Recent Progress in Asymmetric Catalysis and Chromatographic Separation by Chiral Metal – Organic Frameworks

Metal–organic frameworks (MOFs), as a new class of porous solid materials, have emerged and their study has established itself very quickly into a productive research field. This short review recaps the recent advancement of chiral MOFs. Here, we present simple, well-ordered instances to classify the mode of synthesis of chiral MOFs, and later demonstrate the potential applications of chiral MOFs in heterogeneous asymmetric catalysis and enantioselective separation. The asymmetric catalysis sections are subdivided based on the types of reactions that have been successfully carried out recently by chiral MOFs. In the part on enantioselective separation, we present the potentiality of chiral MOFs as a stationary phase for high-performance liquid chromatography (HPLC) and high-resolution gas chromatography (GC) by considering fruitful examples from current research work. We anticipate that this review will provide interest to researchers to design new homochiral MOFs with even greater complexity and effort to execute their potential functions in several fields, such as asymmetric catalysis, enantiomer separation, and chiral recognition.

the separations of chiral isomers [35][36][37].Alternatively, chiral MOFs are regarded as prospective chiral stationary phases in HPLC and GC for enantioselective separation.The main advantages of chiral MOFs over other chiral stationary phases are their well-ordered frameworks containing available chiral pores to interact with guests and their controllable functionalities by varying chiral linkers and metal ions as the separation isomers require.Therefore, the selectivity and the separation of chiral isomers can be efficiently done by chiral MOFs.Quite a few review articles have appeared recently on chiral MOFs [38][39][40][41].The reviews have endeavored to describe the synthesis of those chiral MOFs that are suitable for applications in various fields.As this field is advancing rapidly, a new review article to provide an overview of the recent progress in applications of chiral MOFs is quite necessary.This review article is primarily divided into two parts.The first part mainly focuses on the emerging synthetic strategies for obtaining chiral MOFs and the second part highlights the recent successful applications of chiral MOFs from 2014 in the fields of asymmetric catalysis and chromatographic separation.Each part of the review is subdivided based on the synthetic approaches to chiral MOFs, the type of reactions carried out, and the different methods used for chromatographic separation, aiming to facilitate readers to understand them easily.We envision that this brief overview will provide researchers with means to catch up straightforwardly with recent advancement in the research on chiral MOFs.

Synthetic Strategies of Chiral MOFs
Chiral MOFs can be built by using numerous distinct strategies, each of which has its individual advantages and disadvantages [42,43].In this review, we have classified the synthesis of chiral MOFs broadly into two different classes, namely the straightforward method and the indirect method, which are based on the component used for creating chirality within MOFs.The straightforward method for constructing chiral MOFs uses chiral components, such as enantiopure ligands or chiral Asymmetric catalysis [25] is one of the essential areas of chiral chemistry, which efficiently assists the synthesis of valuable chiral products by selectively making and breaking the chemical bonds in an organic transformation.From the economic and ecological point of view, the use of homochiral MOFs as asymmetric catalysts is considered to be a potential eco-friendly method due to their numerous advantages, including mild reaction conditions, high enantiomeric excess, easy purification of the products, and reusability of the catalysts.Moreover, the reactions can take place in the inner pores of a chiral MOF catalyst, which serve as reaction chambers to facilitate the guest molecules to access the catalytically active sites within the pores.The size of the pores can be changed by changing the linkers of the MOFs.Due to these numerous benefits of homochiral MOF catalysts, a wide variety of chiral MOFs have been designed and explored as asymmetric catalysts.Consequently, the field has expanded rapidly and chiral MOF chemistry has been developing remarkably.
Chiral MOFs also provide a significant role for enantioselective separation [10,11].As we know, the separation of chiral isomers is a challenging task because of their identical physical and chemical properties.A chiral environment is required to separate the chiral isomers as the different affinities grasped by the chiral isomers have different spatial structures.A large number of chiral stationary phases based on crown ethers, polysaccharides, glycopeptides, and proteins have been reported for the separations of chiral isomers [35][36][37].Alternatively, chiral MOFs are regarded as prospective chiral stationary phases in HPLC and GC for enantioselective separation.The main advantages of chiral MOFs over other chiral stationary phases are their well-ordered frameworks containing available chiral pores to interact with guests and their controllable functionalities by varying chiral linkers and metal ions as the separation isomers require.Therefore, the selectivity and the separation of chiral isomers can be efficiently done by chiral MOFs.
Quite a few review articles have appeared recently on chiral MOFs [38][39][40][41].The reviews have endeavored to describe the synthesis of those chiral MOFs that are suitable for applications in various fields.As this field is advancing rapidly, a new review article to provide an overview of the recent progress in applications of chiral MOFs is quite necessary.This review article is primarily divided into two parts.The first part mainly focuses on the emerging synthetic strategies for obtaining chiral MOFs and the second part highlights the recent successful applications of chiral MOFs from 2014 in the fields of asymmetric catalysis and chromatographic separation.Each part of the review is subdivided based on the synthetic approaches to chiral MOFs, the type of reactions carried out, and the different methods used for chromatographic separation, aiming to facilitate readers to understand them easily.We envision that this brief overview will provide researchers with means to catch up straightforwardly with recent advancement in the research on chiral MOFs.

Synthetic Strategies of Chiral MOFs
Chiral MOFs can be built by using numerous distinct strategies, each of which has its individual advantages and disadvantages [42,43].In this review, we have classified the synthesis of chiral MOFs broadly into two different classes, namely the straightforward method and the indirect method, which are based on the component used for creating chirality within MOFs.The straightforward method for constructing chiral MOFs uses chiral components, such as enantiopure ligands or chiral salen, to react Catalysts 2018, 8, 120 3 of 28 with metal salts, where the chirality is directly created to the frameworks from the chiral components.In the indirect method, achiral bridging ligands are used to synthesize achiral MOFs, which are subsequently transferred to chiral MOFs by applying various techniques, such as (a) post-synthetic modification (PSM) by reacting an achiral MOF with a chiral auxiliary and (b) a superficial chiral etching process (SCEP); chiral MOFs can also be attained from achiral bridging ligands by the method called (c) spontaneous resolution and (d) chiral induction.Chiral induction can be done by using the appropriate chiral templates, namely, (i) a chiral-co-ligand or chiral spectator; (ii) a chiral-solvent, and (iii) circularly polarized light.Figure 2

Chiral MOFs Prepared from Chiral Ligands
The conventional synthetic strategy for obtaining chiral MOFs greatly relies on chiral ligands (Scheme 1), in which the crucial step is the selection of suitable chiral ligands.In 2000, Kim and coworkers reported the synthesis of chiral MOFs from the enantiopure tartaric-acid-derived bridging ligands, . Subsequently, the method has been developed, and many research papers have been reported that use naturally occurring enantiopure amino acids and their derivatives [45][46][47][48], tartaric acid derivatives [49,50], and modified 1,1′-binaphthalene-2,2′-diol (BINOL) derivatives [51][52][53] for designing chiral MOFs.Recently, the approach of synthesis has been extended widely with some alteration, which will be described in the review.
Duan and coworkers [54] in 2015 described the synthesis of two new chiral polyoxometalate (POM)-based MOFs.The one-pot solvothermal reaction of chiral ligands L-and D-N-tert-butoxycarbonyl-2-(imidazole)-1-pyrrolidine (L-BCIP/D-BCIP), Zn(NO3)2•6H2O, the bridging ligands NH2bipyridine, and the Keggin-type [ZnW12O40] 6− oxidation catalyst fruitfully furnished chiral POMbased MOFs denoted as ZnW-PYI1(2a) and ZnW-PYI2 (2b), respectively.The synthesized ZnW-PYI can act as an efficient asymmetric catalyst for the conversion of carbon dioxide to cyclic-carbonates on reacting with olefins.The catalyst becomes highly stereoselective as the oxidant [ZnW12O40] 6− and the L-BCIP ligands in the pores control the alignment of the substrate moieties in the reaction medium.Figure 3 presents the synthetic mode of the homochiral MOF and its catalytic application in asymmetric reaction.

