Enantioselective synthesis of gem-diarylalkanes by transition metal-catalyzed asymmetric arylations (TMCAAr)

To date, enantiomerically enriched molecules containing gem(1,1)-diaryl containing tertiary or quaternary stereogenic centers have been readily accessed by transition metal-catalyzed enantioselective or stereoconvergent aryl transfer reactions.


Introduction
Chiral gem(1,1)-diaryl containing tertiary or quaternary stereogenic centers are present in many natural products and important pharmacophores that possess distinct bioactivities, such as anticancer, antidepressant and antifungal properties and so on. 1 In most cases, a single enantiomer (R or S) of gemdiarylalkanes is therapeutically effective and most medicinal molecules are approved in the optically pure form. Thus, the development of effective methods to access enantiomerically enriched diaryl structural motifs will play a signicant role in both academic and industrial settings. Enantiomerically pure drugs or their precursors are usually produced by the chiral kinetic resolution technique. However, access to 1,1-diarylalkanes with a high level of optical purity using this technique is challenging because little differentiates the two aryl groups installed on the stereogenic center electronically and sterically. This issue can be solved by asymmetric synthetic methods through either stereospecic or enantioselective transformations. In the last few decades, an array of catalytic enantioselective approaches towards the construction of nonracemic gem-diaryl compounds have been developed, including asymmetric Friedel-Cras reactions, asymmetric aryl transfer reactions (arylations), asymmetric hydrogenation of 1,1diarylalkenes, asymmetric C-H functionalization of enantiotropic diarylalkanes and so on. Among them, transition metalcatalyzed asymmetric arylations (TMCAArs), which install an aryl group onto the benzylic position of substrates in an enantioselective or stereoconvergent manner, represent the most powerful method. In this eld, development of new reactions, chiral ligand families and metal complexes has enabled the precise construction of various chiral diaryl motifs, including dibenzyl alkanes and alkenes, 1,1-diarylmethanols, 1,1-diarylmethylamines and so on. To the best of our knowledge, TMCAAr for the synthesis of gem-diaryl compounds includes nucleophilic 1,2-or 1,4-additions of arylmetallic reagents across C]O, C]N and C]C bonds; aryl cross-couplings to olens, benzylic (pseudo)halides and aziridines; asymmetric aryl substitution reactions of allylic substrates; isotopic benzylic C-H arylation and so on (Scheme 1). These transformations feature a wide range of substrate scope, good functional group tolerance and the use of easily accessible feedstock chemicals. In contrast to conventional asymmetric methods, TMCAAr distinctively enable the assembly of both enantiomers through  modulation of the reactants, instead of switching the absolute conguration of the chiral ligands.
To date, there have been many excellent reviews summarizing various asymmetric arylation strategies, 2 some of which consist of most of the approaches towards 1,1-diarylmethanols and 1,1-diarylmethylamines. Hence, this review will focus on TMCAAr for the synthesis of chiral gem-diarylalkanes whose alkyl moieties contain at least two carbons. Additionally, transition metal-catalyzed intramolecular arylation reactions for the construction of gem-diaryl containing fused rings are not included herein. In this review, the literature is organized according to the reaction type as well as the category of prochiral substrates. Furthermore, the natural products as well as bioactive compounds prepared in this review are also listed in Fig. 1.

