Advances in the Asymmetric Synthesis of BINOL Derivatives

BINOL derivatives have shown relevant biological activities and are important chiral ligands and catalysts. Due to these properties, their asymmetric synthesis has attracted the interest of the scientific community. In this work, we present an overview of the most efficient methods to obtain chiral BINOLs, highlighting the use of metal complexes and organocatalysts as well as kinetic resolution. Further derivatizations of BINOLs are also discussed.


Introduction
The chirality resulting from restricted rotation around a single bond is called atropisomerism (axial chirality). This phenomenon was first described by Christie and Kenner [1] in 1922 when investigating the biaryl 6,6'-dinitro-2,2'-diphenic acid (Figure 1), and the term "atropisomer", derived from the Greek where "a" means "not" and "tropes" means "turn", was created by Kuhn. Atropisomers belong to the class of axially chiral compounds; however, in this case, the enantiomers exist due to restricted rotation around a single bond [2].

Introduction
The chirality resulting from restricted rotation around a single bond is called atropisomerism (axial chirality). This phenomenon was first described by Christie and Kenner [1] in 1922 when investigating the biaryl 6,6'-dinitro-2,2'-diphenic acid (Figure 1), and the term "atropisomer", derived from the Greek where "a" means "not" and "tropes" means "turn", was created by Kuhn. Atropisomers belong to the class of axially chiral compounds; however, in this case, the enantiomers exist due to restricted rotation around a single bond [2]. Axial chirality has also been considered as an important structural element of many natural products [3] and bioactive compounds, whose enantiomers generally exhibit different pharmacological activities and metabolic processes in vivo and in vitro [4]. Examples of natural products include viriditoxin, produced by fungi with antibacterial activity, and vancomycin, an amphoteric glycopeptide antibiotic produced by soil bacterium (Figure 2).
Due to their relevant biological properties, the asymmetric synthesis of atropisomers has attracted the interest of the scientific community. Furthermore, atropisomers have been important chiral ligands since the 1980s, when BINAP was developed for enantioselective reactions catalyzed by transition metals [3].
Although conventional chiral resolution of racemates and chiral auxiliary reactions are generally used for the construction of axially chiral compounds in enantiomerically Axial chirality has also been considered as an important structural element of many natural products [3] and bioactive compounds, whose enantiomers generally exhibit different pharmacological activities and metabolic processes in vivo and in vitro [4]. Examples of natural products include viriditoxin, produced by fungi with antibacterial activity, and vancomycin, an amphoteric glycopeptide antibiotic produced by soil bacterium (Figure 2).
Due to their relevant biological properties, the asymmetric synthesis of atropisomers has attracted the interest of the scientific community. Furthermore, atropisomers have been important chiral ligands since the 1980s, when BINAP was developed for enantioselective reactions catalyzed by transition metals [3].
ts for axial chirality transfer.

HO vancomycin
ogically active compounds with axial chirality.
yl auxiliaries and catalysts (such as BINOL or BINAP) exhibit fer properties [11]. Due to the importance of axially chiral biaryl eresting methods for their directed atroposelective construction able 1 shows some catalysts used for the transfer of axial chirality, the substrates used do not have any type of chirality, thus ent transfer of this property.

Ref
(S)-1 1-naphthyl yl auxiliaries and catalysts (such as BINOL or BINAP) exhibit fer properties [11]. Due to the importance of axially chiral biaryl eresting methods for their directed atroposelective construction able 1 shows some catalysts used for the transfer of axial chirality, the substrates used do not have any type of chirality, thus ent transfer of this property. ts for axial chirality transfer.
Axially chiral biaryl auxiliaries and catalysts (such as BINOL or BINAP) exhibit excellent chirality transfer properties [11]. Due to the importance of axially chiral biaryl compounds, several interesting methods for their directed atroposelective construction have been developed. Table 1 shows some catalysts used for the transfer of axial chirality, bearing in mind that the substrates used do not have any type of chirality, thus strengthening the excellent transfer of this property.  [12] (R)-1 9-anthryl [13] (R)-1 [12] (R)-1 9-phenanthryl [14,15] (R)-1 1-pyrenyl [16] (R)-1 [17] (R)-1 9-anthryl [16] (S)-1 [18] [23, 31,32] (R)-2 2-naphtyl atalysis meets the demand for high efficiency and economic value omeric compounds as ligands in metal-mediated catalysis has nometallic chemistry and asymmetric synthesis fields. Due to the rtance of these chiral biaryl scaffolds, several synthetic procedures oncepts [10] have been published in the literature. yl auxiliaries and catalysts (such as BINOL or BINAP) exhibit fer properties [11]. Due to the importance of axially chiral biaryl eresting methods for their directed atroposelective construction able 1 shows some catalysts used for the transfer of axial chirality, the substrates used do not have any type of chirality, thus ent transfer of this property. ts for axial chirality transfer.