Chiral MOFs Prepared from Chiral Ligands
The conventional synthetic strategy for obtaining chiral MOFs greatly relies on chiral ligands (Scheme 1), in which the crucial step is the selection of suitable chiral ligands.In 2000, Kim and co-workers reported the synthesis of chiral MOFs from the enantiopure tartaric-acid-derived bridging ligands, [Zn 3 (µ . Subsequently, the method has been developed, and many research papers have been reported that use naturally occurring enantiopure amino acids and their derivatives [45][46][47][48], tartaric acid derivatives [49,50], and modified 1,1 -binaphthalene-2,2 -diol (BINOL) derivatives [51][52][53] for designing chiral MOFs.Recently, the approach of synthesis has been extended widely with some alteration, which will be described in the review.
Duan and coworkers [54] 4b, 4c, and 4d.Reproduced from [56] with permission from the Royal Society of Chemistry.Bharadwaj and co-workers [57] recently designed a chiral tetracarboxylic acid ligand, 5,5 -[(S)-(+)-2-methylpiperazine-1,4-diyl]-diisophthalic acid (H 4 L 3 ), and utilized the ligand to construct the homochiral MOF [Cu 2 (L 3 )(H 2 O)]•4DMF•4H 2 O (5) under solvothermal conditions.The MOF (5) displayed high catalytic activity in an A 3 coupling reaction and a Pechmann reaction for the synthesis of imidazopyridine and coumarin derivatives, respectively.Yaghi and co-workers [58] reported the first instances of two Ca-based MOFs from naturally occurring nontoxic lactate linkers, [Ca 14 (L-lactate) 20  Another direct approach to synthesize chiral MOFs is from metallosalen ligands (Scheme 1).Metallosalen ligands possess a huge size, which facilitates the synthesis of chiral MOFs with extra-large cavities.Consequently, the frameworks are highly stable towards water and heat and can bear harsh chemical environments, which leads them to expand their range of applications.

Post-Synthetic Modification (PSM)
The PSM of previously synthesized MOFs is an efficient approach to produce chiral MOFs.
The key fact for this method is the functional groups in the organic ligands of the pre-synthesized achiral MOFs, which are susceptible to react with the chiral reagents.This approach affords a means of decorating the MOFs with a variety of chiral functionalities, which may be impossible or tedious to synthesize through conventional routes.
Cohen and co-workers demonstrated that the amino groups of IRMOF-3 (IRMOF = isoreticular MOF) can be changed with amides by reacting them with enantiopure anhydride, resulting in the formation of chirality in the framework [66][67][68][69].Bonnefoy et al. [70] designed novel MOFs to which are attached enantiopure peptide moieties.The three different MOFs, Al-MIL-101-NH 2 (11a), In-MIL-68-NH 2 (11b), and Zr-UiO-66-NH 2 (11c), were chosen to react under microwave irradiation with numerous oligopeptides (up to tetrapeptides) for the synthesis of chiral hybrid solids.The microwave irradiation controls the peptide racemization and offers a better grafting yield than the conventional methods for the reaction.
In 2016, Fröba and associates [47] reported the PSM of the oxazolidinone moieties connected to the MOF UHM-25-Val-Evans (12).The acylation of the MOF (12) was attained by reacting it with propionic anhydride in the presence of a nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP) as shown in Figure 6.The reaction was initially stirred for 24 h, yielding 37% of N-acylated product.By increasing the reaction time from 24 h to 72 h, the rate of conversion can be further increased to 90%.
68-NH2 (11b), and Zr-UiO-66-NH2 (11c), were chosen to react under microwave irradiation with numerous oligopeptides (up to tetrapeptides) for the synthesis of chiral hybrid solids.The microwave irradiation controls the peptide racemization and offers a better grafting yield than the conventional methods for the reaction.
In 2016, Fröba and associates [47] reported the PSM of the oxazolidinone moieties connected to the MOF UHM-25-Val-Evans (12).The acylation of the MOF (12) was attained by reacting it with propionic anhydride in the presence of a nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP) as shown in Figure 6.The reaction was initially stirred for 24 h, yielding 37% of N-acylated product.By increasing the reaction time from 24 h to 72 h, the rate of conversion can be further increased to 90%.12).Reproduced from [47] with permission from the American Chemical Society.r.t.: room temperature.
Recently, Chen et al. [71] designed a chiral MOF, (R,R)-salen(Co(III))@IRMOF-3-AM (13), by using a two-step procedure.In the first step, the (R,R)-salen(Co(III)) metal complex was adsorbed in the nanocages of IRMOF-3, and in the second step, by PSM, the free amino groups present on IRMOF-3 were acylated by anhydride (Figure 7).pionic anhydride in the presence of a nucleophilic catalyst 4-(dimethylamino)pyridine (DM hown in Figure 6.The reaction was initially stirred for 24 h, yielding 37% of N-acylated prod increasing the reaction time from 24 h to 72 h, the rate of conversion can be further increased .12).Reproduced from [47] with permission from the American Chemical Society.r.t.: room temperature.

Spontaneous Resolution
In this method, chiral MOFs are built from achiral precursors through crystallization in the enantiomorphous space group within the MOFs.During crystallization, it breaks its symmetry for spatial organization and thus helps to produce chiral MOFs.Such a type of self-resolution process is very common and contains both types of enantiomers, resulting in a racemic mixture.
Aoyama and co-workers [73] were the first to establish that homochiral MOFs can be achieved through self-crystallization.They reported an enantiomerically pure MOF, [Cd(L 8 )(NO3)2(H2O) (EtOH)] ( 17 19) with a unique 3,6-conn topology.The authors stated that the metal ions coordinate with the ligand L 10 , which restricts the rotation of the ligands and results in the chiral network from the selective and directional coordination of metal ions.Moreover, the synthesized chiral MOF was applied as a catalyst in a three-component Strecker reaction with a high conversion yield.

Chiral Induction
An approach to synthesize chiral MOFs is the use of chiral additives that are capable of inducing achiral precursors to generate homochiral MOFs.Common chiral additives are chiral ionic liquid, Reproduced from [72] with permission from the American Chemical Society.

Spontaneous Resolution
In this method, chiral MOFs are built from achiral precursors through crystallization in the enantiomorphous space group within the MOFs.During crystallization, it breaks its symmetry for spatial organization and thus helps to produce chiral MOFs.Such a type of self-resolution process is very common and contains both types of enantiomers, resulting in a racemic mixture.
Aoyama and co-workers [73] were the first to establish that homochiral MOFs can be achieved through self-crystallization.They reported an enantiomerically pure MOF, [Cd(L 8 )(  19) with a unique 3,6-conn topology.The authors stated that the metal ions coordinate with the ligand L 10 , which restricts the rotation of the ligands and results in the chiral network from the selective and directional coordination of metal ions.Moreover, the synthesized chiral MOF was applied as a catalyst in a three-component Strecker reaction with a high conversion yield.

