JBA-06920; No of Pages 22 Biotechnology Advances xxx (2015) xxx–xxx

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Research review paper

Lipases: Valuable catalysts for dynamic kinetic resolutions Amanda S. de Miranda ⁎, Leandro S.M. Miranda, Rodrigo O.M.A. de Souza Laboratory of Biocatalysis and Organic Synthesis, Universidade Federal do Rio de Janeiro, Instituto de Química, Cidade Universitária, Rio de Janeiro CEP21941909, Brazil

a r t i c l e

i n f o

Available online xxxx Keywords: Lipases Dynamic kinetic resolution Chemoenzymatic synthesis Enantioselectivity Racemization Enzyme catalysis

a b s t r a c t Dynamic kinetic resolutions have proven to be a useful method for the preparation of enantiopure compounds from racemates, leading to the formation of a single enantiomer in theoretically 100% yield. Because lipases are ubiquitous, versatile, stereoselective and robust biocatalysts, they have been successfully applied as cocatalysts in these reactions, being mostly combined with metals in the chemoenzymatic dynamic kinetic resolutions of alcohols and amines. © 2015 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipases as biocatalysts in dynamic kinetic resolutions . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Dynamic kinetic resolution catalyzed by lipases and metals . . . . . . . . . . . . . . . . . . . . . 2.1.1. Dynamic kinetic resolution of secondary alcohols and derivatives catalyzed by lipases and metals 2.1.2. Dynamic kinetic resolution of amines catalyzed by lipases and metals . . . . . . . . . . . . 2.2. Dynamic kinetic resolution catalyzed by lipases in the absence of metals . . . . . . . . . . . . . . . 2.2.1. Dynamic kinetic resolution of amino acids and derivatives . . . . . . . . . . . . . . . . . 2.2.2. Dynamic kinetic resolution of cyanohydrins, hemiacetals and derivatives . . . . . . . . . . . 2.2.3. Dynamic kinetic resolution employing biocatalytic racemization . . . . . . . . . . . . . . . 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Chiral molecules that are non-superimposable mirror image of each other, i.e. an enantiomeric pair, present the same physicochemical properties in isotropic conditions but are distinguishable in systems that are Abbreviations: AIBN, α,α′-azoisobutyronitrile; AmP-MCF, amino-functionalized mesocellular foam; AP-SiO2, silica functionalized with 3-aminopropyl groups; BCL, Burkholderia cepacia lipase; Bz, benzyl; CAL-A, Candida antarctica lipase A; CAL-B, Candida antarctica lipase B; CRL, Candida rugosa lipase; DDKR, dynamic double kinetic resolution; DKR, dynamic kinetic resolution; DMP, 2,4-dimethyl-3-pentanol; DSR, dynamic systemic resolution; IPA, isopropyl alcohol; ISCBCL, ionic-surfactant-coated Burkholderia cepacia lipase; KR, kinetic resolution; MCF, mesocellular foam; MPS, mesoporous sílica; NMM, Nmethylmorpholine; NOV435, Novozyme 435; PPL, porcine pancreatic lipase; RT, room temperature; TBME, tert-butyl methyl ether; THF, tetrahydrofurane; TMS, trimethylsilyl; TBAF, tetrabutylammonium fluoride. ⁎ Corresponding author. E-mail address: [email protected] (A.S. de Miranda).

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not isotropic, such as biochemical systems, which are composed of many chiral molecules, such as protein, carbohydrates and nucleic acids (Berthod, 2006). This is the base for the fact that two enantiomers of a chiral substance can have a strikingly different behavior towards a biological system, such as the case of chiral drugs whose enantiopure forms display distinct pharmacological effects. In fact, many bioactive compounds, including pharmaceuticals, agrochemicals, fragrances and nutrients are chiral, many of them sold as a single enantiomer (Wolf, 2008), so that the development of methods to obtain optically pure compounds is crucial for chemical industries. In order to fulfill the increasing demand for enantiopure compounds, significant progress in asymmetric synthesis and catalysis have been achieved. During the evolution of asymmetric synthesis, the exploitation of the natural “pool” of chiral molecules as source of catalysts and ligands has been a valuable strategy. Among these chiral molecules, the use of enzymes, protein-based macromolecules that catalyze

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Please cite this article as: de Miranda AS, et al, Lipases: Valuable catalysts for dynamic kinetic resolutions, Biotechnol Adv (2015), http:// dx.doi.org/10.1016/j.biotechadv.2015.02.015

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Fig. 1. Kinetic resolution of a racemate.

reactions in living organisms, is particularly advantageous. These catalysts developed by nature are biodegradable, able to work under mild, environmentally benign conditions and usually present high chemo-, regio- and stereoselectivity, thus leading to cleaner reactions. On the other hand, enzymes can present some disadvantages, such as limited substrate scope, requirement of narrow reaction conditions and access to only one enantiomeric form. Furthermore, many of these enzymes require co-factors and their use outside the cell environment is a challenge (Faber, 2011). Among numerous enzymes that have been applied to organic synthesis, lipases have gained greater prominence over the years. Lipases are hydrolases [E. C. 3.1.1.3] ubiquitous in living organisms, where they catalyze the hydrolysis of esters of fatty acids (Bornscheuer and Kazlauskas, 2005; Kazlauskas and Bornscheuer, 1998). In the laboratory lipases have found to be versatile, being useful for the catalysis of diverse reactions, such as formation or hydrolysis of amides, epoxidation, aldol reactions, Michael additions, among others (Busto et al., 2010), thus finding wide application in organic synthesis. In addition, these enzymes usually present broad substrate scope, do not require co-factors and many of them present good to excellent stereoselectivity, can be easily used outside the cellular environment and are even active in organic solvents (Bornscheuer and Kazlauskas, 2005; Ghanem and Aboul-Enein, 2005; Kapoor and Gupta, 2012; Kazlauskas and Bornscheuer, 1998). These advantages, added to availability of lipases from various commercial sources, make the reactions catalyzed by these enzymes an area of great academic and industrial interest. Among reactions catalyzed by lipases, formation and cleavage of esters are especially important in the area of asymmetric synthesis, since the high enantioselectivity displayed by many of these enzymes allows the preparation of enantiopure compounds through kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemates. In this review, we highlight the use of lipases as co-catalysts in DKR reactions. Most examples include reactions co-catalyzed by lipases and metals, though combination of lipase with other catalysts are also covered. 2. Lipases as biocatalysts in dynamic kinetic resolutions In the KR of a racemate, one enantiomer interacts in a matched and the other in a mismatched form with the chiral catalyst (chiral recognition), so that the activation energy of the reaction becomes lower for

one of them, i. e. in the presence of the chiral catalysts one enantiomer is converted to the product at a higher rate than its antipode (Fig. 1) (Ahmed et al., 2012; Faber, 2011; Pàmies and Bäckvall, 2002a; Rouf and Taneja, 2014). Kinetic resolutions catalyzed by lipases are mostly based on a stereoselective reaction of nucleophiles with esters or their derivatives. Under physiological conditions, these enzymes catalyze hydrolysis of esters of fatty acids. Since lipases are also stable in non-aqueous media, such as organic solvents, they can also catalyze the reverse reaction as well as reaction of esters with other nucleophiles than water, like alcohols and amines, thus leading to transesterifications and aminolysis of esters. When a racemic nucleophile (Fig. 2a) or an ester (Fig. 2b) is employed, the biocatalyzed reaction can be stereoselective, so that a kinetic resolution takes place. In fact, lipase-catalyzed kinetic resolutions have been described as a useful method for producing compounds with high optical purity, including alcohols, amines, amino acids, carboxylic acids and esters (Ahmed et al., 2012; Bornscheuer and Kazlauskas, 2005; Ghanem, 2007; Ghanem and Aboul-Enein, 2005; Kamaruddin et al., 2009). In the catalytic site of serine hydrolases, the reaction occurs through a bi-bi ping-pong mechanism and a nucleophilic attack on the carbonyl group promoted by a serine, an histidine and an aspartate residue (also referred as “catalytic triad”) (Fig. 3a). The resulting “acyl enzyme” intermediate can, in turn, react with a nucleophile, such as water, alcohols or amines, regenerating the enzyme (Fig. 3b) (Faber, 2011; Pàmies and Bäckvall, 2003). Most lipases show the same enantiopreference towards esters derived of secondary alcohols, the fast-reacting enantiomer featuring the displacement of groups in the stereogenic center as depicted in Fig. 4. This model, known as the Kazlauskas' rule (Kazlauskas et al., 1991), was originally used for predicting the reactivity in KR of alcohols and has also been found to be useful for KR of amines. During the course of a kinetic resolution, the enantiomeric purities of substrate and product vary as the reaction proceeds. In a lipasecatalyzed KR, if the product is irreversibly formed, the values of the enantiomeric excess of the product (eep) and the substrate (ees), which can be experimentally determined, may be used to estimate the enantioselectivity inherent to the process by calculating the enantiomeric ratio (E), whose value is the ratio of the rate constants of the reaction for each enantiomer (Chen et al., 1982; Faber, 2011; Pàmies and Bäckvall, 2003). Thus, an enantiomeric ratio of 1 (E = 1) is the result of a reaction which presents no enantioselectivity, i.e. its chiral catalyst cannot distinguish the enantiomers present in the racemate and the rate of the reaction is the same for both enantiomers. On the other hand, in reactions with E ≥ 100 the chiral catalyst discriminates efficiently the enantiomers present in the racemate. This situation resembles the ideal situation in which by the end of the reaction 50% of the racemate would have been converted in the product and both product and remaining substrate would present enantiomeric excess higher than 99%.

