S S symmetry

Review Helicene-Based Chiral Auxiliaries andand ChirogenesisChirogenesis

Mohammed Hasan andID and Victor Victor Borovkov Borovkov * * ID

Department of Chemistry and Biotechnology, TallinnTallinn UniversityUniversity ofof Technology,Technology, Akadeemia Akadeemia tee tee 15, 15, 12618 Tallinn, Estonia;Estonia; mhasanfi[email protected]@gmail.com ** Correspondence:Correspondence: [email protected];[email protected]; Tel.:Tel.: +372-620-4382+372-620-4382

Received: 7 December 2017; Accepted: 26 December 2017; Published: December 29 December 201 2017

Abstract: Helicenes are unique helical chromophores possessing advanced and well-controlledwell-controlled spectral and chemical properties owing to their diverse functionalization and and defined defined structures. structures. SpecificSpecific modificationmodification of these molecules by introducing aromatic rings of differing nature and different functional groups results in special chiroptical properties, making them effective chiral auxiliaries andand supramolecular supramolecular chirogenic chirogenic hosts. hosts. This This review review aims toaims highlight to highlight these distinct these structural distinct featuresstructural of features helicenes; of helicenes; the different the syntheticdifferent synthetic and supramolecular and supram approachesolecular approach responsiblees responsible for their efficientfor their chiralityefficient chirality control; andcontrol; their and employment their employment in the chirogenic in the chirogenic systems, systems, which are which still not are fully still explored.not fully Itexplored. further coversIt further the limitation, covers the scope, limita andtion, future scope, prospects and future of helicene prospects chromophores of helicene in chiralchromophores chemistry. in chiral chemistry.

Keywords: helicene; chiral auxiliaries; supramolecular chirogenesis; chirality

1. Introduction Aromatic characteristicscharacteristics in in organic organic compounds compounds are veryare interestingvery interesting due to thedue resonance to the resonance electronic features,electronic stability, features, and stability, inter- and inter- intramolecular and intramolecularπ-π interactions π-π interactions along with along the specific with the geometric specific propertiesgeometric properties and reactivity, and makingreactivity, it anmaking important it an important topic for researchers. topic for researchers. Among the Among diverse the aromatic diverse compounds,aromatic compounds, there is athere class is of a the class molecules of the carryingmoleculesortho carrying-annulated ortho-annulated polyaromatic polyaromatic structures, classifiedstructures, as classified helicenes. as helicenes. In order toIn understandorder to understand their unique their structural unique struct features,ural features, helicenes helicenes should beshould compared be compared with the with conventional the conventional aromatic aromatic molecules molecules (Figure1 (Figure). 1).

Figure 1. Conventional aromatic compounds, 1–3, and helicene compounds, 4–6 (numbers in bracket represent ortho-fused-fused aromaticaromatic rings).rings).

Benzene 1, naphthalene 2, and phenanthrene 3 are spatially flat aromatic structures (Figure 1); Benzene 1, naphthalene 2, and phenanthrene 3 are spatially flat aromatic structures (Figure1); hence, they are not helicenes. As the number of ortho-fused aromatic rings is increased beyond three hence, they are not helicenes. As the number of ortho-fused aromatic rings is increased beyond three units, such as in 4–6 (Figure 1), the space constraint in the molecule is also enhanced, forcing it to units, such as in 4–6 (Figure1), the space constraint in the molecule is also enhanced, forcing it adopt a nonplanar helical arrangement. These types of aromatic structures are called helicenes. As a to adopt a nonplanar helical arrangement. These types of aromatic structures are called helicenes. consequence, the electron resonance ability is restricted throughout the molecule. Similar to As a consequence, the electron resonance ability is restricted throughout the molecule. Similar to conventional aromatics, helicenes can be functionalized by various synthetic protocols to further

Symmetry 2018,, 10,, 10;10; doi:doi:10.3390/sym1001001010.3390/sym10010010 www.mdpi.com/journal/symmetrywww.mdpi.com/journal/symmetry Symmetry 2018, 10, 10 2 of 48 conventional aromatics, helicenes can be functionalized by various synthetic protocols to further enhance their spectral and chemical properties. However, the diversity of helical aromatic structures makes helicenes into unique and advanced chromophoric systems with tunable electronic and steric properties for corresponding applications in all types of stereochemical processes, including chiral auxiliaries and supramolecular chirogenesis. It is of note that, whilst there is a great variety of aromatic structures used in different chiral fields [1], helicenes still lag behind, despite their attractive properties discussed below.

2. Overview of Latest Reviews Firstly, the existing reviews on helicenes from within the last five years should be briefly analyzed. Indeed, the chemistry of helicenes has existed for more than a century. However, this topic has been reviewed only recently to a rather limited extent [2–11]. Furthermore, these reviews mainly focused on the synthesis of helicenes and much less on their applications. One of the most comprehensive reviews was published in 2012 by Chen et al., describing helicene synthesis and applications [2]. In 2013, Gingras accumulated three sets of reviews targeting only carbohelicenes and covering the topics of its non-stereoselective [3] and stereoselective synthesis, chiral separation [4], and applications, along with the corresponding properties [5]. Yet, in 2014, three small review articles appeared on the topics of photochemical methods of helicene synthesis [6], helicene-based transition metal complexes [7], and helicene-like chiral auxiliaries [8]. Further, in 2015, Virieux [9] summarized the synthesis and application of helical phosphorus derivatives, where the helicene-based phosphorus ligands were also described. Thus, it is clear that—despite several consecutive reviews and monographs—this field is not fully covered, especially from the point of view of chiral applications. Further, the helicenes, being polyaromatic compounds, have been discussed in several chapters of a few books devoted to polyaromatic compounds and material chemistry [10]. Very recently, in 2017, a book on helicene chemistry [11] was published, covering most of the topic as it had appeared in previous reviews and presenting the progress up until the period of 2015. Despite these recent efforts described above, a general tutorial and critical summary devoted to the design and tuning of helicene structures for suitable general and specific applications in the areas of chiral auxiliaries and chirogenesis is not yet available. Hence, the present review aims to fill in this gap, with a specific focus on the potential applicability and usefulness of helicene chemistry in these chirality fields—including the latest updates.

3. Classification and Nomenclature

3.1. Structural Diversity In order to understand the structure and type of helicene molecules, a brief introduction into the classification and nomenclature should be made. As a part of classical organic chemistry, helicenes can be structurally divided into two major groups: carbohelicenes and heterohelicenes.

3.1.1. Carbohelicenes Carbohelicenes are all benzenoid (aromatic) ortho-fused systems and named as [n]helicenes, where n represents the number of rings forming a helix in the ortho-fused fashion. Thus, the structures 4 [12], 5 [13,14], and 6 [15,16], are [4]helicene, [5]helicene, and [6]helicene, respectively (Figure1). However, any fused ring which is not present in the ortho-fused manner is not included in the n counting. For example, structures 7 [17], 8 [18], and 9 [19] are all [5]helicenes, but not [6]helicenes, despite the presence of six aromatic rings in total (Figure2). The functionalized helicenes such as 10 [20], 11 [21], and 12 [22] (Figure2) which have a heteroatom as a substituent on the aromatic ring, as in the case of amino, hydroxyl (phenolic or alcoholic), thiol, or phosphorus-containing groups, are still carbohelicenes but not heterohelicenes. In order to specify the position of functional group(s), a numbering system is used, as shown in the structure 10. The numbering starts from the Symmetry 2018, 10, 10 3 of 48 innermost position at one end and goes to another end via the outer helical core in such a way that the functional group has the minimal number. Secondly, only unfused carbons (with hydrogen or otherSymmetry groups 2018 as, substituents)10, 10 are counted sequentially (shown in blue), whereas fused carbon3 of 48 atoms (of the helicene core) have the previous number with the corresponding a, b, c suffixes based on the sequencecore) orderhave the of previous fused 1, 2,number 3 atoms, with and the socorresponding on (shown ina, b, red). c suffixes Thus, based the structure on the sequence10 can order be named as 2-acetoxy[5]helicene.of fused 1, 2, 3 atoms, and so on (shown in red). Thus, the structure 10 can be named as 2- Inacetoxy[5]helicene. the case of nonsymmetric heterohelicene, the numbering should be started from the peripheral ring whichIn willthe case give of the nonsymmetric least number heterohelicene, to the heteroatomic the numbering ring core. should In the be case started of more from thanthe one peripheral ring which will give the least number to the heteroatomic ring core. In the case of more substituent, a general nomenclature rule of numbering should be applied. Yet, in both the cases than one substituent, a general nomenclature rule of numbering should be applied. Yet, in both the mentioned,cases mentioned, one should one always should follow always the follow sequential the sequential numbering numbering of the of helicene the helicene core (startingcore (starting from one innermostfrom one atom innermost to another atom innermost to another atominnerm ofost the atom two of peripheral the two peripheral rings). rings).

FigureFigure 2. Examples2. Examples of of carbohelicenes: carbohelicenes: [5]carbohelicenes 7–79 –9withwith additional additional fused fused rings rings and and functionalizedfunctionalized [5]- 10[5]-,10 [6]-, [6]-11,11 and, and [7]- [7]-1212carbohelicenes. carbohelicenes.

3.1.2. Heterohelicenes 3.1.2. Heterohelicenes Another class of helicenes is the heterohelicenes, in which one or more benzenoid ring is Anothersubstituted class with of a helicenesheteroatomic is thering heterohelicenes,(Figure 3). Heterohelicene in whichs oneare generally or more based benzenoid on five- ring is substitutedmembered with rings a heteroatomic such as thiophene, ring (Figure pyrrole,3). furan, Heterohelicenes etc., and six-membered are generally rings based mostly on five-membered containing ringspyridine. such as Additionally, thiophene, pyrrole,they can be furan, fused etc., and andfunctionalized. six-membered rings mostly containing pyridine. Additionally,The corresponding they can be fused heteroatom and functionalized. must be a part of the ring present in the fused ortho fashion but Thenot as corresponding the substituent heteroatomeither in a functional must be group a part or of in the a heteroatomic ring present ring. in the In the fused latter,ortho whilstfashion the but overall molecule is heterocyclic, the helicene core is not. Further, depending on the heteroatom not as the substituent either in a functional group or in a heteroatomic ring. In the latter, whilst nature, the helicene structures are named aza[5]helicenes (13 [23], 14 [24]), oxa[5]helicenes (15 [25]), the overall molecule is heterocyclic, the helicene core is not. Further, depending on the heteroatom and thia[7]helicenes (16 [26]). If there is more than one heteroaromatic ring or heteroatom, the nature,helicene the helicene names are structures simplified are as namedhetero[n]helicenes aza[5]helicenes, [n]heterohelicenes, (13 [23], 14 [ 24or ]),simply oxa[5]helicenes [n]helicenes. (For15 [25]), and thia[7]helicenestwo or three similar (16 [ 26heteroatomic]). If there isrings, more the than prefix onees heteroaromatic “di”, “tri”, etc., ringare oradded heteroatom, with or without the helicene namesindicating are simplified the exact as hetero[n]helicenes,position. For example, [n]heterohelicenes, the structure 17 or[27] simply is called [n]helicenes. 7,8-dioxa[6]helicene For two oror three similarsimply heteroatomic dioxa[6]helicene. rings, the Heterohe prefixeslicenes “di”, containing “tri”, etc., phosphorus are added 18 with [28], or silicon without 19 indicating[29], and boron the exact position.20 [30] For atoms example, are relatively the structure rare and17 [ 27their] is calledchiral properties 7,8-dioxa[6]helicene have not been or simplywell studied dioxa[6]helicene. so far; Heterohelicenestherefore, they containing are excluded phosphorus from this review.18 [28], silicon 19 [29], and boron 20 [30] atoms are relatively rare and their chiral properties have not been well studied so far; therefore, they are excluded from this review.

Symmetry 2018, 10, 10 4 of 48 Symmetry 2018, 10, 10 4 of 48

Symmetry 2018, 10, 10 4 of 48

Figure 3. Examples of heterohelicenes, 13–20. Figure 3. Examples of heterohelicenes, 13–20.

3.1.3. Charged Helicenes Figure 3. Examples of heterohelicenes, 13–20. 3.1.3. Charged Helicenes Helicenes can also be categorized into neutral and charged helicene molecules. Most of the above Helicenes3.1.3.examples Charged are can neutral Helicenes also behelicene categorized molecules, into where neutral the and char chargedge of the helicenearomatic moiety molecules. is zero. Most However, of the if above examplesthereHelicenes areis a neutralcharge can on helicene also the be helicene categorized molecules, structure, into where neutral a coun the teran charged ion charged should of the helicene be aromatic presente molecules. moietyd to balance Most is zero. of the the However,overall above if thereexamplescharge, is a charge hence are onneutral resulting the helicene in different molecules, structure, properties where a counter theand char applications. ionge shouldof the aromatic In be such presented moietyhelicenes, is to zero. balanceexchanging However, the the overall if charge,therecounter hence is aion charge resulting can easily on the in enhance differenthelicene a structure,number properties of a the coun and coterrresponding applications. ion should derivatives, be Inpresente such controllingd helicenes, to balance the exchanging the solubility overall the and pH effect. This counter ion exchange can sometimes offer a new approach towards optical countercharge, ion canhence easily resulting enhance in different a number properties of the correspondingand applications. derivatives, In such helicenes, controlling exchanging the solubility the resolution by changing an achiral counter ion to a chiral one in the case of thermodynamically stable and pHcounter effect. ion can This easily counter enhance ion a exchangenumber of canthe co sometimesrresponding offer derivatives, a new controlling approach the towards solubility optical andstructures. pH effect. For example,This counter quarternized ion exchange azahelicene can sometimes 21 [31] and offer cationic a new helicene approach 22 [32] towards stabilized optical by resolution by changing an achiral counter ion to a chiral one in the case of thermodynamically stable resolutionelectron resonance/conjugation by changing an achiral represen countert typical ion to chargeda chiral helicenesone in the (Figure case of 4). thermodynamically stable structures. For example, quarternized azahelicene 21 [31] and cationic helicene 22 [32] stabilized by structures. For example, quarternized azahelicene 21 [31] and cationic helicene 22 [32] stabilized by electronelectron resonance/conjugation resonance/conjugation represent represent typical typical charged charged helicenes helicenes (Figure (Figure 4). 4).

Figure 4. Charged helicenes, 21–22.

3.1.4. Special Structural Type of Helicene-Like Molecules FigureFigure 4. 4.Charged Charged helicenes, 2121–22–22. . Besides the traditional definition of helicene molecules, there are several special cases which 3.1.4. Special Structural Type of Helicene-Like Molecules 3.1.4.belong Special to Structuralthis structural Type category of Helicene-Like but are not Moleculesassociated with the above-described major groups of carbo-Besides and heterohelicenes; the traditional thesedefinition are discussed of helicene below. molecules, Naphthalene there are 2 andseveral phenanthrene special cases 3 are which the Besidesbelongsimplest to ortho the this traditional-fused structural flat moleculescategory definition but without ofare helicene not any a ssociatedsteric molecules, cons withtraint the thereand, above-described hence, are several are not specialhelicenes,major groups cases whilst of which belongcarbo-four to fused this andstructural aromaticheterohelicenes; rings category induce these but area certain are discussed not steric associated below. hindrance Naphthalene with at the innerm above-described 2 andost phenanthrene peripheral major hydrogen 3 are groups the of carbo-simplest and heterohelicenes; ortho-fused flat molecules these are without discussed any steric below. cons Naphthalenetraint and, hence,2 and are phenanthrenenot helicenes, whilst3 are the simplestfour orthofused-fused aromatic flat rings molecules induce without a certain any steric steric hindrance constraint at the and, innerm hence,ost areperipheral not helicenes, hydrogen whilst four fused aromatic rings induce a certain steric hindrance at the innermost peripheral hydrogen Symmetry 2018, 10, 10 5 of 48

Symmetry 2018, 10, 10 5 of 48 atoms, setting up the first member of helicene family. Thus, in [n]helicenes, n should be >3 to be classifiedatoms, as a helicenesetting up molecule. the first member However, of helicene there arefami somely. Thus, exceptions in [n]helicenes, to this n general should rule.be >3 Interestingly,to be phenanthroline-classified N,Nas a-dioxide helicene 23molecule.[33] (Figure However,5) is alsothere classified are some as exceptions a helicene to in this the general literature, rule. despite the fact thatInterestingly, n = 3. This phenanthroline- is due to theN,N fact-dioxide that the 23 N,N[33] (Figure-dioxide 5) functionalitiesis also classified at as the a helicene peri positions in the in the literature, despite the fact that n = 3. This is due to the fact that the N,N-dioxide functionalities at the bay area of the phenanthroline are able to introduce the corresponding spatial constraint to force the peri positions in the bay area of the phenanthroline are able to introduce the corresponding spatial moleculeconstraint to adopt to aforce configurationally the molecule to adopt stable a configurationally helical conformation. stable helical conformation.

Figure 5. Special structural types of helicene 23 and helicene-like molecules 24–25. 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] Besidesand 25 the [35], well-defined called helicene-like helicene molecules molecules, or helicen thereoids also(Figure exist 5). Helicenoids helical structures, usually contain such asat 24 [34] least one saturated atom as a part of the ring system in the helicene-type core system. Thus, the and 25 [35], called helicene-like molecules or helicenoids (Figure5). Helicenoids usually contain at saturated ring is not able to adopt a flat structure, resulting in the enhancement of helicity. For least oneexample, saturated a series atom of as1,1′ a-Bi-2-naphthol part of the (BINOL)-based ring system inhelical the helicene-typesystems, sometimes core referred system. to Thus,as the saturatedoxahelicenoids, ring is not able have to been adopt reported a flat structure,so far as config resultingurationally in the stable enhancement structures [34,35]. of helicity. Other Fortypes example, a seriesof saturated 1,10-Bi-2-naphthol hydrocarbon- (BINOL)-basedcontaining helicenoids, helical which systems, are actual sometimesly dihydrohelicenes, referred to are as oxahelicenoids,also well have beendocumented reported in soliterature far as as configurationally precursors for helicene stable synthesis. structures [34,35]. Other types of saturated hydrocarbon-containing helicenoids, which are actually dihydrohelicenes, are also well documented 3.2. Spatial Diversity in literature as precursors for helicene synthesis. Besides the structural diversity described above, helicenes can also be categorized, based on their 3.2. Spatialstereochemistry, Diversity 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 Besides3.2.1), thechiral structural (enantiomerically diversity stable described structures), above, and helicenes meso helicenes can also (helical be categorized, structure with based some on their stereochemistry,symmetry intoelements). four different This categorization categories: is highly achiral important (flat structures), for their applications stereodynamically in chiral auxiliaries labile (when P and M spatialand for chirogenic conformations systems. are in fast equilibrium; for the P and M definitions, see Section 3.2.1), chiral (enantiomerically3.2.1. Chiral (Configurationally stable structures), Stable) Helicenes and meso helicenes (helical structure with some symmetry elements). This categorization is highly important for their applications in chiral auxiliaries and for In order to understand the helicene spatial structures and this classification, the term “in-plane chirogenic systems. 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- 3.2.1. Chiral (Configurationally Stable) Helicenes plane angles of the contributing rings becomes 360° or more, the helicene is forced to adopt a helically In orderchiral structure to understand caused by the the helicene corresponding spatial ster structuresic clashes andbetween this the classification, terminal/peripheral the term rings. “in-plane turn angle”Conventional needs to six-membered be introduced. (hexagon) Due to aromatic the ortho ringsfusion such mode,as benzene each and aromatic pyridine ringhave contributesan in-plane to the turn angle of 60° [36]. However, in the case of five-membered heteroaromatic (pentagon) rings, the overall helicityvalue is considerably of the molecule smaller via at 45° an (thiophene), in-plane turn 35° (pyrrole), angle (Figure and 32°6 a).(furan) When [36] thedue sumto the ofdifferent the in-plane ◦ angles ofgeometric the contributing properties of rings aromatic becomes rings as 360 a resultor more,of the variable the helicene atomic issizes forced of heteroatoms to adopt and a helically chiral structurebond length caused of C–X by thebond corresponding (X = heteroatom steric S, clashesN, O in between the five-member the terminal/peripheral aromatic rings, rings. Conventionalcorrespondingly). six-membered Therefore, (hexagon) the helicenes aromatic with at rings least such one five-membered as benzene and heteroaromatic pyridine have ring need an in-plane turn anglen > of6 60to ◦become[36]. However, intrinsically in thechiral, case whereas of five-membered for the helicenes heteroaromatic containing all (pentagon) six-membered rings, the carbo/hetero aromatic rings, n = 6 is sufficient to make them helically chiral. 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. Symmetry 2018, 10, 10 6 of 48 Symmetry 2018, 10, 10 6 of 48

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

In general, a chiral helicene molecule exists in two enantiomeric forms. The right-handed helical Instructure general, (moving a chiral from helicene up to down) molecule is assigned exists in the two name enantiomeric (P)-enantiomer, forms. whereas The right-handed the left-handed helical structurehelical (moving structure from (moving up tofrom down) up to isdown) assigned is designated the name the (PM)-enantiomer,)-enantiomer, according whereas to the the left-handed Cahn– helicalIngold–Prelog structure (moving rule (Figure from 6b). up This to down) type of is designatedhelicene tends the to (M give)-enantiomer, configurationally according stable to the Cahn–Ingold–Prelogenantiomers as therule racemization (Figure6 procb).ess This is typeexpected of heliceneto go through tends the to highly give configurationallyenergetic, strained C stables- enantiomerssymmetrical as thetransition racemization state [37]. process Along with is expected this thermodynamic to go through stability the of highly enantiomers, energetic, helicenes strained also exhibit notable enhanced (chir)optical properties, making them suitable candidates for chiral Cs-symmetrical transition state [37]. Along with this thermodynamic stability of enantiomers, helicenes auxiliaries and other chirogenic processes. Interestingly, in general, (P)-carbohelicenes are observed also exhibit notable enhanced (chir)optical properties, making them suitable candidates for chiral as dextrorotatory, whereas (M)-enantiomers display a levorotatory nature [38]. auxiliaries and other chirogenic processes. Interestingly, in general, (P)-carbohelicenes are observed as dextrorotatory,3.2.2. Achiral whereas Helicenes (M )-enantiomers display a levorotatory nature [38].

3.2.2. AchiralAnother Helicenes 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) Anotherheteroaromatic type ofring, helicene as in [4]heterohelicenes. is the achiral flat molecules;Whilst these for structures example, areortho less-condensed interesting polyaromaticfrom the moleculesviewpoint consisting of chirality, of they four possess rings enhanced with at conjug leastation, one electron ring being transfer, a five-memberedand emission properties, (pentagon) heteroaromaticmaking them ring, suitable as incandidates [4]heterohelicenes. for various material Whilst chemistry these structures applications. are less interesting from the viewpoint of chirality, they possess enhanced conjugation, electron transfer, and emission properties, 3.2.3. Stereodynamic Helicenes making them suitable candidates for various material chemistry applications. Holding an intermediate position between the chiral and achiral helicenes are the stereodynamic 3.2.3.helicene Stereodynamic structures. Helicenes 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 Holding an intermediate position between the chiral and achiral helicenes are the stereodynamic solution, owing to the low (P)–(M) interconversion energy barrier. These include helicenes consisting heliceneof five structures. benzenoid The (hexagon) geometry rings of these or molecules[6]heterohelicenes is close with to flat, two whilst five-membered the van der (pentagon) Waals radii of the innermostheteroaromatic hydrogens rings. However, touch each in a other, solid makingstate, these the structures structure are stereodynamic able to adopt anda chiral nonresolvable helical in solution,conformation. owing The to dioxa[6]helicene the low (P)–( 16M [27]) interconversion is a typical example energy of such barrier. a system. These include helicenes consistingStereodynamic of five benzenoid helicenes (hexagon) are also rings highly or fluorescent [6]heterohelicenes in nature withdue to two the five-membered extended conjugation, (pentagon) heteroaromaticwhilst lacking rings. any intrinsic However, chiroptical in a solid properties state, these in solution. structures Yet, applying are able host–guest to adopt a chemistry chiral helical conformation.with suitable The enantiopure dioxa[6]helicene guests,16 the[27 correspondi] is a typicalng examplechiroptical of properties such a system. can be induced and Stereodynamiccontrolled in this helicenestype of helicene. are also Additionally, highly fluorescent the stereodynamic in nature helicenes due to the can extended be made helically conjugation, chiral by introducing a bulky substitution at the innermost (C1) carbon atom. Computational analysis whilst lacking any intrinsic chiroptical properties in solution. Yet, applying host–guest chemistry with confirmed that attachment of just one methyl group at the innermost position results in the same suitable enantiopure guests, the corresponding chiroptical properties can be induced and controlled steric strength as introduction of one additional ortho-fused benzene ring. Thus, [5]helicene with a in thismethyl type group of helicene. at the innermost Additionally, position the has stereodynamic a structure more helicenes helical canthan bethat made of [6]helicene, helically thus chiral by introducingincreasing a bulky the racemization substitution barrier at the for innermost the former (C1) [37]. carbon atom. Computational analysis confirmed that attachment of just one methyl group at the innermost position results in the same steric strength as introduction3.2.4. Meso Helicenes of one additional ortho-fused benzene ring. Thus, [5]helicene with a methyl group at the innermostMeso helicenes position are hasachiral, a structure yet need to more be classified helicalthan separately. that of Two [6]helicene, helicene fragments thus increasing in one the racemizationmolecule, barrierwith the for presence the former of [a37 plane]. of symmetry, produce an achiral meso helicene. Each equivalent helical part of this molecule possesses the opposite helical sense, whilst the whole 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. Symmetry 2018, 10, 10 7 of 48

Each equivalent helical part of this molecule possesses the opposite helical sense, whilst the whole moleculeSymmetry is symmetrical. 2018, 10, 10 Potentially, it can be suitably desymmetrized by a covalent7 of 48 bond or supramolecular interaction, making it chiroptically active and, hence, usable in various chirogenic molecule is symmetrical. Potentially, it can be suitably desymmetrized by a covalent bond or processes. However, this area has not been well investigated yet, as selective modification of only supramolecular interaction, making it chiroptically active and, hence, usable in various chirogenic one heliceneprocesses. moiety However, out of this two area is has an not arduous been well task; investigated this is yet, due as toselective the factmodification that both of only the helicene parts are chemicallyone helicene moiety equivalent. out of two For is example,an arduous carbocyclictask; this is due helicene to the fact26 that[39 both] and the helicene heterocyclic parts helicene 27–28 [40]are are chemicallymeso double equivalent. helicenes For example, (Figure carbocyclic7). It should helicene be noted 26 [39] thatand heterocyclic the double helicene helicenes 27–28 have three [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 stereoisomers, out of which two are optically active ((P,P) and (M,M)) and one is optically inactive ((P,M) or (((M,PP,M)),) or defined (M,P)), defined as a meso as a mesostructure. structure.