Metal-Mediated Oxidative Enantioselective Coupling
Among the available methods for the synthesis of optically active BINOLs, one of the most explored is the oxidative dimerization of 2-naphthols mediated by complexes of Cu [39][40][41][42][43][44][45][46] Fe [47][48][49], V [50][51][52][53][54][55], Ru [56], and chiral ligands (very often amines), normally generated in situ. In this regard, excellent reviews discussing these methods have been reported by Brunel [57], Wang [58], Bryliakov et al. [59], and Liao et al. [60] (Schemes 1 and 2 With due recognition of the particularities of each case, the radial-anion mechanism [55,61-65] (Scheme 3) usually proceeds via generation of the radical species B resulting from an oxidation of 2-naphthol A by a metal catalyst (M n+ ). B is then added to another neutral 2-naphthol molecule to form a new C-C bond and generate the C-radical, which is further oxidized by O2 to restore aromaticity. Oxidative coupling may occur through three different mechanisms: (1) radical-radical coupling, (2) heterolytic coupling of cationic species with 2-naphthol, or (3) radical-anion coupling, the latter generally being the most accepted to support this type of transformation [55,[61][62][63][64]. An important step is the one where the catalytic species is complexed with directing groups or coordination assistants at the C3 position of 2-naphthols-notably ester groups [41,45]-which, in many cases, is a "sine qua no" condition for the success of the synthetic protocols (Scheme 3). The most recent methods for obtaining enantiomerically pure BINOLs are still based on the catalytic dyad metal-chiral ligands. In this sense, Chen and colleagues [66] (Scheme 4) have developed a new chiral 1,5-N,N-bidentate ligand based on a spirocyclic skeleton of pyrrolidine oxazoline and CuBr to couple 2-naphtols 3b. The efficient catalytic species formed in situ allows for (S)-BINOL derivatives (1) with high enantioselectivity (up to 99% ee) and good yields (up to 87%) to be obtained. Based on experimental results and the literature, the authors proposed that this coupling proceeds via radical-anion coupling, where the complex generated in situ coordinates to form species D in the presence of air, which couples with radical E (generated through an electron transfer from the outer sphere with another Cu(II) complex) to form the intermediate F (Scheme 5). The coupling product is obtained after tautomerization of H. The authors found experimental evidence that, during the coupling process, the attack from E to F by the Si face was favored, probably because of the greater steric impediment to attack by the Re face.  With due recognition of the particularities of each case, the radial-anion mechanism [55,[61][62][63][64][65] (Scheme 3) usually proceeds via generation of the radical species B resulting from an oxidation of 2-naphthol A by a metal catalyst (M n+ ). B is then added to another neutral 2-naphthol molecule to form a new C-C bond and generate the C-radical, which is further oxidized by O 2 to restore aromaticity.
The most recent methods for obtaining enantiomerically pure BINOLs are still based on the catalytic dyad metal-chiral ligands. In this sense, Chen and colleagues [66] (Scheme 4) have developed a new chiral 1,5-N,N-bidentate ligand based on a spirocyclic skeleton of pyrrolidine oxazoline and CuBr to couple 2-naphtols 3b. The efficient catalytic species formed in situ allows for (S)-BINOL derivatives (1) with high enantioselectivity (up to 99% ee) and good yields (up to 87%) to be obtained. Based on experimental results and the literature, the authors proposed that this coupling proceeds via radical-anion coupling, where the complex generated in situ coordinates to form species D in the presence of air, which couples with radical E (generated through an electron transfer from the outer sphere with another Cu(II) complex) to form the intermediate F (Scheme 5). The coupling product is obtained after tautomerization of H. The authors found experimental evidence that, during the coupling process, the attack from E to F by the Si face was favored, probably because of the greater steric impediment to attack by the Re face. the literature, the authors proposed that this coupling proceeds via radical-anion coupling, where the complex generated in situ coordinates to form species D in the presence of air, which couples with radical E (generated through an electron transfer from the outer sphere with another Cu(II) complex) to form the intermediate F (Scheme 5). The coupling product is obtained after tautomerization of H. The authors found experimental evidence that, during the coupling process, the attack from E to F by the Si face was favored, probably because of the greater steric impediment to attack by the Re face. Che and co-workers introduced a chiral aminopyridine-like ligandbisquinolyldiamine [(1R,2R)-N 1 ,N 2 -di(quinolin-8-yl)cyclohexane-1,2-diamine (BQCN)]and applied it to the iron-catalyzed asymmetric cis-dihydroxylation of alkenes [67]. Inspired by this work, Liu's group [68] (Scheme 6) established a methodology for the asymmetric oxidative homo-coupling of 2-naphthols (3c), leading to the synthesis of (S)-BINOL derivatives (1) mediated by a Fe complex and generated in situ from Fe(ClO4)2 and the BQCN ligand. Excellent yields (up to 99%) and enantiomeric excesses (up to 81%) have been reported. Che and co-workers introduced a chiral aminopyridine-like ligand-bisquinolyldiamine [(1R,2R)-N 1 ,N 2 -di(quinolin-8-yl)cyclohexane-1,2-diamine (BQCN)]-and applied it to the iron-catalyzed asymmetric cis-dihydroxylation of alkenes [67]. Inspired by this work, Liu's group [68] (Scheme 6) established a methodology for the asymmetric oxidative homocoupling of 2-naphthols (3c), leading to the synthesis of (S)-BINOL derivatives (1) mediated by a Fe complex and generated in situ from Fe(ClO 4 ) 2 and the BQCN ligand. Excellent yields (up to 99%) and enantiomeric excesses (up to 81%) have been reported.
From the same perspective, Uchida's group [69] (Scheme 7) developed remarkable enantioselective aerobic coupling between 2-naphthols 3d in the presence of the (aqua)ruthenium complex (salen). The protocol provided (R)-BINOLs (1) with yields between 55 and 85% and enantiomeric excesses up to 94%. Through mechanistic studies, these researchers concluded that, in this case, cross-coupling selectivity is dominated by Scheme 6.
From the same perspective, Uchida's group [69] (Scheme 7) developed remarkable enantioselective aerobic coupling between 2-naphthols 3d in the presence of the (aqua)ruthenium complex (salen). The protocol provided (R)-BINOLs (1) with yields between 55 and 85% and enantiomeric excesses up to 94%. Through mechanistic studies, these researchers concluded that, in this case, cross-coupling selectivity is dominated by steric rather than electronic effects, which can be controlled by chemoselective oxidation via single electron transfer (SET) and oxidative carbon-carbon bond formation, a process for which ruthenium(salen) catalyst proved to be suitable [62]. Therefore, the authors have proposed that this transformation proceeds via oxidation of one of the coupling partners to the electrophilic intermediate radical I, which is converted to the desired BINOL after chemoselective coupling [62]. steric rather than electronic effects, which can be controlled by chemoselective oxidation via single electron transfer (SET) and oxidative carbon-carbon bond formation, a process for which ruthenium(salen) catalyst proved to be suitable [62]. Therefore, the authors have proposed that this transformation proceeds via oxidation of one of the coupling partners to the electrophilic intermediate radical I, which is converted to the desired BINOL after chemoselective coupling [62]. Ishihara and co-workers [71] (Scheme 9) developed a method for enantioselective oxidative coupling of 2-naphthol derivatives 3d in the presence of a chiral Fe(II)diphosphine oxide complex. The products of interest were obtained with yields up to 98 % and enantiomeric excesses between 60 and 85%. Scheme 9. Chiral diphosphine oxide-iron(II) complex catalyzed enantioselective aerobic coupling between 2-naphthols to access C1-symmetric BINOL derivatives.
A copper catalyst prepared in situ from a ligand synthesized by the fusion of chelating picolinic acid/substituted BINOLs and CuI was employed in the asymmetric oxidative coupling of 2-naphthols (3e). In this work, published by Zhang et al. [72] (Scheme 10), 6,6'-disubstituted (R)-BINOLs (1) were obtained with yields of up to 89% and excellent enantioselectivities (up to 96% ee). The reaction was accompanied by Mass Spectroscopy, and identification of a peak corresponding to the complex J allowed the authors to propose a mechanism pathway through the transition state K. Ishihara and co-workers [71] (Scheme 9) developed a method for enantioselective oxidative coupling of 2-naphthol derivatives 3d in the presence of a chiral Fe(II)diphosphine oxide complex. The products of interest were obtained with yields up to 98 % and enantiomeric excesses between 60 and 85%. Scheme 9. Chiral diphosphine oxide-iron(II) complex catalyzed enantioselective aerobic coupling between 2-naphthols to access C1-symmetric BINOL derivatives.
A copper catalyst prepared in situ from a ligand synthesized by the fusion of chelating picolinic acid/substituted BINOLs and CuI was employed in the asymmetric oxidative coupling of 2-naphthols (3e). In this work, published by Zhang et al. [72] (Scheme 10), 6,6'-disubstituted (R)-BINOLs (1) were obtained with yields of up to 89% and excellent enantioselectivities (up to 96% ee). The reaction was accompanied by Mass Spectroscopy, and identification of a peak corresponding to the complex J allowed the authors to propose a mechanism pathway through the transition state K. Scheme 9. Chiral diphosphine oxide-iron(II) complex catalyzed enantioselective aerobic coupling between 2-naphthols to access C1-symmetric BINOL derivatives.
A copper catalyst prepared in situ from a ligand synthesized by the fusion of chelating picolinic acid/substituted BINOLs and CuI was employed in the asymmetric oxidative coupling of 2-naphthols (3e). In this work, published by Zhang et al. [72] (Scheme 10), 6,6'-disubstituted (R)-BINOLs (1) were obtained with yields of up to 89% and excellent enantioselectivities (up to 96% ee). The reaction was accompanied by Mass Spectroscopy, and identification of a peak corresponding to the complex J allowed the authors to propose a mechanism pathway through the transition state K.