Asymmetric aryl addition to C]C, C]O and C]N bonds
Transition metal-catalyzed asymmetric aryl addition reactions to C]C, C]O and C]N bonds represent a highly efficient method to construct tertiary or quaternary stereogenic centers, concomitant with the formation of Csp 3 -Csp 2 bonds. These transformations are frequently used to prepare important chiral gem-diaryl containing compounds from activated styrene and aryl-substituted carbonyl substrates. Gem-diaryl stereogenic centers are generated in the key step of aryl migratory insertion across the unsaturated C]C(O or N) bonds, followed by the hydrolysis or b-H elimination of the metal-binding intermediate (Scheme 2).
While chiral olens or phosphines enable control of the 1,4regioselectivity of a,b-unsaturated aldehyde/ketone/ester substrates, the conjugate arylation of b,g-unsaturated a-keto carbonyl compounds is difficult to realize using these ligands, which only promote 1,2-addition. 9 In 2014, Liao and coworkers 10 demonstrated a highly regio-and enantioselective Rhcatalyzed 1,4-addition of arylboronic acids to b,g-unsaturated aketo carbonyl derivatives using a novel chiral sulfoxide-phosphine ligand (L2) (Scheme 5). Nonracemic g,g-diaryl, a-keto amides and esters were produced. The method was applied in the concise syntheses of sertraline and tetrahydroquinoline-2carboxylamide.
Asymmetric 1,4-addition of organoboronates to alkylidene cyanoacetates by copper catalysis was rst demonstrated by Shintani/Hayashi 12 using a chiral N-heterocyclic carbene ligand (L4) (Scheme 7, top). The transformation releases optically active 2-cyano-3,3-diaryl propanoates as a mixture of diastereomers (1 : 1). The author conducted a series of stoichiometric reactions and indicated that only copper(I) mediated the catalytic cycle that consists of transmetalation/insertion/ligand exchange. Zhou and coworkers 13 recently found that the chiral copper complex of phosphoramidite (L5) efficiently promoted the enantioselective 1,4-addition of chalcones with arylboroxines and a direct 1,4-insertion mechanism was proposed and supported by DFT calculations and natural-abundance 13 C KIE experiments (Scheme 7, bottom).
Scheme 5 Rh-catalyzed enantioselective 1,4-additon of b,g-unsaturated-a-ketoamides. In 2010, Xu/Lin 16 reported a highly enantioselective addition of organoboronic acids to nitroalkenes using a rhodium/chiral diene catalyst (Scheme 9, le). Enantioenriched 2,2-diaryl nitroalkanes were obtained with moderate to good enantioselectivities (78-97%) induced by the chiral [3.3.0]-diene ligand (L9). In 2013, Wu and coworkers 17 used a chiral [2.2.1]-diene ligand (L10) in the arylation of nitroalkenes with high enantioselectivities (89-97%) (Scheme 9, right). The catalyst loading of the model reaction can be reduced to 0.1 mol%. Recently, Wu found that the amide-containing C 1 -symmetric [2.2.2]-diene ligand can promote the enantioselective reaction at room temperature. 18 In 2011, the highly efficient rhodium-catalyzed enantioselective addition of arylboronic acids to b-aryl and b-indolyl nitroalkenes was developed by the Liao group using the chiral sulfoxide-phosphine (SOP) ligand L11 19 (Scheme 10, le). Moreover, the utility of this method was documented by Fan in the synthesis of montanine-type amaryllidaceae alkaloids. 20 In 2012, Wan and co-workers 21 reported a rhodium-catalyzed asymmetric addition of arylboronic acids to nitroalkenes using the chiral sulfoxide-olen ligand L12 (Scheme 10, middle). They successfully enlarged the scope of the reaction to aryl, alkyl and heteroaryl nitroalkenes in one catalytic system. Recently, a P-chiral phosphine-olen hybrid ligand L13 has been demonstrated by Sieber to efficiently promote this reaction 22 (Scheme 10, right).
Recently, Zhang and coworkers 23 devoted themselves to developing a cheap and robust palladium catalysis system for conjugate aryl addition to nitroethylenes. When using iPr-IsoQuinox (L14) as a chiral ligand, enantioenriched 2,2-diaryl nitroalkanes can be produced in high yields and good enantioselectivities in air (Scheme 11).
In contrast to the extensive studies on conjugate arylations of nitroalkene substrates, successful conjugate additions of sulfonyl olens have rarely been reported. 24 In 2012, Nishimura and Hayashi disclosed an elegant enantioselective addition of arylboronic acids to a,b-unsaturated sulfonyl compounds with a high enantioselectivity (97 to >99.5% ee) 25 (Scheme 12, top). They demonstrated that the use of a diene ligand (L15) induces the protonation of the alkylrhodium intermediate faster than the b-H elimination process, thus selectively forming the addition product instead of the substitution product. Later on, Xu employed the chiral phosphine-olen ligand (L16) in the same asymmetric reaction to achieve generally high yields and ee values 26 (Scheme 12, bottom).
In contrast to nucleophilic arylation, Gaunt recently reported a novel copper/bisoxazoline (L18)-catalyzed electrophilic arylation of allylic amides 28 (Scheme 14). The protocol enables the asymmetric transfer of the electron-poor aryl group of diaryliodonium salts to the g position of cinnamyl amides and provides chiral b,bdiaryl enamides with a high level of optical purity.

