Besides the traditional definition of helicene molecules, there are several special cases which belong to this structural category but are not associated with the above-described major groups of carbo- and heterohelicenes; these are discussed below. Naphthalene **2** and phenanthrene **3** are the simplest *ortho*-fused flat molecules without any steric constraint and, hence, are not helicenes, whilst four fused aromatic rings induce a certain steric hindrance at the innermost peripheral hydrogen atoms, setting up the first member of helicene family. Thus, in [n]helicenes, n should be >3 to be classified as a helicene molecule. However, there are some exceptions to this general rule. Interestingly, phenanthroline-*N,N*-dioxide **23** [33] (Figure 5) is also classified as a helicene in the literature, despite the fact that n = 3. This is due to the fact that the *N,N*-dioxide functionalities at the peri positions in the bay area of the phenanthroline are able to introduce the corresponding spatial constraint to force the molecule to adopt a configurationally stable helical conformation.

**Figure 5.** Special structural types of helicene **23** and helicene-like molecules **24**–**25**.

Besides the well-defined helicene molecules, there also exist helical structures, such as **24** [34] and **25** [35], called helicene-like molecules or helicenoids (Figure 5). Helicenoids usually contain at least one saturated atom as a part of the ring system in the helicene-type core system. Thus, the saturated ring is not able to adopt a flat structure, resulting in the enhancement of helicity. For example, a series of 1,1 -Bi-2-naphthol (BINOL)-based helical systems, sometimes referred to as oxahelicenoids, have been reported so far as configurationally stable structures [34,35]. Other types of saturated hydrocarbon-containing helicenoids, which are actually dihydrohelicenes, are also well documented in literature as precursors for helicene synthesis.

#### *3.2. Spatial Diversity*

Besides the structural diversity described above, helicenes can also be categorized, based on their stereochemistry, into four different categories: achiral (flat structures), stereodynamically labile (when *P* and *M* spatial conformations are in fast equilibrium; for the *P* and *M* definitions, see Section 3.2.1), chiral (enantiomerically stable structures), and *meso* helicenes (helical structure with some symmetry elements). This categorization is highly important for their applications in chiral auxiliaries and for chirogenic systems.

#### 3.2.1. Chiral (Configurationally Stable) Helicenes

In order to understand the helicene spatial structures and this classification, the term "in-plane turn angle" needs to be introduced. Due to the *ortho* fusion mode, each aromatic ring contributes to the overall helicity of the molecule via an in-plane turn angle (Figure 6a). When the sum of the in-plane angles of the contributing rings becomes 360◦ or more, the helicene is forced to adopt a helically chiral structure caused by the corresponding steric clashes between the terminal/peripheral rings. Conventional six-membered (hexagon) aromatic rings such as benzene and pyridine have an in-plane turn angle of 60◦ [36]. However, in the case of five-membered heteroaromatic (pentagon) rings, the value is considerably smaller at 45◦ (thiophene), 35◦ (pyrrole), and 32◦ (furan) [36] due to the different geometric properties of aromatic rings as a result of the variable atomic sizes of heteroatoms and bond length of C–X bond (X = heteroatom S, N, O in the five-member aromatic rings, correspondingly). Therefore, the helicenes with at least one five-membered heteroaromatic ring need n > 6 to become intrinsically chiral, whereas for the helicenes containing all six-membered carbo/hetero aromatic rings, n = 6 is sufficient to make them helically chiral.

**Figure 6.** Schematic representation of (**a**) in-plane turn angle and (**b**) helicity and enantiomers of [6]helicene.

In general, a chiral helicene molecule exists in two enantiomeric forms. The right-handed helical structure (moving from up to down) is assigned the name (*P*)-enantiomer, whereas the left-handed helical structure (moving from up to down) is designated the (*M*)-enantiomer, according to the Cahn–Ingold–Prelog rule (Figure 6b). This type of helicene tends to give configurationally stable enantiomers as the racemization process is expected to go through the highly energetic, strained *Cs*-symmetrical transition state [37]. Along with this thermodynamic stability of enantiomers, helicenes also exhibit notable enhanced (chir)optical properties, making them suitable candidates for chiral auxiliaries and other chirogenic processes. Interestingly, in general, (*P*)-carbohelicenes are observed as dextrorotatory, whereas (*M*)-enantiomers display a levorotatory nature [38].

#### 3.2.2. Achiral Helicenes

Another type of helicene is the achiral flat molecules; for example, *ortho*-condensed polyaromatic molecules consisting of four rings with at least one ring being a five-membered (pentagon) heteroaromatic ring, as in [4]heterohelicenes. Whilst these structures are less interesting from the viewpoint of chirality, they possess enhanced conjugation, electron transfer, and emission properties, making them suitable candidates for various material chemistry applications.

#### 3.2.3. Stereodynamic Helicenes

Holding an intermediate position between the chiral and achiral helicenes are the stereodynamic helicene structures. The geometry of these molecules is close to flat, whilst the van der Waals radii of the innermost hydrogens touch each other, making the structure stereodynamic and nonresolvable in solution, owing to the low (*P*)–(*M*) interconversion energy barrier. These include helicenes consisting of five benzenoid (hexagon) rings or [6]heterohelicenes with two five-membered (pentagon) heteroaromatic rings. However, in a solid state, these structures are able to adopt a chiral helical conformation. The dioxa[6]helicene **16** [27] is a typical example of such a system.

Stereodynamic helicenes are also highly fluorescent in nature due to the extended conjugation, whilst lacking any intrinsic chiroptical properties in solution. Yet, applying host–guest chemistry with suitable enantiopure guests, the corresponding chiroptical properties can be induced and controlled in this type of helicene. Additionally, the stereodynamic helicenes can be made helically chiral by introducing a bulky substitution at the innermost (C1) carbon atom. Computational analysis confirmed that attachment of just one methyl group at the innermost position results in the same steric strength as introduction of one additional *ortho*-fused benzene ring. Thus, [5]helicene with a methyl group at the innermost position has a structure more helical than that of [6]helicene, thus increasing the racemization barrier for the former [37].

#### 3.2.4. *Meso* Helicenes

*Meso* helicenes are achiral, yet need to be classified separately. Two helicene fragments in one molecule, with the presence of a plane of symmetry, produce an achiral *meso* helicene. Each equivalent helical part of this molecule possesses the opposite helical sense, whilst the whole molecule is symmetrical. Potentially, it can be suitably desymmetrized by a covalent bond or supramolecular interaction, making it chiroptically active and, hence, usable in various chirogenic processes. However, this area has not been well investigated yet, as selective modification of only one helicene moiety out of two is an arduous task; this is due to the fact that both the helicene parts are chemically equivalent. For example, carbocyclic helicene **26** [39] and heterocyclic helicene **27**–**28** [40] are *meso* double helicenes (Figure 7). It should be noted that the double helicenes have three stereoisomers, out of which two are optically active ((*P*,*P*) and (*M*,*M*)) and one is optically inactive ((*P*,*M*) or (*M,P*)), defined as a *meso* structure.

**Figure 7.** Examples of *meso* double helicenes **26**–**28**.

#### **4. General Description and Main Synthetic Approaches toward Helicene-Based Chirogenic Systems**

The early pioneering work on helicene synthesis, resolution, and chiroptical properties has been performed by Newman [15,16,41]**,** Wynberg [36,38], Martin [42], and Katz [26]. In general, classical methods of helicene synthesis include the following approaches: oxidative photocyclization, Diels–Alder reactions, and various aromatic and metal-catalyzed coupling reactions [2–6,11]. The synthesis of helicenes is always a challenging task for organic chemistry due to the steric factors involved and difficulty in controlling the regioselectivity of reactions. The same factors are also responsible for the unique reactivity of the helicene skeleton.

The current advances in synthetic chemistry, resolution, and chiral separation are essentially helpful in designing and obtaining novel enantiopure helicene molecules in sufficient quantities to be used for various applications. As BINOL, (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) (BINAP), and related biaryl systems have been successfully applied as ligands, catalysts, and hosts in stereodiscriminating processes [43–45], it is theoretically possible to thoroughly design helicene-based helical systems possessing advantageous chiral properties. Progress in this area is highlighted below with several selected examples.

Let us look closely at a general structure of (*M*)-[6]helicene **6** (Figure 8a), where the benzene rings at the beginning and at the end of the helical arrangement are called the terminal or peripheral rings. It can be clearly seen that the helix experiences steric clashes towards the inner sides (interior), called the helicene's inner core. This structural organization results in a helical chiral cavity. The restricted space available between and around the two peripheral rings can be explored effectively for various chiral discriminating processes. In general, the introduction of suitable functional groups at the peripheral rings can act as a binding site to hold the reactant or guest molecules to facilitate the enantioselectivity, where the chiral cavity space of the helicene is able to influence the corresponding (diastereomeric) transition state and/or complexation mode. In contrast, the opposite outer skeleton of the helicene, termed as the helicene outer core (exterior), can be functionalized and used to covalently link these molecules on surfaces and for other applications.

The tailor-made design of helicenes for a suitable application can be of two types; first, where the functionalization at one peripheral ring is sufficient (monodentate), and second, where functionalization on both the terminal rings is required (bidentate) (Figure 8b). The bidentate helicenes can be *C*2-symmetric (R = R') or nonsymmetric (R = R') molecules. In accordance with the structural

features and substituent patterns of helicenes, their efficiency in chirogenic processes is observed, as demonstrated throughout this review.

**Figure 8.** (**a**) General explanation of terms used for helicene structures and chiral cavity (shaded area); (**b**) representative [6]- and [7]helicenes (R = R' or R = R') with mono- or di-functionalized peripheral rings.

However, since the majority of recently published reviews [2–6] have focused on helicene synthetic chemistry, there is no need to describe this topic here in detail. Alternatively, this review addresses the structural design and stereochemical aspects of helicene chromophores suitable for various applications in chiral processes, whilst synthesis of these molecules will only be highlighted in brief upon necessity to emphasize their spatial and chiral properties.

#### **5. Helicenes as Chiral Auxiliary/Reagent or Additive**

Due to the difficulties associated with the synthesis of helicenes and obtaining the corresponding enantiopure forms in sufficient amounts, their application as a chiral auxiliary in stoichiometric reactions is limited. However, one of the first results on the use of helicenes as chiral auxiliaries in few diastereoselective reactions was reported in 1985–1987 by Martin et al. with racemic 2-substituted-[7]helicene [46–50]. Hence, racemic **29** was employed as an inbuilt chiral auxiliary for the diastereoselective reaction of the carbonyl group of α-keto esters upon reduction with NaBH4, yielding **30** (99% yield; 100% *de)* [46], and on the nucleophilic addition of Grignard reagent to give **31** (95% yield; 100% *de*) [47] (Scheme 1).

**Scheme 1.** Diastereoselective reaction using racemic [7]helicene **29** as a chiral auxiliary.

Although high diastereoselectivity (100%) was observed, the overall process requires attaching (protection) and detaching (deprotection) the helicene auxiliary, thereby making it difficult to scale up. Similarly, [7]helicene-attached unsaturated ester **32** was also utilized for the highly diastereoselective ene reaction with cyclohexene **33** in the presence of SnCl4 to afford **34** with high yield (86%) and 100% *de* [48] (Scheme 2).

**Scheme 2.** Diastereoselective ene reaction using racemic [7]helicene **32** as a chiral auxiliary.

Further, hydroxyamination of E-stilbene **35** under the Sharpless condition by using helicene **36** as a chiral auxiliary resulted in **37** with 32% yield with 100% *de* [49] (Scheme 3).

**Scheme 3.** Diastereoselective hydroxyamination of stilbene reaction using racemic [7]helicene **33** as a chiral auxiliary.

Another example is based on enantioenriched 2-cyano-[7]helicene **38** employed as a stoichiometric chiral additive (reagent) for the epoxidation of alkenes **35** and **39** using H2O2 as an oxidant to give enantiopure epoxides **40** (92%, 99% *ee*) and **41** (84%, 97% *ee*), respectively [50] (Scheme 4). The mechanism includes the initial reaction between enantiopure 2-cyano-[7]helicene **37** and H2O2 to generate in situ the corresponding chiral hydroperoxyimine, which serves as a chiral oxidizing reagent for the subsequent epoxidation of alkenes **35** and **39**, whilst itself converting finally to [7]helicene-2-carboxamide **42**.

These examples (Schemes 1–4) [46–50] are the first cases of helicenes being used as chiral auxiliaries resulting in a high asymmetric conversion (*de* or *ee*), yet noncatalytic in nature. These excellent results were due to the judicious selection of [7]helicene with corresponding functionalization at the 2-position (monodentate) (refer, Figure 8), which locates inside the helical chiral cavity with sufficient accessibility to the reactants. Besides this, a geometric feature of [7]helicenes is that the two peripheral rings are located one above another, hence inducing steric hindrance to one of the reacting prochiral faces and generating high selectivity via the stereospecific approach.

It is of note that most of the helicene-based catalytic research is focused on the use of [6]helicene and substituted [5]helicene-based systems. In cases where functionalization at both the rings is needed, substituted [5]helicenes and [6]helicenes are more suitable due to possibility of the geometrical accessibility of these groups (refer, Figure 8b). These groups are located on the same side; hence, they are capable of coordinating or bonding together with the reactive partners. However, this situation is difficult to obtain in [7]helicenes, as seven benzenoid rings give the in-plane turn angle of 420◦ (7 × 60◦), forcing the functional groups present on the terminal rings to exist in opposite directions, thus unable to work co-operatively (refer, Figure 8b). Yet, when only one of the peripheral rings is functionalized and acts as an active catalytic site, the [7]helicene-based systems have an additional advantage over substituted [5]- and [6]helicenes. This is owing to the same in-plane turn angle property allowing another peripheral ring to block one of the prochiral faces of the reactant. Nevertheless, surprisingly, asymmetric catalysis with [7]helicenes is not well explored in comparison with that with [5]- and [6]helicenes.

**Scheme 4.** Enantioselective epoxidation of alkenes **35** and **39** using enantioenriched [7]helicene **38** as a chiral additive.

#### **6. Helicenes as Chiral Catalysts**

Since various helicene-based phosphine-related ligands have been reviewed [2,5,7–9], only recent selected examples capable of delivering exceptionally high *ee* values are summarized here.