Electrochemical Synthesis
Despite the inherent advantages of electrochemical synthesis, notably in terms of sustainability [74], few examples of enantioselective coupling for the construction of chiral BINOLs have been reported so far. In 1994, which appears to be the first record of this type of synthesis, Bobbitt et al. [75] (Scheme 12) established a method for enantioselective coupling of 2-naphthols (3f) on a TEMPO-modified graphite electrode in the presence of (-)-sparteine in acetonitrile to afford (S)-BINOL (1) with excellent yields and enantiomeric excesses. Continuing work involving multifunctional chiral catalysis via double activation, Takizawa's group [73] developed complexes A-C (Scheme 11)-from VOSO 4 and Schiff base ligands generated via condensation of (S)-tert-leucine and 3,3 '-formyl-(R)-BINOLwhich have been successfully applied in the synthesis of (R)-and (S)-BINOL (1) with yields between 46 and 76%, in addition to enantiomeric excesses of up to 91%. Continuing work involving multifunctional chiral catalysis via double activation, Takizawa's group [73] developed complexes A-C (Scheme 11)-from VOSO4 and Schiff base ligands generated via condensation of (S)-tert-leucine and 3,3 '-formyl-(R)-BINOLwhich have been successfully applied in the synthesis of (R)-and (S)-BINOL (1) with yields between 46 and 76%, in addition to enantiomeric excesses of up to 91%.

