Inherently chiral concave molecules—from synthesis to applications

4274 Chem. Soc. Rev., 2010, 39, 4274–4285 This journal is c The Royal Society of Chemistry 2010

Inherently chiral concave molecules—from synthesis to applications

Agnieszka Szumna*

Received 17th March 2010

DOI: 10.1039/b919527k

This tutorial review covers the recent development in the synthesis and application of molecules

and finite assemblies that are chiral owing to their curvature. A modified definition of inherent

chirality is provided. Various classes of chiral concave molecules are presented including salphen

complexes, cyclic amides, derivatives of sumanene, trioxatricornan or subphthalocyanine,

cyclotriveratrylenes, homooxacalix[3]arenes, calixarenes, resorcinarenes, phthalocyanines,

corannulenes and cavitands. Some of these bowl shaped compounds exhibit high inversion

barriers, comparable with the stability of classical carbon chirality centres, while the others

(e.g. hydrogen bonded assemblies) can only be detected by NMR. This review is focused

on practical aspects of synthesis, resolution and applications in chiral recognition and

asymmetric synthesis.

Introduction

Chirality is the geometric property of a rigid object (or spatial

arrangement of points or atoms) of being non-superposable on

its mirror image.1 This IUPAC description is an inviolable

principle for all chiral molecules. However, with the growing

complication of molecular systems that are characterised by

chemists, it has been realised that the classical understanding

of molecular chirality is not always sufficient. For instance,

chirality elements like centre, axis or plane are not adequate

to describe the chirality of rotaxanes, catenanes, fullerenes,

cavitands or capsular assemblies.2 With the discovery of these

new molecular arrangements, new possibilities for application

in enantioselective recognition or asymmetric catalysis have

emerged.

This review covers the recent development in the synthesis

and application of molecules and finite assemblies that are

chiral owing to their curvature. Molecules that possess a

concave shape are especially suitable for the construction of

effective recognition sites. These molecules are useful by taking

advantage of their concave cavity and convergent arrangement

of binding sites. They can also be further used as building

blocks for the construction of higher assemblies with other

new types of chirality.

In 1994 the pioneering review on inherently chiral calixarenes

was published by Bohmer.3 The scope of this current review is

to present other types of compounds that can be classified as

inherently chiral and highlight the recent progress in the

chemistry of inherently chiral calixarenes. The current state of

the art in the field justifies the transition from just a curiosity to

practical applications; therefore the review will concentrate on

practical aspects of synthesis, resolution and applications.

Definition and nomenclature

The expression ‘‘inherently chiral’’ was first suggested by

Bohmer for chiral calixarenes and initially applied mainly to

that class of compounds.3 Later, due to the lack of a rigorous

definition, the term was expanded and often intuitively attributed

to compounds that do not strictly fall into definitions of

other types of chirality. The first more general definition was

formulated in 2004 by the group of Mandolini and Schiaffino.4

It states that inherent chirality derives from the ‘‘introduction

of a curvature in an ideal planar structure that is devoid of

symmetry axes in its bidimensional representation’’ (axes

positioned in the 2D plane, explanation by L. Schiaffino).

However, formally, in 2D representations the only allowed

symmetry elements are axes and planes that are positioned

Institute of Organic Chemistry, Polish Academy of Sciences,Kasprzaka 44/52, 01-224, Warsaw, Poland.E-mail: [email protected].; Fax: +48 22 632 66 81;Tel: +48 22 343 21 10

Agnieszka Szumna

Agnieszka Szumna obtainedher MSc in crystal structureanalysis in 1997 at the WarsawUniversity, Poland. Then shejoined the group of Prof.Janusz Jurczak at the Instituteof Organic Chemistry, PolishAcademy of Sciences andcompleted her PhD in 2001working in the field of supra-molecular cation and anioncomplexes of macrocyclicpolylactams. She then wentfor a post-doc with Prof. JerryL. Atwood at the University ofMissouri, Columbia, USA. In

2003 she returned to the Institute of Organic Chemistry, PolishAcademy of Sciences as a habilitation candidate and became aproject leader. She finished habilitation in 2010 and now sheholds an independent research position. Her research focuses onvarious aspects of molecular recognition, new types of chirality,chiral recognition and separation, encapsulation, dynamics andreactivity in confined spaces. Present and future research goalsinclude development of new chiral cavitands, tubular andcapsule-type molecules as reaction vessels for asymmetric reac-tions and for controlled molecular motion.

TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews

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This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4274–4285 4275

perpendicular to the 2D plane. Therefore, to be in agreement

with this formalism, together with L. Schiaffino, we specified

the definition. Now the definition reads ‘‘inherent chirality

arises from the introduction of a curvature in an ideal planar

structure that is devoid of perpendicular symmetry planes in its

bidimensional representation’’ (Fig. 1). Therefore, the resulting

3D molecules have Cn (n = 1,. . .,n) symmetry (Fig. 1b).