Figure 7. Examples of meso double helicenes 26–28. Figure 7. Examples of meso double helicenes 26–28. 4. General Description and Main Synthetic Approaches toward Helicene-Based Chirogenic Systems 4. General DescriptionThe early pioneering and Main work Synthetic on helicene Approaches synthesis, resolution, toward and Helicene-Based chiroptical properties Chirogenic has been Systems performed by Newman [15,16,41], Wynberg [36,38], Martin [42], and Katz [26]. In general, classical The early pioneering work on helicene synthesis, resolution, and chiroptical properties has methods of helicene synthesis include the following approaches: oxidative photocyclization, Diels– been performedAlder reactions, by Newman and various [15 aromatic,16,41] ,andWynberg metal-catalyzed [36,38 coupling], Martin reactions [42], [2–6,11]. and Katz The synthesis [26]. In general, classical methodsof helicenes of is helicene always a challenging synthesis includetask for organic the following chemistry due approaches: to the steric oxidativefactors involved photocyclization, and Diels–Alderdifficulty reactions, in controlling and the various regioselectivity aromatic of reactions. and metal-catalyzed The same factors are couplingalso responsible reactions for the [2–6,11]. unique reactivity of the helicene skeleton. The synthesis of helicenes is always a challenging task for organic chemistry due to the steric factors The current advances in synthetic chemistry, resolution, and chiral separation are essentially involved andhelpful difficulty in designing in and controlling obtaining novel the regioselectivityenantiopure helicene of molecules reactions. in sufficient The same quantities factors to are also responsiblebe forused the for uniquevarious applications. reactivity As of theBINOL, helicene (2,2′-bis(diphenylphosphino)-1,1 skeleton. ′-binaphthyl) (BINAP), The currentand related advances biaryl systems in synthetic have been chemistry, successfully resolution, applied as andligands, chiral catalysts, separation and hosts are in essentially stereodiscriminating processes [43–45], it is theoretically possible to thoroughly design helicene- helpful in designing and obtaining novel enantiopure helicene molecules in sufficient quantities to based helical systems possessing advantageous chiral properties. Progress in this area is highlighted 0 0 be used forbelow various with several applications. selected examples. As BINOL, (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) (BINAP), and related biarylLet us look systems closely haveat a general been structure successfully of (M)-[6]helicene applied 6 as (Figure ligands, 8a), where catalysts, the benzene and hosts in stereodiscriminatingrings at the beginning processes and [ 43at the–45 end], it of is the theoretically helical arrangement possible are called to thoroughly the terminal design or peripheral helicene-based rings. It can be clearly seen that the helix experiences steric clashes towards the inner sides (interior), helical systems possessing advantageous chiral properties. Progress in this area is highlighted below called the helicene’s inner core. This structural organization results in a helical chiral cavity. The with severalrestricted selected space examples. available between and around the two peripheral rings can be explored effectively Let usfor look various closely chiral at discriminating a general structure processes. ofIn genera (M)-[6]helicenel, the introduction6 (Figure of suitable8a), wherefunctional the groups benzene rings at the beginningat the peripheral and at therings end can act of as the a binding helical site arrangement to hold the reactant are called or guest the molecules terminal to facilitate or peripheral the rings. enantioselectivity, where the chiral cavity space of the helicene is able to influence the corresponding It can be clearly seen that the helix experiences steric clashes towards the inner sides (interior), called (diastereomeric) transition state and/or complexation mode. In contrast, the opposite outer skeleton the helicene’sof the inner helicene, core. termed This as structural the helicene organization outer core (exterior), results can in abe helical functionalized chiral cavity.and used The to restricted space availablecovalently between link these and molecules around on the surfaces two and peripheral for other applications. rings can be explored effectively for various chiral discriminatingThe tailor-made processes. design of In helicenes general, for thea suitable introduction application ofcan suitable be of two functionaltypes; first, where groups at the the functionalization at one peripheral ring is sufficient (monodentate), and second, where peripheral rings can act as a binding site to hold the reactant or guest molecules to facilitate the functionalization on both the terminal rings is required (bidentate) (Figure 8b). The bidentate enantioselectivity,helicenes can where be C2 the-symmetric chiral (R cavity = R’) or space nonsymmetric of the helicene (R ≠ R’) molecules. is able to In influence accordance the with corresponding the (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) (Figure8b). The bidentate helicenes can be C2-symmetric (R = R’) or nonsymmetric (R 6= R’) molecules. In accordance with the structural Symmetry 2018, 10, 10 8 of 48

Symmetry 2018, 10, 10 8 of 48 featuresstructural and substituent features and patterns substituent of helicenes, patterns of their helicenes, efficiency their inefficiency chirogenic in chirogenic processes processes is observed, is as demonstratedobserved, as throughout demonstrated this throughout review. this review. Symmetry 2018, 10, 10 8 of 48

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) Figure 8. (a) General explanation of terms used for helicene structures and chiral cavity (shaded representative [6]- and [7]helicenes (R = R’ or R ≠ R’) with mono- or di-functionalized peripheral rings. area); (b) representative [6]- and [7]helicenes (R = R’ or R 6= R’) with mono- or di-functionalized peripheralHowever, rings. since the majority of recently published reviews [2–6] have focused on helicene syntheticFigure chemistry, 8. (a) General there explanation is no need of terms to describe used for helicenethis topic structures here in and detail. chiral Alternatively,cavity (shaded area); this (reviewb) However,addressesrepresentative the since structural the [6]- majorityand [7]helicenesdesign of and recently (R stereochemical= R’ or published R ≠ R’) with aspects reviews mono- or of [di-functionalized 2helicene–6] have chromophores focused peripheral on helicene rings. suitable synthetic for chemistry,various there applications is no need in chiral to describe processes, this whilst topic heresynthesis in detail. of these Alternatively, molecules will this only review be highlighted addresses the However, since the majority of recently published reviews [2–6] have focused on helicene structuralin brief design upon andnecessity stereochemical to emphasize aspects their spatial of helicene and chiral chromophores properties. suitable for various applications synthetic chemistry, there is no need to describe this topic here in detail. Alternatively, this review in chiral processes, whilst synthesis of these molecules will only be highlighted in brief upon necessity 5.addresses Helicenes the as structural Chiral Auxiliary/Reagent design and stereochemical or Additive aspects of helicene chromophores suitable for to emphasizevarious applications their spatial in andchiral chiral processes, properties. whilst synthesis of these molecules will only be highlighted Due to the difficulties associated with the synthesis of helicenes and obtaining the corresponding in brief upon necessity to emphasize their spatial and chiral properties. 5. Helicenesenantiopure as Chiral forms Auxiliary/Reagentin sufficient amounts, or their Additive application as a chiral auxiliary in stoichiometric reactions5. Helicenes is limited. as Chiral However, Auxiliary/Reagent one of the firstor Additive results on the use of helicenes as chiral auxiliaries in Duefew todiastereoselective the difficulties associatedreactions was with reported the synthesis in 1985–1987 of helicenes by Martin and obtaining et al. with the racemic corresponding 2- enantiopuresubstituted-[7]heliceneDue formsto the difficulties in sufficient [46–50]. associated amounts,Hence, with racemic the their synt 29 application washesis employed of helicenes as as a andan chiral inbuilt obtaining auxiliary chiral the auxiliary corresponding in stoichiometric for the reactionsdiastereoselectiveenantiopure is limited. forms However,reaction in sufficient of onethe amounts, ofcarbonyl the firsttheir group results appl ofication α on-keto the as esters usea chiral ofupon helicenesauxiliary reduction in as stoichiometric chiralwith NaBH auxiliaries4, in fewyieldingreactions diastereoselective 30 is (99%limited. yield; However, 100% reactions de) one [46], of was and the onreportedfirst the results nucleophilic in on 1985–1987 the additionuse of helicenes by of Grignard Martin as chiral et reagent al. auxiliaries withto give racemic 31in 2-substituted-[7]helicene(95%few diastereoselectiveyield; 100% de) [47] [46reactions (Scheme–50]. Hence, 1).was reported racemic in 291985–1987was employed by Martin as anet al. inbuilt with chiralracemic auxiliary 2- substituted-[7]helicene [46–50]. Hence, racemic 29 was employed as an inbuilt chiral auxiliary for the for the diastereoselective reaction of the carbonyl group of α-keto esters upon reduction with NaBH4, diastereoselective reaction of the carbonyl group of α-keto esters upon reduction with NaBH4, yieldingyielding30 (99% 30 (99% yield; yield; 100% 100%de) de)[46 [46],], and and on onthe the nucleophilicnucleophilic addition addition of ofGrignard Grignard reagent reagent to give to give31 31 (95%(95% yield; yield; 100% 100%de)[ de47) ][47] (Scheme (Scheme1). 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 Scheme 1. Diastereoselective reaction using racemic [7]helicene 29 as a chiral auxiliary. 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

Symmetry 2018, 10, 10 9 of 48

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-attachedSymmetrySymmetry 2018, 10 2018, 10, 10 , 10 unsaturated ester 32 was also utilized for the highly9 of diastereoselective 48 9 of 48 ene reactionup. withSimilarly,up. Similarly, cyclohexene [7]helicene-attached [7]helicene-attached33 in the unsaturated presenceunsaturated ofesterester SnCl 3232 4was towas also afford also utilized utilized34 withfor thefor high highlythe yield highly (86%) and diastereoselective ene reaction with cyclohexene 33 in the presence of SnCl4 to afford 34 with high 100% de [48diastereoselective] (Scheme2). ene reaction with cyclohexene 33 in the presence of SnCl4 to afford 34 with high yield (86%) and 100% de [48] (Scheme 2). yield (86%) and 100% de [48] (Scheme 2).

Scheme 2. Diastereoselective ene reaction using racemic [7]helicene 32 as a chiral auxiliary. 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 aScheme chiral auxiliary 2. Diastereoselective resulted in 37 enewith reaction 32% yield using with racemic 100% de [7]helicene [49] (Scheme 32 as3). a chiral auxiliary. Further, hydroxyamination of E-stilbene 35 under the Sharpless condition by using helicene 36 as Further, hydroxyamination of E-stilbene 35 under the Sharpless condition by using helicene 36 a chiral auxiliaryas a chiral resulted auxiliary inresulted37 with in 37 32% with yield32% yield with with 100% 100%de de [[49]49] (Scheme (Scheme 3).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 Scheme 3.SchemeDiastereoselectiveoxidant 3. to Diastereoselective give enantiopure hydroxyamination epoxides hydroxyamination 40 (92%, 99% ofof ee st stilbene)ilbene and 41 reaction (84%, reaction 97% using ee), using respectivelyracemic racemic [7]helicene [50] (Scheme [7]helicene 33 as a 33 as a chiral4). The auxiliary. mechanism includes the initial reaction between enantiopure 2-cyano-[7]helicene 37 and H2O2 chiral auxiliary.to generate in situ the corresponding chiral hydroperoxyimine, which serves as a chiral oxidizing Anotherreagent forexample the subsequent is based epoxidation on enantioenriched of alkenes 35 and 2-cyano-[7]helicene 39, whilst itself converting 38 employed finally to as a [7]helicene-2-carboxamide 42. stoichiometric chiral additive (reagent) for the epoxidation of alkenes 35 and 39 using H2O2 as an Another exampleThese isexamples based (Schemes on enantioenriched 1–4) [46–50] are the first 2-cyano-[7]helicene cases of helicenes being used38 employedas chiral auxiliaries as a stoichiometric oxidant to give enantiopure epoxides 40 (92%, 99% ee) and 41 (84%, 97% ee), respectively [50] (Scheme resulting in a high asymmetric conversion (de or ee), yet noncatalytic in nature. These excellent results chiral additive (reagent) for the epoxidation of alkenes 35 and 39 using H2O2 as an oxidant to 4). Thewere mechanism due to the includes judicious theselection initial of reaction[7]helicene between with corresponding enantiopure functionalization 2-cyano-[7]helicene at the 2-position 37 and H2O2 give enantiopureto generate(monodentate) epoxides in situ (refer,the 40corresponding Figure(92%, 8), which 99% chirallocatesee) insidehydroperoxyimine, and th41e helical(84%, chiral 97% cavitywhich eewith serves), sufficient respectively as a accessibilitychiral oxidizing [50 ] (Scheme 4). The mechanismreagentto the includesfor reactants. the subsequent Besides the initial this, epoxidation a geometric reaction feature of between alkenes of [7]helicenes 35 enantiopure and is that 39 ,the whilst two peripheral 2-cyano-[7]helicene itself converting rings are located finally 37 toand H2O2 to generate[7]helicene-2-carboxamide in situone above the another, corresponding hence 42 inducing. chiralsteric hindrance hydroperoxyimine, to one of the reacting prochiral which faces serves and generating as a chiral oxidizing Thesehigh selectivity examples via (Schemes the stereospecific 1–4) [46–50] approach. are the first cases of helicenes being used as chiral auxiliaries reagent forresulting the subsequent inIt ais highof note asymmetric that epoxidationmost of conversionthe helicene-based of (de alkenes or cataee), lyticyet35 researchnoncatalyticand is39 focused ,in whilst nature. on the Theseuse itself of [6]heliceneexcellent converting results finally to and substituted [5]helicene-based systems. In cases where functionalization at both the rings is [7]helicene-2-carboxamidewere due to the judicious42. selection of [7]helicene with corresponding functionalization at the 2-position needed, substituted [5]helicenes and [6]helicenes are more suitable due to possibility of the These(monodentate) examplesgeometrical (refer, (Schemes accessibility Figure1 of8),– these4 which)[ groups46 locates–50 (refer,] inside are Figu the reth 8b).e helical first These caseschiral groups cavity are of located helicenes with onsufficient the same being accessibility side; used as chiral auxiliariesto resultingthe reactants. inBesides ahigh this, a geometric asymmetric feature of conversion [7]helicenes is (thatde theor twoee ),peripheral yet noncatalytic rings are located in nature. one above another, hence inducing steric hindrance to one of the reacting prochiral faces and generating These excellenthigh selectivity results via the were stereospecific due to approach. the judicious selection of [7]helicene with corresponding functionalizationIt is atof note the 2-positionthat most of the (monodentate) helicene-based (refer,catalytic Figure research8), is which focused locates on the use inside of [6]helicene the helical chiral cavity withand sufficient substituted accessibility [5]helicene-based to the systems. reactants. In cases Besides where this,function a geometricalization at featureboth the ofrings [7]helicenes is is that the twoneeded, peripheral substituted rings [5]helicenes are located and one [6]helicenes above another, are more hence suitable inducing due to stericpossibility hindrance of the to one of geometrical accessibility of these groups (refer, Figure 8b). These groups are located on the same side; 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, Figure8b). These groups are located on the same side; hence, they Symmetry 2018, 10, 10 10 of 48

Symmetry 2018, 10, 10 10 of 48 are capable of coordinating or bonding together with the reactive partners. However, this situation is difficulthence, tothey obtain are capable in [7]helicenes, of coordinating as sevenor bonding benzenoid together rings with the give reactive the in-plane partners. turn However, angle this of 420◦ (7 × 60situation◦), forcing is difficult the functional to obtain in groups [7]helicenes, present as seven on the benzenoid terminal rings rings give to the exist in-plane in opposite turn angle directions, of thus420° unable (7 × to 60°), work forcing co-operatively the functional (refer, groups Figure pres8b).ent Yet, on whenthe terminal onlyone rings of to the exist peripheral in opposite rings is functionalizeddirections, thus and unable acts as to an work active co-operatively catalytic site, (refer the, Figure [7]helicene-based 8b). Yet, when only systems one of have the peripheral an additional rings is functionalized and acts as an active catalytic site, the [7]helicene-based systems have an advantage over substituted [5]- and [6]helicenes. This is owing to the same in-plane turn angle property additional advantage over substituted [5]- and [6]helicenes. This is owing to the same in-plane turn allowingangleanother property peripheral allowing another ring toperipheral block one ring of to the block prochiral one of the faces prochiral of the faces reactant. of the Nevertheless,reactant. surprisingly,Nevertheless, asymmetric surprisingly, catalysis asymmetric with [7]helicenes catalysis with is [7]helicenes not well explored is not well in explored comparison in comparison with that with [5]- andwith [6]helicenes. that with [5]- and [6]helicenes.

SchemeScheme 4. Enantioselective 4. Enantioselective epoxidation epoxidation of of alkenes alkenes35 35 andand 39 using enantioenriched enantioenriched [7]helicene [7]helicene 38 as38 as a chirala additive.chiral additive.

6. Helicenes as Chiral Catalysts 6. Helicenes as Chiral Catalysts Since various helicene-based phosphine-related ligands have been reviewed [2,5,7–9], only Sincerecent variousselected helicene-basedexamples capable phosphine-related of delivering exceptionally ligands high have ee been values reviewed are summarized [2,5,7–9], here. only recent selected examplesIn 2016, the capable [5]carbohelicene-based of delivering exceptionally phosphine ligands high ee43values and 44 arewere summarized rationally designed here. for Inapplication 2016, the in [5]carbohelicene-based Pd-catalyzed asymmetric phosphine synthesis ligands[51]. Both43 theand systems44 were were rationally prepared designed from for applicationcorresponding in Pd-catalyzed rac-bromo asymmetric substituted synthesis 45 [51via]. Bothlithiation the systems and weresubsequent prepared fromreaction corresponding with rac-bromochlorodiphenylphosphine substituted 45 via lithiation followed andby oxidation subsequent with reaction hydrogen with peroxide chlorodiphenylphosphine to afford rac-phosphine followed oxide 46 with 63% yield. It was successfully resolved by using spiro-TADDOL (α,α,α,α-tetraphenyl- by oxidation with hydrogen peroxide to afford rac-phosphine oxide 46 with 63% yield. It was successfully 1,3-dioxolane-4,5-dimethanol) 47 as a resolving agent to form the insoluble diastereomer 48 with (P)- resolved by using spiro-TADDOL (α,α,α,α-tetraphenyl-1,3-dioxolane-4,5-dimethanol) 47 as a resolving 46, which in turn gave pure (P)-46 with greater than 99% ee on subsequent treatment. Then, (P)-46 agentwas to formaromatized the insoluble to 49 quantitatively diastereomer by 48usingwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. (P)-46, which in turn gave pure (P)-46 Bothwith the greater thanphosphine 99% ee on oxides subsequent 48 and treatment. 49 were reduced Then, to (P )-the46 correspondingwas aromatized phosphines, to 49 quantitatively 43 and 44, with by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.trichlorosilane and P(OEt)3 with 70–72% yield Both and the 99% phosphine ee (Scheme oxides 5) [51].48 and 49 were reduced to the correspondingIn general, phosphines, unsubstituted43 and [5]helicenes44, with trichlorosilaneare configurationally and P(OEt)unstable3 andwith tend 70–72% to racemize yield andeasily. 99% ee (SchemeHowever,5) [51]. introduction of the diphenylphosphine group at the 1-position results in the Inconfigurational general, unsubstituted stability of 43 [5]helicenes and 44. Of these are configurationally two structures, the unstable7,8-dihydro-derivative and tend to racemize43 tends to easily. However,be more introduction helical due ofto thethe diphenylphosphinesaturated ethane unit, groupwhich athas the greater 1-position conformati resultsonal in flexibility. the configurational From X-ray analysis, it was confirmed that the helical pitch diameter of dihydrohelicene 43 is 3.54–3.50 Å, stability of 43 and 44. Of these two structures, the 7,8-dihydro-derivative 43 tends to be more helical which is larger than that of fully aromatic 44, found to be 3.39–3.34 Å. This rationally changed spatial due to the saturated ethane unit, which has greater conformational flexibility. From X-ray analysis, arrangement has a noticeable influence on its application as a ligand owing to the favorable geometry it wasand confirmed distance, which that the was helical clearly pitch demonstrated diameter by of th dihydrohelicenee metal–ligand and43 areneis 3.54–3.50 interaction. Å, whichHence, isthe larger thandouble that of bond fully (C8a–C14b) aromatic 44 is, coordinated found to be wi 3.39–3.34th the palladium Å. This metal rationally center changedof ligand 44 spatial in a side-on arrangement (η has a2) noticeable fashion, which influence is not on possible its application in the case as a of ligand dihydrohelicene owing to the 43. favorable This difference geometry in geometric 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, Symmetry 2018, 10, 10 11 of 48

whichSymmetry is not 2018 possible, 10, 10 in the case of dihydrohelicene 43. This difference in geometric features11 of controls 48 the outcome of Pd-catalyzed reactions. For example, the alkylation of rac-1,3-diphenylallyl acetate 50 withfeatures dimethyl controls malonate the 51outcomeby using of Pd-catalyzed (M)-dihydrohelicene reactions. 43Foras example, a chiral the ligand alkylation was highly of rac-1,3- efficient, diphenylallyl acetate 50 with dimethyl malonate 51 by using (M)-dihydrohelicene 43 as a chiral resulting in the corresponding (S)-enantiomer 52 with 99% yield and 94% ee (Scheme6)[ 51]. In contrast, ligand was highly efficient, resulting in the corresponding (S)-enantiomer 52 with 99% yield and 94% the fully aromaticSymmetry 2018 (M, 10)-helicene, 10 44, whilst affording the same configuration of the product11 of 48 52, gave ee (Scheme 6) [51]. In contrast, the fully aromatic (M)-helicene 44, whilst affording the same similarconfiguration yield,features but only controlsof the 71% theproductee outcome(Scheme 52 , ofgave6 ).Pd-catalyzed This similar clearly yield,reactions. demonstrates but For only example, 71% that eethe (Scheme alkylation ligands’ 6). geometryof Thisrac-1,3- clearly allowed themdemonstrates to optdiphenylallyl for different that acetatethe transitionligands’ 50 with geometry states.dimethyl allowed malonate them 51 by to usingopt for (M different)-dihydrohelicene transition 43 states.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 5. Synthesis and resolution of enantiopure phosphine ligands 43 and 44. 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 SchemeScheme 6. Pd-catalyzed6. Pd-catalyzed asymmetric asymmetric alkylationalkylation of of racrac-1,3-diphenylallyl-1,3-diphenylallyl acetate acetate 50 using50 using helical helical phosphine ligands 43 and 44. phosphinephosphine ligands ligands43 and 43 and44 .44. Similar types of C1 position substituted phosphinite ligands, helicenoid 53 [52] and helicene 54 Similar[52] (Figure types 9), of were C1 alsoposi preparedtion substituted and successfully phosphinite explored ligands, for the helicenoidPd-catalyzed 53 asymmetric [52] and heliceneallylic 54 Similar types of C1 position substituted phosphinite ligands, helicenoid 53 [52] and helicene [52] (Figurealkylation 9), werebetween also 50 prepared and 51 (see and Scheme successfully 5). In both explored cases, the forhigh the yields Pd-catalyzed and ee of 52 asymmetricwere obtained allylic 54 [52alkylation] (Figureas with between9), 53 were(96%, 50 90% also and ee) prepared51 and (see with Scheme 54and (97%, 5). successfully 99% In eeboth) [52]. cases, It is explored of the note high that yieldsfor this thekinetic and Pd-catalyzed resolutionee of 52 were reaction obtained asymmetric allylicas alkylation withusing 53 (96%, helicene between 90% ligand ee) and50 55and [53]with 51was 54(see (97%,firstly Scheme 99%reported ee)5 [52]. ).in In2000 It both is with of note cases, 100% that conversion the this high kinetic and yields resolution81% andee (Figureee reactionof 52 were obtainedusing as 9).helicene with Although53 ligand(96%, the results 55 90% [53] fromee )was and using firstly with 55 arereported54 comparatively(97%, in 99% 2000ee worse )[with52]. in100% It terms is ofconversion of note ee, the that reaction and this 81%kinetic requires ee (Figureresolution less catalyst loading and proceeds faster compared with other ligands. Interestingly, 55, whilst being reaction9). Although using helicene the results ligand from55 using[53] 55 was are firstly comparatively reported worse in 2000 in terms with 100%of ee, the conversion reaction requires and 81% ee less catalysta bidentate loading ligand, and still proceeds acts as a fastermonophosphine compared (monodentate) with other ligands. ligand during Interestingly, the catalytic 55, whilstprocess being (Figure9).owing Although to the thelarge results distance from (6.481 using Å) between55 are the comparativelytwo phosphorus atoms; worse this in was terms the ofsubjectee, theof reaction a bidentate ligand, still acts as a monophosphine (monodentate) ligand during the catalytic process requires lesspioneering catalyst work loading by Reetz and et proceeds al. [53]. Thus, faster one compared can see that with all phosphine other ligands. (43, 44) and Interestingly, phosphinite 55, whilst owing to the large distance (6.481 Å) between the two phosphorus atoms; this was the subject of being a bidentate(53, 54) ligands ligand, prepared still later, acts possess as a monophosphine only a mono phosphorus (monodentate) atom and are suitable ligand for during application the catalytic pioneeringas monodentate work by ligandsReetz etin al.this [53]. reaction. Thus, one can see that all phosphine (43, 44) and phosphinite process(53, owing 54) ligands to the prepared large distance later, possess (6.481 only Å) a between mono phosphorus the two phosphorus atom and are atoms; suitable this for application was the subject of pioneering work by Reetz et al. [53]. Thus, one can see that all phosphine (43, 44) and phosphinite as monodentate ligands in this reaction. (53, 54) ligands prepared later, possess only a mono phosphorus atom and are suitable for application as monodentate ligands in this reaction. Symmetry 2018, 10, 10 12 of 48 Symmetry 2018, 10, 10 12 of 48

Symmetry 2018, 10, 10 12 of 48

ligand reaction condition yield (%) ee (%) ref. ligand reaction condition yield (%) ee (%) ref. (P)-53 [(η3-C3H5)-PdCl]2 (2.5 mol%), (P)-53 (10 mol%), BSA, LiOAc, CH2Cl2, rt, 24 h 90 96 [52] (P)-53 [(η3-C H )-PdCl] (2.5 mol%), (P)-53 (10 mol%), BSA, LiOAc, CH Cl , rt, 24 h 90 96 [52] (P)-54 [(η3-C3 3H5 5)-PdCl]22 (2.5 mol%), (P)-54 (10 mol%), BSA, LiOAc, CH2Cl22, rt,2 24 h 97 99 [52] (P)-54 [(η3-C H )-PdCl] (2.5 mol%), (P)-54 (10 mol%), BSA, LiOAc, CH Cl , rt, 24 h 97 99 [52] (P)-55 [(η33-C35H5)-PdCl]2 2 (0.25 mol%), (P)-56 (1 mol%), BSA, KOAc, CH2Cl22, rt,2 4 h 100 81 [53] ligand 3 reaction condition yield (%) ee (%) ref. (P)-55 [(η -C3H5)-PdCl]2 (0.25 mol%), (P)-56 (1 mol%), BSA, KOAc, CH2Cl2, rt, 4 h 100 81 [53] 3 (P)-Figure53 [(9.η Other-C3H5)-PdCl] helicene-based2 (2.5 mol%), phos (P)-53phorus-containing (10 mol%), BSA, LiOAc, ligands CH2 Cl532–, 55rt, 24used h for Pd-catalyzed90 96 allylic[52] (P)-54 [(η3-C3H5)-PdCl]2 (2.5 mol%), (P)-54 (10 mol%), BSA, LiOAc, CH2Cl2, rt, 24 h 97 99 [52] Figuresubstitution 9. Other reaction helicene-based of 50 and phosphorus-containingsubsequent kinetic resolution. ligands 53–55 used for Pd-catalyzed allylic (P)-55 [(η3-C3H5)-PdCl]2 (0.25 mol%), (P)-56 (1 mol%), BSA, KOAc, CH2Cl2, rt, 4 h 100 81 [53] substitution reaction of 50 and subsequent kinetic resolution. TheFigure corresponding 9. Other helicene-based enantiopure phos 53phorus-containing and 54 were synthesized ligands 53– using55 used the for Ni-catalyzed Pd-catalyzed [2allylic + 2 + 2] cycloadditionsubstitution reaction reaction of 50alkyne and subsequent 56 to give kinetic 57 resolution.(97%), and the subsequent demethylation and The corresponding enantiopure 53 and 54 were synthesized using the Ni-catalyzed [2 + 2 + 2] esterification as (1S)-camphanate to yield the corresponding diastereomers, 58 and 59. Further, the cycloadditionseparatedThe corresponding diastereomers reaction of enantiopure alkynewere hydrolyzed56 to53 and give with 5457 werealkali(97%), synthesizedto quan andtitatively the using subsequent produce the Ni-catalyzed the demethylation enantiomer [2 + 2 +60 2], and esterificationwhich,cycloaddition on assubsequent (1 Sreaction)-camphanate reaction of alkyne with to yield56 chlorodiphen to thegive corresponding 57 ylphosphine(97%), and diastereomers,thein the subsequent presence of58demethylation sodiumand 59 .hydride, Further, and the separatedresultedesterification diastereomers in the as tetrahydro (1S)-camphanate were phosphinite hydrolyzed to yield ligand, the with corresponding(P alkali)-53. For to 54 quantitatively, andiastereomers, additional producestep 58 ofand dehydrogenation 59 the. Further, enantiomer the 60, separated diastereomers were hydrolyzed with alkali to quantitatively produce the enantiomer 60, which,using on triphenylmethylium subsequent reaction tetrafluoroborate with chlorodiphenylphosphine (Ph3CBF4) was required in theto obtain presence the diastereomer of sodium hydride, 61 resulted(92%),which, in which theon subsequent tetrahydro upon hydrolysis reaction phosphinite gave with [6]helicen-1-ol chlorodiphen ligand, (P)- 6253ylphosphine,. which For 54 was, an in finally additionalthe presence converted step of tosodium of phosphinite dehydrogenation hydride, 54 withresulted 74% in yield the (Schemetetrahydro 7) phosphinite[52]. ligand, (P)-53. For 54, an additional step of dehydrogenation using triphenylmethylium tetrafluoroborate (Ph3CBF4) was required to obtain the diastereomer using triphenylmethylium tetrafluoroborate (Ph3CBF4) was required to obtain the diastereomer 61 61 (92%),(92%), which which upon upon hydrolysishydrolysis gave gave [6]helicen-1-ol [6]helicen-1-ol 62, 62which, which was wasfinally finally converted converted to phosphinite to phosphinite 54 54 withwith 74% 74% yield yield (Scheme(Scheme 77))[ [52].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.