In 2016, the [5]carbohelicene-based phosphine ligands **43** and **44** were rationally designed for application in Pd-catalyzed asymmetric synthesis [51]. Both the systems were prepared from corresponding *rac*-bromo substituted **45** via lithiation and subsequent reaction with chlorodiphenylphosphine followed by oxidation with hydrogen peroxide to afford *rac*-phosphine oxide **46** with 63% yield. It was successfully resolved by using spiro-TADDOL (α,α,α,α-tetraphenyl-1,3-dioxolane-4,5-dimethanol) **47** as a resolving agent to form the insoluble diastereomer **48** with (*P*)-**46**, which in turn gave pure (*P*)-**46** with greater than 99% *ee* on subsequent treatment. Then, (*P*)-**46** was aromatized to **49** quantitatively by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Both the phosphine oxides **48** and **49** were reduced to the corresponding phosphines, **43** and **44,** with trichlorosilane and P(OEt)3 with 70–72% yield and 99% *ee* (Scheme 5) [51].

In general, unsubstituted [5]helicenes are configurationally unstable and tend to racemize easily. However, introduction of the diphenylphosphine group at the 1-position results in the configurational stability of **43** and **44**. Of these two structures, the 7,8-dihydro-derivative **43** tends to be more helical due to the saturated ethane unit, which has greater conformational flexibility. From X-ray analysis, it was confirmed that the helical pitch diameter of dihydrohelicene **43** is 3.54–3.50 Å, which is larger than that of fully aromatic **44**, found to be 3.39–3.34 Å. This rationally changed spatial arrangement has a noticeable influence on its application as a ligand owing to the favorable geometry and distance, which was clearly demonstrated by the metal–ligand and arene interaction. Hence, the double bond (C8a–C14b) is coordinated with the palladium metal center of ligand **44** in a side-on (η 2) fashion,

which is not possible in the case of dihydrohelicene **43**. This difference in geometric features controls the outcome of Pd-catalyzed reactions. For example, the alkylation of *rac*-1,3-diphenylallyl acetate **50** with dimethyl malonate **51** by using (*M*)-dihydrohelicene **43** as a chiral ligand was highly efficient, resulting in the corresponding (*S*)-enantiomer **52** with 99% yield and 94% *ee* (Scheme 6) [51]. In contrast, the fully aromatic (*M*)-helicene **44**, whilst affording the same configuration of the product **52**, gave similar yield, but only 71% *ee* (Scheme 6). This clearly demonstrates that the ligands' geometry allowed them to opt for different transition states.

**Scheme 5.** Synthesis and resolution of enantiopure phosphine ligands **43** and **44**.

**Scheme 6.** Pd-catalyzed asymmetric alkylation of *rac*-1,3-diphenylallyl acetate **50** using helical phosphine ligands **43** and **44**.

Similar types of C1 position substituted phosphinite ligands, helicenoid **53** [52] and helicene **54** [52] (Figure 9), were also prepared and successfully explored for the Pd-catalyzed asymmetric allylic alkylation between **50** and **51** (see Scheme 5). In both cases, the high yields and *ee* of **52** were obtained as with **53** (96%, 90% *ee*) and with **54** (97%, 99% *ee*) [52]. It is of note that this kinetic resolution reaction using helicene ligand **55** [53] was firstly reported in 2000 with 100% conversion and 81% *ee* (Figure 9). Although the results from using **55** are comparatively worse in terms of *ee*, the reaction requires less catalyst loading and proceeds faster compared with other ligands. Interestingly, **55**, whilst being a bidentate ligand, still acts as a monophosphine (monodentate) ligand during the catalytic process owing to the large distance (6.481 Å) between the two phosphorus atoms; this was the subject of pioneering work by Reetz et al. [53]. Thus, one can see that all phosphine (**43**, **44**) and phosphinite (**53**, **54**) ligands prepared later, possess only a mono phosphorus atom and are suitable for application as monodentate ligands in this reaction.

**Figure 9.** Other helicene-based phosphorus-containing ligands **53**–**55** used for Pd-catalyzed allylic substitution reaction of **50** and subsequent kinetic resolution.

The corresponding enantiopure **53** and **54** were synthesized using the Ni-catalyzed [2 + 2 + 2] cycloaddition reaction of alkyne **56** to give **57** (97%), and the subsequent demethylation and esterification as (1*S*)-camphanate to yield the corresponding diastereomers, **58** and **59**. Further, the separated diastereomers were hydrolyzed with alkali to quantitatively produce the enantiomer **60**, which, on subsequent reaction with chlorodiphenylphosphine in the presence of sodium hydride, resulted in the tetrahydro phosphinite ligand, (*P*)-**53**. For **54**, an additional step of dehydrogenation using triphenylmethylium tetrafluoroborate (Ph3CBF4) was required to obtain the diastereomer **61** (92%), which upon hydrolysis gave [6]helicen-1-ol **62**, which was finally converted to phosphinite **54** with 74% yield (Scheme 7) [52].

**Scheme 7.** Synthesis and optical resolution of **53** and **54** by using the Ni-catalyzed [2 + 2 + 2] cycloaddition reaction as a key step.

Inspired by the difference in the catalytic performance of **43** (94% *ee*) and **44** (71% *ee*) (Scheme 6) in Pd-catalyzed asymmetric allylic alkylation, the same group also applied these ligands in other

Pd-catalyzed reactions. Thus, in further investigation, the dihydrohelicene ligand **43** was found to be highly useful in the asymmetric allylation of indoles **63** with 1,3-diphenylallyl acetate **50** to give the 3-alkylated indole product **64** in up to 99% *ee*, and in the etherification with alcohols **65** to yield **66** in up to 94% *ee* (Scheme 8) [51].

**Scheme 8.** Pd-catalyzed asymmetric allylic substitution reactions of **50** by using (*M*)-helicenoid phosphine ligand **43** (**a**) with indole **63** and (**b**) with alcohols **65**.

In the case of fully aromatic helicene **44**, the ligand was highly effective in the stereocontrol of helical chirality in the Suzuki–Miyaura coupling reaction between bromide derivative **67** and boronic acid **68**, resulting in up to 99% *ee* for chiral biaryl products **69** of (*P*)-helicity (Scheme 9) [51].

**Scheme 9.** Pd-catalyzed asymmetric Suzuki–Miyaura coupling between **67** and **68** using (*P*)-**44** as the helicene phosphine ligand.

These examples (**43** and **44**) clearly show that the helicity and space available in the helical groove suitable for a specific transition state play a vital role in the stereoselective control of the reaction pathway. The DFT-based calculation at the B3PW91/6-31G\* level (LANL2DZ for the Pd atoms) revealed that the transition state with minimum steric repulsions between the helicene backbone and the reactant group is responsible for the (*S*)-configuration products (**52**, **64**, and **66**) and *P*-configuration product (**69**) obtained with high *ee* [51].

Helicene-based ligands have been also successfully investigated for the rhodium-catalyzed asymmetric hydrogenation of alkenes. In fact, the first enantioselective catalysis using helical diphosphane **55** was the asymmetric reduction of itaconate **70** as a model compound under mild conditions using in situ generated (*M*)-**55** and [Rh(cod)2] +BF4 −. This results in the corresponding diester (*S*)-**71** with 54% yield and 39% *ee* product, as reported by Reetz et al. [54] (Scheme 10). The synthesis of **55** is based on photochemical cyclization with subsequent conversion of the corresponding helicenedibromide derivative to phosphine **55**, followed by preparative chiral HPLC

separation of the enantiomers [54]. Yamaguchi et al. improved the yield (up to 100%) and enantioselectivity up to 96% *ee* for (*S*)-**71** using the (*M,M,S,l*)-configuration of the bis-helicenic phosphite ligand **72** [55] (Scheme 10). The excellent output in this reaction obtained with **72** was attributed to the matched (suitable) pair of asymmetries, i.e., two (*M*)-helical and one (*S*)-axial chirality. However, the central chirality derived from the *l*-menthyl part does not have much effect on the reaction *ee* outcome.

**Scheme 10.** Comparative Rh-catalyzed asymmetric hydrogenation of itaconate ester **70** using helicene-based ligands **55** and **72**.

Another approach adopted was to design a helicene with the fused phosphole heterocyclic unit at one of the terminal rings where the phosphorus atom has an additional point chirality, denoted as *SP* or *RP*. A key synthetic step includes the diastereoselective photochemical cyclization reaction of a suitable (*SP* or *RP*) enantiopure phosphole-bearing stilbene derivative **73**. The resulting regioisomeric [6]helicene phosphine oxide **74** and phospha[7]helicene **75** were chromatographically separated with 32% and 28% yield, respectively [56] (Scheme 11).

**Scheme 11.** *Cont.*

**Scheme 11.** Photochemical diastereoselective synthesis of [6]helicene phosphine oxide **74** and phospha[7]helicene **75**.

Subsequently, enantiopure **74** was reduced and in situ reacted with gold(I) salts to generate the phospha-substituted helicene–gold complexes, **76** (*endo*) and **77** (*exo*). In *endo*-**76**, the gold atom occupies the internal chiral cavity space, approaching towards the opposite terminal ring, whereas in *exo-***77**, the gold atom is situated at the external face, being away from the helical moiety. Thus, chromatographically separated *endo*-**76** effectively catalyzes the enantioselective cycloisomerization of N-tethered 1,6-enyne **78** to give bicyclo[4.1.0]heptane **79** with 95% yield and 81% *ee*, whilst *exo*-**77** remained almost inactive [56] (Scheme 12). Meanwhile, various phosphole-containing ligands were also prepared and screened in similar reactions with success [8,9,57].

**Scheme 12.** (**a**) Synthesis of *endo* (*SP*,*P*)-**76** and (**b**) its application as a catalyst for the enantioselective cycloisomerization of N-tethered enyne **78**.

However, at present, the scope of the use of helicenes containing phosphorus functionality appears to be limited towards the metal-catalyzed reactions, as described above. A few other attempted asymmetric reactions such as ketoimine reduction (22% *ee*), addition of thioester to benzaldehyde (22% *ee*), and reductive aldol reaction afforded quite low *ee* values, with tetrathia[6]helicene diphosphine oxides as a Lewis base catalyst [58].

Besides these phosphorus-containing helicenes, heterohelicenes with a nitrogen atom at the innermost 1- or 2-position are also able to provide a chiral cavity suitable for various asymmetric organocatalytic processes, where the nitrogen atom plays a crucial role as a Lewis base or hydrogen-bonding auxiliary. The classical synthetic approach for azahelicenes having a nitrogen atom at the peripheral ring as the pyridine subunit is based on the preparation of the corresponding stilbene derivative followed by the photocyclization reaction.

The first use of a pyridine-based helicene as a chiral organocatalyst for promoting the enantioselective acyl group transfer reaction and kinetic resolution of racemic phenylethanol **80** was reported by Stary et al. in 2009 [59]. The preparation of helicenes **81** and **82** [60] involves the [2 + 2 + 2] cyclotrimerization of regioisomeric aromatic triynes **83** and **84** using a Co(I)-catalyzed reaction as the major synthetic step to obtain tetrahydrohelicenes **85** (82%) and **86** (89%), respectively (Scheme 13). Finally, the MnO2-based oxidation resulted in *rac* aza[6]helicene **81** (65%) and **82** (53%). The optical resolution of helicene **81** was carried out through the diastereomeric salt formation with optically pure (+)-*O*,*O* -dibenzoyl-D-tartaric acid, whereas enantiopure **82** was obtained by separation of the corresponding racemic mixture with chiral HPLC (Scheme 13) [60].

It was found that (+)-(*P*)-1-aza[6]helicene **81** is an ineffective catalyst for this process with <5% yield, as the nitrogen atom at the most sterically congested position has very limited accessibility for the reactant. However, the isomeric (−)-(*M*)-2-aza[6]helicene **82**, due to the easily accessible nitrogen atom position, considerably improved the catalytic performance with 46.9% conversion to **87** and 53.1% *ee* for the unreacted starting alcohol **80** (*R*-configuration) with a selectivity factor of 7 for the corresponding (*S*)-enantiomer (Scheme 14) [59].

**Scheme 13.** Synthesis of azahelicenes **81** and **82** via Co+1-catalyzed [2 + 2 + 2] cyclotrimerization reaction.

**Scheme 14.** Kinetic resolution of *rac*-phenylethanol **80** by (*M*)-**81** and (*M*)-**82**.

This example clearly demonstrates how the suitably tailor-made design of azahelicenes can provide a useful chiral pyridine-based nucleophilic organocatalyst comparable to other enantiopure amine-containing catalysts, whilst possessing different elements of asymmetry. In comparison to pyridine, dimethylaminopyridine (DMAP) and DMAP-containing compounds **88**-**90** [61–64] (Figure 10) are better nucleophilic catalysts for acylation of alcohols due to the enhanced nucleophilicity provided by the electron donating nature of the dimethylamino group at the para position. Thus, (*P*)-helicenoids **88** containing a *p*-dialkyl amino substituent turned out to be a more effective enantiodifferentiating catalyst for the resolution of the (*S*)-enantiomer of racemic **80** with the selectivity factor of 17, in 5 h, as compared to 48 h with a selectivity factor of 7 using (*M*)-**82** as the catalyst.

The helicenoidal DMAP **88** has a nitrogen atom at the 2-position and saturated N-alkyl group, whilst the helicenoid core ensures two additional advantages. Firstly, it enhances the nucleophilicity of the pyridine nitrogen at the 2-position by its electron donating ability (+I effect), and secondly, it increases the conformational flexibility to accommodate reactants inside the helical chiral cavity for efficient enantiodifferentiating processes. The attached ethyl substituents at the central ring of the helical outer core were responsible for increasing the lipophilic character and, thus, the solubility in organic solvents for better performance [61]. The helicenoid DMAP **88** displayed a comparatively higher selectivity factor of 17–116, depending on the structure of the racemic aromatic ethanol. In comparison to **88**, the axially chiral DMAP catalyst **89** [62,63] showed selectivity factors of 12–52 (in ether) [62] and 32–95 (in *t*-amyl alcohol) [63] for enantioresolution of different racemic aromatic ethanols. However, the planar chiral DMAP catalyst **90** [64] displayed the smaller selectivity factor of 8.9–29. It is of note that, with planar chiral DMAP **89**, the acylating agent was acetic anhydride, whereas, in other cases, bulkier isobutyric anhydride was used. Thus, the helical DMAP **88** appears to be highly superior to **90** under similar experimental conditions.

**Figure 10.** Structures of simple dimethylaminopyridine (DMAP) and helically, axially, and planar chiral DMAP catalysts **88**–**90**, respectively.

Indeed, the first use of unsubstituted aza[6]helicene **81** and **82** as an organocatalyst for the kinetic resolution of alcohols rationalized the corresponding steric constraint imposed at the 1-position for a bulky acyl moiety and its subsequent group transfer reaction to *rac*-alcohols. However, the additionally functionalized 1-aza[6]helicene was found to be an effective asymmetric catalyst for various reactions [65,66], probably due to the facile access to reactants in the chiral cavity in the transition state, as demonstrated in the following examples.

