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Emergence of Hemicryptophanes: From Synthesis to
Applications for Recognition, Molecular Machines, and
Supramolecular Catalysis
Dawei Zhang, Alexandre Martinez, Jean-Pierre Dutasta
To cite this version:
Dawei Zhang, Alexandre Martinez, Jean-Pierre Dutasta. Emergence of Hemicryptophanes: From Syn-
thesis to Applications for Recognition, Molecular Machines, and Supramolecular Catalysis. Chemical
Reviews, American Chemical Society, 2017, 117 (6), pp.4900 - 4942. �10.1021/acs.chemrev.6b00847�.
�hal-01682799�
Emergence of Hemicryptophanes: From Synthesis to Applications for
Recognition, Molecular Machines, and Supramolecular Catalysis
Dawei Zhang,
†,‡
Alexandre Martinez,*
,‡,§
and Jean-Pierre Dutasta*
,‡
†
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 North Zhongshan Road, Shanghai 200062, People’s Republic of China
‡
Laboratoire de Chimie, E
cole Normale Supe
rieure de Lyon, CNRS, UCBL, 46, Alle
ed’Italie, F-69364 Lyon, France
§
Aix-Marseille University, CNRS, Centrale Marseille, iSm2, Av. Escadrille Normandie-Niemen, F-13397 Marseille, France
ABSTRACT: In the wide area of host−guest chemistry, hemicryptophanes, combining a
cyclotribenzylene (or cyclotriveratrylene CTV) unit with another different C
3
-symmetrical
moiety, appears as a recent family of molecular cages. The synthesis and recognition
properties of the first hemicryptophane were reported in 1982 by Collet and Lehn, but the
very little attention received by this class of host compounds in the 20 years following this
first promising result can account for their apparent novelty. Indeed, in the last 10 years
hemicryptophanes have aroused growing interest, and new aspects have been developed.
Thanks to the rigid shaping unit of the north part (CTV) and also the variable and easily
functionalized south moiety, hemicryptophanes are revealed to be inherently chiral ditopic
host compounds, able to encapsulate various guests, including charged and neutral species.
They also enter the field of stimuli-responsive supramolecular systems exhibiting
controlled functions. Moreover, endohedral functionalization of their inner cavity leads
to supramolecular catalysts. The confinement of the catalytic center a ffords nanoreactors
with improved catalytic activities or selectivities when compared to model systems without a cavity. The current trend shows that
reactions in the confined space of synthetic hosts, mimicking enzyme behavior, will expand rapidly in the near future.
CONTENTS
1. Introduction 4901
2. Synthesis of Hemicryptophanes 4902
2.1. Synthesis of Covalent Hemicryptophanes 4902
2.1.1. Triamide- and Tren-Hemicryptophanes 4903
2.1.2. Trialkanolamine Hemicryptophanes 4905
2.1.3. Hemicryptophanes Based on a Tripodal
Benzenic Platform 4907
2.1.4. Hemicryptophanes Based on a Macro-
cyclic Platform 4908
2.1.5. Hemicryptophanes Based on Heteroa-
tomic Pivot 4911
2.1.6. Hemicryptophanes Formed from a Co-
valent CTV−C
60
Adduct 4912
2.1.7. Hemicryptophanes Constructed from a
Diphenylglycoluril Unit 4912
2.1.8. Hemicryptophanes Obtained by Metal
Coordination 4912
2.2. Formation of Hemicryptophane Capsules by
Reversible Bonds/Interactions 4914
2.2.1. Formation by Boronate Esterification 4915
2.2.2. Formation by Ionic Interactions 4916
2.3. Functionalization of Hemicryptophanes 4917
2.3.1. Water-Soluble Hemicryptophanes 4917
2.3.2. Endohedral Functionalization of Hemi-
cryptophanes 4918
3. Host−Guest Chemistry of Hemicryptophanes 4921
3.1. Guest Inclusion in the Solid State: X-ray
Molecular Structures 4921
3.2. Complexation in Solution 4923
3.2.1. Recognition of Ammonium Guests 4923
3.2.2. Recognition of Ion Pairs 4925
3.2.3. Recognition of Zwitterions 4926
3.2.4. Recognition of Carbohydrates 4928
3.2.5. Recognition of Fullerenes 4929
