Chem. Rev.2008, 108, 5035–5060 5035 Ionic Liquids: New Targets and Media for r-Amino Acid and Peptide Chemistry Jean-Christophe Plaquevent,*,† Jocelyne Levillain,‡ Frederic Guillen,§ Catherine Malhiac,| and ´ ´ Annie-Claude Gaumont‡ CNRS-UMR 5068, LSPCMIB, Universite Paul Sabatier, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France, Laboratoire de Chimie ´ Moleculaire et Thio-organique, ENSICAEN, Universite de Caen Basse-Normandie, FR CNRS 3038, 6 boulevard du Marechal Juin, F-14050 Caen, ´ ´ ´ France, CNRS-UMR 6014, IRCOF, Universite de Rouen, rue Tesniere, F-76821 Mont-Saint-Aignan Cedex, France, and URCOM, EA 3221 FR ´ ` CNRS 3038, Universite du Havre, 25 rue Ph. Lebon, BP 540, F-76058 Le Havre Cedex, France ´ Received April 13, 2007 Contents 1. Introduction 2. Ionic Liquids from Amino Acid Chemistry 2.1. Without Transformation of the Amino Acid Moiety 2.1.1. Amino Acid as Cationic Part 2.1.2. Amino Acid as Anionic Part 2.2. With Modification of the Side Chain and Preservation of the Amino Acid Moiety 2.3. With Modification of Only One Function 2.3.1. Modification of the Carboxyl Group 2.3.2. Modification of the Amino Group 2.4. With Modification of Both Functions 2.4.1. Imidazoliniums 2.4.2. Oxazoliniums 2.4.3. Thiazoliniums 3. Ionic Liquids for Amino Acid Chemistry 3.1. Catalysis by Means of Amino Acids in ILs 3.1.1. Organocatalysis 3.1.2. Organometallic Catalysis 3.2. Transformations of Amino Acids in Ionic Media 3.2.1. Enzymatic Resolutions and Transformations of Amino Acids 3.2.2. Chemical Transformations of Amino Acids 3.3. Peptide Synthesis in Ionic Media 3.3.1. Enzymatic Peptide Synthesis 3.3.2. Chemical Peptide Synthesis 3.3.3. Supported (or Immobilized) Peptide Synthesis 3.4. ILs and Analysis, Chromatography, and Mass Spectrometry of Amino Acids and Peptides 3.4.1. Extraction and Chromatography 3.4.2. Mass Spectrometry 4. Conclusions and Perspectives 5. Acknowledgments 6. References 5035 5036 5036 5036 5037 5040 5041 5041 5041 5042 5042 5042 5043 5043 5043 5043 5047 5048 5048 5053 5053 5053 5054 5055 5056 5056 5057 5058 5058 5058 1. Introduction Owing to their unique properties, ionic liquids nowadays are very fascinating for chemists in various fields. Besides their potential for green chemistry, mainly due to their low vapor pressure, reexamination of organic synthesis in these new media led to a shining series of convincing examples of increases in chemical yields, chemo-, regio-, and stereoselectivity, as well as recycling of catalysts. Most of these studies have been recently reviewed by prominent scientists in the field.1-7 Beyond this impressive series of successes it can be noted that most organic syntheses can be performed at least with equal efficiency in ionic solvents as in molecular solvents. Nevertheless, a new question emerges: in which chemistry could ionic liquids afford more than an alternative reaction medium? In other words, could ionic solvents be used for doing what is either impossible or extremely difficult in molecular solvents? In this context, two new fields emerge: first, the field of ionic liquids and chirality, including the search for new chiral ionic liquids (CIL) and their use in various applications,8-12 and second, the synthesis and behavior of biomolecules in ionic liquids.13-19 Herein we wish to review the cross-fertilizing topics of R-amino acid/peptide chemistry and that of ionic liquids. Indeed, we assume that these new media could be particularly suitable for amino acid and peptide synthesis or transformations since the polarity of ionic solvents is ideal for such species. Also, it is now well established that enzyme catalysis is remarkably efficient in such media.20 Reciprocally, amino acids represent a powerful class of starting materials for construction of new ionic liquids, especially chiral ones, because of their availability in both enantiomeric forms at a reasonable cost. The scope of the review is thus limited to the chemistry of R-amino acids and their simple derivatives such as amino alcohols, amino esters, N-protected amino acids, and small peptides in relation to ionic liquids. Most of the literature summarized below has only been published during the last few years, emphasizing the novelty of these approaches and the interest of chemists in this new research field. This review has the ambition to give an exhaustive overview of published literature up to 2007. “Amino acids for ionic liquids and ionic solvents for peptide chemistry”: a new emergent paradigm? * To whom correspondence should be addressed. † Universite Paul Sabatier. ´ ‡ Universite de Caen Basse-Normandie. ´ § Universite de Rouen. ´ | Universite du Havre. ´ 10.1021/cr068218c CCC: $71.00 2008 American Chemical Society Published on Web 11/20/2008 5036 Chemical Reviews, 2008, Vol. 108, No. 12 Plaquevent et al. Annie-Claude Gaumont studied chemistry at the University of Rennes (France) and joined the research group of Dr. J. M. Denis, graduating with a Ph.D. in 1991. She had postdoctoral experience as a research associate with Professor J. M. Brown at the University of Oxford. From 1992 to 2000 she was appointed by CNRS at the University of Rennes. Since 2001 she has been Professor in Organic Chemistry at the University of Caen. Her research interests concern the design of phosphorus and sulfur ligands, development of new catalytic reactions for C–P and C-S bond formation, chemistry of phosphine-borane complexes, development of new media such as ionic liquids, and synthesis of analogues of biomolecules bearing a sulfur or phosphorus atom. Jocelyne Levillain was born in Saint-Lo (France) in 1963. She studied ˆ chemistry at the University of Caen and in 1994 completed her Ph.D. thesis under the supervision of Dr. M. Vazeux. After a post-doctoral stay at the Royal College of Surgeon in Ireland with Professors K. Nolan and D. Fitzgerald, she returned to Caen University as “Maıtre de Conferences” ˆ ´ in J. L. Ripoll’s group, working on flash vacuum thermolysis. In 2001 she joined the group of Professor A.-C. Gaumont, where she is now involved in the chemistry of chiral ionic liquids. Frederic Guillen obtained his Ph.D. degree in 1999 from Paris XI University ´ ´ (Orsay, France) working with Professor Jean-Claude Fiaud. He moved to Geneva as a postdoctoral fellow in Professor Alexandre Alexakis group and then back to Orsay with Professor Yves Langlois. He his currently Maıtre de Conference at Rouen University. His research interests focus ˆ ´ on asymmetric synthesis and catalysis and ionic liquids. Catherine Malhiac was born in 1962 in Toulouse. She received her Ph.D. degree in 1993 in the laboratory of organic synthesis (Professor J.-C. Combret, Rouen University). In 1997 she joined the laboratory of organic and macromolecular chemistry of Le Havre University, where she works in the “Interactions and interface in polymeric systems” group. Her research interests now focus on polysaccharides interactions studies, aroma compounds, and chromatographic analysis. 2.1. Without Transformation of the Amino Acid Moiety Amino acids can be straightforwardly used to design chiral anions or chiral cations by deprotonation of the carboxylic acid or protonation of the amino group using a suitable Bronstedt base or acid, respectively. The required properties for the CILs, such as the viscosity or the melting point, can be fine tuned by the choice of the organic or inorganic acid or base as well as by protection of the other functions in the amino acid derivative. Obviously, the chirality arising from the starting material is kept in the ionic liquid. 2. Ionic Liquids from Amino Acid Chemistry There are two main strategies to prepare chiral ionic liquids: asymmetric synthesis or use of a chiral starting material. For both economy and facility, using substrates derived from the chiral pool is the most convenient approach.10,12,25 Numerous groups have selected this methodology to construct either the chiral anion,26 the chiral cation, or both in the ionic liquid (Figure 1). Amino acid derivatives (36%) have been preferred for this purpose over amines and alkaloids (12%), terpenes (16%), and hydroxy acid (12%) derivatives (Figure 2). The CILs can be constructed without modification of the amino acid residue, with modification of the side chain and preservation of the amino acid moiety, with alteration of one function (acidic or basic), or with polyfunctional modification of both amine and acid functions (Figure 3). 2.1.1. Amino Acid as Cationic Part Kou’s group prepared a series of chiral ILs from natural amino acids by a simple atom economic reaction. Protonation by a strong acid (HCl, HNO3, HBF4, CF3COOH, H2SO4) of amino acids 1-6 enables access to the corresponding ionic structures 7-12 (Scheme 1). The thermal stabilities of the ILs 7-12 generally range from ca. 160 to 240 °C, as 2. all are immiscible with chloroform. Table 4). Asn. [emim] showed the best results in anion exchange (Scheme 3.27 To minimize hydrogen bonding and decrease the melting point. can be used in pharmaceutical applications. Solubility and miscibility of the new ILs depend on the side chain of the amino acid. No. determined by thermogravimetric analysis (TGA) experiments (Table 1). France. The thermal stabilities determined for 20 ionic liquids [AAE][NO3] and [AAE][sac] range from 150 to 230 °C (under N2). and acetone and immiscible with ethyl acetate. Source of chirality for CILs published from 1999 to 2006. Thermal properties of salts 70-73 were fully studied. pyrrolidinium. alanine salts with different cations (tetraalkylammonium. These new salts are miscible with water. and hexane. these new ILs 41-47 having one of these two anions associated to a cationic amino acid ester [AAE] were termed “fully green” ionic liquids. Kou prepared a variety of alkyl amino acid ester salts from the hydrochloride parents (Scheme 2). They all showed a glass transition at temperatures ranging from -70 to -40 °C (Table 5). Glasstransition temperatures ranging from -65 to 6 °C were measured. Each new chiral IL has a solid-solid transition temperature. Eschenmoser at ETH Zurich and at Rouen University where he studied molecular biology ¨ with Dr. His research interests focus on asymmetric synthesis. Gln. 2008. Asp. and Glu have low ionic conductivities. resulting from strong hydrogen bonding due to the carboxylic group. The authors report physical properties such as optical rotations and densities (from 1. all of them are immiscible with ether and miscible with methanol or acetonitrile. He recently moved to Toulouse. from amino acids). 108. for seven of them the melting point is below 0 °C (Table 2). salt 73 with a phosphonium cation displays a decomposition temperature 120 °C higher than the corresponding ammonium salts. the less toxic [NO3] anion and the saccharinate anion. pink. The authors therefore extended their study to a library of amino acid ionic liquids having a tetrabutylphosphonium cation [TBP] (Scheme 4) and compared the effect of the phosphonium and ammonium groups on the physicochem- Figure 1. ILs with anions containing functionalized side chains derived from Arg. benzene. Among the cations. It is worth noting the acidity of compound 29a for which a 1 M aqueous solution has a pH value of 3. which is a well-known food additive. except for salts 29g and 30g which decompose at 77 and 82 °C. Duhamel. Except for [emim][Cys]. and ionic liquid methodologies.5. amino acid and peptide chemistry. Most of the salts have high melting points as determined by differential thermal analysis (DTA). where he is still employed by CNRS. Use of an anion-exchange resin gave access to the imidazolium hydroxide salt that was used to neutralize a variety of amino acids. In 1977 he joined the CNRS at Rouen University. and P.02 to 1.Ionic Liquids Chemical Reviews. Conductivity studies showed in most cases a linear correlation with Tg measurements. 2. and all [AAE][sac] are liquid at room temperature with mp below 8 °C (Table 3). Figure 2. High viscosities are observed in particular for compound 30a and 32 (Table 2).72 g · cm-1 as determined at 20 °C. Interestingly. Esterification of the acidic function proved to increase the biodegradability of the CILs. Nevertheless.29 These CILs are liquid at room temperature. All salts have . prepared a library of 20 ionic liquids from imidazolium bromide salt 48. the new CILs are stable up to 200 °C. They can dissolve their parent amino acid (as an example [emim][Val] dissolves 2% of (S)-valine at 25 °C). Except for salt 31 and proline derivatives 38-40. Trp. Among the anions. Vol.28 Salts 41-47 have high viscosities due to the presence of the saccharinate anion (Table 3). which decomposes at 173 °C. One-half of them have negative melting points as determined by DSC. When they contain an acidic side chain (Glu. Amino Acid as Anionic Part Ohno et al. Vaudry. To extend the methodology. Optical rotation is given for each salt. chirality arising from all sources. and their density ranges from 1. He had postdoctoral experiences as a research associate with Professor A. pharmaceutical compounds. His.15 to 1. respectively. New series of CILs published from 1999 to 2006 (blue. H. Asp) they are immiscible with chloroform. showing weak Bronsted acidity. Salts 27-40 are heat stable over 139 °C. melting points lower than 105 °C.86 g · cm-1 at 20 °C) but give no yield except for compound 12b (100%). tetraalkylphosphonium) were also investigated and compared to [emim] salt 51. where he completed his thesis in 1980 in the laboratory of L. However. ether.1. 