1,2-Addition to arylketone and arylketimine derivatives
For ketone arylations, Fu reported the rst enantioselective 1,2addition of Ph 2 Zn to unactivated ketones catalyzed by 3-exo-(dimethylamino)isoborneol (L19) 29 (Scheme 15). Although both aryl-alkyl and dialkyl ketones are reactive in the presence of MeOH, aryl-alkyl ketones gave better enantioselectivities (72-91%). Later on, Walsh and Yus/Ramón independently demonstrated that the easily accessible chiral isoborneolsulfonamide and camphorsulfonamide are good ligands. 30 The catalytic system consisting of a combination of chiral diol ligands and Ti(O i Pr) 4 also promoted the enantioselective addition of Ph 3 Al, ArTi(O i Pr) 3 and ArMgBr to ketones, producing chiral diaryl alkyl carbinols. 31 While arylboronic acids or derivatives are stable and frequently used in transition-metal catalyzed arylation reactions, their enantioselective additions to unactivated ketones are limited, 32 probably due to the lack of effective chiral ligands. In 2011, Sakai/Korenaga 32a discovered that electron-poor 2,6bis(triuoromethyl)-4-pyridyl (BFPy) phosphanes enable the acceleration of the Rh-catalyzed 1,2-addition of arylboronic acids to ketones. Accordingly, the enantioselective variant was obtained using BFPy derived biphep (L20) as the chiral ligand, albeit with only 39% ee (Scheme 16, le). Later on, a chiral diene ligand (L21) was demonstrated to promote the addition of arylborons to cyclic or acyclic arylketones with up to 68% ee 32b (Scheme 16, middle). Recently, Deng and Tang 32c reported a highly enantioselective addition of arylboroxines to simple aryl ketones catalyzed by the Rh/L22 complex, which produced a range of chiral diaryl alkyl carbinols with excellent ee (95-99%) (Scheme 16, right). The utility of this method was illustrated by the concise synthesis of the antidepressant drug escitalopram as well as the (+)-clemastine intermediate.

Scheme 15
The first catalytic asymmetric addition of organometallic reagents to ketones. addition of arylboronic acids to a-ketoesters with high enantioselectivities. 33c Due to the unique biological activities of uorinated compounds, many scientists focused on the development of catalytic asymmetric methods for the synthesis of a-chiral CF 3containing compounds. However, enantioselective synthesis of diaryl triuoroethanes through TMCAAr has rarely been reported. 34 In 2006, Vries, Feringa and Minnaard 34a reported the rst asymmetric approach towards 2-hydroxy-2,2-diaryl triuoroethanes through the rhodium(I)/phosphoramidite (L26) catalysed 1,2-addition of arylboronic acids to 2,2,2-triuoroacetophenones (Scheme 18, le). In 2010, Iuliano and coworkers 34b found that optically active 2-hydroxy-2,2-diaryl triuoroethanes could also be produced using a deoxycholic acid derived monophosphite as the chiral ligand, albeit with moderate enantioselectivities. Recently, Tang 34c demonstrated that a new C 2 -symmetrical chiral bisphosphorus ligand (L27) was highly effective in the Rh-catalyzed arylation of triuoroacetophenones (Scheme 18, right).
Benzosultams containing a chiral a-amino acid unit and benzosulfamidates containing a CF 3 group are attractive to organic and medicinal chemists. In 2013, Xu and coworkers developed a rhodium-catalyzed asymmetric addition of arylboronic acids to CF 3 -or alkoxycarbonyl-substituted cyclic ketimines. 40a In this reaction, they utilized a chiral sulfur-olen ligand (L30) which they developed themselves to provide such molecules in high yields with excellent enantioselectivities (Scheme 21). The analogous alkyl-substituted cyclic N-sulfonyl ketimines can also produce enantioenriched a-arylalkyl-substituted benzosulfamidates and benzosultams with excellent ee. 40b,c These adducts allow for further transformation to versatile chiral a-diaryl alkylamines and some bioactive analogues.

Asymmetric allylic arylation (AAAr) reactions
Asymmetric allylic arylation (AAAr) reactions of cinnamyl electrophiles are one of the most important strategies to access chiral 1,1-diarylpropene molecules. Although the transfer of aryl groups to g-aryl substituted substrates resulted mainly in the achiral a product with palladium catalysis, the g-regioselectivity is facile for iridium and copper catalysis. In 2007, Alexakis 43 reported the rst AAAr of arylzinc reagents to cinnamyl carbonates catalyzed by chiral Ir(I)/L34 complexes, which afforded the g product with a high enantioselectivity but moderate g-regioselectivity (Scheme 23, top). Recently, Fu 44 realized the Ir/L35-catalyzed enantioselective arylation of racemic secondary allylic alcohols with aniline derivatives using BF 3 $Et 2 O (30 mol%) as the promoter. The formal S N 2substituted products, gem-diarylpropenes, were obtained with excellent ee (Scheme 23, bottom).