The azahelicene-based systems were converted to the corresponding *N*-oxides and investigated for the asymmetric ring opening of epoxides with chloride as a nucleophile. For example, 1-aza[6]helicene-*N*-oxide derivatives **91**–**93** (Schemes 15 and 16) [67] were prepared in the racemic form using a general three-step synthetic methodology, and their enantiomers were resolved over chiral HPLC [67]. The representative synthesis of **93** starts from the benzoquinoline aldehyde unit **94** and corresponding bromo-substituted phosphonium salt **95** in three steps, where the initial step involves the Z-selective Wittig condensation followed by the palladium-catalyzed Stille–Kelly coupling reaction to result in azahelicene **96**. Finally, oxidation with *meta*-chloroperbenzoic acid gave the desired helicene-*N*-oxide **93** with 32–49% yield (Scheme 15).

**Scheme 15.** Representative general synthetic scheme for 1-azahelicene-*N*-oxide **93** using Stille–Kelly coupling reaction.

Then, the enantiopure (*P*)-helical ligands **91**–**93** were screened for the desymmetrization of *meso* epoxide **97** with chloride as a nucleophile to obtain **98** with satisfactory yields and *ee* (Scheme 16) [67].

Similarly, enantiopure helical 2,2 -bipyridine-*N*-monoxide **99** was prepared in two steps from enantiopure **93** with 95% yield (Scheme 17a) and applied as a Lewis base type catalyst for the highly enantioselective reaction between aldehyde, **100**, and allenyltrichlorosilane **101** to obtain enantiomerically enriched homopropargylic alcohol **102** [68]. The reaction displayed high conversion (78–97%) and 74–96% *ee* for various *ortho-* and *para*-substituted aromatic aldehyde derivatives, with 18 examples in total (Scheme 17b). Further, the catalyst **99** can be recovered (~80%) without any loss of activity and selectivity after the reaction, making it highly attractive for industrial application.

**Scheme 16.** Desymmetrization of *meso* epoxide **97** using 1-azahelicene-*N*-oxide **91**–**93** as catalysts.

**Scheme 17.** (**a**) Two-step synthesis of helicene (*P*)-**99** from (*P*)-**93** and (**b**) asymmetric synthesis of (*S*)-propargylic alcohols **102** from aldehyde **100** and allenyltrichlorosilane **101** by using (*P*)-**99** as a catalyst.

The (*S*)-alcohol **102** was the major product with (*P*)-helicene **99** as a catalyst. It was also observed that *ortho*-substituted aldehydes **100** always provided higher *ee* than the corresponding *para*-substituted derivatives, regardless of the functional group attached. This key experimental observation indicated that, out of two possible transition states (Figure 11a,b), in one of them, the hydrogen or substituent at the *ortho* position of aldehyde **100** results in steric clash with catalyst **99**, which is responsible for the stereoselectivity. Thus, the suggested transition state model showed preference for the *Si*-face addition with π-π stacking between the bound aldehyde **100** and the bezofused helicene framework of **99** (Figure 11a), whereas the *Re*-face approach is disfavored due to the steric hindrance in the transition state (Figure 11b), where the reactants **100** and **101** and catalyst **99** are coordinated through the silicon atom. A separate DFT-based computational study also supported this mechanism [69].

**Figure 11.** Proposed transition state models showing preference for (**a**) favorable *Si*-face attack and (**b**) unfavorable *Re*-face attack, with (*P*)-**99** catalyst. The bottom and top parts of the transition state models are marked in blue and black, respectively, whilst the coordinated SiCl2 group with the corresponding bonds are marked in magenta.

Azahelicenes have also been investigated as hydrogen bond donor chiral catalysts. The asymmetric addition of azole nucleophiles to nitroalkenes using various hydrogen bond catalysts is known. In this respect, aminopyridinium salts are also capable of activating nitroalkenes through the hydrogen bond donating ability to the nitro group. For this purpose, aza[6]helicene derivatives **103** and **104**, having a 2-aminopyridinium ring at the peripheral position, have been prepared [70]. Hence, the asymmetric addition of 4,7-dihydroindole **105** to nitrostyrene **106** using chiral (*P*)-helicenes **103** and **104** as catalysts, followed by oxidative aromatization, afforded exclusively β-nitro-indol-2-yl **107** with relatively high yield and *ee* (Scheme 18).

It was observed that the increased bulkiness of the amino group gives a higher *ee*. Thus, the results of (*P*)-**104** in terms of *ee* ratio were as follows for the corresponding R: H (69:31) = Bn (69:31) < *t*-Bu (92:8) = 1-adamantyl (92:8). Further, the yields were noticeably improved from 79% (for the *t*-Bu derivative) to 88% (for the adamantyl derivative) under similar conditions; hence, adamantyl-containing (*P*)-**104** is the optimal organocatalyst for this reaction (see the corresponding results summarized in Scheme 18). Further, the enhanced effectiveness of **104** in comparison with **103** indicates that the benzofused helicene framework affects the *ee* value by covering the space beneath the two hydrogen bonds [70], and is thus similar to the case shown in Figure 11.

Another example of the activation of nitroalkenes via the hydrogen bonding donor characteristics was demonstrated by using aminopyridinium-based (*M*)-[6]helicene **108** in the asymmetric Diels–Alder reaction between cyclopentadienes **109** and nitroethylene **110** to give the cycloadduct product **111** in moderate 30–40% *ee* [71]. A traditional hydrogen bonded catalyst generally requires the complementary donor–acceptor units in both reactants to orient specifically for asymmetric induction in the addition reaction. However, here is a case where one counterpart is a nonfunctionalized cyclopentadiene **109**, unsuitable for hydrogen bonding. Therefore, the (*M*)-helicene catalyst **108** used has a aminopyridinium

peripheral ring which only binds to nitroethylene **110** (dienophile) through the corresponding hydrogen bonding. The stereospecificity of this reaction was achieved in the following manner: the helical backbone of (*M*)-**108** blocks one of the faces of **110**, leaving another face accessible to **109** (diene), hence making the whole reaction enantioselective in nature (Scheme 19).

Most of the successful examples of azahelicenes (**91**–**93**, **99**, **103**, **104**, **108**) as organocatalysts described here have a nitrogen atom at the 1-position of the innermost part of the helicene with additional substituents at the 1- or 2-position to modify the reactivity as well as the helicity (chiral cavity space), to facilitate accessibility of the reactant in a stereospecific manner, and to enhance asymmetric output.

**Scheme 18.** Asymmetric addition reaction between 4,7-dihydroindole **105** and nitrostyrene **106** using chiral (*P*)-helicenes **103** and **104** as hydrogen bond donor catalysts.

**Scheme 19.** (*M*)-helicene **108** as a hydrogen bond catalyst for asymmetric Diels–Alder reaction between cyclopentadiene **109** and nitroethylene **110**.

Carbohelicenes **5** and **6** and heterohelicene **112**, devoid of any functional group, are also able to act as chirality inducers in selected asymmetric reactions. Soai et al. have successfully used electron-rich nonfunctionalized carbohelicenes **5** and **6** [72] and heterohelicene **112** [73] for the nucleophilic addition of diisopropylzinc to electron-deficient pyrimidine-5-carbaldehyde **113**. In this case, the chirality induction was a result of two main reasons. Firstly, the formation of a charge transfer complex between helicenes **5**, **6**, and **112** and the carbonyl group of **113** results in the blocking of one reactive face while another face is left to react. Secondly, the final alcohol product **114** obtained can catalyze this reaction by itself, leading to overall chirality amplification to yield up to 95–99% *ee* (Scheme 20). In all these cases, the use of (*P*)-enantiomers of **5**, **6**, and **112** as catalysts resulted in the (*S*)-configuration of **114**, whereas the (*M*)-enantiomer produced the corresponding *R*-configuration. Further, even carbohelicenes **5** and **6** with a very low *ee* such as 0.13% and 0.54% were also able to act as chiral inducers, ensuring considerable stereospecificity and affording 56% and 60% *ee* of **114**, respectively, as a result of chirality amplification by asymmetric autocatalysis [72].

This is an interesting example where chiral inducers with a very low *ee* generate significantly enhanced *ee* of the product. This type of chiral amplification is a "soldiers-and-sergeant" principle and often observable in the field of supramolecular chirogenesis [1]. However, this scope appears to be limited in the case of asymmetric autocatalysis.

Indeed, the asymmetric nucleophilic addition of an organozinc compound to the carbonyl group has been mainly investigated with the use of biaryl-based systems such as BINOL and 2,2 -Diphenyl-(4-biphenanthrol)—axially chiral diol systems capable of coordinating to Lewis acids. Inspired by this, Katz et al. developed the bis[5]helicene-based diol system ([5]HELOL) **115**, which contains two identical units of (*P*)-[5]helicene-1-ol **116** connected by a single biaryl bond at the 2-position. Interestingly, the hydroxyl group is attached at the 1-position (the innermost position of [5]helicene), which makes **116** configurationally stable, and hence provides increased steric hindrance for racemization. The HELOL **115** was synthesized in a total of eight steps on the multigram scale with an overall 44% yield (Scheme 21a) [74]. The helicene backbone **117** was synthesized by Diels–Alder reaction between protected enol ether **118** and quinone **119**. The enantiopure (*P*)-[5]helicene-1-ol **116** was oxidatively coupled using Ag2O, to selectively give (*P*,*P*)-[5]HELOL **115**, with only ~2% of the *meso* isomer. The energy barrier for the racemization of **<sup>115</sup>** (ΔH‡ = 106 ± 3 kJ mol−<sup>1</sup> and <sup>Δ</sup>S‡ <sup>=</sup> −10.0 ± 0.1 J mol−<sup>1</sup> <sup>K</sup>−1) as determined by 1H NMR was found to be even higher than that of (*P*)-[5]helicene **<sup>116</sup>** (ΔH‡ = 95.8 kJ mol−<sup>1</sup> and <sup>Δ</sup>S‡ <sup>=</sup> −17.2 J mol−<sup>1</sup> <sup>K</sup>−1) [74] with the optical rotation value of +2580 in acetonitrile (*c* = 0.01 M). Further, the thermal racemization at 45 ◦C did not occur in 72 h as indicated by circular dichroism (CD) spectroscopy. Additionally, in degassed acetonitrile solution, it was configurationally stable for six days at room temperature as also analyzed by CD measurement. The enantiomeric stability toward conversion to the *meso* isomer and racemization made it a suitable candidate for screening in asymmetric catalysis.

The catalyst **115** was screened for diethylzinc addition to a series of aromatic aldehydes **100**. However, for appreciable catalytic activity, catalyst loading as high as 50 mol% was needed to obtain moderate to good *ee* values of the alcohol products (*S*)-**119** (Scheme 21b). Under similar conditions, the (*R*)-(+)-BINOL gave lower yield (56%) and *ee* (34%) for (*R*)-**119** in comparison to (*P,P*)-(+)-HELOL **115** giving (*S*)-**119** (93% yield, 81% *ee*). This high and opposite stereospecificity is apparently due to a greater steric hindrance of HELOL **115** in comparison to BINOL upon chelation of the zinc atom of the reactant diethyl zinc. Additionally, this crowding in **115** is also able to prevent the phenomenon of zinc–oxygen coordination-based aggregation, responsible for catalyst deactivation, making **115** comparatively more reactive than BINOL [74]. Further, the opposite stereochemical outcome of alcohol products **119** obtained with (*P*,*P*)-(+)-[5]HELOL **115** as a catalyst and (*R*)-(+)-BINOL as catalyst is in accordance with the stereochemistry of the biaryl bond present in HELOL **115**, which appears to be of (*S*)-configuration (see structure **115** in Scheme 21a).

Whilst unsubstituted [4]helicene **4** is a planar and achiral structure, the introduction of two methyl groups on both the peripheral rings at the innermost positions gives rise to a helical structure with configurational stability. In this respect, Yamaguchi et al. have extensively explored the synthetic chemistry and applications of functionalized dimethyl[4]helicene in different fields [75]. Thus, (*P,P*)-[4]helicene cycloamides **120**–**122** were prepared from well-known *rac*-diketone **123** via dicyanohelicene **124**, which was converted to helicene diacid **125** by alkaline hydrolysis. Then, helicene diaicid **125** was resolved by using the chiral base quinine through diastereomeric salt formation. Finally, (*P*)-**125** was converted to acid chloride and then coupled with a suitable diamine linker **126** to obtain cycloamides dimer **120** (24%), trimer **121** (23%), and tetramer **122** (19%) (Scheme 22) [76].

**Scheme 20.** Asymmetric autocatalysis initiated by carbohelicenes (*P*)-**5**, (*P*)-**6**, and heterohelicene (*P*)-**112**.

**Scheme 21.** (**a**) Synthesis of (*P*,*P*)-HELOL **115** and (**b**) its application in asymmetric diethyl zinc addition to benzaldehydes **100**.

**Scheme 22.** Synthesis of (*P,P*)-helicene cycloamides **120**–**122** from diketone **123**.

Interestingly, in this example, the functionalized amino groups are present at the outer core of the helicene but not at the helical chiral cavity as in previous examples; this makes it remarkably different. Yet, when it is dimerized with a suitable linker such as cycloamide **120**, the chirality of the helicene is transferred to a macrocycloamide, which essentially provides a chiral pocket for the asymmetric catalytic transformations. Macrocycloamides such as (*P*,*P*)-**120** have been applied for the asymmetric nucleophilic addition of diethyl zinc to aromatic aldehydes **100** with good yields (51–88%) and moderate enantioselectivities (27–50% *ee*) upon use of up to 5 mol % catalyst (Scheme 23) [76].

**Scheme 23.** (*P,P*)-helicene cycloamide dimer **120** catalyzed asymmetric diethyl zinc addition to aromatic aldehydes **100**.

It has been clearly demonstrated that helicene-based asymmetric organocatalysis is a highly promising and exciting field in terms of the enantioselectivity obtained with the lowest catalyst loading. Thus, this area of chemistry has exciting prospects to explore other well-known asymmetric reactions by using helicenes as organocatalysts, with foreseen advances in terms of the *ee* values in comparison

to conventional organocatalysts. For the most asymmetric organocatalysts, it is possible to design and develop helicene-based helical counterparts which are expected to give improved reactivity and stereoselectivity. However, the design of smart catalysts and their multigram synthesis in the enantiopure form still remain a major challenge to further investigations.