Scheme 7. Synthesis and optical resolution of 53 and 54 by using the Ni-catalyzed [2 + 2 + 2] SchemeInspired 7. Synthesis by the difference and optical in the resolution catalytic performance of 53 and 54 ofby 43 using(94% ee the) and Ni-catalyzed 44 (71% ee) [2(Scheme + 2 + 6) 2] cycloaddition reaction as a key step. incycloaddition Pd-catalyzed reaction asymmetric as a key allylic step. alkylation, the same group also applied these ligands in other Pd- Inspired by the difference in the catalytic performance of 43 (94% ee) and 44 (71% ee) (Scheme 6) Inspiredin Pd-catalyzed by the asymmetric difference allylic in the alkylation, catalytic performancethe same group of also43 applied(94% ee these) and ligands44 (71% in eeother) (Scheme Pd- 6) in Pd-catalyzed asymmetric allylic alkylation, the same group also applied these ligands in other

Symmetry 2018, 10, 10 13 of 48

Symmetry 2018, 10, 10 13 of 48 Pd-catalyzed reactions. Thus, in further investigation, the dihydrohelicene ligand 43 was found to be Symmetrycatalyzed 2018 reactions., 10, 10 Thus, in further investigation, the dihydrohelicene ligand 43 was found13 to of be48 highly useful in the asymmetric allylation of indoles 63 with 1,3-diphenylallyl acetate 50 to give the highly useful in the asymmetric allylation of indoles 63 with 1,3-diphenylallyl acetate 50 to give the 3-alkylatedcatalyzed3-alkylated indole reactions. indole product product Thus,64 in64in furtherin up up to to 99%investigation, 99%ee ee,, andand in the the the dihydrohelicene etherification etherification with withligand alcohols alcohols 43 was 65 to 65found yieldtoyield to66 bein 66 in up tohighlyup 94% to 94%ee useful(Scheme ee (Scheme in the8)[ asymmetric 518) ].[51]. 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 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. phosphineScheme ligand 8. Pd-catalyzed43 (a) with asymmetric indole 63 and ally (licb) substitution with alcohols reactions65. of 50 by using (M)-helicenoid phosphineIn the case ligand of fully 43 (aromatica) with indole helicene 63 and 44 (b, )the with ligand alcohols was 65 .highly effective in the stereocontrol of Inhelical the casechirality of fullyin the aromaticSuzuki–Miyaura helicene coupling44, the reaction ligand between was highly bromide effective derivative in the 67 stereocontroland boronic of In the case of fully aromatic helicene 44, the ligand was highly effective in the stereocontrol of helicalacid chirality 68, resulting in the in Suzuki–Miyaura up to 99% ee for chiral coupling biaryl reaction products between 69 of (P)-helicity bromide (Scheme derivative 9) [51].67 and boronic helical chirality in the Suzuki–Miyaura coupling reaction between bromide derivative 67 and boronic acid 68acid, resulting 68, resulting in up in up to 99%to 99%ee eefor for chiral chiral biaryl biaryl productsproducts 6969 ofof (P (P)-helicity)-helicity (Scheme (Scheme 9) [51].9)[51 ].

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

helicene phosphine ligand. SchemeScheme 9. Pd-catalyzed 9. Pd-catalyzed asymmetric asymmetric Suzuki–Miyaura Suzuki–Miyaura coupling coupling between between 67 67andand 68 using68 using (P)-44 (P as)-44 theas the heliceneheliceneThese phosphine examples phosphine ligand. ( 43ligand. 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 reactionThese pathway. examples The (43 DFT-based and 44) clearly calculation show atthat the the B3PW91/6-31G* helicity and space level available(LANL2DZ in thefor thehelical Pd These examples (43 and 44) clearly show that the helicity and space available in the helical groove grooveatoms) suitablerevealed for that a specificthe transition transition state state with play minimum a vital rolesteric in repulsionsthe stereoselective between control the helicene of the suitablereactionbackbone for apathway. and specific the reactant The transition DFT-based group state is responsiblecalculation play a vital forat the role (B3PW91/6-31G*S in)-configuration the stereoselective levelproducts (LANL2DZ control (52, 64, and offorthe 66the) and reactionPd pathway.atoms)P-configuration The revealed DFT-based product that the calculation(69 transition) obtained state atwith the withhigh B3PW91/6-31G* eeminimum [51]. steric level repulsions (LANL2DZ between for the the helicene Pd atoms) revealedbackbone thatHelicene-based theand transition the reactant ligands state group have with is responsiblebeen minimum also successfully for steric the ( repulsionsS)-configuration investigated between products for thethe helicenerhodium-catalyzed(52, 64, and backbone 66) and and the reactantPasymmetric-configuration group hydrogenation is product responsible (69) ofobtained for alkenes. the ( withS)-configuration In highfact, ee the [51]. first products enantioselective (52, 64, and catalysis66) and usingP-configuration helical Helicene-based ligands have been also successfully investigated for the rhodium-catalyzed productdiphosphane (69) obtained 55 was with the high asymmetricee [51]. reduction of itaconate 70 as a model compound under mild asymmetric hydrogenation of alkenes. In fact, the first enantioselective catalysis using helical Helicene-basedconditions using ligandsin situ generated have been (M)- also55 and successfully [Rh(cod)2]+BF investigated4−. This results for in the the rhodium-catalyzed corresponding diphosphanediester (S)-71 55with was 54% the yield asymmetric and 39% reduction ee product, of asitaconate reported 70 by as Reet a modelz et al. compound [54] (Scheme under 10). mild The asymmetric hydrogenation of alkenes. In fact, the first+ enantioselective− catalysis using helical conditionssynthesis ofusing 55 inis situbased generated on photochemical (M)-55 and [Rh(cod)cyclizatio2]nBF with4 . This subsequentresults in conversionthe corresponding of the diphosphane 55 was the asymmetric reduction of itaconate 70 as a model compound under mild diestercorresponding (S)-71 with helicenedibromide 54% yield and 39%derivative ee product, to phosphine as reported 55, followedby Reetz byet al.preparative [54] (Scheme chiral 10). HPLC The conditions using in situ generated (M)-55 and [Rh(cod) ]+BF −. This results in the corresponding synthesisseparation ofof 55the is enantiomers based on photochemical[54]. Yamaguchi cyclizatio et al.2 improvedn with4 subsequent the yield conversion(up to 100%) of andthe diestercorresponding (S)-71 with helicenedibromide 54% yield and derivative 39% ee product, to phosphine as reported 55, followed by Reetzby preparative et al. [ 54chiral] (Scheme HPLC 10).

The synthesisseparation ofof 55the isenantiomers based on photochemical[54]. Yamaguchi cyclizationet al. improved with the subsequent yield (up conversionto 100%) and of the corresponding helicenedibromide derivative to phosphine 55, followed by preparative chiral HPLC Symmetry 2018, 10, 10 14 of 48 separationSymmetry of 2018 the, 10, 10 enantiomers [54]. Yamaguchi et al. improved the yield (up to 100%)14 of 48 and enantioselectivity up to 96% ee for (S)-71 using the (M,M,S,l)-configuration of the bis-helicenic enantioselectivitySymmetry 2018, 10, 10 up to 96% ee for (S)-71 using the (M,M,S,l)-configuration of the bis-helicenic14 of 48 phosphitephosphite ligand ligand72 [7255 ][55] (Scheme (Scheme 10 10).). The The excellentexcellent output output in in this this reaction reaction obtained obtained with with 72 was72 was attributedattributedenantioselectivity to the to matched the matchedup (suitable)to 96% (suitable) ee pairfor ( ofpairS)- asymmetries,71 of using asymmetries, the ( i.e.,M,M,S,l twoi.e.,)-configuration (twoM)-helical (M)-helical and of and onethe (onebis-helicenicS)-axial (S)-axial chirality. However,chirality.phosphite the However, centralligand 72 chirality the [55] central (Scheme derived chirality 10). fromThe derived excellent the froml-menthyl outputthe l-menthyl partin this does partreaction notdoes haveobtained not have much with much effect 72 effect was on the reactiononattributed theee outcome.reaction to the ee outcome.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 Scheme 10. Comparative Rh-catalyzed asymmetric hydrogenation of itaconate ester 70 using helicene-based ligands 55 and 72. helicene-based ligands 55 and 72. Scheme 10. Comparative Rh-catalyzed asymmetric hydrogenation of itaconate ester 70 using helicene-basedAnother approach ligands adopted 55 and 72was. to design a helicene with the fused phosphole heterocyclic unit Anotherat one of the approach terminal adopted rings where was the to phosphorus design a helicene atom has with an additional the fused point phosphole chirality, heterocyclic denoted as unit at oneSP of or theAnother RP. terminalA key approach synthetic rings adopted wherestep includes thewas phosphorusto the design diastereosel a helicen atomectivee haswith photochemical an the additional fused phosphole cyclization point chirality,heterocyclic reaction denoted unitof a as suitableat one of ( theSP or terminal RP) enantiopure rings where phosphole-bearing the phosphorus stilbeneatom has derivative an additional 73. The point resulting chirality, regioisomeric denoted as SP or RP. A key synthetic step includes the diastereoselective photochemical cyclization reaction of a [6]heliceneSP or RP. A keyphosphine synthetic oxide step 74 includes and phospha[7]helicene the diastereoselective 75 were photochemical chromatographically cyclization separated reaction with of a suitable (SP or RP) enantiopure phosphole-bearing stilbene derivative 73. The resulting regioisomeric suitable32% and ( 28%SP or yield, RP) enantiopure respectively phosphole-bearing [56] (Scheme 11). stilbene derivative 73. The resulting regioisomeric [6]helicene[6]helicene phosphine phosphine oxide oxide74 74and and phospha[7]helicene phospha[7]helicene 7575 werewere chromatographically chromatographically separated separated with with 32% and32% 28%and 28% yield, yield, respectively respectively [56 [56]] (Scheme (Scheme 11 11).).

Scheme 11. Cont.

Symmetry 2018, 10, 10 15 of 48 Symmetry 2018, 10, 10 15 of 48

Symmetry 2018, 10, 10 15 of 48

SchemeScheme 11. 11.Photochemical Photochemical diastereoselective diastereoselective synt synthesishesis of of [6]helicene [6]helicene phosphine phosphine oxide oxide 74 and74 and phospha[7]helicene 75. phospha[7]heliceneScheme 11. Photochemical75. diastereoselective synthesis of [6]helicene phosphine oxide 74 and Subsequently,phospha[7]helicene enantiopure 75. 74 was reduced and in situ reacted with gold(I) salts to generate the Subsequently,phospha-substituted enantiopure helicene–gold74 was complexes, reduced and76 ( inendo situ) and reacted 77 (exo with). In gold(I)endo-76 salts, the togold generate atom the Subsequently, enantiopure 74 was reduced and in situ reacted with gold(I) salts to generate the phospha-substitutedoccupies the internal helicene–gold chiral cavity complexes, space, approaching76 (endo) andtowards77 ( exothe). opposite In endo- 76terminal, the gold ring, atom whereas occupies phospha-substituted helicene–gold complexes, 76 (endo) and 77 (exo). In endo-76, the gold atom the internalin exo-77 chiral, the cavitygold atom space, is approachingsituated at the towards external the face, opposite being terminalaway from ring, the whereas helical moiety. in exo-77 Thus,, the gold occupies the internal chiral cavity space, approaching towards the opposite terminal ring, whereas atomchromatographically is situated at the external separated face, endo being-76 effectively away from catalyzes the helical the enantioselective moiety. Thus, cycloisomerization chromatographically in exo-77, the gold atom is situated at the external face, being away from the helical moiety. Thus, of N-tethered 1,6-enyne 78 to give bicyclo[4.1.0]heptane 79 with 95% yield and 81% ee, whilst exo-77 separatedchromatographicallyendo-76 effectively separated catalyzes endo the-76enantioselective effectively catalyzes cycloisomerization the enantioselective of N-tethered cycloisomerization 1,6-enyne 78 remained almost inactive [56] (Scheme 12). Meanwhile, various phosphole-containing ligands were to giveof bicyclo[4.1.0]heptaneN-tethered 1,6-enyne 7879 towith give 95%bicyclo[4.1.0]heptane yield and 81% ee 79, whilstwith 95%exo yield-77 remained and 81% almostee, whilst inactive exo-77 [56] also prepared and screened in similar reactions with success [8,9,57]. (Schemeremained 12). Meanwhile, almost inactive various [56] phosphole-containing (Scheme 12). Meanwhile, ligands various were phosphole-containing also prepared and screened ligands were in similar reactionsalso withprepared success and [screened8,9,57]. 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. Scheme 12. (a) Synthesis of endo (SP,P)-76 and (b) its application as a catalyst for the enantioselective Scheme 12. (a) Synthesis of endo (SP,P)-76 and (b) its application as a catalyst for the enantioselective cycloisomerizationHowever,cycloisomerization at present, of N-tethered of N-tethered the scope enyne enyne of78 78the. . use of helicenes containing phosphorus functionality appears to be limited towards the metal-catalyzed reactions, as described above. A few other However, at present, the scope of the use of helicenes containing phosphorus functionality attempted asymmetric reactions such as ketoimine reduction (22% ee), addition of thioester to However,appears to at be present, limited the towards scope ofthe the metal-catalyzed use of helicenes reactions, containing as described phosphorus above. functionality A few other appears benzaldehyde (22% ee), and reductive aldol reaction afforded quite low ee values, with to beattempted limited towards asymmetric the reactions metal-catalyzed such as reactions,ketoimine reduction as described (22% above.ee), addition A few of other thioester attempted to tetrathia[6]helicene diphosphine oxides as a Lewis base catalyst [58]. asymmetricbenzaldehyde reactions (22% such ee), as and ketoimine reductive reduction aldol reaction (22% ee ),afforded addition quite of thioesterlow ee tovalues, benzaldehyde with Besides these phosphorus-containing helicenes, heterohelicenes with a nitrogen atom at the tetrathia[6]helicene diphosphine oxides as a Lewis base catalyst [58]. (22%innermostee), and 1- reductive or 2-position aldol are reactionalso able to afforded provide quitea chiral low cavityee suitablevalues, for with various tetrathia[6]helicene asymmetric diphosphineBesides oxides these as phosphorus-containing a Lewis base catalyst [helicenes,58]. heterohelicenes with a nitrogen atom at the Besides innermost these 1- or phosphorus-containing 2-position are also able helicenes, to provide heterohelicenes a chiral cavity with suitable a nitrogen for various atom asymmetric 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. Symmetry 2018, 10, 10 16 of 48

Symmetry 2018, 10, 10 16 of 48 The classicalSymmetry 2018 synthetic, 10, 10 approach for azahelicenes having a nitrogen atom at the peripheral16 ring of 48 as the pyridineorganocatalytic subunit is basedprocesses, on thewhere preparation the nitrogen of atom the corresponding plays a crucial role stilbene as a Lewis derivative base or followed hydrogen- by the photocyclizationorganocatalyticbonding auxiliary. reaction. processes, The classical where syntheticthe nitrogen approach atom plays for azahelicenes a crucial role having as a Lewis a nitrogen base or atom hydrogen- at the bonding auxiliary. The classical synthetic approach for azahelicenes having a nitrogen atom at the Theperipheral first usering as of the a pyridine-basedpyridine subunit is helicene based on as the a preparation chiral organocatalyst of the corresponding for promoting stilbene the peripheral ring as the pyridine subunit is based on the preparation of the corresponding stilbene enantioselectivederivative followed acyl group by the transferphotocyclization reaction reaction. and kinetic resolution of racemic phenylethanol 80 derivativeThe firstfollowed use byof thea pyridine-bas photocyclizationed helicene reaction. as a chiral organocatalyst for promoting the was reported by Stary et al. in 2009 [59]. The preparation of helicenes 81 and 82 [60] involves the enantioselectiveThe first use acyl of group a pyridine-bas transfer reactioned helicene and kinetic as a resolutionchiral orga ofnocatalyst racemic phenylethanol for promoting 80 wasthe [2 + 2 + 2] cyclotrimerization of regioisomeric aromatic triynes 83 and 84 using a Co(I)-catalyzed enantioselectivereported by Stary acyl et al.group in 2009 transfer [59]. reactionThe preparation and kinetic of helicenesresolution 81 of and racemic 82 [60] phenylethanol involves the [280 +was 2 + reactionreported2] cyclotrimerization as the by major Stary syntheticet al. of in re 2009gioisomeric step [59]. to The obtain aromatic preparation tetrahydrohelicenes triynes of 83helicenes and 84 81using85 and(82%) a 82 Co(I)-catalyzed [60] and involves86 (89%), thereaction respectively[2 + 2 as + (Scheme2]the cyclotrimerization major13). Finally, synthetic the step of MnO re togioisomeric obtain2-based tetrahydrohelicenes oxidation aromatic triynes resulted 8385 inand(82%)rac 84 aza[6]heliceneand using 86 a (89%), Co(I)-catalyzed respectively81 (65%) reactionand (Scheme82 as(53%). the major synthetic step to obtain tetrahydrohelicenes 85 (82%) and 86 (89%), respectively (Scheme The optical13). Finally, resolution the MnO of helicene2-based oxidation81 was carriedresulted out in rac through aza[6]helicene the diastereomeric 81 (65%) and salt 82 formation(53%). The with 0 optically13).optical Finally, pure resolution (+)- theO ,OMnO of-dibenzoyl- helicene2-based oxidation81D -tartaricwas carried resulted acid, out whereasin through rac aza[6]helicene enantiopure the diastereomeric 8182 (65%)was saltobtainedand formation 82 (53%). by separation withThe optical resolution of helicene 81 was carried out through the diastereomeric salt formation with of theoptically corresponding pure (+)-O racemic,O′-dibenzoyl- mixtureD-tartaric with chiral acid, whereas HPLC (Scheme enantiopure 13)[ 8260 was]. obtained by separation optically pure (+)-O,O′-dibenzoyl-D-tartaric acid, whereas enantiopure 82 was obtained by separation Itof wasthe corresponding found that (+)-( racemicP)-1-aza[6]helicene mixture with chiral81 HPLCis an ineffective (Scheme 13) catalyst [60]. for this process with <5% of the corresponding racemic mixture with chiral HPLC (Scheme 13) [60]. yield, as theIt was nitrogen found atomthat (+)-( at theP)-1-aza[6]helicene most sterically 81 congested is an ineffective position catalyst has veryfor this limited process accessibility with <5% for yield,It aswas the found nitrogen that atom (+)-( Pat)-1-aza[6]helicene the most sterically 81 congested is an ineffective position catalyst has very for limited this process accessibility with <5% for the reactant. However, the isomeric (−)-(M)-2-aza[6]helicene 82, due to the easily accessible nitrogen yield,the reactant. as the nitrogen However, atom the atisomeric the most (− )-(stericallyM)-2-aza[6]helicene congested position 82, due has to thevery easily limited accessible accessibility nitrogen for atom position, considerably improved the catalytic performance with 46.9% conversion to 87 and theatom reactant. position, However, considerably the isomeric improved (−)-( theM)-2-aza[6]helicene catalytic performance 82, due with to the 46.9% easily conversion accessible to nitrogen 87 and 53.1%atom53.1%ee for position, ee the for unreactedthe considerably unreacted starting starting improved alcohol alcohol the80 80catalytic( (RR-configuration)-configuration) performance with withwith a selectivity46.9% a selectivity conversion factor factor of to 7 87 offor 7and the for the corresponding53.1%corresponding ee for ( Sthe)-enantiomer ( Sunreacted)-enantiomer starting (Scheme (Scheme alcohol 14 14))[ 5980[59].]. (R -configuration) with a selectivity factor of 7 for the corresponding (S)-enantiomer (Scheme 14) [59].

+1 SchemeScheme 13. Synthesis 13. Synthesis of azahelicenesof azahelicenes81 81and and 8282 via Co Co+1-catalyzed-catalyzed [2 + [2 2 ++ 2] 2 +cyclotrimerization 2] cyclotrimerization reaction. reaction. 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. SchemeScheme 14. 14.Kinetic Kinetic resolution resolutionof of racrac-phenylethanol-phenylethanol 8080 byby (M ()-M81)- 81andand (M)- (M82)-. 82. This example clearly demonstrates how the suitably tailor-made design of azahelicenes can provideThis a exampleuseful chiral clearly pyridine-based demonstrates nucleophilic how the suit organocatalystably tailor-made comparab designle toof otherazahelicenes enantiopure can This example clearly demonstrates how the suitably tailor-made design of azahelicenes can provideamine-containing a useful chiral catalysts, pyridine-based whilst possessing nucleophilic diffe rentorganocatalyst elements ofcomparab asymmetry.le to otherIn comparison enantiopure to provideamine-containing a useful chiral catalysts, pyridine-based whilst possessing nucleophilic different organocatalyst elements of comparableasymmetry. In to comparison other enantiopure to 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) Symmetry 2018, 10, 10 17 of 48 are better nucleophilic catalysts for acylation of alcohols due to the enhanced nucleophilicity provided Symmetry 2018, 10, 10 17 of 48 by the electron donating nature of the dimethylamino group at the para position. Thus, (P)-helicenoids 88 containingpyridine, a pdimethylaminopyridine-dialkyl amino substituent (DMAP) turnedand DMAP-containing out to be a more compounds effective 88-90 enantiodifferentiating [61–64] (Figure catalyst10) for are the better resolution nucleophilic of the catalysts (S)-enantiomer for acylation of racemic of alcohols80 with due theto the selectivity enhanced factornucleophilicity of 17, in 5 h, as comparedprovided to 48 hby with the electron a selectivity donating factor nature of of 7 the using dimethylamino (M)-82 as group the catalyst. at the para position. Thus, (P)- Thehelicenoids helicenoidal 88 containing DMAP 88 ahas p-dialkyl a nitrogen amino atom substituent at the 2-positionturned out andto be saturated a more N-alkyleffective group, enantiodifferentiating catalyst for the resolution of the (S)-enantiomer of racemic 80 with the selectivity whilst the helicenoid core ensures two additional advantages. Firstly, it enhances the nucleophilicity factor of 17, in 5 h, as compared to 48 h with a selectivity factor of 7 using (M)-82 as the catalyst. of the pyridineThe helicenoidal nitrogen at DMAP the 2-position 88 has a nitrogen by its atom electron at the donating2-position and ability saturated (+I effect), N-alkyland group, secondly, it increaseswhilst the the conformational helicenoid core ensures flexibility two additional to accommodate advantages. reactants Firstly, it inside enhances the the helical nucleophilicity chiral cavity for efficientof enantiodifferentiating the pyridine nitrogen at the processes. 2-position Theby its attached electron donating ethyl substituents ability (+I effect), at the and central secondly, ring it of the helical outerincreases core the were conformational responsible flexibility for increasing to accommodate the lipophilic reactants characterinside the helical and, thus,chiral thecavity solubility for in organicefficient solvents enantiodifferentiating for better performance processes. [61 The]. The attached helicenoid ethyl substituents DMAP 88 atdisplayed the central ring a comparatively of the helical outer core were responsible for increasing the lipophilic character and, thus, the solubility in higher selectivityorganic solvents factor for ofbetter 17–116, performance depending [61]. The on he thelicenoid structure DMAP of88 thedisplayed racemic a comparatively aromatic ethanol. In comparisonhigher selectivity to 88, the factor axially of 17–116, chiral depending DMAP catalyst on the structure89 [62,63 of] the showed racemic selectivity aromatic ethanol. factors In of 12–52 (in ether)comparison [62] and to 32–95 88, the (in axiallyt-amyl chiral alcohol) DMAP [catalyst63] for 89 enantioresolution [62,63] showed selectivity of different factors racemicof 12–52 (in aromatic ethanols.ether) However, [62] and the 32–95 planar (in t-amyl chiral alcohol) DMAP [63] catalyst for enantioresol90 [64] displayedution of different the smaller racemic selectivity aromatic factor of 8.9–29.ethanols. It is of However, note that, the withplanar planar chiral DMAP chiral catalyst DMAP 9089 [64], the displayed acylating the smaller agent wasselectivity acetic factor anhydride, 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 whereas, in other cases, bulkier isobutyric anhydride was used. Thus, the helical DMAP 88 appears be highlyto be superior highly superior to 90 under to 90 under similar similar experimental experimental conditions. conditions.

Figure 10.FigureStructures 10. Structures of simple of simple dimethylaminopyridine dimethylaminopyridine (DMAP) (DMAP) and and helically helically,, axially, axially, and planar and planar chiral DMAPchiral DMAP catalysts catalysts88–90 88,– respectively.90, respectively.