Chiral Induction
An approach to synthesize chiral MOFs is the use of chiral additives that are capable of inducing achiral precursors to generate homochiral MOFs.Common chiral additives are chiral ionic liquid, chiral co-agents, and chiral spectators, which are usually not the building blocks of the MOFs, but assist the MOFs to be chiral.Such chiral induction remains unstated, but the greatest advantage is that the method is cost-effective and not limited to any linkers.The key step for this approach is the selection of chiral induction agents for a given set of precursors.
In 2015, Zaworotko and associates [85] demonstrated that MOF-5 can be easily changed to the chiral variants Λ-CMOF-5 (21a) and ∆-CMOF-5 (21b) through chiral induction by using additive L-proline or D-proline during synthesis.The alteration of the backbone of the MOF-5 leads to the formation of CMOF-5, which further crystallizes in the chiral cubic space group P2 1 3.A new achiral compound, [Zn(BDC)(NMP)], was formed in absence of L-proline or D-proline, indicating that the presence of proline is vital for the crystallization of Λ-CMOF-5 or ∆-CMOF-5.The authors also verified the post-synthetic activity of the achiral solvent N-methyl-2-pyrrolidone (NMP), and surprisingly found that in both cases of CMOF-5 as well as MOF-5, the presence of NMP offered a racemic conglomerate of CMOF-5, whereas other organic solvents transformed CMOF-5 into MOF-5 (Figure 9).that the method is cost-effective and not limited to any linkers.The key step for this approach is the selection of chiral induction agents for a given set of precursors.
In 2015, Zaworotko and associates [85] demonstrated that MOF-5 can be easily changed to the chiral variants Λ-CMOF-5 (21a) and Δ-CMOF-5 (21b) through chiral induction by using additive Lproline or D-proline during synthesis.The alteration of the backbone of the MOF-5 leads to the formation of CMOF-5, which further crystallizes in the chiral cubic space group P213.A new achiral compound, [Zn(BDC)(NMP)], was formed in absence of L-proline or D-proline, indicating that the presence of proline is vital for the crystallization of Λ-CMOF-5 or Δ-CMOF-5.The authors also verified the post-synthetic activity of the achiral solvent N-methyl-2-pyrrolidone (NMP), and surprisingly found that in both cases of CMOF-5 as well as MOF-5, the presence of NMP offered a racemic conglomerate of CMOF-5, whereas other organic solvents transformed CMOF-5 into MOF-5 (Figure 9).Reproduced from [85] with permission from the American Chemical Society.
Li et al. [86] showed the effect of ionic liquid on the synthesis of chiral MOFs, where they designed two 3D MOFs, [Th(TPO)(OH)(H2O)]•8H2O (22a) and [C9H17N2][Th(TPO)Cl2] (22b), from the same achiral starting materials by applying solvothermal and ionothermal methods, respectively.The solvothermal method resulted in a centrosymmetric MOF 22a, whereas, in the ionothermal reaction, chiral MOF 22b was obtained by using the ionic liquid 1-butyl-2,3-dimethylimidazolium chloride.Recently, Su and co-workers [87] constructed an enantiomeric pair of three-dimensional MOFs [Cu4(L 11 )3(NO3)]•3H2O (23) from the achiral ligand L 11 (L 11 = 3,5-diisopropyl-1,2,4-triazolate) by using L-amino acid and D-amino acid as the chiral catalysts, respectively.From a crystallographic study and elemental analysis, it was found that the enantiopure amino acids were not anchored into the final crystal structures of the MOFs.By exchanging L-/D-amino acids with lactic acid or mandelic acid, the authors successfully proved the mechanism of chirality induction.It was noted that lactic acid and mandelic acid were inefficient chiral inducers for this set of precursors, which illustrates that the OH groups of lactic acid and mandelic acid have a weaker affinity to Cu ions than do the NH2 groups of L-/D-amino acids.NH2 groups of L-/D-amino acids firstly bind with Cu ions and are further substituted by achiral ligands to arrange themselves in 3D chiral frameworks (Figure 10).by using L-amino acid and D-amino acid as the chiral catalysts, respectively.From a crystallographic study and elemental analysis, it was found that the enantiopure amino acids were not anchored into the final crystal structures of the MOFs.By exchanging L-/D-amino acids with lactic acid or mandelic acid, the authors successfully proved the mechanism of chirality induction.It was noted that lactic acid and mandelic acid were inefficient chiral inducers for this set of precursors, which illustrates that the OH groups of lactic acid and mandelic acid have a weaker affinity to Cu ions than do the NH 2 groups of L-/D-amino acids.NH 2 groups of L-/Damino acids firstly bind with Cu ions and are further substituted by achiral ligands to arrange themselves in 3D chiral frameworks (Figure 10).An exciting report was presented by Wu et al. [88], where a chiral MOF, [Cu-(succinate)(4,4′bipyridine)]•4H2O (24), was constructed from achiral precursors and the chirality in the MOF was initiated by using the irradiation of circularly polarized light (CPL) during the crystallization.After investigating 92 samples, the authors concluded that CPL irradiation can provide enantiomeric excess and a left-handed helical structure was attained by left-handed CPL irradiation during the reaction or crystallization, and a right-handed helical structure was achieved with right-handed CPL irradiation.
Thus, we have described several new approaches recently explored for the construction of chiral MOFs, which will certainly offer new opportunities to researchers for synthesizing bulk homochiral MOFs.

Asymmetric Catalysis
In the field of heterogeneous catalysis, chiral MOFs can be used as outstanding solid catalysts for many organic reactions, including enantioselective reactions, which cannot be accomplished by the conventional heterogeneous catalysts.The porosity, structural stability, and reusability of chiral MOFs make them highly demanded chiral catalysts for large-scale organic transformations.Some of the recent innovative works on enantioselective reactions are endorsed by chiral MOFs and will be briefly described in the review.This part is subdivided based on the reactions catalyzed by chiral MOFs.
Thus, we have described several new approaches recently explored for the construction of chiral MOFs, which will certainly offer new opportunities to researchers for synthesizing bulk homochiral MOFs.

Asymmetric Catalysis
In the field of heterogeneous catalysis, chiral MOFs can be used as outstanding solid catalysts for many organic reactions, including enantioselective reactions, which cannot be accomplished by the conventional heterogeneous catalysts.The porosity, structural stability, and reusability of chiral MOFs make them highly demanded chiral catalysts for large-scale organic transformations.Some of the recent innovative works on enantioselective reactions are endorsed by chiral MOFs and will be briefly described in the review.This part is subdivided based on the reactions catalyzed by chiral MOFs.
3.1.1.1,4-, 1,2-, and Cyclo-Addition Reactions Lin and co-workers [89] extensively explored the catalytic activities of metal-based homochiral MOFs in a varied range of asymmetric organic transformations.The post-synthetically prepared Rhand Ru-complex-based BINAP-derived chiral MOFs offered high enantioselectivity for a variety of asymmetric reactions.The BINAP-derived dicarboxylic acid, H 2 L 12 , was prepared by a multistep reaction starting from 4,4 -I 2 -BINAP (Figure 11a).The chiral Zr-MOF was prepared from H 2 L 12 and its post-synthetic metalation was done by treating [Zr 6 O 4 (OH) 4 (L 12 ) 6 ] ( 25) with [Rh(nbd) 2 (BF 4 )] to afford [Zr 6 O 4 (OH) 4 (L 12 ) 6 ]•Rh (25a) and with Ru(cod)(2-Me-allyl) 2 followed by HBr to afford [Zr 6 O 4 (OH) 4 (L 12 ) 6 ]•Ru (25b), respectively (Figure 11b).A 1 mol % volume of catalyst (25a) exhibited excellent enantioselectivity-up to >99%-in the 1,4-addition of aryl boronic acids to 2-cyclohexanone.Similarly, outstanding activity was showed by the same catalyst in 1,2-addition of AlMe 3 to α,β-unsaturated ketones to afford chiral allylic alcohols.Ru-functionalized MOF (25b) showed high activity in the hydrogenation of β-keto esters and substituted alkenes, with an ee of up to 97% and 91%, respectively.Later, the same group [90] extended the scope of the BINAP-MOF.Rh catalyst and demonstrated good yield with high enantioselectivity-up to 99%-towards the asymmetric reductive cyclization and Alder-ene cyclo isomerization of 1,6-enynes for constructing cyclized products.The catalyst presented 4-7 times higher catalytic activity and enantioselectivity compared to the conventional homogeneous catalysts.However, the recovered BINAP-MOF.Rh catalyst showed low or no catalytic recyclability.The catalyst exhibited no activity towards sterically hindered asymmetric Pauson-Khand-type reactions.To overcome this problem, Lin and co-workers introduced a mixed ligand concept, for expanding the space near the catalytic sites, to accommodate the intermediates of the reaction, and successfully demonstrated Pauson-Khand-type reactions with 87% ee.The synthesized chiral MOF [Zr 6 (OH) 4 O 4 (L 12 ) 0.78 (L 13   27)) was used to create two efficient catalysts, E 2 -MOF•RhCl and E 2 -MOF•Rh(acac), by post-synthetic metalation with Rh(I) complexes, which subsequently demonstrated high catalytic activity and enantioselectivity for 1,4-additions of arylboronic acids to α, β-unsaturated ketones and asymmetric 1,2-additions of arylboronic acids to aldimines (Figure 12) [91].Both of the reactions were successful for a broad range of substrate moieties under identical reaction conditions.The catalyst E 2 -MOF•Rh(acac) was reused seven times without the loss of yield, ee, and crystallinity.27) from H4L 14 and its post-synthetic metalation and their application in asymmetric catalysis.Reproduced from [91] with permission from the Royal Society of Chemistry.27) from H4L 14 and its post-synthetic metalation and their application in asymmetric catalysis.Reproduced from [91] with permission from the Royal Society of Chemistry.27) from H 4 L 14 and its post-synthetic metalation and their application in asymmetric catalysis.Reproduced from [91] with permission from the Royal Society of Chemistry.
Jeong and co-workers [92] also described an Alder-ene cyclization reaction of 3,3,7-trimethyloct-6enal facilitated by Zn/(R)-KUMOF-1 (28) with a high yield of 92% and 50% ee, respectively.The authors proved, with the experimental data, that the optical purity of the product depended on the crystal size and chiral environment of the voids of chiral MOFs.

