Efficient Separation of Enantiomers Using Stereoregular Chiral

Review pubs.acs.org/CR

Efficient Separation of Enantiomers Using Stereoregular Chiral Polymers Jun Shen† and Yoshio Okamoto*,†,‡ †

Polymer Materials Research Center, Key Laboratory of Superlight Materials and Surface Technology, Ministry of Education, College of Materials Science and Chemical Engineering, Harbin Engineering University, Harbin 150001, People’s Republic of China ‡ Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan 3.4.1. CSPs Derived from Molecular Imprinted Polymers 3.4.2. CSPs Derived from Inorganic Elements 4. Conclusions and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments ABBREVIATIONS References Note Added after ASAP Publication

CONTENTS 1. Introduction 2. Landmarks in the Liquid Chromatographic and Other Resolution Methods of Enantiomers 3. Stereoregular Chiral Polymers as CSPs for HPLC 3.1. CSPs Derived from Synthetic Polymers 3.1.1. Poly(meth)acrylamides 3.1.2. Poly(meth)acrylates 3.1.3. Polystyrenes and Polymaleimides 3.1.4. Polyacetylenes 3.1.5. Polyisocyanides 3.1.6. Polyisocyanates 3.1.7. Poly(α-amino acid)s, Polyamides, and Polyurethanes 3.2. CSPs Derived from Polysaccharides 3.2.1. CSPs Derived from Cellulose and Amylose 3.2.2. Application of Polysaccharide Derivatives for SFC, GC, CE, CEC, and SMB Separations 3.2.3. CSPs Derived from Cellulose and Amylose Derivatives with Regioselective Substituents 3.2.4. Immobilization of Polysaccharide Derivatives on Silica Gel 3.2.5. Structures of Cellulose and Amylose Derivatives 3.2.6. CSPs Derived from Other Polysaccharides 3.2.7. CSPs Derived from Oligosaccharide Derivatives 3.3. CSPs Derived from Proteins and DNA 3.4. CSPs Derived from Other Methods

© 2015 American Chemical Society

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1. INTRODUCTION Biosystems, including ourselves, are very sensitive to the chirality of compounds; for instance, monosodium L-glutamate is tasty, while its D-isomer is tasteless, and in many chiral pharmaceuticals, one of the enantiomers is often much more effective than the other enantiomer. This is mostly due to the homochirality of the amino acids and sugar units consisting of proteins and nucleic acids, respectively. However, before 1980, it was rather difficult to develop enantiomerically pure drugs, and many chiral drugs had been used as a racemate, a mixture of equal amounts of the enantiomers.1 This situation was ascribed to the fact that there existed no effective method for precisely separating a trace amount of enantiomers, which enabled the analysis of chiral compounds extracted from blood or urine. In the 1980s, efficient analytical methods were developed using chiral stationary phases (CSPs) for gas and liquid chromatographies; thus, the trace analysis of chiral compounds had been realized.2−5 On the basis of these facts, drug administration authorities in many countries announced the required development of enantiomerically pure drugs. Since then, the science and technology of chirality including the synthesis, structural analysis, and function of chiral compounds have significantly advanced, and there already exists a big market for chiral compounds, particularly chiral pharmaceuticals. Among the several chromatographic enantioseparation (resolution) methods, such as gas chromatography (GC), supercritical fluid chromatography (SFC), capillary electro-

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Received: May 26, 2015 Published: September 24, 2015 1094

DOI: 10.1021/acs.chemrev.5b00317 Chem. Rev. 2016, 116, 1094−1138

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method is exhibiting prominent advantages from the viewpoint of green chemistry as well as short analysis time, high resolution, and efficiency, and many volatile or thermally unstable racemic compounds can be efficiently resolved by it, providing a complementary choice of the GC and HPLC methods. In this review, we will describe the enantioseparations mainly by HPLC using stereoregular polymers as the CSPs, which are currently most frequently used for both analytical and preparative purposes, and particular attention has been paid on the role of stereoregularity of the polymers for chiral recognition.

phoresis (CE), capillary electrochromatography (CEC), and high-performance liquid chromatography (HPLC), the HPLC method using stereoregular synthetic or natural polymers as CSPs seems to be the most popular and effective way for both the analytical and the preparative separations of chiral compounds, and today, nearly 90% of the chiral compounds may be resolved by this method.6−18 On the other hand, the determination of the enantiomeric excess (ee) of chiral compounds had also been significantly developed using the above-mentioned methods, enabling the ee determination with a trace amount of samples.1,2,16,19 Figure 1 shows the

2. LANDMARKS IN THE LIQUID CHROMATOGRAPHIC AND OTHER RESOLUTION METHODS OF ENANTIOMERS With the development of various stereoregular chiral polymers, the liquid chromatographic (LC) and other resolution methods of enantiomers have made significant advances. Not only chiral molecules but also chiral polymers can be efficiently resolved by these methods. The most significant landmarks in the LC resolutions of enantiomers are summarized in Table 1, together with other resolution methods by paper chromatography (PC), GC, CE, SFC, CEC, and membranes. The history of LC separation will first be briefly introduced. It can be traced to 1938, when the first LC separation of enantiomers was reported by Henderson and Rule with the partial separation of pphenylenebis(iminocamphar) using a column packed with a disaccharide lactose as the CSP.31 Six years later, in 1944, Prelog et al. realized the partial separation of Tröger base with the same CSP.32 Pino et al. reported the first separation of a racemic polymer, poly[(R)- and (S)-4-methyl-1-hexene] mixture, using crystalline isotactic poly[(S)-3-methyl-1-pentene] as the CSP in 1962.33 The first baseline resolution by LC was realized by Davankov et al. in 1971 through ligand exchange chromatography, in which the L-proline residue bonded on polystyrene gel was used as a CSP.34 Also, in 1971, Blaschke prepared optically active polyacrylamides and polymethacrylamides and successfully applied them as the CSPs for LC for the resolution of many chiral drugs,35 which initiated the development of synthetic polymer-based CSPs. Three types of CSPs were then developed in 1973; those were the CSPs by the molecular imprinting method by Wulff et al.,36 the CSPs based on the microcrystalline cellulose triacetate by Hesse and Hagel,37 and the CSPs based on the proteins by Stewart and Dohert,38 leading to a big step in the development of stereoregular synthetic and natural polymers as the CSPs for LC resolution. In 1974, Nolte and Drenth reported the resolution of right- and left-handed helical poly(tert-butyl isocyanide), which has a chirality due to only its helicity using poly[(+)-sec-butyl isocyanide] as a CSP.39 Cram et al. first prepared the CSPs based on a crown ether and attained the complete separation of amino ester salts in 1975.40 Musso et al. demonstrated the baseline separation of biphenyl derivatives using potato starch in 1978,41 and in this year, Harada et al. developed the cross-linked cyclodextrin-based CSPs for the resolution of mandelic acid derivatives.42 Pirkle and House then reported the Pirkle-type CSP for HPLC in 1979 and realized the efficient resolution of a variety of racemates, such as sulfoxides, amines, amino acids, alcohols, and hydroxy acids.43 The successful synthesis of a one-handed helical poly(triphenylmethyl methacrylate) (PTrMA) with a high isotacticity was reported by Okamoto et al. in 1979,44 and in 1980,

Figure 1. Distribution of ee determination methods from 1995 to 2012. Data were obtained from Tetrahedron: Asymmetry published in 1995−2003 and the Journal of the American Chemical Society published in 2005−2012. Reprinted with permission from ref 24. Copyright 2014 Elsevier B.V.

percentage of the ee determination methods that appeared in Tetrahedron: Asymmetry (TA) published from 1995 to 2003 and the Journal of the American Chemical Society (JACS) published from 2005 to 2012.20−22 In every year, approximately 300−350 papers reported the ee determination in TA and 200−290 papers in JACS. It had been a tough job to precisely estimate the ee value before 1980, and the specific optical rotation ([α]D) using a polarimeter was mainly available at that time but tended to die out after 2005, as shown in Figure 1. In the middle of the 1970s, NMR instruments and a related technique including chiral NMR shift reagents were developed and applied for the ee determination.23 However, due to its limit applicability for chiral compounds and the lower analysis accuracy compared to chromatographic methods, this method has become gradually outdated. Since the middle of the 1990s, chiral HPLC has become the most popular method, and nearly 80% ee determinations have been realized by this method.20,22,24 Besides GC and HPLC, SFC has come into our field of view after 2007 and seems to be the third main method for ee determination.25−30 Using the same CSPs as those for HPLC and carbon dioxide as a main mobile phase together with a small amount of organic modifiers, this newly developed 1095


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Table 1. Landmarks in the Liquid Chromatographic and Other Resolution Methods of Enantiomersa

a

LC separation by stereoregular polymers is shown with bold letters; resolution by other chromatographic methods (PC, GC, CE, CEC, and SFC) is shown in green; resolution by membrane is shown in purple; resolution of chiral polymers is shown in orange.

popular CSPs for the resolution of a wide range of compounds. In order to improve the solvent versatility and stability, the immobilized-type CSPs derived from polysaccharide phenylcarbamates were for the first time developed in 1987,58 and the first immobilized CSP based on amylose and cellulose tris(3,5dimethylphenylcarbamate)s were launched by Daicel in 2004 with the commercial names of Chiralpaks IA and IB, respectively.59,60 In 1994, Armstrong et al. reported the macrocyclic glycolide-based CSPs for HPLC,61 and the resolving ability as well as the stability and loadability of these CSPs were investigated. Yashima et al. synthesized the stereoregular helical poly(phenylacetylene) bearing (R)-1phenylethylcarbamoyl groups with a high chiral recognition ability in 1994.62 Allenmark et al. prepared the CSPs based on cross-linked tartardiamides in 1995,63 and Lindner and Lämmerhofer prepared the cinchona alkaloids-based CSPs for HPLC in 1996.64 In 2002, a stereoregular polymaleimide derivative was synthesized by Oishi et al.65 through asymmetric anionic polymerization, and many racemates can be resolved on this chiral polymer. Armstrong et al. reported the native and derivatized cyclofructan-based CSPs,66 and these stereoregular cyclic oligomers exhibited a unique resolving power for a broad range of racemates as the CSPs for HPLC. In addition to the LC resolutions, other resolution methods, including PC, GC, CE, SFC, CEC, and membrane, also play an important role in the separation of enantiomers. As shown in Table 1, in 1951, Kotake performed the resolution of amino

the resolution of many racemic compounds was accomplished using the one-handed helical PTrMA.45 Since then, the study of the synthesis of various stereoregular chiral polymers and their applications in enantioseparation as CSPs has blossomed. The CSP based on PTrMA-coated silica gel was then prepared in 1981,46 and the right- and left-handed PTrMA was efficiently separated using immobilized (+)-PTrMA.47 The resolution of another chiral polymer, poly[(R)- and (S)-1-phenylethyl methacrylate], was also performed by Hatada and Yuki using the one-handed helical polychloral in 1981.48 Due to their excellent recognition abilities for numerous compounds, the Pirkle column and the PTrMA column were commercialized from Regis in 198149 and Daicel in 1982,50 respectively. In 1984, two CSPs based on stereoregular natural polymers, cellulose tribenzoate and trisphenylcarbamate, were developed by Okamoto et al.51,52 and Daicel,53 and four types of cellulosebased CSPs, including the above-mentioned two CSPs, were commercialized from Daicel. Armstrong and DeMond prepared the cyclodextrin-based CSP bonded to silica gel and performed the separation of optical, geometrical, and structural isomers in 1984.54 Saigo et al. prepared the optically active polyamides having (−)-anti head-to-head coumarin dimer component and used them as CSPs in 1985.55 In 1986 the CSPs based on tris(3,5-dimethylphenylcarbamate) of cellulose (commercial name Chiralcel OD)56 and in 1987 the same derivative of amylose (commercial name Chiralpak AD) were reported by Okamoto et al.,57 which have now become some of the most 1096


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Figure 2. Stereoregular chiral polymers used for enantioseparation.

acid derivatives by PC using cellulose.67 Gil-Av achieved the first baseline resolution of N-trifluoroacetyl-α-amino acid esters by GC using a capillary column in 1966.68 The first CSP based on polysiloxanes containing N-propionyl-L-valine tert-butylamide groups for GC (commercial name, Chiralsil-Val) was reported by Bayer in 1977,69 which exhibited an efficient resolving power for almost all α-amino acid enantiomers. In 1985, two papers attracted much attention and have quickly picked up momentum for two kinds of resolution techniques, CE and SFC. One is the first paper on the chiral CE by use of a chiral additive to resolve amino acid derivatives reported by Gassmann et al.70 As the “youngest” separation method with prominent advantages, such as high flexibility, high peak efficiency, and low consumptions of chemicals and solvents, CE has developed rather rapidly and become one of the major techniques for analytical enantioseparations. The other is the first paper on the SFC separation of phosphine oxide enantiomers reported by Rosset et al.,71 and since then, the enantioseparation by SFC has made noticeable growth, and both analytical-scale and preparative-scale applications based on chiral SFC are now experiencing significant advances. In 1988, the cyclodextrin derivatives-based CSPs for GC were independently reported by Schurig et al.72 and König et al.73 During 1990 and 1992, the resolutions by membranes derived from poly(L-glutamate) and a polyacetylene with a chiral side chain were announced by Maruyama et al.74 and Aoki et al.,75 respectively. This resolution method may provide a complementary choice to the LC technique with their prominent advantages in several respects, particularly in preparative separation. However, so far, practical separations have not yet been realized. In addition, Mayer and Schurig reported the first enantioseparations by CEC using open tubular cyclodextrinbased CSP in 1992.76 The miniscale techniques, including CE, CEC, and capillary LC (or nano-LC), have also receieved remarkable progress as motivated by the high demand of the pharmaceutical industry toward high-throughput and fast methodologies in the past decade.