Indeed, the first use of unsubstituted aza[6]helicene 81 and 82 as an organocatalyst for the kinetic Indeed,resolution the of first alcohols use rationalized of unsubstituted the corresponding aza[6]helicene steric constraint81 and imposed82 as an at the organocatalyst 1-position for a for the kinetic resolutionbulky acyl ofmoiety alcohols andrationalized its subseque thent group corresponding transfer reaction steric constraintto rac-alcohols. imposed However, at the the 1-position for a bulkyadditionally acyl moiety functionalized and its 1-aza[6]helicene subsequent group was fo transferund to be reactionan effective to racasymmetric-alcohols. catalyst However, for the various reactions [65,66], probably due to the facile access to reactants in the chiral cavity in the additionally functionalized 1-aza[6]helicene was found to be an effective asymmetric catalyst for transition state, as demonstrated in the following examples. various reactionsThe azahelicene-based [65,66], probably systems due were to converted the facile to accessthe corresponding to reactants N-oxides in the and chiral investigated cavity in the transitionfor state,the asymmetric as demonstrated ring opening in the of following epoxides examples.with chloride as a nucleophile. For example, 1- Theaza[6]helicene- azahelicene-basedN-oxide derivatives systems were 91–93 converted (Schemes 15 to and the 16) corresponding [67] were preparedN-oxides in the racemic and investigated form for theusing asymmetric a general three-step ring opening synthetic of methodology, epoxides with and their chloride enantiomers as a were nucleophile. resolved over For chiral example, 1-aza[6]helicene-HPLC [67].N The-oxide representative derivatives synthesis91–93 of(Schemes 93 starts from 15 andthe benzoquinoline 16)[67] were aldehyde prepared unit in 94 the and racemic corresponding bromo-substituted phosphonium salt 95 in three steps, where the initial step involves form usingthe Z-selective a general Wittig three-step condensation synthetic followed methodology, by the palladium-catalyzed and their enantiomers Stille–Kelly were coupling resolved over chiral HPLCreaction [67 to]. result The representativein azahelicene 96 synthesis. Finally, oxidation of 93 starts withfrom meta-chloroperbenzoic the benzoquinoline acid gave aldehyde the unit 94 and correspondingdesired helicene-N bromo-substituted-oxide 93 with 32–49% phosphonium yield (Scheme 15). 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). Symmetry 2018, 10, 10 18 of 48 Symmetry 2018, 10, 10 18 of 48

Symmetry 2018, 10, 10 18 of 48 Symmetry 2018, 10, 10 18 of 48

SchemeScheme 15. Representative 15. Representative general general synthetic synthetic schemescheme for for 1-azahelicene- 1-azahelicene-N-oxideN-oxide 93 using93 using Stille–Kelly Stille–Kelly coupling reaction. coupling reaction. Scheme 15. Representative general synthetic scheme for 1-azahelicene-N-oxide 93 using Stille–Kelly Then,couplingScheme the 15. reaction. enantiopure Representative (P )-helicalgeneral synthetic ligands scheme91–93 were for 1-azahelicene- screened forN the-oxide desymmetrization 93 using Stille–Kelly of meso Then,epoxidecoupling the 97 enantiopurewith reaction. chloride as (P )-helicala nucleophile ligands to obtain91–93 98 werewith satisfactory screened for yields the and desymmetrization ee (Scheme 16) [67]. of meso epoxide 97Similarly,Then,with the chloride enantiopureenantiopure as a nucleophile (helicalP)-helical 2,2 ligands′-bipyridine- to obtain 91–93N98 were-monoxidewith screened satisfactory 99 forwas the prepared yields desymmetrization and in twoee (Scheme steps of frommeso 16)[ 67]. Similarly,enantiopureepoxideThen, 97 withthe enantiopure 93 enantiopure with chloride 95% as yield helical a(P nucleophile)-helical (Scheme 2,20 -bipyridine-ligands 17a) to obtain and 91– applied93 98N were with-monoxide as screenedsatisfactory a Lewis99 for base wasyields the type desymmetrization prepared and catalyst ee (Scheme infor two the 16) ofhighly steps [67].meso from enantiopureenantioselectiveepoxideSimilarly, 9793 withwith enantiopure chloridereaction 95% yieldas a betweenhelical nucleophile (Scheme 2,2 aldehyde,′-bipyridine- to17 obtaina) and 10098N -monoxide appliedwith, and satisfactory allenyltrichlorosilane as 99 a was Lewis yields prepared baseand ee intype (Scheme 101two catalyst stepsto 16) obtain [67].from for the Similarly, enantiopure helical 2,2′-bipyridine-N-monoxide 99 was prepared in two steps from highlyenantiomericallyenantiopure enantioselective 93 with enriched 95% reaction yield homopropargylic (Scheme between 17a) aldehyde, alcoholand applied 102100 [68]. as, a and The Lewis reaction allenyltrichlorosilane base typedisplayed catalyst high for conversion the101 highlyto obtain enantiopure 93 with 95% yield (Scheme 17a) and applied as a Lewis base type catalyst for the highly enantiomerically(78–97%)enantioselective and enriched74–96% reaction ee homopropargylic for betweenvarious ortho-aldehyde, and alcohol para 100-substituted102, and[68 ].allenyltrichlorosilane The aromatic reaction alde displayedhyde derivatives,101high to conversionobtain with 18enantiomericallyenantioselective examples in total enrichedreaction (Scheme homopropargylicbetween 17b). Further, aldehyde, the alcohol catalyst 100 102, 99and[68]. can Theallenyltrichlorosilane be reactionrecovered displayed (~80%) without high101 conversionto any obtain loss (78–97%) and 74–96% ee for various ortho- and para-substituted aromatic aldehyde derivatives, with 18 of(78–97%)enantiomerically activity and and 74–96% selectivity enriched ee for after homopropargylic various the reaction, ortho- and making alcohol para-substituted it102 highly [68]. attractiveThe aromatic reaction for alde displayedindustrialhyde derivatives, highapplication. conversion with examples18(78–97%) examples in total and in (Scheme74–96% total (Scheme ee 17 forb). various 17b). Further, Further, ortho- the and the catalyst paracatalyst-substituted99 99can can be be aromatic recovered recovered alde (~80%)(~80%)hyde derivatives,without without any any with loss loss of activityof18 activityexamples and selectivity and in selectivitytotal after(Scheme after the 17b). reaction, the reaction,Further, making makingthe catalyst it highlyit highly 99 can attractive attractive be recovered for for industrialindustrial (~80%) without application. application. 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.

SchemeScheme 16. Desymmetrization16. Desymmetrization of ofmeso mesoepoxide epoxide 97 using 1-azahelicene- 1-azahelicene-N-oxideN-oxide 91–9193 –as93 catalysts.as catalysts. 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.

Scheme 17. (a) Two-step synthesis of helicene (P)-99 from (P)-93 and (b) asymmetric synthesis of (S)- Scheme propargylicScheme 17. 17.(a) alcohols( Two-stepa) Two-step 102 synthesisfrom synthesis aldehyde of helicene helicene100 and allenyltrichlorosilane(P ()-P99)- 99fromfrom (P)-93 (P )-and93 101 (andb by) asymmetric using (b) asymmetric (P)-99 synthesis as a catalyst. synthesis of ( S)- of propargylic alcohols 102 from aldehyde 100 and allenyltrichlorosilane 101 by using (P)-99 as a catalyst. (S)-propargylic alcohols 102 from aldehyde 100 and allenyltrichlorosilane 101 by using (P)-99 as a catalyst.

Symmetry 2018, 10, 10 19 of 48

Symmetry 2018, 10, 10 19 of 48

The (TheS)-alcohol (S)-alcohol102 102was was the the major major product product withwith ( P)-helicene)-helicene 9999 asas a catalyst. a catalyst. It was It was also alsoobserved observed that orthothat -substitutedortho-substituted aldehydes aldehydes100 always100 always provided provided higher higheree than ee thethan corresponding the correspondingpara-substituted para- derivatives,substituted regardless derivatives, of the regardless functional of group the attached.functional Thisgroup key attached. experimental This observationkey experimental indicated that,observation out of two possibleindicated transitionthat, out of states two possible (Figure transi 11a,b),tion in states one of(Figures them, 11a, theb), hydrogen in one of orthem, substituent the at thehydrogenortho position or substituent of aldehyde at the ortho100 results position in of steric aldehyde clash 100 with results catalyst in steric99 ,clash which with is responsiblecatalyst 99, for the stereoselectivity.which is responsible Thus, for thethe stereoselectivity. suggested transition Thus, statethe suggested model showed transition preference state model for showed the Si -face additionpreference with π -forπ stacking the Si-face between addition the with bound π-π aldehyde stacking 100betweenand thethe bezofusedbound aldehyde helicene 100 framework and the of bezofused helicene framework of 99 (Figure 11a), whereas the Re-face approach is disfavored due to 99 (Figure 11a), whereas the Re-face approach is disfavored due to the steric hindrance in the transition the steric hindrance in the transition state (Figure 11b), where the reactants 100 and 101 and catalyst state99 (Figure are coordinated 11b), where through the reactants the silicon100 and atom.101 Aand separate catalyst DFT-based99 are coordinated computational through study the also silicon atom.supported A separate this DFT-based mechanism computational[69]. study also supported this mechanism [69].

FigureFigure 11. Proposed 11. Proposed transition transition state state models models showingshowing preference preference for for (a) ( afavorable) favorable Si-faceSi-face attack attack and and (b) unfavorable(b) unfavorableRe-face Re-face attack, attack, with with (P (P)-)-9999catalyst. catalyst. The The bottom bottom and and top top parts parts of the of thetransition transition state state modelsmodels are markedare marked in bluein blue and and black, black, respectively,respectively, whilst whilst the the coordinated coordinated SiCl2 SiCl2 group group with withthe the corresponding bonds are marked in magenta. corresponding bonds are marked in magenta. Azahelicenes have also been investigated as hydrogen bond donor chiral catalysts. The Azahelicenesasymmetric addition have also of azole been nucleophiles investigated to as nitr hydrogenoalkenes bondusing donorvarious chiral hydrogen catalysts. bond The catalysts asymmetric is additionknown. of azole In this nucleophiles respect, aminopyridinium to nitroalkenes salts using are al variousso capable hydrogen of activating bond nitroalkenes catalysts is through known. the In this respect,hydrogen aminopyridinium bond donating salts ability are to also the capable nitro grou ofp. activating For this purpose, nitroalkenes aza[6]helicene through thederivatives hydrogen 103 bond donatingand 104 ability, having to the a 2-aminopyridinium nitro group. For ring this at purpose, the peripheral aza[6]helicene position, have derivatives been prepared103 and [70].104 Hence,, having a 2-aminopyridiniumthe asymmetric addition ring at theof 4,7-dihydroindole peripheral position, 105 to have nitrostyrene been prepared 106 using [70 chiral]. Hence, (P)-helicenes the asymmetric 103 and 104 as catalysts, followed by oxidative aromatization, afforded exclusively β-nitro-indol-2-yl 107 addition of 4,7-dihydroindole 105 to nitrostyrene 106 using chiral (P)-helicenes 103 and 104 as catalysts, with relatively high yield and ee (Scheme 18). β 107 followed byIt was oxidative observed aromatization, that the increased afforded bulk exclusivelyiness of the -nitro-indol-2-ylamino group gives awith higher relatively ee. Thus, high the yield and eeresults(Scheme of (P 18)-104). in terms of ee ratio were as follows for the corresponding R: H (69:31) = Bn (69:31) < Itt-Bu was (92:8) observed = 1-adamantyl that the (92:8). increased Further, bulkiness the yields of thewere amino noticeably group improved gives a higher from 79%ee. Thus,(for the the t-Bu results of (P)-derivative)104 in terms to of88%ee ratio(for the were adamantyl as follows derivative) for the corresponding under similar R: conditions; H (69:31) = hence, Bn (69:31) adamantyl- < t-Bu (92:8) = 1-adamantylcontaining (92:8).(P)-104Further, is the optimal the yields organocatalyst were noticeably for this improved reaction from(see the 79% corresponding (for the t-Bu results derivative) to 88%summarized (for the adamantyl in Scheme derivative) 18). Further, under the similarenhanced conditions; effectiveness hence, of 104 adamantyl-containing in comparison with( P103)-104 is the optimalindicates organocatalyst that the benzofused for this helicene reaction framework (see the affects corresponding the ee value results by covering summarized the space in beneath Scheme 18). Further,the two the hydrogen enhanced bonds effectiveness [70], and isof thus104 similarin comparison to the case shown with 103in Figureindicates 11. that the benzofused Another example of the activation of nitroalkenes via the hydrogen bonding donor helicene framework affects the ee value by covering the space beneath the two hydrogen bonds [70], characteristics was demonstrated by using aminopyridinium-based (M)-[6]helicene 108 in the and isasymmetric thus similar Diels–Alder to the case reaction shown between in Figure cyclopentadienes 11. 109 and nitroethylene 110 to give the Anothercycloadduct example product of the111 activationin moderate of nitroalkenes30–40% ee [71]. via theA traditional hydrogen hydr bondingogen donorbonded characteristics catalyst was demonstratedgenerally requires by using the complementary aminopyridinium-based donor–acceptor (M)-[6]helicene units in both108 reactantsin the asymmetricto orient specifically Diels–Alder reactionfor asymmetric between cyclopentadienes induction in the addition109 and reaction. nitroethylene However,110 hereto giveis a case the where cycloadduct one counterpart product is111 in moderatea nonfunctionalized 30–40% ee [71]. cyclopentadiene A traditional hydrogen 109, unsuitable bonded for catalyst hydrogen generally bonding. requires Therefore, the complementary the (M)- donor–acceptorhelicene catalyst units 108 in used both has reactants a aminopyridinium to orient specifically peripheral for ring asymmetric which only inductionbinds to nitroethylene 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 Symmetry 2018, 10, 10 20 of 48 Symmetry 2018, 10, 10 20 of 48 Symmetry 2018, 10, 10 20 of 48 peripheral110 (dienophile) ring whichthrough only the correspon binds to nitroethyleneding hydrogen110 bonding.(dienophile) The ster througheospecificity the correspondingof this reaction 110 (dienophile) through the corresponding hydrogen bonding. The stereospecificity of this reaction hydrogenwas achieved bonding. in the following The stereospecificity manner: the helical of this backbone reaction wasof (M achieved)-108 blocks in the one following of the faces manner: of 110, was achieved in the following manner: the helical backbone of (M)-108 blocks one of the faces of 110, theleaving helical another backbone face ofaccessible (M)-108 toblocks 109 (diene), one of the hence faces making of 110 ,the leaving whole another reaction face enantioselective accessible to 109 in leaving another face accessible to 109 (diene), hence making the whole reaction enantioselective in (diene),nature (Scheme hence making 19). the whole reaction enantioselective in nature (Scheme 19). nature (Scheme 19). MostMost ofof thethe successfulsuccessful examplesexamples of azahelicenesazahelicenes (91–93,, 99,, 103103,, 104104,, 108108)) asas organocatalystsorganocatalysts Most of the successful examples of azahelicenes (91–93, 99, 103, 104, 108) as organocatalysts describeddescribed here havehave aa nitrogennitrogen atomatom atat thethe 1-position1-position ofof thethe innermostinnermost partpart ofof thethe helicenehelicene withwith described here have a nitrogen atom at the 1-position of the innermost part of the helicene with additionaladditional substituents at the 1- oror 2-position2-position to modifymodify thethe reactivityreactivity asas wellwell asas thethe helicityhelicity (chiral(chiral additional substituents at the 1- or 2-position to modify the reactivity as well as the helicity (chiral cavitycavity space),space), to facilitatefacilitate accessibility of the reactantreactant in a stereospecificstereospecific manner,manner, andand toto enhanceenhance cavity space), to facilitate accessibility of the reactant in a stereospecific manner, and to enhance asymmetricasymmetric output.output. asymmetric output.

SchemeScheme 18.18. Asymmetric addition reaction between 4,7-dihydroindole 105105 andand nitrostyrene 106106 usingusing Scheme 18. Asymmetric addition reaction between 4,7-dihydroindole 105 and nitrostyrene 106 using chiralchiral ((PP)-helicenes)-helicenes 103103 andand 104104 asas hydrogenhydrogen bondbond donordonor catalysts.catalysts. 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 Scheme 19. (M)-helicene 108 as a hydrogen bond catalyst for asymmetric Diels–Alder reaction Schemebetween 19.cyclopentadiene(M)-helicene 108 109as and a hydrogen nitroethylene bond catalyst110. for asymmetric Diels–Alder reaction between cyclopentadienebetween cyclopentadiene109 and nitroethylene 109 and nitroethylene110. 110. Carbohelicenes 5 and 6 and heterohelicene 112, devoid of any functional group, are also able to 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- act as chirality inducers in selected asymmetric reactions. Soai et al. have successfully used electron-

Symmetry 2018, 10, 10 21 of 48

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 2,20-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 115 (∆H‡ = 106 ± 3 kJ mol−1 and ∆S‡ = −10.0 ± 0.1 J mol−1 K−1) as determined by 1H NMR was found to be even higher than that of (P)-[5]helicene 116 (∆H‡ = 95.8 kJ mol−1 and ∆S‡ = −17.2 J mol−1 K−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 Symmetry 2018, 10, 10 22 of 48

with configurational stability. In this respect, Yamaguchi et al. have extensively explored the Symmetrysynthetic 2018, 10 chemistry, 10 and applications of functionalized dimethyl[4]helicene in different fields [7522]. of 48 SymmetryThus, 2018 (P,P, 10)-[4]helicene, 10 cycloamides 120–122 were prepared from well-known rac-diketone 123 via22 of 48 resolveddicyanohelicene by using the124 ,chiral which ba wasse convertedquinine through to helicene diastereomer diacid 125 byic alkaline salt formation. hydrolysis. Finally, Then, helicene(P)-125 was resolvedconverteddiaicid by to125 using acidwas chloridethe resolved chiral and byba sethen using quinine coupled the chiralthrough with base adiastereomer suitable quinine throughdiamineic salt diastereomericlinker formation. 126 to Finally, obtain salt formation. cycloamides(P)-125 was converteddimerFinally, 120 to(24%), (P acid)-125 trimerchloridewas converted 121 and (23%), then to acidand coupled chloridetetramer with and 122 a then suitable(19%) coupled (Scheme diamine with 22) a linker suitable [76]. 126 diamine to obtain linker cycloamides126 to dimerobtain 120 (24%), cycloamides trimer dimer 121 (23%),120 (24%), and trimertetramer121 122(23%), (19%) and (Scheme tetramer 22)122 [76].(19%) (Scheme 22)[76].

Scheme 20. Asymmetric autocatalysis initiated by carbohelicenes (P)-5, (P)-6, and heterohelicene Scheme(P)-112Scheme. 20. 20.AsymmetricAsymmetric autocatalysis initiated initiated by carbohelicenesby carbohelicenes (P)-5,( P()-P6)-,5 and, (P heterohelicene)-6, and heterohelicene (P)-112. (P)-112.

SchemeScheme 21. 21.(a) (Synthesisa) Synthesis of of(P (,PP,)-HELOLP)-HELOL 115115 and ((bb)) itsits application application in in asymmetric asymmetric diethyl diethyl zinc zinc Schemeadditionaddition 21.to benzaldehydes to(a) benzaldehydes Synthesis of100 100(P. ,.P)-HELOL 115 and (b) its application in asymmetric diethyl zinc addition to benzaldehydes 100.

Symmetry 2018, 10, 10 23 of 48

Symmetry 2018, 10, 10 23 of 48 Symmetry 2018, 10, 10 23 of 48

Scheme 22. Synthesis of (P,P)-helicene cycloamides 120–122 from diketone 123. Scheme 22. Synthesis of (P,P)-helicene cycloamides 120–122 from diketone 123. 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 Interestingly,helicene but in not this at the example, helical chiral the cavity functionalized as in previous aminoexamples; groups this makes are it presentremarkably at different. the outer core of Interestingly, in this example, the functionalized amino groups are present at the outer core of the the heliceneYet, butwhen not it is at dimerized the helical with a chiral suitable cavity linker such as inas cycloamide previous 120 examples;, the chirality this of the makes helicene it remarkablyis helicene transferredbut not at tothe a helicalmacrocycloamide, chiral cavity which as inessentially previous provides examples; a chiral this pocket makes for it remarkablythe asymmetric different. different. Yet, when it is dimerized with a suitable linker such as cycloamide 120, the chirality of Yet, whencatalytic it is dimerized transformations. with Macrocycloamides a suitable linker such such as as(P ,cycloamideP)-120 have been 120 applied, the chirality for the asymmetric of the helicene is thetransferred helicenenucleophilic isto transferred a macrocycloamide, addition to of a diethyl macrocycloamide, whichzinc to essentiallyaromatic which aldehydes provides essentially 100 awith chiral providesgood pocket yields a for(51–88%) chiral the pocket asymmetricand for the moderate enantioselectivities (27–50% ee) upon use of up to 5 mol % catalyst (Scheme 23) [76]. asymmetriccatalytic transformations. catalytic transformations. Macrocycloamides Macrocycloamides such as (P,P)- such120 have as (P been,P)-120 appliedhave for been the applied asymmetric for the asymmetricnucleophilic nucleophilic addition of addition diethyl ofzinc diethyl to aromatic zinc to aromaticaldehydes aldehydes 100 with100 goodwith yields good (51–88%) yields (51–88%) and andmoderate moderate enantioselectivities enantioselectivities (27–50% (27–50% ee) uponee) uponuse of use up to of 5 up mol to % 5 molcatalyst % catalyst (Scheme (Scheme 23) [76]. 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

SchemeScheme 23. 23.(P,P (P,P)-helicene)-helicene cycloamide cycloamide dimer dimer120 catalyzed120 catalyzed asymmetric asymmetric diethyl diethyl zinc additionzinc addition to aromatic to aldehydesaromatic 100aldehydes. 100.

It has been clearly demonstrated that helicene-based asymmetric organocatalysis is a highly promisingIt has been and clearlyexciting demonstrated field in terms thatof the helicene-based enantioselectivity asymmetric obtained organocatalysis with the lowest iscatalyst 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 Symmetry 2018, 10, 10 24 of 48 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 = KR/KS = 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 (Figure8). 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 Symmetry 2018, 10, 10 25 of 48

Symmetry 2018, 10, 10 25 of 48 pentahelicene and heptahelicene backbones [78,79]. The synthesis was performed by a classical Symmetry 2018, 10, 10 25 of 48 strategycondensation via Wittig followed condensation by photochemical followed cyclization. by photochemical Finally, the cyclization. construction Finally, of crown the constructionethers and ofsubsequent crowncondensation ethers resolution andfollowed subsequent of byenantiom photochemical resolutioners using cyclization. a ofchiral enantiomers columnFinally, packedthe using construction with a chiral (+)-poly-(triphenylmethyl of columncrown ethers packed and with (+)-poly-(triphenylmethylmethacrylate)subsequent resolutionwith methanol of methacrylate) enantiom as aners eluting using with solventa methanol chiral resultedcolumn as an packedin eluting enantiomers with solvent (+)-poly-(triphenylmethyl of resulted 140 and in 141 enantiomers. Then, of enantiopure140methacrylate)and 141 140. Then, withand 141 enantiopuremethanol were investigated as an140 elutingand towards141 solventwere application resulted investigated in inenantiomers the towards chiral discrimination of application 140 and 141 inof. Then,racemic the chiral discriminationamineenantiopure salts 142of 140– racemic144 and (Figure 141 aminewere 12). investigated saltsThis 142process– 144towards was(Figure applicationbased 12 ).on This thein the processselective chiral discrimination wasdifferent basedial ontransports of theracemic selective of differentialrecognizableamine salts transports enantiomers 142–144 of (Figure recognizable from 12). an aqueousThis enantiomersprocess soluti wason tobased from the correspondingon an the aqueous selective solution organic different solvent toial the transports corresponding(CHCl3 ) ofby a organicliquid–liquidrecognizable solvent extraction (CHCl enantiomers) by procedure. a from liquid–liquid an aqueousThe 1H extraction NMR soluti onanalysis to procedure. the correspondingof the extracted The 1H organic NMR organic analysissolvent layer (CHCldisplayed of the3) extractedby atwo 3 1 distinctliquid–liquid -–CO2Me extraction signals ofprocedure. the representing The H NMR diastereoisomeric analysis of the complexesextracted organic with the layer guest, displayed 142. Finally, two organic layer displayed two distinct –CO2Me signals of the representing diastereoisomeric complexes distinct -–CO2Me signals of the representing diastereoisomeric complexes with the guest, 142. Finally, withthe the amount guest, of142 transported. Finally, theguest amount was analyzed of transported by a reverse guest extraction was analyzed back to by an a reverseaqueous extraction acidic phase back followedthe amount by the of measurementtransported guest of its was UV analyzed absorption. by a reverse extraction back to an aqueous acidic phase to anfollowed aqueous by acidic the measurement phase followed of its UV by theabsorption. measurement of its UV absorption.