12 5037 Jean-Christophe Plaquevent was born in 1953 in Normandy. ethanol. Accordingly.30 No yield was given for the synthesis. ical properties in the [TBP][AA] and [emim][AA] ILs.22 1.5038 Chemical Reviews. respectively. The new CILs thus prepared are thermally stable up to 237 °C. [TBP][AA] ILs present a linear relationship between viscosity and Tg as already observed in [emim][AA] ILs (Table 6). and Density of Compounds 7-12 AA 1Gly 1Gly 1Gly 1Gly 2Ala 2Ala 2Ala 2Ala 2Ala 3Val 4 Ile 5Thr 6 Pro 6 Pro 6 Pro 6 Pro 6 Pro compd 7a 7b 7c 7d 8b 8c 8d 8e 8f 9 10 11 12bc 12c 12d 12e 12f X Cl NO3 BF4 PF6 NO3 BF4 PF6 TFA 1/2SO4 NO3 NO3 NO3 NO3 BF4 PF6 TFA 1/2SO4 Tm/°Ca 186 111 116 101 159 78 d 82 141 134 105 d -18d 76 d 78 92 Tdec/°Cb 195 192 220 157 168 241 176 119 193 169 167 147 138 236 168 192 206 d420/g · cm-1 ((5%) 1. No.05 1. Compounds based on leucine.02 1.56 1. Five of them are liquid at room temperature with glass-transition temperatures ranging from -69 to -37 °C (Table 7). while the phosphoniums are less hydrophilic. Decomposition Temperature (Tdec). (Glass-transition temperature Tg ) -45 °C.63 1. thermal decomposition of phosphonium ILs occurred at higher temperature (292 °C for [TBP][Leu] 77 compared to 220 °C for [emim][Leu] 55).51 1. Ohno’s group then modified the structure of the amino acid anion to gain access to hydrophobic ionic liquids. c Physical properties of 12b were described in ref 28. 108.37 1. Melting Point (Tm). Vol.26 1. showing lower glass-transition tem- peratures than their ammonium congeners. valine. These phosphonium salts display lower viscosities and are liquid at room temperature. b Determined by TGA.40 1.) d No melting point observed. Main strategies for the synthesis of CILs starting from amino acids. While alanine salt is slightly miscible with . All [TBP] ILs were shown to be halogen free. and alanine without functionalization on the side chain were prepared and combined with [TBP][OH] or [bmim][OH]. Figure 3.30 As expected. 12 Plaquevent et al.33 1.48 1. Hydrophobicity strongly depends on the structure of the amino acid derivatives.86 1.55 1. Viscosity ) 5140 ( 3% cP at 30 °C. Scheme 1 Scheme 2 Table 1.58 Scheme 3 a Determined by DTA.31. The [bmim] salts are soluble in water.44 1.38 1.06 1.32 Introduction of a trifluoromethanesulfonyl group on the amino group together with esterification of the acid moiety afforded the expected hydrophobic amino acid derivatives (Scheme 5). 2008. Tg. 12 5039 d420/g · cm-1 ((5%) 1.N-triethylammonium N.0 × 10-8 3. Tdec).0 × 10-7 1.0 × 10-5 9.36 1. η ) 749 cP) and 113 (Tg ) -32.31 1.e Tdec/°Cb 178 182 186 230 209 150 139 172 77 187 82 195 210 172 224 156 179 159 234 221 140 183 208c 163c viscosity/ cP(°C) 92 (70 °C) 96 (30 °C) 103 (80 °C) 2030 (30 °C) 1550 (80 °C) 84 87 79 83 85 89 88 yieldc (%) 88 93 186 (30 °C) 398 (30 °C)c 275 (30 °C)c 90 87 89 a Determined by DSC (differential scanning calorimetry).N.1 × 10-9 1. η) 4913 cP).5 × 10-5 9. all new salts are liquid at room temperature.53 1.34 The guanidinium salts 112-113 were prepared by simple anion Determined by DSC.35 1. No.0 × 10-7 4.72 1.0 × 10-4 6.15 1.22 1. Thermal Properties (Tm.29 1. Table 3.8 × 10-5 1. b Data cited from ref 29.7 °C.53 1. Tdec) of Alanine Derivatives 51 and 70-73 compd 51 70 71 72 73 a cation ethylmethylimidazolium N-hexyl.1 wt % water). prepared a series of 15 CILs starting from [TBA][OH] and natural amino acids (Scheme 6).26 1. . determined by DSC.9 × 10-5 8.67 1. for leucine salt a water content of only 2.8 × 10-5 6. and chloroform and immiscible with ether. Following the same concept.N. and Yields of ILs 41-47 Table 4.7 × 10 6.1 × 10-6 1. Tg. Ionic Conductivity (σi).1 × 10-5 6.Ionic Liquids Chemical Reviews.19 1.N. Tdec).5 × 10-4 7.d -11d Tg/°Ca -26 -10 -34 -48e -35 -61e -38 -23 -24 -45e -29 -33 -31 -36e -32 -32e -30 -67e -20 -22 -20 -50e -71c.33 Apart from [TBA][Asn] 100.07 to 0. nd: not detected.57 Table 2. which has a melting point of 42-44 °C.4 × 10-4 2. Thermal Properties (Tm. and Yield in [emim][AA] compd 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 a AA Gly Ala Met Val Ile Leu Ser Lys Thr Phe Trp His Tyr Cys Arg Asn Gln Asp Glu Pro Tg/°Ca -65 -57 -57 -52 -52 -51 -49 -47 -40 -36 -31 -24 -23 -19 -18 -16 -12 5 6 -48 σi (S/cm) at 25 °C 5.7 × 10-7 1.6 × 10-4 -4 yield (%) 82 86 78 79 82 80 79 78 84 83 82 78 70 77 74 89 66 89 80 83 compd 41 42 43 44 45 46 47 AA Ala Val Leu Ile Thr Pro Pro R2 Me Me Me Me Me Me Et Tm/°Ca -14 -16 7 7 -1 -19 8 Tg/°Cb -27 -29 -1 -8 -9 -29 -42 Tdec/°C 184 185 223 177 200 190 212 viscosity /cP(80 °C) 1380 3040 1050 14500 55 900 3320 3020c yield (%) 89 79 87 78 69 92 88 a No melting transition or solid-liquid transition observed. b Determined by TGA.9 wt % was measured by Karl Fischer titration. they are liquid at room temperature. dichloromethane. Glass-transition temperature and viscosity at 25 °C were determined for 112 (Tg ) -37.N-tetrabutylammonium N-butyl. Glass Transition (Tg).0 × 10-7 1.27 1. Tg. hexane. Maschmeyer et al. e Solid-solid transition temperature. water (ionic phase containing 5. N-methylpyrrolidinium tetrabutylphosphonium Tm/°Ca Tg/°Ca Tdec/°C nd nd 76 77 nd -57b -40 nd -64 -70 212 150 162 176 286 Determined by DSC. exchange and are thermally stable up to 220 °C.55 1. determined by DSC. b Solid-solid transition temperature.20 1. and toluene. N.50 1.47 1. d No melting point or solid-liquid transition temperature observed. They are miscible with water.4 × 10-4 8. Thermal Properties (Tm. 108. Density.45 1. c Data cited from ref 28. Vol. 2008.44 1.e -70c.7 × 10-9 5. acetonitrile. N-protected alanine and hydroxyproline were combined with an original guanidinium cation (Scheme 7). No decomposition was observed after 24 h at 110 °C.16 1. Viscosities.5 °C. and Yields of Compounds 27-40 precursor 13 14 15 15 15 15 15 15 15 16 16 17 18 19 20 21 22 23 23 23 23 24 25 26 AA Gly Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Leu Ile Phe Thr Ser Pro Pro Pro Pro Pro Pro Pro R2 Me Et Me Me Me Me Me Me Me Et Et Me Me Me Me Me Me Me Me Me Me Et Pr nBu compd 27 28 29a 29b 29c 29d 29e 29f 29g 30a 30g 31 32 33 34 35 36 37a 37b 37c 37g 38 39 40 Y NO3 NO3 NO3 BF4 PF6 NTf2 SCN AcO Lac NO3 Lac NO3 NO3 NO3 NO3 NO3 NO3 NO3 BF4 PF6 Lac NO3 NO3 NO3 Tm/°Ca 44 49 61 18d d -17d 62 d 38 -17d 75 74 75 -14d 92 -12d 105 -16d d d d -17d 6c. Table 5.66 ppm for the R-CH proton of the TBA carboxylate salt compared to the parent amino acid (Table 8). c Measured at 50 °C. NMR analysis showed an upfield shift from 0. acetone. Viscosity. provides a chiral bifunctional imidazolium salt whose anion can be subsequently exchanged if needed to adjust the physical and chemical properties of the salt.δ of R-CH (starting amino acid) Scheme 7 Determined by DSC. b Solid or glass at 25 °C. nd: not detected.38 (90 Hz) 0.to give the desired salts 122-124 either as liquids or waxy.1 30.32-0.5 (150 Hz) 0.07 (21 Hz) 0.5 -3.0 -25. For this purpose. Tdec) and Viscosities of Phosphonium Amino Acid Ionic Liquids 75-93 compd 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 a AA (S)-Ala (S)-His (S)-Met (S)-Asn N-Ac-(R)-Cys (S)-HGlu (R)-HGlu 0.5 -56.5 (S)-Glu 0. nd: not detected.4 nd 8.9 Tg/°Ca -63.8 -57.6 30.49 (147 Hz) 0.9 nd Tdec/°C 217 293 292 294 243 286 277 314 223 288 286 316 311 319 190 246 294 224 299 viscosity/ cP(25 °C) 371 415 389 605 902 423 779 851 965 927 b b b b 3029 7437(50°C) b b b 71 98 99 100 101 102 103 104 105 106 107 108 109 110 111 a 0. Tdec) and Viscosities of Salts 95-96 anion derived from Ala Val Leu Ala Val Leu viscosity/ cP(25 °C) 520 3080 4180 700 nd 2130 compd 95a 95b 95c 96a 96b 96c a cation bmim bmim bmim TBP TBP TBP Tm/°Ca nd nd nd nd 61. low-melting solids (Scheme 9).53 (159 Hz) 0.45 (135 Hz) 0.53 (159 Hz) 0.7 nd nd nd 83.1 -36. Thermal Properties (Tm. Scheme 5 Table 7.2 nd Tdec/°C 260 253 237 253 277 264 Determined by DSC.6 -6.0 85.7 -7. Alkylation of both imidazole nitrogen atoms.5040 Chemical Reviews. the most convergent starting material for synthesis of an amino acid based imidazolium IL is (S)histidine which bears a 4-substituted imidazole ring.7 nd nd 101.0 nd 25.0 nd nd 26.1 -58.53-0.5 -63. while leaving the amino and carboxyl groups untouched. With Modification of the Side Chain and Preservation of the Amino Acid Moiety Even though direct reaction with a suitable acid or base is the simplest and fastest way to obtain an ionic liquid from an amino acid.0 -69.7 -63. No.36 (108 Hz) 0.35 Introduction of two different alkyl groups can also be performed by selective protection of one ring nitrogen. Simultaneous protection of the amino group and the N-2 ring nitrogen atom via a cyclic urea allowed selective alkylation of O-protected histidine at the N-1 position: opening of the cyclic urea by an alcohol followed by a subsequent alkylation gave the fully protected unsymmetrical imidazolium salt. Therefore. but retaining the structural integrity of the amino acid.8 Tg/°Ca -62. 2.35 Except for 119 (mp ) 198 °C). Hannig et al.63 (159-189 Hz) 0.3 -20. reported the alkylation of bis-protected PGHis-OMe (PG. these salts are liquids with melting points in the 40-55 °C range (Table 9).5 -54. Bz or Boc) with n-propyl bromide to give the corresponding “symmetrical” imidazolium bromide (Scheme 8). 108.2 13.55 (165 Hz) δ of R-CH (CIL). They have been used as chiral carbene precursors in palladium complexes.63 (159-189 Hz) 0.5 (R)-Glu Gly (S)-Phe (S)-Pro (S)-Ser (S)-Thr (S)-Val yield (%) 98 85 86 74 99 96 99 94 97 93 95 97 88 91 85 ∆δ a in ppm (Hz) amino acid Met Gly Leu Ile Ser Val Lys Pro Thr Phe Arg Trp Gln Glu Cys Asp Tyr Asn His Tm/°Ca nd 13.9 -59.07 (21 Hz) 0.7 -59.4 -60. Thermal Properties (Tm.0 -23. .8 -42.36 The halide anion was then exchanged with PF6-. the resulting materials suffer from an obvious sensitivity to pH conditions.66 (198 Hz) 0. Tg. have been devised. Table 8.5 (150 Hz) 0. BF4-. or NTf2.1 -53.2. 12 Scheme 4 Scheme 6 Plaquevent et al. more sophisticated structures involving nonprotonated cations and weakly basic anions.4 -37.53-0.6 -25. 2008.44 (132 Hz) 0. Yields and ∆δ for the r-CH in 1H NMR compd Table 6. Tg. Vol. X ) BF4). Pro). 12 5041 Table 9. Scheme 9 Similar procedures were used to prepare pyrrolidine salts with a modified imidazolium core using 2-methylimidazole and/or bromoethanol (Scheme 11). They were successfully employed as chiral additives in the asymmetric Michael reaction between cyclohexanone and trans-β-nitrostyrene (25-100% yield with ees between 77% and 99%). They are moderately miscible with polar solvents (chloroform. Val.1. 4 salts among the 15 are reported to be solid (R ) tBu. the new salts 139c-143c have melting points ranging from 6 to 73 °C. Interestingly. alkylation by nBuBr and metathesis by NaPF6 or NaBF4 afforded the new pyrrolidine imidazolium ionic liquids 128-129 (Scheme 10).Ionic Liquids Scheme 8 Chemical Reviews.3. Modification of the Amino Group In 2003 Bao’s group reported the synthesis of chiral ionic liquids derived from natural amino acids (valine. R ) iBu. and good chemical stability toward water. 2.3. while the others are viscous oils (Table 11). Melting Points and Yields of Salts 116-119 compd 116 117 118 119 a PG Bz Bz Boc Boc X I Br I Br R iPr nPr iPr nPr Tm/°Ca 55 39 55 198 yield (%) 95 72 69 92 Determined by DSC.3). Leu. Substitution by the imidazole anion led to the pyrrolidine imidazole 126 in 83% yield.3. Then. Modification of the Carboxyl Group Cheng’s group prepared pyrrolidine chiral ionic liquids in 45% yield starting from (S)-proline.39 Reduction of the amino acid with NaBH4/I2 followed by bromination with PBr3 led to chiral compounds 135-138 with yields higher than 76%. and hexane. 