3. STEREOREGULAR CHIRAL POLYMERS AS CSPS FOR HPLC The versatility of stereoregular chiral polymers as CSPs has been of guarantee to satisfy the increasing needs for the efficient separation of enantiomers for analytical and preparative applications. Figure 2 described the structures of representative stereoregular polymers used for enantioseparation until now, including those (1−10) obtained by polymerization procedures and those (11 and 12) obtained by modification of natural polymers. The syntheses and enantioseparation abilities of these polymers will be first discussed in detail. 3.1. CSPs Derived from Synthetic Polymers

3.1.1. Poly(meth)acrylamides. During the 1970s, a series of polyacrylamides and polymethacrylamides (1 in Figure 2) was synthesized by radical polymerization and applied as the CSPs for LC enantioseparation by Blaschke.77−79 Many chiral compounds, especially chiral drugs, have been successfully resolved into single enantiomers using the optically active polyacrylamide gels. Among the resolved drugs, thalidomide, a sedative and hypnotic drug administered to pregnant women for that time, attracted much attention since it had caused a big tragedy such that a great number of babies with malformations were born. Blaschke first succeeded in the complete separation of the thalidomide enantiomers (Figure 3) and reported that only its (S)-(−)-enantiomer caused the teratogenic effect, while no such effect came from its (R)-(−)-enantiomer.79,80 Although this result aroused controversy due to the fact that each enantiomer of thalidomide can readily racemize in the body, the significance of this study is self-evident and a big innovation in the pharmaceutical industries was initiated. The chiral recognition ability of the polymethacrylamides depends on the synthetic procedures, that is, only the polymers prepared by the radical polymerization of the corresponding chiral monomers possess a high recognition ability. However, the same polymer obtained by the reaction of poly(acryloyl chloride) with the corresponding chiral amine shows a much lower chiral recognition, indicating that the chiral recognition 1097


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recognition of the polymer significantly decreased. For the efficient chiral recognition, the interaction on the amide groups of the polymer may be important. This interaction may be disturbed by the polar carboxylic groups, which can tightly interact with many polar groups. Optically active polymethacrylamides having different tacticities were also synthesized by the radical polymerizations of chiral monomers, 14a and 14b (Figure 4),88 in the absence and presence of Lewis acids. The polymerization in the presence of ytterbium trifluoromethanesulfonate [Yb(OTf)3] produced isotactic-rich polymers compared with those obtained without the Lewis acid. The specific rotations and the CD spectral patterns of the obtained polymers varied with the tacticities, suggesting that the tacticities influence the higher order structures of the polymers. The IR spectra of the polymers indicated that the isotactic polymers favorably formed intramolecular hydrogen bonds. The polymethacrylamides having different tacticities were immobilized on silica gel to be used as the CSPs for the HPLC resolution of various racemates. The chiral recognition abilities of the optically active polymethacrylamides were significantly influenced by their tacticities, and in many cases, the syndiotactic polymers again showed better separations than the isotactic polymers. These results are similar to that for the poly((R)-13) and can be explained by the same reason for the already described poly((R)-13a). Two new chiral acrylamide monomers, (S)-N-(ο-(4-methyl4,5-dihydro-1,3-oxazol-2-yl)phenyl)acrylamide (15a) and (R)N-(ο-(4-phenyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl)acrylamide (15b), have been synthesized by the acylation of chiral 2oxazolinylanilines, and their radical polymerization was performed using (3-mercaptopropyl)trimethoxysilane as a chain-transfer agent to obtain the corresponding optically active prepolymers with a trimethoxysilyl group.89 The prepolymers were then immobilized on silica gel via the grafting-to method to be used as the CSP for HPLC. These CSPs exhibited improved chromatographic performance compared to their brush-type analogs obtained by the alternative grafting-from approach. Several racemic compounds, such as benzoin and 2-amino-1-butanol, were partially resolved under the normal-phase mode. Moreover, the poly-15b-bonded CSP was found to possess the characteristic enantioseparation power toward some unmodified amino acids in the reversedphase mode. 3.1.2. Poly(meth)acrylates. The first successful preparation of one-handed helical polymethacrylate, PTrMA, with a nearly 100% isotacticity was achieved by the helix-senseselective polymerization of an achiral bulky monomer, TrMA, using the complex of n-butyllithium (n-BuLi) with a chiral ligand, (−)-sparteine ((−)-Sp), in 1979 (Figure 5).44 This is the first example of an optically active vinyl polymer, whose chirality is mainly attributed to the stable one-handed helical conformation produced during the polymerization. The helicity

Figure 3. Chromatographic resolution of racemic thalidomide on the derivative of 1 (R1 = CH3, R2 = 1-cyclohexyl ethyl). Eluent, benzene/ dioxane (8/2, v/v). Reprinted with permission from ref 77. Copyright 1980 Wiley-VCH.

sites are formed during the polymerization process.78 Because of the active amide hydrogen, N-monosubsituted (meth)acrylamides can only be polymerized by a radical process, which often leads to atactic or syndiotactic-rich polymers. The chiral recognition power of the polymers seems to depend on their tacticity, which influences their higher order structures. Lewis acids, such as rare earth metal trifluoromethanesulfonates, have been reported to significantly influence the stereochemistry of the radical polymerization of meth(acrylamide)s.81−85 On the basis of this result, a series of optically active poly(N-((R)-α-methoxycarbonylbenzyl)methacrylamides) (poly((R)-13a)) (Figure 4) with isotacticand syndiotactic-rich sequences was prepared, and their chiral recognition abilities were then evaluated as the CSPs for HPLC.86 The evaluation results are shown in Table 2. The syndiotactic (mm/mr/rr = ∼0/13/87), isotactic (mm/mr/rr = 87/13/∼0), and atactic (mm/mr/rr = 6/29/65) polymers exhibited quite different recognition abilities to the three aromatic racemates, indicating that the chiral recognition abilities of poly(meth)acrylamides are significantly influenced by their stereoregularity. Higher enantioselectivities and retention factors were obtained for the racemates of 2,2′dihydroxy-6,6′-dimethylbiphenyl and 1,1′-bi-2-naphthol (BINOL) on the poly-13a with the highest syndiotacticity, and as the syndiotacticity decreased, both parameters decreased. The lowest α values and retention factors of the isotactic poly-13a can be explained as follows, namely, the polymer may preferentially form an intramolecular hydrogen bond, preventing the polymer from sufficiently interacting with the enantiomers by a hydrogen bond. As an analogue of poly((R)-13a), poly((R)-13b) with a more bulky tert-butoxy pendant showed slightly better chiral recognition abilities to some racemates, including BINOL, a cobalt complex, and 2,2-dimethyl-1-phenyl-propanol.87 When the tert-butoxy ester group was converted to the carboxylic group, the circular dichroism (CD) intensity and chiral

Figure 4. Structures of optically active (meth)acrylamides (13−15). 1098


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Table 2. Enantioseparation of Aromatic Racemates on Poly((R)-13a)a,86

Column: 25 cm × 0.20 cm (i.d.). Flow rate: 0.1 mL/min. Eluent: hexane/2-propanol (90/10, v/v). The signs in parentheses indicate the optical rotation of the first-eluted enantiomer.

a

Figure 5. Helix-sense-selective polymerization of TrMA and efficient chiral ligands.

was warmed to room temperature, the optical rotation only slightly changed, implying that the obtained helical conformation is sufficiently stable. Besides the n-BuLi-(−)-Sp complex, many chiral ligands have been explored to control the helicity, and some of them, such as the complexes of fluorenyllithium (FlLi) with (−)-(2R,3R)- or (+)-((2S,3S)-2,3-dimethoxy-1,4bis(dimethylamino)butane (DDB), and (+)-(1-pyrrolidinylmethyl)-pyrrolidine (PMP) (Figure 5), were found to be better ligands to prepare the 100% one-handed helical PTrMA with a controlled molecular weight.90−92 The control of the molecular weight is very important for this kind of polymer due to the fact that the polymer with a degree of polymerization (DP) over 100 is insoluble in solvents, while that with a relatively low DP is soluble in tetrahydrofuran (THF). A soluble polymer with DP = 40−50 is desirable for preparing an effective CSP for HPLC as will be explained later. The optically inactive soluble PTrMA, which is obtained by the polymerization using n-BuLi alone in THF, can be separated into (+)and (−)-PTrMA by chromatography on the insoluble onehanded helical PTrMA as the CSP.47 The polymers with the same helicity can strongly interact, while those with the opposite helicity cannot. This made it possible to isolate the PTrMA with a very high one-handed helicity. On the basis of this separation result, the specific optical rotation of nearly 100% one-handed helical PTrMA was estimated to be around 350−370° at 589 nm (D line) and 1400−1480° at 365 nm. The chiral recognition ability of the optically active PTrMA with a high optical activity was first evaluated by grinding the insoluble polymer into small particles and then packed into an

is maintained by steric repulsion between the bulky side groups by restricting uncoiling of the helical polymer chain even after the reaction. During the polymerization process in toluene at −78 °C, the observed optical rotation significantly varied as shown in Figure 6.90 During the initial stage, the optical rotation did not change and gradually increased after 1 h that reached a very high positive value, indicating that (+)-PTrMA with a prevailing helicity was formed. When the reaction system

Figure 6. Change of optical activity in the polymerization of TrMA (0.15 g) using (−)-sparteine-/n-BuLi complex as anionic initiator in toluene (2.7 mL) at −78 °C (path length 1.0 cm). Reprinted with permission from ref 90. Copyright 1980 John Wiley & Sons. 1099


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HPLC column.45 Many efficient resolutions of various racemates were attained on the packed column, but it was difficult to prepare a stable and efficient CSP due to the brittleness of the polymer itself. After many attempts to develop a practically valuable CSP with a sufficient stability and robustness for the chromatographic resolution, in 1981, a simple coating method was verified to be the most efficient procedure to prepare the practically useful CSP.46 In this method, the THF soluble polymer (ca. 20 wt %) was coated on the surface of the commercially available macroporous silica gel (particle size 10 mm, pore size 100 nm, and surface area 20 m2/ g). The obtained PTrMA-coated packing material was stable, giving a packed column with a high plate number, a higher resistance to compression, and a longer lifetime than the CSP derived from the insoluble polymer. The insoluble and soluble PTrMA-based CSPs showed different chiral recognition abilities for several racemates, which may be ascribed to the different orientation of the PTrMA chains in the bulk and on the surface of the silica gel. Figure 7 demonstrates the resolution of the racemic BINOL on the (+)-PTrMA-coated CSP with methanol as an eluent, in

gel.112 However, due to the slow solvolysis reaction of the ester groups with methanol, this CSP is also not chemically stable. The solvolysis of the ester linkages in the helical PTrMA leads to a loss of the helical conformation and the chiral recognition ability. To reduce this solvolysis, the column has to be kept at a low temperature during the operation and the methanol has to be replaced by a nonalcoholic solvent, hexane, to avoid the possible solvolysis after use. In order to overcome this drawback, a new monomer, diphenyl-2-pyridylmethyl methacrylate (D2PyMA) (Figure 10), with an electron-withdrawing pyridyl group was introduced. The polymer (PD2PyMA) with a prevailing onehanded helicity was also readily prepared by the helix-senseselective anionic polymerization.113−116 However, compared to the polymerization of TrMA, the one-handedness during the polymerization of D2PyMA was much more difficult to control, since the pendant pyridyl group interacts with the countercation of the growing chain end and prevents the coordination of a chiral ligand to a countercation. Many chiral ligands including (−)-Sp and DDB in Figure 6 did not work well, and only PMP gave a completely one-handed helical PD2PyMA with a narrow molecular weight distribution.115,116 The stability of the PD2PyMA against the solvolysis by methanol was estimated to be 16-fold higher than that of PTrMA.116 The chiral recognition of PD2PyMA is slightly lower than that of PTrMA, although various racemates have also been resolved by HPLC using the PD2PyMA as a CSP.117 In addition, a series of optically active PTrMA analogues bearing pyridyl groups or meta-halogen-substituted phenyl groups, such as poly(phenylbis(2-pyridyl)methyl methacrylate) (PPB2PyMA),118 poly(meta-fluoro- or chloro-triphenylmethyl methacrylate) (PFTrMA, PClTrMA),119 and poly(tris(metachloro- or methylphenyl)methyl methacrylate) (PCl3TrMA, PMe3TrMA),119 were also prepared, and their chiral recognition abilities as CSPs were systematically investigated (Figure 10). PPB2PyMA, PFTrMA, and PClTrMA showed slightly lower recognition abilities compared to those of PTrMA. PCl3TrMA and PMe3TrMA showed quite different resolving abilities; the former had almost no ability, although the introduction of the electron-withdrawing chloro group improved the robustness of the polymer against the solvolysis of the ester group, while the latter possessed a high chiral recognition ability, realizing an even more efficient resolution than PTrMA for some racemates. However, the electrondonating methyl groups led to a decrease in the durability of the polymer. With intriguing potentials to achieve a durability against solvolysis and higher isotactic specificity, a relatively more bulky phenyl- or pyridyl-dibenzosuberyl group was introduced in place of the triphenylmethyl group of TrMA, and the obtained PTrMA derivatives, PPDBSMA,120 P2PyDBSMA, 120 and P3PyDBSMA, 121 showed a much lower recognition ability than PTrMA. The ethylene bridge seems to disturb the chiral recognition of the dibenzosuberyl group. A new single-handed helical polymethacrylate bearing a vinyl side chain, poly(1-(p-vinylphenyl)dibenzosuberyl methacrylate) (PVDBSMA in Figure 10), was synthesized by the asymmetric anionic polymerization.122 The resulting PVDBSMA having a vinyl group in the side chain was highly isotactic and showed a high optical activity, implying that the polymer possessed a single-handed helical conformation. The polymer was then treated with BH3 or KMnO4 to synthesize the one-handed helical polymethacrylates with hydroxy or carboxylic pendant groups, respectively. The reaction proceeded without signifi-

Figure 7. Chromatographic resolution of racemic BINOL on (+)-PTrMA. Column, 25 cm × 0.46 cm (i.d.). Eluent, methanol. Flow rate, 0.5 mL/min. Reprinted with permission from ref 46. Copyright 1981 American Chemical Society.

which a baseline separation with a high efficiency was obtained in a short time.46 Apart from BINOL, the CSP exhibited excellent chiral recognition abilities for over 200 racemic compounds, including hydrocarbons, esters, amides, halides, phosphoric compounds, etc., and some of them are shown in Figure 8. A typical advantage of the CSP is its high resolution power for stereochemically interesting compounds, which are difficult to be separated by other methods (Figure 9).46,93−111 With such a high chiral recognition ability, the PTrMA-based CSP has been commercialized from Daicel with the trade name of Chiralpak OT(+).50 However, the solvents that can be used for the PTrMA-coated CSP are very limited, and the use of many polar solvents will lead to serious damage of the packed column by dissolving the polymer inside. As a polar eluent, methanol provides better resolution than a nonpolar eluent, such as a hexane/alcohol mixture, indicating that the hydrophobic interactions between PTrMA and a nonpolar group of a racemate play an important role in the efficient chiral recognition. The most important recognition site of the polymer seems to be the triphenylmethyl group with a chiral propeller structure.111 To enhance the solvent resistance and durability of the PTrMA-coated CSP, the PTrMA was immobilized on silica 1100


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Figure 8. Compounds resolved on chiral PTrMA.

the chiral propeller-like triphenylmethyl group. Figure 11 shows some examples of the optically active polymethacrylates with a chiral recognition ability. A series of polymethacrylates 16 bearing chiral urea groups was synthesized by the radical polymerization of the chiral monomers prepared from 2methacryloyloxyethyl isocyanate and the corresponding optically active amines.127,128 The polymers resolved some racemates, such as 1,2,3,4-tetrahydro-1-naphthol and Nbenzyl-1-(1-methyl-2-methoxy-carbonyl) ethylamine, in the normal-phase HPLC. Compared to the (R)-(+)-1-(1naphthyl)ethylamine-bonded silica gel, the polymethacrylate bearing the same chiral amine moiety exhibited a quite different resolution ability, indicating that the higher order structure of the polymer may influence the chiral recognition. The optically active polymethacrylates with BINOL (17)129 and (+)-5oxobornyl (18)130 pendent groups were also synthesized by radical polymerization. The polymer showed a resolving power to some racemic compounds when coated on silica gel. The influence of the stereoregularity of these types of polymers on their recognition abilities has not yet been reported. The chiral BINOL and oxobornyl groups themselves may be the main factor for the chiral recognition abilities of the polymers 17 and

cantly reducing the one-handed helicity. This method may open a way to prepare one-handed helical polymers with a variety of polar functional groups, which are difficult to synthesize by the direct polymerization of the corresponding monomers. The syndiotactic poly(methyl methacrylate) is known to form a helical conformation in the solid state in the presence of a solvent, such as chloroacetone,123 and a gel in toluene.124 The gel consists of the helical structure with a large cavity that can include fullerenes like C60 and C70.125 Yashima et al. succeeded in the induction of a preferred-handed helical structure in the gel through the gel preparation in the presence of C60 and chiral alcohols, such as (S)-1-phenylethanol.126 The chiral gel can enantioselectively extract chiral fullerenes, such as C76, C84, C86, C90, and etc. This seems to be a valuable method to resolve a series of chiral fullerenes. Except for the one-handed helical PTrMA and its analogues having high chiral recognition abilities, most optically active polymethacrylates bearing a small chiral side chain, such as the (S)-1-phenylethyl group, showed almost no chiral recognition ability.111 This suggests that the chiral recognition of PTrMA may be attributed to the rigid helical structure accompanying 1101


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Figure 9. Stereochemically interesting compounds resolved on chiral PTrMA and PD2PyMA (numbers in parentheses are reference numbers).