Fig. 2. Lipase-catalyzed kinetic resolution reactions. (a) KR of a racemic nucleophile; (b) KR of a racemic ester. Y = NH, OH, Nu = OH, OR, NH2.

Please cite this article as: de Miranda AS, et al, Lipases: Valuable catalysts for dynamic kinetic resolutions, Biotechnol Adv (2015), http:// dx.doi.org/10.1016/j.biotechadv.2015.02.015

A.S. de Miranda et al. / Biotechnology Advances xxx (2015) xxx–xxx

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Fig. 3. Mechanism of lipase-catalyzed reactions of esters and nucleophiles (Nu). (a) Formation of the “acyl-enzyme” intermediate (Acyl-Enz); (b) regeneration of the enzyme (Enz).

An intrinsic feature of kinetic resolution is that each enantiomer can be obtained with a maximum yield of only 50% from its racemate. This limitation, however, can be overcome by racemization of the remaining unreacted enantiomer simultaneously to the kinetic resolution (Fig. 5), that is, in situ, in a process called dynamic kinetic resolution (DKR), whereby a single enantiomer can be obtained with a maximum theoretical yield of 100% from its racemate (Hoyos et al., 2012; Kamal et al., 2008; Martín-Matute and Bäckvall, 2007; Pàmies and Bäckvall, 2003). For a DKR to proceed efficiently and with high enantioselectivity, KR step must be irreversible and present high enantiomeric ratio (K R N NN K S, E N 20, Fig. 5), and the rate of racemization reaction must be equal or greater than the rate of KR reaction (K Rac N Κ R , Fig. 5). If the latter requirement is not fulfilled, the kinetic resolution must present an E value higher than 200 or the rate of racemization must at least be substantially larger than the rate of the reaction of the slow-reacting enantiomer (KRac/KS N 20), which can be accomplished by reducing the enzyme/racemization catalyst ratio (Pàmies and Bäckvall, 2003). Moreover, the conditions required for racemization and KR, such as temperature and pH, must be compatible; the catalyst used for racemization must not interact with the reaction product and its racemization should be minimal under the reaction conditions (Martín-Matute and Bäckvall, 2007; Pàmies and Bäckvall, 2003). If the requirements stated above are satisfied, a DKR can provide the product with maximum yield of 100% and enantiomeric excess higher than that obtained from its corresponding KR, since accumulation of slow-reacting substrate in the reaction medium is avoided during the outcome of the reaction. The enantiomeric excess of the product (eep) of a DKR is related to the enantiomeric ratio (E) of the process by the formula: eep = [(E − 1) / (E + 1)] (Tan et al., 1995). Racemization reactions employed in chemoenzymatic DKR cocatalyzed by lipases (Table 1) include racemization by reversible

Fig. 4. Fast-reacting enantiomer in lipase-catalyzed KR of secondary alcohols as predicted by Kazlauskas' rule.

formation of substrate, racemization mediated by imine formation and thiyl radicals as well as reactions catalyzed by bases, acids, enzymes and particularly transition metals, often used for racemization of alcohols and amines (Choi et al., 2007; Hoyos et al., 2012; Kamal et al., 2008; Pàmies and Bäckvall, 2003). In the past two decades, the combination of lipases with metal catalysts has culminated in the development of several DKR methods, providing access to chiral amines, alcohols and derivatives with high optical purity (Hoyos et al., 2012; Martín-Matute and Bäckvall, 2007), thus being added to the biocatalytic tool box for the preparation of these compounds, which can also be obtained biocatalytically by asymmetric synthesis in 100% yield with the use of ketoreductases (alcohols) (Goldberg et al., 2007; Hollmann

Table 1 Racemization methods used in DKR co-catalyzed by lipases. Racemization method

Substrate

General features

Ru-catalyzed

Secondary alcohols and primary amines

Pd-catalyzed

Allylic alcohols and primary amines

Ir-catalyzed

Secondary amines and secondary alcohols

Co and Ni-catalyzed

Aliphatic amines

Vanadium-catalyzed

Allylic and benzylic alcohols

Al-catalyzed

Secondary alcohols

Pt-catalyzed

1-phenylethylamine

Mediated by thiyl radicals generated photochemically Mediated by imine formation Base and acid-catalyzed

Aliphatic amines

Reversible formation of substrate

Cyanohydrins, hemithioacetals, nitroalcohols, and hemiaminals Hydroxy acids and α-aminonitriles

Homogeneous catalysts, high temperatures or base addition are required, and expensive catalysts Heterogeneous catalysts and high temperatures or long reaction times are required Homogeneous catalysts, mild temperature, and expensive catalysts Heterogeneous catalysts, high temperatures and long reaction times are required Heterogeneous catalysts, long reaction times (allylic alcohols) or high temperatures (benzylic alcohols) are required Mild temperatures, requirement of specific acyl donors Heterogeneous catalyst, high temperature is required, expensive catalysts, and scope was not studied yet Mild temperatures, inexpensive catalysts, and incompatibility with common used acyl donors Mild conditions, limited substrate scope Limited substrate scope and limited compatibility with lipases Mild conditions and scope limited to stereochemically labile substrates

Biocatalyzed Fig. 5. Dynamic kinetic resolution of a racemate.

Amino acids Alcohols and amino acids

Mild conditions and limited substrate scope

Please cite this article as: de Miranda AS, et al, Lipases: Valuable catalysts for dynamic kinetic resolutions, Biotechnol Adv (2015), http:// dx.doi.org/10.1016/j.biotechadv.2015.02.015

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Table 2 Advantages and drawbacks of DKR co-catalyzed by lipases. Advantages

Drawbacks

• 100% yield is feasible • Expensive racemization catalysts usually required • Access to only one enantiomer • Efficiency • Racemization reactions repertoire limited by lipase • High stability enantioselectivity • Broad substrate scope

et al., 2011; Ni and Xu, 2012; Simon et al., 2013) and transaminases (amines) (Kohls et al., 2014; Koszelewski et al., 2010; Mathew and Yun, 2012; Stewart, 2001), among other enzymes. Some advantages and drawbacks of DKR reactions co-catalyzed by lipases are summarized in Table 2. In the following sections, chemoenzymatic DKR co-catalyzed by lipases are discussed in detail according to the substrates and methods used for racemization. 2.1. Dynamic kinetic resolution catalyzed by lipases and metals The combination of lipases and metals in a one-pot kinetic resolution/racemization reaction is a useful method for the DKR of racemic compounds, especially alcohols and amines (Ahn et al., 2008; Hoyos et al., 2012; Martín-Matute and Bäckvall, 2007; Pàmies and Bäckvall, 2003, 2004). In most cases, a lipase-catalyzed transesterification or ester aminolysis reaction is performed to produce, respectively, an enantioenriched ester or amide (Fig. 6a), while a racemization reaction catalyzed by a metal or a metallic complex, via hydrogen transfer (Fig. 6b) or via the formation of π-allyl complex (Fig. 6c), takes place simultaneously (Pàmies and Bäckvall, 2003, 2004). Compatibility between the lipase and the metal catalyst is crucial for a DKR to occur. It must be taken in account that mutual inactivation may occur and that some metal catalysts work only at high temperatures or require additives, such as strong bases, which may be detrimental to enzymatic performance. The use of bulky organometallics and physical entrapment of the metal or biocatalyst has been reported to minimize interaction between chemo and biocatalyst, though it can slow reaction rates due to diffusion limitations (Pollock et al., 2012). The efficiency of a lipase/metal-catalyzed DKR reaction can also be affected by parameters such as solvent, temperature and nature of the acyl donor. In general, lipases show better activity in aprotic organic solvents of low polarity like hexane (Carrea and Riva, 2000; Schneider, 2011), while racemization rates can be lower in such solvents due to poor solubility of the metal catalysts (Pàmies and Bäckvall, 2001). The selected acyl donor should not release substances during the reaction that can interfere