Diels-Alder Reaction
In 2016, Tanaka et al. [93] designed a novel homochiral biphenol-based MOF (29) from the solvothermal reaction of chiral organic ligand (R)-2,2'-dihydroxy-1,1'-binaphthyl-4,4'-dibenzoic acid (H 2 L 15 ) and Cu(NO 3 ) 2 •3H 2 O in a mixed solvent (DMF-H 2 O) at 55 • C for 4 days.The MOF crystallizes in the trigonal space group R32.The ligand H 2 L 15 was synthesized by Suzuki cross-coupling reaction of 4-methoxycarbonyl phenylboronic acid and (R)-4,4'-dibromo-2,2'-diacetyl-1,1'-binaphthyl followed by hydrolysis and acidification, respectively.The synthesized chiral MOF (29) was found to be an effective asymmetric catalyst in the Diels-Alder reaction between isoprene and N-ethyl maleimide, with up to 81% yield and 75% ee (Scheme 3).The optimized conditions for the reaction were explored and it was found that the best yield was obtained when the reaction was performed at 0 • C for 48 h in EtOAc solvent.The scope of the reaction was further studied with various N-substituted maleimides with isoprene, and lower reactivity and enantioselectivity were observed for bulky substrates due to their weak interactions with the synthesized chiral MOF.
Catalysts 2018, 8, x FOR PEER REVIEW 13 of 26 Jeong and co-workers [92] also described an Alder-ene cyclization reaction of 3,3,7-trimethyloct-6-enal facilitated by Zn/(R)-KUMOF-1 (28) with a high yield of 92% and 50% ee, respectively.The authors proved, with the experimental data, that the optical purity of the product depended on the crystal size and chiral environment of the voids of chiral MOFs.

Diels-Alder Reaction
In 2016, Tanaka et al. [93] designed a novel homochiral biphenol-based MOF (29) from the solvothermal reaction of chiral organic ligand (R)-2,2'-dihydroxy-1,1'-binaphthyl-4,4'-dibenzoic acid (H2L 15 ) and Cu(NO3)2•3H2O in a mixed solvent (DMF-H2O) at 55 °C for 4 days.The MOF crystallizes in the trigonal space group R32.The ligand H2L 15 was synthesized by Suzuki cross-coupling reaction of 4-methoxycarbonyl phenylboronic acid and (R)-4,4'-dibromo-2,2'-diacetyl-1,1'-binaphthyl followed by hydrolysis and acidification, respectively.The synthesized chiral MOF (29) was found to be an effective asymmetric catalyst in the Diels-Alder reaction between isoprene and N-ethyl maleimide, with up to 81% yield and 75% ee (Scheme 3).The optimized conditions for the reaction were explored and it was found that the best yield was obtained when the reaction was performed at 0 °C for 48 h in EtOAc solvent.The scope of the reaction was further studied with various Nsubstituted maleimides with isoprene, and lower reactivity and enantioselectivity were observed for bulky substrates due to their weak interactions with the synthesized chiral MOF.(30) and demonstrated its significant application as a catalyst for a variety of asymmetric organic transformations.The Diels-Alder reaction was explored with a range of methyl-substituted dienes, which successfully reacted with the substituted acrolein in the presence of 5 mol% of the synthesized MOF, affording the corresponding products in moderate conversions with an ee up to 91% (Scheme 4a).Similarly, the catalytic activity of the synthesized Cr(salen)-based MOF (30) in hetero-Diels-Alder reactions was also evaluated.The reactions proceeded smoothly with the substituted benzaldehydes and Danishefsky dienes, and the desired products were obtained with a conversion of 77-89% and 72-79% enantioselectivity after 48 h (Scheme 4b).The reaction afforded <5% conversion when a sterically hindered group was attached to the benzaldehyde moiety, indicating that a bulky substrate could not enter inside the MOF pores where the heterogeneous catalysis mainly occurred.Recently, the same group [65] described a Diels-Alder reaction with identical reactants using the MTV-MOF catalyst (R)-10 CuCo , which successfully afforded 88-94% ee of the cycloadducts.30) and demonstrated its significant application as a catalyst for a variety of asymmetric organic transformations.The Diels-Alder reaction was explored with a range of methyl-substituted dienes, which successfully reacted with the substituted acrolein in the presence of 5 mol% of the synthesized MOF, affording the corresponding products in moderate conversions with an ee up to 91% (Scheme 4a).Similarly, the catalytic activity of the synthesized Cr(salen)-based MOF (30) in hetero-Diels-Alder reactions was also evaluated.The reactions proceeded smoothly with the substituted benzaldehydes and Danishefsky dienes, and the desired products were obtained with a conversion of 77-89% and 72-79% enantioselectivity after 48 h (Scheme 4b).The reaction afforded <5% conversion when a sterically hindered group was attached to the benzaldehyde moiety, indicating that a bulky substrate could not enter inside the MOF pores where the heterogeneous catalysis mainly occurred.Recently, the same group [65] described a Diels-Alder reaction with identical reactants using the MTV-MOF catalyst (R)-10 CuCo , which successfully afforded 88-94% ee of the cycloadducts.

Cyanosilylation of Aldehydes
Cui and co-workers [95] exemplified a homochiral biphenol-based MOF (31) with chiral dihydroxyl auxiliaries.These chiral dihydroxyl auxiliaries were partially exchanged by Li + ions and converted to a highly efficient and recyclable heterogeneous catalyst for the asymmetric cyanation of aldehydes with up to >99% ee (Scheme 5).
Scheme 5. Cyanation of aldehydes by a biphenol-based catalyst.Reproduced from [95] with permission from the American Chemical Society.
Later, the same group [96] illustrated the cyanation of aldehydes with two new chiral MOFs that were constructed from pairs of VO(salen) ligand for 32a, and VO(salen) and Cu(salen) mixed ligands for 32b.After oxidation with (NH4)2Ce(NO3)6, V(IV) centers in the pairs of VO(salen)-MOF (32a) were transformed to V(V) and the MOF became an effective catalyst for catalytic reactions, with stereoselectivity up to >99%.The reaction offered better results with respect to conversion and enantioselectivity when the electron-donating group was attached with benzaldehydes compared to the presence of an electron-withdrawing group on the ring.Less than 5% conversion was obtained when a bulky aldehyde was used as a substrate.The MOF (32b) decorated with both VO(salen) and Cu(salen) units showed much lower reactivity and stereoselectivity compared to the VO(salen)-MOF (32a).This was due to the monometallic activation pathway that was observed in the MOF (32b), whereas a VO-VO cooperative activation mechanistic pathway was evidenced in the pairs of VO(salen)-MOF (32a) (Figure 13).