Figure 10. Structures of optically active PTrMA analogues.

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3.1.3. Polystyrenes and Polymaleimides. An optically active styrene derivative with a chiral sulfoxide moiety, (S)(−)-p-(p-tolylsulfinyl)styrene, was prepared by optical resolution and polymerized by a radical process using α,α′azobis(isobutyronitrile) (AIBN) as the initiator.132 The obtained polymer (20 in Figure 13) was ground into a powder with a mean particle size of 7 μm and then packed into a column to be used as a CSP for HPLC. Several aromatic alcohols and amines, such as o-(1-methylbenzyl)phenol and αisopropylbenzylamine, were effectively resolved on the polystyrene-based CSP, while the aliphatic alcohols and amines were not resolved. The ability of the chiral sulfoxide group to form hydrogen bonds with the aromatic enantiomers seemed to play an important role in the chiral recognition ability of this polystyrene derivative 20. However, the influence of tacticity on the chiral recognition was not reported. The poly(N-substituted maleimide)s with a variety of optically active substituents, such as 21−24 in Figure 13, have been prepared by the anionic polymerization with organometal/chiral ligand complexes as initiators.65,133−137 The obtained polymers exhibited higher specific rotations compared to those of the radically obtained polymers. The high optical activity of the polymers was ascribed not only to the chirality of the N-substituents but also to the excessive chiral centers of the main chains induced through the asymmetric polymerizations. The preferential-handed helical conformation may also contribute to the high optical activity. Better resolutions were observed for some racemic compounds on the CSPs based on 23 with a higher stereoregularity, indicating that the stereoregularity has a significant effect on the chiral recognition ability of the poly(N-substituted maleimide)-based CSPs.133,134 3.1.4. Polyacetylenes. The studies of the optically active polyacetylenes have significantly advanced since the 1970s. A great number of optically active acetylenes bearing various chiral pendants have been polymerized mostly using the transition metal catalysts. The polymers possess a repetition of double and single bonds, and at least four possible structures exist on the basis of these bonds, i.e., cis-transoid, cis-cisoid, trans-transoid, and trans-cisoid. The stereoregularity of the poly(phenylacetylene)s can be examined by 1H NMR spectroscopy in which the chemical shift and line shape of the main chain’s olefinic protons and aromatic protons are sensitive to the structurally different isomers. By using a rhodium catalyst, phenylacetylene derivatives are able to be readily polymerized, giving the stereoregular polymers with an almost completely cis-transoidal structure.138 The poly(phenylacetylene) derivative bearing an (R)-phenylethylcarbamoyl pendant at the para position of the phenyl ring (25a in Figure 14) has been prepared using [RhCl(nbd)2] (nbd, norbornadiene), and its chiral recognition ability was

Figure 11. Structures of optically active polymethacrylates with chiral recognition ability.

18. An optically active helical polyacrylate, poly(2,7-bis(4-tertbutylphenyl)fluoren-9-yl acrylate) (poly(BBPFA), 19 in Figure 12), was synthesized by the asymmetric polymerization using

Figure 12. Structure of optically active poly(2,7-bis(4-tertbutylphenyl)fluoren-9-yl acrylate) (19).131

the complex of FlLi with PMP as an anionic initiator in toluene at −78 °C.131 Although BBPFA is an achiral monomer, the polymer 19 exhibited optical activity and intense CD signal, which can be ascribed to the preferred-handed helical mainchain conformation as well as the preferred-handed twist sidechain conformation. Interestingly, effective racemization was induced by photoirradiation, and the stereomutation of this polymer seemed to be governed by simple rotation of the single bonds between the side chain fluorenyl moieties and the tertbutylphenyl groups without any rearrangement of the chemical bonds.

Figure 13. Structures of polystyrene (20) and poly(N-substituted maleimide)s (21−24). 1103


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Figure 14. Structures of optically active polyacetylenes with chiral recognition ability.

evaluated as the first helical polyacetylene-based CSP for HPLC after being coated onto silica gel.62 Several racemates including Tröger base and spiropyran derivatives could be efficiently resolved on it. The preferred-handed helical conformation of the polymer was confirmed by the intense CD signals mainly derived from the rigid conjugated structure of the main chain. To investigate the effect of the stereoregularity on the chiral recognition ability, 25a was synthesized by a different method, in which 4-(tert-butyldimethylsiloxy)phenylacetylene was first polymerized in toluene using a tungsten-containing catalyst, WCl6/Ph4Sn, followed by desilylation with tetrabutylammonium fluoride. The resultant poly(4-hydroxyphenylacetylene) was then allowed to react with (R)-(+)-1-phenylethyl isocyanate to form 25a. The obtained stereoirregular polymer showed a poor chiral recognition, clearly demonstrating that the preferred-handed helical conformation induced by the stereoregular main chain with chiral pendants is essential for an effective chiral recognition power. The chemically bonded 25bbased CSP was also prepared by the polymerization catalyzed by a rhodium complex in the presence of silica gel with a phenylacetylene residue on its surface.139 The obtained CSP similarly exhibited a high chiral recognition ability to that of the coated-type CSP, and the durability in polar solvents including THF and chloroform was much improved. An optically active hydroxy group-containing N-propargylamide was polymerized with [(nbd)RhCl]2-Et3N as the catalyst, and the obtained polymer (26) took a predominantly preferred-handed helical structure.140 The helicity of the polymer was significantly affected by the solvents, and the polar solvents seemed preferable to induce a helical structure, which was opposite to the previous observation on the poly(Npropargylamide)s without hydroxy groups. The hydroxy group presumably prevents the polar solvents from disturbing the intramolecular hydrogen bonding between the amide groups,

which is a crucial point in order to keep a stable and stereoregular structure. The gel derived from the helical polymer 26 exhibited a relatively high chiral recognition ability compared to that of the polymer without a helix, revealing that the stereoregularity of this type of polymer has a big influence on the chiral recognition ability. The preferred-handed helical poly(phenylacetylene)s carrying a chiral pinanyl group (27a, 27b, and 28) were synthesized by the polymerization of the corresponding monomers with a [Rh(nbd)Cl]2 catalyst to be used as a solid membrane for the enantioseparation by permeation.141−143 The obtained polymers possessed high molecular weights (105−106 ) and showed high molar ellipticities in the main-chain region of the CD spectra, suggesting that chiral helical structures were formed in the main chain. The membranes fabricated from these polymers showed enantioselective permeabilities for two amino acids and an alcohol. The complete removal of the chiral pinanyl groups of 28 gave the poly(phenylacetylene) derivative with multihydroxy groups, which still showed the enantioselectivity, implying that the helical structure was memorized even after removal of the chiral groups.143 The enantioselectively permeable membrane derived from the preferred-handed helical polymers may afford a practically useful technique for chiral separation, especially for preparative purpose, although some weak points, such as the brittleness of the membranes and the relatively low efficiency, still need to be improved. A series of stereoregular helical poly(phenylacetylene)s bearing an amide linkage and L-leucine (29a),144 L-phenylalanine (29b),145 or L-phenylglycine (29c)145 ethyl esters as the pendant groups was synthesized to be used as the CSPs in HPLC. The polymers coated on the surface of the macroporous silica gel possessed effective resolution abilities for several racemates. It is noteworthy that the chiral recognition abilities of the 29-series polymers were influenced by the solvents used 1104


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Figure 15. Switchable enantioseparation as a CSP for HPLC based on reversible helicity induction and subsequent memory in poly(phenyacetylene)-33. Reprinted with permission from ref 149. Copyright 2014 Nature Publishing Group.

for coating them onto the silica gel. This has been ascribed to the fact that the conformation of the polymer main chain can be changed by the coating solvents due to the dynamic nature of the main-chain helical conformation. The molecular weight and optical rotation of the obtained polymers were influenced by the polymerization solvents, monomer concentration, and structure of the pendant groups, and these factors affected the chiral recognition ability. Optically active polyacetylene-based gels were also prepared by the copolymerization of the Npropargylamides derivative (30) bearing an L-lysine residue with an achiral diacetylene or dipropargyl adipate as a crosslinker using a rhodium catalyst in THF.146 The obtained gels exhibited the preferential adsorption of N-benzyloxycarbonyl Lalanine, N-benzyloxycarbonyl L-alanine methyl ester, and (S)(+)-1-phenyl-1,2-ethanediol in the adsorption experiment for the racemates. The fluorenylmethoxycarbonyl groups of the gels were partially removed by the treatment with piperidine, leading to an increase in the adsorptivity and a decrease in the chiral recognition ability.

Cinchona alkaloids have been extensively used as the chiral organocatalysts for a wide range of asymmetric syntheses. Among their four diastereomers, including cinchonidine (Cd), cinchonine (Cn), quinine (Qn), and quinidine (Qd), the Qn and Qd derivatives bonded to silica gel have been reported to show high recognition abilities for acidic racemates in the anion-exchange HPLC, and some of them have already been commercialized. On the basis of these results and with the expectation of a preferred-handed helical conformation of the polymers induced by the cinchona alkaloid pendants, a series of optically active helical poly(phenylacetylene)s (31a and 31b) bearing cinchona alkaloid pendant groups and an amide linkage was prepared for use as the CSPs for HPLC after coating on the silica gel.147 The CD spectral patterns between the diastereomeric pairs, such as (poly-ACd)/(poly-ACn) and (poly-AQn)/ (poly-AQd), appeared to be mirror images of each other, revealing that the opposite helices were induced by the amidelinked cinchona alkaloid moieties. The obtained CSPs exhibited efficient resolving powers to various racemates, such as 1105


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Figure 16. Preparation of polyacetylene-containing chiral nanoparticles bearing Au as core and helical poly(N-propargylamide) as shell for enantioselective adsorption. Reprinted with permission from ref 150. Copyright 2013 Wiley-VCH.

alcohols, diols, metal acetylacetonate complexes, and N-Bocamino acids, under the normal-phase conditions with a hexane/ 2-propanol mixture or in the anion-exchange conditions with the aqueous eluents. The importance of the macromolecular helicity for the chiral recognition ability was supported by the fact that the trans-enriched poly-ACn, which was prepared by grinding the cis-poly-ACn, showed a poor chiral resolving ability, since the polymer almost lost its helical conformation, as shown by the disappearance of the CD in the polymer backbone regions. It was apparent that the chiral recognition ability was significantly influenced by the helicity of the polymer backbone induced by the alkaloid pendants. This example provides an attractive instruction to endow the helical polymers with an asymmetric organocatalytic activity with other new functions including that as the CSPs for enantioseparation. The same group has recently reported novel polyacetylenes (32) bearing an optically active or racemic [6]helicene unit as the pendant groups.148 The polymers obtained using a rhodium catalyst showed a clear CD signal in the polymer backbone chromophore region due to the preferred-handed helical conformation induced by the chiral helicene groups, although the molecular weights of the polymers were rather low due to the poor solubility of the helicene. Like the (+)-PTrMA-based CSP, the optically active helicene-bonded polyacetylene exhibited high chiral resolving abilities for the aromatic racemic compounds, for instance, the BINOL derivatives, in the enantioselective adsorption experiments. This is probably attributed to the preferred-handed helical arrangement of the helicene pendant residues along the helical polymer backbone. Both the helical chiralities in the polyacetylene main chain as well as the helicene pendants may contribute to the chiral recognition ability. A novel optically inactive helical polyacetylene carrying 2,2′biphenol-derived pendant groups (33 in Figure 15) was recently synthesized.149 Both the macromolecular helicity of the polymer backbone and the axial chirality of the side chains are switchable in the solid state through the noncovalent weak interaction with a chiral alcohol and can be maintained even after removal of the chiral alcohol due to a memory effect. The induced macromolecular helicity and axial chirality can be reversibly switched and automatically memorized in the solid state as well as in solution. In contrast to the previously

reported memory of chirality in polyacetylenes, the replacement of a chiral induction agent with an achiral analogue is no longer necessary for this unique switchable dual memory. This is completely achieved in the solid state. It is known that during the enantioseparation by liquid chromatography, the elution order of the enantiomers is usually determined by the strength of the diasteromeric interactions between the enantiomers and a CSP. For analytical purpose, it is preferable that the minor component elutes before the major component to achieve an accurate quantification of the minor enantiomer, while for preparative purpose, the faster elution of the major component is desirable. Both requirements for the analytical and preparative chromatographies can be satisfied using a switchable CSP. This seems to be the first CSP capable of inverting the elution order of the enantiomers. The obtained CSP was actually applied to separate the enantiomers of trans-stilbene oxide (Figure 15). This switchable memory effect is also attractive for the enantioselective permeable membranes and asymmetric catalysts. The optically active helical polyacetylenes have also been extensively used to create a number of interesting materials for various applications. Among them, the chiral gold nanoparticles have attracted much attention due to their unique properties and promising applications, such as asymmetric catalysts, chiral dopants in liquid crystals, etc. A series of novel chiral gold nanoparticles having Au nanoparticles as a core and optically active helical copoly(N-propargylamide) ligands as a shell has been prepared (Figure 16).150 The nanoparticles showed significant optical activities. The copoly(N-propargylamide) endowed the gold nanoparticles with the chirality and excellent dispersibility in a variety of organic solvents, while the gold core rendered the chiral nanoparticles with much stronger UV−vis absorption and CD signals than the corresponding original helical copolymer. The fabricated chiral gold nanoparticles displayed an enantioselective adsorption to the 1-phenylethylamine enantiomers. This method appears to be attractive for preparing novel chiral materials from gold nanoparticles and synthetic polymers. 3.1.5. Polyisocyanides. Several optically active helical homopolymers and copolymers of the phenyl isocyanides have also been synthesized for use as the CSPs for the enantioseparation by HPLC. Four kinds of glycosylated 1106


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poly(phenyl isocyanide)s (34 in Figure 17) carrying the chirality of both the helical polyisocyanide main chain and

Figure 18. Structures of optically active copolymers of phenyl isocyanides with chiral recognition ability.155,157