2. A very similar methodology was used for the synthesis of chiral di-imidazolium molecular tweezers. Luo et al. or (CF3SO2)2NLi in H2O (Scheme 15).41 UV spectrometric titration experiments showed that these chiral diimidazolium receptors exhibit excellent enantioselective recognition toward (S). KPF6 in H2O.and C-terminal positions (see section 3. and acetone and immiscible with ether and 1. enantioselectivity. If anion exchange is performed with KPF6.and (R)-amino acid derivatives in water or acetonitrile. Anion exchange with AgBF4 gave access to roomtemperature ionic liquids 139b-143b that have no melting point but a glass-transition temperature ranging from -49 to -35 °C (Table 10). and syn/anti diastereoselectivity. methanol) and immiscible with diethyl ether. ethyl acetate. Most of these salts are viscous liquids at room temperature.40 Condensation of amino acids with aldehydes under basic conditions enabled formation of the imidazole ring. thermal stability up to 180 °C. imidazolium salts 160-164 are transformed into ionic liquids 165-179 by anion exchange with KBF4 in MeOH-H2O. With Modification of Only One Function In order to gain access to more structurally diverse ionic liquids. methanol. and the ionic amino acid can undergo peptide-coupling reactions at both the N. 2. . alanine. X ) Br or BF4. These new ILs are thermally stable up to 210 °C.42 Condensation of a natural chiral amino alcohol with 1-methyl-2-imidazolecarboxaldehyde 156 is followed by two steps: reduction of the imine by sodium borohydride and then alkylation by bromobutane. the melting point of the salt having the “reversed” substitution pattern (with X ) NTf2) is much lower (-37 °C) than that for the isomeric 1-methyl-3-butylsubstituted one (46 °C).3. 108. which was then easily alkylated using ethyl bromide (Scheme 13). The salts have low melting points ranging from 5 to 16 °C. Vol. starting from (S)-alanine and (S)-phenylalanine (Scheme 14). Although no melting point or glass temperature was reported. The bromide and tetrafluoroborate salts performed the reaction much better than (S)-proline itself in ionic liquid in terms of yields. No.1. prepared chiral imidazolium salts 139-143 starting from natural amino acids (Ala. They are miscible with water. Ile.38 Reduction with LiAlH4 in tetrahydrofuran followed by N-Boc protection and tosylation in pyridine led to tosyl intermediate 125 in 68% yield. one can use either the amino or the carboxyl function of the amino acid as precursor to build the anionic or cationic part of the salt. Then. Alkylation with methylimidazole and then neutralization with NaOH gave the bromide salts 139a-143a in excellent yields (over 92%) (Scheme 12).1trichloroethane. Chirality on the side chain of the C2 atom of the imidazolium core was first proposed by Li and Headley’s team. 2008. The ionic liquid moiety acts as a phase tag for recycling the catalyst and an efficient chiral inductor group to ensure high selectivity. leucine) by modification of the amino group.2. Esterification followed by reduction led to the corresponding alcohol. The 1-butyl-3-methyl-substituted histidine-derived salt can be obtained by reversing the order of the alkylation steps. dichloromethane.37 Both residual functions can then be selectively deprotected. 1. it was demonstrated that only SnAr occurs instead of the expected Zincke process (Scheme 16).4. Several groups have selected this strategy. Dichloromethane solutions of the salts were washed several times with neutral or acidic water without degradation. The polarity of one compound was determined using a solvatochromic dye (DAPNE) as a probe. Both a hydroxyl group and a bulky group (tBu) are crucial for good separation of the diastereomeric methoxy and CF3 group NMR signals.2. prepared oxazolinium salts from (S)valinol. Oxazoliniums Wasserscheid et al.4. Vol. An interesting approach to a new class of reversible ILs was presented by the Weiss group. while treatment with KPF6 gave salts with high melting points (>168 °C) (Table 11. which after deprotection and reduction gave the corresponding diamine 216. 2008. 12 Scheme 10 Plaquevent et al. Anion exchange was done by treatment of the iodide salt with potassium tetrafluoroborate in methanol/water and potassium hexafluorophosphate or (CF3SO2)2NLi in water (Scheme 17. but the system tolerates the presence of 10% water. reported the use of N-methylimidazole as a starting material to react with 1-chloro-2. but loss of CO2 gas was important above room temperature under nitrogen or air. Imidazoliniums Imidazolinium-based ILs were prepared from natural amino acid N-Boc-(S)-valine 215. all of these compounds were liquid at room temperature. Diastereomeric interactions with racemic Mosher acid salt were proved by 1H and 19F NMR spectroscopy. oxazolinium. 2. Anion exchange with PF6 anion led to solid salts. However. The produced ILs returned to their initial state when exposed to nitrogen atmosphere (Scheme 18).48 After alkylation by an alkyl bromide and then metathesis with HPF6 the new oxazolinium salts 224-225 were obtained in ca. Then (S)-amino alcohols were engaged with 189 in a Zincke-type reaction. 2. With Modification of Both Functions The last option to design ionic liquids from chiral amino acids is to use both the amino and the carboxylic functions to build the cationic moiety. A yield of 96% in 1-(2. five imidazolinium ionic liquids 218-222 were prepared (Scheme 20).47 Reaction between the protected amino acid and tBu-aniline afforded the amide.4-dinitrophenyl)-3-methylimidazolium chloride 189 was achieved.44b Indeed. the original paper was recently retracted. These new salts were reported to be unstable in aqueous medium. acid treatment led to rapid loss of CO2 from the carbamic acid. while NTf2 anion gave a liquid one. Scheme 15). which were then methylated with excellent overall yields (>95%). The amino alcohols 157-159 when treated by tosylchloride led to a bis-tosylate intermediate that underwent a ringclosure reaction on heating. it was recently demonstrated by Genisson and co-workers that this study is ´ erroneous.43 Exchange of the tosylate anion in 180-182 by treatment with (CF3SO2)2NLi in H2O gave salts 183-185 that are liquid at room temperature. Except for tyrosine derivatives. Alkylation of the ring followed by metathesis leads to the new chiral ionic liquid (Scheme 19). The imidazoline cycle was then obtained after formation of the hydrochloride derivative followed by condensation with triethylorthoformate. Thus. After alkylation and anion exchange. Table 12).46 Exposure to 1 atm of CO2 gas for less than 15 min of an equimolar mixture of substituted acetamidine and various amino acid methyl esters led to amidinium carbamates with excellent conversion. No. Synthesis of compounds 214 was performed 2. Ou et al.4-dinitrobenzene.5-hydrogenated five-membered heterocycles. leading to ring opening.4. 108. allowing synthesis of salts having imidazolinium.45 Treatment of aminopropylimidazole with isocyanates 200-202 afforded the urea derivatives. The amidinium carbamates are thermally stable up to 50 °C under CO2 atmosphere. . Condensation of (S)-valinol with propionic acid in xylene led to the oxazoline 223. The authors claimed that chiral imidazolium ionic liquids 190-198 were obtained in good yields.44a However.5042 Chemical Reviews. 90% yield (Scheme 21). or thiazolinium cations. Most of these ILs are described as yellow oils. The strategy is similar whatever the cation: the two functions of the amino acid precursors are engaged in a series of reactions to form the 4. Isocyanate derivatives of amino acids were also used as precursors of a new family of chiral imidazolium ionic liquids. Scheme 11 under dry conditions. entry 2). are excellent solvents for dissolving very polar molecules such as amino acids and small peptides among other biomolecules that are beyond the scope of this review.37. The best splitting of the two diastereomeric signals was observed with salt 232 and the racemic Mosher acid potassium salt. 3. These salts were found to generate diastereomeric interactions in 1H and 19F NMR with various racemic Mosher acid salts. All examples reported in section 2 show the prominence of amino acids in the preparation of chiral ionic liquids. 108. The new salts display interesting physical properties like thermal stability (higher than 170 °C). cyclohexanone and cyclopentanone behave quite differently in this reaction: whereas reaction of cyclohexanone with p-trifluoromethylbenzaldehyde in the presence of proline in [bmim][PF6] gives almost pure anti diastereomer with high enantiopurity (de > 20:1. However. respectively. which are very polar aprotic solvents. 12 5043 Table 10.53. entries 4-7). conjugate additions. are the media of choice for the chemistry involving amino acids and their derivatives. Thus. Numerous ionic liquids. because of their unique properties. 2008. with the iodide salt. Most of these alternative solvents are immiscible with water. Thiazoliniums Since 2003 thiazolinium salts were prepared by some of us. Ionic Liquids for Amino Acid Chemistry Tdec/°Cb 226 261 218 270 281 287 267 291 287 268 285 281 257 291 274 derived from Ala Ala Ala Val Val Val Leu Leu Leu Ile Ile Ile Pro Pro Pro anion Br BF4 PF6 Br BF4 PF6 Br BF4 PF6 Br BF4 PF6 Br BF4 PF6 Tm or Tg/°Ca 131 (Tm) -46 (Tg) 6 (Tm) 145 (Tm) -49 (Tg) 38 (Tm) 134 (Tm) -47 (Tg) 69 (Tm) 135 (Tm) -35 (Tg) 73 (Tm) 141 (Tm) -45 (Tg) 67 (Tm) Ionic liquids. Reaction of aldehydes with 1-chloropropanone in [emim][OTf] in the presence of proline regioselectively produces chlorohydrins that can be converted to the corresponding epoxides by reaction with NEt3 in [emim][OTf] (Scheme 23). similar to those obtained in molecular solvents (Table 14. Vol. and Knoevenagel reactions. Since they are readily soluble in ionic liquids. entries 9-20). melting points ranging from 42 to 175 °C for iodide. Up to three recyclings were carried out without significant loss of yield or ee (Table 14.55 . and NTf2 thiazolinium salts remain intact after these treatments. These aspects are discussed in the following part of the review. unlike polar molecular solvents that are able to dissolve unprotected amino acids. The amount of catalyst could be as low as 1% with only a small decrease of the yield. Thermal Properties of Salts 139a-143c compd 139a 139b 139c 140a 140b 140c 141a 141b 141c 142a 142b 142c 143a 143b 143c a 3. Determined by DSC. cyclopentanone gives a 1:1 syn/anti mixture (anti 32% ee. aminoxylations. syn 86% ee). ee 93%). The proline-catalyzed aldolization reaction in ionic liquids was first reported in 2002 independently by Loh et al. In most cases an elimination product was also observed: when [omim][Cl] is used as solvent. (S)-phenylalaninol 227) to give the hydroxythioamide intermediate. No ring opening was observed upon treatment with water (neutral.1.1. the enone is the major product (Table 14. basic. Classical alkylation with different alkyl iodides followed by anion exchange (BF4.Ionic Liquids Scheme 12 Chemical Reviews. Mannich reactions. The proline-[bmim][PF6] system was also successfully evaluated with other aldehydes (Table 14. No. PF6. and glasstransition temperatures ranging from -68 to -40 °C for NTf2 derivatives as measured by DSC (Table 13). b Determined by TGA.3.4.1. the opposite is also true. various reactions involving amino acid derivatives have been performed successfully in ionic liquid media. However.1. Aldolizations. 3. PF6.1. Organocatalysis Amino acids such as proline are among the cheapest and most widely used organocatalysts. 3. The methyl isopropyldithioformiate was condensed on the appropriate chiral amino alcohol ((R)-2-aminobutanol 226.54 Reaction of benzaldehyde with an excess of propanone in the presence of 30 mol % proline in several imidazolium-based ionic liquids gave the expected aldol products in moderate yield (30-59%) and good ee (58-78%). entries 1-4). Catalysis by Means of Amino Acids in ILs Homogeneous catalysis is probably the field of organic synthesis that has been the most studied in ionic liquids. The BF4. NTf2) led to a variety of thiazolinium salts 235-241 (Scheme 22). mainly because of the potential of these new solvents for recycling of the catalyst/solvent system.1. 