Cyanosilylation of Aldehydes
Cui and co-workers [95] exemplified a homochiral biphenol-based MOF (31) with chiral dihydroxyl auxiliaries.These chiral dihydroxyl auxiliaries were partially exchanged by Li + ions and converted to a highly efficient and recyclable heterogeneous catalyst for the asymmetric cyanation of aldehydes with up to >99% ee (Scheme 5).Cyanosilylation of Aldehydes ui and co-workers [95] exemplified a homochiral biphenol-based MOF (31) with c roxyl auxiliaries.These chiral dihydroxyl auxiliaries were partially exchanged by Li + ions rted to a highly efficient and recyclable heterogeneous catalyst for the asymmetric cyanatio ydes with up to >99% ee (Scheme 5).cheme 5. Cyanation of aldehydes by a biphenol-based catalyst.Reproduced from [95] with ermission from the American Chemical Society.
ater, the same group [96] illustrated the cyanation of aldehydes with two new chiral MOFs constructed from pairs of VO(salen) ligand for 32a, and VO(salen) and Cu(salen) mixed lig b.After oxidation with (NH4)2Ce(NO3)6, V(IV) centers in the pairs of VO(salen)-MOF (32a) ormed to V(V) and the MOF became an effective catalyst for catalytic reactions, selectivity up to >99%.The reaction offered better results with respect to conversion Scheme 5. Cyanation of aldehydes by a biphenol-based catalyst.Reproduced from [95] with permission from the American Chemical Society.
Later, the same group [96] illustrated the cyanation of aldehydes with two new chiral MOFs that were constructed from pairs of VO(salen) ligand for 32a, and VO(salen) and Cu(salen) mixed ligands for 32b.After oxidation with (NH 4 ) 2 Ce(NO 3 ) 6 , V(IV) centers in the pairs of VO(salen)-MOF (32a) were transformed to V(V) and the MOF became an effective catalyst for catalytic reactions, with stereoselectivity up to >99%.The reaction offered better results with respect to conversion and enantioselectivity when the electron-donating group was attached with benzaldehydes compared to the presence of an electron-withdrawing group on the ring.Less than 5% conversion was obtained when a bulky aldehyde was used as a substrate.The MOF (32b) decorated with both VO(salen) and Cu(salen) units showed much lower reactivity and stereoselectivity compared to the VO(salen)-MOF (32a).This was due to the monometallic activation pathway that was observed in the MOF (32b), whereas a VO-VO cooperative activation mechanistic pathway was evidenced in the pairs of VO(salen)-MOF (32a) (Figure 13).  1)][Cd2(NiL 17 )(H2L 16 )]•6DMF•5MeOH (33).The synthesized MOF acted as an efficient heterogeneous catalyst in the asymmetric cyanosilylation of aldehydes, and the reactions afforded excellent conversions of 81-96% and enantioselectivities of 55-98% for benzaldehyde and other aromatic aldehydes bearing electron-donating as well as electronwithdrawing groups.The conversion was radically decreased in the case of a bulky moiety, such as 9-anthraldehyde, suggesting that the selectivity and catalytic activity occurred inside the channels of the catalyst (33).The use of (S-) catalyst ( 33) afforded (S-) enantiomers as a product, which verified that the stereoselectivity of the products was directly controlled by the fundamental chiral nature of the catalyst.

Epoxidation of Alkenes and Cleavage of Epoxide Ring
The asymmetric epoxidation of alkenes and the corresponding ring opening of epoxides by MTV-MOFs were enlightened by Cui and co-workers [65].The binary MTV-MOFs 10 CuMn and 10 CuFe were found to be active catalysts for the asymmetric epoxidation of alkenes, affording up to 93% and 90% ee of the epoxides with 89% and 94% conversion, respectively.After the success of the catalytic activity of binary MTV-MOFs, the tripartite MTV-MOFs (R)-10 CuMnCr and (R)-10 CuMnCo were also explored for the epoxidation of 2,2-dimethyl-2H-chromene and its derivatives, and the products were obtained with good conversion rates and high enantioselectivities.Similarly, the catalysts were further verified for the ring opening reaction of epoxides by the nucleophile aniline and water, but the enantioselectivities were less than 25% in both cases.Next, the consecutive reaction of the asymmetric epoxidation of alkene followed by ring-opening reactions of epoxides by various nucleophiles, such as aniline, TMSN3, and ArCH2SH, was explored successfully by employing the catalyst (R)-10 CuMnCr .The various substituents on anilines had a slight effect on both the conversion and selectivity of the reactions, and overall the conversions obtained were 78-95% with an ee of 86-96%.A satisfactory conversion (74-92%) with high enantioselectivity (84-99%) was achieved for  (33).The synthesized MOF acted as an efficient heterogeneous catalyst in the asymmetric cyanosilylation of aldehydes, and the reactions afforded excellent conversions of 81-96% and enantioselectivities of 55-98% for benzaldehyde and other aromatic aldehydes bearing electron-donating as well as electron-withdrawing groups.The conversion was radically decreased in the case of a bulky moiety, such as 9-anthraldehyde, suggesting that the selectivity and catalytic activity occurred inside the channels of the catalyst (33).The use of (S-) catalyst ( 33) afforded (S-) enantiomers as a product, which verified that the stereoselectivity of the products was directly controlled by the fundamental chiral nature of the catalyst.

Epoxidation of Alkenes and Cleavage of Epoxide Ring
The asymmetric epoxidation of alkenes and the corresponding ring opening of epoxides by MTV-MOFs were enlightened by Cui and co-workers [65].The binary MTV-MOFs 10 CuMn and 10 CuFe were found to be active catalysts for the asymmetric epoxidation of alkenes, affording up to 93% and 90% ee of the epoxides with 89% and 94% conversion, respectively.After the success of the catalytic activity of binary MTV-MOFs, the tripartite MTV-MOFs (R)-10 CuMnCr and (R)-10 CuMnCo were also explored for the epoxidation of 2,2-dimethyl-2H-chromene and its derivatives, and the products were obtained with good conversion rates and high enantioselectivities.Similarly, the catalysts were further verified for the ring opening reaction of epoxides by the nucleophile aniline and water, but the enantioselectivities were less than 25% in both cases.Next, the consecutive reaction of the asymmetric epoxidation of alkene followed by ring-opening reactions of epoxides by various nucleophiles, such as aniline, TMSN 3 , and ArCH 2 SH, was explored successfully by employing the catalyst (R)-10 CuMnCr .The various substituents on anilines had a slight effect on both the conversion and selectivity of the reactions, and overall the conversions obtained were 78-95% with an ee of 86-96%.A satisfactory conversion (74-92%) with high enantioselectivity (84-99%) was achieved for azido alcohols derived from TMSN 3 .Similarly, a variation with benzyl mercaptan derivatives was also accompanied by suitable conversions (74-94%) and good to high enantioselectivities (86-99% ee).The heterogeneous catalyst (R)-10 CuMnCo confirmed its efficiency in the sequential reaction of epoxidation and cleavage of epoxide by nucleophile H 2 O, alcohol, and ArCOOH.Later, the same group [98] constructed two other new binary MOFs by the cocrystallization of dipyridine and dicarboxylate-functionalized M(salen) complexes and demonstrated their efficiency as heterogeneous catalysts in the asymmetric sequential epoxidation of alkenes and epoxide ring-opening reactions.
Duan and associates [54] exemplified the fruitful catalytic activity of chiral ZnW-PYI (2) in the epoxidation of substituted styrenes with excellent yields (76-92%) and enantioselectivities (75-79%).After an effective transformation, the coupling of CO 2 to an (R) or (S)-styrene oxide was examined and showed an outstanding efficiency of conversion of >99% and high enantioselectivity of >90%.Chiral ZnW-PYI (2) proved its efficiency in the sequential one-pot transformation of olefins to cyclic carbonates via epoxide: 72-92% conversions and 55-80% enantioselectivities were obtained for sequential reactions with different substituted styrene derivatives.The author revealed that the hydrogen-bonding interactions between pyrrolidine-2-yl-imidazole (PYI) and the oxidation catalyst ZnW 12 O 40 6− and the π-π interactions between the benzene rings of styrene oxide and the imidazole rings of PYI prompted the smooth conversion of olefins into epoxides.In the case of cinnamaldehyde, only 25% conversion was obtained with zero ee under the same reaction conditions, which is due to the fact that the interactions of aldehyde groups with the NH 2 moieties deactivated sites for the activation of CO 2 molecules (Figure 14).and showed an outstanding efficiency of conversion of >99% and high enantioselectivity of >90%.Chiral ZnW-PYI (2) proved its efficiency in the sequential one-pot transformation of olefins to cyclic carbonates via epoxide: 72-92% conversions and 55-80% enantioselectivities were obtained for sequential reactions with different substituted styrene derivatives.The author revealed that the hydrogen-bonding interactions between pyrrolidine-2-yl-imidazole (PYI) and the oxidation catalyst ZnW12O40 6− and the π-π interactions between the benzene rings of styrene oxide and the imidazole rings of PYI prompted the smooth conversion of olefins into epoxides.In the case of cinnamaldehyde, only 25% conversion was obtained with zero ee under the same reaction conditions, which is due to the fact that the interactions of aldehyde groups with the NH2 moieties deactivated sites for the activation of CO2 molecules (Figure 14).The chiral MOF, (R,R)-salen(Co(III))@IRMOF-3-AM (13), was explored as a heterogeneous asymmetric catalyst in the one-pot synthesis of optically active cyclic carbonates from racemic epoxides.The reactions were studied with various epoxides, but the conversion, as well as the enantioselectivity, was reported to be quite low.In the case of styrene oxide, only 8% conversion and less than 1% ee were obtained, which implied that the bulky substituent reduced the rate of diffusion over the catalyst and thereby decreased the catalytic activity [71].