with the metal catalyst or compete with the substrate by metal center, thus affecting racemization (Larsson et al., 1997; Persson et al., 1999). High temperatures can cause lipase denaturation and therefore should be avoided, though the use of immobilization techniques and thermostable lipases, such as Candida antarctica lipase B (CAL-B), has helped to broaden the range of temperature under which a DKR can be performed, thus enabling the use of metal catalysts that require thermal activation. 2.1.1. Dynamic kinetic resolution of secondary alcohols and derivatives catalyzed by lipases and metals The use of metals in chemoenzymatic dynamic kinetic resolution of alcohols has its origin in the work of Williams, who described in 1996 the dynamic kinetic resolution of 1-phenylethanol by combining [Rh2(OAc)4] with Pseudomonas fluorescens lipase in a one-pot reaction. The reaction was carried out at 20 °C using vinyl acetate as acyl donor, in the presence of stoichiometric amount of acetophenone, to give (R)-1-phenylethanol with optical purity of 98%, but only 60% conversion after 72 h (Dinh et al., 1996). Shortly thereafter, Bäckvall and co-workers succeeded to perform the chemoenzymatic dynamic kinetic resolution of 1-phenylethanol (Fig. 7a) and other aliphatic and benzylic alcohols with high optical purity and moderate yields at 70 °C and reaction times of 24–72 h (Larsson et al., 1997; Persson et al., 1999). The catalytic system used was composed of immobilized C. antarctica lipase B (CAL-B) and the Shvö catalyst (Menashe and Shvo, 1991) (1, Fig. 7b), a Ru (II) complex that is homogeneous under conditions employed in dynamic kinetic resolutions and requires heat activation to dissociate in the active species 1a and 1b (Fig. 7b) (Casey et al., 2001; Comas-Vives et al., 2007). The choice of both chemo and biocatalyst was crucial for the success of the method. Because one of the oxygens of 1b acts as a base to abstract a proton from the alcohol, Shvö catalyst, unlike many Ru-based racemization catalysts, does not require external base addition, an advantage regarding compatibility with enzymes. On the other hand, 1 requires heat activation, a potential drawback for a chemoenzymatic DKR that was overcome by the choice of an immobilized thermostable biocatalyst, namely Novozyme 435, a commercially immobilized form of the thermostable C. antarctica lipase B, an enzyme that, for this reason, is widely applied in chemoenzymatic DKR reactions. Another key issue was the fact that usual acylating agents, such as vinyl and isopropenyl acetate, were found to be ineffective in the dynamic kinetic resolution of 1-phenylethanol co-catalyzed by Shvö catalyst. Alkenyl esters are widely employed in kinetic resolution of alcohols, since they release aldehydes and ketones instead of alcohols during the outcome of the reaction, thus avoiding the reversible reaction. These carbonyl compounds, however, were found to interfere with Shvö catalyst and to

Fig. 6. Reactions involved in DKR co-catalyzed by lipases and metals. (a) Lipase-catalyzed acyl transfer; (b) metal-catalyzed racemization via hydrogen transfer; (c) metal-catalyzed racemization via π-allyl complex. M = metal, Nu = nucleophile with weak C–Nu bond.

Please cite this article as: de Miranda AS, et al, Lipases: Valuable catalysts for dynamic kinetic resolutions, Biotechnol Adv (2015), http:// dx.doi.org/10.1016/j.biotechadv.2015.02.015

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Fig. 7. (a) Dynamic kinetic resolution of 1-phenylethanol co-catalyzed by Candida antarctica lipase B and Shvö catalyst; (b) Shvö catalyst (1) and its monomers 1a and 1b.

act as hydrogen acceptor, thus resulting in low yields due to oxidation of the substrate. Simple or activated alkyl esters, such as trifluoroethyl esters, were not suitable either, due to low reactivity or release of alcohols that competed with the substrate for the racemization catalyst. Finally, p-chlorophenyl acetate was proven to be a proper acyl donor, since it was found to be more reactive than alkyl esters and to release phenol during the reaction, which does not act as a hydrogen acceptor, thus minimizing substrate oxidation. The choice of an aryl ester as acylating agent was, therefore, crucial for the success of the DKR of 1phenylethanol catalyzed by CAL-B and Shvö catalyst. (Larsson et al., 1997; Persson et al., 1999). Since the pioneer work of Bäckvall (Larsson et al., 1997; Persson et al., 1999), 1 has been applied to the DKR of a wide range of substrates (Atuu and Hossain, 2007; Felluga et al., 2009; Hoyos et al., 2006, 2008, 2011a, 2011b; Huerta et al., 2000; Jung et al., 2000a, 2000b; Kiełbasiński et al., 2005; Kim et al., 2001; Millet et al., 2010; Pàmies and Bäckvall, 2001, 2002a, 2002b; Runmo et al., 2002; Strübing et al., 2007; Vallin et al., 2009; Verzijl et al., 2005) and new Ru (II)-based racemization catalysts compatible with lipases were discovered and developed, many of which are free from some drawbacks exhibited by 1 in DKR reactions, such as: the need for high temperatures, long reaction times and, in some cases, requirement of additives such as the substrate corresponding ketone (Larsson et al., 1997; Persson et al., 1999) or hydrogen sources to minimize substrate oxidation (Kim et al., 2001; Pàmies and Bäckvall, 2002a; Runmo et al., 2002); incompatibility with the use of alkenyl esters such as vinyl acetate (Larsson et al., 1997; Persson et al., 1999) and instability under aerobic conditions. Several complexes of Ru (II) have been combined with lipases for DKR of alcohols, some of which are depicted in Fig. 8 (Agrawal et al., 2014; Akai et al., 2004; Benaissi et al., 2009; Bogár and Bäckvall, 2007; Bogár et al., 2007a, 2007b; Chen and Yuan, 2010; Choi et al., 2002, 2004; Csjernyik et al., 2004; Das and Nanda, 2012; Do et al., 2010; Edin et al., 2006; Ema et al., 2012; Engstrom et al., 2011; Fransson et al., 2006; Hilker et al., 2006; Johnston et al., 2010; Kim et al., 2003, 2004, 2005, 2008; H. Kim et al., 2011; C. Kim et al., 2013; S. Kim et al., 2013; Ko et al., 2007; Koh et al., 1999; Krumlinde et al., 2009; Larsson et al., 1997; Lee et al., 2000; Leijondahl et al., 2009; Lihammar et al., 2011; Mangas-Sánchez et al., 2009; Martín-Matute et al., 2004, 2005, 2006; Mavrynsky et al., 2009, 2013; Merabet-Khelassi et al., 2011; Norinder et al., 2007; Päiviö et al., 2011; Riermeier et al., 2005; Thalén et al., 2010; Träff et al., 2008, 2011; Warner et al., 2012). These catalysts are homogeneous under the conditions employed in DKR reactions and present differences regarding scope, mode of activation, requirement of additives, compatibility with acyl donors, stability, efficiency and cost. Catalyst 4 is particularly one of the most efficient Ru (II) complexes used for racemization in chemoenzymatic dynamic kinetic resolutions (Csjernyik et al., 2004; Martín-Matute et al., 2004, 2005). This catalyst