Figure 17. Rigid helical poly(phenyl isocyanide)s with carbamoylated sugars (34) and flexible poly(N-phenylacrylamide) (35).151

racemates, such as a cyclic ether and dibenzamides, and that based on the right-handed helical polyisocyanide (P-copoly1(+)) exhibited a complementary resolving power, especially for the racemic metal acetylacetonate complexes, which were difficult to be resolved on the former CSP. The reversal elution order of some racemates was also observed on both the CSPs carrying opposite helices, demonstrating that the chiral recognition abilities of the polyisocyanide-based CSPs were significantly influenced by the helical conformation of the polyisocyanides. Some optically active copolymers composed of helical poly(phenyl isocyanide)s having achiral benzanilide pendant groups (P-copoly-2(+) and M-copoly-2(−) in Figure 18) were prepared.157 The helical sense of the polymers was controlled via the noncovalent bonding interactions based on the concept of “helicity induction and memory strategy”.158−161 The CSPs based on these polymers were prepared by coating or chemically bonding the polymer to silica gel.157 Efficient separations of many racemic compounds were realized on these poly(phenyl isocyanide)-based CSPs. In particular, the CSP derived from the helical poly(phenyl isocyanide) with an achiral anilide group showed a better chiral recognition ability to some racemates, including cyclic ether, amine, ketone, and metal acetylacetonate complexes. The elution orders of all enantiomers were consistent with the expected helical senses of the polymers. Suginome et al. developed a new class of optically active poly(quinoxaline-2,3-diyl)s by the living polymerization of the 1,2-diisocyanoarene using the (quinoxalinyl)palladium complexes and applied the polymers as the chiral phosphine ligands for various reactions.162,163 The polymer-based chiral ligands showed remarkably high enantioselectivities, especially during the Pd-catalyzed hydrosilylation of styrenes and Suzuki− Miyaura coupling of phosphinyl-substituted 1-naphthyl bromide with o-methylarylboronic acids. Interestingly, the helical chirality of the polymer ligands was reversible and switchable by the solvent effect, leading to the production of both enantiomers from a single catalyst with a high enantioselectivity. This chirality-switchable property may also show a potential application as the CSPs for the enantioseparation. 3.1.6. Polyisocyanates. Since the pioneering studies of the optically active polyisocyanates by Goodman,164,165 a number

the saccharide side chain (3,5-dimethylphenylcarbamate derivatives of α-/β-glucose and α-/β-galactose) were prepared, and their chiral recognition abilities were compared with that of the poly(N-phenylacrylamide) derivative (35 in Figure 17) with a flexible backbone.151 The CD spectra of the 34 polymers above 250 nm suggest that the α-glycoside polymers (34(Glcα) and 34(Gal-α)) probably have a right-handed helicity, and the β-glycoside polymers (34(Glc-β) and 34(Gal-β)) have a left-handed helicity. These rigid helical structures may be regulated by the chirality of the α- or β-anomeric center of the sugar moieties. The polymers showed efficient separation abilities for some racemates, depending on the stereostructure of the sugar pendants. Among the four poly(phenyl isocyanide)s, the α-galactose-type (34(Gal-α)) exhibited the highest chiral recognition ability. However, the CD intensity of each polymer was lower than those expected for the completely right- or left-handed helices, indicating that the obtained poly(phenyl isocyanide)s were probably composed of a mixture of the right- or left-handed helices or sequences. On the basis of this speculation, it can be expected that the chiral recognition abilities of this series of polymers would be much improved if the helical poly(phenyl isocyanide)s with a higher onehandedness could be prepared. One enantiomer of a phenyl isocyanide (L-36 in Figure 18) bearing an L-alanine pendent with a long n-decyl chain through an amide linkage has been polymerized by the helix-senseselective polymerization using the μ-ethynediyl Pt−Pd as a catalyst, producing both diastereomeric right (P)- and left (M)handed helical polyisocyanides (P-poly-36 and M-poly-36) with different molecular weights.152,153 The disastereomeric polymer pairs can be readily separated by the solvent fractionation using acetone, and the helical structure of each single-handed helical polymer was clearly observed by high-resolution atomic force microscopy (AFM) when depositing the polymer on a graphite substrate.154 The fractionated preferred-handed helical polyisocyanides were then used as the macromolecular initiators for the block copolymerization of the isocyanides.155 The obtained copolymers were immobilized onto silica gel, and their chiral recognition abilities were evaluated as the CSPs for HPLC.156 The CSP based on the left-handed helical polyisocyanide (Mcopoly-1(−)) showed a high resolving ability to some 1107


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Poly(4′-isocyanatobenzo-18-crown-6) (39) with crown ether pendants was synthesized by polymerization using an optically active initiator, which is incorporated at the chain end.174 The intense CD signals of the polymer provided evidence to support the helical structure of the obtained polymer, which was mainly induced by the chiral terminal residue. Some racemic amino acid derivatives could be effectively discriminated on the polymer 39 by enantioselective extraction, while no discrimination could be observed on the unimer of 39, suggesting that the chiral discrimination was mainly created by the macromolecular helicity of the achiral crown ether pendants with an excess helix sense along the polymer backbone. 3.1.7. Poly(α-amino acid)s, Polyamides, and Polyurethanes. Optically active poly(α-amino acid)s have been synthesized for use as the CSPs for HPLC (Figure 20).175,176 The cross-linked porous polystyrene beads incorporating poly(N-benzyl-L-glutamine) (40) were prepared via the poly(γ-methyl-L-glutamate) and showed a recognition ability for some racemates, such as mandelic acid and hydantoin derivatives.175 An α-helical structure was expected to be formed along the main chain of the immobilized poly(N-benzyl-Lglutamine), which may be responsible for its chiral recognition ability. The chiral recognition ability of this polymer significantly depended on the number of repeated units (m). For example, a dimer with m = 2 showed no chiral recognition, while the polymers with m = 14 or 36 attained the baseline separation for a hydantoin derivative, while those with m = ca. 250 showed a lower recognition ability. These results suggest that the vicinities of the helical chain end may recognize the enantiomers. Some amino acid derivatives were resolved on the poly(L-leucine) (41) or the poly(L-phenylalanine) (42) chemically bonded on the poly(methyl acrylate) macroporous beads or on the spheres consisting of only the poly(α-amino acid).176 A variety of optically active polyamides have been prepared for the enantioseparation by HPLC. A class of network polymers incorporating the bifunctional C2-symmetric selector (43 in Figure 21) was prepared by the acylation of N,N′-diallylL-tartardiamide, followed by cross-linking and covalent bonding to the vinyl-substituted silica by the reaction with a multifunctional hydrosilane.63 The obtained CSPs have been proved to possess high recognition abilities for a broad range of racemates, especially for the pharmaceutically interesting compounds including benzodiazepinones, profens, benzothiadiazines, amino alcohols, etc. The resolution capabilities of the CSPs prepared from the carbamate derivatives were generally inferior to those of the CSPs from the corresponding esters, which may be associated with the additional hydrogen-bond donor (NH) present in the carbamates, possibly giving rise to unfavorable competitive bonding modes. The retention and resolution can be regulated by the addition of modifiers like alcohols or ethers. The observed high efficiency and loading

of poly(alkyl isocyanate)s with a predominantly one-handed helical sense have been synthesized by Green et al.166−169 by the anionic polymerization of optically active isocyanates or by the copolymerization of an achiral isocyanate and a small amount of an optically active isocyanate. It is known that the poly(alkyl isocyanate)s possess a stiff dynamic helical structure of the main chain consisting of successive amide bonds in solution. On the other hand, poly(aromatic isocyanate)s had been much less studied, probably due to the low stability of the polymers. However, from the viewpoint of chiral recognition, preferred-handed helical poly(aromatic isocyanate)s seem more attractive.170−172 Maeda and Okamoto synthesized two kinds of optically active aromatic isocyanates, 3-((S)-(α-methtybenzyl)carbamoyl)phenyl isocyanate ((S)-3MBCPI) and 4-((S)-(αmethtybenzyl)carbamoyl)phenyl isocyanate ((S)-4MBCPI), and homopolymerized or copolymerized with m-methoxyphenyl isocyanate (mMeOPI) with an anionic initiator in THF at −98 °C.173 Poly((S)-3MBCPI) (37 in Figure 19) exhibited a

Figure 19. Structures of optically active poly(phenyl isocyanate)s with chiral recognition ability.

large levorotatory specific rotation ([α]36525 = −1969) and an intense CD absorption due to a predominantly one-handed helical conformation of the polymer main chain. The copolymers of (S)-3MBCPI with mMeOPI even showed a much higher specific rotation than that expected from the (S)3MBCPI content. The specific rotation of the obtained copolymer significantly increased with a decrease in temperature, but that of poly((S)-3MBCPI) showed almost no change, indicating that the latter homopolymer may take a perfectly single-handed helical conformation in solution even at room temperature. Poly((S)-4MBCPI) (38 in Figure 19) showed a high dextrorotatory specific rotation opposite to that of 37. The rotation of 38 gradually increased in THF with time from +1000° to a constant value +2059°. This change was considered to be associated with the slow conformational change from the GPC and CD analyses of the polymer. The clear discrimination of the racemic BINOL was observed on both poly(phenyl isocyanate)s 37 and 38 in the 1H NMR spectra, which was probably the first observation of the chiral recognition ability of the polyisocyanates.

Figure 20. Structures of optically active poly(α-amino acid)s with chiral recognition ability. 1108


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Figure 21. Structures of chiral amide monomers (43−49) and polymers (50−54) for CSPs.

Figure 22. Structures of optically active polyurethanes.

amides, alcohols, amino acids, esters, imines, thiols, and sulfoxides, and complementary separation capabilities were observed for many analytes. The new CSPs showed comparable or better separation abilities compared with the commercial column in both HPLC and SFC. In particular, CSP-47 seems to have a good sample loading capacity while maintaining the enantioselectivity. Several optically active polyamides (50−52) were also synthesized from chiral diamines or chiral dicarboxylic acids by polycondensation, and some polar racemates were separated by the obtained polymers through the hydrogen-bonding interactions with them.181−185 The chiral recognition ability of 52 (R1 = alkylene) was significantly influenced by its crystallizability, which depended on the length of the alkylene groups in the main chain.185 An odd−even effect of the m values on the chiral recognition was interestingly observed, and the polyamides 52 with an even number of methylene groups exhibited a higher chiral recognition ability than those with an odd number of methylene groups. Many L-proline-based CSPs with various L-proline unit lengths and linkers have been prepared and their chiral recognition abilities were evaluated by HPLC.186−188 Among these, the oligoproline-based CSPs 53186 with diproline and 54187 with triproline were prepared by the stepwise coupling of

capacity of the polyamide-based CSPs were attractive for the chiral separation particularly on a preparative scale. The preparation of the new polymeric CSPs from the chiral amide monomers, 44−46, has been reported.177−179 These polyamide-based CSPs realized the efficient separations of many chiral compounds in the multiple mobile phases including normal phase, reversed phase, or polar organic mode. The three CSPs had good stability and complementary selectivities for the examined racemates. The interactions between the CSPs and the analytes, such as hydrogen-bond, dipolar, and π−π interactions, as well as a function of steric fit seem to be responsible for the resolutions on these polyamidebased CSPs. Apart from these, three chiral amide monomers based on the (1S,2S)-(−)-1,2-diphenylethylenediamine derivatives (47−49) have also been polymerized via a free radical process.180 These monomers are structurally related to the (1S,2S)-(−)-1,2-diphenylethylenediamine-based monomer (46), which is the chiral monomer used for the commercialized CSP of P-CAP-DP (Advanced Separation Technologies Inc.).178 Their chiral recognition abilities were evaluated as the CSPs in the normal phase HPLC and SFC, and the results were compared with the commercial P-CAP-DP.180 All three new CSPs showed recognition abilities for a large number of racemates with a variety of functional groups, including amines, 1109


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Figure 23. (A) Distribution of ee determination methods reported in Angew. Chem. Int. Ed. in 2012. Numbers in parentheses show the number of papers. (B) CSPs for HPLC and SFC. (C) Polysaccharide-based CSPs, OD, AD, OJ, and AS are coated-type CSPs and IA, IB, IC, ID, and IE are immobilized-type CSPs. Reprinted with permission from ref 24. Copyright 2014 Elsevier B.V.

least 199 of them reported ee determinations. As well as the methods in 2012 in Figure 1, HPLC and SFC analyses were predominantly performed with the cellulose-based CSPs, Chiralcel OD and OJ, and amylose-based CSPs, Chiralpak AD and AS. The structures of the commercialized polysaccharide-based CSPs, including these four coated-type columns and six immobilized-type ones, are shown in Figure 24. OD (CSP 57a in Figure 24) and AD (CSP 58a in Figure

L-proline

to the amine terminal linker on silica gel. The obtained CSPs exhibited efficient chiral recognition abilities for a broad range of racemates. According to the authors, in addition to the adjacent hydrogen-bond acceptor (CO and N) and a rigid proline ring, the α hydrogen atom on the asymmetric carbon seems to play a crucial role in the enantioseparation. Optically active polyurethanes (55 in Figure 22) have been synthesized by the polyaddition of chiral 1,3-diols to various diisocyanates at 100 °C in anisole or dimethyl sulfoxide (DMSO).189 The diisocyanate residues were the main influential factor for their chiral recognition abilities. The polyurethanes derived from (1S,3S)-diphenylpropanediol and aliphatic diisocyanates exhibited good chiral recognition abilities for the BINOL derivatives, while those from the aromatic diisocyanates showed a poor recognition. The wideangle X-ray diffraction studies revealed that the chiral recognition ability depends on the crystallinity of the polymers. Other types of optically active polyurethanes (56) were also prepared by the polyaddition of the diamide and diester derivatives of the chiral coumarin dimer to 4,4′-diphenylmethane diisocyanate.190 The polyurethanes derived from the diamide showed efficient resolutions for some aromatic racemates. The hydrogen-bonding interaction as well as the aromatic stacking mainly contributed to the chiral recognition. 3.2. CSPs Derived from Polysaccharides

Figure 24. Structures of commercialized polysaccharide-based CSPs, including coated-type OD, AD, OJ, and AS and immobilized-type IA, IB, IC, ID, IE, and IF.