For the description of inherent chirality two types of

notations have been suggested: (cR)/(cS),4 where c stands for

curvature and (P)/(M) notation.5 The latter approach seems to

be more justified, in analogy to axially chiral and cyclochiral

compounds, for which (P)/(M) notation is highly recommended.1

The (P)/(M) chirality description involves determination of

ring/bridging atoms/substituents priorities according to

standard stereochemistry rules (Fig. 2). The observer is situated

on the concave side of the surface (Fig. 1a) and a clockwise

priority of the sequence of groups is defined to have P chirality

while counterclockwise priority is defined as M chirality. In

the case of calix[4]arenes, the bridging carbons are labelled as

a, b, c, d according to the stereochemistry rules (Fig. 2a). In

the case of resorcinarenes the sequence of the groups that

are attached to the phenolic groups are determined (Fig. 2b).5

In the case of complexes, the observer is placed at the metal

centre and ligand priority is determined (Fig. 2c).4 For the

priority determination of hydrogen bonded assemblies, the

hydrogen bond is treated as a regular bond (Fig. 2d).6

Definition of inherent chirality underlines the crucial role of

curvature that clearly distinguishes the faces of the object.

Racemisation can, in principle, occur through inversion of the

curvature, therefore an inversion barrier is a crucial stability

parameter. In this review, examples of compounds that exhibit

high inversion barriers comparable with the stability of

classical carbon chirality centres are described. A lower limit

is set by inversion barrier for molecules that cannot be isolated

but only detected by NMR (DG Z 10 kcal mol�1).

In the chemical literature there are many terms that are used

to describe phenomena similar to inherent chirality. They

include: bowl chirality (used for fullerene fragments derived

from their three-dimensional geometry), residual enantio-

mers (applied after Mislow for sterically hindered molecular

propellers), intrinsic chirality, helicity or cyclochirality.

IUPAC defines helicity as the chirality of a helical, propeller

or screw-shaped molecular entity.1 This general definition

applies to some examples discussed in this review. However,

we think that helicity is too general and therefore ‘‘inherent

chirality’’ gives a more specific description of the pheno-

menon. The term ‘‘cyclochirality’’ was introduced in 1964 by

Prelog and Gerlach for cyclopeptides. It refers to a clockwise

or counterclockwise array of chiral building blocks in the

cyclopeptide that imply directionality of the ring (at least

6 units are required). Chirality of the building blocks is the

prerequisite. However, for chiral rotaxanes, the cyclochirality

is ensured by ring directionality and differentiation of the faces

by the asymmetric axle. In some cases the term ‘‘cyclochiral’’

can be also applied to compounds classified as ‘‘inherently

chiral’’. However, in most cases cyclochirality can be

distinguished as it comes from the directional connection array

of chiral units and the inversion of the curvature does not

cause racemisation (see discussion of cyclic amides).

In natural systems inherent chirality can be observed for

rhodopsin, the naturally occurring pigment responsible for

perception of light. Rhodopsin consists of a protein and a

photoreactive polyene chromophore—retinal 1 (Fig. 3). It was

shown that although the polyene chain contains no chirality

Fig. 1 Inherent chirality upon transformation from 2D to 3D space:

(a) for an object devoid of symmetry, (b) for an object with 4-fold axis

perpendicular to the 2D plane (partially adapted from ref. 4 with

permission from The Royal Society of Chemistry (RSC) on behalf

of the Centre National de la Recherche Scientifique (CNRS) and

the RSC).

Fig. 2 Examples of (P)/(M) notation of inherently chiral molecules: (a) calix[4]arenes, (b) resorcinarenes, (c) metal complexes, (d) hydrogen

bonded assemblies.

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centres, substantial effects in the UV/Vis CD spectrum are

observed. Although the polyene chain should be planar, steric

conflict imposed by methyl group precludes a completely flat

conformation. In solution the molecules exist as racemic pairs

of non-planar inherently chiral conformers in rapid equili-

brium. The X-ray structure corroborates the view that the

protein binding site accommodates a chiral conformer of

the chromophore. The ab initio calculations indicate that the

inherently chiral conformation of the chromophore is the

dominant factor in the CD spectrum.7

Realisation of inherent chirality in synthetic systems is

dependent on the synthetic availability of scaffolds with a

permanent curvature. Concave molecules made of identical

building blocks are mostly used for these purposes: they are

available through relatively easy synthesis and their chemistry

is in most cases well established. In this review the application

of various scaffolds, their stability against inversion and

modification possibilities will be discussed.

C2-symmetric scaffolds

Salphen

Complexes of salphen-type ligands with metals are widely used

as sensors, carriers and catalysts. The salphen complexes with

the uranyl dication are forced to assume a nonplanar

U-shaped geometry to accommodate the large uranium atom

(Fig. 4). This means that once curvature inversion is blocked

and if the R3 and R4 substituents are not identical then the

structure is inherently chiral (2, 3).8 Enantiomers of 2 are in

fast equilibrium but the motion can be restricted by applica-

tion of bulky substituents at the R1, R2 positions or by a

linker of the proper length. The most stable complexes that

were obtained in this way have enantiomerisation barriers of

26–27 kcal mol�1.9 The stability limit is set by the lability of

the coordination bonds (inversion through dissociation-

reassociation). Enantiomerically pure samples can be efficiently

stored as solids and their racemisation in solution is relatively

slow when compared with usual timescales of recognition and

catalytic processes and therefore they can still be suitable for

these applications.

The recognition site in the uranyl–salphen complex is

located at the metal centre. Four coordination sites are

occupied by the ligand while the fifth site is free and can be

used for recognition of anions and neutral molecules. Inherently

chiral receptor 3 exhibits recognition abilities towards amines,

sulfoxides and quaternary ammonium cations.10 The stability

constants in CDCl3 are high while recognition of enantiomers

is moderate (de’s were in the range of 13–36%).