is activated by bases such as t-BuOK and is able to quickly racemize alcohols under mild temperatures in the presence of lipases, so that it has been employed in the DKR of several alcohols (Bogár and Bäckvall, 2007; Bogár et al., 2007a, 2007b; Csjernyik et al., 2004; Edin et al., 2006; Ema et al., 2012; Engstrom et al., 2011; Fransson et al., 2006; Johnston et al., 2010; S. Kim et al., 2013; Krumlinde et al., 2009; Leijondahl et al., 2009; Lihammar et al., 2011, 2013; Mangas-Sánchez et al., 2009; Martín-Matute et al., 2004, 2006; Norinder et al., 2007; Shuklov et al., 2014; Solarte et al., 2014; Thalén et al., 2010; Träff et al., 2008, 2011; Warner et al., 2012), including the large-scale DKR of 1phenylethanol to give (R)-1-phenylethanol (Bogár et al., 2007a). The recently reported catalyst 12 is the first cationic ruthenium catalyst to be applied in a chemoenzymatic DKR. It is able to racemize secondary alcohols at room temperature in the presence of mild bases, such as K2CO3, thus being suitable for combination with lipases. This catalyst was used to prepare optically pure aliphatic and aromatic alcohols from ketones in a sequential reduction/DKR reaction (Fernández-Salas et al., 2014) (Fig. 9). Some examples of the application of dynamic kinetic resolutions using lipases and complexes of Ru (II) include: obtaining of 1,3aminoacetates with high optical purity and diastereomeric ratio in an efficient process involving an organocatalytic step and a tandem reaction of reduction and dynamic kinetic resolution catalyzed by 1 and immobilized CAL-B (Fig. 10) (Millet et al., 2010); resolution of a haloalcohol using 4 and immobilized Burkholderia cepacia lipase (BCL) as the key step in the synthesis of (R)-bufuralol, a β-adrenoceptor blocking agent (Fig. 11) (Johnston et al., 2010); application of a DKR of homoallyl alcohols catalyzed by 4 and CAL-B to the synthesis of (R)goniothalamin, a cytotoxic natural product (Fig. 12) (Warner et al., 2013); synthesis of decalines by a one-pot “domino” reaction involving a DKR co-catalyzed by CAL-B and 2b, a particularly useful catalyst for racemization of allylic alcohols, and a Diels Alder reaction, in an efficient and green process with high atomic economy (Fig. 13) (Akai et al., 2004). In addition to the aforementioned examples, a wide variety of optically pure hydroxylated compounds have been obtained by dynamic kinetic resolution co-catalyzed by lipases and Ru (II) complexes, including benzyl and aliphatic alcohols, diols, hydroxyesters, hydroxyamides, αhydroxy ketones and benzoins (Agrawal et al., 2014; Felluga et al., 2009; Hoyos et al., 2006, 2008, 2011a, 2011b). Recently, Kim and colleagues described the combination of Ru-based racemization catalysts with an ionic-surfactant-coated B. cepacia lipase (ISCBCL) as a promising catalytic system for the DKR of secondary alcohols (H. Kim et al., 2011; C. Kim et al., 2013). The ISCBCL was found to be much more active in DKR reactions than Novozyme 435, the widely used commercial immobilized CAL-B, being able to perform the so far fastest DKR of 1-phenylethanol (1 h). The new biocatalyst also showed

Please cite this article as: de Miranda AS, et al, Lipases: Valuable catalysts for dynamic kinetic resolutions, Biotechnol Adv (2015), http:// dx.doi.org/10.1016/j.biotechadv.2015.02.015

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Fig. 8. Ru-based racemization catalysts used with lipases in chemoenzymatic DKR of alcohols.

a broader substrate scope and could be employed together with Ru (II) catalysts such as 3 and 6 in the DKR of sterically demanding substrates, including propargylic alcohols, diarylmethanols and alkyl aryl alcohols with long alkyl side chains to give enantiomeric pure (R)-esters. Importantly, a switch in enantiopreference was observed when TMSprotected α-aryl propargyl alcohols were used as substrate, so that not only optically pure (R)-esters could be obtained, but also their complementar S enantiomer, which could be recovered by desilylation with TBAF after DKR reaction (Fig. 14). In addition to Ru, racemization catalysts based in other metals such as Ir, Pd and V (Fig. 15) have also been employed in the chemoenzymatic DKR of alcohols. Dynamic kinetic resolutions of benzylic and aliphatic alcohols catalyzed by CAL-B in the presence of Ir complexes 13 (Marr et al., 2007) and 14 (Sato et al., 2012) with moderate to high yields and reaction times between 8 and 12 h have been described. Notably, both catalysts operate without addition of an external base and 14 can also be used in DKR of secondary alcohols under mild temperatures (Fig. 16).

Pd complexes such as 15 (Allen and Williams, 1996) and 16 (Choi et al., 1999) catalyze racemization of allylic esters under conditions compatible with use of lipases via π-allyl complex formation. The catalyst 16 is more effective than 15 and has been combined with immobilized B. cepacia and C. antarctica lipase B at room temperature to furnish allylic alcohols with moderate to high yields (70–87%) and high optical purity (97–99% ee), although longer reaction times are required (1.5–6 days). Deska and co-workers described the first DKR of allenols with axial chirality through a combination of a Pd catalyst (17) with immobilized porcine pancreatic lipase (PPL) (Fig. 17) (Deska et al., 2010). The resulting esters were obtained with moderate optical purity, which was increased by a subsequent hydrolysis step catalyzed by the same enzyme. The combination of oxovanadium catalysts and lipases have been reported to be useful for DKR of allylic alcohols (Akai, 2014; Akai et al., 2004, 2006; Egi et al., 2013; Komaki et al., 2013). Akai et al. described a method for the preparation of optically pure allylic alcohols by combining reactions of racemization and isomerization catalyzed by

Fig. 9. Chemoenzymatic one-pot ketone reduction/DKR of alcohol.

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Fig. 10. Synthesis of chiral 1,3-aminoacetates via organocatalyzed Mannich reaction followed by ketone reduction and chemoenzymatic DKR of alcohol.

Fig. 11. Application of chemoenzymatic DKR in the synthesis of (R)-bufuralol.

18 or 19 (a polymer-bound vanadyl phosphate) and a chemo- and enantioselective transesterification catalyzed by immobilized CAL-B to give a single allyl ester from regio- and stereoisomeric substrates (Fig. 18a) (Akai et al., 2010). The reaction includes vanadiumcatalyzed racemization and 1,3-transposition of hydroxyl group, resulting in a dynamic equilibrium of regioisomers which converge to a single optically pure product by chemo- and stereoselective lipasecatalyzed acylation. Recently, the method has been optimized with the immobilization of 18 in a mesoporous silica (18–MPS), resulting in a reusable and more efficient catalyst, which also presents better compatibility with lipases. The catalyst was applied in combination with immobilized B. cepacia lipase in the synthesis of (R)-imperanene (Fig. 18b) and has also been found to be useful for the DKR of benzyl, furyl and propargyl alcohols (Egi et al., 2013). VOSO4 has been also reported to be useful as a heterogeneous racemization catalyst in the DKR of alcohols (Wuyts et al., 2007). This catalyst is cheap and readily available, non-sensitive to oxygen and catalyzes the racemization of benzylic alcohols without additives or

co-catalysts, probably via formation of a carbocation by acid catalyzed water loss followed by re-addition. However, the catalyst was found to be incompatible with some commonly used acyl donors, such as vinyl and isopropenyl acetate, and physical separation of lipase and metal catalyst was required for an efficient VOSO4/CAL-B co-catalyzed DKR of 1-phenylethanol. In addition to Ru, Ir and V, the use of Al-based racemization catalysts for DKR of alcohols has also been reported (Berkessel et al., 2006). Racemization is catalyzed by aluminum alkoxides and is thought to occur through Oppenauer oxidation of the alcohol followed by nonstereoselective Merweein–Pondorf–Verley reduction of the resulting ketone. Interestingly, Al(OtBu)3 was found to lose its activity in the presence of lipases, while aluminum alkoxides generated in situ from AlMe3 and bidentate ligands, such as binol and 2,2′-bisphenol, were shown to be compatible with lipases and exhibited increased activity, probably by avoiding catalyst aggregation. These catalysts were combined with immobilized CAL-B at room temperature to perform a DKR of some aliphatic and benzylic alcohols with high yields (95–99%) and

Fig. 12. Application of chemoenzymatic DKR in the synthesis of (R)-goniothalamin.

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Fig. 13. Synthesis of decalins by one-pot “domino” chemoenzymatic DKR and Diels Alder reaction.

Fig. 14. Preparation of enantiopure (S)- and (R)-propargyl esters. (a) (S)-selective chemoenzymatic DKR of a TMS-protected propargyl alcohol catalyzed by ISCBCL and Ru followed by desilylation; (b) (R)-selective KR of a non-silylated propargyl alcohol catalyzed by ISCBCL.

enantioselectivity (92–98% ee) in 3–24 h. However, the method is limited by the requirement of “specific acylating agents”, i.e. the enol ester of the ketones derived from the substrates. In spite of numerous works reporting the chemoenzymetic DKR of alcohols in the literature, the application of this method beyond the academy is limited, mainly due to the high cost and low stability of racemization catalysts, which are predominantly homogeneous. In fact, there are few examples of heterogeneous and immobilized racemization catalysts compatible with lipases (Akai et al., 2010; Egi et al., 2013; Han et al., 2010a; Långvik et al., 2010; Nieguth et al., 2014;

Thalén et al., 2010; Wieczorek et al., 2011). The development of these catalysts, which are in general reusable and more suitable for industrial applications, is still a challenge. Nevertheless, immobilized lipases combined to some heterogeneous acid catalysts, such as zeolite and nanozeolite microspheres, have emerged as an efficient catalytic system for DKR of benzylic alcohols (Chen et al., 1987; Li et al., 2012; Lozano et al., 2006, 2009; J. Wang et al., 2013; Z. Wang et al., 2013; Wuyts et al., 2003, 2005; Zhu et al., 2007) and acyloins (Ödman et al., 2005). The reported methods include one-pot and two-pot reactions in biphasic systems, ionic liquids and

Fig. 15. Ir-, Pd- and V-based racemization catalysts used in chemoenzymatic DKR of alcohols.