Electrochemical Synthesis
Despite the inherent advantages of electrochemical synthesis, notably in terms of sustainability [74], few examples of enantioselective coupling for the construction of chiral BINOLs have been reported so far. In 1994, which appears to be the first record of this type of synthesis, Bobbitt et al. [75] (Scheme 12) established a method for enantioselective coupling of 2-naphthols (3f) on a TEMPO-modified graphite electrode in the presence of (-)-sparteine in acetonitrile to afford (S)-BINOL (1) with excellent yields and enantiomeric excesses. Scheme 11. Atroposelective synthesis of (R)-and (S)-BINOLs (1) via mono-and binuclear vanadium catalysts.

Electrochemical Synthesis
Despite the inherent advantages of electrochemical synthesis, notably in terms of sustainability [74], few examples of enantioselective coupling for the construction of chiral BINOLs have been reported so far. In 1994, which appears to be the first record of this type of synthesis, Bobbitt et al. [75]  Recently, Mei's group [74] (Scheme 13) demonstrated the first example of a Nicatalyzed enantioselective electrochemical reductive coupling of 2-naphtols (4) in an undivided cell for the construction of axially chiral BINOL derivatives (1) with good yields (up 91%) and enantiomeric excess of up to 98%. Scheme 13. Enantioselective Ni-promoted electrochemical synthesis of (R)-BINOL derivatives (1).

Organocatalyzed Synthesis/Kinetic Resolution of BINOLs/BINAPs
Among the methods for the synthesis/kinetic resolution (KR) of axially chiral biaryl and binaphthyl compounds, the organocatalyzed approach has been more explored in the last decade. Some examples were described in the review by Cheng et al. [76]. In this topic, the kinetic synthesis/resolution of BINOL skeletons will be addressed using organocatalysts that do not have axial chirality, thus providing induction to the products of interest.

Organocatalyzed Synthesis/Kinetic Resolution of BINOLs/BINAPs
Among the methods for the synthesis/kinetic resolution (KR) of axially chiral biaryl and binaphthyl compounds, the organocatalyzed approach has been more explored in the last decade. Some examples were described in the review by Cheng et al. [76]. In this topic, the kinetic synthesis/resolution of BINOL skeletons will be addressed using organocatalysts that do not have axial chirality, thus providing induction to the products of interest.

Organocatalyzed Synthesis/Kinetic Resolution of BINOLs/BINAPs
Among the methods for the synthesis/kinetic resolution (KR) of axially chiral biaryl and binaphthyl compounds, the organocatalyzed approach has been more explored in the last decade. Some examples were described in the review by Cheng et al. [76]. In this topic, the kinetic synthesis/resolution of BINOL skeletons will be addressed using organocatalysts that do not have axial chirality, thus providing induction to the products of interest.