The conformational inherent chirality of metal-free salphen

ligands, e.g., 4 has also been detected (Fig. 5).11 The curvature

of 4 comes from the nonplanar arrangement of tetramethyl-

phenyl ring and neighbouring phenyl-substituted imine

groups. The racemisation proceeds through rotation about

the formally single Car–Nimine bond and a racemisation barrier

of 21.9 kcal mol�1 was observed. It allowed for separation of

enantiomers via HPLC at low temperatures and observation

of diastereomeric complexes by NMR using Pirkle’s reagent.


Cyclic amides

The scaffolds based on the directionality of the amide bond

seem to be closely analogous to cyclochiral peptides. However,

cyclic aromatic amides reported by the group of Azumaya12

are actually the best examples to emphasise the difference

between cyclochirality and inherent chirality. The cyclic amide

trimers 5 and 6 have been reported to exist in enantiomeric

bowl shaped conformations (Fig. 6). Contrary to cyclochiral

peptides, no directional array of chiral building blocks is

required. Face differentiation is achieved by a curvature of

the bowl shaped molecule. In the basic structure 5 the ring

inversion is fast, but it can be efficiently blocked by cupping.

Cupping with trimesic acid leads to chiral spherical capsules

(separation by chiral HPLC).13 However, the internal volume

of the resulting capsule is very small and does not seem to be

suitable for guest encapsulation. However, one can envision

that application of other cupping groups can result in larger

capsules. The alternative strategy to prevent racemisation

involves application of bulky substituents at the nitrogen

atoms and aromatic rings. In this way configurationally stable

inherently chiral amides 7 were obtained (Fig. 6).14

Sumanene

The bowl shape of sumanene (Fig. 7a), a hydrocarbon that can

be considered as a part of a fullerene, has been recently

Fig. 3 (a) Retinal chromophore, (b) X-ray structure of its inherently

chiral conformation.

Fig. 4 (a) Inherently chiral uranyl–salphen complexes, (b) X-ray

structure of the basic skeleton. Fig. 5 Inherently chiral salphen.

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exploited for the construction of C3-symmetric inherently

chiral molecules.15 The synthesis of 9 is one of the very few

examples of direct induction of inherent chirality with

the chirality centres of the precursor 8 giving up to 90% ee

(Fig. 7b). The bowl-to-bowl inversion barrier for 9 was

estimated to be 21.6 kcal mol�1, which allowed for isolation

and analysis at low temperatures only. However, the inversion

barrier can be efficiently increased by substitution at the

dibenzylic positions. Substitution with the TMS group, which

bonds preferentially at the exo position, gives diastereomeric

derivative 10 that is resistant to bowl-to-bowl epimerisation.

Tricornan

Derivatives of triangulene with one or more sp2-atoms

replaced by sp3-carbons or heteroatoms form concave struc-

tures with a bowl depth dependent on the central atom type

(Fig. 8). The concave structure of trioxatricornan is blocked

against bowl inversion and once dissymetrically substituted it

produces inherently chiral structures (11).16 The inherently

chiral pattern can be also generated for diazaoxatricornan

structures using two different amines, e.g. 12.17

Regioselective formation of the C3-symmetric substitution

pattern is challenging due to the statistical tendency to form

C1-symmetric structures. However, it was shown that by

application of proper chelation, triacid 11 can be obtained in

55% yield.16 The enantiomers of 11 were resolved using amino

acid or menthol auxiliaries and absolute configurations were

deduced based on comparison of experimental and calculated

VCD/ECD spectra. The diastereomeric amino acid derivatives

of 11 are postulated to adopt considerably different conforma-

tions in terms of cavity depth. The structures are stabilised by

intramolecular hydrogen bonding and are highly dynamic and

therefore both can be potentially useful for further recognition

studies.

Subphthalocyanines

Subphthalocyanines are 14 p-electron aromatic boron macro-

cycles that consist of three N-fused iso-indole units arranged in

a permanently non-planar cone-shaped structure (Fig. 9). The

synthesis involves cyclotrimerisation of phthalonitrile in the

presence of boron derivatives. While the precursor phthalo-

nitrile lacks C2v symmetry, it yields a mixture of two sub-

phthalocyanine regioisomers with C1 and C3 symmetries, each

as a mixture of enantiomers. The statistical product distribution

(C3 :C1 = 1 : 3) can be influenced by electronic (in favor of C3

isomer) or steric factors (in favor of C1 isomer). Only very

recently, the enantiomers of the C1 and C3 isomers of 13 were

separated by Torres and co-workers on an analytical scale by

chiral HPLC.18 Interestingly, it was shown that inherent bowl

chirality can cause asymmetric induction in the formation of

chirality centres positioned in the side chains. Side chains

containing thioether groups were oxidised to give chiral

Fig. 6 Inherently chiral cyclic amides and their X-ray structures.

Fig. 7 (a) X-ray structure of the basic skeleton of sumanene,

(b) diastereoselective synthesis of inherently chiral sumanene.

Fig. 8 (a) Inherently chiral tricornan derivatives, (b) X-ray structure

of the basic skeleton of trioxatricornan.

Fig. 9 (a) Subphthalocyanine derivatives, (b) X-ray structure of the

fluorinated basic skeleton (fluorine atoms-light blue).