SchemeScheme 24. ( 24.a) Synthesis(a) Synthesis and and resolution resolution of ofHELIXOL HELIXOL host, host, 127127; (;(b)b Structures) Structures of chiral of chiral guest guest amines amines Scheme128–131 24. and (a) amino Synthesis alcohols and 132resolution–135 used of for HELIXOL enantioselective host, 127 recognition; (b) Structures studies. of chiral guest amines 128128–131–131and and amino amino alcohols alcohols132 132–135–135used usedfor for enantioselectiveenantioselective recognition studies. 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. FigureFigure 12. 12.[5]helicene- [5]helicene- and and [6]helicene-bearing [6]helicene-bearing crown ethers ethers 140140 andand 141141 capablecapable of of enantioselective enantioselective extraction of chiral amine salts 142–144 from aqueous to organic layer. extractionIt was of observed chiral amine that salts the 142[5]helicene-based–144 from aqueous crown to organicether 140 layer. showed higher enantioselective extracting ability than the [6]helicene-based crown ether 141. For example, (M)-140 was able to It was observed that the [5]helicene-based crown ether 140 showed higher enantioselective Ittransport was observed 6% of (S)- that142, with the optical [5]helicene-based purity of 75% crown in 6 h, comparatively ether 140 showed better than higher (M)- enantioselective141 with 2% extracting ability than the [6]helicene-based crown ether 141. For example, (M)-140 was able to extractingtransport ability of 26% than optical the [6]helicene-basedpurity of opposite crownenantiomer ether (R141)-142. in For the example, same time. (M )-The140 observedwas able to transport 6% of (S)-142, with optical purity of 75% in 6 h, comparatively better than (M)-141 with 2% transport 6% of (S)-142, with optical purity of 75% in 6 h, comparatively better than (M)-141 with transport of 26% optical purity of opposite enantiomer (R)-142 in the same time. The observed

Symmetry 2018, 10, 10 26 of 48

2% transportSymmetry 2018 of, 26%10, 10 optical purity of opposite enantiomer (R)-142 in the same time. The26 observed of 48 opposite enantioselectivity extraction using helicenes 140 and 141 with the same helical sense was opposite enantioselectivity extraction using helicenes 140 and 141 with the same helical sense was rationalizedrationalized by the by phenomenonthe phenomenon of changingof changing the the crown crown ether ether conformation conformation [ 80[80];]; this this isis evidentevident inin their CPKtheir models. CPK Additionally,models. Additionally, the inner the inner methyl methyl groups groups also also assist assist in in the the chiral chiral recognition process, process, as suggestedas suggested by the by same the modelssame models [78,79 [78,79].]. AnotherAnother approach approach to chiral to chiral recognition recognition was was undertaken undertaken by Katzby Katz et al. et via al. developingvia developing the helicene-the basedhelicene-based biaryl diol compound biaryl diol namedcompound (M,M named)-[5]HELOL, (M,M)-[5]HELOL,115 [81], which115 [81], was which based was on based enantiopure on 1-hydroxyenantiopure substituted 1-hydroxy [5]helicene substituted (see [5]helicene116 in Scheme (see 116 20in ).Scheme The in 20). situ The generated in situ generated chloro chloro phosphite derivativephosphite145 wasderivative used as145 a chiralwas used NMR as a derivatizing chiral NMR agentderivatizing to discriminate agent to discriminate alcohols or alcohols amines servingor amines serving as nucleophilic guests. From the 31P NMR analysis of diastereomeric mixture 146, the as nucleophilic guests. From the 31P NMR analysis of diastereomeric mixture 146, the enantiomeric enantiomeric excess of guests (alcohols or amines) was easily determined. An interesting feature of excess of guests (alcohols or amines) was easily determined. An interesting feature of this sensor this sensor is its ability to sense a remote chirality, which locates far away from the phosphite group. is itsThis ability is related to sense to the a remotefact that chirality,the combined which inne locatesr cavity farformed away by fromindividual the phosphite helicene units group. and the This is relatedbiaryl to the bond fact yields that an the extended combined chiral inner space cavity in 115 formed. For example, by individual this chiral helicene space is able units to andrecognize the biaryl bondthe yields asymmetric an extended centers chiral of 8-phenylnonanol space in 115 .147 For (as example, far as up thisto seven chiral methylene space is units) able toand recognize vitamin the asymmetricE 148 (Scheme centers 25). of Additionally, 8-phenylnonanol the recognition147 (as abilit far asy of up this to sensor seven was methylene related to units) 100% abundance and vitamin E 148 (Schemeof phosphorus 25). Additionally, as NMR active the nuclei recognition with high ability sensitivity of this and sensor accuracy was in related measurement; to 100% thus, abundance the of phosphorusenantiomeric as excess NMR of active up to nuclei3% can with be easily high an sensitivityalyzed [81]. and The accuracyscope of this in measurement;HELOL host and thus, its the enantiomericstructural excessanalogue of were up to further 3% can extended be easily toward analyzeds other [nucleophiles81]. The scope such of as thisalcohols, HELOL phenols, host and amines, and carboxylic acids, also containing a remote chirality, under similar methodology to the its structural analogue were further extended towards other nucleophiles such as alcohols, phenols, 31P NMR-based enantiodiscrimination [82]. amines, and carboxylic acids, also containing a remote chirality, under similar methodology to the 31P NMR-based enantiodiscrimination [82].

SchemeScheme 25. ( a25.) 31 (aP) based31P based diastereomeric diastereomeric NMR NMR sensingsensing of of alcohols alcohols and and amines amines using using (M,M (M,M)-HELOL)-HELOL 115 and115 (andb) examples (b) examples of remoteof remote chirality chirality sensing sensing withwith molecules 147147 andand 148148. .

Symmetry 2018, 10, 10 27 of 48 Symmetry 2018, 10, 10 27 of 48

A new chiral application as a chiroptical switch along with chiral recognition properties was demonstrated using using enantiom enantiomericallyerically pure pure [6]helicene [6]helicene o-quinoneo-quinone 149149. The. The synthesis synthesis was was carried carried out outby using by using the Nickel-catalyzed the Nickel-catalyzed [2 + 2 [2 + +2] 2cyclotrimerization + 2] cyclotrimerization reaction reaction of triyne of triyne150, followed150, followed by the bydeprotection the deprotection of the methoxy of the methoxy group groupin 151 into 151resultto resultin helicene in helicene diol 152 diol in152 a racemicin a racemic form. form. The Theenantiomers enantiomers of 152 ofwere152 separatedwere separated on chiral on HPLC, chiral followed HPLC,followed by the silver by theoxide-mediated silver oxide-mediated oxidation, oxidation,to give the toquinone give the 149 quinone in quantitative149 in quantitative yield (Scheme yield 26) (Scheme [83]. 26)[83]. In general,general, quinonesquinones are are electrochemically electrochemically redox redox active active molecules molecules which which undergo undergo reduction reduction as diol as anionsdiol anions and re-oxidation and re-oxidation back to quinone,back to withquinone, the corresponding with the corresponding measurable structural measurable transformations structural intransformations chromophoric in absorption chromophoric (Figure absorption 13a). Therefore, (Figure the 13a). helicene-based Therefore, the quinone helicene-based149 was also quinone tested 149 for thewas same, also tested with an for additional the same, possibility with an additional of chiroptical possibility switching of aschiroptical observed byswitching CD measurement. as observed Both by theCD enantiomersmeasurement. of Both149 exhibitedthe enantiomers a one-electron of 149 exhibited reduction a one-electron process to form reduction the semiquinone process to form radical the − + anions,semiquinone149 radical, as evident anions, from 149 cyclic●−, as voltammetryevident from studiescyclic voltammetry with E1/2 = −studies1.00 V with (vs Fc E1/2/0, = −∆1.00Ep = V 0.07 (vs − V)Fc+ in/0, acetonitrile,ΔEp = 0.07 V) with in aacetonitrile, reversible electrochemical with a reversible behavior. electrochemical Since 149 behavior.is a stable Since species, 149●− itsis UVa stable and CDspecies, measurements its UV and were CD measurements performed by using were anperfor opticallymed by transparent using an thinoptically layer transparent electrochemical thin cell. layer It waselectrochemical observed that cell. the It helicenewas observed quinone that149 theis helicene able to be quinone reversibly 149 reduced is able to to be the reversibly radical anion reduced149 to− andthe radical re-oxidized anion over149●− severaland re-oxidized cycles, and over is several an example cycles, of and chiroptical is an example switching of chiroptical to be conveniently switching monitoredto be conveniently with CD monitored spectroscopy with at CD different spectroscopy wavelengths at different (Figure wavelengths 13b) owing (Figure to the distinguishable 13b) owing to − spectralthe distinguishable profiles of spectral149 and profiles149 . However,of 149 and as149 there●−. However, is no change as there in theis no (P change) or (M in) helicity the (P) or of ( theM) chromophorehelicity of the chromophore upon electrochemical upon electrochemical transformations, transformations, the Cotton effect the Cotton (CE) signs effect of (CE)149 signsand 149of 149− remainedand 149●− remained the same. the same. Besides electrochemical switching, 149●−− waswas tested tested for for chiral chiral recognition recognition against against 2,2 ′0-- bis(diphenylphosphanyl)-1,1bis(diphenylphosphanyl)-1,1′0-binaphthyldioxide-binaphthyldioxide (BINAPO) (BINAPO) using using electron electron paramagnetic resonance and electron–nuclear double resonance (ENDOR) spectroscopy.spectroscopy. The diastereomeric species formed by coordinatedcoordinated lithiatedlithiated semiquinonesemiquinone radicalradical anionsanions [Li+{( [Li+{(±)-±)-149 ●−−}]}] and and enantiomers enantiomers of BINAPOBINAPO generated noticeable changes of the lithium and proton hyperfinehyperfine coupling measured by ENDOR spectroscopy. TheThe diastereoisomericdiastereoisomeric complex complex153 153exhibits exhibits a hyperfinea hyperfine coupling coupling constant constant (A) (A) value value for 7forLi 7 atLi− at1.62 −1.62 MHz, MHz, in in comparison comparison to to− −1.761.76 MHz MHz forfor anotheranother diastereomericdiastereomeric complexcomplex 154,, indicatingindicating the appreciable difference betweenbetween thethe diastereomersdiastereomers (Figure(Figure 1414).). ItIt is of note that the racemic sample gives an average value of −1.691.69 MHz. MHz.

Scheme 26.26. SynthesisSynthesis and and resolution resolution of heliceneof helicene quinone quinone149 from 149 triynefrom 150triyneusing 150 the using nickel-catalyzed the nickel- [2catalyzed + 2 + 2] [2 cyclotrimerization + 2 + 2] cyclotrimerization reaction as reaction a key step. as a key step.

Symmetry 2018, 10, 10 28 of 48 Symmetry 2018, 10, 10 28 of 48 Symmetry 2018, 10, 10 28 of 48

Figure 13. (a) Mechanism of reversible electrochemical switching of helicene quinone 149 to helicene Figure 13. (a) Mechanism of reversible electrochemical switching of helicene quinone 149 to helicene semiquinoneFigure 13. (a ) radicalMechanism anions of reversible149●−; (b) electrochemicalobserved reversible switching chiroptical of helicene switching quinone between 149 to 149helicene and semiquinone radical anions 149 −;(b) observed reversible chiroptical switching between 149 and 149semiquinone●−; monitored radical by CD anions spectroscopy 149●−; (b in) observedacetonitrile. reversible Reversible chiroptical electrochemical switching switching between for 149 several and 149 −; monitored by CD spectroscopy in acetonitrile. Reversible electrochemical switching for several cycles149●−; monitoredis shown for by theCD (spectroscopyM)-(−) enantiomer in acetonitrile. at two di Reversiblefferent wavelengths electrochemical (top right) switching along for with several the cycles is shown for the (M)-(−) enantiomer at two different wavelengths (top right) along with the correspondingcycles is shown CD for spectra. the (M (Fig)-(−)ure enantiomer 13b) reprinted at two from diff erent[83]. © wavelengths 2014, American (top Chemical right) along Society. with the correspondingcorresponding CD CD spectra. spectra. (Figure (Figure 13 13b)b) reprinted reprinted fromfrom [[83].83]. © 2014, American Chemical Chemical Society. Society.

Figure 14. ENDOR spectra of diastereomeric species, 153 (black) and 154 (red) in THF at 210 K, only FiguretheFigure low-frequency 14. 14.ENDOR ENDOR spectra region spectra is of ofshown. diastereomeric diastereomeric Reprintedspecies, species, from [83]. 153153 © (black) 2014, American and and 154154 (red) (red)Chemical in in THF THF Society. at at 210 210 K, K, only only thethe low-frequency low-frequency region region is is shown. shown. Reprinted Reprinted from from [ [83].83]. ©© 2014,2014, American Chemical Chemical Society. Society. The previously described examples, 127 [77] and 115 [81], represent the inbuilt chiral helicene chromophoricThe previously hosts describedfor the chiral examples, recognition 127 [77] of anda general 115 [81], class represent of chiral the molecules inbuilt chiral using helicene some The previously described examples, 127 [77] and 115 [81], represent the inbuilt chiral helicene selectedchromophoric analytical hosts techniques for the chiral such asrecognition fluorescenc ofe anda general NMR spectroscopy.class of chiral An molecules essentially using different some chromophoric hosts for the chiral recognition of a general class of chiral molecules using some approachselected analytical has been techniques recently developed such as fluorescenc by Karnike and et al.NMR on spectroscopy.the basis of aAn new essentially supramolecular different selected analytical techniques such as fluorescence and NMR spectroscopy. An essentially different chirogenicapproach hassystem, been 155 recently, the key developed element ofby whichKarnik was et al.a stereodynamic on the basis ofdioxa[6]helicene a new supramolecular diol 156 approach has been recently developed by Karnik et al. on the basis of a new supramolecular chromophore.chirogenic system, This system155, the was key applied element as ofa spec whichific sensor,was a stereodynamicsuitable for chirality dioxa[6]helicene sensing of trans diol-1,2- 156 chirogeniccyclohexanediaminechromophore. system, This155 system 157, the and keywas monitored applied element asby of avarious whichspecific spectroscopic was sensor, a stereodynamic suitable methods for chirality [84]. dioxa[6]helicene The sensing helicene of trans 156 diol was-1,2-156 chromophore.synthesizedcyclohexanediamine from This 2,7-dihydroxynaphthalene system 157 and wasmonitored applied by various as a158 specific spectroscopic[85]. sensor,The first methods suitable step [84].involved for The chirality helicene acid-catalyzed sensing 156 was of transcondensationsynthesized-1,2-cyclohexanediamine frombetween 2,7-dihydroxynaphthalene two 157moleculesand monitored of 158 and 158 by glyoxal various[85]. Theto spectroscopic obtain first dihydrofurofuranstep methodsinvolved [ 84acid-catalyzed]. 159 The (>95%), helicene 156followedcondensationwas synthesized by the between protection from two 2,7-dihydroxynaphthalene ofmolecules phenolic of groups 158 and to glyoxalgive158 acetate[85 to]. obtain The 160 first (95%).dihydrofurofuran step Then, involved one-pot acid-catalyzed 159 benzylic (>95%), condensationbrominationfollowed by between andthe dehydrobrominationprotection two molecules of phenolic of(aromatization) groups158 and to glyoxal give of acetate160 to using obtain 160 N (95%).-bromosuccinamide dihydrofurofuran Then, one-pot 159led benzylic to(>95%), 161 followed(45%),bromination followed by the and protection by dehydrobromination basic hydrolysis of phenolic resulting (aromatization) groups in to dioxa[6]helicene give of acetate 160 using160 diol N(95%).-bromosuccinamide 156 (96%). Then, Finally, one-pot ledselective benzylic to 161 bromination(45%), followed and dehydrobromination by basic hydrolysis resulting (aromatization) in dioxa[6]helicene of 160 using diolN-bromosuccinamide 156 (96%). Finally, selective led to 161

Symmetry 2018, 10, 10 29 of 48

Symmetry 2018, 10, 10 29 of 48 (45%), followed by basic hydrolysis resulting in dioxa[6]helicene diol 156 (96%). Finally, selective mono esterificationesterification with with chiral chiral (1 (1S)-camphanicS)-camphanic chloride chloride in acetonein acetone afforded afforded the desiredthe desired host, host,155, with155, 90%with yield90% yield (Scheme (Scheme 27)[85 27)]. [85].

Scheme 27. Multistep synthesis of helicene camphanate 155 from 2,7-dihydroxynaphthalene2,7-dihydroxynaphthalene 158158..

Indeed,Indeed, the parent dioxa[6]helicenedioxa[6]helicene diol 156 isis almostalmost aa flatflat stereodynamic-typestereodynamic-type fluorescentfluorescent compound, whichwhich was selectively modifiedmodified withwith aa chiral (1S)-camphanate)-camphanate groupgroup toto givegive 155,, leavingleaving one of the (phenolic) hydroxyl groups free. This inherently free phenolic group and (1S)-camphanate chiral handle on on the the opposite opposite peri peripheralpheral ring ring provided provided a suitable a suitable sui suigeneris generis chiralchiral space space for guest for guest 157. 157In particular,. In particular, this perfect this perfect stereosp stereospecificecific matching matching results in results an effective in an turn-on effective fluorescent turn-on fluorescent sensor for the (S,S)-enantiomer of 157 with a relatively high enantioselective factor, α = KSS/KRR = 6.3 (in sensor for the (S,S)-enantiomer of 157 with a relatively high enantioselective factor, α = KSS/KRR = 6.3 (inbenzene). benzene). The favorable The favorable hydrogen-bonding hydrogen-bonding interactio interactionsns in nonpolar in media nonpolar (benzene media and (benzene toluene) and are toluene)responsible are for responsible the efficient for chiral the efficient recognition chiral observ recognitioned by fluorescence observed by spectroscopy fluorescence (Figures spectroscopy 15a,b). (FigureIn nonpolar 15a,b). media, In nonpolar the donor–acceptor media, the donor–acceptor type cooperative type hydrogen cooperative bonding hydrogen between bonding host between155 and hostguest155 157and (Figure guest 15715c)(Figure resulted 15c) in resulted a high in turn-on a highturn-on enantioselective enantioselective fluorescence fluorescence response. response. The Theenantiodiscrimination enantiodiscrimination behavior behavior was found was found to be to so belvent-dependent solvent-dependent as the as polarity the polarity of solvent of solvent can caninfluence influence the theextent extent of hydrogen of hydrogen bonding bonding betwee betweenn the the host host and and guest. guest. In In turn, turn, this this induces a unidirectional switch in the helical conformation of the helicenehelicene chromophore, resulting in reversereverse selectivity forfor thethe ((R,RR,R)-enantiomer)-enantiomer ofof 157157 inin acetonitrile,acetonitrile, THF,THF, andand chloroformchloroform [ [84].84]. Further, thethe NMRNMR studies performed in deuterated chloroform exhibited the chiral camphanate −6 −7 −3 −1 group transfertransfer reaction reaction (Scheme (Scheme 28 28a)a) with with the the reaction reaction rate rate of 5.83 of 5.83× 10 ×− 610and and5.97 5.97× 10 × −107 mol mol dm dm−3 s −s 1 1 forfor ((R,RR,R)-)-157157 andand ((S,SS,S)-)-157157,, respectively, respectively, as as monitored monitored by by1H H NMR NMR (Figure (Figure 15 15d).d). This This tenfold tenfold increase increase of theof the reaction reaction rate rate for thefor (R,Rthe )-enantiomer(R,R)-enantiomer allowed allowed the host the155 hostto behave155 to asbehave a kinetic as a resolving kinetic resolving agent for (agentR,R)-157 for, ( withR,R)- up157 to, with 68% deupat to room 68% temperaturede at room temperature within 4 h (Figure within 15 4 d)h (Figure [84]. 15d) [84].

Symmetry 2018, 10, 10 30 of 48 Symmetry 2018, 10, 10 30 of 48

Figure 15. Fluorescence response of helicene camphanate 155 for trans-1,2-cyclohexanediamine Figure 15. Fluorescence response of helicene camphanate 155 for trans-1,2-cyclohexanediamine 157 157 (a) in benzene and (b) in toluene solvent; (c) Schematic representation of the donor–acceptor (a) in benzene and (b) in toluene solvent; (c) Schematic representation of the donor–acceptor hydrogen hydrogen bonding between 155 and 157 in nonpolar solvent with turn-on fluorescence response; bonding between 155 and 157 in nonpolar solvent with turn-on fluorescence response; (d) Time- (d) Time-dependent changes observed in 1H NMR spectra of host 155 with 1:1 (R,R)-157 in CDCl3. Reprinteddependent from changes [84]. observed Source: http://pubs.acs.org/doi/abs/10.1021/acsomega.6b00522 in 1H NMR spectra of host 155 with 1:1 (R,R)-157 in CDCl. 3. Reprinted from [84]. Source: http://pubs.acs.org/doi/abs/10.1021/acsomega.6b00522.

Indeed, thisthis is is a rarea rare example example of theof thesui genericsui generichost–guest host–guest pair as pair evident as evident from the from fact thatthe fact diamine that 157diamine, upon 157 supramolecular, upon supramolecular interaction withinteraction the parent with stereodynamic the parent stereodynamic helicene diol 156 helicene(Scheme diol 28 b)156 is able(Scheme to induce 28b) is a specificable to induce helicity a and specific shift helicity the stereodynamic and shift the equilibrium stereodynamic of 156 equilibrium, as monitored of 156 by CD, as spectroscopymonitored by inCD the spectroscopy region of helicene in the chromophoreregion of helicene absorption. chromophore absorption. Further, the same group also developed Cs-symmetric rigid achiral organophosphoric acid 163 Further, the same group also developed Cs-symmetric rigid achiral organophosphoric acid 163 in intwo two steps, steps, starting starting from from dihyrofurofuran dihyrofurofuran helicene helicene 159 159as aas supramolecular a supramolecular chirogenic chirogenic system system for forthe theabsolute absolute configuration configuration determination determination of 1,2-amino of 1,2-amino alcohols alcohols by induced by inducedCD (ICD) CD studies (ICD) [86]. studies The two- [86]. Thestep two-stepsynthesis synthesisincludes includesthe reacti theon reactionof dihyrofurofuran of dihyrofurofuran helicene 159 helicene with 159formaldehydewith formaldehyde to form an to form an additionally bridged diol, 164, and subsequent reaction with POCl to obtain the target, 163 additionally bridged diol, 164, and subsequent reaction with POCl3 to obtain the3 target, 163 (Scheme 29). (Scheme 29).

Symmetry 2018, 10, 10 31 of 48 SymmetrySymmetry 20182018,, 1010,, 1010 3131 ofof 4848

SchemeScheme 28. 28. ((aa()a) )ChiralChiral Chiral groupgroup group transfertransfer transfer reactionreaction reaction betweenbetween between 155155155 andandand ((R,RR,R (R,R)-)-157157)-157 inin chloroforminchloroform chloroform andand and ((bb)) (proposedproposedb) proposed shiftshift shift inin conformationalconformational in conformational dynamicdynamic dynamic equilibriumequilibrium equilibrium ofof 156156 of 156 inin theinthe the presencepresence presence ofof ( of(R,RR,R (R,R)-)-157157)-157 inin inchloroform.chloroform. chloroform.

SchemeScheme 29.29. SynthesisSynthesis of of 163163 fromfrom dihyrofurofuran dihyrofurofuran helicenehelicene 159 159...

Interestingly, due to the Cs-symmetric nature of phosphoric acid, 163 has two tautomeric Interestingly,Interestingly, duedue toto thethe CsCs-symmetric-symmetric naturenature ofof phosphoricphosphoric acid,acid, 163163 hashas twotwo tautomerictautomeric structures. This structural feature of 163, in combination with the substituent bulkiness of the guest structures.structures. ThisThis structuralstructural feature of 163163,, inin combinationcombination withwith thethe substituentsubstituent bulkinessbulkiness ofof thethe guestguest amino alcohols, together decide the preferred mode of two-point hydrogen bonding on equilibration, aminoamino alcohols,alcohols, togethertogether decidedecide thethe preferredpreferred modemode ofof two-pointtwo-point hydrogenhydrogen bondingbonding onon equilibration,equilibration, which gave a resultant ICD signal correlating with the absolute configuration of the guest [86]. whichwhich gavegave aa resultantresultant ICD signal correlating with with the the absolute absolute configuration configuration of of the the guest guest [86]. [86].

7.2.7.2. Polymeric Polymeric Helicene-BaHelicene-BasedHelicene-Basedsed ChiralChiral RecognitionRecognition Polymer chains can also serve as suitable carriers for chiral helicenes, especially in the case of PolymerPolymer chains can also serve serve as as suitable suitable carriers carriers for for chiral chiral helicenes, helicenes, especially especially in inthe the case case of prospective applications. Thus, using 2-acetylene-[6]helicene 165, Yashima et al. prepared a series of ofprospective prospective applications. applications. Thus, Thus, using using 2-acetylen 2-acetylene-[6]helicenee-[6]helicene 165, Yashima165, Yashima et al. prepared et al. prepared a series of a polymeric helicene pendants, poly-1-166, via the rhodium-catalyzed polymerization reaction seriespolymeric of polymeric helicene helicene pendants, pendants, poly-1- poly-1-166, 166via, viathe therhodium-catalyzed rhodium-catalyzed polymerization polymerization reactionreaction (Scheme 30) [87]. This polymerization reaction gave stereoregular (cis-transoidal) polyacetylenes (Scheme(Scheme 30 30))[87 [87].]. This This polymerization polymerizati reactionon reaction gave stereoregulargave stereoregular (cis-transoidal (cis-transoidal) polyacetylenes) polyacetylenes bearing bearing the corresponding helicene pendants 166 with (P)- and (M)-polymeric chains with average thebearing corresponding the corresponding helicene pendantshelicene pendants166 with (166P)- andwith ( M(P)-polymeric)- and (M)-polymeric chains with chains average with molecular average 3 molecular weight Mn 3= 2.6 × 10 3. However, the formation of a precipitate during the reaction makes weightmolecularMn weight= 2.6 × M10n .= However,2.6 × 10 . However, the formation the formation of a precipitate of a precipitate during the during reaction the makes reaction it difficult makes it difficult to reproduce. The careful analysis of the CD spectra of monomer 165 and polymers 166, toit difficult reproduce. to reproduce. The careful The analysis careful of analysis the CD spectraof the CD of monomerspectra of 165monomerand polymers 165 and 166polymers, and their 166, and their corresponding differential CD spectra, suggests that the helical polyacetylenes with the correspondingand their corresponding differential CDdifferential spectra, suggestsCD spectra, that suggests the helical that polyacetylenes the helical polyacetylenes with the optically with active the optically active pendant group exist as a single-handed structure, apparently due to the attractive pendantoptically groupactive existpendant as a group single-handed exist as a structure, single-han apparentlyded structure, due apparently to the attractive due to intramolecular the attractive intramolecular π-π interactions. πintramolecular-π interactions. π-π interactions.

Symmetry 2018, 10, 10 32 of 48 Symmetry 2018, 10, 10 32 of 48

SchemeScheme 30. 30.(a )(a One) One step step synthesis synthesis ofof polymericpolymeric helicene helicene 166166 andand (b) ( bits) itsapplication application against against enantioselectiveenantioselective adsorption adsorption of of racemic racemic guests guests165 165,, 167167, and and 168168. .