#### **7. Helicene in Supramolecular Chirogenesis**

Besides asymmetric catalysis, helicenes are efficiently used in a modern branch of chiral science called supramolecular chirogenesis, which covers all aspects of asymmetry induction, transfer, amplification, and modulation through noncovalent interactions. In numerous chromophoric systems [1] available to date, helicenes are also successfully employed. Indeed, helicenes have turned out to be one of the most attractive chromophores, which are suitable for several chirogenic applications including chiral recognition, sensors, and self-assembly, and are applicable to various areas ranging from classical solution chemistry, nanoparticles, and polymers, up to the sensing of biologically relevant molecules. Owing to their conjugated aromaticity, these chromophoric systems can be conveniently studied by diverse spectroscopic methods, such as UV, fluorescence, NMR, CD, etc., which are described below with selected examples.

#### *7.1. Helicene-Based Chiral Recognition of Small Molecules*

Since chirality is an essential part of life on Earth, its recognition and sensing play a vital role in such important fields of human activity as scientific research and modern technologies. Therefore, various methods of obtaining enantiopure molecules by optical resolution and by asymmetric synthesis are attractive areas of chemical research. Besides preparation, the analysis of all types of chiral molecules is also an equally important part of physical–organic chemistry. So far, existing analytical methods are based on the enantiodifferentiation procedure conventionally performed by using chiral HPLC, NMR, fluorescence, and CD techniques. In this respect, chiral helicenes are highly prospective host molecules to serve as specific chirality sensors.

One of the first reports of such an application was published in 2001 by Reetz et al. [77]. To this end, 2,5-dihydroxy[6]helicene **127** (HELIXOL) was prepared for chiral recognition of amines **128**–**131** and amino alcohols **132**–**135** by using fluorescence as a detection tool (Scheme 24). The synthetic strategy includes classical Wittig olefination and photochemical cyclization steps. The condensation of **136** with **137** gives cyclic **138**, ether linkage of which ensures structural control during the double photocyclization reaction to obtain helicene cyclophane **139**. The chiral HPLC separation of racemic **139**, followed by the deprotection of the ether group using BBr3, affords enantiopure HELIXOL **127** (Scheme 24).

It was found that the host **127** served as an excellent fluorescent sensor, able to display enantioselective quenching by several amines and amino alcohols through the hydrogen bonding interactions. The best results were obtained for alaninol **133** with enantioselective factor α = K*R*/K*<sup>S</sup>* = 2.1 upon using the levorotary (*M*)-**127**. Although the results obtained with **127** for chirality sensing are moderate, this work is a pioneering contribution for the use of helicenes for the purpose of chirality sensing. Further studies have demonstrated that this new, emerging area is challenging and highly prospective in chemical sciences.

Meanwhile, HELIXOL **127** is a bidentate compound with two hydrogen bonding units (phenolic groups) in the chiral space cavity, which can be used for stereodiscriminating recognition (Figure 8). Thus, it was assumed that amino alcohols may form the corresponding 1:1 host–guest complex, resulting in stronger fluorescence quenching than amines. Indeed, the best result among amines and amino alcohols was obtained for alaninol **133** due to the optimal steric matching in the chiral space available, while displaying the strongest fluorescence quenching output.

Another approach was demonstrated by the application of crown ether-based systems, which are known to bind various cations ranging from metal ions to organic ammonium ions. Hence, the helicene-based crown ethers **140** and **141** were firstly prepared in 1983 by using 1,14-dimethyl pentahelicene and heptahelicene backbones [78,79]. The synthesis was performed by a classical strategy via Wittig condensation followed by photochemical cyclization. Finally, the construction of crown ethers and subsequent resolution of enantiomers using a chiral column packed with (+)-poly-(triphenylmethyl methacrylate) with methanol as an eluting solvent resulted in enantiomers of **140** and **141**. Then, enantiopure **140** and **141** were investigated towards application in the chiral discrimination of racemic amine salts **142**–**144** (Figure 12). This process was based on the selective differential transports of recognizable enantiomers from an aqueous solution to the corresponding organic solvent (CHCl3) by a liquid–liquid extraction procedure. The 1H NMR analysis of the extracted organic layer displayed two distinct –CO2Me signals of the representing diastereoisomeric complexes with the guest, **142**. Finally, the amount of transported guest was analyzed by a reverse extraction back to an aqueous acidic phase followed by the measurement of its UV absorption.

**Scheme 24.** (**a**) Synthesis and resolution of HELIXOL host, **127**; (**b**) Structures of chiral guest amines **128**–**131** and amino alcohols **132**–**135** used for enantioselective recognition studies.

**Figure 12.** [5]helicene- and [6]helicene-bearing crown ethers **140** and **141** capable of enantioselective extraction of chiral amine salts **142**–**144** from aqueous to organic layer.

It was observed that the [5]helicene-based crown ether **140** showed higher enantioselective extracting ability than the [6]helicene-based crown ether **141**. For example, (*M*)-**140** was able to transport 6% of (*S*)-**142**, with optical purity of 75% in 6 h, comparatively better than (*M*)-**141** with 2% transport of 26% optical purity of opposite enantiomer (*R*)-**142** in the same time. The observed opposite enantioselectivity extraction using helicenes **140** and **141** with the same helical sense was rationalized by the phenomenon of changing the crown ether conformation [80]; this is evident in their CPK models. Additionally, the inner methyl groups also assist in the chiral recognition process, as suggested by the same models [78,79].

Another approach to chiral recognition was undertaken by Katz et al. via developing the helicenebased biaryl diol compound named (*M,M*)-[5]HELOL, **115** [81], which was based on enantiopure 1-hydroxy substituted [5]helicene (see **116** in Scheme 20). The in situ generated chloro phosphite derivative **145** was used as a chiral NMR derivatizing agent to discriminate alcohols or amines serving as nucleophilic guests. From the 31P NMR analysis of diastereomeric mixture **146**, the enantiomeric excess of guests (alcohols or amines) was easily determined. An interesting feature of this sensor is its ability to sense a remote chirality, which locates far away from the phosphite group. This is related to the fact that the combined inner cavity formed by individual helicene units and the biaryl bond yields an extended chiral space in **115**. For example, this chiral space is able to recognize the asymmetric centers of 8-phenylnonanol **147** (as far as up to seven methylene units) and vitamin E **148** (Scheme 25). Additionally, the recognition ability of this sensor was related to 100% abundance of phosphorus as NMR active nuclei with high sensitivity and accuracy in measurement; thus, the enantiomeric excess of up to 3% can be easily analyzed [81]. The scope of this HELOL host and its structural analogue were further extended towards other nucleophiles such as alcohols, phenols, amines, and carboxylic acids, also containing a remote chirality, under similar methodology to the 31P NMR-based enantiodiscrimination [82].

**Scheme 25.** (**a**) 31P based diastereomeric NMR sensing of alcohols and amines using (*M,M*)-HELOL **115** and (**b**) examples of remote chirality sensing with molecules **147** and **148**.

A new chiral application as a chiroptical switch along with chiral recognition properties was demonstrated using enantiomerically pure [6]helicene *o*-quinone **149**. The synthesis was carried out by using the Nickel-catalyzed [2 + 2 + 2] cyclotrimerization reaction of triyne **150**, followed by the deprotection of the methoxy group in **151** to result in helicene diol **152** in a racemic form. The enantiomers of **152** were separated on chiral HPLC, followed by the silver oxide-mediated oxidation, to give the quinone **149** in quantitative yield (Scheme 26) [83].

In general, quinones are electrochemically redox active molecules which undergo reduction as diol anions and re-oxidation back to quinone, with the corresponding measurable structural transformations in chromophoric absorption (Figure 13a). Therefore, the helicene-based quinone **149** was also tested for the same, with an additional possibility of chiroptical switching as observed by CD measurement. Both the enantiomers of **149** exhibited a one-electron reduction process to form the semiquinone radical anions, **<sup>149</sup>** <sup>−</sup>, as evident from cyclic voltammetry studies with E1/2 <sup>=</sup> −1.00 V (vs Fc+/0, <sup>Δ</sup>Ep = 0.07 V) in acetonitrile, with a reversible electrochemical behavior. Since **149** − is a stable species, its UV and CD measurements were performed by using an optically transparent thin layer electrochemical cell. It was observed that the helicene quinone **149** is able to be reversibly reduced to the radical anion **149** − and re-oxidized over several cycles, and is an example of chiroptical switching to be conveniently monitored with CD spectroscopy at different wavelengths (Figure 13b) owing to the distinguishable spectral profiles of **149** and **149** −. However, as there is no change in the (*P*) or (*M*) helicity of the chromophore upon electrochemical transformations, the Cotton effect (CE) signs of **149** and **149** − remained the same.

Besides electrochemical switching, **149** − was tested for chiral recognition against 2,2 bis(diphenylphosphanyl)-1,1 -binaphthyldioxide (BINAPO) using electron paramagnetic resonance and electron–nuclear double resonance (ENDOR) spectroscopy. The diastereomeric species formed by coordinated lithiated semiquinone radical anions [Li+{(±)-**149** <sup>−</sup>}] and enantiomers of BINAPO generated noticeable changes of the lithium and proton hyperfine coupling measured by ENDOR spectroscopy. The diastereoisomeric complex **153** exhibits a hyperfine coupling constant (A) value for 7Li at −1.62 MHz, in comparison to −1.76 MHz for another diastereomeric complex **<sup>154</sup>**, indicating the appreciable difference between the diastereomers (Figure 14). It is of note that the racemic sample gives an average value of −1.69 MHz.

**Scheme 26.** Synthesis and resolution of helicene quinone **149** from triyne **150** using the nickel-catalyzed [2 + 2 + 2] cyclotrimerization reaction as a key step.

**Figure 13.** (**a**) Mechanism of reversible electrochemical switching of helicene quinone **149** to helicene semiquinone radical anions **149** −; (**b**) observed reversible chiroptical switching between **149** and **149** −; monitored by CD spectroscopy in acetonitrile. Reversible electrochemical switching for several cycles is shown for the (*M*)-(−) enantiomer at two different wavelengths (top right) along with the corresponding CD spectra. (Figure 13b) reprinted from [83]. © 2014, American Chemical Society.

**Figure 14.** ENDOR spectra of diastereomeric species, **153** (black) and **154** (red) in THF at 210 K, only the low-frequency region is shown. Reprinted from [83]. © 2014, American Chemical Society.

The previously described examples, **127** [77] and **115** [81], represent the inbuilt chiral helicene chromophoric hosts for the chiral recognition of a general class of chiral molecules using some selected analytical techniques such as fluorescence and NMR spectroscopy. An essentially different approach has been recently developed by Karnik et al. on the basis of a new supramolecular chirogenic system, **155**, the key element of which was a stereodynamic dioxa[6]helicene diol **156** chromophore. This system was applied as a specific sensor, suitable for chirality sensing of *trans*-1,2-cyclohexanediamine **157** and monitored by various spectroscopic methods [84]. The helicene **156** was synthesized from 2,7-dihydroxynaphthalene **158** [85]. The first step involved acid-catalyzed condensation between two molecules of **158** and glyoxal to obtain dihydrofurofuran **159** (>95%), followed by the protection of phenolic groups to give acetate **160** (95%). Then, one-pot benzylic bromination and dehydrobromination (aromatization) of **160** using *N*-bromosuccinamide led to **161** (45%), followed by basic hydrolysis resulting in dioxa[6]helicene diol **156** (96%). Finally, selective mono esterification with chiral (1*S*)-camphanic chloride in acetone afforded the desired host, **155**, with 90% yield (Scheme 27) [85].

**Scheme 27.** Multistep synthesis of helicene camphanate **155** from 2,7-dihydroxynaphthalene **158**.

Indeed, the parent dioxa[6]helicene diol **156** is almost a flat stereodynamic-type fluorescent compound, which was selectively modified with a chiral (1*S*)-camphanate group to give **155**, leaving one of the (phenolic) hydroxyl groups free. This inherently free phenolic group and (1*S*)-camphanate chiral handle on the opposite peripheral ring provided a suitable *sui generis* chiral space for guest **157**. In particular, this perfect stereospecific matching results in an effective turn-on fluorescent sensor for the (*S,S*)-enantiomer of **157** with a relatively high enantioselective factor, α = K*SS*/K*RR* = 6.3 (in benzene). The favorable hydrogen-bonding interactions in nonpolar media (benzene and toluene) are responsible for the efficient chiral recognition observed by fluorescence spectroscopy (Figure 15a,b). In nonpolar media, the donor–acceptor type cooperative hydrogen bonding between host **155** and guest **157** (Figure 15c) resulted in a high turn-on enantioselective fluorescence response. The enantiodiscrimination behavior was found to be solvent-dependent as the polarity of solvent can influence the extent of hydrogen bonding between the host and guest. In turn, this induces a unidirectional switch in the helical conformation of the helicene chromophore, resulting in reverse selectivity for the (*R,R*)-enantiomer of **157** in acetonitrile, THF, and chloroform [84].

Further, the NMR studies performed in deuterated chloroform exhibited the chiral camphanate group transfer reaction (Scheme 28a) with the reaction rate of 5.83 × <sup>10</sup>−<sup>6</sup> and 5.97 × <sup>10</sup>−<sup>7</sup> mol dm−<sup>3</sup> <sup>s</sup>−<sup>1</sup> for (*R,R*)-**157** and (*S,S*)-**157**, respectively, as monitored by 1H NMR (Figure 15d). This tenfold increase of the reaction rate for the (*R,R*)-enantiomer allowed the host **155** to behave as a kinetic resolving agent for (*R,R*)-**157**, with up to 68% *de* at room temperature within 4 h (Figure 15d) [84].

**Figure 15.** Fluorescence response of helicene camphanate **155** for *trans*-1,2-cyclohexanediamine **157** (**a**) in benzene and (**b**) in toluene solvent; (**c**) Schematic representation of the donor–acceptor hydrogen bonding between **155** and **157** in nonpolar solvent with turn-on fluorescence response; (**d**) Time-dependent changes observed in 1H NMR spectra of host **155** with 1:1 (*R,R*)-**157** in CDCl3. Reprinted from [84]. Source: http://pubs.acs.org/doi/abs/10.1021/acsomega.6b00522.

Indeed, this is a rare example of the *sui generic* host–guest pair as evident from the fact that diamine **157**, upon supramolecular interaction with the parent stereodynamic helicene diol **156** (Scheme 28b) is able to induce a specific helicity and shift the stereodynamic equilibrium of **156**, as monitored by CD spectroscopy in the region of helicene chromophore absorption.

Further, the same group also developed *Cs*-symmetric rigid achiral organophosphoric acid **163** in two steps, starting from dihyrofurofuran helicene **159** as a supramolecular chirogenic system for the absolute configuration determination of 1,2-amino alcohols by induced CD (ICD) studies [86]. The two-step synthesis includes the reaction of dihyrofurofuran helicene **159** with formaldehyde to form an additionally bridged diol, **164**, and subsequent reaction with POCl3 to obtain the target, **163** (Scheme 29).