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Fig. 16. DKR of 1-phenylethanol catalyzed by lipase and iridium complex 14.

Fig. 17. Chemoenzymatic DKR of allenols followed by lipase-catalyzed ester hydrolysis.

supercritical CO2, as well as reactions in continuous flow microreactors. A recent work describes the DKR of 1-phenylethanol inside a flow microreactor, where nanozeolites were used as racemization catalyst and also as support for lipases in separate compartments. The reaction was performed under continuous flow conditions, providing (R)-1phenylethanol with high yield (97%) and optical purity (N 99% ee) in less than 30 min (Z. Wang et al., 2013). Very recently, Wang and coworkers (Li et al., 2015; W. Wang et al., 2014) described a core-shell nanozeolite@enzyme bi-functional microsphere catalyst, consisting

of CAL-B supported on H-β zeolite microspheres coated with polydiallydimethylammonium chloride. The core acts as racemization catalysts while the enzymatic shell catalyzes the kinetic resolution step and protects products and substrates from the acidic core, thus minimizing by-product formation and product racemization. The bifunctional catalyst was applied in the DKR of four aromatic secondary alcohols, leading to optically pure esters with moderate to high yields (83–91%) and was proven to be more effective than the mechanically mixed H-β zeolite microspheres and commercial immobilized CAL-B.

Fig. 18. DKR reactions co-catalyzed by lipase and vanadium. (a) Chemoenzymatic DKR of regioisomeric allylic alcohols; (b) application of chemoenzymatic DKR in the synthesis of (R)-imperanene.

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Fig. 19. Chemoenzymatic DKR of benzylic amines from their respective ketoximes.

Fig. 20. DKR of 1-phenylethylamine catalyzed by CAL-B and Pd supported on silica functionalized with 3-aminopropyl groups (Pd/AP-SiO2).

2.1.2. Dynamic kinetic resolution of amines catalyzed by lipases and metals In a similar way to alcohols, optically pure amines can be obtained from racemates with a maximum yield of 100% by DKR reactions cocatalyzed by lipases and metals. Because amines are strong ligands for metals, their racemization is usually more challenging, presenting some drawbacks related to requirement of harsh conditions, possibility of C–N cleavage by metal catalysts and sensitivity of imine intermediates to moisture (Y. Kim et al., 2011; Lee et al., 2010). In fact, in comparison to alcohols, there are fewer catalysts able to racemize amines under conditions compatible with the use of lipases, so that the repertoire of methods for chemoenzymatic DKR of these substrates are narrower. Metal catalysts currently available for this purpose comprise heterogeneous catalysts based on Pd, Ni and Co and homogeneous catalysts based on Ru and Sr (Jiang and Cheng, 2013). The first chemoenzymatic DKR of amines was reported by Reetz and Schimossek (1996). The reaction was co-catalyzed by immobilized CALB and Pd/C in triethylamine at 50–55 °C and ethyl acetate was used as acyl donor. By using this method, 1-phenylethylamine was resolved leading to the corresponding amide with high optical purity (99% ee) but long reaction time (8 days) and moderate conversion (75–77%). From this pioneer work, other Pd-based catalysts were studied, culminating in the development of more efficient methods for DKR of amines by combination of metal and lipases. Pd-catalyzed racemization of amines occurs via hydrogen transfer and involves the formation of imines, which are prone to hydrolysis and condensation with other amines, thus leading to several byproducts, such as secondary amines and imines, hydrocarbons and ketones (de

Miranda et al., 2014; Kim et al., 2007; Parvulescu et al., 2005, 2007; Reetz and Schimossek, 1996). In order to minimize the formation of these byproducts in DKR of amines, Choi and co-workers reported a strategy based on the employment of ketoximes as substrates, which are reduced in situ to generate the corresponding amines gradually, so as to maintain free amines at low concentration during the reaction (Choi et al., 2001). This strategy was used in a DKR of amines catalyzed by CAL-B and Pd/C, leading to amides with high conversions (N98%) and optical purity (94–99% ee) (Fig. 19). The method, however, requires long reaction time (5 days) and is restricted to benzylic amines. Parvulescu and co-workers reported the racemization of amines using Pd on various supports, including BaSO4, CaCO3, SrCO3, SiO2, zeolites and carbon, among others (Parvulescu et al., 2005, 2007). It was found that Pd on neutral supports, such as BaSO4, CaCO3 and SrCO3, catalyzes amine racemization more selectively than Pd on acidic supports, such as charcoal, silica and zeolites, since the rate of condensation of imine intermediate with the substrate is higher for the latter, favoring the formation of byproducts. It was also found that the rate and selectivity of racemization could be increased by the presence of H2 at an optimal pressure of 0.01 MPa, while racemization was inhibited at higher H2 pressures due to suppress of substrate dehydrogenation. The effect of the method of heating was also studied for racemization of amines catalyzed by Pd/BaSO4 and Pd/CaCO3. Microwave irradiation was found to lead to more selective and significantly faster racemization reactions in comparison to conventional heating (A. Parvulescu et al., 2008). Among supported Pd catalysts studied by Parvulescu and colleagues, Pd/BaSO4, Pd/CaCO3 and Pd supported on silica functionalized

Fig. 21. Application of chemoenzymatic DKR of amines in the synthesis of rasagiline.

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Fig. 22. Application of chemoenzymatic DKR in the synthesis of (R)-cinacalcet.

Fig. 23. Application of chemoenzymatic DKR in peptide synthesis.

with 3-aminopropyl groups (Pd/AP-SiO2) were found to be the most suitable catalysts for combination with lipases, the latter being the most efficient for chemoenzymatic DKR of 1-phenylethylamine and reusable for at least three cycles in this reaction (Fig. 20) (Parvulescu et al., 2009). Pd/BaSO4 has been employed with immobilized CAL-B at 70 °C for DKR of several benzylic amines (Parvulescu et al., 2007, 2009), including selenium-containing amines (Andrade et al., 2009), with satisfactory yields in 24–72 h, being reused in some cases (Parvulescu et al., 2009). Pd/CaCO3 has been employed with immobilized CAL-B at 100 °C to furnish chiral benzylic amides with high conversions (84–97%) and optical purity (95–98% ee) in less than 2 h by using microwave irradiation (A. Parvulescu et al., 2008).

The aforementioned catalysts, however, present a scope limited to primary benzylic amines, being inefficient and poorly selective for the racemization of aliphatic amines. For this purpose, Kim and coworkers described a catalyst consisting of Pd nanoparticles supported on aluminum hydroxide (Pd/AlO(OH)), which have been combined with immobilized CAL-B in the DKR of aliphatic amines to furnish enantiopure amides with high yields and short reaction times (Kim et al., 2007). The reaction is performed at high temperature, with relatively high Pd loading and H2 is needed to avoid the formation of byproducts, but it is fast (4 h) and the lipase/metal catalyst system is reusable for at least eight cycles. Kim and colleagues also described an efficient method for the DKR of benzylic amines using a similar

Fig. 24. Chemoenzymatic DKR of mexiletine followed by enzymatic polymerization and formation of micelles.

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Fig. 25. Chemoenzymatic DDKR of mexiletine.

Pd/AlO(OH) catalyst with smaller average diameter of Pd nanoparticles in combination with immobilized CAL-B to provide optically pure amides in 6 h at 70 °C (Kim et al., 2010). The method was proven to be useful for the preparation of a chiral intermediate in the synthesis of rasagiline, a selective monoamine oxidase B inhibitor used in the management of Parkinson's disease (Ma et al., 2014) (Fig. 21). Shakeri at al. recently reported an even more robust and efficient racemization catalyst, which consists of Pd nanoparticles supported on aminofunctionalized mesocellular foam (AmP-MCF) (Shakeri et al., 2011). This catalyst is able to racemize benzylic amines at low catalyst loadings (1.25–2.5 mol%) and at relatively low temperature (50 °C), which allowed it to be combined with lipases that are not stable at higher temperatures. In fact, Pd nanoparticles supported on AmP-MCF were employed in the first successful DKR of amines catalyzed by B. cepacia lipase, whose use in such reactions was not possible so far due to harsh conditions required for amine racemization (Gustafson et al., 2014). In a recent approach, Bäckvall and co-workers (Engström et al., 2013) created a heterogeneous hybrid catalyst by co-immobilizing

CAL-B and Pd nanoparticles in mesocelullar foam (MCF), so that each pore of it contains both an anzymatic and a metal component. This “artificial metalloenzyme” was able to efficiently catalyze the DKR of 1-phenylethylamine, thus presenting a “deracemase” activity, which is not displayed by any known natural enzyme. Moreover, immobilization of metal and lipase in the same cavities of the support led to more efficient and robust DKR, showing the potential of the concept of coimmobilization of catalysts with different activities for the development of new catalysts for tandem and one-pot reactions. Some relevant examples of the application of the Pd/lipase catalytic system in organic synthesis include: obtaining of optically pure benzylic amide from its racemic ketoxime through DKR catalyzed by Pd/AlO(OH) and immobilized CAL-B as a key step in the synthesis of cinacalcet, a potent calcimimetic (Fig. 22) (Han et al., 2010b); DKR of amides derived from amino acids for the synthesis of optically active di- and tripeptides (Fig. 23) (Choi et al., 2009); and dynamic kinetic resolution of the antiarrhythmic mexiletine in a tandem reaction with enzymatic polymerization in the preparation of micelles containing this drug (Fig. 24) (Qian et al., 2013).