2. or acidic) unlike what was observed with oxygen analogs (vide supra). partial dealkylation was observed (10-20%) under these conditions. PF6. Mesylation under basic conditions gave access to thiazolines 228 and 229. and BF4 anions. and Toma et al.49-51 The sulfur atom was introduced via a dithioester reagent. Interestingly. their use as homogeneous catalysts in ionic liquids has been studied since 2002 in various reactions52 such as aldolizations. In all cases. The catalytic system (IL + proline) was reused 4 times with cyclohexanone without any loss of de and ee. used [bmim][BF4] and [bmim][PF6] as solvent for the prolinecatalyzed Mannich reaction of N-PMP-protected R-imino ethyl glyoxylate with various aldehydes and ketones (Table 18). [Bmim][PF6] was also successfully used for the synthesis of pyranose analogues via two successive aldol reactions (Scheme 25). No.60 Reaction of tris(methoxy)silyl-substituted ionic liquids having various cations and anions with pretreated silica gel gave a range of covalently bonded supported ionic liquids (Scheme 26) to which proline was subsequently added. In order to improve ease of use and recycling of the catalyst.2.1) is excellent.2S)-2-hydroxy-1. although diastereoselectivity (19. a recycling experiment showed a drop in yield on the third cycle. and the aldol product was obtained with a good diastereoselectivity (anti/ syn 5:1) and complete enantioselectivity for the major diastereomer. some supported ionic liquids have also been used as immobilization media for proline. yields and ee were equivalent to or greater than those obtained at -25 °C in excess propanone as solvent (Table 16). An improved solvent system in which DMF was added was used successfully for direct cross aldol reaction of aldehydes with complete enantioselectivity and good to excellent diastereoselectivity depending on the substrates (Table 15). the catalyst/IL system was recycled 6 times with only minor decreases in product yield and constant ee. Surprisingly. The three-component Mannich reaction was also investigated in . Wang and coworkers synthesized CIL 251 (Scheme 27) in which the catalytically active proline moiety is linked to the imidazolium part via an ether function:63 use of 10 mol % of 251 promoted the aldol reaction of various aromatic aldehydes with acetone in [bmim][BF4] with satisfactory yields (53-94%) and ees (65-93%). Also starting from 4-hydroxyproline. After washing and drying. 3. it can easily be recycled after reaction by concentration of the reacting mixture followed by extraction with dichloromethane. were obtained with the pyridinium-based supported IL having the tetrafluoroborate anion. Mannich Reactions.1. 108.5044 Chemical Reviews. Use of DMSO can therefore be avoided in this reaction. The proline-derived (S)-N-((1S. whereas hydroxyproline-derived 248 gave better yield and ee than free proline (Scheme 27).58 As low as 1 mol % catalyst was used to obtain both excellent yield and ee with o-nitrobenzaldehyde (entry 1). 2008.1. The catalyst/IL system was reused up to 3 times without significant loss in yield and ee using 5 mol % catalyst. ee > 93%. The supported catalysts 244-246 were assessed in the aldol reaction of benzaldehyde with propanone. It should be noted that for all these supported catalysts crotonization is the major issue with an enone/aldol ratio ranging from 17/83 to 46/ 54. In 2003 Barbas et al. typically > 99%).64 The Mannich adducts were obtained in very good yield and excellent diastereomeric and enantiomeric ratio (de > 19:1 except for hexanal (13:1) and 3-methylbutanal (5:1).57 Excellent yields and ees were obtained in the reaction of various (mostly aromatic) aldehydes with propanone at 0 °C. The reaction performed well in each tested IL (62-85% yield. Similarly. The ionic liquid/catalyst system could be recycled up to 4 times without loss of either yield or selectivity. although with a slow fall of the yield. Use of catalyst 248 was studied on several aromatic aldehydes in neat acetone and DMSO: whereas free proline usually performs better in DMSO than in acetone. The catalyst was reused 3 times with comparable yield and ee values. however. Vol. Lombardo and co-workers62 used the related catalysts 249 and 250 (Scheme 27) in various ionic solvents in the aldol reaction of p-nitrobenzaldehyde with acetone. Scheme 14 The ionic liquid [bmim][PF6] also proved to be a good solvent for the proline-catalyzed asymmetric aldol reaction of propionaldehyde (Scheme 24). 12 Scheme 13 Plaquevent et al.2-diphenylethyl)-pyrrolidine-2-carboxamide 242 was also used as a catalyst for the asymmetric aldol reaction in [bmim][BF4] (Table 16). Up to five recyclings of the catalytic system with only a slight decrease in yield and ee were carried out with a modified system including an added unsupported IL.56 Less than 5% of catalyst was required.59. 80-85% ee). The catalytic system was reused twice without any loss in yield or ee. (4S)-phenoxy-(S)-proline 243 catalyzes the aldol reaction between propanone and various substituted benzaldehydes (Table 17). As 248 is not soluble in dichloromethane. there is only a slight difference for these two solvents when the reaction is catalyzed by 248.61 The presence of the carboxylic acid function is essential for the activity and selectivity of the catalyst: proline-derived catalyst 247 performed poorly in this reaction. enantioselectivity is rather low (49%). The best results. in terms of both yield (55%) and enantioselectivity (70%). Miao and co-workers reported the synthesis of ionic liquid supported proline catalysts and used them in asymmetric aldol reaction. Using electron-poor substituted benzaldehydes the authors were able to reduce the amount of crotonization product while enhancing the yield. Additions to DEAD. However. proline showed the best activity (Table 20. entry 5). 90% de (syn). Toma and co-workers performed the enantioselective addition of aldehydes to diethylazadicarboxylate (DEAD) in ionic liquids.1.1. With (S)-proline as catalyst. The reaction rate and enantioselectivity were quite dependent on the structure of the aldehyde: the best results .67 Kitazume and co-workers used a stoichiometric amount of proline to promote addition of ketones to 2-trifluoromethyl acrylic acid phenethyl ester in various ionic liquids (Scheme 28). Yield of Salts 160-188 compd 160a 161a 162a 163a 164a 165a 166a 167a 168a 169a 170a 171a 172a 173a 174a 175a 176a 177a 178a 179a 180b 181b 182b 183b 184b 185b 186b 187b 188b a derived from (S)-Val (S)-Leu (R)-Leu (S)-2-amino-3. Vol.68 Although the yields were quite satisfactory. b Reference 43.66.. 3. Enantiomeric excesses ranged from 3% to 60%.3. 13-16).3-dimethylbutanoic (S)-2-amino-3. the diastereomeric ratio (when applicable) was close to 1:1 and no enantiomeric excess was reported. entries 1-9). 12 5045 Table 11. recycling of the catalyst/IL system was quite efficient (up to five reuses without loss of ee or yield). 2008.3-dimethylbutanoic (S)-2-amino-3. The study of this reaction with other aldehydes and ketones revealed that IL and catalyst loading should be optimized for each substrate. Among the catalysts tested in this study.3-dimethylbutanoic (S)-Phe (S)-Phe (S)-Phe (S)-Val (S)-Leu (S)-Phe (S)-Val (S)-Leu (S)-Phe (S)-Val (S)-Leu (S)-Phe anion Br Br Br Br Br BF4 PF6 NTf2 BF4 PF6 NTf2 BF4 PF6 NTf2 BF4 PF6 NTf2 BF4 PF6 NTf2 OTs OTs OTs NTf2 NTf2 NTf2 PF6 PF6 PF6 yield (%) 82 77 80 90 75 92 86 95 91 87 93 91 95 93 95 100 98 95 94 92 91 92 90 95 92 92 96 95 95 acid acid acid acid Reference 42.3-dimethylbutanoic (S)-Phe (S)-Val (S)-Val (S)-Val (S)-Leu (S)-Leu (S)-Leu (R)-Leu (R)-Leu (R)-Leu (S)-2-amino-3. entries 1-3). (S)-proline gave the best results. Addition of cyclohexanone on β-nitrostyrene catalyzed by proline was also studied in various ILs. catalyzed by proline or proline derivatives. Use of serine required increased catalyst loading and higher temperatures and gave disappointing results (entry 12). Study of the catalyst recycling revealed that the yield and de dropped from the first reuse. this example is the first one reporting the use of an amino acid other than proline (or a proline analogue or derivative) as organocatalyst in an ionic liquid.70 [Bmim][BF4] proved to be the best solvent in this reaction (Table 21. 108. The reaction was usually run at room temperature. ionic liquids (Table 19). almost no selectivity was observed in this reaction (ee < 6%). Michael Reactions. and 75% ee for catalyst loading of 40%. 88% for addition of dibenzoylmethane to methylvinylketone). 3.69 Although the yields are rather good in some cases (i.65 Among the various catalysts studied.Ionic Liquids Scheme 15 Chemical Reviews. affording slightly better ee but a much lower yield even after a prolonged reaction time.e.1. the reaction was completed in 1-18 h depending on the aldehyde structure with ee ranging from 70% to 89% (entries 1.3-dimethylbutanal was found to be unreactive even upon heating. In these conditions reuse of the catalyst/IL system led to the same yield but a decreased ee.1. as determined by HPLC measurement of “selected samples”.66 An excellent yield of 98% was obtained in [hmim][Cl] at the cost of a lower ee (40%): in this case.67 The best results were obtained in (methoxyethyl)-methylimidazolium mesylate ([moemim][OMs]) with 75% yield. but the less reactive substrates required heating to 70-80 °C for the reaction to reach completion (3. Michael reaction of active methylene coumpounds with enones could also be catalyzed by proline in [bmim][PF6] at room temperature (Scheme 29). Results similar to those obtained in molecular solvents were reported. trans-4-hydroxy-(S)proline 252 (entry 10) and (S)-thiazolidine-2-carboxylic acid 253 (entry 11). No. The initial products were directly converted into the configurationally stable oxazolidinones in order to prevent racemization (Table 21).4. In 2004 Kotrusz and coworkers reported the use of [bmim][PF6] as solvent in the organocatalyzed Michael addition of aldehydes and ketones to β-nitrostyrene (Table 20). Although the recycling of the IL/ catalyst system was possible. Scheme 17 Table 12. Proline has also been shown to catalyze the R-aminoxylation of aldehydes and ketones with nitrosobenzene.5.71 The catalyst/IL system can be reused up to 5 times without loss of yield or ee. The proline-catalyzed Knoevenagel reaction has also been studied in ionic solvents. Preliminary studies on ketones showed a much lower reaction rate. Aminoxylation Reactions.1.5046 Chemical Reviews.1.71.73 Reaction of diethylmalonate with several aromatic aldehydes in [bmim][BF4]. 3. b Tm. . No.6. [bmim][PF6].1. the yield and ee of the reaction dropped from the first reuse. Thermal Properties (Tm and Tg) and Yields of Salts 230-241 compd 230 231 232 233 234 235 236 237 238 239 240 241 a R1 (R) Et (R) Et (S) Bn (S) Bn (S) Bn (R) Et (R) Et (R) Et (R) Et (R) Et (S) Bn (S) Bn R2 Bu C12H25 Bu Et C12H25 Bu Bu Bu C12H25 C12H25 Bu Bu anion I I I I I PF6 NTf2 BF4 PF6 NTf2 PF6 NTf2 yield 66 30 64 66 24 60 54 60 25 25 44 46 Tm or Tg/°Ca 137b 63b 172b 175b 106b 136b -68c 111b 42b -67c 115b -40c ref 46 46 48 48 48 46 46 46 46 46 48 48 Determined by DSC. Yields of Salts 203-213 compd 203 204 205 206 207 208 209 210 211 212 213 derived from Val Leu Phe Val Phe Val Leu Phe Val Leu Phe X I I I BF4 BF4 PF6 PF6 PF6 NTf2 NTf2 NTf2 yield (%) 95 96 99 92 92 94 95 95 96 97 97 Scheme 18 Scheme 19 Table 13. 12 Scheme 16 Plaquevent et al.72 3. 108. c Tg.1. entry 15). 2008.72 This reaction can be efficiently carried out in [bmim][BF4] with 5 mol % of proline (Scheme 30). were obtained when R was an aliphatic chain (except if R ) tBu. whereas phenylacetaldehyde gave no measurable ee (entry 17). Vol. Knoevenagel Reactions. and [emim][BF4] gives average to good yields of the desired olefins (Table 22). 12 5047 Table 14. c Second run. b First run. alanine. g Using 1% (S)-proline. f An improved procedure gave 68% yield (65% ee). d Third run. catalyzed by CuBr/Proline.75 Better yields are obtained in ionic liquids than in polar molecular solvents: among them.2. The IL/catalytic system can be easily recycled with a slow decrease of yield at each reuse. up to three recyclings were done without loss of activity of the catalytic system. . 2008. The coupling of various thiols with vinyl bromide.Ionic Liquids Scheme 20 Chemical Reviews. Enantioselective Aldolization in Ionic Liquids entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 a R Ph Ph Ph Ph Ph Ph Ph Ph 2-naphthyl 4-Br-C6H4 4-F-C6H4 4-NO2-C6H4 4-OMe-C6H4 4-CF3-C6H4 4-CF3-C6H4 2-Br-C6H4 2-OMe-C6H4 2-NO2-C6H4 3-NO2-C6H4 cyclohexyl IL [hmim][BF4] [omim][Cl] [omim][BF4] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] [bmim][PF6] yield/% ee/% ST/EP/APa ref 50 30 59 58b 56c 53d 52e 55 60 72 90 21f 69 91 74g 61 69 93 94 65 58 78 71 71b 71c 69d 67e 76 69 67 68 48f 50 73 75g 63 68 82 70 89 6/34/60 0/55/45 11/16/73 13/12/75b 19/10/71c 17/16/67d 11/23/66e 15/14/71 6/8/86 53 53 53 53 53 53 53 54 53 53 54 54 54 54 54 54 54 54 54 53 Scheme 21 8/11/81 ST: starting material. Analogous conditions can be used for the Ullman-type coupling of vinyl bromide with imidazoles (Scheme 32). [bmim][BF4] and [BuPy][BF4] perform best.74 Yields are higher in [bmim][BF4] than in molecular solvents (DMF. Vol. DMSO) with the added advantage of shorter reaction times. Scheme 23 Scheme 22 Scheme 24 Table 15. The IL/CuBr/proline system can be reused three times with little effect on the rate or yield of the reaction. No. 3. moreover. Enantioselective Aldolization in [bmim][PF6] entry R1 Me iPr iBu c-hexyl iPr R2 Me Me Me Me nBu yield/% 73 76 69 77 69 dr 4:1 >19:1 3:1 >19:1 >19:1 ee/% 99 >99 99 >99 >99 The yields obtained are usually higher than those observed in molecular solvents. AP: aldolization product (relative ratio determined by NMR analysis of the crude mixture). e Fourth run.1. or lysine gave satisfying but lower yields than proline (Scheme 31). amino acids can also serve as ligands for organometallic catalysis. 