**Scheme 28.** (**a**) Chiral group transfer reaction between **155** and (*R,R*)-**157** in chloroform and (**b**) proposed shift in conformational dynamic equilibrium of **156** in the presence of (*R,R*)-**157** in chloroform.

**Scheme 29.** Synthesis of **163** from dihyrofurofuran helicene **159**.

Interestingly, due to the *Cs*-symmetric nature of phosphoric acid, **163** has two tautomeric structures. This structural feature of **163**, in combination with the substituent bulkiness of the guest amino alcohols, together decide the preferred mode of two-point hydrogen bonding on equilibration, which gave a resultant ICD signal correlating with the absolute configuration of the guest [86].

#### *7.2. Polymeric Helicene-Based Chiral Recognition*

Polymer chains can also serve as suitable carriers for chiral helicenes, especially in the case of prospective applications. Thus, using 2-acetylene-[6]helicene **165**, Yashima et al. prepared a series of polymeric helicene pendants, poly-1-**166**, via the rhodium-catalyzed polymerization reaction (Scheme 30) [87]. This polymerization reaction gave stereoregular (*cis-transoidal*) polyacetylenes bearing the corresponding helicene pendants **166** with (*P*)- and (*M*)-polymeric chains with average molecular weight *<sup>M</sup>*<sup>n</sup> = 2.6 × <sup>10</sup>3. However, the formation of a precipitate during the reaction makes it difficult to reproduce. The careful analysis of the CD spectra of monomer **165** and polymers **166**, and their corresponding differential CD spectra, suggests that the helical polyacetylenes with the optically active pendant group exist as a single-handed structure, apparently due to the attractive intramolecular π-π interactions.

**Scheme 30.** (**a**) One step synthesis of polymeric helicene **166** and (**b**) its application against enantioselective adsorption of racemic guests **165**, **167**, and **168**.

The chiral recognition abilities of these polymers were studied in the context of the enantioselective adsorption of three racemic guests, namely, parent helicene **165**, BINOL **167**, and 2,2 -dibromo-binaphthalene **168**. The enantiomers were adsorbed by the polymer in methanol solution and desorbed in a mixture of methanol/THF [1:1, *v*/*v*] followed by chiral HPLC analysis. The poly-1-(*P*)-**166** preferentially adsorbed (*P*)-helicene **165** with 3.6% *ee*; both have similar configurations. As expected, in the case of **166** with opposite absolute configuration, the adsorption preference was observed for (*M*)-helicene **165** with a similar 3.7% *ee*. However, interesting results were obtained for binaphthyl derivatives **167** and **168**, where poly-1-(*P*)-**166** selectively adsorbed the opposite (*S*)-enantiomers with up to 36% *ee*, whilst poly-1-(*M*)-**166** showed similar selectivity towards the (*R*)-enantiomers of **167** and **168**. The calculated separation factor was sufficiently high (1.71–2.18), indicating that these polymers can be used as a stationary phase for the practical separation of racemic mixtures.

#### *7.3. Helicene-Based Chiral Recognition via Nanoparticles*

Another prospective approach for chiral recognition by helicene structures is based on nanomaterials. In this respect, individually racemic, (*P*)-, and (*M*)-helicene thiols **169** were grafted onto gold nanoparticles of 5–22 nm [88] in a mixture of ethanol/water (1:3, *v/v*) under sonication to form the corresponding Au-(*P*/*M*)-, (*P*)-, and (*M*)-**169**-nanoparticles (helicene-grafted nanoparticles) (Figure 16). These helicene-based nanoparticles show chirality-based inter(nano)molecular attractive interaction, resulting in the corresponding aggregation phenomenon followed by a time-dependent precipitation process, as analyzed by UV spectroscopy. All three types of nanoparticles dispersed in DMF gave a stable solution for a period of one week. The addition of the DMF solutions to an aromatic solvent such as benzonitrile resulted in different colors due to the surface plasmonic bands of the gold nanoparticles, as studied by UV–vis spectroscopy and a dynamic light scattering technique. Additionally, the time-dependent aggregates were of different sizes, based on the type of helicene nanoparticles present. The observed chiral recognition induced by the homo- (Au-(*P*/*M*)-**169** nanoparticle : Au-(*P*/*M*)-**169** nanoparticle, Au-(*P*)-**169** nanoparticle : Au-(*P*)-**169** nanoparticle, and Au-(*M*)-**169** nanoparticle : Au-(*M*)-**169** nanoparticle) and hetero self-aggregation (Au-(*M*)-**169** nanoparticle : Au-(*P*)-**169** nanoparticle) of the helicene nanoparticles was found to be enhanced according to the following sequence: Au-(*P*/*M*)-**169** nanoparticle : Au-(*P*/*M*)-**169** nanoparticle < Au-(*M*)-**169** nanoparticle : Au-(*M*)-**169** nanoparticle = Au-(*P*)-**169** nanoparticle : Au-(*P*)-**169** nanoparticle < Au-(*P*)-**169** nanoparticle : Au-(*M*)-**169** nanoparticle. This tendency relates to the interaction strength between the corresponding nanoparticles, which is controlled by stereochemical matching.

Another example of optically active nanoparticles **170** with 70 nm diameter size was obtained by grafting (*P*)-1,12-dimethyl-8-methoxycarbonylbenzo[c]phenanthrene-5-carboxyamide on 3-aminopropylated silica (Figure 17) [89,90]. These nanoparticles were prepared by reacting 3-aminopropylated silica nanoparticles with the corresponding (*P*)-helicene carboxylic acid chloride by refluxing in isopropyl ether for 4 hours using ethyldiisopropylamine as a base.

**Figure 16.** Enantiomeric structures of helicene thiol **169** and representations of the gold nanoparticles formed from **169**. Modified and reprinted, with permission from [88] © 2012, Royal Society of Chemistry.

It was found that these nanoparticles enantioselectively precipitated at a faster speed with (*S*)-configuration of aryl alcohols **80** (47% *ee*) and **171** (61% *ee*) [89] in *m*-bis(trifluoromethyl)benzene (Figure 17). To elucidate the corresponding *ee* values, the precipitate was centrifuged and separated, followed by mixing in 2-propanol. Then, the insoluble material (nanoparticles) was removed and the organic layer was concentrated and analyzed with chiral HPLC, indicating the optical resolution of up to 29–61% *ee* for various aromatic alcohols for the (*S*)-configuration [89]. The mechanism of this stereoselectivity was related to chiral recognition on the basis of the electrostatic aggregation phenomenon. This nanoparticle-based kinetic resolution requires a relatively smaller amount (10 mol %) of **-**nanoparticles **170** as the resolving agent compared with the requirement of conventional 0.5 equivalence, with providing additional possibility for resolving noncrystalline substances, making it an attractive and greener method of choice.

Further, the helicene-based nanoparticles **170** were able to recognize the shape of (*P*)-ethynylhelicene oligomers **172** in solution [90]. It preferentially forms the precipitate with a double helix of the oligomeric structure of **172** in comparison to its random coil structure in trifluoromethylbenzene (Figure 17). The analysis was carried out by CD spectroscopy, where the double helix oligomer shows a strong positive CE followed by a negative one, whilst in the case of the random coil oligomer, a weak CE of opposite sign was observed. This phenomenon was related to the chiral shape recognition on the surface of the nanoparticle by stereospecific absorption, resulting in the visualized selective aggregation-based precipitation, which is useful for the separation of the double helix structure of **172** from its random coil conformation [90]. These examples clearly show the potential of helicene-based chiral nanomaterials for applications in the resolution of chiral molecules ranging from a simple alcohol to complex polymeric structures.

**Figure 17.** Helicene silica nanoparticle **170** and its ability towards chiral recognition and resolution of aromatic alcohol **80** and **171** and double helix oligomer **172**.

#### *7.4. Helicene-Based Chiral Recognition Involving Biologically Relevant Molecules*

The stereodynamic helicenes are also effectively employed for the induced CD-based sensing, where a chiral guest can induce a specific helicity via covalent or supramolecular interactions, thus generating the corresponding CD signals in the helicene absorption region. The guests range from simple organic molecules (Scheme 28b) to complicated biological molecules, as described here.

Thus, Yamada's group explored hydroxymethyl trithia[5]helicene **173** [91–96], which is a stereodynamic compound. Both the (*P*)- and (*M*)-enantiomeric structures are configurationally labile, nonresolvable, and exist in a fast equilibrium. However, due to the presence of an electron-rich aromatic chromophore and polar hydroxymethyl group capable of hydrogen bonding, suitable complexation of the chiral guest (such as biomolecules) [91,93–96] is able to shift the equilibria to one of unidirectional helicity, which, in turn, can be monitored by CD spectroscopy (Figure 18).

**Figure 18.** Stereodynamic hydroxymethyl trithia[5]helicene **173** and a principle of its use as an induced CD host.

The corresponding host–guest studies were successfully implemented with serum albumin [91], (*R*)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy)propionic acid (TAPA) [92], alkyl b-D-pyranoside [93], and bilayered phosphatidylcholine vesicles [94–96] using CD spectroscopy as a major tool. As the extent of helicity induced in **173** by these guest molecules is small, the resultant CD signals are also small. Yet, as CD is a highly sensitive technique, even with a small signal, it can be applied for understanding molecular behavior and chirality in solution.

Tanaka et al. synthesized bis(hydroxymethyl)thia[7]helicene **174** to study its further synthetic chemistry and corresponding applications in the chirality recognition of biological molecules [97–100]. Hence, the helicene **174** was synthesized in a total of nine steps with an overall 33% yield, where the

photochemical cyclization of alkene **175** was a key step to give silyl group protected *rac*-**176**. Further, deprotected racemic **174** was optically separated using the lipase-based enzymatic kinetic resolution method. For example, with the use of *Pseudomonas cepacia* enzyme, (*P*)-**174** (44%, 98% *ee*) was obtained as a slow reactive isomer with simultaneous formation of the corresponding mono- and diacetates, (*M*)-**177** and (*M*)-**178**. Similarly, the use of *Candida antarctica* enzyme resolved opposite (*M*)-**174** (44%, 92% *ee*) with the formation of mono- and diacetates, (*P*)-**177** and (*P*)-**178** (Scheme 31) [97].

**Scheme 31.** Photochemical synthesis and enzymatic resolution of helicene **174**; (**a**) *hv*, I2, propylene oxide, benzene, room temperature; (**b**) tetra-*n*-butylammonium fluoride, THF, 0 ◦C; (**c**) *Pseudomonas cepacia*, CH2Cl2, vinyl acetate, room temprature, 25 h; (**d**) *Candida antarctica*, CH2Cl2, vinyl acetate, 28–29 ◦C, 9.5 h.

Further, enantiopure alcohol **174** was converted to its dichloride **179**, which was converted to **180** [98] and cyclic thia ethers **181**–**183** [99] using suitable synthetic procedures (Scheme 32). These helicene molecules were explored in terms of possible chiral recognition of biologically relevant molecules such as DNA [98,100].

It is well known that, under physiological conditions, a DNA duplex exists as a mixture of the right-handed B-DNA and left-handed Z-DNA forms. The supramolecular association of chiral *C2*-symmetrical **180** with DNA revealed that the (*P*)-enantiomer of **180** displays chiral selection for binding Z-DNA over B-DNA [98]. The corresponding binding constants were found to be (8.0 ± 0.5) × <sup>10</sup><sup>4</sup> <sup>M</sup>−<sup>1</sup> and (1.4 ± 0.3) × 104 <sup>M</sup>−<sup>1</sup> for Z- and B-DNA, as measured by fluorescence titration. Besides, this interaction can be clearly monitored with CD spectroscopy, where, upon binding Z-DNA, there is a considerable decrease in the signal intensity of (*P*)-**180** of up to 70% at 330 nm at neutral pH. Under similar conditions, B-DNA failed to show any significant change in the CD spectra of (*P*)-**180**, indicating (*P*)-helicity-based recognition of Z-DNA. In contrast, although the (*M*)-**180** also showed a 20% reduction, it was observed upon binding both B- and Z-DNA, thus indicating the lack of its discrimination ability.

**Scheme 32.** Synthesis of functionalized helicene **180** and thiaethers **181**–**183** from [7]helicene **174**.

Additionally, it was observed that the (*P*)-**180** not only selectively binds Z-DNA but is also able to force B-DNA to adopt an opposite left-handed helical form, like Z-DNA. Apparently, the methylene-*N*,*N*-dimethylamine functionality in (*P*)-**180** plays a crucial role in this behavior, as the same helicene backbone but with hydroxy methyl substituents, as in the case of **174**, did not show any binding response towards B- and Z-DNA. It is likely that the protonated form of amino substituents in **180** becomes a crucial site for binding DNA, whilst the helicene chirality is an important factor in the enantioselective recognition of left-handed helical Z-DNA.

Further extending the chiral recognition research of biologically important molecules resulted in the development of cyclic helicenes with thiaether linkage, **181**–**183** (Scheme 32) [99,100]. The (*M*)-enantiomers of **181**–**183** turned out to be potential inhibitors against telomerase enzyme activity based on the chiral and steric matching, while binding to the G-quadruplex superhelix structure. The recognition phenomenon is based on the chiral space available at the cleft-pocket and the presence of Z-DNA assisting this helicene binding. Initially, **180** was studied and exhibited no chiral selectivity. This result led to the assumption that the dihedral angle in helicene chromophores plays a key role in the interaction efficiency. On this basis, three different cyclic helicene thiaethers, **181**–**183**, having different length of linkers, were designed to yield the dihedral angles of 22◦, 53◦, and 58◦, respectively.

It was shown that the (*M*)-enantiomer of **181** with the smallest interplanar angle was able to inhibit the telomerase enzyme activity efficiently, presumably as a result of the chiral and steric matching. However, the exact binding mode of this helicene to the G-quadruplexes is not fully understood yet. Here, again, the binding studies relied on CD and fluorescence spectroscopy [100].

In 2013, chiral [5]helicene **184**, containing methyl groups at the innermost positions, was suitably connected with the spermine moiety **185** at the outer sphere of the helicene backbone to act as a host capable of recognizing the DNA conformation [101]. This host was synthesized by the Suzuki–Miyaura coupling of 8-methylnaphthalene-2-boronic acid **186** with dibromo-maleimide **187** to obtain **188**, followed by photocyclization to result in racemic **189** with 92% yield. The enantiomers of **189** were separated on a chiral column followed by further transformation to **190** and, finally, to the target enantiopure **184** (Scheme 33) [101].

