Dynamic Covalent Kinetic Resolution

Abstract

Implemented with the highly efficient concept of Dynamic Kinetic Resolution (DKR), dynamic covalent chemistry can be a useful strategy for the synthesis of enantioenriched compounds. This gives rise to dynamic covalent kinetic resolution (DCKR), a subset of DKR that over the last decades has emerged as increasingly fruitful, with many applications in asymmetric synthesis and catalysis. All DKR protocols are composed of two important parts: substrate racemization and asymmetric transformation, which can lead to yields of >50% with good enantiomeric excesses (ee) of the products. In DCKR systems, by utilizing reversible covalent reactions as the racemization strategy, the substrate enantiomers can be easily interconverted without the presence of any racemase or transition metal catalyst. Enzymes or other chiral catalysts can then be adopted for the resolution step, leading to products with high enantiopurities. This tutorial review focuses on the development of DCKR systems, based on different reversible reactions, and their applications in asymmetric synthesis.

1. Introduction

With the increasing importance of enantiopure compounds in biological and medicinal applications, asymmetric synthesis has since long become a cornerstone in chemistry. New, and progressively more efficient strategies to obtain enantiomerically enriched compounds have thus been developed [1], continuously serving the needs from the society. Among the different approaches, kinetic resolution (KR) has proven one of the most useful methods, due to its high efficiency coupled to a straightforward operation [2]. In the KR concept, a chiral catalyst preferentially acts on one of the enantiomers, so that its transformation rate is considerably higher than that of the isomer. For example, if k_R >> k_S, then mainly the R-enantiomer will be transformed into the corresponding product, leaving the S-enantiomer largely untouched. When the rates are sufficiently different, this process can yield the product in high enantiomeric excess (ee), as well as the corresponding enantioenriched starting material. However, the process results in a theoretical maximum yield of 50% of the targeted product, while maintaining a high ee, thereby constituting an inherent limitation of KR when higher yields are desired. In order to overcome this potential drawback, an alternative approach was devised, in which in situ racemization was introduced into the system, thereby resulting in a Dynamic Kinetic Resolution (DKR) protocol [3]. Thus, with continuous consumption of the fast-reacting enantiomer and simultaneous racemization of its antipode, a theoretical yield of 100% can in principle be reached together with a high ee.

As an important parameter in DKR systems, the racemization process can greatly affect the overall yield and ee of the reaction. Until now, a range of racemization methods have been developed and applied in DKR systems, such as processes based on biocatalysts, organocatalysts, and transition metal catalysts [4]. The applied biocatalysts include different types of racemases, while lipases have also been found dual activities of racemization and asymmetric amidation towards α-aminonitrile substrates [5]. In most cases of organo-/metal-catalyzed racemizations, direct catalyst-assisted inversion of the chiral centers have been applied, generally through redox, ionic, or radical processes [6]. In contrast, indirect interconversion of the two enantiomers can in principle also be realized through reversible covalent formation of the chiral centers. This process can be referred to as Dynamic Covalent Kinetic Resolution (DCKR, Figure 1), where the equilibration process of the reversible covalent reactions results in racemization of the substrates.

Figure 1.

Concept of dynamic covalent kinetic resolution (DCKR).

In order to maximize the reaction yields and ee’s of the final products, the same requirements as in other DKR methods should be fulfilled in DCKR systems [4c]: 1) the equilibration rate of the reversible reaction should be higher than the reaction rate of the slow-reacting enantiomer in the asymmetric transformation step; 2) the asymmetric transformation step should be highly selective towards only one enantiomer; and 3) the equilibration conditions should be compatible with the asymmetric transformation step. With respect to compatibility, reversible covalent reactions generally have an advantage over other racemization methods, since many of these reactions are sufficiently fast under mild conditions. Therefore, these reactions can generally be efficiently connected to either enzymatic catalysis or transition metal-/organocatalyst-mediated asymmetric transformations, and easily adapted to the conditions of the asymmetric transformation step. Moreover, most racemization protocols based on reversible reactions rely on metal-free chemistry, thereby facilitating purification. These reactions are generally also more straightforward to operate than, e.g., racemizing enzymes, demonstrating a highly useful strategy for efficient enantiomer racemization.