3.2.1. CSPs Derived from Cellulose and Amylose. Polysaccharides, such as cellulose and amylose, are some of the most abundant naturally occurring optically active macromolecules. Although cellulose and amylose have stereoregular sequences consisting of D-glucose units, their chiral recognition abilities are not sufficiently high enough to be utilized as the CSPs for HPLC. On the other hand, they can be readily derivatized to the esters and carbamates through the modification of the hydroxy groups on the glucose ring with the corresponding reagents. The derivatized polysaccharidebased CSPs show a much better enantioselectivity and chromatographic properties compared to the native polymers.191−198 Thus far, more than 10 polysaccharide-based CSPs have been commercialized and extensively applied for both analytical and preparative enantioseparations due to their high efficiency and loadability for a wide range of racemates. Figure 23 illustrates the distributions of the ee determination methods, the CSPs for chiral HPLC, and the types of polysaccharide-based CSPs reported in the Angewandte Chemie, International Edition in 2012.24 In this year, the journal published approximately 2100 communication papers, and at

24) include several other brand names, such as CellCoat and AmyCoat (Kromasil), RegisCell and RegisPack (Regis), Eurocel 01 and Europak 01 (Knauer), Lux Cellulose-1 (Phenomenex), Sepapak-1 (Sepaserve), and Chiral CelluloseC (YMC), if they are based on the same cellulose or amylose derivatives. Besides these coated-type CSPs, the immobilizedtype CSPs (Chiralpak IA, IB, IC, ID, IE, and IF) have recently become commercially available.199 In 1973, Hesse and Hagel reported the first useful polysaccharide-based CSP, which was derived from the microcrystalline cellulose triacetate (CTA-I, 59 in Figure 25), prepared by the heterogeneous acetylation of native microcrystalline cellulose in benzene.37,200 The microcrystalline structure of the native cellulose was believed to be maintained in the obtained CTA-I,200,201 which probably greatly contributed to the good chiral recognition ability of the CTA-I for a number of racemates, such as nonpolar compounds and 1110


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Figure 25. Structures of polysaccharide esters including cellulose triacetate (CTA, 59), cellulose benzoates(60), and amylose benzoates (61). Figure 26. Structures of all isomers of chrysanthemic acid ethyl ester (62) and chromatographic resolution of 62 on 60b prepared in the (a) absence and (b) presence of methyl benzoate as an additive in coating process. Reprinted with permission from ref 215. Copyright 2006 Wiley Periodicals.

aromatic drugs, using an ethanol−water mixture as the eluent.77,79,202 Interestingly, quite different chiral recognition abilities were observed after dissolving it in a solvent.37,51,53,201,203 For instance, the elution order of Tröger base (66) enantiomers was reversed between the microcrystalline CTA-I and the CSP fabricated by coating a solution of CTA-I on silica gel.51 This indicated that the higher order structure of the CTA plays a central role in its chiral recognition ability. Although the coated-type CTA exhibited a lower chiral recognition compared to the CTA-I, it had apparent merits, including the higher resolution efficiency and the higher mechanical strength.51,53 As stimulated by the intriguing findings on CTA-I, many attempts must have been carried out to develop better CSPs. However, until 1984, really useful CSPs had not been found. In 1984, Okamoto et al. and Daicel reported that the cellulose esters51,53 and phenylcarbamates52 coated on silica gel provide very attractive CSPs for HPLC. These findings initiated the systematic studies of the benzoate and phenylcarbamate derivatives of polysaccharides, particularly cellulose and amylose. A series of cellulose (60 in Figure 25)203 and amylose tribenzoates (61 in Figure 25)204 has been prepared in our group. The obtained cellulose tribenzoates with electrondonating substituents, such as an alkyl group, exhibited a higher chiral recognition ability than those with electron-withdrawing substituents, such as a halogen.203 The significant effect of the substituents on the chiral recognition ability is probably associated with the fact that the electron density of the carbonyl groups of the benzoate derivatives is significantly influenced by the substituents on the phenyl rings through an inductive effect. Among the benzoate derivatives, cellulose tris(4-methylbenzoate) (60b) showed an excellent chiral recognition for a variety of racemates.192,193,205−212 The chiral recognition ability of 60 also significantly depended on the coating conditions, such as the solvents used for coating the polymers onto the silica gel to prepare the CSPs.53,192,193,213,214 As for the amylose tribenzoates, much poorer recognition abilities were observed compared to that of the cellulose analogues. The reason may be due to the lower stability of the helical conformation of the amylose backbone, which leads to the formation of many conformational isomers. Chrysanthemate acid ethyl esters (62 in Figure 26) are important intermediates for synthetic pesticides and contain

four isomers.215 Their pesticidal activities significantly depend on their structures. These isomers have been separated by HPLC using 60b as the CSP. The chiral recognition ability of 60b was much improved depending on the coating process on the silica gel.215 When the CSP was prepared by coating 60b on silica gel in the usual way without any additive, all four stereoisomers of 62 could not be discriminated and were eluted at almost the same time. On the contrary, when the CSP was coated in the presence of 10 equiv of methyl benzoate to a glucose residue, the (1R)-trans isomer, which is the most active form of the pesticide, was very efficiently separated from the other three isomers resulting in the separation factor α = 7.26 (Figure 26b). The construction of the imprinted structure may be formed with the orientation of the benzoate side chains as well as the higher order structure of the cellulose benzoate chain, due to the dipole−dipole and π−π interactions between the additive and the benzoate moieties. The imprinted structure can be maintained even after the removal of the imprinted molecule. The phenylcarbamates of cellulose and amylose have been readily synthesized by the modification of the hydroxy groups with various phenyl isocyanates. Their chiral recognition abilities were evaluated as the CSPs by coating the derivatives onto silica gel. The chiral recognition abilities of the polysaccharide phenylcarbamates are significantly dependent on the nature, position, and number of the substituents on the aromatic moieties. 52,56,57 In particular, the tris(3,5dimethylphenylcarbamate)s of cellulose and amylose (57a and 58a in Figure 24), which have been commercialized with the trade names of Chiralcel OD and Chiralpak AD, exhibited excellent recognition abilities for a wide range of racemates and have become some of the most popular and practically valuable CSPs for the enantioseparation in many fields. The chiral compounds resolvable on the OD include hydrocarbon, halide, ether, ester, ketone, sulfoxide, alcohol, amine, acid, amide, amino alcohol, metal complex, etc., as shown in Figure 27.22,193 Figure 28 includes examples of the racemates efficiently 1111


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Figure 27. Compounds resolved on Chiralcel OD (57a).

Figure 28. Compounds resolved on Chiralpak AD (58a).

separated on AD.22,193 The enantiomer pairs are often eluted out with a reversed order on OD and AD, and some racemates that cannot be recognized on one of them can be recognized on the other, revealing that these two CSPs have complementary chiral resolution powers. Approximately 80% of ca. 500 racemates in our group could be resolved on at least one of the CSPs.

Amylose can include polymers216,217 as well as small molecules218 in its hydrophobic cavity. Yashima et al. obtained an amylose complex including the poly(p-phenylenevinylene) (PPV), which was synthesized by the polymerization of a suitable monomer in the presence of amylose.219 This amylose complex was treated with an excess of 3,5-dimethylphenyl isocyanate to convert the amylose to the tris(3,5-dimethylphe1112


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nylcabamate) 58a.220 It was confirmed that the obtained product still contained the PPV chain inside the helical 58a. The chiral recognition of the 58a-PPV complex was evaluated by HPLC after coating it on silica gel. The complex exhibited high chiral recognitions like Chiralpak AD, and some racemates showed the reversed elution order of enantiomers, suggesting that the structure of 58a in the complex may be different from that of 58a alone. Intensive investigations of the chiral recognition mechanism of the cellulose phenylcarbamates revealed some correlations between the substituent properties and chiral recognition abilities of the derivatives. It has been empirically established that the introduction of either an electron-donating or an electron-withdrawing group at the meta or para position on the phenyl rings can significantly improve the chiral recognition, while the ortho substitution induces a significant decrease in the chiral recognition.56,221−229 It was proposed that the chiral recognition ability can be controlled by varying the polarity of the carbamate residues via the introduction of substituents on the phenyl group. Compared to the cellulose derivatives, the amylose derivatives with a monosubstituent have not been thoroughly studied, although some para-substituted or disubstituted derivatives have been known to show a high chiral recognition.227,229−231 Interestingly, contrary to the cellulose derivatives, the amylose derivatives with two substituents including the ortho position, such as the 2methyl-5-chloro- or 2-methyl-5-fluoro-phenylcarbamates, exhibit a very high enantioseparation power for many racemates.229,230 The difference in the helical conformation of cellulose (left-handed 3/2 helix) and amylose (left-handed 4/3 helix) is considered to be the possible reason for their different chiral recognition.230−234 In order to obtain a better understanding of the substituent effect at the ortho or meta position on the chiral recognition of the amylose phenylcarbamates and to elucidate the relationship between the electronic and the structural characteristics of the substituents and the chiral recognition ability, a series of amylose phenylcarbamates bearing ortho or meta substituents (63 and 64 in Figure 29) was prepared and their chiral recognition abilities were evaluated as the CSPs for HPLC.235 A

better resolution of many racemates can be achieved on the meta-substituted amylose phenylcarbamates compared to those on the ortho-substituted derivatives, which was similar to that of the cellulose phenylcarbamates. The 2-methyl derivative (63d) showed a much lower resolving power than the 2methyl-5-halogen derivatives. On the other hand, the 3-methyl4-halogen derivatives showed slightly lower enantioselectivities than the 3-methyl derivatives (64d). The methyl group can enhance the intramolecular hydrogen bond of the polysaccharide phenylcarbamates, and the halogen groups can enhance the acidity of the NH group.56,224,230 An explanation for the high chiral recognition ability of the amylose 2-methyl5-chlorophenylcarbamate has been proposed based on the balance between the combined effects from both substituents,230 although the total reason is still not fully known yet. Interestingly, the effects from both the electron-donating methyl and the electron-withdrawing chloro or fluoro appeared to be “reciprocal”. On one hand, although introduction of the 2-methyl group may help for the derivative to maintain a higher order structure through the intramolecular hydrogen bonding, it may reduce its adsorbing power on the NH groups of the carbamate moieties to solutes due to the steric hindrance. In contrast, the introduction of the 5-chloro and fluoro may lead to a disordered structure of the derivative, while it may simultaneously enhance its adsorbing power. Apart from this, considering the structure of the 2,5-disubstituted phenylcarbamate (Figure 29B),236 a higher dipole moment may be directionally induced by the introduction of both the 2-methyl and the 5-halogen onto the aromatic group,237 which may also be involved in the construction of a stereoregular structure for the amylose phenylcarbamate derivatives. This effect of the dipole moment may contribute to the superiority of the 2methyl-5-halogen phenylcarbamates over the 2-methyl derivative. However, the introduction of the 3-methyl and 4-halogen onto the phenyl ring cannot generate this effect. The very poor recognition ability of the 2-nitro derivative (63a) may be ascribed to the rather stiff structure of 63a through the formation of the hydrogen bond between the NH and the 2NO2 groups of the phenylcarbamate (Figure 29C). Some correlations were also observed between the chiral resolution powers of the derivatives and the IR frequencies of the NH groups and 1H NMR chemical shifts of the NH protons of the carbamate moieties.235 These results imply that the chiral recognition ability of the amylose phenylcarbamate derivatives significantly depends on the position, nature, and number of substituents on the carbamate residues, which may influence the higher order structure of the amylose derivatives mainly via intramolecular hydrogen bonding. Much attention has also been paid to the influence of chromatographic conditions on the enantioseparation of various racemates on the polysaccharide-based CSPs from the viewpoint of analytical or preparative separations. Interestingly, the reversal of enantiomer elution order in HPLC was demonstrated depending on not only the column temperature and content of the polar or acidic modifier in eluents under the normal phase but also the chiral selector or composition of eluents under the polar organic mobile phase.238,239 The enantiomer elution order of basic chiral compounds was unexpectedly reversed even by adjusting minor acidic additives under the polar organic mobile phase.240 In addition, the polysaccharide-based CSPs coated on the superficially porous (core−shell) silica was reported recently, and their separation performance was evaluated by CEC.241 With the advantage of

Figure 29. (A) Structures of amylose ortho- or meta-substituted phenylcarbamate derivatives. (B) Structure of 2,5-disubstituted phenylcarbamate. (C) Hydrogen bond between NH and NO2 groups of the phenylcarbamate of 63a.235 1113


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Figure 30. Chiral pharmaceutical compounds resolved by SFC on polysaccharide-based CSPs.246

chiral compounds.27−30,242−246 Some chiral pharmaceutical compounds that have been effectively resolved by SFC on the polysaccharide-based CSPs are shown in Figure 30.246 From the viewpoint of a higher cost efficiency, much faster separation, and convenient removal of solvents compared to those of HPLC, chiral SFC will find much wider applications especially in the field of large-scale preparative separations. Although polysaccharide derivatives are not popular for chiral GC due to the solid state at high temperatures, some enantioseparation attempts using these derivatives have also been reported. Schurig et al. performed the GC enantioseparations based on the per-n-pentylated amylose as a CSP coated on the phenyl-deactivated fused-silica capillary columns in 1989.247 Subsequently, a series of linear carbohydrates was evaluated as the alkylcarbamates and phenylcarbamates. Some alkylcarbamates, such as tris(n-butylcarbamate), show characteristic resolution abilities for some aromatic compounds. The hydrogen bonding, coordination, and inclusion are expected to

faster mass transfer and more uniform particle size distribution allowing faster separations without significant loss in column performance, the core−shell silica appears to be a potential alternative to the totally porous silica as the chromatographic adsorbent for HPLC enantioseparation. 3.2.2. Application of Polysaccharide Derivatives for SFC, GC, CE, CEC, and SMB Separations. In addition to the contribution to the development of HPLC, polysaccharidebased CSPs can also be applied to SFC. As a green technique getting special attention in the past two decades, the implementation of chiral SFC for various enantioseparations, especially for the separation of pharmaceuticals, has experienced a noticeable growth, leading to a big market for optically pure pharmaceuticals.25 In 1988, Tambute et al. accomplished the first chromatographic enantioseparation on polysaccharidebased CSPs by SFC.26 Since then, a substantial number of SFC separations using the polysaccharide-based CSPs have been successfully performed for the resolution of a broad range of 1114


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Table 3. Chiral Drugs Produced by SMB on Polysaccharide-Based CSPs253

Figure 31. Structures of regioselective amylose derivatives as CSPs for HPLC.260

restricted only between the 6 position and the 2 and 3 positions by a protection−deprotection technique at the 6 position.254−256 The selective introduction of different substituents between the 2 and the 3 position had been more difficult for many years mainly due to the similar reactivities between the secondary hydroxy groups at these two positions. On the basis of the method first reported by Dicke,257 the regioselective esterification only at the 2 position of amylose via the reaction with vinyl benzoate in DMSO, the regioselective introduction of different substituents onto each of the 2, 3, and 6 positions has been successfully realized by our group.258 The two obtained amylose derivatives, carrying a benzoate group at the 2 position and different phenylcarbamate groups at the 3 and 6 positions, showed rather different chiral recognitions from those of the derivatives carrying the same substituents at all three positions, and some racemates were better resolved on the regioselective derivatives than those on the commercially available Chiralpak AD consisting of amylose tris(3,5dimethylphenylcarbamate). On the basis of the previous results, the amylose derivatives appear to be more influenced by the substituents at the 2 or 3 position than that at the 6 position, although the mechanism still remains obscure.259 The polysaccharide derivatives bearing different substituents at the three positions must be valuable candidates for elucidating the relationship between the structures of polysaccharide derivatives and their chiral recognition abilities at a molecular level. With the expectation of expanding the family of efficient polysaccharide-based CSPs with high chiral recognition abilities and also of elucidating their chiral recognition mechanism, a class of regioselectively substituted amylose derivatives bearing various benzoate groups at the 2 position and various phenylcarbamate groups at the 3 and 6 positions (Figure 31) have been synthesized by a sequential process based on the selective esterification of the 2 position of the glucose unit,

be the three dominating interactions responsible for the resolution in the chiral GC using polysaccharide-based CSPs. Some miniaturized separation techniques, including CE, CEC, and capillary LC, have also noticeably developed by applying polysaccharide derivatives as CSPs for analytical enantioseparations, and their analytical characteristics have been thoroughly evaluated recently.248−250 The great advantages presented by these miniaturized techniques, including high-throughput and resolution efficiency, rapid analysis, as well as minimal consumption of samples and solvents, make them an attractive alternative to the traditional chromatographic methods for chiral drug analysis. Combined with the high chiral recognition ability of the polysaccharide-based CSPs, these renascent miniscale techniques are now making an indispensable contribution to the recent analytical-scale enantioseparations and analyses of chiral drugs, although some improvements are still in high demand to solve several drawbacks, for example, low sample loading, limited sensitivity related to on-column detection, and so on, for their practical applications.251,252 In recent decades, simulated moving bed (SMB) chromatography, an efficient large-scale separation technique, has gained significance in the pharmaceutical industry due to its higher productivity derived from the efficient utilization of stationary and mobile phases compared to the conventional batchwise chromatography.253 The polysaccharide-based CSPs have often been employed for the large-scale preparative separations of chiral drugs by SMB as shown in Table 3 due to their high chiral recognition and high loading capacity compared to the other types of CSPs.253 3.2.3. CSPs Derived from Cellulose and Amylose Derivatives with Regioselective Substituents. The polysaccharide derivatives usually have the same substituents at three positions on a glucose unit as already described, and the regioselective derivatization of the polysaccharides has been 1115