The chiral recognition abilities of these polymers were studied in the context of the enantioselective Theadsorption chiral of recognitionthree racemic abilities guests, namely, of these parent polymers helicene were 165, BINOL studied 167 in, and the 2,2 context′-dibromo- of the enantioselectivebinaphthalene adsorption 168. The enantiomers of three were racemic adsorbed guests, by the namely, polymer parent in methanol helicene solution165, and BINOL desorbed167, and 2,20-dibromo-binaphthalenein a mixture of methanol/THF168. The[1:1, v/v enantiomers] followed by were chiral adsorbed HPLC analysis. by the polymerThe poly-1-( inP methanol)-166 solutionpreferentially and desorbed adsorbed in(P)-helicene a mixture 165 with of methanol/THF 3.6% ee; both have [1:1,similarv /configv] followedurations. As by expected, chiral in HPLC analysis.the case The of poly-1-( 166 withP )-opposite166 preferentially absolute configuration, adsorbed th (Pe)-helicene adsorption 165preferencewith 3.6% was observedee; both havefor (M similar)- helicene 165 with a similar 3.7% ee. However, interesting results were obtained for binaphthyl derivatives configurations. As expected, in the case of 166 with opposite absolute configuration, the adsorption 167 and 168, where poly-1-(P)-166 selectively adsorbed the opposite (S)-enantiomers with up to 36% ee, preference was observed for (M)-helicene 165 with a similar 3.7% ee. However, interesting results whilst poly-1-(M)-166 showed similar selectivity towards the (R)-enantiomers of 167 and 168. The werecalculated obtained separation for binaphthyl factor was derivatives sufficiently 167highand (1.71–2.18),168, where indicating poly-1-( that theseP)-166 polymersselectively can be adsorbedused the oppositeas a stationary (S)-enantiomers phase for the practi withcal up separation to 36% ofee ,racemic whilst mixtures. 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),7.3. Helicene-Based indicating Chiral that these Recognition polymers via Nanoparticles can be used as a stationary phase for the practical separation of racemicAnother mixtures. 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 7.3. Helicene-Basedgold nanoparticles Chiral of 5–22 Recognition nm [88] in via a Nanoparticlesmixture of ethanol/water (1:3, v/v) under sonication to form the Anothercorresponding prospective Au-(P/M)-,approach (P)-, and (M for)-169 chiral-nanoparticles recognition (helicene-grafted by helicene nanoparticles) structures (Figure is based 16). on These helicene-based nanoparticles show chirality-based inter(nano)molecular attractive interaction, nanomaterials. In this respect, individually racemic, (P)-, and (M)-helicene thiols 169 were grafted onto resulting in the corresponding aggregation phenomenon followed by a time-dependent precipitation gold nanoparticles of 5–22 nm [88] in a mixture of ethanol/water (1:3, v/v) under sonication to form the process, as analyzed by UV spectroscopy. All three types of nanoparticles dispersed in DMF gave a stable correspondingsolution for Au-( a periodP/M )-,of one (P)-, week. and (TheM)- 169addition-nanoparticles of the DMF (helicene-grafted solutions to an aromatic nanoparticles) solvent such (Figure as 16). Thesebenzonitrile helicene-based resulted nanoparticles in different colors show due chirality-based to the surface plasmoni inter(nano)molecularc bands of the gold attractive nanoparticles, interaction, as resultingstudied in theby correspondingUV–vis spectroscopy aggregation and a dynamic phenomenon light scattering followed technique. by a time-dependent Additionally, the precipitation time- process,dependent as analyzed aggregates by UVwere spectroscopy. of different sizes, All based three on types the type of nanoparticles of helicene nanoparticles dispersed present. in DMF The gave a stableobserved solution chiral for a periodrecognition of one induced week. Theby additionthe homo- of the(Au-( DMFP/M)- solutions169 nanoparticle to an aromatic : Au-(P solvent/M)-169 such as benzonitrilenanoparticle, resulted Au-(P)- in169 different nanoparticle colors : Au-( dueP)- to169 the nanoparticle, surface plasmonic and Au-(M bands)-169 nanoparticle of the gold nanoparticles,: Au-(M)- as studied169 nanoparticle) by UV–vis and spectroscopy hetero self-aggregation and a dynamic(Au-(M)-169 light nanoparticle scattering : Au-( technique.P)-169 nanoparticle) Additionally, of the the helicene nanoparticles was found to be enhanced according to the following sequence: Au-(P/M)-169 time-dependent aggregates were of different sizes, based on the type of helicene nanoparticles nanoparticle : Au-(P/M)-169 nanoparticle < Au-(M)-169 nanoparticle : Au-(M)-169 nanoparticle = Au-(P)- present. The observed chiral recognition induced by the homo- (Au-(P/M)-169 nanoparticle : 169 nanoparticle : Au-(P)-169 nanoparticle < Au-(P)-169 nanoparticle : Au-(M)-169 nanoparticle. This Au-(Ptendency/M)-169 relatesnanoparticle, to the interaction Au-( Pstrength)-169 nanoparticle between the corresponding : Au-(P)-169 nanoparticles,nanoparticle, which and is controlled Au-(M )-169 nanoparticleby stereochemical : Au-(M matching.)-169 nanoparticle) and hetero self-aggregation (Au-(M)-169 nanoparticle : Au-(P)-169Anothernanoparticle) example of of optically the helicene active nanoparticles nanoparticles 170 was with found 70 nm todiameter be enhanced size was accordingobtained to the followingby grafting sequence: (P)-1,12-dimethyl-8-methoxycarbonylbenzo[ Au-(P/M)-169 nanoparticle : Au-(c]phenanthrene-5-carboxyamideP/M)-169 nanoparticle < Au-(on M3-)-169 nanoparticleaminopropylated : Au-(M silica)-169 (Figurenanoparticle 17) [89,90]. = Au-( TheseP)- 169nanoparticlesnanoparticle were: prepared Au-(P)- 169by reactingnanoparticle 3- < Au-(Paminopropylated)-169 nanoparticle silica : Au-(nanoparticlesM)-169 nanoparticle. with the corresponding This tendency (P)-helicene relates carboxylic to the interactionacid chloride strength by betweenrefluxing the corresponding in isopropyl ether nanoparticles, for 4 hours using which ethyldiisopropylamine is controlled by stereochemical as a base. 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. Symmetry 2018, 10, 10 33 of 48 Symmetry 2018, 10, 10 33 of 48

Figure 16. Enantiomeric structures of helicene thiol 169 and representationsrepresentations of thethe goldgold nanoparticlesnanoparticles formed from from 169169. Modified. Modified and reprinted, and reprinted, with permission with permission from [88] © from 2012, [88 Royal] © Society2012, Royalof Chemistry. 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 It was found that these nanoparticles enantioselectively precipitated at a faster speed with (Figure 17). To elucidate the corresponding ee values, the precipitate was centrifuged and separated, (S)-configuration of aryl alcohols 80 (47% ee) and 171 (61% ee)[89] in m-bis(trifluoromethyl)benzene followed by mixing in 2-propanol. Then, the insoluble material (nanoparticles) was removed and the (Figure 17). To elucidate the corresponding ee values, the precipitate was centrifuged and separated, organic layer was concentrated and analyzed with chiral HPLC, indicating the optical resolution of followed by mixing in 2-propanol. Then, the insoluble material (nanoparticles) was removed and up to 29–61% ee for various aromatic alcohols for the (S)-configuration [89]. The mechanism of this the organic layer was concentrated and analyzed with chiral HPLC, indicating the optical resolution stereoselectivity was related to chiral recognition on the basis of the electrostatic aggregation of up to 29–61% ee for various aromatic alcohols for the (S)-configuration [89]. The mechanism of phenomenon. This nanoparticle-based kinetic resolution requires a relatively smaller amount (10 mol this stereoselectivity was related to chiral recognition on the basis of the electrostatic aggregation %) of -nanoparticles 170 as the resolving agent compared with the requirement of conventional 0.5 phenomenon. This nanoparticle-based kinetic resolution requires a relatively smaller amount equivalence, with providing additional possibility for resolving noncrystalline substances, making it (10 mol %) of -nanoparticles 170 as the resolving agent compared with the requirement of conventional an attractive and greener method of choice. 0.5 equivalence, with providing additional possibility for resolving noncrystalline substances, making Further, the helicene-based nanoparticles 170 were able to recognize the shape of (P)- it an attractive and greener method of choice. ethynylhelicene oligomers 172 in solution [90]. It preferentially forms the precipitate with a double Further, the helicene-based nanoparticles 170 were able to recognize the shape of helix of the oligomeric structure of 172 in comparison to its random coil structure in (P)-ethynylhelicene oligomers 172 in solution [90]. It preferentially forms the precipitate with trifluoromethylbenzene (Figure 17). The analysis was carried out by CD spectroscopy, where the a double helix of the oligomeric structure of 172 in comparison to its random coil structure in double helix oligomer shows a strong positive CE followed by a negative one, whilst in the case of trifluoromethylbenzene (Figure 17). The analysis was carried out by CD spectroscopy, where the the random coil oligomer, a weak CE of opposite sign was observed. This phenomenon was related double helix oligomer shows a strong positive CE followed by a negative one, whilst in the case of the to the chiral shape recognition on the surface of the nanoparticle by stereospecific absorption, random coil oligomer, a weak CE of opposite sign was observed. This phenomenon was related to resulting in the visualized selective aggregation-based precipitation, which is useful for the the chiral shape recognition on the surface of the nanoparticle by stereospecific absorption, resulting separation of the double helix structure of 172 from its random coil conformation [90]. These in the visualized selective aggregation-based precipitation, which is useful for the separation of the examples clearly show the potential of helicene-based chiral nanomaterials for applications in the double helix structure of 172 from its random coil conformation [90]. These examples clearly show the resolution of chiral molecules ranging from a simple alcohol to complex polymeric structures. potential of helicene-based chiral nanomaterials for applications in the resolution of chiral molecules ranging from a simple alcohol to complex polymeric structures.

Symmetry 2018, 10, 10 34 of 48 Symmetry 2018, 10, 10 34 of 48 Symmetry 2018, 10, 10 34 of 48

Figure 17. Helicene silica nanoparticle 170 and its ability towards chiral recognition and resolution of 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. aromaticaromatic alcoholalcohol 8080 andand 171171 andand doubledouble helixhelix oligomeroligomer 172172.. 7.4. Helicene-Based Chiral Recognition Involving Biologically Relevant Molecules 7.4. Helicene-Based Chiral Recognition InvolvingInvolving BiologicallyBiologically RelevantRelevant MoleculesMolecules The stereodynamic helicenes are also effectively employed for the induced CD-based sensing, The stereodynamicstereodynamic helicenes are also effectivelyeffectively employed for the induced CD-based sensing, where a chiral guest can induce a specific helicity via covalent or supramolecular interactions, thus wherewhere aa chiralchiral guestguest cancan induceinduce aa specificspecific helicityhelicity viavia covalentcovalent oror supramolecularsupramolecular interactions,interactions, thusthus generating the corresponding CD signals in the helicene absorption region. The guests range from generating the corresponding CD signalssignals inin thethe helicenehelicene absorptionabsorption region.region. The guests rangerange fromfrom simple organic molecules (Scheme 28b) to complicated biological molecules, as described here. simplesimple organicorganic moleculesmolecules (Scheme(Scheme 2828b)b) toto complicatedcomplicated biologicalbiological molecules,molecules, asas describeddescribed here.here. Thus, Yamada’s group explored hydroxymethyl trithia[5]helicene 173 [91–96], which is a Thus, Yamada’s groupgroup exploredexplored hydroxymethylhydroxymethyl trithia[5]helicene 173173 [91–96],[91–96], which which is aa stereodynamic compound. Both the (P)- and (M)-enantiomeric structures are configurationally labile, stereodynamicstereodynamic compound. Both the ((P)-)- andand ((MM)-enantiomeric)-enantiomeric structuresstructures areare configurationallyconfigurationally labile,labile, nonresolvable, and exist in a fast equilibrium. However, due to the presence of an electron-rich aromatic nonresolvable, and exist in a fastfast equilibrium.equilibrium. However, due to thethe presencepresence ofof anan electron-richelectron-rich aromaticaromatic chromophore and polar hydroxymethyl group capable of hydrogen bonding, suitable complexation of chromophorechromophore andand polarpolar hydroxymethylhydroxymethyl groupgroup capablecapable ofof hydrogenhydrogen bonding,bonding, suitablesuitable complexationcomplexation ofof the chiral guest (such as biomolecules) [91,93–96] is able to shift the equilibria to one of unidirectional thethe chiralchiral guestguest (such(such asas biomolecules)biomolecules) [[91,93–96]91,93–96] is able toto shiftshift thethe equilibriaequilibria toto oneone ofof unidirectionalunidirectional helicity, which, in turn, can be monitored by CD spectroscopy (Figure 18). helicity, which, in turn, turn, can can be be moni monitoredtored by by CD CD spectroscopy spectroscopy (Figure (Figure 18). 18 ).

Figure 18. Stereodynamic hydroxymethyl trithia[5]helicene 173 and a principle of its use as an Figure 18.18.Stereodynamic Stereodynamic hydroxymethyl hydroxymethyl trithia[5]helicene trithia[5]helicene173 and173 aand principle a principle of its useof asits anuse induced as an induced CD host. CDinduced host. CD host. The corresponding host–guest studies were successfully implemented with serum albumin [91], The corresponding host–guest studies were successfully implemented with serum albumin [91], (R)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy)propionicThe corresponding host–guest studies were successfully implementedacid (TAPA) [92], with alkyl serum b-D albumin-pyranoside [91], (R)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy)propionic acid (TAPA) [92], alkyl b-D-pyranoside ([93],R)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy)propionic and bilayered phosphatidylcholine vesicles [94–96] using acid (TAPA)CD spectroscopy [92], alkyl b-asD a-pyranoside major tool. [ 93As], [93], and bilayered phosphatidylcholine vesicles [94–96] using CD spectroscopy as a major tool. As andthe extent bilayered of helicity phosphatidylcholine induced in 173 vesiclesby these [ 94guest–96] molecules using CD is spectroscopy small, the resultant as a major CD tool. signals As theare the extent of helicity induced in 173 by these guest molecules is small, the resultant CD signals are extentalso small. of helicity Yet, as induced CD is a inhighly173 by sensitive these guest technique, molecules even is with small, a small the resultant signal, it CD can signals be applied are also for also small. Yet, as CD is a highly sensitive technique, even with a small signal, it can be applied for small.understanding Yet, as CDmolecular is a highly behavior sensitive and chirality technique, in solution. even with a small signal, it can be applied for understanding molecular behavior and chirality in solution. understandingTanaka et molecularal. synthesized behavior bis(hydroxymethyl)thia[7]helicene and chirality in solution. 174 to study its further synthetic Tanaka et al. synthesized bis(hydroxymethyl)thia[7]helicene 174 to study its further synthetic chemistryTanaka and et corresponding al. synthesized applications bis(hydroxymethyl)thia[7]helicene in the chirality recognition174 of biologicalto study its molecules further synthetic[97–100]. chemistry and corresponding applications in the chirality recognition of biological molecules [97–100]. chemistryHence, the and helicene corresponding 174 was synthesized applications in in a thetotal chirality of nine recognition steps with ofan biologicaloverall 33% molecules yield, where [97–100 the]. Hence, the helicene 174 was synthesized in a total of nine steps with an overall 33% yield, where the Hence,photochemical the helicene cyclization174 was of synthesizedalkene 175 was in a a total key ofstep nine to stepsgive silyl with group an overall protected 33% yield,rac-176 where. Further, 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 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 method. For example, with the use of Pseudomonas cepacia enzyme, (P)-174 (44%, 98% ee) was obtained

Symmetry 2018, 10, 10 35 of 48 photochemical cyclization of alkene 175 was a key step to give silyl group protected rac-176. Further, deprotectedSymmetry 2018, racemic10, 10 174 was optically separated using the lipase-based enzymatic kinetic resolution35 of 48 method. For example, with the use of Pseudomonas cepacia enzyme, (P)-174 (44%, 98% ee) was obtained asas a slow reactive reactive isomer isomer with with simultaneous simultaneous form formationation of the of the corresponding corresponding mono- mono- and anddiacetates, diacetates, (M)- (177M)- and177 and(M)- (178M)-. 178Similarly,. Similarly, the use the of use Candida of Candida antarctica antarctica enzymeenzyme resolved resolved opposite opposite (M)-174 (M)- (44%,174 (44%, 92% 92%ee) withee) withthe formation the formation of mono- of mono- and diacetates, and diacetates, (P)-177 (P and)-177 (Pand)-178 (P (Scheme)-178 (Scheme 31) [97]. 31 )[97].

Scheme 31. Photochemical synthesis and enzymatic resolution of helicene 174; (a) hv, I2, propylene Scheme 31. Photochemical synthesis and enzymatic resolution of helicene 174;(a) hv,I2, propylene oxide,oxide, benzene,benzene, roomroom temperature;temperature; ((bb)) tetra-tetra-nn-butylammonium-butylammonium fluoride,fluoride, THF,THF, 00 ◦°C;C; ((cc)) PseudomonasPseudomonas cepacia, CH2Cl2, vinyl acetate, room temprature, 25 h; (d) Candida antarctica, CH2Cl2, vinyl acetate, cepacia, CH2Cl2, vinyl acetate, room temprature, 25 h; (d) Candida antarctica, CH2Cl2, vinyl acetate, 28–2928–29 ◦°C,C, 9.5 h.

Further, enantiopure alcohol 174 was converted to its dichloride 179, which was converted to Further, enantiopure alcohol 174 was converted to its dichloride 179, which was converted 180 [98] and cyclic thia ethers 181–183 [99] using suitable synthetic procedures (Scheme 32). These to 180 [98] and cyclic thia ethers 181–183 [99] using suitable synthetic procedures (Scheme 32). helicene molecules were explored in terms of possible chiral recognition of biologically relevant These helicene molecules were explored in terms of possible chiral recognition of biologically relevant molecules such as DNA [98,100]. molecules such as DNA [98,100]. It is well known that, under physiological conditions, a DNA duplex exists as a mixture of the It is well known that, under physiological conditions, a DNA duplex exists as a mixture of right-handed B-DNA and left-handed Z-DNA forms. The supramolecular association of chiral C2- the right-handed B-DNA and left-handed Z-DNA forms. The supramolecular association of chiral symmetrical 180 with DNA revealed that the (P)-enantiomer of 180 displays chiral selection for C -symmetrical 180 with DNA revealed that the (P)-enantiomer of 180 displays chiral selection binding2 Z-DNA over B-DNA [98]. The corresponding binding constants were found to be (8.0 ± 0.5) for binding Z-DNA over B-DNA [98]. The corresponding binding constants were found to be × 104 M−1 and (1.4 ± 0.3) × 104 M−1 for Z- and B-DNA, as measured by fluorescence titration. Besides, (8.0 ± 0.5) × 104 M−1 and (1.4 ± 0.3) × 104 M−1 for Z- and B-DNA, as measured by fluorescence this interaction can be clearly monitored with CD spectroscopy, where, upon binding Z-DNA, there titration. Besides, this interaction can be clearly monitored with CD spectroscopy, where, upon binding is a considerable decrease in the signal intensity of (P)-180 of up to 70% at 330 nm at neutral pH. Z-DNA, there is a considerable decrease in the signal intensity of (P)-180 of up to 70% at 330 nm at Under similar conditions, B-DNA failed to show any significant change in the CD spectra of (P)-180, neutral pH. Under similar conditions, B-DNA failed to show any significant change in the CD spectra indicating (P)-helicity-based recognition of Z-DNA. In contrast, although the (M)-180 also showed a of (P)-180, indicating (P)-helicity-based recognition of Z-DNA. In contrast, although the (M)-180 also 20% reduction, it was observed upon binding both B- and Z-DNA, thus indicating the lack of its showed a 20% reduction, it was observed upon binding both B- and Z-DNA, thus indicating the lack discrimination ability. of its discrimination ability.

Symmetry 2018, 10, 10 36 of 48 Symmetry 2018, 10, 10 36 of 48

SchemeScheme 32. Synthesis32. Synthesis of functionalizedof functionalized helicene helicene 180 andand thiaethers thiaethers 181181–183–183 fromfrom [7]helicene [7]helicene 174. 174.

Additionally, it was observed that the (P)-180 not only selectively binds Z-DNA but is also able Additionally,to force B-DNA it wasto adopt observed an opposite that the left-handed (P)-180 not helical only form, selectively like Z-DNA. binds Apparently, Z-DNA but the is also able tomethylene- force B-DNAN,N-dimethylamine to adopt an functionality opposite left-handed in (P)-180 plays helical a crucial form, role like in Z-DNA. this behavior, Apparently, as the the methylene-same heliceneN,N-dimethylamine backbone but with functionality hydroxy me inthyl (P )-substituents,180 plays aas crucial in the case role of in 174 this, did behavior, not show as the sameany helicene binding backbone response but towards with hydroxy B- and methylZ-DNA. substituents, It is likely that asin the the protonated case of 174 form, did of not amino show any bindingsubstituents response in towards 180 becomes B- and a Z-DNA. crucial site It is for likely binding that theDNA, protonated whilst the form helicene of amino chirality substituents is an in 180 becomesimportant a crucialfactor in site the forenantioselective binding DNA, recognition whilstthe of left-handed helicene chirality helical Z-DNA. is an important factor in the Further extending the chiral recognition research of biologically important molecules resulted in enantioselective recognition of left-handed helical Z-DNA. the development of cyclic helicenes with thiaether linkage, 181–183 (Scheme 32) [99,100]. The (M)- Furtherenantiomers extending of 181–183 the turned chiral out recognition to be potential research inhibitors of biologically against telomerase important enzyme molecules activity based resulted in theon developmentthe chiral and ofsteric cyclic matching, helicenes while withbinding thiaether to the G-quadruplex linkage, 181 superhelix–183 (Scheme structure. 32)[ The99, 100]. The (recognitionM)-enantiomers phenomenon of 181 is– 183basedturned on the outchiral to space be potential available at inhibitors the cleft-pocket against and telomerase the presence enzyme of activityZ-DNA based assisting on the this chiral helicene and binding. steric matching,Initially, 180while was studied binding and to exhibited the G-quadruplex no chiral selectivity. superhelix structure.This result The recognitionled to the assumption phenomenon that the is dihedral based on angle the in chiral helicene space chromophores available at plays the cleft-pocketa key role in and the presencethe interaction of Z-DNA efficiency. assisting On this this basis, helicene three binding.different cyclic Initially, helicene180 wasthiaethers, studied 181 and–183 exhibited, having no chiraldifferent selectivity. length This of linkers, result were led to designed the assumption to yield the that dihedral the dihedral angles of angle22°, 53°, in and helicene 58°, respectively. chromophores plays a keyIt was role shown in the that interaction the (M)-enantiomer efficiency. of 181 On with this the basis, smallest three interplanar different angle cyclic was helicene able to inhibit thiaethers, the telomerase enzyme activity efficiently, presumably as a result of the chiral and steric matching. 181–183, having different length of linkers, were designed to yield the dihedral angles of 22◦, 53◦, and ◦ However, the exact binding mode of this helicene to the G-quadruplexes is not fully understood yet. 58 , respectively.Here, again, the binding studies relied on CD and fluorescence spectroscopy [100]. It wasIn shown 2013, chiral that [5]helicene the (M)-enantiomer 184, containing of 181 methylwith groups the smallest at the interplanarinnermost positions, angle was was able suitably to inhibit the telomeraseconnected with enzyme the spermine activity moiety efficiently, 185 at presumably the outer sphere asa of result the helicene of the backbone chiral and to stericact as a matching. host However,capable the of exact recognizing binding the mode DNA of co thisnformation helicene [101]. to the This G-quadruplexes host was synthesized is not fully by the understood Suzuki– yet. Here,Miyaura again, thecoupling binding of 8-methylnaphthalene-2-boronic studies relied on CD and fluorescence acid 186 with spectroscopy dibromo-maleimide [100]. 187 to obtain In188 2013,, followed chiral by [5]helicene photocyclizati184on, containing to result in methyl racemic groups 189 with at the92% innermost yield. The positions,enantiomers was of 189 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, Symmetry 2018, 10, 10 37 of 48

Symmetry 2018, 10, 10 37 of 48 followed by photocyclization to result in racemic 189 with 92% yield. The enantiomers of 189 were separatedwere separated on a on chiral a chiral column column followed followed by by further further transformation transformation to to190 190and, and, finally, finally, to to thethe target enantiopure 184 (Scheme(Scheme 3333))[ [101].101].

Scheme 33. Synthesis of helicene-spermine 184..

The designing concept was such that the cationic spermine unit is able to provide the 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, 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 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 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- over Z-DNA. The opposite trend was observed with (M)-184, which displayed strong binding for DNA over B-DNA, as studied by performing CD, UV melting temperature, surface plasmon 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 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 184 [101], it appears that the cationic functional groups assist in binding with DNA through electrostatic electrostatic interactions; along with this, the chiral helicity-based steric fit allows selectivity. The (P)- interactions; along with this, the chiral helicity-based steric fit allows selectivity. The (P)-180 prefers 180 prefers Z-DNA, whereas in the case of 184, the (M)-enantiomer binds strongly to Z-DNA. As Z-DNA, whereas in the case of 184, the (M)-enantiomer binds strongly to Z-DNA. As structures, structures, tetrathia[7]helicene 180 having functional groups on the terminal rings (in chiral cavity tetrathia[7]helicene 180 having functional groups on the terminal rings (in chiral cavity space) and space) and 1,14-dimethyl[5]helicene 184, where spermine 185 is situated at the helicene outer core, 1,14-dimethyl[5]helicene 184, where spermine 185 is situated at the helicene outer core, are completely are completely different in terms of the functional groups and their positions, therefore the exact different in terms of the functional groups and their positions, therefore the exact mode of binding mode of binding with DNA cannot be generalized and is still not completely understood. with DNA cannot be generalized and is still not completely understood. Chiral cationic [4]helicenes 191 (Figure 19), having methoxy substituents at the innermost Chiral cationic [4]helicenes 191 (Figure 19), having methoxy substituents at the innermost position, position, were also able to bind with DNA molecules, as evident from a noticeable change in were also able to bind with DNA molecules, as evident from a noticeable change in absorption, absorption, fluorescence, and CD spectra obtained during the corresponding host–guest studies fluorescence, and CD spectra obtained during the corresponding host–guest studies [102]. It was [102]. It was concluded that the molecular plane of the helicene dye lies essentially parallel to the concluded that the molecular plane of the helicene dye lies essentially parallel to the DNA bases, DNA bases, implying intercalation mode rather than groove binding. Further, the chiral selectivity implying intercalation mode rather than groove binding. Further, the chiral selectivity based on based on association constant evaluation indicates that the (M)-enantiomer of 191 interacts more association constant evaluation indicates that the (M)-enantiomer of 191 interacts more strongly with strongly with DNA than the corresponding (P)-enantiomer of 191. DNA than the corresponding (P)-enantiomer of 191.

Symmetry 2018, 10, 10 38 of 48 SymmetrySymmetry 2018 2018, 10, 10, 10, 10 38 of38 48 of 48

FigureFigure 19. 19.Structure Structure of ( M)-enantiomers)-enantiomers of of191191. . 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- Yang et al. developed chiral 3-aza[6]helicene-modified β-cyclodextrin 192 by reacting 6-deoxy- 6-iodo-Yangβ -cyclodextrinet al. developed 193 withchiral (P 3-aza[6]helicene-modified)/(M)-helicene 194, resulting β in-cyclodextrin two water soluble 192 by cationic reacting charged 6-deoxy- β 6-iodo-6-iodo-diastereomeric-cyclodextrinβ-cyclodextrin species—(193 193with withP)- (192 P(P)/(/)/(β-cyclodextrin,MM)-helicene 194 194and,, resulting resulting (M)-192 in/β in -cyclodextrintwo two water water soluble soluble(Scheme cationic cationic 34)—with charged charged diastereomericdiastereomericdifferent fluorescence species—( species—( behaviorP)-P)-192192/ [103]./ββ-cyclodextrin,-cyclodextrin, The concept wasand and to ( Muse)- 192192water-insoluble//ββ-cyclodextrin-cyclodextrin 3-aza[6]helicene (Scheme (Scheme 34)—with 19434)—with in differentdifferentaqueous fluorescence fluorescence media in combination behavior behavior [ 103 [103].with]. the The The β-cyclodextrin conceptconcept was asymmetry to use use water-insoluble water-insoluble for the chiral 3-aza[6]helicenerecognition 3-aza[6]helicene of amino 194194 in in aqueousaqueousacids media in media water. in in combination combination with with the theβ β-cyclodextrin-cyclodextrin asymmetry asymmetry for for the the chiral chiral recognition recognition of ofamino amino acidsacids in in water. water.

