic

center in the guest structure, i.e., switching from ephedrine to

pseudoephedrine, led to complete reverse of the enantiose-

lectivity: an enantioselectivity of 8.2 in favor of P-(R,R,R)-1 was

observed with pseudoephedrine as a guest. As a consequence,

the host P-(R,R,R)-1 exhibits a strong substrate selectivity

toward pseudoephedrine: a K_p_s_e_u_d_o_e_p_h_e_d_r_i_n_e/K_n_o_r_e_p_h_e_d_r_i_n_eratio of

63 is reached and the substrate selectivity is even exclusive

when pseudoephedrine is compared to ephedrine. Interest-

ingly, the lower enantioselectivity obtained with L-adrenaline as

substrate induced changes in substrate selectivities: the M-

(

S,S,S)-1 enantiomer preferentially binds norephedrine or

ephedrine than adrenaline (with K_n_o_r_e_p_h_e_d_r_i_n_e/K_a_d_r_e_n_a_l_i_n_eof 30,

and K_e_p_h_e_d_r_i_n_e/K_a_d_r_e_n_a_l_i_n_eof 8, respectively), whereas the

enantiomer P-(R,R,R)-1 is adrenaline-selective with a selectiv-

ity K_a_d_r_e_n_a_l_i_n_e/K_n_o_r_e_p_h_e_d_r_i_n_eof 28 and even exclusive when

compared to ephedrine. Thus, switching from one enantiomer

to another completely changed the substrate selectivity,

allowing building selective receptors for a given neuro-

transmitter by simply using the mirror image of a cage.

As cage P-(R,R,R)-1 and obviously its enantiomer M-(S,S,S)-

Picrate was used as counterion. K values were determined by ﬁtting

the H NMR titration curves of proton of the guest using Bindﬁt, the

error bars arise from the ﬁtting.

K₍_o_t_h_e_r_e_n_a_n_t_i_o_m_e_r₎

18 c

Deﬁned as K₍_o_n_e_e_n_a_n_t_i_o_m_e_r₎

17 d

No complexation was observed.

are able to switch from a globular form to a fully imploded

conformation upon an acidic stimulus (vide supra), we

wondered if this nanoscale molecular motion could occur

with a guest already encapsulated in the cavity, thereby

expelling the included guest outside the cavity. Addition of

picric acid to a solution of encapsulated ephedrine led

immediately to the imploded structure of the cage M-(S,S,S)-

1 associated with the release of the ephedrine guest in the

media (Figure 4). This result demonstrates that this molecular

motion of the cage is possible despite the high stability of the

achieved with a 1:1 host/guest stoichiometry, except for (i)

norephedrine guest and M-(S,S,S)-1 host and (ii) pseudoephe-

drine guest and M-(S,S,S)-1 and P-(R,R,R)-1 hosts where two

complexes were formed subsequently with a 1:1 and then a 1:2

host/guest ratio. The two enantiomeric hosts M-(R,R,R)-1 and

P-(S,S,S)-1 displayed good substrate selectivities with K_e_p_h_e_d_r_i_n_e

K_a_d_r_e_n_a_l_i_n_eof 2.3 and 2.5 and with K_n_o_r_e_p_h_e_d_r_i_n_e/K_a_d_r_e_n_a_l_i_n_eof 34.8

and 33.5, respectively. However, when complexed with

tested guests, only low enantioselectivities were achieved, the

best result being obtained with pseudoephedrine, with a

modest enantioselectivity K_P_‑₍_S_,_S_,_S₎_‑₁/K_M_‑₍_R_,_R_,_R₎_‑₁of 4.2. In

−

initial host−guest complex (K = 19 000 M ). After

subsequent addition of triethylamine, the host was reinﬂated

and able to encage the ephedrine guest simultaneously, giving

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Marseille, iSm2, Marseille 13397, France; orcid.org/0000-

Letter

AUTHOR INFORMATION

■

Corresponding Author

Alexandre Martinez − Aix Marseille Univ., CNRS, Centrale

002-6745-5734 ; Email: alexandre.martinez@centrale-

marseille.fr

Authors

Jian Yang − Aix Marseille Univ., CNRS, Centrale Marseille,

iSm2, Marseille 13397, France

Bastien Chatelet − Aix Marseille Univ., CNRS, Centrale

Marseille, iSm2, Marseille 13397, France; orcid.org/0000-

001-7456-4704

Veronique Dufaud − Laboratoire de Chimie, Catalyse,

Polymeres, Procedes CNRS, UMR 5265, Universite Claude

Bernard Lyon1, Villeurbanne 69616 Cedex, France;

orcid.org/0000-0001-5312-7177

Damien Herault − Aix Marseille Univ., CNRS, Centrale

Marseille, iSm2, Marseille 13397, France; orcid.org/0000-

0001-7753-3276

Marion Jean − Aix Marseille Univ., CNRS, Centrale Marseille,

iSm2, Marseille 13397, France; orcid.org/0000-0003-

0524-8825

Figure 4. (a−d) H NMR (400 MHz, CD Cl , 298 K) spectra of: (a)

(

1R,2S)-(−)-ephedrine; (b) (1R,2S)-(−)-ephedrine and equimolar of

M-(S,S,S)-1; (c) (1R,2S)-(−)-ephedrine and equimolar of M-(S,S,S)-1

and 3 equiv of picric acid, the peak at −0.3 ppm was zoomed to

highlight the imploded conformation of M-(S,S,S)-1 after proto-

nation; (d) (1R,2S)-(−)-ephedrine and equimolar of M-(S,S,S)-1 and

Nicolas Vanthuyne − Aix Marseille Univ., CNRS, Centrale

Marseille, iSm2, Marseille 13397, France; orcid.org/0000-

0003-2598-7940

picric acid and excess of Et N. (e) Schematic representation of

reversible uptake and release of guest by M-(S,S,S)-1 upon

protonation/deprotonation. White, black, yellow, and blue ◆

Jean-Christophe Mulatier − Laboratoire de Chimie, Ecole

Normale Superieure de Lyon, F-69364 Lyon, France

Delphine Pitrat − Laboratoire de Chimie, Ecole Normale

Superieure de Lyon, F-69364 Lyon, France

represent CHDCl , Et N, acetone, and grease, respectively.

Laure Guy − Laboratoire de Chimie, Ecole Normale Superieure

back the initial host−guest complex. Thus, simple proto-

nation/deprotonation induces a strong change of the

conformation of the receptor allowing for the control of the

reversible trap and release of the ephedrine neurotransmitter.

In summary, we have described the synthesis of four new C₃-

symmetric enantiopure cages and their enantioselective

recognition toward chiral ammonium neurotransmitters. The

enantioselectivity reached with these new enantiopure cages is

unprecedented for a receptor with 3-fold symmetry as well as

the selectivity change observed for a given substrate with

enantiomeric receptors. A nanomechanical process from an

imploded to a reinﬂated form upon protonation/deprotona-

tion was demonstrated. This motion occurs both with the host

alone and with the host−guest complex, which allows simple

control of the uptake and release of the enantiopure

neurotransmitter.

de Lyon, F-69364 Lyon, France; orcid.org/0000-0002-

8728-7213

Jean-Pierre Dutasta − Laboratoire de Chimie, Ecole Normale

Superieure de Lyon, F-69364 Lyon, France; orcid.org/0000-

0003-0948-6097

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.9b04440

Notes

The authors declare no competing ﬁnancial interest.

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