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Figure 32. (A) Immobilization process of amylose derivative onto silica gel only at the reducing terminal residue.268 (B) Immobilization of cellulose derivatives bearing a vinyl group onto silica gel by radical copolymerization with a vinyl monomer.265,266,271

followed by 3,5-dimethyl- or 3,5-dichloro-phenylcarbamoylation at the 3 and 6 positons.260 Their chiral recognition abilities as the CSPs for HPLC were evaluated by coating them on silica gel. Each amylose derivative had its own characteristic chiral recognition ability depending on the arrangement of the side chains at the three positions. The substituents on the aromatic moieties at each position, especially those at the 2 position, play an important role in the enantioselectivity and the elution orders of the enantiomers. These substituents were expected to change the structure and local polarity of the derivatives. For instance, the chiral recognition abilities of the amylose derivatives 65-(1a−f) significantly varied depending on the substituents of the benzoate at the 2 position, although the derivatives had the same 3,5-dimethylphenylcarbamate group at the 3 and 6 positions. Racemates 66, 68, 70, 72, and 74 were even better resolved on 65-(1a−f) than on Chiralpak AD, one of the most popular CSPs. As for the derivatives 65-(2a−f), the elution orders of some enantiomeric pairs were reversed depending on the benzoate substituents at the 2 position, suggesting that the higher order structures of the derivatives may be changed through the introduction of different substituents at each position. Usually the chiral recognition abilities of the amylose derivatives are subtly influenced by the electronic properties and steric effects of the substituents and also by the higher order structure of the derivatives.230,259 Among the obtained derivatives, the amylose 2-(4-tertbutylbenzoate) and 2-(4-chlorobenzoate) series bearing different phenylcarbamates at the 3 and 6 positions exhibited a relatively higher chiral resolution ability, and most of the examined racemates (66−75) could be resolved on these two CSPs, indicating that the regioselectively substituted amylose

derivatives are practically useful CSPs with a versatility for the enantioseparation. The higher order structures of the amylose derivatives were also investigated by circular dichroism (CD) spectroscopy, supplying a better understanding of the relationship between the structures and the chiral recognition ability of the amylose derivatives. 3.2.4. Immobilization of Polysaccharide Derivatives on Silica Gel. The polysaccharide-based CSPs are usually prepared by coating the polysaccharide derivatives on a macroporous silica gel. The coated-type CSPs have many limitations in the selection of organic solvents (eluents), such as THF, chloroform, ethyl acetate, toluene, acetone, etc., which can damage the packed columns by dissolving or swelling the inside polymer. These solvents often lead to a better solubility of the analytes and a more efficient enantioseparation for both analytical and preparative HPLC. Therefore, the immobilization of the polysaccharide derivatives is highly desired to enhance their solvent durability and versatility as well as resolution efficiency. Several immobilization methods have been so far developed to overcome this drawback, including (1) linkage with diisocyanates, (2) linkage at the reactive terminal, (3) radical polymerization of vinyl groups, (4) photoirradiation, (5) click reaction, and (6) polycondensation of the alkoxysilyl groups,24,261 and as described before, several immobilized CSPs are commercially available.59,199,239,262,263 To exhibit a high chiral recognition, the polysaccharide derivatives are usually required to have a regular helical structure. The phenylcarbamates of polysaccharides possess more regular structures constructed by the intramolecular hydrogen bonds within the polysaccharide chain compared to the benzoates,264 which are more flexible and can change the structure depending on the 1116


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coating conditions as previously described.51,53,203 The variation in the chemical composition of a polysaccharide derivative by the introduction of reactive groups for immobilization often reduces the chiral recognition power as a CSP compared to that of the original polysaccharide derivative. This means that the introduction of the minimum amount of the reactive groups is preferable, if the immobilization can be efficiently attained. Furthermore, the immobilization of the polysaccharide derivatives often impairs their chiral recognition ability, because this makes it difficult for the polysaccharide chain to maintain a regular structure. Therefore, in order to obtain the immobilized-type CSPs with a chiral recognition ability comparable to that of the coated-type phases, the degree of immobilization must be as low as possible.265−267 The immobilization at a reducing terminal of a polysaccharide chain seems to be very attractive since the immobilized CSPs can be prepared with a low number of chemical bonds without significantly disturbing the regularity of the polysaccharide chain, as shown in Figure 32A.268 During this process, an amylose oligomer, maltopentaose, was first oxidized at the reducing end to a lactone, and the obtained oligomer was then extended to a polymer using α-D-glucose 1phosphate dipotassium and potato phosphorylase as the catalyst.269 The amylose with a lactone end was allowed to react with 3-aminopropyl silica gel (A-silica), followed by the reaction with an excess of 3,5-dimethylphenyl isocyanate to covert the hydroxy groups to carbamate residues. The obtained immobilized-type CSP exhibited a chiral recognition analogous to that of the coated-type CSP. However, this method can be applied only to the amylose, and the corresponding cellulosebased CSPs cannot be synthesized by a similar procedure. Immobilization has also been carried out by the radical polymerization of several cellulose and amylose derivatives bearing vinyl groups. The first attempt for this purpose was done in 1993 by Kimata et al., who synthesized cellulose tris(4vinylbenzoate) and coated it on silica gel having acryloyl groups.270 The coated silica gel was then suspended in a solvent and heated with a radical initiator to form an immobilized CSP. Although the obtained CSP could be used with a variety of organic solvents, its chiral recognition ability was low probably due to the existence of too many cross-linkages, disturbing the formation of the regular structure of the cellulose backbone. A more efficient immobilization using a similar strategy was realized by the immobilization of cellulose tris(3,5-dimethylphenylcarbamate) bearing reactive vinyl groups like 4-vinylphenylcarbamate (76) and 2-methacryloylxyethylcarbamate (77) at the 6 position in the presence of inert hydrocarbon monomers such as styrene and 2,3-dimethyl-1,3-butadiene (DMBD) (Figure 32B).265,266,271 The addition of styrene significantly improved the immobilization efficiency of 4vinylphenylcarbamate coated on both A-silica and methacyloyl-functionzalized silica gel (M-silica) through the copolymerization, and the immobilization efficiency on the M-silica was only slightly higher than that on the A-silica, suggesting that the vinyl groups on the M-silica are not the main factor for the immobilization, but the immobilization mainly occurs through the formation of a network among the cellulose derivatives. The immobilization was carried out by heating 76 coated on A-silica gel with a radical initiator, α,α′-azobis(isobutyronitrile) (AIBN) in hexane at 60 °C. While in the absence of styrene, only 50% of 76 coated on the silica gel was immobilized, the addition of 10 wt % styrene of 76 enabled the

almost quantitative immobilization (99%) of 76. Similarly, a high immobilization efficiency (88%) was also obtained by the addition of 10 wt % DMBD of 77 in the radical copolymerization system. The CSPs immobilized with 5−10 wt % of either styrene or DMBD showed efficient chiral resolution abilities, but for some racemates, the enantioselectivities were still lower than those on the coated-type cellulose tris(3,5-dimethylphenylcarbamate). One of the main reasons must be ascribed to the high content of the vinyl groups introduced in these derivatives, which may disturb the stereoregularity of the cellulose main chain. When the content of the DMBD group decreased, the chiral recognition ability of 77 was apparently improved with a slightly lower immobilization efficiency, providing evidence to support the above speculation. Another analogous immobilization by radical polymerization was also performed using cellulose derivatives carrying 10-undecenoyl and 3,5-dimethylphenylcarbamate on allyl silica gel.272−276 In addition, the immobilization of the phenylcarbamates of amylose and chitosan was also investigated by this method.276−279 The photochemical immobilization of polysaccharide derivatives, the 3,5- and 3,4-dichlorophenylcarbamates and 3trifluoromethyl-4-chlorophenylcarbamate of cellulose, was reported by Francotte et al.60,280,281 In this method, the polysaccharide derivatives could be immobilized onto the silica support by UV light exposure in a water−methanol mixture, even though the derivatives did not contain any photopolymerizable groups. The immobilization mechanism has not yet been elucidated, but the cross-linking reaction between the polysaccharide derivatives was expected to occur during the UV irradiation. The immobilized CSPs could resolve a broad range of racemates by selecting a suitable eluent. The cellulose derivatives bearing azido and hydroxy groups have also been immobilized on A-silica gel and γ-glycidoxypropyl-functionalized silica gel (G-silica gel), respectively.282,283 Recently, a more efficient and versatile immobilization method of the 3,5-dimethylphenylcarbamates of cellulose bearing a small amount of a 3-(triethoxysilyl)propyl (R2) residue as a cross-linkable group was developed via the intermolecular polycondensation of the triethoxysilyl groups (Figure 33).267,284 The 3-(triethoxysilyl)propyl group is known to readily polymerize by acid, and base catalyzes to form polysiloxanes. This high reactivity of the alkoxysilyl group can be utilized for immobilizing the polysaccharide derivatives. In 2003, Chen et al. tried to introduce the 3-triethoxysilylpropylcarbamate group using the 3-triethoxysilylpropyl isocyanate

Figure 33. Immobilization of polysaccharide derivative bearing 3(triethoxysilyl)propyl groups onto silica gel through intermolecular polycondensation.267 1117


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Figure 34. Structures of stereochemically interesting catenanes, knots, and C76 resolved on immobilized amylose tris(3,5-dimethylphenylcarbamate), Chiralpak IA.286−289

on cellulose.285 However, the effective immobilization of the cellulose derivatives on silica could not be attained since the actual amount of the 3-triethoxysilylpropyl group introduced to cellulose was much less than the amount necessary to obtain an efficient immobilization. By optimizing the reaction conditions, the above reaction was carried out and the introduction of a controlled small amount of the 3-triethoxysilylpropylcarbamate group to cellulose was successfully achieved by our group.267 By this method, the cellulose derivatives with 1−4% of R2 contents were synthesized. After being coated on the silica gel, the derivatives were immobilized by heating with a mixture of ethanol/water/Si(CH3)3Cl for 10 min at 110 °C (Figure 33). Even a 3% R2 group enabled an almost quantitative immobilization, indicating the much higher reactivity of the 3-triethoxysilylpropyl group for immobilization than the other groups. The chiral recognition abilities of the immobilized-type CSPs having a 1−4% R2 group were similar or slightly lower than that of the coated-type CSPs with the standard eluent consisting of a hexane/2-propanol mixture. From the viewpoint of the preparation of a practically useful immobilized CSP, a compromise has to be maintained between the chiral recognition ability and the immobilization efficiency. The cellulose derivative bearing a 2% R2 group seems to be preferable based on the above-mentioned balance. By using any proportion of polar THF or chloroform in the eluents, which cannot be used with the coated CSPs, the chiral resolution abilities of the immobilized CSPs were improved for many racemates without any damage. The immobilization even by a tiny amount of an R2 group may still change the structure of the cellulose derivative. This method is also suitable for the preparation of the immobilized CSPs based on the amylose phenylcarbamates.267 Compared to the coated-type CSPs from the viewpoint of practical use, the immobilized-type CSPs possess several typical advantages, such as a higher stability of CSPs, versatile eluent selection for analytical and preparative separation, and easy recovery of the chiral recognition ability of the CSPs with some treatment after partial loss of chiral recognition ability. Chiralpak IA and Chiralpak IB were the first immobilized CSPs commercialized from Daicel in 2004.59 The structures of the two CSPs are shown in Figure 24, together with those of

the other four immobilized CSPs, IC, ID, IE, and IF. Among these, IA, IB, and IF had already been commercialized as the coated-type columns, Chiralpak AD, Chiralcel OD, and Chiralpak AZ, respectively, and the other three, Chiralpaks IC, ID, and IE, are available only as the immobilized-type, mainly due to the high solubility of the corresponding polysaccharide derivatives. The valuable merits of the immobilized CSPs significantly expand the range of the resolvable racemates that cannot be separated by the coatedtype CSPs. For instance, some stereochemically interesting catenanes and molecular knots were successfully resolved on the immobilized amylose 3,5-dimethylphenylcarbamate, Chiralpak IA, using a hexane/chloroform/2-propanol mixture, as shown in Figure 34.286−288 The first direct resolution of the smallest chiral fullerene C76 by HPLC was also achieved on this immobilized CSP using a hexane/chloroform (80/20, v/v) mixture as the eluent,289 accompanied by a recycling process to obtain a high enantiomeric purity. As already discussed, the chiral recognition abilities of the immobilized CSPs are often slightly lower than those of the coated CSPs since the regular structures of the polysaccharide chains are more or less disturbed by the incorporation of the different side groups for the immobilization purpose. Nevertheless, this weak point of the immobilized CSPs can often be overcome by the suitable selection of the prohibited eluents, such as chloroform (CHCl3), dichloromethane (CH2Cl2), THF, methyl tert-butyl ether (MtBE), and ethyl acetate (EA) as described below. Figure 35 shows examples of a variety of racemates resolved on the immobilized-type Chiralpak IA, and the eluents used for their resolutions are also included.59,290−310 Most of the eluents cannot be used for the corresponding coated-type CSP, Chiralpak AD, and often realized better resolutions compared to the standard eluents used for the coated-type CSPs. By using the prohibited eluents for the coated CSPs, a number of structurally different compounds could be efficiently resolved on Chiralpaks IB, IC, and ID, and some of them are shown in Figure 36.199,262,263,311−321 In most cases, Chiralpak IB exhibited a lower chiral recognition than its coated-type counterpart, Chiralcel OD, when the typical hexane/alcohol eluents were used.311,312,322 Similarly, after using nonstandard eluents, this problem has been solved. 1118


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Figure 35. Structures of chiral compounds efficiently resolved on Chiralpak IA with various eluents. Reprinted from permission of ref 24. Copyright 2014 Elsevier B.V.

dichlorophenylcarbamate and a small controlled amount of 3(triethoxysilyl)propylcarbamate groups at the 3 and 6 positions were synthesized based on the esterification of the 2 position of a glucose unit (Figure 37).326 The immobilization of the amylose derivatives on the surface of silica gel was then performed via the intermolecular polycondensation of the triethoxysilyl groups as already described. A small amount of 3(triethoxysilyl)propyl residues (2.0% for 79 and 1.6% for 81) was sufficient for the efficient immobilization, and the immobilization efficiency has a significant influence on the chiral recognition abilities of these immobilized CSPs. The 79immobilized (79-IM) and 81-immobilized (81-IM) CSPs showed a high chiral recognition as well as the coated-type