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

SchemeSchemeIn polar 34. 34. Synthesissolvents ofsuchof 3-aza[6]helicene3-aza[6]helicene as methanol, modified ethanol, modified β -cyclodextrinand βwater,-cyclodextrin the192 ashelicene a water-soluble192 chasromophore a water-soluble amino acidoccupies sensor. amino the β-cyclodextrin cavity to a different extent in two diastereomers: (P)-192/- and (M)-192/β-cyclodextrin— acid sensor. favoringIn polar monomeric solvents formssuch ratheras methanol, than self-aggregated ethanol, an dspecies. water, Both the thhelicenee diastereomers chromophore were investigated occupies the β-cyclodextrinfor complexation cavity towards to a different proteinogenic extent amino in two acids diastereomers: by using the (fluorescenceP)-192/- and technique (M)-192/ βin-cyclodextrin— an aqueous In polar solvents such as methanol, ethanol, and water, the helicene chromophore occupies favoringbuffer ofmonomeric pH 7.3. It formsturned rather out that th anhydrophobic self-aggregated interactions species. appeared Both th eto diastereomers be a dominant were binding investigated mode the β-cyclodextrin cavity to a different extent in two diastereomers: (P)-192/- and (M)-192/ forwith complexation additional towardselectrostatic proteinogenic forces between amino the acids cationic by using charge the of fluorescence helicene and technique carboxylate in ananion aqueous of β -cyclodextrin—favoringbuffercorresponding of pH 7.3. aminoIt turned acids; monomeric out besides that hydrophobic formsthis, π rather-π interaction interactions than self-aggregated may appeared also contribute to species. be a indominant the Both case the bindingof diastereomers aromatic mode werewithguests. investigated additional The chiral electrostatic for discrimination complexation forces abilities between towards were the also proteinogenic cationic found to chargebe highly amino of dependent helicene acids byandon pH. using carboxylate A relatively the fluorescence anion high of techniquecorrespondingL/D selectivity in an aqueous amino of amino acids; buffer acids, besides of up pH to 12.4,this, 7.3. Itwasπ- turnedπ observedinteraction out as that amay consequence hydrophobic also contribute of the interactions synergetic in the case appearedeffects of aromaticof the to be a helicene auxiliary and β-cyclodextrin cavity [103]. dominantguests. The binding chiral modediscrimination with additional abilities electrostaticwere also found forces to be between highly dependent the cationic on chargepH. A relatively of helicene high and carboxylateL/D selectivity anion of ofamino corresponding acids, up to amino12.4, was acids; observed besides as a this, consequenceπ-π interaction of the synergetic may also effects contribute of the in 7.5. Helicene-Based Chiral Recognition via Self-Assembly thehelicene case of auxiliary aromatic and guests. β-cyclodextrin The chiral cavity discrimination [103]. abilities were also found to be highly dependent on pH. AA relatively new approach high L/Dfor chiral selectivity recognition of amino via self-a acids,ssembly up to was 12.4, applied was observedby Yamaguchi as a et consequence al. on the of the7.5. synergeticbasis Helicene-Based of functionalized effects Chiral of the Recognitionchiral helicene [4]carbohelicene. auxiliary via Self-Assembly and Theβ -cyclodextrinoverall studies cavitydemonstrated [103]. that the helicenes exhibit a noncovalent chiral recognition behavior via different functions, such as charge transfer A new approach for chiral recognition via self-assembly was applied by Yamaguchi et al. on the 7.5. Helicene-Basedcomplexation, Chiralcrystallization, Recognition homocoupling via Self-Assembly reaction, layer structure formation, self-aggregation, basis of functionalized chiral [4]carbohelicene. The overall studies demonstrated that the helicenes exhibitA new a approachnoncovalent for chiral chiral recognition recognition behavior via self-assembly via different was functions, applied by such Yamaguchi as charge et transfer al. on the basiscomplexation, of functionalized crystallization, chiral [4]carbohelicene. homocoupling reaction, The overall layer studies structure demonstrated formation, self-aggregation, that the helicenes exhibit a noncovalent chiral recognition behavior via different functions, such as charge transfer

Symmetry 2018, 10, 10 39 of 48

Symmetry 2018, 10, 10 39 of 48 complexation, crystallization, homocoupling reaction, layer structure formation, self-aggregation, and even even upon upon double double helix helix formation formation [75]. [75 Their]. Their observations observations indicated indicated that the that right-handed the right-handed helix structurehelix structure favors favors the same the helicity same helicity of its counterpart, of its counterpart, which whichis not generally is not generally observed observed in the case in the of pointcase of chirality point chirality (i.e., an (i.e., (R)- an or (R )-(S or)-host (S)-host does does not notalways always prefer prefer a guest a guest of of the the same same absolute configuration).configuration). Out Out of of several several examples, examples, the the following following one one is is sufficient sufficient to understand this helicity matching phenomenon. Tetranitro, dicyano-substituted [4]helicene [4]helicene 195195,, being being an electron-deficientelectron-deficient system, strongly interacts with diamino-substituted [4]helicene 196 via a charge transfer complex [104], [104], the formation of which was monitored by UV and NMR techniques. Part Particularly,icularly, in the UV spec spectrum,trum, a charge transfer band was observed at 500–800 nm in THF. TheThe associationassociation constant of the complex with the same −1 configuration—(configuration—(MM)-)-195195 andand ( M)-196—was—was found to be 12.212.2 MM−1; ;this this was was noticeably noticeably higher higher than than the −1 constant 10.2 M−1 observedobserved for for the the opposite opposite configuration—( configuration—(PP)-)-195195 andand ( (MM)-)-196196 (Figure(Figure 20).20). Further, Further, the NMR-based NOE experiments re revealedvealed that the face-to-face syn-conformation of two 1,12-dimethyl groups was preferred over the the antianti-orientation-orientation in in the the corresponding corresponding charged charged transfer transfer complexes complexes [104]. [104].

Figure 20. HelicalHelical discrimination discrimination upon upon supramolecular supramolecular charge charge tr transferansfer complexation between electron-deficientelectron-deficient helicene 195 and electron-rich helicene 196196..

In related studies, a series of racemicracemic [7]helicene[7]helicene derivatives, 197–199, containingcontaining pyridinone rings at both the terminals, were prepared using a classical methodology of Wittig olefinationolefination and photochemical cyclization, and were characterized both in solution and in solid state [[105].105]. Despite a variety of self-assembly modes according to the stereochemicalstereochemical and topological relationships, these helicenes formed only enantiomerically pure pure dimers held together by two pairs of the cooperative hydrogen bonds. The The self-assembly self-assembly process process was was found found to to be be enantiospecific enantiospecific in in solution and diastereoselective in solid crystal (Figure 21). diastereoselective in solid crystal (Figure 21). The terminal pyridinone rings were capable of hydrogen bonding via the corresponding amidic 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 N–H functionalities. The solution-phase NMR studies indicated that the helicenes exist as enantiomeric enantiomeric dimers. For example, the NH proton in 2-quinolinone 200 (10−4–10−2 M), as a reference, dimers. For example, the NH proton in 2-quinolinone 200 (10−4–10−2 M), as a reference, appeared at appeared at 12.9 ppm, whilst the position of this proton in 198 was downfield-shifted by 1 ppm in 12.9 ppm, whilst the position of this proton in 198 was downfield-shifted by 1 ppm in dilute solution dilute solution (>10−5 M), clearly indicating the cooperative hydrogen bonding and self-assembly (>10−5 M), clearly indicating the cooperative hydrogen bonding and self-assembly phenomenon. phenomenon. In turn, the chemical shift was found to be concentration-independent in CDCl3 and In turn, the chemical shift was found to be concentration-independent in CDCl3 and THF. In pyridine, THF. In pyridine, as expected, it was concentration-dependent, as pyridine itself is able to compete as expected, it was concentration-dependent, as pyridine itself is able to compete for the hydrogen for the hydrogen bonding. Additionally, the dimeric binding model was confirmed by dilution bonding. Additionally, the dimeric binding model was confirmed by dilution experiments with the experiments with the association constant of 207 M−1. The molecular modelling studies also indicated association constant of 207 M−1. The molecular modelling studies also indicated that each dimer is that each dimer is preferably constructed from a monomeric species of the same helicity. 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 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 (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 crystallization. These enantiopure dimers are held together by four strong intermolecular hydrogen bonds between two terminal pyridinones. bonds between two terminal pyridinones.

Symmetry 2018, 10, 10 40 of 48 Symmetry 2018, 10, 10 40 of 48

Symmetry 2018, 10, 10 40 of 48

Figure 21. Hydrogen bonding-based self-assembly in pyridinone-containing helicenes 197–199 and Figure 21. Hydrogen bonding-based self-assembly in pyridinone-containing helicenes 197 –199 and 2-quinolinone 200, as a NMR refrence.2-quinolinone 200, as a NMR refrence. 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 8. Enantiopure Helicenes: Enantioselective Synthesis, Chiral Separation, and Racemization The chiroptical properties and applications discussed above prompted the development of efficientefficient syntheticThe chiroptical procedures properties to obtainand applications enantiopureenantiopur discussede helicenes above in sufficientpromptedsufficient the quantities development required of for theseefficient investigations synthetic [[2,4].2procedures,4]. Although Although to obtain this this enantiopurtopic topic is is not note helicenes directly directly in related relatedsufficient to quantitiesthe category required of helicenehelicenefor applications,these investigations itit is is an an important important[2,4]. Although background background this fortopic the foris whole notthe directly helicenewhole related helicene chemistry; to thechemistry; hence,category abrief ofhence, helicene description a brief applications, it is an important background for the whole helicene chemistry; hence, a brief shoulddescription be included should asbe aincluded special section. as a special The major section. methods The major of obtaining methods enantiopure of obtaining helicenes enantiopure from a description should be included as a special section. The major methods of obtaining enantiopure racemichelicenes mixture from a areracemic based mixture on optical are resolution based on byoptica chirall resolution HPLC [60 by,77 ,chiral78,83, 101HPLC], diastereomeric [60,77,78,83,101], salt diastereomerichelicenes from salt a racemicformation mixture [51,60,76] are based (for on opticarepresentativel resolution resolvingby chiral HPLC agents, [60,77,78,83,101], see Figure 22), formationdiastereomeric [51,60,76 ]salt (for formation representative [51,60,76] resolving (for representative agents, see Figure resolving 22), chromatographicagents, see Figure separation 22), chromatographic separation of diastereomers [52,56,74], and enzymatic-based approaches [97]. of diastereomerschromatographic [52, 56separation,74], and of enzymatic-based diastereomers [52,56,74], approaches and enzymatic-based [97]. approaches [97].

FigureFigure 22. 22.Selected Selected examples examples of of chiralchiral reagentsreagents for for helicene helicene optical optical resolution. resolution. Figure 22. Selected examples of chiral reagents for helicene optical resolution. For example, racemic nonfunctionalized helicenes were successfully resolved through charge For example, racemic nonfunctionalized helicenes were successfully resolved through charge Fortransfer example, complexation racemic with nonfunctionalized electron-deficient helicenes molecules, were such successfully as TAPA [15,16] resolved or HPLC-basedthrough charge transfer complexation with electron-deficient molecules, such as TAPA [15,16] or HPLC-based transferseparation complexation with the withuse of electron-deficient silica coated with TAmoPAlecules, [106]. suchIn the ascase TAPA of functionalized [15,16] or helicene-HPLC-based separationcontaining with phenolic the use groups of silica at the coatedterminal with ring, (1 TAPAS)-camphanic [106]. Inchloride the case acts as of the functionalized best resolving agent helicene- separation with the use of silica coated with TAPA [106]. In the case of functionalized helicene- containingfor chromatographically phenolic groups atseparable the terminal diastereomers ring, (1S obtained.)-camphanic Furthermore, chloride their acts asabsolute the best configuration resolving agent containing phenolic groups at the terminal ring, (1S)-camphanic chloride acts as the best resolving agent for chromatographicallydetermination was carried separable out by diastereomers the 2D ROESY obtained. NMR technique Furthermore, [52,74,107]. their Particularly, absolute configuration it was for chromatographically separable diastereomers obtained. Furthermore, their absolute configuration determinationobserved that was in carried19 examples out of by helicenes the 2D ROESYstudied, ( NMRM,S)-diastereomers technique [ 52were,74 ,less107 ].polar, Particularly, whilst (P,S)- it was determinationdiastereomers was were carried more outpolar, by hence the eluting2D ROESY as the firstNMR and technique second fractions, [52,74,107]. correspondingly, Particularly, upon it was observed that in 19 examples of helicenes studied, (M,S)-diastereomers were less polar, whilst observedthe chromatographic that in 19 examples separation of helicenes on silica gelstudied, [107]. Another(M,S)-diastereomers resolving agent, were which less is polar,also frequently whilst ( P,S)- (P,S)-diastereomers were more polar, hence eluting as the first and second fractions, correspondingly, diastereomersemployed werefor optical more polar,resolution, hence is elutingan l-menthyl as the derivativefirst and second [4,56]. fractions,This approach correspondingly, has a distinct upon upon the chromatographic separation on silica gel [107]. Another resolving agent, which is also the chromatographicadvantage of attaching separation and detaching on silica a chiral gel [107]. auxili aryAnother before resolvingand after the agent, diastereomeric which is alsoseparation, frequently l frequentlyemployedmaking for employed the opticalwhole procedure forresolution, optical recyclab resolution,is anle andl-menthyl highly is an efficient. -menthylderivative Interestingly, derivative [4,56]. inThis the [4, 56 caseapproach]. of This azahelicene approach has a 201distinct has a distinctadvantagecontaining advantage of attaching the chloro of attaching and group detaching as and a substituent detaching a chiral auxili on a chiraltheary outer before auxiliary peripheral and before after pyridine the and di afterastereomeric ring, thethe diastereomericuse separation,of Pd- separation,makingcatalyzed the whole making Buchwald–Hartwig procedure the whole recyclab procedurecouplingle and highlywith recyclable ( Sefficient.)-phenylethyl and Interestingly, highly amine efficient. gave in the chromatographically case Interestingly, of azahelicene in 201 the separable diastereomers201 202 and 203 (Scheme 35) [108,109]. However, the absolute configuration of the casecontaining of azahelicene the chloro groupcontaining as a substituent the chloro on the group outer as peripheral a substituent pyridine on the ring, outer the peripheraluse of Pd- 2-ethylhexyl alkyl chain was not discussed in the paper [108]. S pyridinecatalyzed ring,Buchwald–Hartwig the use of Pd-catalyzed coupling Buchwald–Hartwigwith (S)-phenylethyl coupling amine withgave ( )-phenylethylchromatographically amine gaveseparable chromatographically diastereomers 202 separable and 203 (Scheme diastereomers 35) [108,109].202 and However,203 (Scheme the absolute 35)[108 ,configuration109]. However, of the absolute2-ethylhexyl configuration alkyl chain of was the not 2-ethylhexyl discussed alkylin the chainpaper was [108]. not discussed in the paper [108].

SymmetrySymmetry 20182018,, 1010,, 1010 4141 ofof 4848 Symmetry 2018, 10, 10 41 of 48

Scheme 35. Synthesis of chromatographically separable diastereomers 202 and 203 obtained by Pd- Scheme 35. Synthesis of chromatographically separable diastereomers 202 and 203 obtained by Pd- Schemecatalyzed 35. reactionSynthesis between of chromatographically rac-azahelicene 201 and separable (S)-phenylethylamine. diastereomers 202 and 203 obtained by catalyzedPd-catalyzed reaction reaction between between rac-azahelicenerac-azahelicene 201201 andand (S)-phenylethylamine. (S)-phenylethylamine. Besides the optical resolution of racemates, another approach to enantiopure helicenes is based Besides the optical resolution of racemates, another approach to enantiopure helicenes is based on theBesides stereospecific the optical synthesis, resolution where of racemates, the originally another chiral approach precursors to enantiopure or reagents helicenes are converted is based into on on the stereospecific synthesis, where the originally chiral precursors or reagents are converted into thethe stereospecificcorresponding synthesis, helicenes wherewith unidirectional the originally helici chiralty precursors [110]. In particular, or reagents the are asymmetric converted synthesis into the the corresponding helicenes with unidirectional helicity [110]. In particular, the asymmetric synthesis correspondingof helicene can helicenesbe performed with unidirectionalby using various helicity synthetic [110]. methods, In particular, such the as asymmetricphotocyclization, synthesis Diels– of of helicene can be performed by using various synthetic methods, such as photocyclization, Diels– heliceneAlder reaction, can be performedor metal-catalyzed by using variousannulation, synthetic in the methods, presence such of chiral as photocyclization, auxiliaries attached Diels–Alder to the Alder reaction, or metal-catalyzed annulation, in the presence of chiral auxiliaries attached to the reaction,reactant(s). or metal-catalyzedThese topics have annulation, been comprehensivel in the presencey covered of chiral in auxiliaries previous attached reviews to[2,4]. the reactant(s).Therefore, reactant(s). These topics have been comprehensively covered in previous reviews [2,4]. Therefore, Theseonly a topics few of have those been recently comprehensively published examples covered inof previousasymmetric reviews helicene [2,4 ].synthesis Therefore, are only highlighted a few of only a few of those recently published examples of asymmetric helicene synthesis are highlighted thosebelow. recently published examples of asymmetric helicene synthesis are highlighted below. below. InIn 2016,2016, SakoSako etet al.al. successfully used thethe modifiedmodified BINOL-based vanadium(V) complex 204, In 2016, Sako et al. successfully used the modified BINOL-based vanadium(V) complex 204, capablecapable ofof functioningfunctioning bothboth asas redoxredox andand LewisLewis acidacid catalysts,catalysts, forfor thethe enantioselectiveenantioselective synthesissynthesis ofof capable of functioning both as redox and Lewis acid catalysts, for the enantioselective synthesis of oxa[9]helicenesoxa[9]helicenes205 205starting starting from from polycyclic polycyclic phenols phenols206. The206. reaction The reaction proceeds proceeds via oxidative via oxidative coupling oxa[9]helicenes 205 starting from polycyclic phenols 206. The reaction proceeds via oxidative atcoupling first, followed at first, byfollowed intramolecular by intramolecular cyclization. cyclizat This resultsion. This in theresults one-step in the enantioselective one-step enantioselective synthesis coupling at first, followed by intramolecular cyclization. This results in the one-step enantioselective ofsynthesis oxa[9]helicenes of oxa[9]he in goodlicenes yields in good with yields up to with 94% upee [ to111 94%] (Scheme ee [111] 36 (Scheme). 36). synthesis of oxa[9]helicenes in good yields with up to 94% ee [111] (Scheme 36).

SchemeScheme 36.36. ModifiedModified BINOL-based vanadium complex 204, catalyzedcatalyzed asymmetricasymmetric synthesissynthesis ofof Scheme 36. Modified BINOL-based vanadium complex 204, catalyzed asymmetric synthesis of oxa[9]helicenesoxa[9]helicenes 205205 fromfrom polycyclicpolycyclic phenolsphenols 206206.. oxa[9]helicenes 205 from polycyclic phenols 206. In 2015, a new general asymmetric synthetic methodology was successfully developed for [5]-, In 2015, a new general asymmetric synthetic methodology was was successfully successfully developed developed for for [5]-, [5]-, [6]-, and [7]helicenes with ultimate enantioselectivity (ee >99) based on the controlled transfer of [6]-, and [7]helicenes with ultimate enantioselectivity ( (ee >99) based based on on the controlled transfer of reactant point chirality to the product with unidirectional helicity [112]. At first, triyne207, having reactant point chirality to the product with unidirectionalunidirectional helicity [[112].112]. At first, first, triyne207, having inbuilt point chirality, was converted into tetrahydrohelicene diastereomers 208 and 209, being in the inbuilt point point chirality, chirality, was was converted converted into into tetrahydrohelicene tetrahydrohelicene diastereomers diastereomers 208 and208 209and, being209, in being the thermodynamic equilibrium, by cobalt-catalyzed tandem [2 + 2 + 2] cycloisomerization. The (M)- thermodynamicin the thermodynamic equilibrium, equilibrium, by cobalt-catalyzed by cobalt-catalyzed tandem [2 tandem + 2 + 2] [2 cycloisomerization. + 2 + 2] cycloisomerization. The (M)- conformational helicity results in the 1,3-allylic strain, hence making 208 a highly energetic conformationalThe (M)-conformational helicity helicityresults resultsin the in1,3-allylic the 1,3-allylic strain, strain, hence hence making making 208208 a ahighly highly energetic diastereomer in comparison to 209, the (P)-conformational helicity of which gives relief from this diastereomer in comparison to 209, the (P)-conformational helicity helicity of of wh whichich gives gives relief relief from this strain, when the point chirality is of (R)-configuration at the 9-position. Subsequently, the favored strain, when the point chirality is of (R)-configuration)-configuration at the 9-position.9-position. Subsequently, the favored diastereomer under acidic conditions yielded fully aromatic helicenes 210 with greater than 99% ee diastereomer under acidic conditions yielded fully aromatic helicenes 210210 with greater than 99% ee (Scheme 37). Thus, (P)- and (M)-helicenes can be readily prepared starting from the (R)- and (S)- (Scheme 37).37). Thus, Thus, ( (PP)-)- and and ( (MM)-helicenes)-helicenes can can be be readily readily prepared prepared starting starting from from the the ( (RR)-)- and and ( (SS)-)- absolute configurations at the 9-position of the precursor, correspondingly. absolute configurations configurations at the 9-position of the precursor, correspondingly.correspondingly.

Symmetry 2018, 10, 10 42 of 48 Symmetry 2018, 10, 10 42 of 48

Scheme 37. 37. AsymmetricAsymmetric synthesis synthesis of helicenes of helicenes 210 based210 based on the on principle the principle of point-to-helical of point-to-helical chirality conversion.chirality conversion.

One of the most important points of chiral helicenes is their configurational stability, which can One of the most important points of chiral helicenes is their configurational stability, which be analyzed by using CD spectroscopy and chiral HPLC in combination with other techniques. 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 Evidently, understanding the mechanism of racemization helps in designing more stable helicene structures. Recently, detailed theoretical racemization studies have been performed on [n]helicenes 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 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 mechanism of racemization. The smallest member of the carbohelicene-1 family, [4]helicene has a symmetric transition state (TS) with an energy barrier of 4.0 kcal mol -1. However, the TS of n = 5–7 C2V symmetric transition state (TS) with an energy barrier of 4.0 kcal mol . 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−1, respectively. This possesses a C -geometry with the energy barriers of 24.4, 36.9, and 42.0 kcal mol−1, respectively. This is a result of thes steric hindrance, which accounts for the high TS energies of racemization. For n ≥ 8, 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 besides the steric hindrance, an additional factor of the π-π interaction starts to contribute to the overall overall structural stability, making the racemization process a multistep process and thus further structural stability, making the racemization process a multistep process and thus further increasing increasing the energy barrier. For example, when n = 8,9, or 10, helicenes displayed 2, 4, and 6 the energy barrier. For example, when n = 8,9, or 10, helicenes displayed 2, 4, and 6 intermediates intermediates for the racemization process, respectively. Thus, in general, when n = 8–24, helicenes for the racemization process, respectively. Thus, in general, when n = 8–24, helicenes involve (2n-14) involve (2n - 14) consecutive displacements, traversing intermediates in the molecule during the consecutive displacements, traversing intermediates in the molecule during the racemization process racemization process for corresponding carbohelicenes. These theoretical results should be taken into for corresponding carbohelicenes. These theoretical results should be taken into account to control the account to control the desired properties of helicene structures in future research. desired properties of helicene structures in future research. 9. Conclusions 9. Conclusions Helicenes are versatile compounds existing in achiral, stereodynamic, meso, and chiral forms. 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 Additionally, they could be neutral, charged, carbocyclic, heterocyclic, or polymeric in nature, electron-rich or -deficient characteristics. These conjugated molecules exhibit unique physical 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 properties such as fluorescence and strong chiroptical features, making them exclusively useful for the the chirogenesis processes, including chiral recognition using both fluorescence and circular chirogenesis processes, including chiral recognition using both fluorescence and circular dichroism dichroism spectroscopies. Their polyaromatic helical structures are also suitable for providing spectroscopies. Their polyaromatic helical structures are also suitable for providing shielding and shielding and deshielding effects, making them potentially applicable as chiral NMR sensors. deshielding effects, making them potentially applicable as chiral NMR sensors. The high configurational stability and facile functionalization of the helicene structures open 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. 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 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

Symmetry 2018, 10, 10 43 of 48 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

1. Hembury, G.A.; Borovkov, V.V.; Inoue, Y. Chirality sensing supramolecular systems. Chem. Rev. 2008, 108, 1–73. [CrossRef] [PubMed] 2. Shen, Y.; Chen, C.F. Helicenes: Synthesis and applications. Chem. Rev. 2012, 112, 1463–1535. [CrossRef] [PubMed] 3. Gingras, M. One hundred years of helicene chemistry. Part 1: Non-stereoselective syntheses of carbohelicenes. Chem. Soc. Rev. 2013, 42, 968–1006. [CrossRef][PubMed] 4. Gingras, M.; Félix, G.; Peresuttiab, R. One hundred years of helicene chemistry. Part 2: Stereoselective syntheses and chiral separations of carbohelicenes. Chem. Soc. Rev. 2013, 42, 1007–1050. [CrossRef][PubMed] 5. Gingras, M. One hundred years of helicene chemistry. Part 3: Applications and properties of carbohelicenes. Chem. Soc. Rev. 2013, 42, 1051–1095. [CrossRef][PubMed] 6. Hoffmann, N. Photochemical reactions applied to the synthesis of helicenes and helicene-like compounds. J. Photochem. Photobiol. C Photochem. Rev. 2014, 19, 1–19. [CrossRef] 7. Saleh, N.; Shena, C.; Crassous, J. Helicene-based transition metal complexes: Synthesis, properties and applications. Chem. Sci. 2014, 5, 3680–3694. [CrossRef] 8. Aillard, P.; Voituriez, A.; Marinetti, A. Helicene-like chiral auxiliaries in asymmetric catalysis. Dalton Trans. 2014, 43, 15263–15278. [CrossRef][PubMed] 9. Virieux, D.; Sevrain, N.; Ayad, T.; Pirat, J.-L. Helical phosphorus derivatives. In Advances in Heterocyclic Chemistry; Eric, F.V.S., Christopher, A.R., Eds.; Academic Press: Cambridge, MA, USA, 2015; Volume 116, pp. 37–83. 10. Rajca, A.; Miyasaka, M. Functional Organic Materials; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2007; Chapter 15, pp. 547–558. 11. Chen, C.-F.; Shen, Y. Helicene Chemistry—From Synthesis to Applications; Springer: Berlin/Heidelberg, Germany, 2017, ISBN 978-3-662-53168-6. 12. Weitzenbock, R.; Lieb, H. New synthesis of chrysene. Monatshefte Chem. 1913, 33, 549–565. [CrossRef] 13. Weitzenbock, R.; Klingler, A. Synthesis of the isomeric hydrocarbons 1,2,5,6-dibenzanthracene and 3,4,5,6-dibenzophenanthrene. J. Chem. Soc. 1918, 114, 494. 14. Cook, J.W. Polycyclic aromatic hydrocarbons. Part XII. The orientation of derivatives of 1:2-benzanthracene, with notes on the preparation of some new homologues, and on the isolation of 3:4:5:6-dibenzphenanthrene. J. Chem. Soc. 1933, 0, 1592–1597. [CrossRef] 15. Newman, M.S.; Lutz, W.B.; Lednicer, D. A new reagent for resolution by complex formation; the resolution of phenanthro-[3,4-c]phenanthrene. J. Am. Chem. Soc. 1955, 77, 3420–3421. [CrossRef] Symmetry 2018, 10, 10 44 of 48