4. Hemicryptophanes in Motion: Toward Molecular
Machines 4930
4.1. Molecular Gyroscope 4930
4.2. Molecular Propeller 4930
4.3. Molecular Breathing 4931
5. Hemicryptophanes: Supramolecular Catalysts 4931
5.1. Hemicryptophanes as Organocatalysts 4932
5.1.1. Encaged Verkade’s Superbases: Cata-
lysts for Diels−Alder Reactions 4932
5.1.2. Encaged Azaphosphatrane Catalysts for
CO
2
Conversion 4932
5.2. Metal-Hemicryptophane Complexes as Cat-
alysts 4933
5.2.1. Encaged Vanadium(V) Catalysts for
Sulfoxidation Reactions 4933
5.2.2. Encaged Zinc(II) Catalysts for Carbonate
Hydrolysis 4934
Received: December 26, 2016
Published: March 9, 2017
5.2.3. Encaged Ruthenium(II) Catalysts for the
Oxidation of Alcohols 4935
5.2.4. Encaged Copper(II) Catalysts for Cyclo-
alkane Oxidation 4935
6. Conclusions 4936
Author Information 4937
Corresponding Authors 4937
ORCID 4937
Notes 4937
Biographies 4937
Acknowledgments 4937
References 4937
1. INTRODUCTION
Molecular cages, defined as hollow structures delineating a
three-dimensional cavity, are attracting considerable attention
in modern supramolecular chemistry due to their possible
applications in molecular recognition, catalysis, drug delivery,
biosensing, separation, and storage.
1−8
Among the classes of
molecular containers, such as crown ethers,
9,10
cryptands,
10
calixarenes,
11−13
resorcinarenes,
14,15
curcurbiturils,
16−18
cyclo-
dextrins,
19,20
or pillararenes,
21−23
cryptophanes and hemi-
cryptophanes based on a cyclotribenzylene core, most of the
time identified to a derivative of the cyclotriveratrylene (CTV)
unit (Figure 1), have recently received growing interest.
Cryptophanes are homotopic host compounds built from two
CTV units, which can efficiently encapsulate small molecules
such as methane or epoxides, cations, anions, and xenon or
radon noble gases.
24,25
A previous comprehensive review on
cryptophanes by Brotin and Dutasta highlighted the synthesis
methods, their binding and chiroptical properties, and their
potential applications as biosensors and chiral agents.
24
In
contrast, the related hemicryptophanes combining a CTV unit
with another C
3
-symmetrical moiety via covalent bonds or
noncovalent interactions are heteroditopic hosts able to
recognize various charged or neutral guests, such as ion pairs,
zwitterions, ammoniums, carbohydrates, and fullerenes. Cur-
rently, hemicryptophanes are mainly used as molecular
receptors, supramolecular catalysts, and functional molecules
anticipating molecular machines.
The chemistry of hemicryptophane was developed quite
slowly before 2005.
26
In 1982, Lehn and Collet described the
first two members of a new type of molecular cages called
speleands (1 and 2 in Figure 2a), which associated a CTV and a
crown ether unit, showing potential recognition properties
toward methylammonium cations.
27
Then in 1989 Nolte et al.
reported the synthesis of a molecular host derived from CTV
and diphenylglycoluril units presenting potential catalytic
properties related to its easily functionalized arm (5 in Figure
2a).
28
Ten years later, Diederich and Echegoyen described the
synthesis of the two covalent CTV−C
60
adducts 3 and 4
(Figure 2a) prepared by the tether-directed Bingel reaction.
29
The C
3
symmetry of the two cage adducts was evidenced by
NMR spectroscopy. Nevertheless, it is obvious that the free
space in the cavity of the two compounds is quite restricted due
to the interactions between the electron-rich aromatic rings of
the CTV and the electron-poor C
60
, limiting their applications
as receptors. The same year Dutasta and co-workers reported
the synthesis and crystal structure of the thiophosphorylated
molecular cage 6 (Figure 2a) based on the CTV unit and
proposed the term hemicryptophane for this type of molecular
cages, which has been widely used thereafter.