Chiralpaks IC and ID with an electron-withdrawing substituent enhance the possibility of enantioseparation.199 The high stability of the immobilized-type CSPs allows them to be used for the direct analysis of reaction mixtures carried out in the prohibited solvents like dichloromethane.323,324 In addition to the immobilization of the polysaccharide derivatives with the same substituents at the 2, 3, and 6 positions, the efficient immobilization of the regioselectively substituted polysaccharide derivatives has also been performed.325,326 In a continuation of the previous study on the coated-type CSPs for the regioselectively derivatized amylose,260 the amylose derivatives bearing a 4-tert-butylbenzoate or 4-chlorobenzoate group at the 2 position and 3,51119


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Figure 36. Structures of chiral compounds efficiently resolved on Chiralpak IB, Chiralpak IC, and Chiralpak ID with various eluents. Reprinted from permission of ref 24. Copyright 2014 Elsevier B.V.

recognition ability for some racamates compared to Chiralpaks IA, IB, and IC using the hexane/2-propanol (90/10, v/v) mixture as the eluent. Interestingly, 79-IM attained a much more efficient resolution for racemates 68 and 70, which were not efficiently resolved on the three commercial immobilized columns. The separation factor for racemate 70, 2-phenylcyclohexanone, on the 79b-immobilized CSP also appears to be the highest one compared to several commercially available Daicel columns (Table 4).325 The improvement of the chiral recognition and reversed elution orders for some racemates were achieved by the extended use of chloroform or THF with a suitable content, which may be partially attributed to the conformation alteration of the amylose derivatives in these eluents. This method for the immobilization of the CSPs based on the regioselectively substituted amylose derivatives is useful to improve the chiral recognition ability and the solvent compatibility. The 3,5-dimethylphenylcarbamates of cellulose and amylose bearing a small amount of the R2 residue in Figure 33 can also be utilized for the preparation of the spherical hybrid-type CSPs

Figure 37. Structures of amylose derivatives bearing regioselective substituents for immobilized-type CSPs.326

CSPs and can be used with the eluents containing chloroform and THF. The CSPs 79-IM bearing a 4-tert-butylbenzoate group at the 2 position exhibited an equivalent or higher chiral 1120


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Table 4. Separation Factors (α) of Racemic 2-Phenyl Cyclohexanone on Immobilized CPMsa, 78-Coated CPMa and Commercial Columnsb Daicel Chiralcel or Chiralpak OD

AD

OB

OJ

IA

IB

IC

78-coated

79a-IM

79b-IM

1.13

1.03

1.65

1.33

1.06

1.14

1.28

2.15

1.85

2.08

Column: 25 × 0.20 cm (i.d.). Flow rate: 0.1 mL/min. Eluent: hexane/2-propanol = 9/1, v/v. bData taken from refs 260 and 267. Column: 25 × 0.46 cm (i.d.). Flow rate: 0.5 mL/min. Signs in parentheses indicate optical rotation of the first-eluted enantiomer. a

consisting of a nanocomposite of silica gel and the polysaccharide derivatives formed by a sol−gel reaction in an aqueous surfactant solution.327 The CSP is a totally organic− inorganic hybrid material, and the contents of the immobilized polysaccharide derivatives are much higher compared to the CSPs prepared by a coating process. The high content of the polysaccharide derivatives is preferable especially for the preparative separation due to the higher loading capacity of the CSPs. The efficient preparative resolutions of some racemates have been observed on this hybrid CSP. 3.2.5. Structures of Cellulose and Amylose Derivatives. For a polymer-based CSP, a regular structure of the polymer chain is usually required in order to attain an efficient resolution of enantiomers.8,9,22 This is also the case for the polysaccharide-based CSPs. The structural analyses of the cellulose benzoate and phenylcarbamate have been carried out by Zugenmaier based on an X-ray analysis,232,233 and the cellulose trisphenylcarbamate 57c has been shown to possess a left-handed 3/2 helix.264 To gain insight into the detailed mechanism of the chiral recognition on the phenylcarbamate derivatives of cellulose and amylose, several attempts of a structural analysis of the derivatives have been performed using various methods including computer simulation264,328 and NMR spectroscopy.329−333 On the basis of the X-ray structure analysis of 57c, the structure optimizations of the trisphenylcarbamate 57c and tris(3,5-dimethylphenylcarbamate) 57a of cellulose have been performed by molecular mechanics and molecular dynamic calculations, and the results are shown in Figure 38a and 38b.264 Both optimized structures show a similar left-handed 3/2 helix, and the glucose residues are regularly arranged along the helical axis. Around the main chain exists a chiral helical groove with the polar carbamate groups. The polar carbamate groups are preferably located inside, and the hydrophobic aromatic groups are located outside of the polymer chain so that the polar enantiomers can predominantly interact with the carbamate residues in the groove through hydrogen bonds and dipole−dipole interactions, which play a key role in the achievement of the efficient enantioseparations, especially in the normal-phase HPLC with nonpolar eluents.227 Apart from these polar interactions, the π−π interaction between the phenyl moieties of the phenylcarbamate derivatives and the aromatic groups of an enantiomer may also play an essential role in the chiral discrimination, since a class of nonpolar compounds has also been resolved, particularly by reversed-phase HPLC with the polar eluents.334,335 The aromatic rings of 57a show different arrangements from those of 57c, and the three phenyl groups of 57a are stacked on each other. This structural difference may be responsible for the reversed elution orders of some racemates on the 57c and 57a CSPs. The structure of the amylose tris(3,5-dimethylphenylcarbamate) 58a has also been estimated based on the NMR analysis using an amylose derivative with a low degree of polymerization (DP = 100),333 because no useful information is available from

Figure 38. Optimized structures of (a) cellulose phenylcarbamate 57c and 3,5-dimethylphenylcarbamates of (b) cellulose 57a and (c) amylose 58a. Perpendicular to (bottom) and along (top) the helix axis. Reprinted from permission of refs 264 and 333. Copyright 1999 The Chemical Society of Japan and 2002 American Chemical Society.

the X-ray analysis of the amylose derivatives. The amylose derivative 58a is soluble in chloroform, which allowed the investigation of the polymer structure by NMR using the 2D NOESY technique combined with computer modeling. As shown in Figure 38c, the optimized structure of the amylose phenylcarbamate 58a has a left-handed 4/3 helix, and the glucose units are regularly arranged along the helical axis.333 The polar carbamate groups and the hydrophobic aromatic groups are preferably located inside and outside of the polymer chain, respectively. This structure is similar to that of the cellulose analogue 57a. On the other hand, based on the solidstate NMR study, a helical structure with less than 6 folds has also been proposed for the amylose 3,5-dimethylphenylcarbamate 58a.336 Detailed knowledge of the chiral recognition mechanism at a molecular level would allow us to design and prepare a better selector for discriminating any chiral compounds. The chiral recognition mechanism of the small molecular-type CSPs has so far been successfully evaluated.337−343 However, this is not the case for the polymertype selectors, since these chiral polymers often provide too many possible interacting sites for enantiomers and it is difficult to determine their exact structures both in the solid and in solution states. Over the past three decades, some progress regarding the elucidation of the chiral recognition mechanism on the polysaccharide-based CSPs has been achieved by chromatography,56,228,344 NMR spectroscopy,329−333,345,346 Xray diffraction,347 computational simulations,264,328,348 and 1121


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vibrational circular dichroism spectroscopy,349 based on the structures of the derivatives described above. 3.2.6. CSPs Derived from Other Polysaccharides. In addition to cellulose and amylose, other polysaccharides, such as chitin, chitosan, xylan, dextran, etc., have also been used to prepare the CSPs for enantioseparation.52,277,350−356 Among these, the 3,5-dimethylphenylcarbamates of chitosan and xylan exhibited relatively higher recognition abilities for some racemates compared to those on the cellulose and amylose derivatives, implying the potential to develop new CSPs with a high chiral recognition ability. The chitosan possesses a structure similar to that of the cellulose except for the groups at the 2 position: the former has an amino group and the latter a hydroxy group.356,357 The treatment of chitosan with a phenyl isocyanate affords a 3,6-diphenylcarbamates-2-urea derivative (82 in Figure 39).357 This structural difference between the

HPLC resolutions on these coated-type CSPs without immobilizing them on silica gel, leading to much improved resolutions for some racemates. On the basis of this study, a series of 2-, 3-, and 4-substituted and 3,5-disubstituted phenylcarbamate-ureas of chitosan has been prepared.360 These coated-type CSPs exhibited different chiral recognition abilities depending on the position, nature, and number of the substituents introduced on the phenyl group, and the introduction of either an electron-withdrawing or an electrondonating substituent improved the chiral recognition ability of the chitosan-based CSPs. The correlations between the structure and the chiral recognition ability have been systematically discussed on the basis of the 1H NMR and IR spectra. A series of xylan derivatives bearing meta- and parasubstituted phenylcarbamates (84) has also been prepared by the reaction of xylan with various phenyl isocyanates (Figure 40).361 The structure of xylan is similar to that of cellulose

Figure 39. Possible structures of chitosan derivatives.357 Figure 40. Synthesis of xylan derivatives.361

cellulose and the chitosan phenylcarbamate derivatives makes it possible for the chitosan derivatives to show rather different chiral recognition from that of the cellulose derivatives.276,277,350 On the other hand, Nishio et al. reported that different derivatives with biuret A, biuret B, and allophanate groups (83 in Figure 39) were also formed358,359 if an excess phenyl isocyanate was allowed to react with the chitosan. In order to correlate the detailed structures of the chitosan derivatives with their chiral recognition abilities, the reaction of chitosan with an excess of 4-chlorophenyl isocyanate has been carried out from 12 to 384 h, and the structures of the obtained 3,6-diphenylcarbamate-2-urea derivatives were examined in detail.357 From this study, it became clear that at 12 h, both the hydroxy and the amino groups of the chitosan are almost quantitatively converted to 4-chlorophenylcarbamate and urea groups, respectively, and a further continuation of the reaction results in the formation of biuret or allophanate moieties. The derivative having the pure 2-urea and 3,6-diphenylcarbamate moieties exhibited a comparable or higher chiral resolution power for most of the examined racemates than the other derivatives bearing biuret or allophanate groups. The side reactions seem to reduce the chiral recognition of the produced derivatives. As a distinct advantage of the chitosan-based CSPs over the other coated polysaccharide-based CSPs, the eluents containing chloroform or methanol can be applied for the

except for the absence of the hydroxy methylene group at the 6 position.52,350 Again, the chiral recognition abilities of the xylanbased CSPs significantly depended on the nature, position, and number of the substituents on the phenyl moieties. The introduction of an electron-donating group was more desirable than an electron-withdrawing group to improve the chiral recognition ability of the xylan bisphenylcarbamate derivatives. However, the derivatives bearing more polar nitro (84d) or methoxy groups (84i) showed much lower recognition abilities for most of the racemates, revealing the negative effect of the polar substituents on the chiral recognition ability of the xylan phenylcarbamates. Analogous results have also been obtained for the cellulose phenylcarbamates.56 The polar groups located far from the chiral glucose unit must result in the decreased chiral recognition ability of the CSPs due to the strong nonenantioselective interaction with the racemates. This assumption also seems suitable to explain the poor chiral recognition of the xylan derivatives 84d and 84i. Among these derivatives, the xylan 2,3-bis(3,5-dimethylphenylcarbamate) 84k possessed the highest resolving power for many racemates, and the meta-substituted derivatives showed relatively better chiral recognitions than the para-substituted ones. The resolutions for some racemates on the xylan bis(3,51122


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collagen, have poor chiral recognition, while some functional proteins, such as bovine373 or human374 serum albumins, α-acid glycoproteins,375 ovomucoid from the chicken egg whites,376 and avidin,377 and enzymes including cellobiohydrolase I378 and pepsin379 can show high chiral recognitions, and some of these have been commercialized as CSPs. The protein-based CSPs can directly resolve the chiral drugs without derivatization under the reversed-phase conditions using aqueous mobile phases, which is valuable to examine the metabolism of chiral drugs in the body. However, these CSPs also have some shortcomings, such as a low loadability and stability, which makes them only suitable for analytical purposes and not for preparative separation. The retention and enantioselectivity of the racemates on the protein-based CSPs were significantly affected by the chromatographic conditions, including the eluent, column temperature, and pH, which may lead to the alternation of the protein conformation. Some efforts have been performed in order to improve the loadability and stability of the protein-based CSPs. For instance, the stability of the CSPs was enhanced by the cross-linking of the proteins,380 and the loading capacity was improved by using the protein fragment or protein domain,381,382 which includes the chiral recognition sites. The preparation of more suitable protein-based CSPs for a target molecule may be realized by genetic technology in the future. Nucleic acid, DNA, and RNA aptamers have been employed for affinity chromatography. The aptamer can be chemically synthesized within a short time with a good reproducibility and accuracy, and its sequence can be easily modified at precise positions in order to adjust the binding selectivity. A DNA aptamer specifically designed for a target D-peptide (argininevasopressin) was prepared and immobilized on a streptavidin chromatographic support.383 The D-peptide was strongly retained on the obtained CSPs, while the L-peptide was eluted out in the dead volume under the optimal binding conditions. These CSPs were stable in a phosphate buffer containing MgCl2. All of the above results indicate that the DNA aptamers seem to be attractive target-specific chiral selectors for HPLC.

dimethylphenylcarbamate) were even better than those on the well-known cellulose tris(3,5-dimethylphenylcarbamate). The xylan bisphenylcarbamates may have a more flexible structure than the corresponding trisphenylcarbamates of cellulose due to the absence of the carbamate groups at the 6 position, which can make the hydrogen bond with the carbamate groups on a neighboring glucose unit to fix the polymer chain. Therefore, the structures of the xylan phenylcarbamates may be more sensitive to the solvents to be dissolved.361 3.2.7. CSPs Derived from Oligosaccharide Derivatives. Oligosaccharides, such as the linear oligomers of cellulose (cellooligosaccharide) and amylose (maltooligosaccharide),344 and the cyclic oligomers, such as the cyclodextrins (cycloamylose)54,341,344,362−365 and cyclofructans,66,366−372 also possess chiral recognition abilities and can be used as the CSPs for HPLC. The 3,5-dimethylphenylcarbamates of the 4−7-mer linear maltooligosaccharides showed similar resolution abilities to that of amylose tris(3,5-dimethylphenylcarbamate), while the 3,5-dimethylphenylcarbamate of 4-mer cellooligosaccharide showed a lower recognition ability than that of the cellulose tris(3,5-dimethylphenylcarbamate).344 The CD spectra of the 3,5-dimethylphenylcarbamates of 3−7-mer maltooligosaccharides were very similar to that of the same amylose derivative, whereas the CD spectrum of the 3,5-dimethylphenylcarbamate of 4-mer cellooligosaccharide was different from that of the same cellulose derivative. These results suggest that the amylose oligomers more readily have a similar higher order structure to that of the polymer than the cellulose oligomers. The less ordered structures of the cellooligosaccharide derivatives may be associated with their lower chiral recognition abilities. On the other hand, the α-, β-, and γ-cyclodextrins are 6-, 7-, and 8-member cyclic oligomers consisting of an α-1,4glycopyranose unit as well as amylose, respectively, and they are themselves well known to exhibit chiral recognition.54,341,344,362−365 The chiral recognition of the 3,5dimethylphenylcarbamates of the cyclodextrins is rather different from that of amylose tris(3,5-dimethylphenylcarbamate).344 This difference must be due to the very different higher order structures between these derivatives. In many cases, the amylose derivative seems to have superior recognition than the cyclodextrin derivatives. This may be associated with the rigid helical conformation of the amylose derivatives. Armstrong et al. synthesized a series of carbamate or ether derivatives of cyclofructan 6 consisting of six fructose units.66,366 The obtained derivatives were then bonded to the aminopropyl- or epoxy-functionalized silica gel to be used as the chemically bonded CSPs for HPLC. The aliphatic- and aromatic-functionalized cyclofructan derivatives possess quite different chiral resolving powers from that of the native cyclofructan and can resolve a variety of racemic compounds. The substituents of the carbamate or ether moieties had a significant influence on the chiral recognition abilities of the cyclofructan derivatives. The cyclofructan-based CSPs exhibited a high stability and high loading capability, which are desirable for the preparative separation.