16. Newman, M.S.; Lednicer, D. The synthesis and resolution of hexahelicene. J. Am. Chem. Soc. 1956, 78, 4765–4770. [CrossRef] 17. Morrison, D.J.; Trefz, T.K.; Piers, W.E.; McDonald, R.; Parvez, M. 7:8,9:10-Dibenzo-1,2,3,4-tetrafluoro- triphenylene: Synthesis, structure, and photophysical properties of a novel [5]helicene. J. Org. Chem. 2005, 70, 5309–5312. [CrossRef][PubMed] 18. Xue, X.; Scott, L.T. Thermal cyclodehydrogenations to form 6-membered rings: Cyclizations of [5]helicenes. Org. Lett. 2007, 9, 3937–3940. [CrossRef][PubMed] 19. Minuti, L.; Taticchi, A.; Marrocchi, A.; Gacs-Baitz, E. Diels-Alder reaction of 3,30,4,40-tetrahydro-1,10- binaphthalene. One-pot synthesis of a pentahelicenebenzoquinone. Tetrahedron 1997, 53, 6873–6878. [CrossRef] 20. Ogawa, Y.; Ueno, T.; Tarikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Synthesis of 2-acetoxy[5]helicene by sequential double aromatic oxy-Cope rearrangement. Tetrahedron Lett. 2002, 43, 7827–7829. [CrossRef] 21. Pieters, G.; Gaucher, A.; Prim, D.; Marrot, J. First expeditious synthesis of 6,11-diamino-[6]carbohelicenes. Chem. Commun. 2009, 32, 4827–4828. [CrossRef][PubMed] 22. El Abed, R.; Aloui, F.; Genet, J.-P.; Ben Hassine, B.; Marinetti, A. Synthesis and resolution of 2-(diphenylphosphino)heptahelicene. J. Organomet. Chem. 2007, 692, 1156–1160. [CrossRef] 23. Abbate, S.; Bazzini, C.; Caronna, T.; Fontana, F.; Gambarotti, C.; Gangemi, F.; Longhi, G.; Mele, A.; Sora, I.N.; Panzeri, W. Monoaza[5]helicenes. Part 2: Synthesis, characterisation and theoretical calculations. Tetrahedron 2006, 62, 139–148. [CrossRef] 24. Meisenheimer, J.; Witte, K. Reduction of 2-nitronaphthalene. Chem. Ber. 1903, 36, 4153–4164. [CrossRef] 25. Sundar, M.S.; Sahoo, S.; Bedekar, A.V. Synthesis and study of the structural properties of oxa[5]helicene derivatives. Tetrahedron Asymmetry 2016, 27, 777–781. [CrossRef] 26. Dreher, S.D.; Weix, D.J.; Katz, T.J. Easy synthesis of functionalized hetero[7]helicenes. J. Org. Chem. 1999, 64, 3671–3678. [CrossRef][PubMed] 27. Eskildsen, J.; Krebs, F.C.; Faldt, A.; Sommer-Larsen, P.; Bechgaard, K. Preparation and structural properties of 7,8-dioxa[6]helicenes and 7a,14c-dihydro-7,8-dioxa[6]helicenes. J. Org. Chem. 2001, 66, 200–205. [CrossRef] [PubMed] 28. Nakano, K.; Oyama, H.; Nishimura, Y.; Nakasako, S.; Nozaki, K. k5-Phospha[7]helicenes: Synthesis, properties, and columnar aggregation with one-way chirality. Angew. Chem. Int. Ed. 2012, 51, 695–699. [CrossRef][PubMed] 29. Oyama, H.; Nakano, K.; Harada, T.; Kuroda, R.; Naito, M.; Nobusawa, K.; Nozaki, K. Facile synthetic route to highly luminescent sila[7]helicene. Org. Lett. 2013, 15, 2104–2107. [CrossRef][PubMed] 30. Hatakeyama, T.; Hashimoto, S.; Oba, T.; Nakamura, M. Azaboradibenzo[6]helicene: Carrier inversion induced by helical homochirality. J. Am. Chem. Soc. 2012, 134, 19600–19603. [CrossRef][PubMed] 31. Zhang, X.; Edward, L.; Clennan, E.L.; Arulsamy, N. Photophysical and electrochemical characterization of a helical Viologen, N,N0-dimethyl-5,10-diaza[5]helicene. Org. Lett. 2014, 16, 4610–4613. [CrossRef][PubMed] 32. Guin, J.; Besnard, C.; Lacour, J. Synthesis, resolution, and stabilities of a cationic chromenoxanthene [4]helicene. Org. Lett. 2010, 12, 1748–1751. 33. Rozen, S.; Dayan, S. At Last, 1,10-Phenanthroline-N,N0-dioxide, A new type of helicene, has been synthesized using HOF small middle dotCH(3)CN. Angew. Chem. Int. Ed. 1999, 38, 3471–3473. [CrossRef] 34. Talele, H.R.; Sahoo, S.; Bedekar, A.V. Synthesis of chiral helical 1,3-oxazines. Org. Lett. 2012, 14, 3166–3169. [CrossRef][PubMed] 35. Jierry, L.; Harthong, S.; Aronica, C.; Mulatier, J.-C.; Guy, L.; Guy, S. Efficient dibenzo[c]acridine helicene-like synthesis and resolution: Scaleup, structural control, and high chiroptical properties. Org. Lett. 2012, 14, 288–291. [CrossRef][PubMed] 36. Wynberg, H. Some observations on the chemical, photochemical, and spectral properties of thiophenes. Acc. Chem. Res. 1971, 4, 65–73. [CrossRef] 37. Janke, R.H.; Haufe, G.; Würthwein, E.-U.; Borken, J.H. Racemization barriers of helicenes: A computational study. J. Am. Chem. Soc. 1996, 118, 6031–6035. [CrossRef] 38. Groen, M.B.; Wynberg, H. Optical properties of some heterohelicenes. Absolute configuration. J. Am. Chem. Soc. 1971, 93, 2968–2974. [CrossRef] Symmetry 2018, 10, 10 45 of 48

39. Fujikawa, T.; Segawa, Y.; Itami, K. Synthesis, structures, and properties of π-extended double helicene: A combination of planar and nonplanar π-systems. J. Am. Chem. Soc. 2015, 137, 7763–7768. [CrossRef] [PubMed] 40. Liu, X.; Yu, P.; Xu, L.; Yang, J.; Shi, J.; Wang, Z.; Cheng, Y.; Wang, H. Synthesis for the mesomer and racemate of thiophene-based double helicene under irradiation. J. Org. Chem. 2013, 78, 6316–6321. [CrossRef] [PubMed] 41. Newman, M.S.; Wise, R.M. The synthesis and resolution of 1,12-dimethylbenzo[c]phenanthrene-5-acetic acid. J. Am. Chem. Soc. 1956, 78, 450–454. [CrossRef] 42. Martin, R.H. The Helicenes. Angew. Chem. Int. Ed. 1974, 13, 649–660. [CrossRef] 43. McCarthy, M.; Guiry, P.J. Axially chiral bidentate ligands in asymmetric catalysis. Tetrahedron 2001, 57, 3809–3844. [CrossRef] 44. Chen, Y.; Yekta, S.; YudiA, K. Modified BINOL ligands in asymmetric catalysis. Chem. Rev. 2003, 103, 3155–3212. [CrossRef] [PubMed] 45. Berthod, M.; Mignani, G.; Woodward, G.; Marc Lemaire, M. Modified BINAP: The how and the why. Chem. Rev. 2005, 105, 1801–1836. [CrossRef][PubMed] 46. Hassine, B.B.; Gorsane, M.; Pecher, J.; Martin, R.H. Diastereoselective sodium borohydride reductions of (dl) α-keto esters. Bull. Soc. Chim. Belg. 1985, 94, 597–603. [CrossRef] 47. Hassine, B.B.; Gorsane, M.; Geerts-Evrard, F.; Pecher, J.; Martin, R.H.; Castelet, D. Payne syntheses and enantioselective syntheses of epoxides from (E)-stilbene and α-methylstyrene. Bull. Soc. Chim. Belg. 1986, 95, 557–566. [CrossRef] 48. Hassine, B.B.; Gorsane, M.; Pecher, J.; Martin, R.H. Potential asymmetric syntheses via the ene reaction. Bull. Soc. Chim. Belg. 1987, 96, 801–808. 49. Hassine, B.B.; Gorsane, M.; Pecher, J.; Martin, R.H. Asymmetric syntheses and potential asymmetric synthesis of α-amino alcohols: Hydroxyamination of olefins by the Sharpless method. Bull. Soc. Chim. Belg. 1985, 94, 759–769. [CrossRef] 50. Hassine, B.B.; Gorsane, M.; Pecher, J.; Martin, R.H. Atrolactic synthesis in the evaluation of the efficiency of inducers of asymmetric synthesis. Bull. Soc. Chim. Belg. 1986, 95, 547–556. 51. Yamamoto, K.; Shimizu, T.; Igawa, K.; Tomooka, K.; Hirai, G.; Suemune, H.; Usui, K. Rational design and synthesis of [5]helicene-derived phosphine ligands and their application in Pd-catalyzed asymmetric reactions. Sci. Rep. 2016, 6, 36211. [CrossRef][PubMed] 52. Tsujihara, T.; Inada-Nozaki, N.; Takehara, T.; Zhou, D.-Y.; Suzuki, T.; Kawano, T. Nickel-catalyzed construction of chiral 1-[6]helicenols and application in the synthesis of [6]helicene-based phosphinite ligands. Eur. J. Org. Chem. 2016, 2016, 4948–4952. [CrossRef] 53. Reetz, M.T.; Sostmann, S. Kinetic resolution in Pd-catalyzed allylic substitution using the helical PHelix ligand. J. Organomet. Chem. 2000, 603, 105–109. [CrossRef] 54. Reetz, M.T.; Sostmann, S. First enantioselective catalysis using a helical diphosphane. Tetrahedron Lett. 1997, 38, 3211–3214. [CrossRef] 55. Nakano, D.; Yamaguchi, M. Enantioselective hydrogenation of itaconate using rhodium bihelicenol phosphite complex. Matched/mismatched phenomena between helical and axial chirality. Tetrahedron Lett. 2003, 44, 4969–4971. [CrossRef] 56. Yavari, K.; Aillard, P.; Zhang, Y.; Nuter, F.; Retailleau, P.; Voituriez, A.; Marinetti, A. Helicenes with embedded phosphole units in enantioselective gold catalysis. Angew. Chem. Int. Ed. 2014, 53, 861–865. [CrossRef] [PubMed] 57. Aillard, P.; Voituriez, A.; Dova, D.; Cauteruccio, S.; Licandro, E.; Marinetti, A. Phosphathiahelicenes: Synthesis and uses in enantioselective gold catalysis. Chem. Eur. J. 2014, 20, 12373–12376. [CrossRef] [PubMed] 58. Cauteruccio, S.; Dova, D.; Benaglia, M.; Genoni, A.; Orlandi, M.; Licandro, E. Synthesis, characterisation, and organocatalytic activity of chiral tetrathiahelicene diphosphine oxides. Eur. J. Org. Chem. 2014, 2014, 2694–2702. [CrossRef] 59. Šamal, M.; Misek, J.; Stara, I.G.; Stary, I. Organocatalysis with azahelicenes: The first use of helically chiral pyridine-based catalysts in the asymmetric acyl transfer reaction. Collect. Czechoslov. Chem. Commun. 2009, 74, 1151–1159. [CrossRef] Symmetry 2018, 10, 10 46 of 48

60. Misek, J.; Teply, F.; Stara, I.G.; Tichy, M.; Saman, D.; Cisarova, I.; Vojtisek, P.; Stary, I. A straightforward route to helically chiral N-heteroaromatic compounds: Practical synthesis of racemic 1,14-diaza[5]helicene and optically pure 1- and 2-aza[6]helicenes. Angew. Chem. Int. Ed. 2008, 47, 3188–3191. [CrossRef][PubMed] 61. Crittall, M.R.; Rzepa, H.S.; Carbery, D.R. Design, synthesis, and evaluation of a helicenoidal DMAP Lewis base catalyst. Org. Lett. 2011, 13, 1250–1253. [CrossRef][PubMed] 62. Ruble, J.C.; Latham, H.A.; Fu, G.C. Effective kinetic resolution of secondary alcohols with a planar−chiral

analogue of 4-(Dimethylamino)pyridine. Use of the Fe(C5Ph5) group in asymmetric catalysis. J. Am. Chem. Soc. 1997, 119, 1492–1493. [CrossRef] 63. Ruble, J.C.; Tweddell, J.; Fu, G.C. Kinetic resolution of arylalkylcarbinols catalyzed by a planar-chiral derivative of DMAP: A new benchmark for nonenzymatic acylation. J. Org. Chem. 1998, 63, 2794–2795. [CrossRef] 64. Spivey, A.C.; Fekner, T.; Spey, S.E. Axially chiral analogues of 4-(Dimethylamino)pyridine: Novel catalysts for nonenzymatic enantioselective acylations. J. Org. Chem. 2000, 65, 3154–3159. [CrossRef][PubMed] 65. Chen, J.; Takenaka, N. Helical chiral pyridine N-oxides: A new family of asymmetric catalysts. Chem. Eur. J. 2009, 15, 7268–7276. [CrossRef][PubMed] 66. Narcis, M.J.; Takenaka, N. Helical-chiral small molecules in asymmetric catalysis. Eur. J. Org. Chem. 2014, 2014, 21–34. [CrossRef] 67. Takenaka, N.; Sarangthem, R.S.; Captain, B. Helical chiral pyridine N-oxides: A new family of asymmetric catalysts. Angew. Chem. Int. Ed. 2008, 47, 9708–9710. [CrossRef][PubMed] 68. Chen, J.; Captain, B.; Takenaka, N. Helical chiral 2,20-bipyridine N-monoxides as catalysts in the enantioselective propargylation of aldehydes with allenyltrichlorosilane. Org. Lett. 2011, 13, 1654–1657. [CrossRef][PubMed] 69. Lu, T.; Zhu, R.; An, Y.; Wheeler, S.E. Origin of enantioselectivity in the propargylation of aromatic aldehydes catalyzed by helical N-oxides. J. Am. Chem. Soc. 2012, 134, 3095–3102. [CrossRef][PubMed] 70. Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R.S.; Chandrakumar, A. Helical chiral 2-aminopyridinium ions: A new class of hydrogen bond donor catalysts. J. Am. Chem. Soc. 2010, 132, 4536–4537. [CrossRef] [PubMed] 71. Narcis, M.J.; Sprague, D.J.; Captain, B.; Takenaka, N. Enantio- and periselective nitroalkene Diels–Alder reaction. Org. Biomol. Chem. 2012, 10, 9134–9136. [CrossRef][PubMed] 72. Sato, I.; Yamashima, R.; Kadowaki, K.; Yamamoto, J.; Shibata, T.; Soai, K. Asymmetric induction by helical hydrocarbons: [6]- and [5]helicenes. Angew. Chem. Int. Ed. 2001, 40, 1096–1098. [CrossRef] 73. Kawasaki, T.; Suzuki, K.; Licandro, E.; Bossi, A.; Maiorana, S.; Soai, K. Enantioselective synthesis induced by tetrathia-[7]-helicenes in conjunction with asymmetric autocatalysis. Tetrahedron Asymmetry 2006, 17, 2050–2053. [CrossRef] 74. Dreher, S.D.; Katz, T.J.; Lam, K.-C.; Rheingold, A.L. Application of the Russig-Laatsch reaction to synthesize a bis[5]helicene chiral pocket for asymmetric catalysis. J. Org. Chem. 2000, 65, 815–822. [CrossRef] 75. Amemiya, R.; Yamaguchi, M. Chiral recognition in noncovalent bonding interactions between helicenes: Right-handed helix favors right-handed helix over left-handed helix. Org. Biomol. Chem. 2008, 6, 26–35. [CrossRef][PubMed] 76. Okubo, H.; Yamaguchi, M.; Kabuto, C. Macrocyclic amides consisting of helical chiral 1,12- dimethylbenzo[c]phenanthrene-5,8-dicarboxylate. J. Org. Chem. 1998, 63, 9500–9509. [CrossRef] 77. Reetz, M.T.; Sostmann, S. 2,15-Dihydroxy-hexahelicene (HELIXOL): Synthesis and use as an enantioselective fluorescent sensor. Tetrahedron 2001, 57, 2515–2520. [CrossRef] 78. Nakazaki, M.; Yamamoto, K.; Ikeda, T.; Kitsuki, T.; Okamoto, Y. Synthesis and chiral recognition of novel crown ethers incorporating helicene chiral centres. J. Chem. Soc. Chem. Commun. 1983, 0, 787–788. [CrossRef] 79. Yamamoto, K.; Ikeda, T.; Kitsuki, T.; Okamoto, Y.; Chikamatsu, H.; Nakazaki, M. Synthesis and chiral recognition of optically active crown ethers incorporating a helicene moiety as the chiral centre. J. Chem. Soc. Perkin Trans. 1 1990, 0, 271–276. [CrossRef] 80. Pandey, A.D.; Mohammed, H.; Pissurlenkar, R.R.S.; Karnik, A.V. Size-induced chiral discrimination switching by (S)-(-)-2(α-hydroxyethyl)benzimidazole-derived azacrowns. ChemPlusChem 2015, 80, 475–479. [CrossRef] 81. Weix, D.J.; Dreher, S.D.; Katz, T.J. [5]HELOL phosphite: A helically grooved sensor of remote chirality. J. Am. Chem. Soc. 2000, 122, 10027–10032. [CrossRef] Symmetry 2018, 10, 10 47 of 48

82. Wang, D.Z.; Katz, T.J. A [5]HELOL analogue that senses remote chirality in alcohols, phenols, amines, and carboxylic acids. J. Org. Chem. 2005, 70, 8497–8502. [CrossRef][PubMed] 83. Schweinfurth, D.; Zalibera, M.; Kathan, M.; Shen, C.; Mazzolini, M.; Trapp, N.; Crassous, J.; Gescheidt, G.; Diederich, F. Helicene quinones: Redox-triggered chiroptical switching and chiral recognition of the semiquinone radical anion lithium salt by electron nuclear double resonance spectroscopy. J. Am. Chem. Soc. 2014, 136, 13045–13052. [CrossRef][PubMed] 84. Hasan, M.; Khose, V.N.; Mori, T.; Borovkov, V.; Karnik, A.V. Sui generis helicene-based supramolecular chirogenic system: Enantioselective sensing, solvent control, and application in chiral group transfer reaction. ACS Omega 2017, 2, 592–598. [CrossRef] 85. Hasan, M.; Pandey, A.D.; Khose, V.N.; Mirgane, N.A.; Karnik, A.V. Sterically congested chiral 7,8-dioxa[6]helicene and Its dihydro analogues: Synthesis, regioselective functionalization, and unexpected domino Prins reaction. Eur. J. Org. Chem. 2015, 2015, 3702–3712. [CrossRef] 86. Hasan, M.; Khose, V.N.; Pandey, A.D.; Borovkov, V.; Karnik, A.V. Tailor-made supramolecular chirogenic system based on Cs-symmetric rigid organophosphoric acid host and amino alcohols: Mechanistic studies, bulkiness effect, and chirality sensing. Org. Lett. 2016, 18, 440–443. [CrossRef][PubMed] 87. Anger, E.; Iida, H.; Yamaguchi, T.; Hayashi, K.; Kumano, D.; Crassous, J.; Vanthuyne, N.; Roussel, C.; Yashima, E. Synthesis and chiral recognition ability of helical polyacetylenes bearing helicene pendants. Polym. Chem. 2014, 5, 4909–4914. [CrossRef] 88. An, Z.; Yamaguchi, M. Chiral recognition in aggregation of gold nanoparticles grafted with helicenes. Chem. Commun. 2012, 48, 7383–7385. [CrossRef][PubMed] 89. Ichinose, W.; Miyagawa, M.; An, Z.; Yamaguchi, M. Optical resolution of aromatic alcohols using silica nanoparticles grafted with helicene. Org. Lett. 2012, 14, 3123–3125. [CrossRef][PubMed] 90. Miyagawa, M.; Ichinose, W.; Yamaguchi, M. Equilibrium shift in solution: Molecular shape recognition and precipitation of a synthetic double helix using helicene-grafted silica nanoparticles. Chem. Eur. J. 2014, 20, 1272–1278. [CrossRef][PubMed] 91. Yamada, K.; Ishii, R.; Nakagawa, H.; Kawazura, H. Inclusion of Trithia[5]heterohelicene by various serum albumins. An effective probe for chiral discrimination. Chem. Pharm. Bull. 1997, 45, 936–938. [CrossRef] [PubMed] 92. Nakagawa, H.; Kobori, Y.; Yamada, K. Spontaneous chirality conversion of [5]thiaheterohelicene in charge-transfer complexes in SDS micelles. Chirality 2001, 13, 722–726. [CrossRef][PubMed] 93. Nakagawa, H.; Gomi, K.; Yamada, K. Chiral recognition of thiaheterohelicenes by alkyl b-D-pyranoside micelles. Influence of extension of helix. Chem. Pharm. Bull. 2001, 49, 49–53. [CrossRef][PubMed] 94. Nakagawa, H.; Kobori, Y.; Yoshida, M.; Yamada, K. Chiral recognition by single bilayered phosphatidylcholine vesicles using [5]thiaheterohelicene as a probe. Chem. Commun. 2001, 0, 2692–2693. [CrossRef] 95. Nakagawa, H.; Yoshida, M.; Kobori, Y.; Yamada, K. Study of chiral recognition of bilayered phosphatidylcholine vesicles using a helicene probe: Characteristic function of cholesterol. Chirality 2003, 15, 703–708. [CrossRef] [PubMed] 96. Nakagawa, H.; Yamada, K. Difference in chiral recognition of gel and liquid-crystalline phases of phosphatidylcholine vesicles as determined by circular dichroism spectroscopy. Chem. Pharm. Bull. 2005, 53, 52–55. [CrossRef][PubMed] 97. Tanaka, K.; Osuga, H.; Suzuki, H.; Shogase, Y.; Kitahara, Y. Synthesis, enzymic resolution and enantiomeric enhancement of bis(hydroxymethyl)[7]thiaheterohelicenes. J. Chem. Soc. Perkin Trans. 1 1998, 0, 935–940. [CrossRef] 98. Xu, Y.; Zhang, Y.X.; Sugiyama, H.; Umano, T.; Osuga, H.; Tanaka, K. (P)-Helicene displays chiral selection in binding to Z-DNA. J. Am. Chem. Soc. 2004, 126, 6566–6567. [CrossRef][PubMed] 99. Tanaka, K.; Osuga, H.; Kitahara, Y. Elongation and contraction of molecular springs. Synthesis, structures, and properties of bridged [7]thiaheterohelicenes. J. Org. Chem. 2002, 67, 1795–1801. [CrossRef][PubMed] 100. Shinohara, K.; Sannohe, Y.; Kaieda, S.; Tanaka, K.; Osuga, H.; Tahara, H.; Xu, Y.; Kawase, T.; Bando, T.; Sugiyama, H. A chiral wedge molecule inhibits telomerase activity. J. Am. Chem. Soc. 2010, 132, 3778–3782. [CrossRef][PubMed] 101. Tsuji, G.; Kawakami, K.; Sasaki, S. Enantioselective binding of chiral 1,14-dimethyl[5]helicene–spermine ligands with B- and Z-DNA. Bioorg. Med. Chem. 2013, 21, 6063–6068. [CrossRef][PubMed] Symmetry 2018, 10, 10 48 of 48

102. Kel, O.; Frstenberg, A.; Mehanna, N.; Nicolas, C.; Laleu, B.; Hammarson, M.; Albinsson, B.; Lacour, J.; Vauthey, E. Chiral selectivity in the binding of [4]helicene derivatives to double-stranded DNA. Chem. Eur. J. 2013, 19, 7173–7180. [CrossRef][PubMed] 103. Huang, Q.; Jiang, L.; Liang, W.; Gui, J.; Xu, D.; Wu, W.; Nakai, Y.; Nishijima, M.; Fukuhara, G.; Mori, T.; et al. Inherently chiral azonia[6]helicene-modified β-cyclodextrin: Synthesis, characterization, and chirality sensing of underivatized amino acids in water. J. Org. Chem. 2016, 81, 3430–3434. [CrossRef][PubMed] 104. Okubo, H.; Nakano, D.; Anzai, S.; Yamaguchi, M. Synthesis of symmetrical polynitrohelicenes and their chiral recognition in the charge transfer complexation. J. Org. Chem. 2001, 66, 557–563. [CrossRef][PubMed] 105. Murguly, E.; McDonald, R.; Branda, N.R. Chiral discrimination in hydrogen-bonded [7]helicenes. Org. Lett. 2000, 2, 3169–3172. [CrossRef][PubMed] 106. Mikes, F.; Boshart, G.; Gil-Av, E. Resolution of optical isomers by high-performance liquid chromatography, using coated and bonded chiral charge-transfer complexing agents as stationary phases. J. Chromatogr. A 1976, 122, 205–221. [CrossRef] 107. Thongpanchang, T.; Paruch, K.; Katz, T.J.; Rheingold, A.R.; Lam, K.-C.; Liable-Sands, L. Why (1S)-camphanates are excellent resolving agents for helicen-1-ols and why they can be used to analyze absolute configurations. J. Org. Chem. 2000, 65, 1850–1856. [CrossRef][PubMed] 108. Bucinskas, A.; Waghray, D.; Bagdziunas, G.; Thomas, J.; Grazulevicius, J.V.; Dehaen, W. Synthesis, functionalization, and optical properties of chiral carbazole-based diaza[6]helicenes. J. Org. Chem. 2015, 80, 2521–2528. [CrossRef][PubMed] 109. Waghray, D.; Bagdziunas, G.; Jacobs, J.; Meervelt, L.V.; Grazulevicius, J.V.; Dehaen, W. Diastereoselective strategies towards thia[n]helicenes. Chem. Eur. J. 2015, 21, 18791–18798. [CrossRef][PubMed] 110. Nakano, K.; Hidehira, Y.; Takahashi, K.; Hiyama, T.; Nozaki, K. Stereospecific synthesis of hetero[7]helicenes by Pd-catalyzed double N-arylation and intramolecular O-arylation. Angew. Chem. Int. Ed. 2005, 44, 7136–7138. [CrossRef] [PubMed] 111. Sako, M.; Takeuchi, Y.; Tsujihara, T.; Kodera, J.; Kawano, T.; Takizawa, S.; Sasai, T. Efficient enantioselective synthesis of oxahelicenes using redox/acid cooperative catalysts. J. Am. Chem. Soc. 2016, 138, 11481–11484. [CrossRef][PubMed] 112. Šámal, M.; Chercheja, S.; Rybáˇcek,J.; Chocholoušová, J.V.; Vacek, J.; Bednárová, L.; Šaman, D.; Stará, I.G.; Starý, I. An ultimate stereocontrol in ssymmetric synthesis of optically pure fully aromatic helicenes. J. Am. Chem. Soc. 2015, 137, 8469–8474. [CrossRef][PubMed] 113. Barroso, J.; Cabellos, J.L.; Pan, S.; Murillo, F.; Zarate, X.; Fernandez-Herrera, M.A.; Merino, G. Revisiting the racemization mechanism of helicenes. Chem. Commun. 2018, 54, 188–191. [CrossRef][PubMed]

© 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/).