30
Last, based on
suitably functionalized CTVs, metal complexes were obtained
that possess the hemicryptophane structure. In some specific
cases, the CTV cap was used as ligand platform for iron(II) and
iron(III) coordination.
31
Hence, it can be seen that this class of
host compounds received little attention before 2005 since only
a few relevant papers were reported during this period and even
Figure 1. (a) Cyclotribenzylene and cyclotriveratrylene (CTV, X = Y
= OCH
3
). (b) Cryptophane-E.
24
Figure 2. (a) Hemicryptophanes 1−6 synthesized between 1982 and
2005. (b) Structures of Kuck’s hemicryptophanes based on the TBTQ
unit.
less have really focused on their applications. Unexpectedly,
after 2005, this chemistry received growing interest leading to a
blossoming field of research, particularly for molecular
recognition. For instance, a series of sophisticated enantiopure
hemicryptophanes has been synthesized benefitting from the
inherent chirality of the CTV unit and used for stereoselective
recognition of chiral guest molecules. They have also entered
the field of controlled molecular motions, exhibiting solvent-
responsive properties. Moreover, confinement of catalytic sites
in the inner space of the cavity of hemicryptophanes resulted in
supramolecular organic and organometallic catalysts with
remarkable properties. We should mention herein the
important contribution of Kuck et al., who synthesized
cryptophane and hemicryptophane-like molecular cages based
on the tribenzotriquinacene (TBTQ) scaffold. Recently, they
reported the synthesis of hemicryptophanes where the CTV
part is replaced by the TBTQ unit. This type of molecular
receptor does not strictly belong to the CTV-based derivatives,
but their closely related structures deserve to be pointed out in
this review (Figure 2b).
32
In this review, we will first introduce the general synthetic
methods (section 2) to obtain racemic, enantiopure, water-
soluble, and metalated hemicryptophane hosts. Next, the
applications of hemicryptophanes in molecular recognition
(section 3) as molecules with controllable motions (section 4)
and as supramolecular catalysts (section 5) will be presented.
Finally, we will conclude and present perspectives on the future
development of hemicryptophanes and highlight the key
challenges in this emerging area of research (section 6).
2. SYNTHESIS OF HEMICRYPTOPHANES
Hemicryptophane hosts can be classified into two main families
according to the method of preparation used: covalent
hemicryptophanes and self-assembled hemicryptophane capsu-
les. Covalent hemicryptophanes refer to compounds, where the
two main C
3
-symmetrical units defining the ditopic character of
these hosts are connected by covalent bonds. Access to
covalent cages most of time needs multistep syntheses, and
often the main drawback of these syntheses is a low overall
yield. Although some cage compounds are only accessible on a
milligram scale, a range of laboratory-scale synthesis schemes
has been developed to afford hemicryptophanes with various
functionalities that can be obtained easily on gram scale,
allowing wider applications. The different approaches to the
syntheses of covalent hemicryptophane hosts will be presented
in section 2.1. The formation of self-assembled hemi-
cryptophane capsules is currently attracting great attention
due to the developments in self-assembling strategies and will
be described in section 2.2. For instance, hemicryptophanes
formed of two interacting molecular subunits have been
reported using reversible dynamic covalent interactions such
as the reversible formation of boronate esters or supramolecular
ionic interactions between charged moieties. Finally, section 2.3
is devoted to the functionalization of hemicryptophanes to
develop specific properties and to investigate their applications
in catalysis and sensing in organic or aqueous media.
An important aspect of hemicryptophanes is their inherent
chirality arising from the CTV unit. A greatly growing demand
for chiral hosts exists, and consequently, the production of
enantiopure hemicryptophanes should be considered as a
significant breakthrough for applications in chiral recognition or
catalysis. Particular attention will be paid to this aspect
throughout this section. The C
3
symmetry of the CTV moiety
confers to the hemicryptophanes an inherent chirality with P or
M configuration.
33
When associated with other stereogenic
centers the hemicryptophane molecules exist as diastereomers.
Thus, the synthesis of enantiopure compounds leads to either
enantiomers or diastereomers, and it is essential to determine
their absolute configuration. A convenient method relies on
determination of the X-ray crystal structure of the enantiopure
compounds. However, obtaining crystals suitable for X-ray
analysis is not always easy and successful.