Organocatalyzed Synthesis/Kinetic Resolution of BINOLs/BINAPs
Among the methods for the synthesis/kinetic resolution (KR) of axially chiral biaryl and binaphthyl compounds, the organocatalyzed approach has been more explored in the last decade. Some examples were described in the review by Cheng et al. [76]. In this topic, the kinetic synthesis/resolution of BINOL skeletons will be addressed using organocatalysts that do not have axial chirality, thus providing induction to the products of interest.
In 2005, Tsuji and co-workers [77] reported a kinetic resolution of 2,2'-dihydroxy-1,1'biaryls using a palladium-catalyzed atroposelective alcoholysis of racemic vinyl ethers (5). The method uses the organocatalyst (R,R)-1,2-cyclohexanediamine (6) and a mixture of methanol and dichloromethane as solvent at 20 °C. Five examples were obtained and it was observed that the volume of the acyl group directly influences selectivity, as shown in Scheme 14 where the larger substituent (1-adamantyl) provided high selectivity.
In 2012, Dan and co-workers [78] evaluated the Ferrier-type rearrangement using chiral bicyclic guanidine as a catalyst; however, the reaction was sluggish, affording an optically active product with low yield and enantioselectivity (Scheme 15A). Upon these results, the authors used another strategy, based on studies by Masatoshi and Reiko [79] for synthesis of the optically active biaryl through optical resolution of the corresponding racemate using chiral diamine (12) (Scheme 15B). Initially, there was deprotection of the methyl ether, and in the second step the racemic binaphthol derivative was recrystallized from toluene in the presence of (S,S)-1,2-diphenyl-1,2-ethanediamine (12), leading to compound (R)-11 with 95% ee and 22% yield. In 2012, Dan and co-workers [78] evaluated the Ferrier-type rearrangement using chiral bicyclic guanidine as a catalyst; however, the reaction was sluggish, affording an optically active product with low yield and enantioselectivity (Scheme 15A). Upon these results, the authors used another strategy, based on studies by Masatoshi and Reiko [79] for synthesis of the optically active biaryl through optical resolution of the corresponding racemate using chiral diamine (12) (Scheme 15B). Initially, there was deprotection of the methyl ether, and in the second step the racemic binaphthol derivative was recrystallized from toluene in the presence of (S,S)-1,2-diphenyl-1,2-ethanediamine (12), leading to compound (R)-11 with 95% ee and 22% yield. In 2014, Sibi and co-workers [80] proposed a new kinetic resolution that employs a chiral 4-(dimethylamino)pyridine (DMAP) derivative 14 as a catalyst via O-acylation (Scheme 16). The method proved to be efficient, and both secondary alcohols and axially chiral biaryl compounds were obtained with selectivity factors of up to 37 and 51, respectively. Increased conversion was also observed for binaphthyl substrates with an electron-rich group in the ortho position. In 2014, Sibi and co-workers [80] proposed a new kinetic resolution that employs a chiral 4-(dimethylamino)pyridine (DMAP) derivative 14 as a catalyst via O-acylation (Scheme 16). The method proved to be efficient, and both secondary alcohols and axially chiral biaryl compounds were obtained with selectivity factors of up to 37 and 51, respectively. Increased conversion was also observed for binaphthyl substrates with an electron-rich group in the ortho position. In 2012, Dan and co-workers [78] evaluated the Ferrier-type rearrangement using chiral bicyclic guanidine as a catalyst; however, the reaction was sluggish, affording an optically active product with low yield and enantioselectivity (Scheme 15A). Upon these results, the authors used another strategy, based on studies by Masatoshi and Reiko [79] for synthesis of the optically active biaryl through optical resolution of the corresponding racemate using chiral diamine (12) (Scheme 15B). Initially, there was deprotection of the methyl ether, and in the second step the racemic binaphthol derivative was recrystallized from toluene in the presence of (S,S)-1,2-diphenyl-1,2-ethanediamine (12), leading to compound (R)-11 with 95% ee and 22% yield. In 2014, Sibi and co-workers [80] proposed a new kinetic resolution that employs a chiral 4-(dimethylamino)pyridine (DMAP) derivative 14 as a catalyst via O-acylation (Scheme 16). The method proved to be efficient, and both secondary alcohols and axially chiral biaryl compounds were obtained with selectivity factors of up to 37 and 51, respectively. Increased conversion was also observed for binaphthyl substrates with an electron-rich group in the ortho position. In 2014, Zhao and co-workers [81] reported an atroposelective kinetic resolution using N-heterocyclic carbene (NHC) 18 as a catalyst to resolve the enantiomers of BINOL (Scheme 17). The 1,1'-biaryl-2,2'-diol derivatives 16 were explored, where the products obtained, both acylated 19 and the recovered BINOL 16, had high selectivity. In 2014, Zhao and co-workers [81] reported an atroposelective kinetic resolution using N-heterocyclic carbene (NHC) 18 as a catalyst to resolve the enantiomers of BINOL (Scheme 17). The 1,1'-biaryl-2,2'-diol derivatives 16 were explored, where the products obtained, both acylated 19 and the recovered BINOL 16, had high selectivity.

Scheme 17. Kinetic resolution of a BINOL derivative promoted by a NHC catalyst 18.
Sparr and Link [82] described a highly enantioselective synthesis of binaphthyl 20 by intramolecular aldol condensation using (S)-pyrrolidinyl-tetrazole 21 as a catalyst (Scheme 18). The authors described that the high selectivity of the process stems from the efficient transfer of stereochemical information from the catalyst into the axis of chirality of biaryl products. The examples obtained showed good yields and high enantiomeric ratios. Scheme 18. Synthesis of binaphthyl derivatives through an intramolecular aldol condensation using catalyst 21.
In 2017, Shirakawa and co-workers [83] reported a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls through cation-directed O-alkylation. Reaction of racemic 1-aryl-2-tetralones (23) with the ammonium salt 24 (obtained from chiral quinidine) under basic conditions and using an alkylation agent leads to highly enantioselective O-alkylation (up to 98:2 er). According to the proposed mechanism, the basic medium initially promotes deprotonation and makes it possible to generate two enolate enantiomers associated with the chiral salt that form diastereomeric ion pairs; however, the chiral ammonium counterion is capable of rapidly differentiating balancer atropisomeric enolates, leading to highly atropselective O-alkylation. The in situ oxidation step with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) then takes place to obtain the BINOL derivatives (25) without loss of the enantiomeric ratio. The authors also noted that enantioselectivity can be controlled by the catalyst structure and the type of Sparr and Link [82] described a highly enantioselective synthesis of binaphthyl 20 by intramolecular aldol condensation using (S)-pyrrolidinyl-tetrazole 21 as a catalyst (Scheme 18). The authors described that the high selectivity of the process stems from the efficient transfer of stereochemical information from the catalyst into the axis of chirality of biaryl products. The examples obtained showed good yields and high enantiomeric ratios. In 2014, Zhao and co-workers [81] reported an atroposelective kinetic resolution using N-heterocyclic carbene (NHC) 18 as a catalyst to resolve the enantiomers of BINOL (Scheme 17). The 1,1'-biaryl-2,2'-diol derivatives 16 were explored, where the products obtained, both acylated 19 and the recovered BINOL 16, had high selectivity.