3.4. CSPs Derived from Other Methods

3.4.1. CSPs Derived from Molecular Imprinted Polymers. Since Wulff et al. prepared a CSP from the molecular imprinted polymer (MIP) in 1973,36 the molecular imprinting technique has been extensively developed for chiral separation.384−388 The MIPs consist of the highly cross-linked polymer gels bearing chiral cavities and exhibit a chiral recognition ability for the target molecules. The MIP-based gels can be obtained by polymerizing a monomer having a removable chiral template moiety with a cross-linking agent, followed by the removal of the template groups from the polymerized products. Figure 41 shows a typical example of the preparation of the MIP employing 85 as a template monomer and ethylene dimethacrylate as a cross-linker.384,385 The template moiety, the α-D-mannopyranoside derivative (86), was split off by hydrolysis of the gel with H2O or methanol, providing the MIP gel with a selectivity to the template.389 The chiral recognition ability of this gel was significantly influenced by the type and amount of the cross-linker agent. Alternatively, the MIP-based gels can also be prepared by polymerizing a monomer with a cross-linking agent in the presence of a nonpolymerizable template molecule and removing the template. On the basis of this method, Mosbach et al. developed several MIPs using methacrylic acid as a monomer,

3.3. CSPs Derived from Proteins and DNA

In addition to the polysaccharides, proteins are also well known to exhibit chiral recognition abilities. The chiral recognition abilities of the proteins significantly depend on their resources and structures. Most structural proteins, such as wool, silk, and 1123


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assembly of NCC with tetramethoxysilane.417 The synthesis of the inorganic mesoporous materials with both mesoporous structures and inherent chirality is challenging, since their combination usually results in the loss of one of these achievements.422,423 Interestingly, CNMS does not lose its chirality after the removal of the template by calcination. The chiral nematic organization of NCC replicated in CNMS showed a left-handed helical conformation as well as a chiral nanoporous structure generated by the imprinting of cellulose at multiple levels. In addition, some liquid crystalline properties were also observed in CNMS. Yuan et al. first reported the fabrication of a CNMS-coated open tubular column as a CSP for high-resolution GC, as shown in Figure 42.424 The CNMS-coated capillary column

Figure 41. Structures of templates for the molecular imprinted polymers with chiral recognition ability.

ethylene dimethacrylate as a cross-linker, and amino acid derivatives as the templates.390−393 Efficient resolutions of some amino acid derivatives and β-blockers besides the template racemates were attained on these MIP-based CSPs. In particular, a baseline separation of the racemic thimolol (87)392 and an improved separation of naproxen393,394 were also achieved using this kind of gel as the CSPs. Moreover, by directly performing the imprinting polymerization in an HPLC column, a packed column can be prepared without a packing process, and these packed columns also showed chiral recognition abilities.395,396 Increasing interest has been noticed in the design of highly selective catalysts using MIPs, providing more insight into the mechanisms of molecular recognition and catalysis in enzymes.386 A good example was demonstrated by the highly cross-linked MIPs with a high stereoselectivity and catalytic activities, prepared in bulk by a radical polymerization using the stable transition-state analogue as a template, the triamine molecules as the functional monomers, and the ethylene dimethacrylate as a cross-linker in the presence of Cu2+.397,398 The stereoselectivity and catalytic activity of these MIPs significantly depend on the conformation of the active site formed during the imprinting process. The high efficiency and selectivity accompanied by strong chemical, mechanical, and thermal stabilities may enable these MIP-based catalysts to be good alternatives compared to the natural enzymes and may also afford promising CSPs for enantioseparation. 3.4.2. CSPs Derived from Inorganic Elements. Silica gel is a typical inorganic polymer, and its structure control also plays an essential role in the chiral recognition of the polymers. The ordered mesoporous materials have been significantly developed since 1992399,400 due to their potential applications in catalysis,401−404 separation,405,406 sensors,407 etc. Their properties include a large internal surface area and narrow pore size distribution, affording a new class of separation media in chromatography.408−413 On the other hand, the nanocrystalline cellulose (NCC), prepared by the acid hydrolysis of cellulosic materials,414−416 possesses several advantages over cellulose, such as nanometer dimensions, high surface area, high specific strength and modulus, and unique optical activities. These unique properties of NCC make it an attractive potential template for preparing novel ordered porous materials. MacLachlan and co-workers prepared several materials with chiral nematic structures using NCC templates.417−421 Among these, the chiral nematic mesoporous silica (CNMS) has attracted much attention due to its nematic structure, chirality, large pore size, high-temperature resistance, low cost, and facile preparation. As a novel inorganic mesoporous material, CNMS was prepared by the high-temperature calcination of chiral nematic composite films synthesized by the spontaneous self-

Figure 42. Chiral nematic mesoporous silica for capillary gas chromatography. Reprinted from permission of ref 424. Copyright 2014 American Chemical Society.

exhibited not only good chiral recognition abilities for some racemates, including the 2-amino-1-butanol derivative, menthol, and several amino acid derivatives, but also good separation abilities for linear alkanes, aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and some isomers. The chiral discrimination ability of the CNMS-coated CSP mainly depended on the preferred-handed helical porous structure of CNMS, in which the chiral steric fit between the nanoporous structure and the conformation of the analyte enantiomers is the main interactive force.22,193 The long-range chiral nematic ordering phase properties of CNMS also seems important for the efficient recognition of the enantiomers and isomers, since the chiral nematic organization and high surface area of the nanocrystalline cellulose is accurately replicated in the inorganic silica gel.193 In addition, the dispersion, hydrogen-bonding, dipole−dipole, and van der Waals forces may also contribute to the chiral recognition. The CNMS-based column also showed a good stability and reproducibility for the separation, indicating its potential applications in the high-temperature GC as well as the enantioseparation by HPLC. Metal−organic frameworks (MOFs), also called coordination polymers, have been prepared by the association of metal ions (nodes) and multitopic organic ligands (rods). Due to their unique crystalline structures and properties including high thermal and chemical stabilities, a number of chiral MOF materials have been synthesized and exhibited attractive potentials in gas storage,425−428 separation,429−431 catalysis,432−435 etc. Since 2007 when Bryliakov and Fedin reported the pioneering work on the preparation of an optically active three-dimensional porous Zn−organic framework and its application in the resolution of a racemic alkyl aryl sulfoxide 1124


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as a CSP in HPLC,436 significant efforts have been devoted to the development of chiral MOFs for chromatographic separations.437−440 In order to improve the relatively low resolution ability of MOF packed columns, which may be ascribed to the considerable diffusion resistance of the bulky packing, MOF-coated capillary columns were prepared to afford an improved separation efficiency in thin coatings.440 Yuan et al. prepared chiral MOF-coated open tubular columns consisting of a three-dimensional chiral channel framework synthesized by the addition of cupric acetate to N-(2hydroxybenzyl)-L-analine and utilized it as the CSP for highresolution GC after coating on a fused silica open tubular column.441 The obtained MOFs showed high recognition abilities to various racemates, such as aldehydes, ketones, amino acids, and alcohols. The chiral recognition abilities of MOFs mostly depended on the single-handed helical channels on the surface of the crystal MOFs, in which the steric fit between the chiral channel framework and conformation of the enantiomers was the main interactive force, accompanied by the dispersion, hydrogen-bond, and dipole−dipole interaction. Quite recently, Tang et al. reported a noninterpenetrated three-dimensional homochiral MOF, {[ZnLBr]·H2O}n, using enantiopure pyridylfunctionalized salen [(N-(4-pyridylmethyl)-L-leucine·HBr)] as a starting material.442 The obtained MOF exhibited high enantioselectivities for some chiral compounds including 1phenyl-1-propanol, 1-phenylethylamine, benzoin, and some chiral drug like ibuprofen when applied as a CSP for HPLC. This novel MOF material can function as a molecular sieve-like material with a chiral separation function based on the relative sizes of the chiral helical channels and the resolved racemic molecules.

ethanes. Compared to the stereoregular polymers, the irregular polymers often show much lower chiral recognition, clearly indicating that the preferred-handed helical conformation induced by the stereoregular polymer main chain is essential for attaining an effective chiral recognition. Nevertheless, in order to well control the stereochemistry and the higher order structure of various polymers during the polymerization process, more efficient synthetic procedures are still highly demanded. As for the CSPs derived from the naturally occurring polymers, such as the polysaccharides, proteins, and DNAs, the regular helical structures of the polymer backbones endow them with effective recognition abilities. In particular, the CSPs based on the cellulose and amylose derivatives exhibited powerful chiral resolution abilities for a broad range of racemates, and more than 10 polysaccharide-based CSPs have been commercially available for both analytical and preparative scales. Their high chiral recognition abilities as well as their high stability and loadability enable them to be the most popular CSPs applied in not only HPLC but also SFC and SMB. The exact structural analyses of the polysaccharide derivatives with a high ability will provide useful hints to the design of novel chiral synthetic polymers with a high chiral recognition ability. A better understanding of the diastereomeric interactions between the polymer and the enantiomers at a molecular level is also beneficial to further growth in the structural control of the chiral polymers employed in various chirality-related fields. The development of CSPs based on inorganic materials including chiral silica gel and MOF not only enriches the diversity of the CSPs for chiral separation but also opens the possibility to prepare novel functional materials with optical activities.

4. CONCLUSIONS AND OUTLOOK Numerous CSPs derived from optically active synthetic and naturally occurring polymers have been significantly emerging and exhibit attractive properties for the efficient separation of enantiomers over the past several decades. Their superior properties significantly contribute to the advances in the enantioseparation by various techniques, including HPLC, GC, SFC, CE, CEC, membrane, etc. In this review, we summarized these methods, particularly HPLC, using the stereoregular synthetic and natural polymers, as the CSPs. Interestingly, the stereoregularity of the polymers often plays an important role in the chiral recognition abilities of these polymer-based CSPs regardless of whether they are prepared by polymerization or the modification of natural materials. The chiral recognition abilities of the polymethacrylamides are very dependent on their tacticities, which are controlled by the synthetic procedures and influence their higher order structures. The optically active polymethacrylates bearing a bulky side chain, like PTrMA, can form an almost 100% isotactic polymer with a stable one-handed helix, giving rise to high chiral recognition abilities for a variety of racemates, while those bearing a small chiral side chain show almost no chiral recognition ability, implying that the chiral recognition of PTrMA may be attributed to the rigid helical structure accompanying the chiral propeller-like triphenylmethyl group. In addition to the polymethacrylamides and polymethacrylates, close correlations between the tacticity or the higher order structure and the chiral recognition ability can also be observed in the other optically active synthetic polymers, including polystyrenes, polymaleimides, polyacetylenes, polyisocyanides, polyisocyanates, poly(α-amino acid)s, polyamides, and polyur-

AUTHOR INFORMATION Corresponding Author

*Phone: +81-52-753-7292. Fax: +81-52-753-7292. E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Jun Shen received her Bachelor’s degree (1995) from Harbin Architecture University and received her Master’s degree (2002) and Doctorate degree (2006) from the School of Materials Science and Engineering, Harbin Institute of Technology. She joined the College of Materials Science and Chemical Engineering, Harbin Engineering University, as a Lecturer in 2006 and was promoted as Associate Professor in 2007. She spent 1 year (2008−2009) at Nagoya 1125


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CEC HPLC TA JACS LC PC PTrMA n-BuLi (−)-Sp DDB PMP FlLi DP THF D2PyMA PD2PyMA CD DMSO CTA-I SMB MIP NCC CNMS MOF

University with Professor Y. Okamoto as a postdoctoral fellow and another year (2013−2014) at Nagoya University with Professor M. Kamigaito as a visiting Associate Professor. She received the Distinguished Lectureship Award of The Chemical Society of Japan (2011). Her current research concerns the development of novel optically active polymers and enantioseparation by HPLC and asymmetric polymerization.

Yoshio Okamoto received his B.Sc. degree (1964) under Prof. Shunsuke Murahashi and Ph.D. degree (1969) under Prof. Heimei Yuki from the Faculty of Science, Osaka University. In 1969, he joined the Faculty of Engineering Science, Osaka University, as Assistant Professor and spent 2 years (1970−72) at the University of Michigan with Prof. Charles G. Overberger as a postdoctoral fellow. In 1983, he was promoted to Associate Professor, and in 1990 he moved to Nagoya University as Professor. In 2004, he retired from Nagoya University with the title of Professor Emeritus and was appointed as Guest Professor of EcoTopia Science Institute, Nagoya University, until 2009. Since 2009, he has been Distinguished Invited University Professor of Nagoya University. He has also been appointed as Chair Professor of Harbin Engineering University in China since 2007. His research interests include stereocontrol in polymerization reaction, asymmetric polymerization, optically active polymers, and enantioseparation by HPLC. He has received Award of the Society of Polymer Science, Japan (1982), Chemical Society of Japan Award for Technical Development (1991), Chemical Society of Japan Award (1999), Molecular Chirality Award (1999), Chirality Medal (2001), the National Medal with Purple Ribbon (2002), Fujiwara Prize (2005), Thomson Scientific Research Front Award 2007 (2007), SPSJ Award for Outstanding Achievement in Polymer Science and Technology (2009), and The Ryoji Noyori Prize (2010), Charles G. Overberger International Prize in Polymer Science (2011), and The Japan Academy Prize (2014).

capillary electrochromatography high-performance liquid chromatography Tetrahedron: Asymmetry Journal of the American Chemical Society liquid chromatography paper chromatography poly(triphenylmethyl methacrylate) n-butyllithium (−)-sparteine 2,3-dimethoxy-1,4-bis(dimethylamino)butane (+)-(1-pyroridylmethyl)-pyrroridine fluorenyllithium degree of polymerization tetrahydrofuran diphenyl-2-pyridylmethyl methacrylate poly(D2PyMA) circular dichroism dimethyl sulfoxide microcrystalline cellulose triacetate simulated moving bed molecular imprinting polymer nanocrystalline cellulose chiral nematic mesoporous silica metal organic framework

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ACKNOWLEDGMENTS The authors thank all co-workers who significantly contributed to our study. Part of our recent work was supported by the National Natural Science Foundation of China (Nos. 21474024 and 51073046), the Natural Science Foundation of Heilongjiang Province (No. B2015022), the Fundamental Research Funds for the Central Universities (HEUCFT1009, HEUCF20151009), and the Daicel Corp. (Tokyo, Japan). ABBREVIATIONS CSP chiral stationary phase GC gas chromatography SFC supercritical fluid chromatography CE capillary electrophoresis 1126


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NOTE ADDED AFTER ASAP PUBLICATION This paper was published to the Web on September 24, 2015, with an error in Figure 30. This error was corrected in the version published to the Web on October, 2, 2015.

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Efficient Separation of Enantiomers Using Stereoregular Chiral

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