34
The use of
electronic circular dichroism (ECD) spectroscopy has been
widely described in the literature and is particularly suitable to
determine the absolute configuration of compounds bearing the
CTV unit.
35
Indeed, the spectra can be interpreted as the result
of the excitonic coupling of the three aromatic rings of the CTV
unit, which gives a specific ECD signature.
35−38
This method is
relatively easy and reliable but may also fail in some specific
cases when the ECD signals of the CTV overlap with those of
other aromatic groups. In such cases, chemical correlation
methods were developed and successfully applied to hemi-
cryptophane molecules.
When compared to racemic hemicryptophanes, enantiopure
cages are more useful since chirality plays a crucial role in most
of the biological even ts, and chira l synthetic bi oinspired
supramolecular systems can be designed to mimic and
understand these processes.
39−41
However, the easy synthesis
of this type of enantiopure molecular cages is a difficult
challenge because of the high complexity of such molecules.
Two main strategies can be followed to prepare enantiopure
hemicryptophanes. (i) One is the resolution of racemic
mixtures using chiral semipreparative high-performance liquid
chromatography (HPLC). The major drawbacks of this method
are the necessity of a chiral HPLC and the difficulty in
providing sizable amounts of compounds. (ii) Another is
introduction of additional stereocenters to form diastereomers.
This second strategy needs more complex synthesis pathways,
and in most cases, the separation of two diastereomers is
tedious but affords more sizable amounts of enantiopure cages.
Both methods appear in the literature and will be discussed in
the following sections. Throughout this review, without specific
indications, the chiral compounds described are racemates.
2.1. Synthesis of Covalent Hemicryptophanes
Covalent hemicryptophanes can be obtained by three main
pathways. The first one is a cage-closing reaction to form the
CTV unit (arbitrarily named the north part) and is related to
the “template method” used for the synthesis of cryptophanes
(Figure 3a).
24
The Friedel−Crafts condensation of the veratryl
precursors is a convenient and common approach for the
synthesis of cryptophanes and hemicryptophanes. The acid-
catalyzed cyclization reaction using mainly HCOOH or
Sc(OTf)
3
gives rise to the CTV moiety leading to the desired
hemicryptophanes. The performance of this intramolecular
cyclodehydration to generate the CTV in the last step, in terms
of yield and difficulty in their purification, usually depends on
the structures of the hemicryptophane precursors.
The second way is the [1 + 1] coupling between the north
part and the other C
3
unit (arbitrarily named the south part),
which is very effective in many cases and is particularly well
suited for the preparation of enantiopure hemicryptophanes
(Figure 3b). Moreover, this strategy allows the preparation of a
wide range of ditopic molecules thanks to the numerous and
versatile available southern moieties and involves different
approaches such as reactions of acyl chloride with primary or
secondary amine, carboxyl with primary amine, Ugi reaction
type, and disulfide-bon d formation most commonly. For
instance, sophisticated structures such as crown ethers,
calixarenes, and cyclodextrins were combined with the CTV
cap to afford ditopic hosts with fairly good yields. This method
usually requires high-dilution conditions to avoid formation of
polymeric compounds.
The third way is to introduce the southern C
3
unit from the
suitably functionalized CTV sca ffold (Figure 3c). In this way
hemicryptophanes are formed by appending on the CTV three
linkages bearing suitable functions for an intramolecular
reaction that leads to the cage structure. This approach has
been seldom used compared to strategies based on the cage-
closure reaction at the north part or the [1 + 1] coupling
presented above.
For a given compound, the authors often used either of the
methods described above to increase the yields and/or produce
sizable amounts of enantiopure compounds. For instance, the
[1 + 1] coupling between two modules has been often
advantageously applied to the synthesis of hemicryptophanes
already obtained by formation of the CTV cap according to the
first synthetic pathway. In the following sections we thus
emphasize the various approaches reported in the literature for
the synthesis of racemic and enantiomerically pure hemi-
cryptophanes according to the nature of the southern units.