108. Other amino 1 2 3 4 5 acids like glycine. histidine. EP: elimination product. was performed in an ionic liquid. Organometallic Catalysis In addition to their use as organocatalysts. On the other hand.S)-amino acid ester 256 and BL-alcalase. the current understanding of the IL effect on enzyme activity is still in its infancy. when hydrophilic ILs are dissolved in aqueous media they dissociate into anions and cations. Therefore. Transformations of Amino Acids in Ionic Media Table 16. and polarity of the solvent. a systematic study was undertaken with variations in ionic liquid structure and concentration (Scheme 33). 3. just like water) with polar and nonpolar regions. Great improvements (yield. b Reaction performed at -25 °C. which is observed by switching the reaction media from molecular solvents to ILs or systems containing ILs. High ees (94. One of the simplest and most efficient methods of synthesizing enantiomerically pure R-amino acids is the enzymatic resolution of racemic parents. 12 Scheme 25 Plaquevent et al. Vol. basicity. the 255/CuI system was successfully reused 3 times. Enantioselective Aldolization Catalyzed by 243 in Ionic Liquids entry 1 2 3 4 5 6 7 8 9 a Ar 2-NO2-C6H4 3-NO2-C6H4 4-NO2-C6H4 2-Cl-C6H4 3-Cl-C6H4 4-Cl-C6H4 4-Br-C6H4 Ph 4-Me-C6H4 yielda/% 93 91 80 76 92 73 74 61 56 (90) (75) (75) (79) (79) eea/% 86 74 75 76 72 62 54 49 47 (78) (71) (76) (63) (74) Values in parentheses are obtained in acetone. when the reaction was performed in a 15% concentration of [EtPy][BF4] in water. When using [emim][BF4].79 Increasing the amount of ionic liquid beyond 20% decreases the performance of the enzyme. 2008. lower yield (32%) and enantioselectivity (89%) were obtained. ions that are known to stabilize enzymes (Hofmeister series). ee. No. Moreover. Therefore. The stereoselectivities toward the Z isomer obtained with ionic liquids 254-255 are higher than those observed with the [bmim][BF4]/amino acid/K2CO3 system (compare entries 1 and 2 with entries 5 and 6). 3. These coupling conditions can also be extended to the coupling of vinyl bromides with sulfinic acid salts.8%) and good yields (48%) in (S)-homophenylalanine isomer 257 were obtained using the N-acetyl-protected (R. However. What can be said is that in hydrophobic ILs enzymes have shown very high stabilities in a number of applications. kosmotropic (strongly hydrated species) anions and chaotropic (weakly hydrated species) cations stabilize proteins while chaotropic anions and kosmotropic cations destabilize them.78 This is mainly due to the improvement in enzyme catalytic performances (activity.2.76 No improvement of the yield or reaction rate compared to molecular solvents was observed. and in some cases enantioselectivity). character. and anion nucleophilicity. stability. polarity.1. stability. This can be explained by the fact that the hydrophobic solvents have a lesser tendency to take away the essential water from the enzyme surface. Enantioselective Aldolization in [bmim][BF4] Enzymatic and chemical transformations of amino acid derivatives are among the most important reactions in organic synthesis. Another explanation to interpret the enzyme stability is based on the observation that ILs may form so-called organized “nanostructures” (hydrogen-bonded polymeric supramolecules. a commercially available endoproteinase of the serine type obtained from Bacillus licheniforms. the same group reported the use of amino acid-derived ionic liquids to perform coupling of Z-vinylbromides with thiols or diphenyl diselenide without any added base or “free” amino acid (Table 23). The kinetic resolution of amino acids was influenced by the concentration. and the best yields are observed with dimethylglycine-derived 255 (entry 6). hydrogen bonding. Enzymatic Resolutions and Transformations of Amino Acids entry 1 2 3 4 5 6 7 8 9 10 11 12 13 R1 Ph 4-NO2-C6H4 4-Br-C6H4 4-Cl-C6H4 4-CN-C6H4 4-Me-C6H4 β-naphthyl 3-NO2-C6H4 2-NO2-C6H4 2-Cl-C6H4 c-hexyl t-Bu 4-NO2-C6H4 R2 Me Me Me Me Me Me Me Me Me Me Me Me Et yielda/% 50 82 75 76 67 50 85 82 84 84 70 46 62 (51) (66) (77) (75) (63) (48) (93) (63) (52) (83) (85) (51) (32) eea/% 92b (83) 94 (93) 91 (90) 95b (93) 93 (88) 92b (84) 91 (94) 96b (87) 96b (78) 91 (85) 99 (97) 99 (>99) >99 (90) a Values in parentheses are obtained in acetone. ions also make an individual contribution in the stabilization and level of activity of the enzyme.2.5048 Chemical Reviews. . 108. there is no simple correlation between one parameter and the enzyme activity. Table 17. and recycling of the catalyst) have been reported for a number of these reactions when performed in ionic liquids.77 An exciting development in the use of ionic liquids is their application in the field of enantioselective biocatalysis. Very recently. In many cases. Several factors seem to be responsible for the enzyme activity and stability including ionic character. but the IL/catalyst system enabled recycling and reuse three times. production of two amino acids ((S)-serine and (S)-4chlorophenylalanine) was not achievable in acetonitrile-water using NoVo alcalase. Porcine pancreas lipase (PPL) in [EtPy][TFA] also displayed high activity and selectivity in the kinetic resolution of various N-acetyl amino acids (Scheme 35). 12 5049 Scheme 27 Table 20. As already observed. In particular.4% conversion) toward . Kinetic resolution processes for producing (S)-N-(2-ethyl6-methylphenyl)alanine 278. 108.80 Enhanced synthetic activity and enantioselectivity (86-97%) were observed in the presence of this ionic liquid in comparison with acetonitrile (Table 24).Ionic Liquids Scheme 26 Chemical Reviews.82 As already mentioned. from racemic methyl ester 277 using the CAL-B-catalyzed hydrolysis was studied in buffer with alkyl-guanidinium-based ionic liquids as additive (Scheme 36). These results demonstrate that ILs can be good substitutes to molecular solvents. No. Vol.81. the best results being obtained when a 15% solution (v/v) of IL in water was used. the concentration of the ionic liquid in the solvent strongly influences the ee and yield. while excellent ee and conversion were obtained in [EtPy][TFA]/water.83 Optimum conditions using [ETOMG][BF4]/buffer in a 1/1 ratio afforded enhanced enantioselectivity (ee ) 92. an important precursor in the synthesis of herbicides such as metolachlor. higher ees (73-98%) and better conversions (28-41%) were obtained if compared with the conventional acetonitrile/water medium (Table 25).3% at 38. Mannich Reactions in Ionic Liquids entry 1 2 3 4 5 6 R1 H H H Me -(CH2)2Me R2 n-Bu n-Pent i-Pr Me -(CH2)2H yield/% 87 96 90 77 99 80 dr 13:1 >19:1 5:1 >19:1 >19:1 ee/% >99 >99 93 >99 >99 97 a nd: not determined. increasing the activity and selectivity of the enzymes. Three-Component Mannich Reactions in Ionic Liquids Scheme 29 entry 1 2 3 4 5 6 R1 H H allyl allyl H H R2 4-NO2-C6H4 1-naphthyl 4-NO2-C6H4 1-naphthyl i-Bu CH2-OBn yield/% 54 63 60 52 80 98 ee/% 95 82 87 93 43 93 [EtPy][TFA] also proved to be a good substitute for molecular solvent in the kinetic resolution of N-acetyl amino acid esters by NoVo alcalase. c Reaction Scheme 28 Table 19. the IL concentration is critical and 15% sol (v/ v) IL in water gave the best results. Reaction performed at 80 °C. performed at 70 °C. Under these conditions. 2008. another protease also obtained from Bacillus licheniforms (Scheme 34). Michael Reactions in Ionic Liquidsa entry 1 2 3 4 5 6 7 8 9 10 R1 H H H H H Me Me -(CH2)2-(CH2)3-(CH2)4- R2 iPr iPr iPr Et tBu H iPr -(CH2)2-(CH2)3-(CH2)4b catalyst (S)-proline 252 253 (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline yield/% (syn/anti) 83 0 (16)b 0 (51)b 58 0 (0)b 35 (77)b 0 (23)b 0 (53)c 69 4 (87)b dr (syn/anti) 9:1 (10:1)b (4:3)b 3:1 nd nd nd (4:3)c 3:2 nd (5:1)b Table 18. Knoevenagel Reactions in Ionic Liquids entry 1 2 3 4 5 6 a conditionsa [bmim][BF4]/(S)-proline/K2CO3 [bmim][BF4]/N.3% conversion). Table 22. Very low amount of coupling product Scheme 33 After 24 h. (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline 252 253 (S)-serine (S)-proline (S)-proline (S)-proline (S)-proline (S)-proline time/ min yield/% ee/% 65 65 65 65 65 65 65 65 65 380 480 420 100 70 360 200 120 85 68 88 44 65 48 46 44 45 27 17 <4 63 63 34 43 42 84 79 36 81 83 70 17 11 nd 94 92 nd 89 83 70 76 e1 Scheme 32 Table 23. Addition to DEAD in Ionic Liquids Plaquevent et al. 12 Table 21. Zhao et al. As already mentioned.5050 Chemical Reviews.4-dioxane/N.5M)./% 46a 51a 25a 89b 93b 65b 81b 97b 27b 63b 45b 60b 100c R ) Ar ) Ph. b Tetradecyl(trihexyl)phosphonium chloride (Cytec). Scheme 31 entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 R iPr iPr iPr iPr iPr iPr iPr iPr iPr iPr iPr iPr Me Et tBu Bn Ph IL [bmim][BF4] [bmim][PF6] [hmim][BF4] [hmim][PF6] [bbim][PF6] [C10mim][PF6] [bmim][C8H17SO4] AMMOENGTM 100a CYPHOSIL 101b [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] cat. 108. Coupling Reactions in Ionic Liquids a Polyethylene glycol substituted ammonium methyl sulfate (Solvent Innovation). No. Recycling of the ionic liquid was performed in four consecutive runs without loss of activity or enantioselectivity. explored the effect of kosmotropicity on the enantioselectivity in the enzymatic hydrolysis of phenylalanine methyl ester in aqueous solutions of various ILs with the aim to develop an empirical guideline in designing ILs for specific enzymatic applications.N-dimethylglycine/K2CO3 DMF/N.N-dimethylglycine/K2CO3 1. 2008. b After 12 h c after 6 h Scheme 30 Scheme 34 the (S)-enantiomer 278 compared to the one obtained in pure buffer (78. 16 h observed. higher conversions were obtained with lower concentrations in IL (0.N-dimethylglycine/K2CO3 254 255 b yield/% 80 87 56 b 60 90 Z:E 93:7 93:7 85:15 98:2 98:2 entry 1 2 3 4 5 6 7 8 9 10 11 12 13 a R Ph Ph Ph Ph Ph Ph Ph i-Pr 4-NO2-C6H4 4-OH-C6H4 4-Cl-C6H4 4-OMe-C6H4 furan-2-yl IL [emim][BF4] [bmim][BF4] [bmim][PF6] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] [bmim][BF4] T/°C 15 15 15 35 50 65 80 50 50 50 50 50 50 conv.84 Bacillus licheniforms was selected for the study. The protease enantioselectivity was greatly enhanced using IL solutions containing kosmo- .7% at 45. Vol. Both the buffer concentration and the IL concentration considerably modify the enzymatic hydrolysis rate of phenylalanine methyl ester. which stabilize the enzyme. The higher kosmotropicity of the (R)-amino acids compared to that of the (S)-isomer was proposed by the authors to explain this result.85 Activities were better in [omim] than in [bmim] (Scheme 37). studied the lipase-catalyzed ammonolysis of (R. These values are comparable to those obtained in pure water.3% for the substrate (S). presumably because of the high nucleophilicity of the anions.> CH3COO.281) for a high conversion (Table 26. No. tert-amylalcohol). Among two lipases and three proteases.S)HPGME) with ammonium carbamate as the ammonia donor in nine different ionic liquids (Table 26.87 Better results were obtained with this IL compared to acetonitrile and ILs having chaotropic anions such as [emim][OTs]. The reaction became faster and more enantioselective with elongation of the alkyl chain on the cation.S)-HPGME 281 was observed in two ILs. Enzymatic resolution of phenylalanine methyl ester was also conducted as a model reaction for examining protease activity and enantioselectivity in aqueous solutions of ionic liquids carrying anions derived from amino acids.8% yield). Interestingly. 108.> citrate3. Br. In other ILs an enhancement in the enantioselectivity was always observed compared to the different molecular solvents tested. A study of the influence of the concentration (0-4M.86 The [emim] cation was selected for the study as it is a chaotropic cation. which stabilizes the enzyme while 5-aminopentanoic acid [5-APA] was selected as the anion. [C6mim][BF4] giving the highest ee (94. [bmim][Br] and [bmim][NO3]. 87. 4-chlorophenylalanine. 20% (v/v) [hmim][BF4]/BuOH (Table 26.3). p-hydroxyphenylglycine) in 2. enantioselectivity.> BF4-) and chaotropic cations (emim > bmim> hmim).88 The results obtained clearly demonstrate that use of ILs as a cosolvent can markedly boost the activity.Ionic Liquids Table 24.281 for a 46. No ammonolysis activity toward (R. However. Enzymatic Resolution of N-Acetyl Amino Acids in [EtPy][TFA] ILa acetonitrile compd 257 264 265 266 267 268 269 a Chemical Reviews.S)-phenylalanine methyl ester (activity and enantioselectivity) was performed by Zhao. lower yields were obtained at high IL concentration. The enantiomeric excess in favor of the (S)-derivative proved to be almost independent of the IL concentration. Of the cosolvent mixture assayed.6% for the substrate (S). The high thermal . Lipase Resolution of N-Acetyl Amino Acids in Ionic Liquids acetonitrile compd 270 271 272 273 274 275 276 ee (%) 92 63 35 36 62 95 18 yield (%) 33 26 21 19 31 26 32 95 81 78 89 86 98 73 [EtPy][TFA] ee (%) yield (%) 39 30 28 24 29 41 30 Scheme 36 tropic anions (PO4 3.5 M). entry 16) gave both the highest initial rate and enantioselectivity (92.