Enantioconvergent cross-coupling reactions of racemic benzylic substrates
Transition metal-catalyzed stereospecic aryl cross-couplings allow for the transformation of secondary enantioenriched benzylic electrophiles or nucleophiles to 1,1-diarylalkane compounds. However, the catalytic enantioselective transformations of racemic benzylic compounds to enantiomerically enriched products still remain limited 46 (Scheme 25).
The catalytic asymmetric a-arylation of styrenyl aziridines is one of the most important methods to access nonracemic 2,2-diarylethylamine derivatives. However, successful cross-coupling reactions rely on the stereospecic transformation of enantiomerically enriched aziridines. Recently, Sigman and Doyle developed an elegant Ni-catalyzed stereoconvergent reductive cross-coupling of racemic N-Ts aziridines and aryl iodides with Mn(0) as the reductant (Scheme 27, bottom). Intrigued by the discovery that enantiopure aziridine produces the corresponding amine as the racemate, they examined chiral amine-and phosphine-based ligands and found that 4-heptyl substituted bioxazoline (L40, BiOx) was the best ligand for the asymmetric transformation. 48 An array of 2,2-diarylethylamines were afforded with high enantioselectivities and moderate to good yields.

Enantioselective arylation of benzyl C-H bonds
Transition metal-catalyzed asymmetric functionalizations of unreactive C-H bonds have been extensively investigated in recently years. 49 The enantioselective arylation of benzylic C-H bonds enables direct access to optically active gem-diarylalkanes, wherein the precoordination of the metal catalyst with prochiral substrates in a bidentate or monodentate manner is usually demanded. In 2015, Duan 50 rstly introduced a chiral phosphoric amide (L41) into the Pd(II)-catalyzed direct b-arylation of aminoquinoline derived aliphatic amides with aryl iodides. An array of b,b-diaryl carboxylic acid derivatives were produced in moderate to good enantiomeric ratios (Scheme 28, top). One year later, He and Chen 51 investigated the enantioselective g-arylation of N-picolinic protected alkylamines with a combination of chiral phosphoric acid and Pd(II) catalysts. In the end, both high yields and enantioselectivities were obtained using a substoichiometric amount of chiral phosphoric acid (L42) under solvent-free conditions (Scheme 28, bottom).
In 2016, Yu employed chiral a-amino acids as transient directing groups in the enantioselective benzylic C(sp 3 )-H arylation of benzaldehydes via the precoordination of Pd(II) with the in situ generated imine intermediate 52 (Scheme 29). In the presence of 20 mol% L-tert-leucine, 10 mol% Pd(OAc) 2 and 3 equiv. H 2 O, o-alkyl benzaldehydes reacted with a wide range of aryl iodides to produce 1,1-diaryl alkanes in moderate yields with high enantiomeric ratios.
Although transition-metal catalysed asymmetric a-arylation of carbonyl compounds has been widely reported, the use of this method for the construction of gem-diarylalkanes has rarely been studied. In 2009, Buchwald 54 disclosed a highly enantioselective Pd-catalyzed intermolecular C-C coupling of oxindoles and arylbromides using an axially chiral P-stereogenic ligand. Enantioenriched oxindoles containing a gem-diaryl quaternary center were afforded with 95-99% ee. Recently, Hartwig 55 reported a palladium-catalyzed enantioselective a-arylation of a-uorooxindoles with aryl triates, using (R)-segphos as a chiral ligand. Enantioenriched 3-aryl-3-uorooxindoles including a chiral quaternary center were obtained in high yields with excellent enantioselectivities (Scheme 31).

Enantioselective arylation of benzyl carbene precursors
In 2015, Zhu and Zhou 56 reported an enantioselective arylation of a-aryl-a-diazoacetates with anilines catalysed by dirhodium(II) triuoroacetate and a chiral spiro phosphoric acid (SPA) (Scheme 32). Chiral a-diaryl acetates were produced in good yields (up to 95%) and high enantioselectivities (up to 97% ee). A step-wise reaction mechanism was proposed based on deuterium-labeling experiments. The Rh 2 (TFA) 4 catalyst is responsible for the generation of the zwitterion (I). The 1,2proton shi occurs via a proton shuttle model, which is mediated and stereochemically controlled by the chiral SPA (L44).