2.1.1. Triamide- and Tren-Hemicryptophanes. The
triamide and the tris(2-aminoethyl)amine (tren) structures
have been used to build receptors for complexation of
anionic
42,43
and cationic species.
44
In particular, transition
metal ions such as cobalt, zinc,
45
and copper
46
form complexes
with these ligands, presenting interesting catalytic or recog-
nition properties. Di fferent heteroelements have been also
trapped into a tren moiety, leading, in the case of phosphorus,
to pro-azaphosphatrane compounds, which constitute a
remarkable class of basic and nucleophilic organocatalysts.
47
The racemic triamide- and tren-hemicryptophanes 14 and
15a were first synthesized following the first method (Figure
3a) as depicted in Scheme 1.
48
The reaction of vanillyl alcohol
7 with dibromoethane in EtOH at 80 °Caffords compound 8,
which is protected with THP to give 9 with an overall yield of
27%. The C
3
symmetry precursor of the south part of the host
is obtained from the nitrilotriacetic acid 10 that reacts with 3
equiv of p-methoxy benzylamine in the presence of P(OPh)
3
to
give the tripodal triamidoamine derivative 11. The methoxy
groups in 11 are then removed using BBr
3
to give the triphenol
derivative 12. Reacting 9 and 12 in DMF in the presence of
Cs
2
CO
3
affords the hemicryptophane precursor 13.The
cyclization is then performed in HCOOH to give the desired
hemicryptophane 14 in 30% yield. Finally, the reduction of the
amide functions is achieved with BH
3
in THF to give the tren-
hemicryptophanes 15a in 30% yield. Similar to the synthesis of
14, the hemicryptophanes 16 and 17 (Scheme 1b) bearing
fluorinated aromatic rings in the three linkages were also
obtained.
49
The racemic triamide-hemicryptophane rac-14 was
resolved by chiral semipreparative HPLC, leading to the
enantiopure compounds M-14 and P-14.
50
Applied to rac-15a
the resolution is unsuccessful, underlining the limitation of the
method.
The convenient and efficient modular approach of the [1 +
1] coupling reaction (Figure 3b) was developed for the
synthesis of the tren-based hemicryptophanes 15a−i (Scheme
2).
51
The alkyl-brominated CTV 18a is first synthesized in two
steps from vanillyl alcohol and dibromoethane according to the
procedure described by Dmochowski et al.
52
The preparation
of the hemicryptophane precursor 20a is then conducted under
standard conditions by reacting 18a with 4-hydroxybenzalde-
hyde (19a) in DMF in the presence of Cs
2
CO
3
with excellent
yields and without purification by column chromatography.
The condensation of 20a with tris(2-aminoethyl)amine in
CHCl
3
/CH
3
OH mixture, followed by a reduction step with
NaBH
4
,affords 15a in 77% yield. Hemicryptophane 15a is thus
obtained in 8% overall yield via a four-step synthetic route,
which improves the previous seven-step procedure (3% overall
yield; Scheme 1) and allows the synthesis of 15a on a gram
scale. Moreover, the size, shape, and functionalities of the
molecular cavity are easily modified by changing the nature of
the aromatic linkages (Scheme 2). For instance, the cavity size
was modified by changing the relative position of the aldehyde
and the hydroxy groups on the aromatic rings (hemi-
cryptophanes 15b and 15c). An electron-donating group was
also incorporated in the aromatic part of the linkages at
different positions, leading to hemicryptophanes 15d and 15e,
and the chlorine electron-withdrawing group was successfully
integrated in the aromatic wall of the hemicryptophane 15f.
Hemicryptophanes 15g−i with larger aromatic walls (naphthyl
moieties) were obtained and showed fluorescent properties.
Thus, this synthetic pathway constituted an important step in
the chemistry of hemicryptophanes as it allowed production of
larger amounts of compounds, which helped in further
applications as receptors or supramolecular catalysts.
Dutasta and Martinez et al. followed the pathway shown in
Scheme 2 to develop the gram-scale preparation of enantiopure
Figure 3. Synthesis strategies for the preparation of hemicryptophane
hosts: (a) by formation of the CTV unit; (b) by [1 + 1] coupling of
north and south parts; (c) by closure reaction at the south part (X, Y,
and F are suitable functions).