> EtSO4> CF3COO-.0 M [emim][AcO]. The activity of R-chymotrypsin in imidazolium-based ionic liquids was studied using the transesterification reaction of N-acetyl-L-phenylalanine ethyl ester 279 with 1-propanol.S)-p-hydroxyphenylglycine methyl ester 281 ((R. 60% IL. entries 14-16). 12 5051 Scheme 37 [EtPy][TFA] ee (%) 93 86 90 97 89 96 88 yield (%) 38 33 35 36 29 39 30 ee (%) 95 63 NA 92 83 NA 18 yield (%) 35 31 NA 15 30 NA 32 NA: no activity. lyophilized Bacillus licheniforms exhibited the best activity (yield > 99) and enantioselectivity (ee ) 96. The results follow the Hofmeister series. Destabilization of the enzyme was proposed to rationalize this result.> OTs. slightly higher ees were obtained in (R)-amino acid-based ILs than in those based on (S)-amino acids.6% ee for the product (R).1% for the product (R). v/v) of the [emim][AcO] ionic liquid on the enzymatic resolution of (R. Zong et al. A good compromise between activity and selectivity was obtained using mixtures of BuOH and ILs (Table 26. High enantioselectivity was also obtained with several other amino acid methyl esters (methionine. Scheme 35 Table 25. whatever the IL used a lower activity of the enzyme was noticed compared to that observed in pure butanol. THF.2 dichloroethane. phenylglycine. 2008. Vol. 1.2%) of (S)-phenylalanine were obtained in low concentrations of IL (0. and stability of Candida antartica lipase B (CAL-B) immobilized on an acrylic resin (Novozim 435). At higher IL concentrations both ee and yield decrease.282. Therefore (R)-amino acid anions are stronger enzyme stabilizers than their (S)-isomers. Both the cation and the anion have a significant effect on the reaction. High enantiomeric excess (92%) and yield (97. However.282 and 86. Scheme 38) and compared the results to those obtained in four organic solvents (butanol. In various other amino acid-based ILs a moderate to high enzyme activity and enantioselectivity were observed. entries 1-4). 31 0. The (R)-phenylalanine conversion using DAAO without addition of catalase was lower in the presence of [bmim][BF4] (40%) than in pure buffer (70% after 240 min compared to 100% in 80 min.S)-phenylglycine methyl ester (PGME) 283 to enantiopure (R)-phenylglycine 284 (Scheme 39). respectively).8 nr nr 71.18 2.2-dichloroethane.5 50.45 2.45 0. The best medium is obtained by mixing a phosphate buffer and [bmim][BF4] in a 80/20 (v/ v) ratio. (R.93 Markedly enhanced activity and enantioselectivity were obtained in the system containing [bmim][BF4] compared to several organic solvents. nr ) no reaction.4 72.4 94.S)-4-chlorophenylalanine ethyl ester.5% (v/v)). Performing the hydrolysis under low pressure allows methanol to be removed and affords higher activity and enantioselectivity.8 44.5 78.S)-phenylglycine methyl ester. 2008.7 35.3 26.5 38. Cl-.17 time/h 48 48 48 48 48 68 86 48 48 4 4 40 60 4 4 4 4 4 4 6 yieldb (%) 33.57 0. From these preliminary tests the most promising IL seems to be [bmim][MMPO4].56 2. .6 23. ees (%) 48.7 76.4 94. CCL: Candida cylindrace lipase.83 1.92 Note that DAAO serves as the first enzyme in a two-step enzymatic process for industrial production of 7-aminocephalospranic acid (7-ACA).42 3.38 0. 12 Table 26.2 28.2 90. Lipase-Catalyzed Ammonolysis of (R.4 40.7 46.7 74.6 92.5 70. (R.5 nr nr 38. A higher stability of DAAO in the water-insoluble ILs was reported.5052 Chemical Reviews. studied the catalytic activity and stability of (R)-amino acid oxidase (DAAO EC 1. The biotransformations of enantiopure and racemic phenylalanine and ceph-C were performed in the presence of ILs. No. Br-. This was explained by the deceleration in the nonenzymatic hydrolysis of the amino acid in IL compared to phosphate buffer.7 95. (R.5 65.7 E 25 43 59 67 68 63 50 nr nr 12 22 13 8 48 52 63 27 19 15 3 a CAL-B: Candida antartica lipase B.66 2.4 85.S)-phenylalanine in the presence of [mmim][MMPO4] and [bmim][BF4] with addition of a free catalase resulted in conversion rates similar to those reported in pure aqueous medium. c DCE ) 1.1 94. 108.3 45.32 2.4 28.7 87.7 86.7 89.0 47. Wu et al. and HSO42-. No activity or low enantioselectivities were obtained with ionic liquids having halides or hydrogenosulfate anions. Fischer et al.6 78.7 30.6 Plaquevent et al.2 24.5 35. A clear enhancement of the enantioselectivity was observed when [bmim][BF4] was used as a cosolvent (optimum concentration 12.78 0.8 46. Scheme 38 Scheme 39 stability of the enzyme in the IL-butanol solution was also demonstrated.54 0. This lower activity was explained by the reduced enzyme stability in the IL.9 79.0 31.4 43. Vol.5 54.3 61.S)-p-Hydroxyphenylglycine Methyl Ester 281 in ILsa entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 lipase CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CAL-B CCL medium [C3mim][BF4] [C4 mim][BF4] [C5 mim][BF4] [C6 mim][BF4] [C7 mim][BF4] [C8 mim][BF4] [C4 mim][PF6] [C4 mim][Br] [C4 mim][NO3] t-BuOH t-AmOH DCEc THF 30% (v/v) [C5mim][BF4]-t-BuOH 15% (v/v) [C7mim][BF4]-t-BuOH 20% (v/v) [C6mim][BF4]-t-BuOH 50% (v/v) t-AmOH-t-BuOH 10% (v/v) DCEc-t-BuOH 10% (v/v) DCEc-t-BuOH 20% (v/v) [C6mim][BF4]-t-BuOH initial rate (mM · min-1 · mg-1) 0.63 0.6 83.24 1.8 78.7 92.3) from Trigonopsis Variabilis immobilized on a macroporous carrier in different water-soluble and water-insoluble ionic liquids as well as in organic solvents.S)-methionine ethyl ester.74 0.4.3 34.3.1 nr nr 57. The biotransformation of (R.2 82. b Yield of the product on a mole basis.89-91 studied the papain-mediated asymmetric hydrolysis of four racemic amino acid esters ((R.3 eep (%) 88.5 42.6 36.1 35.19 nr nr 1. ILs can also serve as excellent cosolvents to buffer in place of traditional organic solvent for immobilized Candida antartica lipase B (Novozim 435) mediated hydrolysis of (R.9 91.2 42.S)-β-phenylalanine methyl ester) in different media containing various concentrations (from 0 to 99% (v/v)) of methyl imidazolium-based ionic liquids having anions such as BF4-. 2. second. All this information clearly shows the enhanced stability and activity of enzymes when diluted in ionic solvents. such as Vancomycin resistance in pathogenic bacteria. With In(OTf)3 in [hmim][BF4] the heterogenized catalyst was reused three times with a significant decrease in yield for the third cycle. and the use of synthetic peptides in the total chemical synthesis and semisynthesis of proteins.6). A series of recent reviews summarizes the current approaches used in peptide synthesis. Loh et al. Chemical Transformations of Amino Acids Different approaches that relate transformations of both functional moieties of amino acids have already been reported. cheap reagents. such as the conotoxins and the cyclotides. The authors had shown good synthetic activity of PGA-450 in these ionic liquids. SeVeral factors contribute to this rebirth: the discoVery of new classes of diVerse and potent peptide natural products. future studies will probably focus on use of simplified procedures. the rebirth of fundamental research in this field. 3.. recently stated:97“. the field of synthetic peptide chemistry is in the early stages of a renaissance.95 The chiral amino acid used was (S)-valine methyl ester 17. Regarding this last point. a resurgence of interest in peptides for use as human therapeutics. creating a cosolvent aqueous mixture that denatures the IL and leads to no synthetic activity of the enzyme. especially for ethyl esters (see Table 27). from Chicago University.2. ionic solvents are increasingly tested for peptide chemistry both for synthetic and analytical purposes. Malhotra investigated for the first time the use of ionic liquid [EtPy][TFA] as a catalyst for esterification of amino acids. Ionic liquid with sulfate anion such as CH3OSO3 requires more than 20% water.. one can wonder why peptide synthesis still suffers from severe drawbacks. No. and possibly the absence of protecting groups (see some examples in the Conclusions and Prospectives).102 The first successful study reported deals with the synthesis of Z-protected aspartame 287. their recycling.94 Reactions carried out in [bmim][PF6] were comparable to that obtained in toluene (complete in 3 h). which will thus not be discussed herein. Esterification of Amino Acids with [EtPy][TFA] as Catalyst R CH2OH (serine) n-Bu (norleucine) Cl (2-chloroglycine) Ph (phenylglycine) PhCH2CH2 (homophenylalanine) 4-Cl-C6H4-CH2 indolylmethyl (tryptophan) ethyl ester yield (%) 25 70 93 72 77 89 95 i-propyl ester yield (%) 12 72 52 78 70 87 54 Scheme 41 or isopropyl alcohol followed by adding the ionic liquid. the still growing importance of peptide synthesis and. 3. and [omim][Cl].Ionic Liquids Scheme 40 Chemical Reviews. and the first results from this research area are reported below. Shorter chain lengths on the cationic part of the ionic liquid afforded better yields and lowered the amount of aldol side product.8. However. Vol. One of the main topics of this chemistry consists of peptide coupling.. Professor S. Enzymatic Peptide Synthesis Much information is available now that clearly shows the greater stability and activity of enzymes when diluted in ionic solvents. Reactions proceeded with high diastereoselectivity in [BF4] ionic liquids. highcost coupling reagents. and tedious processes. 12 5053 Table 27. In [bmim][BF4] the reaction was complete after 24 h. In this context.3. Regarding amino group substitution. will place extreme demands on innoVatiVe synthetic peptide science. including unnatural compounds. which was obtained in a thermolysin-catalyzed reaction of Z-aspartate .96 After N-acetylation. Some of these very recent studies highlight a real potential as well as new opportunities. the N-protected amino acid was dissolved in anhydrous ethyl 3. not only can enzymatic transformations of amino acids benefit from the numerous advantages of ILs but also the chemical transformations of these species in ILs proved fruitful. such as low atom economy (protection/deprotection steps).1.. Some of the most important challenges currently facing the worldwide biomedical research community. and no hydrolysis of the product occurred. Yields were generally good. [hmim][BF4]. Peptide Synthesis in Ionic Media The activity of immobilized penicillin G amidase (PGA450) in ionic liquids in a reaction between methyl phenylacetate and L-PhGlyOMe 283 was studied at controlled hydration (aw > 0. Kent. At the beginning of the 21st century.” This stimulating text highlights at least two major points: first. All attempts to recycle the ionic liquid/InCl3 system failed.3. these promising results highlight the potential of ionic liquids for amino acid chemistry.14 A rather obvious consequence was to incite chemists to examine construction of peptide bonds in ionic media by means of proteolytic enzymes. 2008. Obviously. [omim][BF4]. In a recent book review. described the indium-catalyzed asymmetric three-component Mannich reaction in ionic liquids (Scheme 41). 