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sulfoxides as a 95 : 5 mixture of diastereoisomers.19 The

main problem encountered in the functionalisation of these

molecules is their chemical instability, which usually leads to

decomposition via ring-opening. In addition, the harsh con-

ditions required for their synthesis limit to a great extent

the kind of functional groups that can be introduced in the

precursor phthalonitriles.

Cyclotriveratrylene

The cyclotriveratrylene molecule (CTV, Fig. 10) is a

convenient concave scaffold due to its easy availability

(one step synthesis from simple and cheap substrates), stability

and straightforward modifications. The bowl inversion barrier

(DG E 26.2–27.4 kcal mol�1) is sufficient to allow the separa-

tion of the two enantiomers at room temperature. In the

dominant crown conformation inherent chirality is realised

when each aromatic ring bears two different substituents. The

simplest inherently chiral C3-symmetric CTV analogue, cyclo-

triguaiacylene 14, can be easily obtained as a racemic mixture

by a one step synthesis and enantiomers were separated by

chromatography of the respective diastereomeric esters.20

Another simple C3-symmetric derivative, nonamethoxy-CTV 15,

was also obtained in a one step synthesis in 54% yield21 and

resolved by chiral phase HPLC.22 Optically pure CTVs have

not been reported for chiral recognition, probably due to their

relatively shallow and wide cavities. However, they have been

effectively used as platforms to prepare chiral cryptophanes of

D3 symmetry. Such modifications enhance their binding abilities

and also prevent racemisation.23 Chiral cryptophane-C

forms complexes with one of the smallest chiral molecules,

CHFClBr. Although enantiomeric discrimination is not high

(DDG = 1.1 kJ mol�1) cryptophane-C enabled the first resolu-

tion and assisted with configuration assignment of CHFClBr.

Other chiral cryptophanes also formed diastereomeric

complexes with CHFClBr under slow exchange condition at

the NMR timescale allowing for detection of enantiomers. The

association constants of up to 100 M�1 were determined by

NMR for different host–guest systems, although with almost no

enantioselective preference.

Homooxacalix[3]arenes

Homooxacalix[3]arenes are more flexible than the previously

reported scaffolds and in their basic forms rotation of the

subunits is almost unrestricted (Fig. 11). Ring inversion can be

blocked by appropriate O-substitution. It was shown that by

di-O-alkylation the pseudo-C2 symmetric inherently chiral

molecule 16 can be obtained (with enantiomers separated by

chiral HPLC).24 Although the third aromatic ring can still pass

though the macrocyclic ring, the molecule retains its chirality

since the resulting structure is identical due to C2 symmetry

(Fig. 11b). With that design the authors reported an impressive

de of 72% for complexation of amino acid esters (as picrate

salts). The complexation is driven by the high affinity of the

homooxacalix[3]arene bowl towards alkylammonium ions

while inherent chirality, based only on different alkyl chains,

is responsible for enantiomer discrimination.

Once the ring inversion is blocked by complete O-alkylation

homooxacalix[3]arenes with an ABC substitution pattern at

the upper rim are inherently chiral. For example, homooxacalix-

[3]arene 17, with three different aliphatic substituents at the

upper rim, was synthesised by stepwise condensation and

resolved by chiral phase HPLC.25 Macrocycle 17 was shown

to distinguish enantiomers of amino acid esters by differences

in NMR shifts.


Calix[4]arenes

Calix[4]arenes were the first scaffolds for which the term

‘‘inherent chirality’’ was applied and still are very popular

for this use. Their versatility is caused by their stability,

relatively easy synthesis and various available modification

procedures. Calixarenes are cyclic oligomers made up of

phenolic units connected by methylene bridges (Fig. 12). The

tetramer, the most widely used calixarene, undergoes through-

annulus inversion that can be blocked by proper O-substitution

of at least n-Pr in size. The parent calix[4]arene can exist in

different non-planar conformations: cone, partial cone, 1,2-

alternate and 1,3-alternate. Each of these conformations can

produce inherently chiral structures with proper substitution.

The inherent chirality is observed for calix[4]arenes containing

at least three different subunits, i.e., ABCC or ABCD patterns.

The subunit differentiation may be achieved by different

substituents (positioned either at the lower or upper rim or a

combination of both) or by different spatial arrange-

ment (different conformations), making a large number ofFig. 10 (a) Inherently chiral cyclotriveratrylene derivatives, (b) X-ray

structure of the basic skeleton.

Fig. 11 (a) Inherently chiral homooxacalix[3]arenes, (b) schematic

representation of the hydrogen atom passing through the ring of 16,

producing superposable structures.

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possibilities and factors to control.26 Another strategy

to introduce directionality to the calixarene ring involves

meta-substitution of the phenolic ring that differentiates

the edges. Calixarenes consisting of a single or multiple

meta-substituted aromatic rings are inherently chiral. A few

examples of calixarenes with chirality induced by asymmetrical

bridges are also known.

The early synthetic procedures for producing inherently

chiral calixarenes, based on stepwise fragment condensations,

were reviewed in 1994 and 1997 by Bohmer.3,27 This approach

is strenuous and rarely used now. Instead, modern synthetic

procedures utilize selective functionalisations. Effective synthesis

of inherently chiral calix[4]arenes via selective modifications

became feasible with the discovery of procedures that lead to

mono-O-substituted or proximal 1,2-di-O-substituted derivatives

and cation templated conformational control.