**Scheme 33.** Synthesis of helicene-spermine **184**.

The designing concept was such that the cationic spermine unit is able to provide the corresponding electrostatic interactions with the DNA's phosphate backbone of the minor groove, whereas the chiral helicene is expected to form end-stacking mode complexes, altogether resulting in a strong chiral recognition. Indeed, it was demonstrated that (*P*)-**184** binds preferentially to B-DNA over Z-DNA. The opposite trend was observed with (*M*)-**184**, which displayed strong binding for Z-DNA over B-DNA, as studied by performing CD, UV melting temperature, surface plasmon resonance measurements, and isothermal titration calorimetry. From the examples of **180** [98] and **184** [101], it appears that the cationic functional groups assist in binding with DNA through electrostatic interactions; along with this, the chiral helicity-based steric fit allows selectivity. The (*P*)-**180** prefers Z-DNA, whereas in the case of **184**, the (*M*)-enantiomer binds strongly to Z-DNA. As structures, tetrathia[7]helicene **180** having functional groups on the terminal rings (in chiral cavity space) and 1,14-dimethyl[5]helicene **184,** where spermine **185** is situated at the helicene outer core, are completely different in terms of the functional groups and their positions, therefore the exact mode of binding with DNA cannot be generalized and is still not completely understood.

Chiral cationic [4]helicenes **191** (Figure 19), having methoxy substituents at the innermost position, were also able to bind with DNA molecules, as evident from a noticeable change in absorption, fluorescence, and CD spectra obtained during the corresponding host–guest studies [102]. It was concluded that the molecular plane of the helicene dye lies essentially parallel to the DNA bases, implying intercalation mode rather than groove binding. Further, the chiral selectivity based on association constant evaluation indicates that the (*M*)-enantiomer of **191** interacts more strongly with DNA than the corresponding (*P*)-enantiomer of **191**.

**Figure 19.** Structure of (*M*)-enantiomers of **191**.

Yang et al. developed chiral 3-aza[6]helicene-modified β-cyclodextrin **192** by reacting 6-deoxy-6-iodo-β-cyclodextrin **193** with (*P*)/(*M*)-helicene **194**, resulting in two water soluble cationic charged diastereomeric species—(*P*)-**192**/β-cyclodextrin, and (*M*)-**192**/β-cyclodextrin (Scheme 34)—with different fluorescence behavior [103]. The concept was to use water-insoluble 3-aza[6]helicene **194** in aqueous media in combination with the β-cyclodextrin asymmetry for the chiral recognition of amino acids in water.

**Scheme 34.** Synthesis of 3-aza[6]helicene modified β-cyclodextrin **192** as a water-soluble amino acid sensor.

In polar solvents such as methanol, ethanol, and water, the helicene chromophore occupies the β-cyclodextrin cavity to a different extent in two diastereomers: (*P*)-**192**/**-** and (*M*)-**192**/ β-cyclodextrin—favoring monomeric forms rather than self-aggregated species. Both the diastereomers were investigated for complexation towards proteinogenic amino acids by using the fluorescence technique in an aqueous buffer of pH 7.3. It turned out that hydrophobic interactions appeared to be a dominant binding mode with additional electrostatic forces between the cationic charge of helicene and carboxylate anion of corresponding amino acids; besides this, π-π interaction may also contribute in the case of aromatic guests. The chiral discrimination abilities were also found to be highly dependent on pH. A relatively high L/D selectivity of amino acids, up to 12.4, was observed as a consequence of the synergetic effects of the helicene auxiliary and β-cyclodextrin cavity [103].

#### *7.5. Helicene-Based Chiral Recognition via Self-Assembly*

A new approach for chiral recognition via self-assembly was applied by Yamaguchi et al. on the basis of functionalized chiral [4]carbohelicene. The overall studies demonstrated that the helicenes exhibit a noncovalent chiral recognition behavior via different functions, such as charge transfer complexation, crystallization, homocoupling reaction, layer structure formation, self-aggregation, and even upon double helix formation [75]. Their observations indicated that the right-handed helix structure favors the same helicity of its counterpart, which is not generally observed in the case of point chirality (i.e., an (*R*)- or (*S*)-host does not always prefer a guest of the same absolute configuration). Out of several examples, the following one is sufficient to understand this helicity matching phenomenon.

Tetranitro, dicyano-substituted [4]helicene **195**, being an electron-deficient system, strongly interacts with diamino-substituted [4]helicene **196** via a charge transfer complex [104], the formation of which was monitored by UV and NMR techniques. Particularly, in the UV spectrum, a charge transfer band was observed at 500–800 nm in THF. The association constant of the complex with the same configuration—(*M*)-**195** and (*M*)-**196**—was found to be 12.2 M−1; this was noticeably higher than the constant 10.2 M−<sup>1</sup> observed for the opposite configuration—(*P*)-**195** and (*M*)-**196** (Figure 20). Further, the NMR-based NOE experiments revealed that the face-to-face *syn*-conformation of two 1,12-dimethyl groups was preferred over the *anti*-orientation in the corresponding charged transfer complexes [104].

**Figure 20.** Helical discrimination upon supramolecular charge transfer complexation between electron-deficient helicene **195** and electron-rich helicene **196**.

In related studies, a series of racemic [7]helicene derivatives, **197**–**199**, containing pyridinone rings at both the terminals, were prepared using a classical methodology of Wittig olefination and photochemical cyclization, and were characterized both in solution and in solid state [105]. Despite a variety of self-assembly modes according to the stereochemical and topological relationships, these helicenes formed only enantiomerically pure dimers held together by two pairs of the cooperative hydrogen bonds. The self-assembly process was found to be enantiospecific in solution and diastereoselective in solid crystal (Figure 21).

The terminal pyridinone rings were capable of hydrogen bonding via the corresponding amidic N–H functionalities. The solution-phase NMR studies indicated that the helicenes exist as enantiomeric dimers. For example, the NH proton in 2-quinolinone **200** (10<sup>−</sup>4–10−<sup>2</sup> M), as a reference, appeared at 12.9 ppm, whilst the position of this proton in **198** was downfield-shifted by 1 ppm in dilute solution (>10−<sup>5</sup> M), clearly indicating the cooperative hydrogen bonding and self-assembly phenomenon. In turn, the chemical shift was found to be concentration-independent in CDCl3 and THF. In pyridine, as expected, it was concentration-dependent, as pyridine itself is able to compete for the hydrogen bonding. Additionally, the dimeric binding model was confirmed by dilution experiments with the association constant of 207 M−1. The molecular modelling studies also indicated that each dimer is preferably constructed from a monomeric species of the same helicity.

The X-ray crystallographic structure of **199** showed only homochiral dimers; where the R-group (acetyl) is present in the *cis*-orientation to ensure the diastereoselective recognition process during crystallization. These enantiopure dimers are held together by four strong intermolecular hydrogen bonds between two terminal pyridinones.

**Figure 21.** Hydrogen bonding-based self-assembly in pyridinone-containing helicenes **197**–**199** and 2-quinolinone **200**, as a NMR refrence.

#### **8. Enantiopure Helicenes: Enantioselective Synthesis, Chiral Separation, and Racemization**

The chiroptical properties and applications discussed above prompted the development of efficient synthetic procedures to obtain enantiopure helicenes in sufficient quantities required for these investigations [2,4]. Although this topic is not directly related to the category of helicene applications, it is an important background for the whole helicene chemistry; hence, a brief description should be included as a special section. The major methods of obtaining enantiopure helicenes from a racemic mixture are based on optical resolution by chiral HPLC [60,77,78,83,101], diastereomeric salt formation [51,60,76] (for representative resolving agents, see Figure 22), chromatographic separation of diastereomers [52,56,74], and enzymatic-based approaches [97].

**Figure 22.** Selected examples of chiral reagents for helicene optical resolution.

For example, racemic nonfunctionalized helicenes were successfully resolved through charge transfer complexation with electron-deficient molecules, such as TAPA [15,16] or HPLC-based separation with the use of silica coated with TAPA [106]. In the case of functionalized helicenecontaining phenolic groups at the terminal ring, (1*S*)-camphanic chloride acts as the best resolving agent for chromatographically separable diastereomers obtained. Furthermore, their absolute configuration determination was carried out by the 2D ROESY NMR technique [52,74,107]. Particularly, it was observed that in 19 examples of helicenes studied, (*M,S*)-diastereomers were less polar, whilst (*P,S*)-diastereomers were more polar, hence eluting as the first and second fractions, correspondingly, upon the chromatographic separation on silica gel [107]. Another resolving agent, which is also frequently employed for optical resolution, is an *l*-menthyl derivative [4,56]. This approach has a distinct advantage of attaching and detaching a chiral auxiliary before and after the diastereomeric separation, making the whole procedure recyclable and highly efficient. Interestingly, in the case of azahelicene **201** containing the chloro group as a substituent on the outer peripheral pyridine ring, the use of Pd-catalyzed Buchwald–Hartwig coupling with (*S*)-phenylethyl amine gave chromatographically separable diastereomers **202** and **203** (Scheme 35) [108,109]. However, the absolute configuration of the 2-ethylhexyl alkyl chain was not discussed in the paper [108].

**Scheme 35.** Synthesis of chromatographically separable diastereomers **202** and **203** obtained by Pd-catalyzed reaction between *rac*-azahelicene **201** and (*S*)-phenylethylamine.

Besides the optical resolution of racemates, another approach to enantiopure helicenes is based on the stereospecific synthesis, where the originally chiral precursors or reagents are converted into the corresponding helicenes with unidirectional helicity [110]. In particular, the asymmetric synthesis of helicene can be performed by using various synthetic methods, such as photocyclization, Diels–Alder reaction, or metal-catalyzed annulation, in the presence of chiral auxiliaries attached to the reactant(s). These topics have been comprehensively covered in previous reviews [2,4]. Therefore, only a few of those recently published examples of asymmetric helicene synthesis are highlighted below.

In 2016, Sako et al. successfully used the modified BINOL-based vanadium(V) complex **204**, capable of functioning both as redox and Lewis acid catalysts, for the enantioselective synthesis of oxa[9]helicenes **205** starting from polycyclic phenols **206**. The reaction proceeds via oxidative coupling at first, followed by intramolecular cyclization. This results in the one-step enantioselective synthesis of oxa[9]helicenes in good yields with up to 94% *ee* [111] (Scheme 36).

**Scheme 36.** Modified BINOL-based vanadium complex **204**, catalyzed asymmetric synthesis of oxa[9]helicenes **205** from polycyclic phenols **206**.

In 2015, a new general asymmetric synthetic methodology was successfully developed for [5]-, [6]-, and [7]helicenes with ultimate enantioselectivity (*ee* >99) based on the controlled transfer of reactant point chirality to the product with unidirectional helicity [112]. At first, triyne**207**, having inbuilt point chirality, was converted into tetrahydrohelicene diastereomers **208** and **209**, being in the thermodynamic equilibrium, by cobalt-catalyzed tandem [2 + 2 + 2] cycloisomerization. The (*M*)-conformational helicity results in the 1,3-allylic strain, hence making **208** a highly energetic diastereomer in comparison to **209**, the (*P*)-conformational helicity of which gives relief from this strain, when the point chirality is of (*R*)-configuration at the 9-position. Subsequently, the favored diastereomer under acidic conditions yielded fully aromatic helicenes **210** with greater than 99% *ee* (Scheme 37). Thus, (*P*)- and (*M*)-helicenes can be readily prepared starting from the (*R*)- and (*S*) absolute configurations at the 9-position of the precursor, correspondingly.

**Scheme 37.** Asymmetric synthesis of helicenes **210** based on the principle of point-to-helical chirality conversion.

One of the most important points of chiral helicenes is their configurational stability, which can be analyzed by using CD spectroscopy and chiral HPLC in combination with other techniques. Evidently, understanding the mechanism of racemization helps in designing more stable helicene structures. Recently, detailed theoretical racemization studies have been performed on [n]helicenes where n = 4–24 [113]. Consequently, it was found that n = 4–7 involves the one-step concerted mechanism of racemization. The smallest member of the carbohelicene family, [4]helicene has a *C2V* symmetric transition state (TS) with an energy barrier of 4.0 kcal mol-1. However, the TS of n = 5–7 possesses a *Cs*-geometry with the energy barriers of 24.4, 36.9, and 42.0 kcal mol<sup>−</sup>1, respectively. This is a result of the steric hindrance, which accounts for the high TS energies of racemization. For n ≥ 8, besides the steric hindrance, an additional factor of the π-π interaction starts to contribute to the overall structural stability, making the racemization process a multistep process and thus further increasing the energy barrier. For example, when n = 8,9, or 10, helicenes displayed 2, 4, and 6 intermediates for the racemization process, respectively. Thus, in general, when n = 8–24, helicenes involve (2n-14) consecutive displacements, traversing intermediates in the molecule during the racemization process for corresponding carbohelicenes. These theoretical results should be taken into account to control the desired properties of helicene structures in future research.

#### **9. Conclusions**

Helicenes are versatile compounds existing in achiral, stereodynamic, meso, and chiral forms. Additionally, they could be neutral, charged, carbocyclic, heterocyclic, or polymeric in nature, with electron-rich or -deficient characteristics. These conjugated molecules exhibit unique physical properties such as fluorescence and strong chiroptical features, making them exclusively useful for the chirogenesis processes, including chiral recognition using both fluorescence and circular dichroism spectroscopies. Their polyaromatic helical structures are also suitable for providing shielding and deshielding effects, making them potentially applicable as chiral NMR sensors.

The high configurational stability and facile functionalization of the helicene structures open intriguing prospects in the fields of chiral catalysts and auxiliaries for various asymmetric reactions. In the last three decades, there has been much research effort focusing on newer, simpler, and

multigram synthetic procedures including different asymmetric methodologies for obtaining sufficient quantities of enantiopure helicenes for various practical applications, including chirogenesis. It has been established that modified helicene molecules with important properties can be developed by merging the helical structure with other (central, axial, and planar) chirality elements for specific applications. The helicity control may be conveniently achieved by means of the intramolecular cyclization of terminal rings, resulting in a decrease in the helicity. Alternatively, the introduction of functional groups on the terminal rings or presence of saturated bond(s) inside the molecule (helicenoid) increases the helicity. These modifications also govern the helicene chiral cavity space properties, and may thus be adopted for desired applications.

Besides chiral auxiliaries and chirogenesis, the helicene structures are good candidates for material chemistry and nanotechnology. We believe that there is still a large and diverse scope for helicene chemistry and application to be studied in the upcoming future, which will result in novel and interesting discoveries. We are yet to fully explore the real potential of helicene and related molecules.