108.98-101 Indeed. Different ionic liquids were tested: [bmim][BF4]. see Conclusions and Perspectives). Dipeptide Synthesis in [bmim][PF6] Plaquevent et al. . this approach would avoid protection/deprotection steps (for discussion. In addition to the benefit for the purification procedure. dipeptide coupling agent HATU HATU HATU HATU HATU HATU HATU HATU BOP HATU HATU HATU yield (%) 93 99 99 93 43 99 96 99 82 45 52 49 286 and phenylalanine methyl ester hydrochloride 20 · HCl in [bmim][PF6] (Scheme 42). A more selective chemical pathway. and practical method has been devised. one interesting aspect of this method is the high purity of the crude peptides obtained. good yields were obtained in most cases. or the classical coupling with EDC and HBTU.. and an effective. and serine was coupled without protection of the side chain.and tripeptides were successfully obtained in 70-75% yield. More recently. Yen and Chu showed that diketopiperazine 291 was efficiently obtained in [bdmim][PF6] using low-power microwave irradiation (Scheme 43). The authors observed a competitive rate with respect to the same reaction in molecular solvents as well as a remarkable stability of the enzyme. ZTyrGlyGlyOEt. and cycloocta-peptides were formed with ca. No. 80-85% yield. Vol. The main advantage was the higher purity of the crude dipeptides obtained when the reaction was performed in an ionic liquid. We first coupled quaternary R-amino acids 288-290 which are much more difficult to couple than their tertiary proteinogenic congeners. tetra-. in a congress abstract. Six different methylimidazolium hexafluorophosphates and tetrafluoroborates were screened.106 examined the incubation of amino acid mixtures in [bmim][PF6] in the absence of any coupling reagent. In 2004 we considered peptide coupling in ionic media by looking at modern coupling agents such as HATU and BOP as reagents of choice for this approach since they present strong structural similarities with ionic solvents.104 In 2007 R-chymotrypsin-catalyzed peptide synthesis was examined in ILs. the Weinreib amidation of esters. simple. this could indicate the feasibility of recycling the activation agent. Our ongoing studies focus on examining the direct coupling of amino acid salts.110 During a related study on the synthesis of various amides via either the Schotten-Baumann procedure. This methodology could potentially be used on a large scale. to the ability of ionic solvents to retain the residues of the activation agent in solution.2. Shortly thereafter two research groups reported new results that confirmed the interest of chemical peptide coupling in ionic liquids and highlighted the main conclusions of our studies.e.3.. Chemical Peptide Synthesis Although efficient peptide coupling has already been demonstrated by means of enzyme catalysis (vide supra). this kind of study is obviously relevant to prebiotic chemistry since the origin of peptide bond construction still remains obscure. 2008.105 ZGly-GlyOMe ZGly-MPGOMe ZGly-MPBrGOMe ZGly-Ac5cOMe BocAib-Ac5cOMe BocPhe-PheOMe BocPhe-GlyOMe BocPhe-Ac5cOMe BocMPG-GlyOMe BocMPG-MPGOMe BocAib-MPGOMe BocMPG-AibOMe 3. After optimization of reaction conditions and extraction process. In addition. Trulove et al.5054 Chemical Reviews. octa-. After aqueous extraction peptides (as unidentified and unquantified mixtures) were obtained when the reaction temperature was greater than 100 °C. Although not useful from a preparative point of view. The key reaction steps were a Schotten-Baumann acylation and a Pictet-Spengler cyclization. A comparative study with molecular solvents finds the approach simple and more effective in ILs. in 2005. Indeed.109 Another interesting contribution was reported by Sega et al. and it was shown that the water content of the reaction medium had a great influence on the enzyme activity and product yield. 12 Scheme 42 Table 28. which can be dissolved in ionic solvents. Various ionic liquids have been tested under different reaction conditions. one can expect this approach to be of real potential since amino acid derivatives are easily dissolved in ionic medium. This was assumed to be due. In optimized conditions several di. due to the stabilization effect of the ionic liquid on both the coupling reagent and the charged intermediates. As mentioned before. If successful. at least in part. 108. i. is assumed to explain this behavior.103 Recycling of the ionic liquid was successfully performed.107. which compared favorably with yields in molecular solvents such as dichloromethane or THF (Table 28).108 We expected them to be both easily dissolved in ionic liquids and stabilized by the solvent in order to produce slow and selective reactions. the authors published an example of peptide bond construction with 90% yield (obtained peptide Cbz-Phe-Ser-OMe). and coupling could be favored because of anhydrous conditions as well as stabilization of charged coupling reagents and reaction intermediates. A series of simple amino amides was also produced followed by direct reduction to amines in the same flask. A simple ether extraction afforded the desired product. the protease-catalyzed synthesis of peptides from natural amino acids was achieved in ionic liquids. no reports about controlled chemical peptide coupling in ionic liquids were available in the literature till 2004. The model reaction was the synthesis of a fragment of Leu-enkephalin. The issues that we wanted to address were the following: (1) Can histidinium salts be coupled under standard peptide synthesis methods on both terminal positions? (2) Do racemization and epimerization occur using these new species? (3) Are ionic liquid dipeptides stable and easy to purify. Vaultier and co-workers highlighted the interest of such a strategy for peptide synthesis. a series of reports proposed new insight into supported peptide synthesis. easily removed by simple washing (Scheme 45).Ionic Liquids Scheme 43 Chemical Reviews. This would allow both homogeneous reactions as well as high loading. synthetic performance compared well with other methods.115 In this case.2). 108. Finally. Indeed.112 In a patent. Amide coupling with Boc-(S)-Ala was successful on this support and deprotection carried out as usual (Scheme 47). as expected. one can imagine strategies in which peptide elongation could be performed on immobilized species using ionic liquid moieties as soluble support. this group developed a general strategy for construction of various structures using onium salts as tools for immobilization in either organic. not . More recently. peptide coupling was efficient. the ionic support was compatible with peptide synthesis methodologies. the same group described structurally defined imidazolium-type ionic oligomers as soluble/solid support to synthesize peptides efficiently in gram scale. A related approach was reported by Lavastre in 2006. section 2. 12 5055 Scheme 44 Scheme 46 Scheme 45 Scheme 47 3. although in a different context. our group examined the related construction of dipeptides starting from our previously reported histidinium salts (vide supra. The same conclusions were drawn as in Chan’s study.113 Indeed.114.111 The authors showed that after the first reactant was anchored to an ionic liquid support the excess reagents and byproducts were. Vol. Although these approaches do not strictly belong to the field of synthesis in ionic liquid media.3. Also. For a first example. or ionic media (Scheme 46). 2008. Miao and Chan developed this strategy for the synthesis of Leu5-enkephalin 292 (Scheme 44). and no racemization occurred. One of the most promising approaches used these TSIL in peptide synthesis. Thus. opening a new class of functionalized chiral ionic liquids? Fortunately. they seem to be of major interest in the context of this review since they highlight the strong potential of task-specific ILs used for tagging the elongating peptide chain. the functionalized ionic liquid 298 carried an amino group instead of the hydroxyl function.3. Supported (or Immobilized) Peptide Synthesis Almost simultaneously with the demonstration that ionic liquids were particularly convenient solvents for peptide coupling. No. aqueous. the solute transport is governed by the solute affinity for the ionic liquid. The mechanism established by the authors consisted of two steps. the resolution increased with the concentration of the ionic liquid in the mobile phase.120 Two different liquid membranes were used in this work. and this bulk liquid membrane was also studied. amino esters (proline benzyl ester. 3. Then. Ionic liquids provide new media and tools such as devoted TSILs.1. Their potential for this purpose was evaluated for the transport of amino acids and amino esters between aqueous phases. R-phenylglycine. and some selectivity can be observed. 108. Extractions of amino acids from pharmaceutical products were also performed with good efficiency.118 The hydrophobicity of amino acids is an important factor governing their partition in IL.4.121 [Bmim][BF4] has also been used as a mobile phase additive in reversed phase chromatography for separation of amino and nucleic acids. they can serve as stationary phase or additive of mobile phase for enantioselective separation. N-butyl-N-methyl pyrrolidium and choline saccharinate dihydrogen phosphate (20% water) were used to dissolve significant amounts of cytochrome c. phenylalanine. seem to indicate a strong potential for future insights in peptide synthesis. Phe.N-trimethyl-2-aminobutanol-bis(trifluoromethane-sulfon)imidate as chiral selector for chromatography.119 As numerous ILs have very low solubility in water. Nevertheless. and tyrosine) was . the supported liquid membrane was used to separate a glass diffusion cell with two compartments. With amino acids. Chromatography. racemizing. no transport was noted even after a long phase contact. An acidic pH is also required. dibenzo-18-crown-6. on the other hand. ILs can be used as additives for liquid chromatography to reduce the surface acidity of silica-based stationary phases. The dependence of amino acid extraction on crown ether concentration confirmed the binding of the crown ether with the ammonium group of the cationic form of the amino acid. First. ILs can be used for chromatographic applications: two main fields have been investigated. free silanol groups often disturb the separation of basic solutes such as organic bases. 3. during the lag time.116 Although still moderate.36 The promising results reported in section 3. As discussed before. ILs and Analysis. no relationship was noted between the polarity of the IL (alkyl chain length) and the partition coefficient of the amino acid. Vol. they can be used as liquid membranes. Yuan and co-workers tested the ability of a chiral IL ((R)N. On one hand. Adding a crown ether. which will surely afford some improvements in peptide synthesis. On the other hand. their properties also make them good candidates as solvents for chemical analyses. at 25. and Mass Spectrometry of Amino Acids and Peptides In addition to the use of ionic liquids as solvents for organic and bioorganic synthesis reactions.117 In acidic conditions extraction is nearly quantitative even for hydrophobic amino acids such as glycine and without the need of adding any hydrophobic counteranion. extraction of amino acids is more efficient in the IL phase in the presence of a crown ether.6 mM to the [bmim][PF6] liquid phase at pH 1 proved to increase the solubility of some aromatic amino acids (Trp.14 ATF-FTIR spectra showed that the secondary structure of the protein is retained even at high temperatures (110 °C) in this IL. His) in the IL media by forming a complex with the cationic form of the amino acids. which corresponds to formation of water microenvironments inside the ionic liquid.122 In the case of two amino acids (tryptophan and phenylalanine derivatives).4.5056 Chemical Reviews. Factors controlling recovery of amino acids from aqueous solutions by several imidazolium-based ILs were studied. After this period. and the transport of amino acids was investigated. Silica-based stationary phases are most frequent in liquid chromatography. However. Two main applications were investigated: their potential for separation of amino acids and proteins and use as MALDI matrices for peptide and protein mass spectrometry analysis. although preliminary. while working with more classical ionic liquids led to structural changes for Candida antartica lipase B. Finally. phenylalanine methyl ester. recovery of the amino acid is acceptable. Extraction and Chromatography Amino acids generally exhibit a low solubility in IL. and. Separation of four different AAs (tryptophan. A detailed study of amino acid extraction from aqueous solutions by [bmim][PF6] in the presence of dicyclohexyl18-crown-6 ether was reported.123 The IL was used as a chiral buffer additive in high-performance capillary electrophoresis (HPCE) for the enantioselective resolution of several solutes.3. A commercial polyvinylidene fluoride membrane was impregnated with the ionic liquid [omim][PF6]. Imidazolium tetrafluoroborate ionic liquids have been used as additives in the mobile phase to block those negative effects induced by the presence of silanol groups. no selectivity is observed and the solute transport through water microenvironments controlled the solute transfer.N. Using a U-shaped tube the feed and receiving aqueous phase can be directly separated by an ionic liquid phase. and the required targets were obtained in a straightforward manner (Scheme 48). Then. 12 Scheme 48 Plaquevent et al. due to their high solubility in water and polar character. No. the current methodologies are powerful and efficient but should progress in terms of atom economy and cost of reagents and protecting groups. especially in the case of tryptophan. phenylglycine methyl ester) were transported after an induction time. 2008. Extraction of amino acids from the aqueous phase is more efficient when a [BF4] IL is used instead of a [PF6] IL. Since more conventional hydrophobic ionic liquids dissolved very low amounts of proteins. respectively). The behavior of peptides and computer-assisted optimization of peptide separations in a normal-phase thin layer chromatography system with and without addition of ionic liquid in the eluent was also reported. As chiral additive of mobile phase in reversed high-performance liquid chromatography the tested IL enabled the chiral separation of different compounds with correct resolution (e. and 6. peptides. Water-immiscible ionic liquid is better for AA and peptide analysis. the [M + H+] signal is produced with a similar or higher intensity than that obtained for solid matrix analogues. Thus.126 The ILM chosen was a pyridinium salt of R-cyano-4-hydrocinnamic acid. great ability to dissolve complex biomolecules. nonvolatile amine salts of R-cyano-4-hydrocinnamic acid (RCHCA) and sinapinic acid (SA) were synthesized and tested for protein analysis (Scheme 49). Ionic liquids can also be successfully used as MALDI matrices for characterization of peptides and proteins. 