Aldol Condensation
In 2015, Bonnefoy et al. [70] scrutinized the asymmetric aldol condensation reaction between acetone and 4-nitrobenzaldehyde by employing peptide-based chiral MOFs as catalysts.The authors specified that an Al-MIL-101-NH-Gly-Pro (11aa) loading with 15 mol% of proline afforded an aldol product of 26% yield with 25% ee, and, likewise, Al-MIL-101-NH-Pro (11ab) showed an ee of 18%; whereas 100 mol% of proline moieties in Al-MIL-101-NH-Gly-Pro (11aa) increased the yield of product to 80%, but no significant change in enantioselectivity (only 27% ee) was observed.The chiral MOF, (R,R)-salen(Co(III))@IRMOF-3-AM (13), was explored as a heterogeneous asymmetric catalyst in the one-pot synthesis of optically active cyclic carbonates from racemic epoxides.The reactions were studied with various epoxides, but the conversion, as well as the enantioselectivity, was reported to be quite low.In the case of styrene oxide, only 8% conversion and less than 1% ee were obtained, which implied that the bulky substituent reduced the rate of diffusion over the catalyst and thereby decreased the catalytic activity [71].
Fröba and associates [47] synthesized a series of UHM-25 MOFs by introducing chiral amino acid substituents in diisophthalate linkers.Out of these synthesized chiral MOFs, the asymmetric catalytic activity of UHM-25-Pro (34) on aldol condensation was examined, over which the self-directed aldol condensation of acetaldehyde and the subsequent conversion of 3-hydroxybutanal to 1,1-Dimethoxy-3-hydroxybutane was scrutinized (Scheme 6).The yield obtained over both steps was 45% with the (R)-enantiomer as the major product, and the enantiomeric ratio of the products was 70:30.
Catalysts 2018, 8, x FOR PEER REVIEW 17 of 26 Scheme 6. Asymmetric aldol condensation and formation of hemiacetal product catalyzed by UHM-25-Pro.Reproduced from [47] with permission from the American Chemical Society.

Imine Reduction
Recently, Zhang and associates [99] designed a chiral MOF, CMIL-101 (35), by grafting chiral pyridyl-modified N-formyl-L-proline derivatives with MIL-101(Cr), which were further explored for the reduction of ketimine derivatives.The yield of the reaction was good when the reaction was performed at room temperature, and the ee was moderate (only 37%) but higher compared to the corresponding homogeneous catalyst.

Enantioselective Separation
The enantioselective separation of analytes is an alternative significant field of application for homochiral MOFs.Discovery of chiral adsorbents leads to the development of the rapid separation of individual enantiomers in a cost-effective manner.The method is especially in demand in pharmaceutical, agrochemical, and biomedical research for the enantiopure separation of numerous drugs, as the enantiomers always possess different physiological and pharmacological activities [100].Homochiral MOFs can be easily designed with chiral channels which are accessible to the analytes along with the ability to change the size and shape of the MOF pores to hold compounds with precise dimensions and assist in separating the isomers.This part of the review describes recent examples of enantiopure separation of racemates by applying chiral MOFs as a stationary phase for highperformance liquid chromatography (HPLC) and high-resolution gas chromatography (GC).

Imine Reduction
Recently, Zhang and associates [99] designed a chiral MOF, CMIL-101 (35), by grafting chiral pyridyl-modified N-formyl-L-proline derivatives with MIL-101(Cr), which were further explored for the reduction of ketimine derivatives.The yield of the reaction was good when the reaction was performed at room temperature, and the ee was moderate (only 37%) but higher compared to the corresponding homogeneous catalyst.