The synthetically simplest route to obtain inherently chiral

calixarenes of ABCC type is to introduce two different

substituents at the neighbouring hydroxyl groups at the

lower rim. In the group of Kalchenko 1,2-di-O-substituted

inherently chiral calix[4]arene 18 was synthesised by mono-

alkylation and subsequent regioselective proximal substitution

(Scheme 1).28 The asymmetric induction by chiral auxiliary

was low (de up to 15%), but resolution of diastereoisomers

was complete and experimentally practical.29 In order to get

purely inherently chiral derivatives, diastereoisomers of 18

were modified at the upper rim of the remaining rings (acti-

vated due to the presence of free OH groups) and the chiral

auxiliary was removed to give 19. Higher inherent chirality

inductions (up to de 60%) were obtained by lower rim 1,3-

substitution using chiral auxiliary and subsequent proximal

modification under mild reaction conditions.30

The design based on proximal bridging using crown ether

linkers and additional O-substitution to introduce chirality

was used by the group of Pappalardo.31 The derivative with a

crown[6] type ring at the lower rim (20, as racemate) has been

used for recognition of (R) and (S)-1-phenyl-ethylammonium

picrates. Although doubling of the signals occurred suggesting

that a diastereomeric complex was formed, no chiral discrimi-

nation was observed.

A similar design was used in the group of Chen and Huang

to obtain a series of inherently chiral acid derivatives in

cone and partial cone conformations (21, separated using

(S)-BINOL as a chiral auxiliary) (Fig. 13).32 The presence of

an additional acid group, as in 22 (partial-cone conformation)

assures formation of diastereomeric salts with leucinol with

considerably different association constants for enantiomers

(Ka = 50 M�1 and 143 M�1 in CD2Cl2, de 48%).32,33 The

interaction pattern employs electrostatic interactions and

hydrogen bonding between the ether oxygen atoms on the

host and amino/ammonium groups of the guest.

The ABCC pattern can also be realised with different spatial

positions of identical substituents. A proximally di-O-alkylated

calixarene with two identical substituents can be chiral

provided that the substituents have an anti relationship,

i.e. the skeleton is locked in the partial cone conformation

(Fig. 14). The through-annulus rotation of the remaining two

hydroxyl groups does not have to be restricted since it does not

change the structure (dynamically averaged C2 symmetry).

Proximal dialkylation to produce an anti relationship between

alkyl groups was accomplished by proximal protection and

templated dialkylation to give 23.34 Optical resolution was

achieved by derivatisation to diastereomeric esters and flash

chromatography.35

Another approach for differentiation of substituents at the

lower rim involves directional bridging. Directional linkages

composed of carboxamide36 or ester37 moieties can be introduced

by a cyclisation reaction to give inherently chiral calixarenes,

e.g. 24.

Lower rim modifications are synthetically relatively easy;

however, the products do not take advantage of the unique

inclusion properties of the calixarene hydrophobic cavity and

Fig. 12 (a) Calix[4]arene in cone conformation, (b) X-ray structure of

the basic skeleton.

Scheme 1

Fig. 13 Inherently chiral calixarenes with polyetheral bridges.

Fig. 14 Inherently chiral calixarenes by: (a) conformational,

(b) directional linking.

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binding sites are limited to the ones that were introduced with

substituents. Binding sites and chiral groups positioned

at the upper rim can take full advantage of the calixarene

bowl. Modification of the upper rim usually starts with func-

tionalisation of the lower rim to prevent structure inversion

(racemisation) and to differentiate upper rim reactivity. The

most common synthetic strategy involves selective alkylation

of the debutylated calixarene and subsequent electrophilic

aromatic substitution of the remaining rings.

This approach has been used by the groups of Shimizu to

obtain amino phenol 25, amino acid 26 and amino alcohol 27

presenting inherent chirality based on upper rim functionali-

sation (Fig. 15). Amino phenol 25 is able to recognise enantio-

mers of mandelic acid through formation of diastereomeric

salts (de 37.5%).38 Both polar groups and the hydrophobic

calixarene cavity are involved in the recognition pattern as can

be deduced from NMR. Although the de value is moderate it is

sufficient to facilitate effective resolution of enantiomers of

amino phenol 25 by crystallisation. Dual functions that are

present in the structures of the amino alcohol derivatives can

be utilised in catalysis: the basic moiety is believed to activate

nucleophiles, while, at the same time, the hydrogen donor

group can activate the electrophiles through hydrogen bonding.

In line with this catalytic mechanism enantiomerically pure

inherently chiral amino phenol 2538 and amino alcohol 2739

were applied as catalysts in a Michael addition of thiophenol

and 2-cyclohexen-1-one giving products with 15% ee. The

efficiency of the catalyst was improved up to 31% ee (1 mol%

catalyst loading) by functionalisation of the third phenolic

ring with a voluminous group producing a deeper cavity.40

Amino alcohol 27 was further modified to give an inherently

chiral ammonium salt that was applied as an asymmetric

phase-transfer catalysts in various Michael additions giving

products in excellent yield with low enantioselectivities.39

Inspired by the very successful amino acid catalysis of the

aldol reaction, amino acid 26 was tested as an organocatalyst

in the direct aldol reaction of acetone.39 However, no catalytic

activity of 26 was observed which was attributed to the low

nucleophilicity of the nitrogen atom. However, it seems that

likely explanations can also be based on too long a distance

between amino and acid functions which lowers effectiveness

of primary amino functions.