Scheme 17. Kinetic resolution of a BINOL derivative promoted by a NHC catalyst 18.
Sparr and Link [82] described a highly enantioselective synthesis of binaphthyl 20 by intramolecular aldol condensation using (S)-pyrrolidinyl-tetrazole 21 as a catalyst (Scheme 18). The authors described that the high selectivity of the process stems from the efficient transfer of stereochemical information from the catalyst into the axis of chirality of biaryl products. The examples obtained showed good yields and high enantiomeric ratios. Scheme 18. Synthesis of binaphthyl derivatives through an intramolecular aldol condensation using catalyst 21.
In 2017, Shirakawa and co-workers [83] reported a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls through cation-directed O-alkylation. Reaction of racemic 1-aryl-2-tetralones (23) with the ammonium salt 24 (obtained from chiral quinidine) under basic conditions and using an alkylation agent leads to highly enantioselective O-alkylation (up to 98:2 er). According to the proposed mechanism, the basic medium initially promotes deprotonation and makes it possible to generate two enolate enantiomers associated with the chiral salt that form diastereomeric ion pairs; however, the chiral ammonium counterion is capable of rapidly differentiating balancer atropisomeric enolates, leading to highly atropselective O-alkylation. The in situ oxidation step with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) then takes place to obtain the BINOL derivatives (25) without loss of the enantiomeric ratio. The authors also noted that enantioselectivity can be controlled by the catalyst structure and the type of In 2017, Shirakawa and co-workers [83] reported a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls through cation-directed O-alkylation. Reaction of racemic 1-aryl-2-tetralones (23) with the ammonium salt 24 (obtained from chiral quinidine) under basic conditions and using an alkylation agent leads to highly enantioselective O-alkylation (up to 98:2 er). According to the proposed mechanism, the basic medium initially promotes deprotonation and makes it possible to generate two enolate enantiomers associated with the chiral salt that form diastereomeric ion pairs; however, the chiral ammonium counterion is capable of rapidly differentiating balancer atropisomeric enolates, leading to highly atropselective O-alkylation. The in situ oxidation step with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) then takes place to obtain the BINOL derivatives (25) without loss of the enantiomeric ratio. The authors also noted that enantioselectivity can be controlled by the catalyst structure and the type of base and solvent used. Under optimized conditions, they obtained a broad scope of 20 examples with moderate to excellent yields (Scheme 19). In 2019, Sparr and co-workers [84] described a non-canonical polyketide cyclization, affording atropisomeric tetra-ortho-substituted binaphthalenes. Using hexacarbonyl substrates 26 and aminoethanol-derived proline-based catalyst 27 via the cascade of two arene ring formation reactions (Scheme 20), it was possible to obtain enantioenriched tetra-ortho-substituted binaphthalenes 28 through atroposelective aldol condensation. The explanation of the mechanism was based on NMR studies, where it was observed that two sequential aldol additions take place before a double dehydration, hence alleviating the acute nonbonding interaction during C−C bond formation. With product 28 (without substituents), it was possible to perform a derivatization through a triflation and arene coupling, obtaining (S)-29 with 84% yield (over two steps) and >99:1 er. Scheme 20. Synthesis of (S)-29 via atroposelective aldol condensation using catalyst 27.
Based on a previous work, where high atroposelectivity was acquired starting from racemic 2-tetralones, Jones et al. [85] extended the strategy for the use of BINOLs (Scheme 21). The reaction proceeds under basic conditions using cinchona derived catalyst 32 in a mixture of toluene and ethyl ether at room temperature for 48 h, leading to the formation of compound (R)-30 with 47% yield and 96% ee and compound (S)-31 with 49% yield and 80% ee. In 2019, Sparr and co-workers [84] described a non-canonical polyketide cyclization, affording atropisomeric tetra-ortho-substituted binaphthalenes. Using hexacarbonyl substrates 26 and aminoethanol-derived proline-based catalyst 27 via the cascade of two arene ring formation reactions (Scheme 20), it was possible to obtain enantioenriched tetra-orthosubstituted binaphthalenes 28 through atroposelective aldol condensation. The explanation of the mechanism was based on NMR studies, where it was observed that two sequential aldol additions take place before a double dehydration, hence alleviating the acute nonbonding interaction during C−C bond formation. With product 28 (without substituents), it was possible to perform a derivatization through a triflation and arene coupling, obtaining (S)-29 with 84% yield (over two steps) and >99:1 er. In 2019, Sparr and co-workers [84] described a non-canonical polyketide cyclization, affording atropisomeric tetra-ortho-substituted binaphthalenes. Using hexacarbonyl substrates 26 and aminoethanol-derived proline-based catalyst 27 via the cascade of two arene ring formation reactions (Scheme 20), it was possible to obtain enantioenriched tetra-ortho-substituted binaphthalenes 28 through atroposelective aldol condensation. The explanation of the mechanism was based on NMR studies, where it was observed that two sequential aldol additions take place before a double dehydration, hence alleviating the acute nonbonding interaction during C−C bond formation. With product 28 (without substituents), it was possible to perform a derivatization through a triflation and arene coupling, obtaining (S)-29 with 84% yield (over two steps) and >99:1 er. Scheme 20. Synthesis of (S)-29 via atroposelective aldol condensation using catalyst 27.
Based on a previous work, where high atroposelectivity was acquired starting from racemic 2-tetralones, Jones et al. [85] extended the strategy for the use of BINOLs (Scheme 21). The reaction proceeds under basic conditions using cinchona derived catalyst 32 in a mixture of toluene and ethyl ether at room temperature for 48 h, leading to the formation of compound (R)-30 with 47% yield and 96% ee and compound (S)-31 with 49% yield and 80% ee. Based on a previous work, where high atroposelectivity was acquired starting from racemic 2-tetralones, Jones et al. [85] extended the strategy for the use of BINOLs (Scheme 21). The reaction proceeds under basic conditions using cinchona derived catalyst 32 in a mixture of toluene and ethyl ether at room temperature for 48 h, leading to the formation of compound (R)-30 with 47% yield and 96% ee and compound (S)-31 with 49% yield and 80% ee. The reversible deprotonation of compound 30 leads to the formation of a diastereoisomeric BINOlate ammonium salt, which reacts at different rates in the alkylation step. The proposed transition state involves a hydrogen bonding of the ammonium salt with the secondary alcohol of the BINOlate anion, and an additional hydrogen bonding of the benzyl electrophile to the methyl ether.