3. tested the behavior of nine homologous peptides in normal TLC with and without IL in the eluent and also performed computed optimization of the separation. Thus. the pyridinium salt of R-cyano-4-hydrocinnamic acid has been successfully used for ionization of human insulin. This matrix was then tested for identification of six standard proteins and in in vivo experiments after trypic digests. 1. a value near 1 is measured for the separation factor R in the case of valine (or leucine) trifluoroacetyl propanoyl ester analysis. so. while water-miscible ionic liquid is required for protein analysis. Jones et al. the mixture of pyridine/R-cyano-4-hydrocinnamic acid in a 2:1 ratio seems to be a good matrix for identification and characterization of proteins by peptide mass-fingerprint analysis. analysis of chemical or enzymatic reactions in ionic liquid media can be performed by MALDI MS.127 Tholey and co-workers showed that it is possible to analyze conventional ionic liquid (e. Vol. The results obtained show that the ionic matrix must have an acidic proton in addition to UV absorbance.5% of IL [emim][BF4]. 3. 2008. and the pyridine/matrix ratio was tested by comparing the MALDI signal intensities of model peptides. Many works thus concern employment of new matrices limiting the lack of homogeneity by favoring dispersion of the sample in the matrix. and the mixtures proved to be stable in a vacuum. The conditions of separation must be optimized to provide better performance. whereas a third degree polynomial dependence occurred in the presence of ILs. Li and Gross completed the previous studies by quantitative analysis with several peptides (Melittin. For example.g. The other analytical use of ILs concerns their use as a matrix for mass spectrometry analysis..4.124 Baczek et al.00. dispersion of the solute throughout the ionic matrices is homogeneous. very useful for mass spectrometry analysis of high-weight biomolecules. phenylalanine R ) 1.129 To have a rapid and quantitative method which does not require the use of an internal standard for analysis of peptides and proteins is essential particularly for development of new biocatalysts. amino acids. a classical matrix for MALDI MS. due to a heterogeneous dispersion of the solute throughout the matrix. The best results were calculated and obtained with 46% (v/ v) acetonitrile/water and 1. No. Armstrong and co-workers synthesized and tested new and conventional ionic liquids for peptide or protein analysis. Simulation for nine homologous peptides using a third degree polynomial model allowed moderate separation. and high thermal stability of ionic liquids make them good candidates as MALDI matrix. The results summarized in this part show the growing importance of ILs for extraction and analytical separation of AA and peptides. showed that using ILMs as MALDI matrices allowed rapid and quantitative measurements. In this case. bradykinin. Tholey et al. therefore reducing the limit of detection. solid matrices (e. and the signal obtained for the MALDI spectra is twice as intense as that obtained with an equivalent solid matrix.30. The best results were obtained with a matrix to pyridine molar ratio of 2:1. and proteins could be characterized in solution in ionic liquid after addition of solid matrix. Quantification of AA in solution with large amounts of IL is achieved in the presence of isotope-labeled internal standard. improved the ionic liquid matrices (ILM) for analysis of proteins digests. Thus. Zabet-Moghaddam et al. and development of enzyme inhibitors.Ionic Liquids Chemical Reviews. Results obtained with the chiral IL as stationary phase are acceptable.g. proved that ionic liquid matrices (nonvolatile amine salts of R-cyano-4-hydrocinnamic acid CHCA or 2. Experiments confirmed that the predicted separations were good enough.5dihydrobenzoic acid DHB) increased the fragmentation observed with MALDI FTMS analysis of peptides compared with those observed when using MALDI TOF analysis and thus supplied complementary information. 1. Moreover.128 In addition. 12 5057 Scheme 49 achieved with satisfactory to excellent results (R ) 1. a quadratic relationship between the retention parameter and organic concentration in the mobile phase was simulated without IL in the mobile phase.00. In all cases identification was unambiguous. investigation of substrate specificity.11).. In spite of a low shot-to-shot reproducibility. In this paper the authors discussed a more theoretical approach of ion formation in the presence of ionic liquids in LDI and MALDI analysis. For example. 108. Mass Spectrometry Matrix-assisted laser desorption/ionization (MALDI) is a powerful analytical tool.5dihydrobenzoic acid) are mostly used as MALDI matrices.5% IL) still allowed a satisfactory separation. and . to the mobile phase (20-40% acetonitrile.and negativeion mode and also by matrix-assisted laser desorption/ ionization.125 All conventional ionic liquids produced no MALDI signal and are not suitable for use as a MALDI matrix.. The low volatility. In most cases. [bmim][PF6]) by laser desorption/ionization (LDI) MS in positive.g.2.70. R-cyano-4-hydrocinnamic acid or 2. compatible with further MALDI MS identification. This work represents the first application of a chiral IL for enantioselective chromatography and shows that chiral ILs can be efficient selectors for different chromatographic techniques. suitable for screening processes. Addition of R-cyano-4-hydroxycinnamic acid (CHCA). the spot-to-spot reproducibility is good. analysis. (6) Parvulescu. No. T. 2938. Among the various applications we consider the following points as major scientific challenges. Finally.131 Qualitative and quantitative MALDI MS analyses of amino acids have been successfully carried out with these ionic liquid matrices. de Souza. and ´ the European Union (FEDER funding).132 and ILs are key media for chemical and biochemical modifications of amino acid derivatives. 152. Tetrahedron: Asymmetry 2003.. C. easily prepared with a standard solid acid MALDI matrix in the presence of an amine base. 108. Catal. 5. Winterton for his help and fruitful suggestions during the revision process of the manuscript. Conclusions and Perspectives As has been seen. J. 2615.107.. Chem. 6. W.. some structural similarities exist between the coupling reagents (HATU. H. P. Suarez. 39. For example. L.. Several approaches aiming to use unprotected amino acids have recently been reported. Among a wide family of structures. described guanidinium salts with a chiral counteranion and their use in enantioselective dihydroxylation with high asymmetric induction (up to 85% ee). (9) Handy. synthesis of new coupling reagents as well as their recycling will certainly be a promising research area in the near future. Chem. 3484. E. Chimie 2007. Vol. ReV. etc. 27. Z. (2) Wasserscheid.148 Obviously. Gaumont. 2000. 12 Plaquevent et al. the previously described ionic liquid matrices. Plaquevent. is a very efficient matrix system for MALDI MS analysis of proteins and peptides and more generally for high molecular mass compounds. Tetrahedron: Asymmetry 2005.. lower critical solution temperature (LCST) changes of a mixture of water and ionic liquids derived from amino acids was recently reported by Fukumoto and Ohno. led to bifunctional CILs in the series of ammonium dimalatoborates and their use in aza-Baylis-Hilmann reaction with ee as high as 84%136 as well as the use of simple ionic liquid obtained by protonation of amino acid as exclusive source of chiral information in a homogeneous transition-metal-catalyzed reaction using tropoisomeric ligands with ee up to 69%. twoconceptually rich approaches from Leitner et al. P. (5) Dyson. V. A.-C. in contrast to popular opinion.. (1) Synthesis and applications of novel chiral ionic liquids derived from amino acids using simple and straightforward methodologies. ´ J.C. J. J. Teuma. J. and spectrometry of amino acids and derivatives. 16. Chem. Chem. As outlined before. C. D. (10) Baudequin.. Gaumont. In this context. 10.138 (2) New insights into peptide synthesis.147 Also. (8) Baudequin. A. Guillen. Hardacre. These new ionic liquid matrices (ILM) facilitated sample preparation and sample procedures and gave better and more reproducible results compared with classical solid matrix. Novel physicochemical behavior could also arise. also allowed low molecular mass compound analysis by MALDI MS.. 76% ee).. “Ministere de la Recherche et des Nouvelles ` Technologies”. 3772. 9. these suggestions are not the only topics to be promoted by the “ionic liquid/amino acid” approach. which offers the unprecedented possibility to use neither aqueous nor organic conditions. we are currently investigating the use of chiral ionic liquids for liquid-liquid resolution procedures and crystallization-induced transformations of racemic amino acids. which need further development in terms of atom economy. ReV..-C. through these applications it has been shown that a new kind of IL. separation.) and ionic liquids. Cahard. P. including peptides and proteins. ionic media. 2007. giving access to fundamentally new concepts in the field. Chem. J. S. BOP. ionic liquids and amino acid derivatives are complementary to each other. Transition Met. the reversible folding-unfolding and long period stabilization against aggregation and hydrolysis of peptide solutions was reported in 2007. 99. seminal successes regarding asymmetric induction promoted by CILs used as solvents have been disclosed during the last years. Acknowledgments We gratefully acknowledge financial support from PUNCHOrga interregional network (Pole Universitaire de Chimie ˆ Organique). The outstanding series of new approaches summarized in this review highlight the role that could be played by ionic liquids for amino acid and peptide chemistry in the near future.-C. bovine insulin) having different molecular weights but similar hydrophobicity.108.. References (1) Welton.135 Finally. easily prepared with an equivalent of the usual acid matrices and amine bases. 1999. Gomez. Mol. 1. Certainly. and ionic tools for this unique chemistry of amino acids and derivatives.130 Calibration curves with good regression coefficients and low standard deviations were achieved without standard calibration. the “Regions Basse-et Haute Normandie”. ReV. Levillain.. F.5058 Chemical Reviews. 2071. 2002. T. Plaquevent. D. 14. Int. 3667. R. 2002. Chem. (3) Dupont. We also thank Professor P. Afonso et al. Use of these CILs in chirality transfer should be successful since the chemistry of chiral ionic media has recently proven its high efficiency. 2002. Eur. Levillain. C. the most exciting aspect that we would like to highlight is use of ionic solvents. Bregeon. For example. use of a novel family of solvents in which amino acids and their salts are directly soluble could open the way to strategies avoiding (or at least limiting) the use of costly protecting groups. F..139-144 In addition. (7) Durand. application of chiral solvents (or chiral reaction media) in enantioselective synthesis can be successful! The growing interest for CILs in asymmetric synthesis is also based on the use of immobilized chiral catalysts that are designed for a specific task and belong to the class of TSILs (task-specific ionic liquids). ILM exhibits great potential for the still not fully exploited MALDI MS analysis. R. C.146 For example.. J.145 (3) New processes in synthesis. (4) Olivier-Bourbigou. Amino acids are key substrates for the synthesis of ILs. Magna.. Angew.. . In conclusion. J. 3921. Thus... Ed.133-138 indeed.134 Malhotra described copper-catalyzed enantioselective addition of diethylzinc to enones in the presence of CILs with a high asymmetric induction (ca. 353.. CNRS (Centre National de la Recherche Scientifique). 2008. a novel thiazolium salt was shown to be an excellent coupling reagent for hindered amino acids. 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