Asymmetric aryl cross-coupling across C]C bonds
Inspired by the efficiency of direct aryl-benzyl coupling, transition metal-catalyzed three-component cross-coupling reactions of olens have been developed as an important and complementary method in the construction of gem-diaryl moieties. The conceptual strategy of this method involves the enantioselective formation from the styrene and stereospecic coupling of metal bound benzyl intermediates. These species are either nucleophilic or electrophilic depending on the nature of the initiator (M1-R 0 ) (Scheme 33). In this regard, initiators include in situ Scheme 30 Pd-catalyzed enantioselective b-arylation of aliphatic amides induced by chiral acetyl-protected aminoethyl quinoline ligands.
Scheme 33 The conceptual strategy for the three-component crosscouplings.

The net hydroarylation of styrene derivatives
In 2010, the Sigman group initially studied the palladiumcatalyzed asymmetric hydroarylation of styrenes with arylboron esters in the presence of an i-PrOH solvent and in an O 2 atmosphere 57 (Scheme 34). Through investigating chiral NHC and bisoxazoline ligands, they found that bisoxazoline ligands (L45) could give the best enantioselective induction (up to 64%).
In 2016, Sigman and Toste developed an elegant enantioselective 1,1-diarylation method via double aryl cross-coupling to acrylates. 58 They introduced the chiral anion phase transfer strategy into this diarylation transformation. Catalyzed by chiral phosphoric acid L46 and Pd 2 (dba) 3 , optically active 3,3-diaryl esters with a high enantioselectivity were produced (Scheme 35). The process possibly involves a stereospecic hydroarylation of a chiral benzyl cinnamate-associated Pd(II)-H complex intermediate.
Recently the Buchwald group developed an alternative strategy to realize highly enantioselective hydroarylation of styrenes through CuH/Pd(0) cooperative catalysis 59 (Scheme 36).
In the presence of a chiral copper and achiral palladium catalyst, the three-component cross-coupling of styrenes, arylbromides and MePh 2 SiH proceeded smoothly to produce enantioenriched 1,1-diarylethanes in good yields with good to excellent enantioselectivities.

Borylarylation of styrene derivatives
The Cu/Pd cooperatively catalysed enantioselective 1,2-arylboration of styrenes was also demonstrated by the Brown 60 and Liao 61 groups independently. Brown found that the chiral NHC-carbene Scheme 34 Pd-catalyzed hydroarylation of styrenes using bisoxazoline ligands.
Liao and co-workers utilized a chiral sulfoxide-phosphine ligand (L48) to promote the Cu/Pd-catalyzed enantioselective arylboration of terminal vinylarenes with aryl iodides under mild conditions (Scheme 38). The method was particularly effective for the synthesis of chiral 2,2 0 -heteroaryl-aryl-ethylborates from either heteroaryl alkenes or heteroaryl iodides. Furthermore, the author merged this transformation and Suzuki-Miyaura coupling into a streamlined procedure for the modular synthesis of a series of important 1,1,2-triarylethane molecules, including CDP840.

Triuoromethyl and aminoarylation of styrene derivatives
Recently, Liu and coworkers developed a novel copper catalysis strategy to construct a gem-diarylmethine stereogenic center via enantioselective arylation of a secondary benzyl radical intermediate. 62 In the presence of a Cu(I)/L49 catalyst, the enantioselective triuoromethyl and aminoarylation of styrenes proceeded smoothly and afforded gem-diarylethane derivatives in moderate to high yields and with good ees (Scheme 39).

Conclusion and perspective
In this review, a large number of TMCAAr reactions, which target the construction of chiral gem-diaryl tertiary or quaternary stereogenic centers, have been described. These reactions are versatile methods to site-selectively and stereochemically couple prochiral or racemic starting materials with various aryl reagents (almost always aryl metals or halides) to provide nonracemic gem-diarylalkane compounds. Due to distinguishing features including the wide range of substrate scope, good functional group tolerance and the use of easily accessible substrates, the related methodologies have received increasing interest from synthetic and pharmaceutical chemists, aiding the latter in synthesising medicinal molecules in a highly efficient manner.
Predictably, the development of strategies that transform commercially available feedstocks to highly valuable gem-diaryl molecules has recently been highlighted and will be the focus of continuous research. The present methods, including hydro-or borylarylation, direct benzyl C-H bond arylation and so on, need improvement of the efficiency (i.e. enantioselectivities and catalyst loadings) and broadening of the substrate scope, and their use in the construction of quaternary carbon stereogenic centres remains challenging.

Conflicts of interest
There are no conicts to declare.