Enzymatic Kinetic Resolution of BINOL
For decades, enzymatic kinetic resolution was considered the most reliable strategy for obtaining optically enriched compounds. In 1989, the first efficient method for enzymatic resolution of rac-BINOL (33) was described by Kazlaukas [86], which was based on enantiospecific hydrolysis catalyzed by cholesterol esterase (Scheme 22). The procedure uses low-cost bovine pancreatic acetone powder (PAP). The enantiomer (S)-1 was obtained with 66% yield and 99% ee and recrystallized with toluene, with compound (R)-33 formed after hydrolysis; enantiomer (R)-1 was obtained with 63% yield and 99% ee after filtration and being washed with cold toluene. The potential of enantioselective kinetic resolution to prepare atropisomeric compounds was initially proven by designing an enzymatic kinetic resolution, as illustrated by the elegant work of Aoyagi et al. [87]. Lipase (Candida antarctica) was used to catalyze the hydrolysis of BINOL monoester-derivatives 34, affording (R)-1 and (S)-34 with excellent yields and good enantioselective excesses (Scheme 23). The reversible deprotonation of compound 30 leads to the formation of a diastereoisomeric BINOlate ammonium salt, which reacts at different rates in the alkylation step. The proposed transition state involves a hydrogen bonding of the ammonium salt with the secondary alcohol of the BINOlate anion, and an additional hydrogen bonding of the benzyl electrophile to the methyl ether.

Enzymatic Kinetic Resolution of BINOL
For decades, enzymatic kinetic resolution was considered the most reliable strategy for obtaining optically enriched compounds. In 1989, the first efficient method for enzymatic resolution of rac-BINOL (33) was described by Kazlaukas [86], which was based on enantiospecific hydrolysis catalyzed by cholesterol esterase (Scheme 22). The procedure uses low-cost bovine pancreatic acetone powder (PAP). The enantiomer (S)-1 was obtained with 66% yield and 99% ee and recrystallized with toluene, with compound (R)-33 formed after hydrolysis; enantiomer (R)-1 was obtained with 63% yield and 99% ee after filtration and being washed with cold toluene. The reversible deprotonation of compound 30 leads to the formation of a diastereoisomeric BINOlate ammonium salt, which reacts at different rates in the alkylation step. The proposed transition state involves a hydrogen bonding of the ammonium salt with the secondary alcohol of the BINOlate anion, and an additional hydrogen bonding of the benzyl electrophile to the methyl ether.

Enzymatic Kinetic Resolution of BINOL
For decades, enzymatic kinetic resolution was considered the most reliable strategy for obtaining optically enriched compounds. In 1989, the first efficient method for enzymatic resolution of rac-BINOL (33) was described by Kazlaukas [86], which was based on enantiospecific hydrolysis catalyzed by cholesterol esterase (Scheme 22). The procedure uses low-cost bovine pancreatic acetone powder (PAP). The enantiomer (S)-1 was obtained with 66% yield and 99% ee and recrystallized with toluene, with compound (R)-33 formed after hydrolysis; enantiomer (R)-1 was obtained with 63% yield and 99% ee after filtration and being washed with cold toluene. The potential of enantioselective kinetic resolution to prepare atropisomeric compounds was initially proven by designing an enzymatic kinetic resolution, as illustrated by the elegant work of Aoyagi et al. [87]. Lipase (Candida antarctica) was used to catalyze the hydrolysis of BINOL monoester-derivatives 34, affording (R)-1 and (S)-34 with excellent yields and good enantioselective excesses (Scheme 23). The potential of enantioselective kinetic resolution to prepare atropisomeric compounds was initially proven by designing an enzymatic kinetic resolution, as illustrated by the elegant work of Aoyagi et al. [87]. Lipase (Candida antarctica) was used to catalyze the hydrolysis of BINOL monoester-derivatives 34, affording (R)-1 and (S)-34 with excellent yields and good enantioselective excesses (Scheme 23).