Fig. 26. Mechanism of amine racemization catalyzed by Shvö-type Ru complexes.

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Fig. 27. Application of chemoenzymatic DKR in the synthesis of norsertraline.

Fig. 28. Chemoenzymatic DKR of aromatic and heteroaromatic bioactive β-isopropylamines.

Despite the advances in the development of catalysts based on Pd, its application in chemoenzymatic DKR of amines is still limited to a small range of substrates, so that more studies are required to define or expand the scope of existing methods as well as to develop more versatile methods. In addition to Pd, Ni nanoparticles (Geukens et al., 2013) and cheaper metals such as Raney-Co and Raney-Ni (A.N. Parvulescu et al., 2008) have been described as heterogeneous catalysts for racemization of amines, the latter being useful for one-pot chemoenzymatic DKR of

aliphatic amines, though only at high temperature (70–80 °C) and with long reaction times (48–96 h). Efficient DKR of benzylic amines with this catalyst, however, were not possible in one-pot reaction. Raney Nicatalyzed racemization was recently applied in the chemoenzymatic dynamic double kinetic resolution (DDKR) of the antiarrhythmic agent mexiletine (Xia et al., 2014) (Fig. 25). In this process, a racemic ester derived from an alcohol containing a stereogenic center is employed as acyl donor for the resolution of the amine, so that the DKR of the amine and the KR of the ester are performed simultaneously. Raney Ni was found

Fig. 29. Chemoenzymatic DKR of β-amino esters. (a) Preparation of (S)-β-amino esters via DKR co-catalyzed by CAL-A and Shvö catalyst; (b) preparation of (S)-β-amino esters via DKR co-catalyzed by Pd and CAL-A.

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Fig. 30. Chemoenzymatic DKR of 1-methyl-1,2,3,4,-tetrahydroisoquinoline.

to be especially suitable for DDKR of mexiletine, since it avoided the formation of side products derived from alcohols, which were observed when Pd-based catalysts were used. Recently, Shi and colleagues described the preparation and use of a platinum-encapsulated zeolitically microcapsular catalyst in the DKR of 1-phenylethylamine. The corresponding optically pure amide was obtained with conversion of 80% after 35 h and the catalyst could be reused for at least 5 times (Shi et al., 2012). Among homogeneous racemization catalysts, Shvö catalyst (1) and its p-methoxy derivative 20 have proven to be useful in the DKR of benzylic and aliphatic primary amines (Paetzold and Bäckvall, 2005; Thalén et al., 2009), the latter being less active, but more selective. A proposed mechanism for amine racemization catalyzed by complexes of this nature is depicted in Fig. 26. Studies based on kinetic isotopic effect suggest that, at least for racemization of 1-phenylethylamine, the βhydride elimination is the rate-determining step of the reaction (Thalén et al., 2009). Recent studies also suggest that the reaction occurs by means of an inner-sphere mechanism, i. e. H-transfer occurs inside the coordination sphere of the metal in a stepwise fashion (Vaz et al., 2013). The chemoenzymatic DKR of amines co-catalyzed by lipase and 1 or 20 generally requires reaction times of 24–72 h and temperatures of 90–110 °C, since 1 and 20 are thermally activated. Addition of

Na2CO3 usually results in more efficient racemization, probably by neutralizing traces of acids derived from the acyl donor, the enzyme or the support, which may interfere with catalyst activity (Paetzold and Bäckvall, 2005). Addition of 2,4-dimethyl-3-pentanol (DMP), an alcohol that is not accepted as substrate by lipases used in these reactions, can enhance racemization selectivity by acting as a hydrogen donor, thus minimizing the formation of byproducts from the imine intermediate generated during the reaction (Fig. 26) (Veld et al., 2007). This effect can also be observed when acyl esters that release isopropanol are used as acyl donors for the enzymatic step (Paetzold and Bäckvall, 2005). However, acetone generated from isopropanol oxidation can condense with the substrate to give imines, whose subsequent reduction results in isopropylamines as byproducts. On the other hand, acyl donors such as alkyl methoxyacetates (Mavrynsky and Leino, 2014; Rodriguez-Mata et al., 2011; Thalén and Bäckvall, 2010; Veld et al., 2007) and benzyl carbonate (Hoben et al., 2008; Thalén et al., 2009) have been successfully applied in DKR reactions co-catalyzed by lipases and Ru. Alkyl methoxyacetates are more reactive than simple alkyl acetates towards lipase-catalyzed aminolysis, leading to faster reactions (Veld et al., 2007) while the use of carbonates produces carbamates, which can be easily hydrolyzed, thus allowing the recovery of the corresponding optically pure chiral amines under mild conditions after the DKR reaction (Hoben et al., 2008).

Fig. 31. DKR of amines employing racemization mediated by thiyl radicals.

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Fig. 32. Application of chemoenzymatic DKR in the synthesis of ampicillin.

Fig. 33. DKR of proline and pipecolic acid esters.

Some examples of DKR of amines catalyzed by lipase and Ru (II) complexes include: DKR of 1-phenylethylamine in 45 mmol scale using immobilized CAL-B, catalyst 20 and alkyl methoxyacetates with high yields (83–90%) and optical purity (97–98% ee) in 72 h (Thalén and Bäckvall, 2010) and application in the synthesis of norsertraline from commercial racemic 1,2,3,4-tetrahydro-1-naphthylamine (Fig. 27) (Thalén et al., 2009); dynamic kinetic resolution of aromatic β-isopropylamines and bioactive heteroaromatic amines (Fig. 28) (Rodriguez-Mata et al., 2011). Recently, a method for obtaining (S)-β-amino esters was developed by Bäckvall's group (Shakeri et al., 2010). The method relies on the combination of catalysts 1 or 20 with the enzyme C. antarctica lipase A (CAL-A) immobilized on amino functionalized mesocellular foam (AmP-MCF) (Fig. 29a). The immobilization of this enzyme was crucial, since it not only led to a significant increase in its enantioselectivity but also improved its thermal stability, thus enabling it to work under the conditions required for racemization catalyzed by Ru (II) complexes. Thereafter, the method was optimized by replacement of Ru (II) complexes by a reusable heterogeneous catalyst based on Pd nanoparticles supported on aluminum hydroxide (Pd/AlO(OH)), which was successfully applied in the DKR of benzylic and aliphatic β-aminoesters (Fig. 29b) (Engström et al., 2011). In addition to Ru (II)-based racemization catalysts, a complex of Ir (III) ([IrI2(Cp*)]2) (21) (Fig. 30) was described as homogeneous catalyst for racemization of amines under conditions compatible with the use of lipases. This complex is stable to air and moisture and catalyzes the racemization of secondary and tertiary amines under mild conditions and low catalyst loadings, though it is not suitable for racemization of primary amines due to extensive byproduct formation (Blacker et al., 2007;

Stirling et al., 2007). By combining 21 with Candida rugosa lipase (CRL) for the DKR of isoquinoline-based amine (Fig. 30), Page and coworkers conducted the first chemoenzymatic DKR of a secondary amine (Stirling et al., 2007), a type of substrate that are difficult to racemize with most catalysts used in chemoenzymatic DKR reactions and for whose resolution there are still few methods available. The reaction occurs at 40 °C, requires low racemization catalyst loading (0.2 mol%) and can be performed on a gram scale leading to the product with high yield and optical purity. Alternatively, a metal-free racemization of some primary and secondary amines can be mediated by thiyl radicals photochemically generated from suitable alkylthiols in the presence of α,α′azoisobutyronitrile (AIBN) (El Blidi et al., 2009; Escoubet et al., 2006a, 2006b; Gastaldi et al., 2007; Poulhès et al., 2011; Routaboul et al., 2007). This approach has been used in chemoenzymatic DKR of aliphatic amines, including functionalized amines, providing amides under mild conditions and short reaction times with good yield and high enantiomeric excess in many cases (Fig. 31) (Poulhès et al., 2011). This method, however, presents limited scope, being ineffective for racemization of primary benzylic amines, and it is incompatible with the use of alkyl 2-methoxyacetates, acyl donors often employed in DKR of amines.