The alternative approach to upper rim inherently chiral

calix[4]arenes involves differentiation of the edges of a single

phenolic ring that can potentially give products with more

compact chiral binding sites (Fig. 16). The synthetic strategies

involve initial selective activation of one of the phenolic rings

and subsequent meta substitution. This way various inherently

chiral derivatives were obtained in the group of Chen and

Huang, involving calix[4]quinoline,41 salphen42 or proline

derivatives, as for example 28.43 The resolution of inherently

chiral enantiomers was achieved during reaction with

Boc-L-proline that was kinetically controlled.44 The asymmetric

synthesis approach has also been used for meta substitution.45

Initial introduction of the chiral auxiliary at the upper rim and

the subsequent ortholithiation reaction gave inherently chiral

calix[4]arenes with high de (93%).

The efficiency of 28, a calixarene that combines inherent and

classical chirality, has been tested in the enantioselective aldol

reaction between 4-nitroaldehyde and cyclohexanone.43 High

yields and ee values up to 66% were obtained. Comparison

with the monomeric catalyst (no calixarene ring, no inherent

chirality) indicated that the monomeric catalyst at room

temperature exhibited lower reactivity but with slightly higher

enantioselectivity than both diastereoisomers of 28. At lower

temperatures one of the diastereoisomers of 28 gave higher

enantioselectivity. The other diastereoisomer gave lower enantio-

selectivity than the monomeric catalyst, suggesting that inherent

chirality can be matched or mismatched with proline chirality.

Heterocalixarenes

The bridging methylene groups of calixarenes can be replaced

by other linkers. Thiacalix[4]arenes are most widely used due

to their easy preparation and many chemical similarities to the

parent calix[4]arene. In most cases thiacalixarenes can be

modified in analogous ways to calixarenes, e.g., for preparation

of 29.46 Chiral recognition properties of 29 towards amines

and amino acid esters were assessed. Diastereomeric salts,

stable at the NMR timescale, were formed in most cases

allowing for effective enantiomer discrimination by chemical

shifts.

An interesting possibility, typical only for thiacalixarenes, is

modification of the bridging sulfur atoms. Oxidation of the

adjacent sulfide functional groups in an anti relationship

leads to inherently chiral structure 30 (Fig. 17), analogous to

1,2-anti-disubstituted calixarenes.47 It should be noted however,

that the inherent chirality in this case is inextricably bound to

chirality centres at the sulfur atoms.

Fig. 15 Inherent chirality introduced by upper rim substitution.

Fig. 16 Inherent chirality by edge substitution.

Fig. 17 Chiral thiacalixarenes.

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Resorcinarenes

The substitution pattern that is used to generate inherent

chirality of calix[4]arene can be also placed on the structurally

similar scaffold, resorcin[4]arene (Fig. 18). Resorcin[4]arenes

have several advantages over calix[4]arenes: (a) their synthesis

is easier and more efficient; (b) presence of aliphatic chains at

the bridging atoms permanently blocks bowl inversion; and

(c) the upper rim modifications are easier due to available

reactive 2-position of the resorcinol rings. The disadvantage of

resorcinarenes is that they are practically available only as

tetramers (no higher isomers). It should be also noted that an

inherently chiral substitution pattern while positioned on the

resorcinarene skeleton induces the presence of chirality centres

at the bridging atoms. Therefore resorcinarenes, closely

analogous to the respective calixarenes, possess a classical type

of chirality. However, the distinction of those two types of

compounds seems to be formal only. Reviews on the synthetic

strategies to produce various types of chiral resorcinarenes48

and Cn-symmetric calixarenes and resorcinarenes49 have just

recently been published.

Resorcinarenes in their cone conformation are stabilised by

a system of hydrogen bonds at the upper rim. This has a

beneficial influence on the regioselectivity of their reactions. In

many cases, preferential formation of C4-symmetric products

is observed due to stabilisation of their structures by the

maximum number of intramolecular hydrogen bonds.

One of the simplest C4-symmetric inherently chiral resorcin-

[4]arenes is obtained by regioselective substitution of one of

the hydroxyl groups at each ring in a C4-symmetric manner.

Resorcinarene 31 (Fig. 19), with four methoxy groups, was

synthesised with high regioselectivity by simple Lewis acid

catalysed condensation of 3-methoxyphenol with aldehydes

(80% yield).50 Separation of enantiomers was accomplished by

conversion into diastereomeric amides51 or camphorosulfonates.52

The absolute configuration, originally erroneously ascribed,51 has

been established.52

In 1992 it was shown that theMannich reaction of resorcinarene

with primary amines and formaldehyde gives tetrabenzoxazines

32.53,54 The unambiguous proof of the regioselective forma-

tion of a C4-symmetric isomer (among four possible) and its

chirality due to directional closing of the benzoxazine rings

was discovered by further analyses.55 The regioselectivity of

the ring closing reaction is attributed to the stabilisation

effect of four intramolecular hydrogen bonds. Using chiral

amines, diastereoselective tetrabenzoxazine syntheses were

accomplished.56–58 Even with simple aliphatic amines, stereo-

selectivity can reach high values (up to >97%) but it is rather

unpredictable since it is often driven by precipitation of one of

the diastereoisomers.59 The Mannich reaction can be also

performed with amino acids as amine partners, giving up to

>98% ee (e.g., L-phenylglycine methyl ester gives (P)-34,

Fig. 20).60 Although the products have potential recognition

groups they adopt very crowded conformations that are not

suitable for complexation.