**Acknowledgments:** M.H. and V.B. acknowledge funding from the European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration under Grant Agreement No. 621364 (TUTIC-Green).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

## *Review* **Chiral Buckybowl Molecules**

**Kuppusamy Kanagaraj 1,†, Kangjie Lin 1,†, Wanhua Wu 1, Guowei Gao 1, Zhihui Zhong 2, Dan Su <sup>2</sup> and Cheng Yang 1,\***

Received: 27 July 2017; Accepted: 21 August 2017; Published: 30 August 2017

**Abstract:** Buckybowls are polynuclear aromatic hydrocarbons that have a curved aromatic surface and are considered fragments of buckminsterfullerenes. The curved aromatic surface led to the loss of planar symmetry of the normal aromatic plane and may cause unique inherent chirality, so-called bowl chirality, which it is possible to thermally racemize through a bowl-to-bowl inversion process. In this short review, we summarize the studies concerning the special field of bowl chirality, focusing on recent practical aspects of attaining diastereo/enantioenriched chiral buckybowls through asymmetric synthesis, chiral optical resolution, selective chiral metal complexation, and chiral assembly formation.

**Keywords:** buckybowl; corannulene; sumanene; bowl chirality; bowl inversion; asymmetric synthesis; chiral resolution

#### **1. Introduction**

Studies on the physical and chemical characteristics of buckybowls have attracted significant interest owing to their direct structural correlation with fullerenes and potential applications in the realm of material science (Figure 1) [1–3]. Corannulene **1** and sumanene **2**, two prototypical buckybowls, are both highly curved π-conjugated aromatic molecules representing the substructures of fullerene. The smallest *C*3v-symmetric fragment **2** comprises a central six-membered ring surrounded by three five- and three six-membered rings fused in an alternating fashion (Figure 1), whereas the smallest *C*5-symmetric fragment **1** contains a central five-membered ring surrounded by five six-membered rings (Figure 1). Regioselective allocation of the five- or six-membered ring subunits around the centroid pentagon or hexagon, respectively, gave the curved bowl-shaped structures. Certain buckybowls are inherently chiral and difficult to separate from the racemates due to their rapid bowl inversion [4]. Controlling the bowl chirality of these π-conjugates and obtaining enantioenriched buckybowls are challenging tasks for chemists, while buckybowls application in chiral materials is highly promising [5–14]. Further extension of the π-conjugation of these chiral enantioenriched buckybowls leads to homochiral carbon nanotubes, and these chiral carbon materials create new perspectives in chiral catalysis, chiral sensing, chiral separation sciences, etc. [15–27]. A better understanding of bowl chirality will help researchers find a good way to control the chiral self-assembly of carbon nanotubes (CNTs) or fullerenes, which have already exhibited exciting potential as next-generation functional materials [28–38].

**Figure 1.** Chemical structures and bowl-shaped fragments of **1** (**left**) and **2** (**right**) as rim hydrogenated subunits of spherical buckminsterfullerene C60.

While several buckybowl-related reviews have been published in recent years [6,39–44], most of them focused on the synthetic strategy and derivation method. Only a few publications involve the stereochemistry or chirality of the buckybowls. In this short review, we summarize recent progress on the stereochemistry of buckybowls and their derivatives. It covers recent developments in the asymmetric synthesis and optical resolution of buckybowls from their racemates, and application of the enantioenriched buckybowls in the chiral aggregate formation and homochiral CNT syntheses [45,46]. These structurally well-defined single-chiral CNTs exploit truly exciting applications ranging from space elevator to armchair quantum wire and bio-related applications [47]. Chiral buckybowls that possess a stable concave or convex shape are suitable for the construction of chiral molecular recognition sites [48]. They may also coordinate metals by virtue of their electron-rich/-deficient properties and thus have the potential for enantioselective organocatalysis [49,50]. Chiral buckybowls, acting as chiral building blocks, can also be used for constructing helical assemblies and preparing homochiral crystalline organic materials.

#### **2. Classification of Bowl Chirality**

Bowl-shaped carbon-based π-conjugated aromatic compounds, so-called "buckybowls", are the partial structure of fullerenes or CNTs (Figure 1). These three-dimensional (3D) curved π-electron systems may possess inherent chirality and present many similarities to chiral fullerenes and CNTs, which is often defined as "bowl chirality" for convenience. The bowl-shaped polyaromatic hydrocarbon chiral buckybowl molecules can be broadly classified into three categories (Figure 2) based on the origin of their chirality. The conjugated bowl structure itself possesses the chirality, such as π-extended buckybowls, e.g., hemifullerene **3**; bowl chirality caused by introduction of one or more substituents on the rim of the buckybowl, e.g., trimethylsumanene **4**; and bowl chirality originated from the introduction of heteroatom into the π-bowl carbon skeleton, e.g., triazasumanene **5**.

**Figure 2.** Classification of chiral buckybowl molecules.

Unlike common aromatic compounds, which often have a symmetry plane along the aromatic ring, buckybowls loss the cross-ring symmetry plane due to the curved shape. Unsubstituted buckybowls **1** and **2** are not chiral due to the presence of the reflection symmetry with respect to the mirror planes containing the rotational axis to show *C*5v and *C*3v symmetry, respectively. Introducing the addends may break the reflection symmetry to cause chirality, and alter their properties, such as bowl-to-bowl inversion [12–22], chirality [12,17,19,23], bowl depth [14,19,20], crystal structure [19,24,25], molecular recognition [2,26,27,51] and supramolecular assembly [3,28–30,52,53] behavior, metal complexation [23,31–36], electronic conductivity [19,37,38], and so on. Although the chirality is an important element in three-dimensional curved π-electron systems, thus far there have been no reports of the enantioselective synthetic control of the bowl chirality.

#### **3. Stereodescriptor System of Buckybowls**

Until now, the absolute configuration of bowl chirality of chiral buckybowl molecules was followed by two independent stereodescriptor systems: The stereodescriptor *C* or *A* based on fullerene nomenclature [17,54] and the another stereodescriptor *P* or *M* based on the Cahn–Ingold–Prelog (CIP) sequence rule [32]. The numbering system of fullerenes follows in general a helical numbering path, starting from the lowest set of numbers for substituents. To assign a descriptor in the chiral fullerene system, the viewer looks from the outside of the fullerene cage at the polygon to start the numbering and trace the path of numbering C(1)–C(6) (Figure 3a) [54]. The chirality of buckybowls is assigned in the same way, and a viewer looks from the convex face and traces the path of numbering from atom C(1) to C(6) (Figure 3b) [17]. If the numbering path describes a clockwise direction/travel, the configuration of the chiral bowl is designated as *C*. In contrast, if the path describes a counterclockwise direction/travel, the configuration of the chiral bowl is designated as *A*.

**Figure 3.** (**a**) Three-dimensional diagram of C60 with the subunit of sumanene including enantiomeric travel numbering schemes and the related stereodescriptor systems *C* and *A*; (**b**) The stereodescriptor system of some *C*<sup>3</sup> symmetric chiral buckybowls.

ᬅ ᬆᬅ ᬅ ᬆ Another stereodescriptor system *P* or *M* for chiral buckybowls uses the CIP sequence rule [32]. Based on the CIP priority rule [55], the "non-fusion peripheral atoms" of buckybowl molecules are compared, and one atom with the highest CIP priority is chosen as the first priority (point of origin, **<sup>1</sup>** , Figure 4) [17,18]. Furthermore, for the next highest CIP priority atom **<sup>2</sup>** versus **<sup>1</sup>** , compare the two neighboring rim atoms attached to this original point, and subsequent atoms attached thereto. For a viewer looking from the concave face of the buckybowl molecule, i.e., looking "into" the cavity of the bowl, the path of CIP priority numbering is from the original point atom to the neighboring atom with higher priority ( **<sup>1</sup>** → **<sup>2</sup>** ). If the path of CIP priority numbering direction describes clockwise travel, the configuration of the chiral bowl is designated as *P*. Otherwise, if the path of CIP priority numbering travels in a counterclockwise direction, the descriptor is *M*. The numbering to specify the positions of substituents follows the nomenclature of fused ring systems.

**Figure 4.** The *P* and *M* stereodescriptor system for some *C*<sup>3</sup> symmetric chiral buckybowl molecules based on the CIP priority rule.

#### **4. Bowl Inversion/Racemization of Chiral Buckybowls**

A unique property of buckybowls lies in that these molecules can thermally flip their curvature in solution via bowl-to-bowl inversion or concave–convex transition. During the bowl inversion process, the inherent bowl chirality inverts; this process is also called racemization (Figure 5a) [12,17–19]. The nonpolar polyaromatic small bowl molecules, like **1** and **2** can thermally flip through a planar transition state and the required energy to cross this transition barrier is defined as bowl inversion energy (Δ*E*) (Figure 5b) [20]. In the solid state, buckybowl molecules exist in a stack structure and show excellent physical properties, such as electron conductivity [24].

The thermally driven bowl-to-bowl inversion is of interest to basic science and can find various applications in functional materials for sensors, chemical machines, or ferroelectric memories. The lifetime of enantiopure chiral buckybowls is controlled by the bowl inversion energy (Δ*E*). The enantiopure chiral buckybowls are expected to contribute to a variety of applications such as asymmetric molecular recognition, homochiral crystal organic materials, chiral self-assembly, and chiral organometallic catalysis [6,7,9].

The introduction of substituents or heteroatoms in the carbon skeleton of buckybowls changes the bowl inversion energy within the range of 20–40 kcal/mol, and therefore could change the lifetimes of chiral buckybowls considerably. Furthermore, the nature, position, number of substituents, and stereoelectronic effects also significantly influence the bowl shape, depth (*x*), lifetime of keeping chirality, electron-deficient/-rich nature, and other physicochemical properties [56]. The bowl-inversion energy of corannulene derivatives was first determined by Scott and co-workers [13]. The interesting dynamic behavior of various buckybowl molecules has been extensively studied by Scott [57], Siegel [14,16], Hirao [15,35], Sakurai [12,17–20], and others. In particular, Sakurai and co-workers studied the effect of the substituent R at the benzylic position of sumanene **11**, which possesses two different conformers, *endo*-R and *exo*-R, differing in the direction of the aromatic bowl shape, concave or convex (Figures 6 and 7) [56].

**Figure 5.** (**a**) Racemization of chiral **2** through bowl-to-bowl inversion/racemization; (**b**) the double-well potential energy profile. Reprinted from [20]. © 2014 Pure & Applied Chemistry.

**Figure 6.** The *endo*-R and *exo*-R conformers of monosubstituted-sumanene **11** as determined by DFT calculations and the involved stereoelectronic effects. Reprinted from [56]. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

**Figure 7.** (**a**) Monosubstituted sumanene derivatives **11**; (**b**) Its graphical representation bowl depth and cone angle.

Introduction of substituents will influence the geometries/conformations of buckybowls and bowl inversion energies as well. The effect of substituents in corannulene has been studied by Siegel and co-workers [14,16]. They demonstrated that introducing the acyclic substituents in corannulene usually decreases the bowl depth and increases the bowl inversion energy. Based on the results of the experimental and theoretical study, they proposed a quantitative equation for bowl inversion energy, which relates the bowl depth to the bowl inversion energy (Figure 7) [14,16]. Steric and electronic factors of substituents also affect the bowl structure and bowl inversion energy of sumanene. Recently, Sakurai and co-workers found that sumanene **2** attached with a mono-iodo substituent induces a slightly deeper bowl depth and a higher bowl inversion energy compared with other sumanene derivatives because of its steric effect, whereas the electronic effects caused by formyl and nitro substituents induced a shallower bowl depth and a lower bowl inversion energy [20].

Siegel and co-workers studied the bowl-to-bowl inversion of corannulene **1** and ethylcorannulene derivatives mediated by extended tetracationic cyclophane (Figure 8) [22,30]. This synthetic host forms a supramolecular complex with **1** and ethylcorannulene via induced fit, and the bowl-to-bowl inversion process was accelerated by a factor of 10 at room temperature. Upon host–guest complexation, the transition state of the guest is stabilized through the stereoelectronic reorganization of the host, which switched from a strained conformation to an energetically favored conformation. Further, the experimental and DFT calculations for bowl-to-bowl inversion process of the host-guest complexion of **1** demonstrates the decrease of bowl-to-bowl inversion energy barrier of corannulene (Figure 8).

**Figure 8.** Comparison of energy profile of bowl-to-bowl inversion of corannulene **1** (black) and tetracationic cyclophane: **1**, complex (green) in Me2CO; absolute contributions of ground-state (GS) destabilization (0.5 kcal mol<sup>−</sup>1) and transition-state (TS) stabilization (2.0 kcal mol−1) to the overall energy-barrier decrease (ΔΔ*G*‡ catalysis) of the bowl-to-bowl inversion process of **1** inside the tetracationic cyclophane calculated by DFT (B97D/Def2-TZVPP). Reprinted from [22]. © 2014 Nature Publishing Group.

#### **5. Heterobuckybowls**

Doping of heteroatoms to the carbon frameworks of bowl-shaped aromatic compounds drastically modulates their geometrical structure and physical and chemical properties. After the successful synthesis of corannulene and sumanene derivatives, researchers began to try to synthesize hetero atom-doped buckybowl molecules, so-called "heterobuckybowls". The introduction of heteroatoms into the carbon skeleton is expected to yield altered electronic properties of basic carbon skeleton buckybowls, especially electron-deficient or -rich in nature. Notably, the substitution of a hetero atom in its carbon skeleton also causes the geometrical change, especially the depth of the bowl. As a result of the change in depth of the bowl, the activation energy for the bowl-to-bowl inversion energy is also altered. The higher the bowl inversion energy is, the more stable the chiral conformer will be. Several heterobuckybowls have been reported in the literature, some of them chiral (Figure 9) [12,58–66].

**Figure 9.** Heterobuckybowls with their bowl depth.

The heteroatoms embedded in the reported heterobuckybowls are mainly the group 14, 15, and 16 elements, such as nitrogen (second row), silicon, phosphorus and sulfur (third row), germanium and selenium (fourth row), and tin and tellurium (fifth row) (Figure 9). Introduction of heteroatoms in the periphery of buckybowls usually resulted in a decrease of the bowl depth of heterobuckybowls, because the bond lengths of carbon–heteroatom increased with the atomic size (Figure 9). The bowl depths of trithiasumane **16** (0.79 Å) and triselenasumane **18** (0.47 Å) [64] have a shallower bowl depth than that of normal sumanene **2** (1.11 Å) [24]. Trisilicasumanene **12** [59,63] and tritellurasumanene **19** have a plane structure, whereas triazasumanene **10** has a deeper bowl depth of 1.30 Å because the C–N bond length (1.47 Å) is shorter than the C–C bond length (1.54 Å) [12]. The high reactivity of nitrogen facilitates the formation of the highly strained triazasumanene derivative with higher bowl-to-bowl inversion energy. More recently, Saito and co-workers prepared a triphosphasumanene trisulfide **13** derivative with a large dipole moment (12.0 D) [67]. The bowl depth of *syn*-isomer **13** is 0.46 Å, which is identical to triselenasumane **18** (0.47 Å) [64] and shallower than sumanene [24], whereas the *anti*-isomer of triphosphasumanene trisulfide **13** exists in an almost plane structure [67].