2.2. Dynamic kinetic resolution catalyzed by lipases in the absence of metals 2.2.1. Dynamic kinetic resolution of amino acids and derivatives Lipases may be useful biocatalysts in the DKR of amino acids and derivatives whose racemization are feasible without metal catalysis. In these reactions, lipases can catalyze the acylation of the amino group

Fig. 34. DKR of isoindolinic methyl ester.

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Fig. 35. Preparation of (S)-γ-fluoroleucine through lipase-catalyzed dynamic kinetic resolution under continuous flow.

Fig. 36. DKR of cis-cyclopentane-1,2-diamine derivatives.

or hydrolysis of esters of amino acids, while the racemization can be mediated by imine formation or catalyzed by bases. A method for obtaining enantiomerically pure (R)-phenylglycine amide, an intermediate in the synthesis of ampicillin, through DKR of the methyl ester of phenylglycine by CAL-B-catalyzed aminolysis coupled to racemization mediated by pyridoxal was developed by Sheldon and co-workers (Fig. 32) (Hacking et al., 1998; Wegman et al., 1999). During the outcome of the reaction, condensation of aldehyde (pyridoxal) with the substrate generates an imine that is prone to racemization under mild conditions. Similarly, in a DKR of methyl esters of proline and pipecolic acid racemization is mediated by acetaldehyde released from (S)-enantioselective CAL-A-catalyzed aminolysis of vinyl ester (Fig. 33) (Liljeblad et al., 2004). A similar method was also applied in the DKR of piperazine-2-carboxylic acid methyl ester derivatives (Hietanen et al., 2012). DKR of amino acid esters catalyzed by lipase in which substrate racemization can be catalyzed by base (Paál et al., 2007) or occur without addition of any external catalyst (Morán-Ramallal et al., 2012) has been reported, the latter being a useful method for preparation of optically pure isoindolinic carbamates (Fig. 34), which are intermediates for the synthesis of bioactive compounds. Lipases may also be useful in obtaining optically pure amino acids by catalyzing the enantioselective opening of stereochemically labile racemic precursors, such as azalactones (Limanto et al., 2005; Truppo and Hughes, 2011; Truppo et al., 2008) and oxazolones (Bevinakatti et al., 1990; Brown et al., 2000; Crich et al., 1993; Gu et al., 1992). Truppo and Hughes recently described a method to prepare the enantiopure ester of (S)-γ-fluoroleucine, an intermediate in the synthesis of the drug odanacatibe, from continuous enzymatic alcoholysis of its respective azalactone using CAL-B immobilized in polymethacrylate resin (Truppo and Hughes, 2011). The process is performed in a continuous flow plug reactor and can be used for production of the amino acid on large scale (100 kg) with high yield and optical purity (Fig. 35).

A lipase-catalyzed DKR of monoprotected vicinal diamines in the absence of metal was also reported (Quijada et al., 2010). During the outcome of the reaction the asymmetric centers remain unaltered and racemization occurs due to migration of alkoxycarbonyl group. By using this method, cis-cyclopentane-1,2-diamine derivatives could be obtained with moderate to high yields and high optical purity (Fig. 36). 2.2.2. Dynamic kinetic resolution of cyanohydrins, hemiacetals and derivatives The addition of nucleophiles to prochiral aldehydes and ketones produces asymmetric hydroxylated compounds, which in turn can be substrates for lipase-catalyzed enantioselective transterifications. Under conditions in which the formation of these hydroxylated compounds is reversible, DKR reactions can be performed, so that all the substrate is converted into only one enantiomer (Fig. 37) (Kamal et al., 2008). This approach has been used for the DKR of cyanohydrins, hemithioacetals, hemiaminals and β-hydroxylated nitrocompounds. Cyanohydrins are versatile substrates in organic synthesis, being useful as precursors of various functionalized compounds (Holt and Hanefeld, 2009). Reversible base-catalyzed formation of cyanohydrins in situ from prochiral aldehydes and cyanide group donors, such as 2hydroxy-2-methylpropanenitrile, has been performed concurrently with enantioselective lipase-catalyzed acylation resulting in DKR of aliphatic (Veum and Hanefeld, 2005) and aromatic (Paizs et al., 2003, 2004; Sakai et al., 2008; Sundell et al., 2013; Veum and Hanefeld, 2004; Veum et al., 2005) cyanohydrins. This method was successfully applied in the preparation of chiral phenonothiazinic cyanohydrins, which are useful intermediates in the synthesis of bioactive substances (Fig. 38) (Paizs et al., 2004). Similarly, esters of optically pure hemithioacetals may be obtained by lipase-catalyzed transesterification of the respective hemithioacetal formed by reversible reaction from aldehydes and thiols (Brand et al., 1995; Hu et al., 2014; Sakulsombat et al., 2012a; Sanfilippo et al., 2005; Zhang et al., 2014a). This approach has proven to be useful for

Fig. 37. DKR of hydroxylated compounds by enzymatic resolution and racemization by reversible addition of nucleophile to carbonyl group.

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Fig. 38. Preparation of chiral cyanohydrins via lipase-catalyzed DKR.

the preparation of optically pure 1,3-oxathiolan-5-ones, structural motifs that are featured in antiretroviral drugs (Fig. 39a) (Zhang et al., 2014a), as well as in the synthesis of an intermediate of the enantiomer of lamivudine (Fig. 39b) (Hu et al., 2013). Other lipase-catalyzed DKR reactions whose racemization step is based on reversible addition of nucleophiles to carbonyl compounds include DKR of N-acyl hemiaminals (Sharfuddin et al., 2003) (Fig. 40) and preparation of optically pure β-nitroesters through one-pot lipasecatalyzed transesterification and nitroaldol reaction (Henry reaction) (Fig. 41) (Vongvilai et al., 2008). It is also worthy to note that lipase-catalyzed reactions have been used in “dynamic systemic resolutions” (DSR) (Herrmann, 2014; Sakulsombat et al., 2012b) of hemithioacetals (Zhang and Ramström, 2014), nitroalcohols (Vongvilai et al., 2007; Zhang et al., 2014b) and aminotriles (Vongvilai and Ramström, 2009), a process in which a dynamic system under thermodynamic control, consisting of compounds generated from reversible reactions, is coupled to an irreversible kinetically controlled reaction, thus resulting in re-equilibration of the system and amplification of the optimally reacting species. This technique cannot only lead to optically active products but is also useful

for evaluating the enzyme specificities. A recent example is the lipasecatalyzed DSR of a dynamic system composed of nitroalcohols and hemithiaocetals generated in situ by two different reversible reactions operated in parallel under the same conditions (Fig. 42). The reaction led to the amplification of only one product, which was obtained with high optical purity (91% ee), and also provided information about substrate specificity of B. cepacia lipase (Zhang et al., 2013). 2.2.3. Dynamic kinetic resolution employing biocatalytic racemization Biocatalytic racemizations are useful reactions for DKR and deracemizations, since they can be performed under mild conditions, thus leading to more selective and cleaner reactions. Moreover, due to compatibility issues, combination of biocatalysts is more likely to be successful than combination of bio- and chemocatalysts. Therefore, DKR of racemates employing biocatalytic reaction would be advantageous, especially for stereochemically stable substrates, such as alcohols and amines, which are difficult to racemize. Because biochemical process are predominantly stereospecific, racemization reactions are not often required in living organisms and there is only a small number of enzymes, called racemases, that are known to

Fig. 39. Lipase-catalyzed DKR of hemithioacetals. (a) Preparation of chiral 1,3-oxathiolan-5-ones via lipase-catalyzed lactonization (absolute configuration was not determined); synthesis of ent-lamivudine (b).

Fig. 40. DKR of N-acyl hemiaminals catalyzed by lipase.