Chemical Derivatizations on the BINOL Skeleton
As previously mentioned, most chiral catalysts with the BINOL backbone are now commercially available. In this section, we will discuss the synthesis of new chiral catalysts.
Since 1999, Maruoka's group [89,90] (Scheme 25) has synthesized a series of chiral phase transfer catalysts based on quaternary ammonium bromides salts prepared from 1-(S)-BINOL, which have been successfully applied in the synthesis of natural and unnatural amino acids. In the same context, the group reported, in 2013 [12], the preparation of catalyst 40 (via insertion of piperazine 37) from the brominated strategic derivative 36, with 49% yield. In this case, the new chiral auxiliary was employed in the asymmetric phase transfer functionalization of 1-alkylalene-1,3-dicarboxylates with Narylsulfonyl imines and allylic/benzyl bromides for the preparation of tetrasubstituted allenes. In 2018, Moustafa and co-workers [88] described the lipase-catalyzed KR process, which uses immobilized Pseudomonas sp. lipoprotein lipase (Toyobo LIP301). Lipase selectively catalyzes readily available racemic substrates and provides stability to acylated products against racemization, promoting the formation of product (R)-35 with 24% yield and 99% enantiomeric excess (Scheme 24). In 2018, Moustafa and co-workers [88] described the lipase-catalyzed KR process, which uses immobilized Pseudomonas sp. lipoprotein lipase (Toyobo LIP301). Lipase selectively catalyzes readily available racemic substrates and provides stability to acylated products against racemization, promoting the formation of product (R)-35 with 24% yield and 99% enantiomeric excess (Scheme 24). Scheme 24. Kinetic resolution with immobilized Pseudomonas sp. lipoprotein lipase.

Chemical Derivatizations on the BINOL Skeleton
As previously mentioned, most chiral catalysts with the BINOL backbone are now commercially available. In this section, we will discuss the synthesis of new chiral catalysts.
Since 1999, Maruoka's group [89,90] (Scheme 25) has synthesized a series of chiral phase transfer catalysts based on quaternary ammonium bromides salts prepared from 1-(S)-BINOL, which have been successfully applied in the synthesis of natural and unnatural amino acids. In the same context, the group reported, in 2013 [12], the preparation of catalyst 40 (via insertion of piperazine 37) from the brominated strategic derivative 36, with 49% yield. In this case, the new chiral auxiliary was employed in the asymmetric phase transfer functionalization of 1-alkylalene-1,3-dicarboxylates with Narylsulfonyl imines and allylic/benzyl bromides for the preparation of tetrasubstituted allenes.

Chemical Derivatizations on the BINOL Skeleton
As previously mentioned, most chiral catalysts with the BINOL backbone are now commercially available. In this section, we will discuss the synthesis of new chiral catalysts.
Since 1999, Maruoka's group [89,90] (Scheme 25) has synthesized a series of chiral phase transfer catalysts based on quaternary ammonium bromides salts prepared from 1-(S)-BINOL, which have been successfully applied in the synthesis of natural and unnatural amino acids. In the same context, the group reported, in 2013 [12], the preparation of catalyst 40 (via insertion of piperazine 37) from the brominated strategic derivative 36, with 49% yield. In this case, the new chiral auxiliary was employed in the asymmetric phase transfer functionalization of 1-alkylalene-1,3-dicarboxylates with N-arylsulfonyl imines and allylic/benzyl bromides for the preparation of tetrasubstituted allenes.
For the catalysts based on BINOL derivatives with phosphoric acid, the most efficient method described in the literature for the insertion of phosphoric acid is phosphorylation with POCl 3 (Scheme 27), which can be performed in both enantiomerically pure and racemic BINOL [92,93]. Recently, Schaus' group [91] designed and prepared the (S)-3,3',6,6'tetrakis(trifluoromethyl)-BINOL 42 from (S)-1 by the subsequent protection, bromination, and insertion of the CF3 groups into the desired position (Scheme 26). This chiral catalyst was employed in the asymmetric synthesis of 1,3-substituted chiral allenes via boronate addition to sulfonyl hydrazones. For the catalysts based on BINOL derivatives with phosphoric acid, the most efficient method described in the literature for the insertion of phosphoric acid is phosphorylation with POCl3 (Scheme 27), which can be performed in both enantiomerically pure and racemic BINOL [92,93]. Recently, Schaus' group [91] designed and prepared the (S)-3,3',6,6'tetrakis(trifluoromethyl)-BINOL 42 from (S)-1 by the subsequent protection, bromination, and insertion of the CF3 groups into the desired position (Scheme 26). This chiral catalyst was employed in the asymmetric synthesis of 1,3-substituted chiral allenes via boronate addition to sulfonyl hydrazones. For the catalysts based on BINOL derivatives with phosphoric acid, the most efficient method described in the literature for the insertion of phosphoric acid is phosphorylation with POCl3 (Scheme 27), which can be performed in both enantiomerically pure and racemic BINOL [92,93].

Conclusions
There have been significant advances in the aerobic enantioselective coupling methods of 2-naphthols for the synthesis/kinetic resolution of chiral BINOLs via transition metal-mediated, electrochemical, organocatalytic, and enzymatic resolution. However, it was evident that there are still challenges to be overcome in both fields, such as the Scheme 27. Synthesis of BINOL derivatives containing phosphoric acid.

Conclusions
There have been significant advances in the aerobic enantioselective coupling methods of 2-naphthols for the synthesis/kinetic resolution of chiral BINOLs via transition metal-mediated, electrochemical, organocatalytic, and enzymatic resolution. However, it was evident that there are still challenges to be overcome in both fields, such as the relatively high reaction time in some cases and the use of toxic reagents and solvents such as dichloromethane and toluene. In addition, as already highlighted by other authors, the mechanistic discussions that govern asymmetric induction in these cases are still preambular, denoting the need for deepened theoretical exploration in this particular area.