Tetrabenzoxazines are quite stable as solids but in solution

they undergo epimerisation due to chemical instability of the

N,O-acetal bridge, this instability is considerably enhanced by

traces of acids. For the benzylamine derivative the enantio-

merisation barrier is 22 kcal mol�1 in n-hexane/2-propanol

(9 : 1),61 but it reaches higher values with bulkier substituents

and a less polar medium.

Facile epimerisation of tetrabenzoxazines limits their

practical applications. However, they can still be used as regio-

and diastereoselectively protected intermediates for further

modifications.62 A combination of the Mannich reaction and

O-alkylation resulted in a number of derivatives synthesised,

that were applied as catalysts to the addition of dialkylzinc to

benzaldehyde.5 When ligand 33 was used (possessing purely an

inherent type of chirality, Fig. 19), 42% ee was obtained.

Enantioselectivity can be enhanced by formation of matched

systems with a chiral amine. With this approach, for deriva-

tives with additional chiral amines, a 95% conversion with an

83% ee was obtained. It has been shown that the resorcinarene

skeleton is crucially important as evidenced by the reduced acti-

vity and low enantioselectivity when a monomeric benzoxazine

was applied.

The alternative to the ring closing Mannich reaction

involves coordination to boron atoms (Fig. 21). In this way

L-prolinol and L-proline derivatives of resorcin[4]arenes were

transformed into inherently chiral bora-derivatives 35 and 36

Fig. 18 Resorcinarene and the schematic representation of its

C4-symmetric structure.

Fig. 19 Inherently chiral C4-symmetric resorcinarenes.

Fig. 20 (a) Amino acid substituted tetrabenzoxazine, (b) X-ray

structure (H atoms removed for clarity).

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with moderate to high de (60% and >98% for 35 and 36,

respectively).63,64 The dominant diastereoisomers were found

in open conformations (Fig. 21b).

Formation of the tweezers-like structures based on

resorcinarenes is realised by selective tosylation of four out

of the eight hydroxy groups of resorcinarene and further

transformation into Mannich products (Fig. 22). Interestingly,

among two possible regioisomers of this type only chiral

C2-symmetric structures are formed.65 By application of

chiral amines (e.g. 1-cyclohexylethylamine) two diastereomeric

dibenzoxazines 37 were obtained as a 60 : 40 mixture. Dia-

stereomeric excess can be much higher (>97% ee) and the

products more stable with application of amino acid derivatives

as the amine partners, e.g., for 38.66 Intramolecular hydrogen

bonding that is formed between amino acid arms of 38

assures high diastereoselectivity but it locks 38 into the

boat conformation and makes the molecule incapable of

complexation.

Phthalocyanines

Metal complexes of phthalocyanines are essentially planar.

However, deformation of their skeleton by unsymmetrical

complexation leads to optically active derivatives (Fig. 23).

This approach was used to construct inherently chiral

phthalocyanine-VO complexes like 39. Its unusual circular

dichroism observed for Q bands was used to study factors

that can influence CD spectra of inherently chiral structures.67

It turned out that the signs of the CD bands are much more

sensitive to small conformational changes (e.g. rotation of a

methyl group) than is usually observed for other types of

chiral compounds.

Higher symmetries

Calixarenes

For calix[n]arenes with higher number of subunits (n > 4)

selective derivatisation is more difficult. The only inherently

chiral calix[5],68 calix[6] and calix[8]arenes69 were formed by

polyether linkages at their lower rims and no applications have

been reported.

Corannulenes

Corannulenes are bowl shaped molecules with a unique

C5 symmetry (Fig. 24). The barrier for bowl inversion of

unsubstituted corannulenes is 11.5 kcal mol�1. An inherently

chiral pattern was generated in the structure of annelated

corannulene 40 by rim substitution that also resulted in a

deeper bowl more resistant to racemisation (experimental

inversion barrier >25 kcal mol�1, ab initio calculations predict

29.8 kcal mol�1).70 However, no separation or applications

were reported.

Inherent chirality by hydrogen bonding

Inherent chirality discussed thus far is based on asymmetric/

dissymmetric covalent substitution of non-planar compounds.

The chiral arrangement can be also achieved using directional

non-covalent interactions, e.g., hydrogen bonds mounted on a

non-planar skeleton. Hydrogen bond networks are considerably

less stable and separation of inherently chiral enantiomers is

not possible. However, the introduction of additional chiral

auxiliaries can bias the equilibrium and increase the popula-

tion of one of the diastereomeric inherently chiral conformers.

Since the cooperative system of many hydrogen bonds

Fig. 21 (a) Inherently chiral bora-derivatives, (b) X-ray structure of

the main diastereoisomer 35.

Fig. 22 C2-symmetric dibenzoxazines.

Fig. 23 Inherently chiral phthalocyanine complex.

Fig. 24 Corannulenes.

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contributes significantly to the overall stability of the systems,

induced inherent chirality can substantially modulate

properties. Therefore, one can envision that inherent chirality

can greatly support (or hamper) efficiency and selectivity in

chiral recognition.