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Fig. 41. Preparation of optically pure β-nitroesters by one-pot enzymatic transesterification and nitroaldol reaction.

catalyze such reactions (Schnell et al., 2003; Strauss and Faber, 1999). Most of them catalyze the racemization of amino acids or hydroxy acids, as is the case of mandelate racemase, one of the most studied racemases, which are able to accept a broad range of acyloins as substrate (Felfer et al., 2005). Racemases have been combined with other enzymes, such as aminomutase, acylases and amidases, in DKR reactions to provide optically pure α-hydroxyacids, amino acids and amino acid derivatives (Asano and Yamaguchi, 2005; Baxter et al., 2012; Cox et al., 2009; Hsu et al., 2006; Resch et al., 2010; Soriano-Maldonado et al., 2014; J. Wang et al., 2013; Z.-Y. Wang et al., 2014; Yasukawa and Asano, 2012). Nevertheless, only few DKR reactions co-catalyzed by racemases and lipases have been reported so far, since the former usually present low stability in non-aqueous solvents (Choi et al., 2007; Larissegger-Schnell et al., 2005; Strauss and Faber, 1999). In addition to the use of racemases, biocatalytic racemizations have also been accomplished by means of reversible hydrogen transfer or ketone amination catalyzed by a low stereoselective (Musa et al., 2013; Voss et al., 2010) or two stereocomplementary dehydrogenases (Bodlenner et al., 2009; Gruber et al., 2007; Voss et al., 2010) and ω-transaminases (Koszelewski et al., 2011). It is worthy to note that these approaches lead to racemization of secondary alcohols (Gruber et al., 2007; Musa et al., 2013) and amines (Koszelewski et al., 2011), substrates whose racemization usually requires metal catalysis. Application of these reactions in DKR process, however, is still to be done. On the other hand, whole cells of fungi and bacteria have been reported

to racemize hydroxyl acids, acyloins and secondary alcohols (Nestl et al., 2006a, 2006b; B. Nestl et al., 2007; B.M. Nestl et al., 2007). Among them, Lactobacillus paracasei, a microorganism that racemizes hydoxy acids, probably via an oxidation-reduction reactions sequence (Nestl et al., 2006a), was employed with lipases in a stepwise kinetic resolution/racemization reaction to furnish enantiopure 2-hydroxy-4phenylbutanoic acid and 3-phenyllatic acid (Larissegger-Schnell et al., 2006). The method provides access to both enantiomers of each substrate by switching between lipase catalyzed hydrolysis and transesterification. An interestingly and advantageous approach would be to use a single enzyme to perform both racemization and kinetic resolution steps. Such approach was made possible by the discovery that the lipase from B. cepacia displays a “racemase-type” activity towards α-aminonitriles, which are synthetically versatile compounds that can provide access to several building blocks (Vongvilai et al., 2011). The racemization was found to be specific for this kind of substrate and is suggested to occur at the hydrolase active site and proceed through a C–C bond-breaking/retro Strecker/Strecker reaction. Thereafter it was found that other lipases, such as Candida antartica lipase B and lipases from Pseudomonas sp, also present such racemizetype activity towards α-aminonitriles, so that it is possible to obtain enantiomeric complementary optically pure α-amidonitriles by choosing the lipase with the desired enantiopreference (Sakulsombat et al., 2014). Taking advantage of the dual-function “acylase-racemase” activity of lipases, Sakulsombat and co-workers performed the DKR of

Fig. 42. Double parallel dynamic systemic resolution of nitroalcohols and hemithiaocetals.

Fig. 43. DKR of tetrahydroquinolines catalyzed by a single “dual-function” biocatalyst.

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cyano-tetrahydroquinolines, which are intermediates for the synthesis of alkaloids (Fig. 43). 3. Conclusion Dynamic kinetic resolutions through combination of lipases and racemization catalysts provide access to a wide range of enantiopure compounds, being a valuable tool in organic synthesis. Advances in areas such as protein engineering, immobilization techniques and metalloenzymes are expected to push the development of more versatile and robust (bio)catalysts or catalytic entities, thus overcoming the limitations of current available DKR methods reactions and enabling it to be applied also beyond academic arena. Acknowledgments We thank CAPES (Coordenação de aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), FAPERJ (Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro) and FINEP (Agência Financiadora de Estudos e Projetos) for financial support. References Agrawal S, Martínez-Castro E, Marcos R, Martín-Matute B. Readily available ruthenium complex for efficient dynamic kinetic resolution of aromatic α-hydroxy ketones. Org Lett 2014;16:2256–9. Ahmed M, Kelly T, Ghanem A. Applications of enzymatic and non-enzymatic methods to access enantiomerically pure compounds using kinetic resolution and racemisation. Tetrahedron 2012;68:6781–802. Ahn Y, Ko S-B, Kim M-J, Park J. Racemization catalysts for the dynamic kinetic resolution of alcohols and amines. Coord Chem Rev 2008;252:647–58. Akai S. Dynamic kinetic resolution of racemic allylic alcohols via hydrolase-metal combo catalysis: an effective method for the synthesis of optically active compounds. Chem Lett 2014;43:746–54. Akai S, Tanimoto K, Kita Y. Lipase-catalyzed domino dynamic kinetic resolution of racemic 3-vinylcyclohex-2-en-1-ols/intramolecular Diels–Alder reaction: one-pot synthesis of optically active polysubstituted decalins. Angew Chem Int Ed 2004;43:1407–10. Akai S, Tanimoto K, Kanao Y, Egi M, Yamamoto T, Kita Y. A Dynamic kinetic resolution of allyl alcohols by the combined use of lipases and [VO(OSiPh3)3]. Angew Chem Int Ed 2006;45:2592–5. Akai S, Hanada R, Fujiwara N, Kita Y, Egi M. One-pot synthesis of optically active allyl esters via lipase–vanadium combo catalysis. Org Lett 2010;12:4900–3. Allen JV, Williams JMJ. Dynamic kinetic resolution with enzyme and palladium combinations. Tetrahedron Lett 1996;37:1859–62. Andrade LH, Silva AV, Pedrozo EC. First dynamic kinetic resolution of selenium-containing chiral amines catalyzed by palladium (Pd/BaSO4 ) and Candida antartica lipase (CAL-B). Tetrahedron Lett 2009;50:4331–4. Asano Y, Yamaguchi S. Dynamic kinetic resolution of amino acid amide catalyzed by D-aminopeptidase and α-amino-ε-caprolactam racemase. J Am Chem Soc 2005; 127:7696–7. Atuu MR, Hossain MM. Dynamic kinetic resolution of racemic tropic acid ethyl ester and its derivatives. Tetrahedron Lett 2007;48:3875–8. Baxter S, Royer S, Grogan G, Brown F, Holt-Tiffin KE, Taylor IN, et al. An improved racemase/acylase biotransformation for the preparation of enantiomerically pure amino acids. J Am Chem Soc 2012;134:19310–3. Benaissi K, Poliakoff M, Thomas NR. Dynamic kinetic resolution of rac-1-phenylethanol in supercritical carbon dioxide. Green Chem 2009;11:617–21. Berkessel A, Sebastian-Ibarz ML, Müller TN. Lipase/aluminum-catalyzed dynamic kinetic resolution of secondary alcohols. Angew Chem Int Ed 2006;45:6567–70. Berthod A. Chiral recognition mechanisms. Anal Chem 2006;78:2093–9. Bevinakatti HS, Newadkar RV, Banerji AA. Lipase-catalysed enantioselective ring-opening of oxazol-5(4H)-ones coupled with partial in situ racemisation of the less reactive isomer. Chem Commun 1990;16:1091–2. Blacker AJ, Stirling MJ, Page MI. Catalytic racemisation of chiral amines and application in dynamic kinetic resolution. Org Process Res Dev 2007;11:642–8. Bodlenner A, Glueck SM, Nestl BM, Gruber CC, Baudendistel N, Hauer B, et al. Biocatalytic racemization of α-hydroxycarboxylic acids using a stereo-complementary pair of α-hydroxycarboxylic acid dehydrogenases. Tetrahedron 2009;65:7752–5. Bogár K, Bäckvall J-E. High-yielding metalloenzymatic dynamic kinetic resolution of fluorinated aryl alcohols. Tetrahedron Lett 2007;48:5471–4. Bogár K, Martín-Matute B, Bäckvall J-E. Large-scale ruthenium- and enzyme-catalyzed dynamic kinetic resolution of (rac)-1-phenylethanol. Beilstein J Org Chem 2007a;3:50. Bogár K, Vidal PH, Alcántara León AR, Bäckvall J-E. Chemoenzymatic dynamic kinetic resolution of allylic alcohols: a highly enantioselective route to acyloin acetates. Org Lett 2007b;9:3401–4. Bornscheuer UT, Kazlauskas RJ. Hydrolases in organic synthesis: regio- and stereoselective biotransformations. 2th ed. VCH-Wiley: Weinheim; 2005.

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Please cite this article as: de Miranda AS, et al, Lipases: Valuable catalysts for dynamic kinetic resolutions, Biotechnol Adv (2015), http:// dx.doi.org/10.1016/j.biotechadv.2015.02.015

Lipases: Valuable catalysts for dynamic kinetic resolutions.

Dynamic kinetic resolutions have proven to be a useful method for the preparation of enantiopure compounds from racemates, leading to the formation of...
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