Enantioselective Separation
The enantioselective separation of analytes is an alternative significant field of application for homochiral MOFs.Discovery of chiral adsorbents leads to the development of the rapid separation of individual enantiomers in a cost-effective manner.The method is especially in demand in pharmaceutical, agrochemical, and biomedical research for the enantiopure separation of numerous drugs, as the enantiomers always possess different physiological and pharmacological activities [100].Homochiral MOFs can be easily designed with chiral channels which are accessible to the analytes along with the ability to change the size and shape of the MOF pores to hold compounds with precise dimensions and assist in separating the isomers.This part of the review describes recent examples of enantiopure separation of racemates by applying chiral MOFs as a stationary phase for high-performance liquid chromatography (HPLC) and high-resolution gas chromatography (GC).
In 2016, Yuan and associates [107] designed a homochiral MOF, [Cd 2 (d-cam) 3 ]•2Hdma•4dma (42), and applied it as a novel chiral stationary phase in HPLC.Nine racemates, including 1-(1-naphthyl) ethanol, 1-(4-chlorophenyl) ethanol, 1-(9-anthryl)-2,2,2-trifluoroethanol, 1,1'-bi-2-naphthol, benzoin, hydrobenzoin, trans-stilbene oxide, praziquantel, and warfarin sodium, were well-separated on the Cd-MOF column and the highest resolution value obtained was for 1-(1-naphthyl) ethanol (R S = 4.55).The same group [108] recently synthesized six amino-acid-based chiral MOFs, [Zn(L-tyr)] n (L-tyrZn) Employing these MOFs as a chiral stationary phase in HPLC, several chiral compounds were well-separated in their enantiopure form.Hartlieb et al. [109] reported a CD-MOF (44) built from alkali metal salts and γ-cyclodextrin (γ-CD), which has 40 stereo genic centers.The chirality of γ-CD was induced throughout the structure of CD-MOF (44) and assisted the framework to accomplish the separation of a wide variety of compounds, including alkyl-, vinyl-, and haloaromatics, saturated and unsaturated alicyclic compounds, and chiral compounds, such as limonene and 1-phenylethanol.In the case of the structural isomers of pinene and terpinine, it was observed that the isomer with the exocyclic double bond can be gripped by the CD-MOF for a longer time compared to another isomer possessing an endocyclic double bond.In the case of the separation of haloaromatics, molecular simulations established that both the size of the substituted halogen and the strength of the noncovalent bonding interactions between the analyte and the CD-MOF affect the separation process.Cui and co-workers [110] 15).Although the Cd-DHIP MOF (45b) showed almost no enantioselective adsorption ability under identical conditions due to the small hole size of the interpenetrating network of the Cd-DHIP MOF (45b), it was noted that electron-donating substituents attached to the aromatic rings of aromatic sulfoxides afforded a higher ee compared to the electron-withdrawing substituents present in the rings, and the highest ee of 46.8% was obtained in case of methyl phenyl sulfoxide.
Hailili et al. [111] studied the enantioselective separation of the chiral compounds (±)-ibuprofen and (±)-1-phenyl-1,2-ethanediol by the chiral MOF (Me 2 NH 2 ) 2 [Mn 4 O(D-cam) 4 ]•5H 2 O (46), which acted as a stationary phase in HPLC.A hexane-isopropyl alcohol (96:4, v/v) system was used as a mobile phase, which afforded a prominent baseline resolution for the separation of both pairs of the compounds with high resolution.In case of (±)-ibuprofen, 80% valley separation with a good selectivity factor (α = 6.48) and resolution (R s = 2.02) was accomplished within only 12 min.The authors stated that the calculated van der Waals energy for adsorbed (+)-and (−)-ibuprofen is −16.5 and −20.1 kcal mol −1 , respectively, which indicates a stronger interaction with the chiral MOF resulting in a long retention time of (−)-ibuprofen (Figure 16).Reproduced from [111] with permission from the American Chemical Society.
Martí-Gastaldo and co-workers [112] recently designed a chiral Cu(II) 3D MOF, [Cu(GHG)] (47), based on the tripeptide Gly-L-His-Gly (GHG) for the enantioselective separation of the chiral polar drugs metamphetamine and ephedrine.More than 50% of the (+)-ephedrine enantiomer was isolated when MOF (47) was used as a chiral solid phase extraction holder (Figure 17).HPLC chromatograms of ephedrine racemate before (dashed line) and after (solid line) passing through the MOF bed.Reproduced from [112] with permission from the American Chemical Society.

Gas Chromatographic (GC) Analysis
The selection of chromatographic methods is mainly dependent on the properties of the chiral molecules.GC analysis is primarily done for those samples which are thermally stable and volatile.Good resolution, sensitivity, reproducibility, good efficiency, fast analysis, and no need of liquid  46) viewed along the c-axis direction.Reproduced from [111] with permission from the American Chemical Society.
Martí-Gastaldo and co-workers [112] recently designed a chiral Cu(II) 3D MOF, [Cu(GHG)] (47), based on the tripeptide Gly-L-His-Gly (GHG) for the enantioselective separation of the chiral polar drugs metamphetamine and ephedrine.More than 50% of the (+)-ephedrine enantiomer was isolated when MOF (47) was used as a chiral solid phase extraction holder (Figure 17).Reproduced from [111] with permission from the American Chemical Society.
Martí-Gastaldo and co-workers [112] recently designed a chiral Cu(II) 3D MOF, [Cu(GHG)] (47), based on the tripeptide Gly-L-His-Gly (GHG) for the enantioselective separation of the chiral polar drugs metamphetamine and ephedrine.More than 50% of the (+)-ephedrine enantiomer was isolated when MOF (47) was used as a chiral solid phase extraction holder (Figure 17).HPLC chromatograms of ephedrine racemate before (dashed line) and after (solid line) passing through the MOF bed.Reproduced from [112] with permission from the American Chemical Society.

Gas Chromatographic (GC) Analysis
The selection of chromatographic methods is mainly dependent on the properties of the chiral molecules.GC analysis is primarily done for those samples which are thermally stable and volatile.Good resolution, sensitivity, reproducibility, good efficiency, fast analysis, and no need of liquid (b) HPLC chromatograms of ephedrine racemate before (dashed line) and after (solid line) passing through the MOF bed.Reproduced from [112] with permission from the American Chemical Society.

Gas Chromatographic (GC) Analysis
The selection of chromatographic methods is mainly dependent on the properties of the chiral molecules.GC analysis is primarily done for those samples which are thermally stable and volatile.Good resolution, sensitivity, reproducibility, good efficiency, fast analysis, and no need of liquid mobile phases are some of the benefits of GC analysis compared to other chromatographic methods.In 2011, Xie et al. [113] 54) can separate only aromatic alcohols rather than aliphatic alcohols.Two reasons for this unusual behavior of the MOF (54) were stated by the authors: firstly, the entry of large molecules was quite impossible through the 1D narrow network.Thus, enantioselective separation was likely to occur on the chiral surface of the MOF, where aromatic alcohols could be separated more easily compared to aliphatic alcohols.Secondly, enantiomeric separation of aromatic alcohols was possible due to the existence of three types of interaction, i.e., the π-π interactions between the surface of the MOF and aromatic alcohols, and H-bonding and stereochemical interactions with the chiral L 20 ligands on the MOF surface.In the case of aliphatic alcohols, only H-bonding interactions happened, which led to no enantioselective separation.Figure 18 shows the possible mechanism of enantioselective separation by the chiral MOF.
Catalysts 2018, 8, x FOR PEER REVIEW 20 of 26 racemic alcohols and it was found that the MOF (54) can separate only aromatic alcohols rather than aliphatic alcohols.Two reasons for this unusual behavior of the MOF (54) were stated by the authors: firstly, the entry of large molecules was quite impossible through the 1D narrow network.Thus, enantioselective separation was likely to occur on the chiral surface of the MOF, where aromatic alcohols could be separated more easily compared to aliphatic alcohols.Secondly, enantiomeric separation of aromatic alcohols was possible due to the existence of three types of interaction, i.e., the π-π interactions between the surface of the MOF and aromatic alcohols, and H-bonding and stereochemical interactions with the chiral L 20 ligands on the MOF surface.In the case of aliphatic alcohols, only H-bonding interactions happened, which led to no enantioselective separation.Figure 18 shows the possible mechanism of enantioselective separation by the chiral MOF.
Figure 18.Possible interactions between the chiral framework and chiral alcohols.Reproduced from [119] with permission from the American Chemical Society.
Recently, Lang et al. [120] reported a homochiral MOF, Co-L-GG (55) (L-GG = dipeptide H-Gly-L-Glu), as a stationary phase for the enantiomeric separation of racemates.Around 30 racemates, including halohydrocarbons, ketones, esters, ethers, organic acids, epoxy alkanes, sulfoxides, alcohols, and isomers, were studied and it was demonstrated that the column has significant ability Possible interactions between the chiral framework and chiral alcohols.Reproduced from [119] with permission from the American Chemical Society.
Recently, Lang et al. [120] reported a homochiral MOF, Co-L-GG (55) (L-GG = dipeptide H-Gly-L-Glu), as a stationary phase for the enantiomeric separation of racemates.Around 30 racemates, including halohydrocarbons, ketones, esters, ethers, organic acids, epoxy alkanes, sulfoxides, alcohols, and isomers, were studied and it was demonstrated that the column has significant ability towards chiral recognition and the selective separation of enantiomers.