The first examples of inherently chiral hydrogen bonded

compounds were reported by the group of Rebek. They created

deep cavitands with ‘‘doors’’ at the upper rim that were

controlled by a unidirectional cooperative belt of hydrogen

bonds, formed by either the amide (41, Fig. 25)71 or hydroxyl

groups.72 The ‘‘doors’’ can close clockwise or counterclock-

wise and in the presence of additional chirality centres one of

the directions is preferred (de 50%).71 The chiral vessels

exhibit preferential binding of enantiomers of various small

molecules, e.g., trans-cyclohexanediol (60% de).72 The great

advantage of cavitand-type molecules is their ability, as a rule,

to form kinetically stable complexes on the NMR timescale. It

often allows for easy determination of enantiomeric composi-

tion by chemical shifts even without preferences toward one of

enantiomers.

Other cavitands with inherently chiral conformations were

reported by Schmidt et al.,73 during the accidental synthesis of

the N-acetyl derivative of resorcin[4]arene, and in our group.6

Our group has shown that amide substituted resorcin[4]arenes

like 42 (Fig. 26a) exist in inherently chiral kite conformations

that are stabilised by a unidirectional system of eight hydrogen

bonds (in solid state and in solution, Fig. 26b). This dynamic

system of hydrogen bonding undergoes inversion characterised

by a relatively high energy barrier (14.6–18.5 kcal mol�1)

consistent with simultaneous rupture of all eight hydrogen

bonds. This is quite a surprising result, considering that the

hydrogen bond system is not strictly cooperative. However,

rotation of just one unit creates an unfavourable pattern in the

adjacent hydrogen bonds, which is responsible for apparent

cooperativity. For the analogous resorcinarenes substituted

with amino acid derivatives, inherently chiral conformations

are stabilised by twelve hydrogen bonds and therefore are even

more stable.74 The presence of additional stereogenic centres

causes formation of two diastereomeric inherently chiral con-

formations M and P in unequal amounts (de in the range of

72% up to >95%).6,74 The relatively slow exchange and high

de allowed for the determination of the directions of the

hydrogen bonding seam and their correlation with CD spectra.

Although the stability is impressive, the open kite conforma-

tion was not suitable for guest complexation.

In the group of Badjic, the C3-symmetric basket molecule 43

was constructed which is sealed at the top by a seam of three

hydrogen bonds (Fig. 27).75 Directionality of the seam is

responsible for the existence of two inherently chiral enantio-

meric conformers that were detected at low temperatures. The

activation energy for racemisation was found to be in the

order of 10.8 kcal mol�1. Although this barrier is rather small,

the open/close mechanism is claimed to be responsible for

modulating guest uptake/release mechanisms.76

Fig. 25 Cavitand 41 with an inherently chiral system of hydrogen

bonds: (a) X-ray structure, (b) schematic view of the H-bond array.

Fig. 26 (a) Inherently chiral hydrogen bonded resorcinarenes, (b)

X-ray structure, top view with hydrogen bonds (green-MeCN

molecules).

Fig. 27 Calculated structure of the basket molecule 43 sealed by

hydrogen bonds: (a) side view, (b) top view, (c) schematic view of the

hydrogen bond array.

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Conclusions and outlook

A wide array of inherently chiral molecules based on various

building blocks and noncovalent interactions has been synthesised

in the past few decades. In some cases, spectacular examples of

very simple synthetic approaches have been developed that

can be credited with the high symmetry of the products or

favourable intramolecular interactions. In other cases synthetic

procedures are longer; however, the synthetic effort does not

seem to be harder than syntheses of other target molecules of

this size. However, obtaining inherently chiral molecules in an

optically pure form remains a challenging task. In many

cases it can be accomplished using chiral phase HPLC, which

is suitable for analytical purposes and simple screening of

properties. For applications or further modifications this

technique is not sufficient. Therefore other methods of synthesis

and separation have to be developed. Diastereoselective syntheses

are currently considered the most cost-effective. Although the first

examples of diastereoselective syntheses of inherently chiral

compounds have been reported, development of more effective

routes is still required in this field.

The pyramidal shape and convergent binding modes of

inherently chiral compounds make them excellent receptor

candidates. Examples of first applications, mostly towards

simple model guests, have been presented in this review.

However, it can be envisioned that molecules with relatively

large binding pockets and multiple binding sites are not a good

fit for small molecules and therefore inherently chiral receptors

can demonstrate their full potential towards recognition of

larger guests. The internal space constricted by the walls often

allows for encapsulation of more than one guest molecule

and imposes specific conformations. These features create

further possibilities for application of inherently chiral

concave molecules as scaffolds for the construction of nano-

reactors—potential chiral reaction vessels with catalytic func-

tions. This area is developing rapidly and for capsular assemblies

promising results with rate enhancements comparable to those

observed for enzymes were reported (recent results from the

group of K. N. Raymond). However, the creation of a chiral

internal environment in capsules has proved to be difficult.

Therefore inherently chiral concave molecules may turn out to

be invaluable for these purposes.

The growing interest in nanotechnology propels the bottom-

up fabrication of molecular machines. Chiral parts, like for

example ratchets that are able to produce directional motion

are of great interest. It can be envisioned that inherently chiral

molecules, with their cavities and pinwheel-like shapes can

also serve as parts in the construction of molecular machines.

Although the research in the field of advanced applications of

inherently chiral concave molecules is still in its infancy, the future

development should demonstrate their potential advantages.

Notes and references

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Inherently chiral concave molecules—from synthesis to applications

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