#### **6. Asymmetric Synthesis of Buckybowl and Azabuckybowl**

Synthesis of buckybowls was a highly challenging task for chemists. The first synthesis of the pristine corannulene was accomplished in 1966 by applying a long synthetic route [68]. The synthetic investigation was postponed until Scott et al. [69] and Siegel et al. [70] reinitiated the synthesis of corannulene with a succinct synthetic route by using the flash vacuum pyrolysis (FVP) method in the early 1990s. In the FVP method, the planar π-conjugated precursors are directly converted into buckybowls under high temperature to yield a racemic mixture [71]. Many buckybowls were thus synthesized using this FVP method, whereas FVP method was unsuccessful for the synthesis of **2** [72]. In 1996, Siegel and co-workers developed the first solution phase synthesis of **1** [73]. Adopting this simple and short solution phase strategy, another pristine buckybowl **2** was obtained by Sakurai and co-workers [74].

In 2008, Sakurai and co-workers reported the first asymmetric synthesis of trimethylsumanene **4** using stepwise conversion strategy under milder reaction conditions [17]. The synthetic strategy is described in Scheme 1.

**Scheme 1.** Strategy for the asymmetric synthesis of chiral (*C*)-trimethylsumanene **4**.

In this strategy, chiral norbornene possessing stereogenic carbon center was used as the precursor, which was converted into planar nonconjugated bowl by Pd catalyzed *syn*-selective cyclotrimerization [75,76], and the *sp3* chirality was thus transmitted to the bowl chirality of **4**. The key concern of this strategy is the rate of racemization, which is directly correlated to the inversion barrier of buckybowls. Many buckybowls have a low bowl-to-bowl inversion barrier at room temperature and are unable to separate their enantiomers. For example, most corannulene derivatives are not able to enantiomerically isolate because of their bowl inversion energy of ca. 11.5 kcal/mol (bowl-bowl-inversion is >20,000 times per second at room temperature) [14]. In contrast, the bowl inversion energy of **2** and **4** is around 20.3 kcal/mol (one time per 143 s) [15,19] and 21.6 kcal/mol [19], respectively. Since the half-life of the bowl inversion of **4** are 2 h at 0 ◦C and 23 min at 20 ◦C [17], the isolation of an enantiomer would be possible if the last aromatization step is carried out at a low temperature.

Thus, the aromatization step, converting the nonconjugated bowl into a conjugated bowl, was carried out using excess DDQ in a very short reaction time (1 min) at 0 ◦C, and the resulting (*C*)-**4** quickly purified at <−20 ◦C. The isolated (*C*)-**4** was stored at −80 ◦C. The chirality of (*C*)-**4** was analyzed by the circular dichroism (CD) spectra at −40 ◦C, which show two positive Cotton effect curves at 247 nm and 284 nm, respectively (Figure 10a). In contrast, the intensity of CD signals gradually decreased at 10 ◦C (Figure 10b), indicating the racemization of (*C*)-**4** through bowl inversion. The experimentally observed bowl inversion energy is 21.6 kcal/mol, which is close to the calculated value (21 kcal/mol). The chiral (*C*)-**4** was converted into (*C*)-**7** (Scheme 2) using (*S*)-MTPA as a derivatization reagent [17]. The bowl inversion energy barrier of (*C*)-**7** is further increased and the *de* values can be determined using NMR or HPLC analysis.

**Figure 10.** (**a**) CD spectra of (*C*)-**4** in CH3CN at −40 ◦C (red line) and UV spectra of (*C*)-**4** in CH3CN at room temperature (blue line); (**b**) Decay of CD spectra of (*C*)-**4** in CH3CN at 10 ◦C for 3 h. Reprinted from [17]. © 2008 American Chemical Society.

**Scheme 2.** Derivatization of (*C*)-**4** using chiral derivatizing reagent for the determination of *ee*.

It has been proven that the bowl inversion energy of buckybowls increased with bowl depth [14]. Theoretical studies suggested that doping of nitrogen will lead to deeper and curved bowl depth compared to the all-carbon counterparts [77]. Sakurai and co-workers reported the first chiral nitrogen-doped buckybowl (Scheme 3) [12]. Pure chiral (*C*)-(−) and (*A*)-(+)-tris(methylthio)triazasumanene **9** was synthesized from corresponding enantiopure nonconjugated simple precursors, which was further converted into corresponding chiral sulfone derivative **10** by oxidation using *meta-*chloroperoxybenzoic acid (*m*-CPBA). From the single crystal analysis, the bowl depth of compound **10** is 1.30 Å, which is deeper than that of **2** (1.11 Å), indicating a higher bowl inversion barrier than the pristine **2**. The bowl inversion energy of triazasumanene is calculated to be 39.9 kcal/mol by DFT method at the B3LYP/6-311 + G(d,p) level. In contrast, the calculated values for **2** and **4** are 18.3 and 19.2 kcal/mol, respectively. This means that chiral triazasumanene **10** takes 1.1 billion years to racemize at 20 ◦C.

Both chiral derivatives of **9** and **10** exhibit the opposite Cotton effect curves (Figure 11), which are a mirror image of the corresponding enantiomers. The CD spectra of **9** and **10** demonstrated the existence of bowl chirality and remained intensive even after a week, indicative of a chiral memory effect. To measure the rate constant and bowl inversion energy of **9**, a racemization experiment was carried out at 488 K and analyzed by chiral HPLC. The racemization rate and energy of **9** were determined to be 1.24 × <sup>10</sup>−<sup>6</sup> <sup>s</sup>−<sup>1</sup> (488 K) and 42.2 kcal/mol, respectively [12].

**Scheme 3.** Strategy for the asymmetric synthesis of chiral triazasumanene **9** and **10**; Insert: X-ray crystal ORTEP drawing structure of **10**; all hydrogen atoms omitted for clarity: (**A**) top view (with thermal ellipsoids set at 50% probability); (**B**) side view with bowl depth. Reprinted from [12]. © 2012 Nature Publishing Group.

**Figure 11.** CD and ultraviolet/visible spectra of (**a**) compound **<sup>9</sup>** in CH2Cl2 solution (1.2 <sup>×</sup> <sup>10</sup>−<sup>5</sup> M). The blue line and red line are CD spectra of (*C*)-(−)-**9** and (*A*)-(+)-**9**, respectively; (**b**) Compound **10** in CH2Cl2 (5.0 <sup>×</sup> <sup>10</sup>−<sup>5</sup> M). The green line is an ultraviolet/visible spectrum. Reprinted from [12]. © <sup>2012</sup> Nature Publishing Group.

The above-discussed solution phase enantioselective synthesis of trimethylsumanene **4** and triazasumanene **9** and **10** represents a useful and versatile strategy for the construction of other homochiral curved π-electron systems from non-conjugated precursors. The chiral transmission from sp3 stereogenic chirality to bowl chirality creates a new dimension for chiral-controlled 3D carbon materials like fullerene and CNTs.

#### **7. Chiral Resolution of Buckybowls**

The optical resolution of racemic chiral buckybowls has also been accomplished using derivatization method [13,71,78–81]. Derivatization at the outer rim of the buckybowl results in a deeper bowl with high bowl inversion energy and makes it resolvable from its racemates using chiral HPLC [12,17,18]. The purity of enantio-enriched chiral buckybowls and its bowl chirality is mainly analyzed using CD spectroscopy, NMR, and chiral HPLC methods [82–87].

As shown above, **2** has less bowl inversion energy than **4**, and it undergoes much slower racemization at 0 ◦C (*t*1/2 = 2 h) [17]. Based on this, Sakurai et al. reported the first asymmetric synthesis of chiral **4** [17], and the enantiomeric excess (*ee*) of **4** is determined by measuring the 1H-NMR spectrum of **7**, which was derivatized from **4** using Mosher's acid chloride (Scheme 2) [17,18]. Upon introducing stereogenic centers at the *sp*<sup>3</sup> carbons at the benzylic positions, it became more stable and could be stored for a long time. The enantioselectivity of **6** was determined to be 89% *ee*, which matches the 1H-NMR analysis of chiral derivatized compound **4** (90% *ee*). The chiral (*A*)-**6** buckybowl was eluted first with a retention time (*t*R) of 38 min and another chiral buckybowl (*C*)-**6** was eluted later with a retention time of 42 min (Figure 12a). The separated enantiomers of buckybowl **6** were analyzed using CD spectroscopy, which showed the mirror image Cotton effect curves generated from its inherent bowl chirality (Figure 12b).

**Figure 12.** Synthesis of racemic (±)-**6** and (±)-**21** derivatives from racemic (±)-**4**. (**a**) Optical resolution of (±)-**6** by chiral HPLC (DAICEL CHIRALPAK IA, 2-propanol, retention time (*t*R); 38 min for (*A*)-**6**, 42 min for (*C*)-**6**); (**b**) CD spectra of each enantiomers **6** in CHCl3; (**c**) Optical resolution of (±)-**21** by chiral HPLC (DAICEL CHIRALPAK IA, hexane/2-propanol = 60/40, 9 ◦C, retention time (*t*R); 17 min for (*A*)-**21**, 18 min for (*C*)-**21**); (**d**) CD spectra of enantioenriched **21** in CH3CN at 27 ◦C. Blue line: CD spectra of (*A*)-**6** and (*A*)-**21**, respectively. Red line: CD spectra of (*C*)-**6** and (*C*)-**21**, respectively. Reprinted from [18]. © 2010 The Chemical Society of Japan.

Racemic (±)-**21** was prepared by aerobic oxidation of racemic (±)-**4** (Figure 12) [18]. The estimated bowl inversion energy of **21** was 23.5 kcal/mol, which corresponds to ca. 44 h half-life at 10 ◦C. Racemic (±)-**21** was optically resolved using a chiral HPLC (Figure 12c). The absolute configuration of each enantiomer was assigned based on the CD spectrum of the enantioenriched (*C*)-**21** prepared from (*C*)-**4**. The bowl chirality of the optically resolved enantioenriched buckybowls (*A*)- and (*C*)-**21** was analyzed using CD spectroscopy, which is shown in Figure 12d. In addition, the bowl inversion barrier of enantio-riched **21** was estimated to be 23.4 and 23.3 kcal/mol in CH3CN and CH2Cl2, respectively, by measuring the time-dependent decay of the intensity of CD spectra at 255 nm at 30 ◦C [18]. These results led to the elucidation of the substituent effect and the correlation between bowl structure and bowl inversion energy [19].

Azasumanene **10** had a deeper bowl depth (1.30 Å) than **2** (1.10 Å) and showed extremely stable bowl chirality (*t*1/2 = 54 billion years at 20 ◦C) because of its high bowl inversion energy (Δ*E* = 42.2 kcal/mol) [12]. Similarly, *C*<sup>3</sup> symmetric chiral **8** was prepared by a Pd-catalyzed cross-coupling reaction between chiral **9** and (*p*-trifluoromethyl)phenyl boronic acid (Figure 13) [88]. The chirality of the obtained **8** was confirmed by chiral HPLC at 25 ◦C using a Daicel Chiralpak® IA column (Figure 13a,b). The CD and UV spectra were measured in a CH2Cl2 solution of enantioenriched **8** derivatives (Figure 13c), which shows the CD signals of the mirror image, indicating that the compounds are of opposite bowl chirality.

**Figure 13.** Strategy for the asymmetric synthesis of chiral **8** from chiral **9**: (**a**) HPLC chart of (*C*)-(−)-**8**; *t*<sup>R</sup> = 5.31 min (UV) and 5.84 min (CD); (**b**) HPLC chart of (*A*)-(+)-**8**; *t*<sup>R</sup> = 8.21 min (UV) and 8.76 min (CD). HPLC analysis was performed at 25 ◦C on a Daicel Chiralpak® IA column with hexane/CH2Cl2 = 50/50. Flow rate: 1 mL/min, detector wavelength: UV, 254 nm; CD, 270 nm; (**c**) CD and UV spectra of compound **<sup>8</sup>** in CH2Cl2 solution (1.5 <sup>×</sup> <sup>10</sup>−<sup>5</sup> M). Blue and red lines: CD spectra of (*A*)-(+)-**<sup>8</sup>** and (*C*)-(−)-**8**, respectively. Green line: UV spectrum of **8**. Reprinted from [88]. © 2017 The Chemical Society of Japan.

Recently, Yang and co-workers prepared azonia[*6*]helicene tethered with supramolecular host *β*-cyclodextrin, and used a chirality sensing probe for underivatized amino acids in water [89–94]. Indeed, tethered azonia[*6*]helicene acts as a conformationally robust chiral auxiliary to improve the chiral recognition ability of native cyclodextrins. Scott and co-workers successfully synthesized the first corannulene-[*n*]helicenes hybrids **22**–**25** by combining two classical nonplanar conjugated systems: the chiral bowl-shaped π-system, corannulene, and the helically chiral helicene (Figure 14). These compounds show unique molecular dynamics in their enantiomerization processes, including inversion motions of both the bowl and the helix [95].

Helix inversion renders *P* and *M* isomers, while corannulene bowl inversion results in concave and convex isomers, so it is predicted to have four isomers (convex-*P*, concave-*P*, convex-*M*, and concave-*M*) in equilibrium. Among the different conformers of corannulene-[*n*]helicenes, the conformer with a terminal helicene ring facing the convex surface of the bowl is more stable than the terminal ring facing the concave bowl surface, as the two forms display different degrees of steric congestion. For **22** and **23**, the energy barriers for bowl-to-bowl inversions were calculated to be 10.6 kcal/mol and 10.1 kcal/mol, respectively, and the helix inversions were 20.9 kcal/mol and 34.6 kcal/mol, respectively.

The enantiomers of corannulene-[*n*]helicenes hybrid were successfully resolved using a chiral-stationary-phase HPLC. The kinetics of thermal racemization of obtained conformers with the *ee* of >99% was studied under different temperature, and the helix inversion barrier value of Δ*G*‡ = 33.5 kcal/mol obtained experimentally is in consensus with the calculated one (34.6 kcal/mol) (Figure 14b). This hybrid system indicates that the chirality mainly arises from the rigid [6]helicene unit, and the non-rigid corannulene unit undergoes a rapid bowl-to-bowl inversion under ambient conditions.