Conclusions and Prospects
This review summarizes the present progress of the synthesis of chiral MOFs and their applications as catalysts in asymmetric reactions and chiral stationary phase in the enantioselective separation of chiral molecules.Although the process is expensive, the synthesis of chiral MOFs has greatly expanded from pre-synthesized chiral ligands.Other methods for the synthesis of chiral MOFs are still in progress.The applications of chiral MOFs as heterogeneous catalysts in asymmetric reactions have proved themselves to be outstanding catalysts by affording greater yields and enantioselectivities of reactions compared to those of the homogeneous control catalysts.However, these MOF catalysts are facing trouble in the case of sterically hindered reagents, which have been found to be futile for proceeding with asymmetric reactions with good enantioselectivities.It was observed that numerous organic transformations were done by post-metalated MOFs or MOFs prepared from salen ligands.Chromatographic separation with chiral MOFs has expanded very rapidly in the last 10 years and many more suitable chiral MOFs have been designed for the separation of various organic racemates.Some of the promising results were elaborately discussed in this review to present the advancement of the field.Besides the chiral MOFs, other alternative frameworks, such as covalent organic frameworks (COFs) [121,122] and defect porous organic frameworks (dPOFs) [123], are newly emerging fields in the chiral world.The present review hopefully benefits researchers to design chiral MOFs by various methods and serves as a driving force for them to explore applications of the synthesized chiral MOFs in various new fields.

Figure 1 .
Figure 1.Typical structural requirement for chiral MOFs for their applications.

Figure 1 .
Figure 1.Typical structural requirement for chiral MOFs for their applications.
presents the classification of the synthetic strategies of chiral MOFs.Catalysts 2018, 8, x FOR PEER REVIEW 3 of 26 salen, to react with metal salts, where the chirality is directly created to the frameworks from the chiral components.In the indirect method, achiral bridging ligands are used to synthesize achiral MOFs, which are subsequently transferred to chiral MOFs by applying various techniques, such as (a) post-synthetic modification (PSM) by reacting an achiral MOF with a chiral auxiliary and (b) a superficial chiral etching process (SCEP); chiral MOFs can also be attained from achiral bridging ligands by the method called (c) spontaneous resolution and (d) chiral induction.Chiral induction can be done by using the appropriate chiral templates, namely, (i) a chiral-co-ligand or chiral spectator; (ii) a chiral-solvent, and (iii) circularly polarized light.Figure 2 presents the classification of the synthetic strategies of chiral MOFs.

Figure 2 .
Figure 2. Schematic representation of the classification of the synthetic strategies of chiral MOFs.SCEP: superficial chiral etching process.

Figure 2 .
Figure 2. Schematic representation of the classification of the synthetic strategies of chiral MOFs.SCEP: superficial chiral etching process.

26 Scheme 1 .
Scheme 1. Ligands commonly used for the synthesis of chiral MOFs.

Figure 3 .
Figure 3. Synthetic procedure of the homochiral MOF ZnW-PYI (2) and schematic representation of the catalytic synthesis of cyclic-carbonates.Reproduced from[54] with permission from Nature Publishing Group.

Figure 3 .
Figure 3. Synthetic procedure of the homochiral MOF ZnW-PYI (2) and schematic representation of the catalytic synthesis of cyclic-carbonates.Reproduced from[54] with permission from Nature Publishing Group.

Figure 5 .
Figure 5. (a) Construction of MOF 10 Cu and corresponding multivariate (MTV)-MOFs 10 CuM and 10 CuMM ′ with different metallosalen linkers; (b) one three-dimensional (3D) unit of MOF 10 CuM ; (c) twofold interpenetrating 10 Cu (red indicates the interpenetrated 3D network); (d) close-up view of two L 7Cu units brought into proximity to each other by 2-fold interpenetration.Reproduced from [65] with permission from the American Chemical Society.

Figure 5 .
Figure 5. (a) Construction of MOF 10 Cu and corresponding multivariate (MTV)-MOFs 10 CuM and 10 CuMM with different metallosalen linkers; (b) one three-dimensional (3D) unit of MOF 10 CuM ; (c) two-fold interpenetrating 10 Cu (red indicates the interpenetrated 3D network); (d) close-up view of two L 7Cu units brought into proximity to each other by 2-fold interpenetration.Reproduced from[65] with permission from the American Chemical Society.

Figure 8 .
Figure 8. Schematic representation of the superficial chiral etching process for MOF 16.Reproduced from[72] with permission from the American Chemical Society.

Figure 8 .
Figure 8. Schematic representation of the superficial chiral etching process for MOF 16.Reproduced from[72] with permission from the American Chemical Society.

Figure 9 .
Figure 9. Synthesis of CMOF-5 in the presence of L-or D-proline additives induces chirality and postsynthetic activity of the achiral solvent N-methyl-2-pyrrolidone (NMP).Reproduced from[85] with permission from the American Chemical Society.

Figure 9 .
Figure 9. Synthesis of CMOF-5 in the presence of Lor D-proline additives induces chirality and post-synthetic activity of the achiral solvent N-methyl-2-pyrrolidone (NMP).Reproduced from[85] with permission from the American Chemical Society.

Figure 10 .
Figure10.The plausible mechanism of the chiral induction effect.Reproduced from[87] with permission from the Royal Society of Chemistry.

Figure 10 .
Figure10.The plausible mechanism of the chiral induction effect.Reproduced from[87] with permission from the Royal Society of Chemistry.

Figure 11 .
Figure 11.(a) Synthesis of the ligand H2L 12 .(b) Synthesis of homochiral MOFs by post-synthetic metalation of 25a and 25b and their applications in asymmetric catalysis.Reproduced from[89] with permission from the American Chemical Society.

Figure 11 .
Figure 11.(a) Synthesis of the ligand H 2 L 12 .(b) Synthesis of homochiral MOFs by post-synthetic metalation of 25a and 25b and their applications in asymmetric catalysis.Reproduced from[89] with permission from the American Chemical Society.

Figure 12 .
Figure 12.Synthesis of the homochiral E2-MOFs (27) from H4L14 and its post-synthetic metalation and their application in asymmetric catalysis.Reproduced from[91] with permission from the Royal Society of Chemistry.

Figure 12 .
Figure 12.Synthesis of the homochiral E2-MOFs (27) from H4L14 and its post-synthetic metalation and their application in asymmetric catalysis.Reproduced from[91] with permission from the Royal Society of Chemistry.

Figure 12 .
Figure 12.Synthesis of the homochiral E 2 -MOFs (27) from H 4 L 14 and its post-synthetic metalation and their application in asymmetric catalysis.Reproduced from[91] with permission from the Royal Society of Chemistry.

Catalysts 2018, 8 , 26 Figure 13 .
Figure 13.Proposed bimolecular (a) and unimolecular (b) activation pathways for the cyanation of aldehyde by 32a and 32b.Reproduced from[96] with permission from the American Chemical Society.

Figure 13 .
Figure 13.Proposed bimolecular (a) and unimolecular (b) activation pathways for the cyanation of aldehyde by 32a and 32b.Reproduced from[96] with permission from the American Chemical Society.

Figure 14 .
Figure 14.Diagram of potential mechanism for auto tandem catalysis.Reproduced from [54] with permission from Nature Publishing Group.

Figure 14 .
Figure 14.Diagram of potential mechanism for auto tandem catalysis.Reproduced from [54] with permission from Nature Publishing Group.

Figure 17 .
Figure 17.(a) Solid phase extraction separation of ephedrine by using MOF (47) as a chiral bed.(b)HPLC chromatograms of ephedrine racemate before (dashed line) and after (solid line) passing through the MOF bed.Reproduced from[112] with permission from the American Chemical Society.

Figure 16 .
Figure 16.Possible interaction of the (−)-ibuprofen isomer and MOF (46) viewed along the c-axis direction.Reproduced from[111] with permission from the American Chemical Society.

Figure 17 .
Figure 17.(a) Solid phase extraction separation of ephedrine by using MOF (47) as a chiral bed.(b)HPLC chromatograms of ephedrine racemate before (dashed line) and after (solid line) passing through the MOF bed.Reproduced from[112] with permission from the American Chemical Society.

Figure 17 .
Figure 17.(a) Solid phase extraction separation of ephedrine by using MOF (47) as a chiral bed.(b)HPLC chromatograms of ephedrine racemate before (dashed line) and after (solid line) passing through the MOF bed.Reproduced from[112] with permission from the American Chemical Society.

Figure 18 .
Figure 18.Possible interactions between the chiral framework and chiral alcohols.Reproduced from[119] with permission from the American Chemical Society.