Besides these advantages, DCKR also has limitations since a limited number of reversible reactions are applicable to the substrate racemization step. An essential criterion of these reactions is that the creation of new chiral centers should be a consequence of the reversible covalent bond formation. For this reason, some of the most commonly used reversible reactions in organic chemistry are excluded from the DCKR systems, such as disulfide exchange and transamination [7]. Successfully applied covalent reactions in DCKR have instead been centered around nucleophilic addition of alcohols, thiols, amines, etc., to double bonds, such as aldehydes, imines, nitrones, and Michael acceptors. Typical reactions thus include cyanohydrin formation, hemiacetal/hemiaminal formation, conjugate additions, etc.

As the key step of DCKR systems, the reversible covalent reactions determine the outcome of the whole process to a large extent. In this tutorial review, a variety of DCKR examples will be illustrated and classified according to the type of reversible covalent reactions applied. It will cover both the more widely applied reactions, such as hemiacetal-, hemithioacetal-, hemiaminal-, and cyanohydrin formation, as well as other reversible covalent reactions, such as nitroaldol and thia-Michael reactions. Besides the equilibration features leading to racemization, this review of existing DCKR systems will also discuss the asymmetric transformation strategies and the scope of the substrate structures, thus providing a view of the overall DCKR protocol.

By expanding the composition of the DCKR system, from only one starting material to a series of substrate structures, and allowing all constituents to reversibly interchange with each other in one pot, a systems approach to kinetic resolution can be realized. This gives rise to Dynamic Systemic Resolution (DSR) processes, in which the overall system adapts to the associated kinetic selection process [8]. Any kinetic step applied to the system, e.g., through catalyzed processes, will exert a selection pressure that requires the optimal substrate to be selectively transformed to the corresponding product. The reversibility of the system will then replenish the starting components from the remaining constituents, bestowing an amplification effect of the optimal substrate in the system (Figure 2).

Figure 2.

Schematic concept of DSR.

To date, a broad range of DSR systems have been illustrated, composed of single reactions [9], double cascade/parallel reactions [10], and complex reaction networks [11]. While cascade reactions can provide straightforward access to complex structures, parallel reactions generally expand the chemical space of the constituent structures. Thus, with a more extensive variety of reversible processes involved in one system, identification and screening processes become more efficient. DSR has also been applied to different areas, such as ligand identification [10], catalyst screening [12], enzyme classification [13], etc. In addition, drug discovery has been proposed as a potentially important application [14]. For example, if the external selector is a drug target enzyme, then activator or inhibitor candidates can be identified/evaluated systemically rather than tested individually. Starting with a range of components, all the constituents can be dynamically formed through reversible reactions and interact with the target enzyme, resulting in identification of the best substrate in situ.

2. DCKR systems with various reversible reaction types

2.1. DCKR based on reversible hemiacetal formation

Intramolecular hemiacetal formation, including acylhemiacetals (hemiacylals), has been shown to display good reversibility and has been applied for asymmetric synthesis since the 1980s [15]. Spontaneous racemization of the substrates usually goes through ring opening and closing processes, where hemiacetal intermediates are continuously present at equilibrium. In most cases, reversible hemiacetal formation is straightforward at room temperature even without the addition of any catalysts.

Using this type of DCKR method, Feringa, Kellogg and co-workers synthesized chiral furanones through reversible acylhemiacetal formation, leading to products with high enantiopurities (Scheme 1) [16]. By using immobilized lipases for the selective esterification of the intermediate enantiomers, the catalysts could also be recycled. As a result, a range of furanones were produced, of which, e.g., compound 3 could be obtained in > 99% ee at 90% conversion.

Scheme 1.

Lipase-catalyzed DCKR of furanone structures [16].

Substituted furanones were subsequently synthesized following the DCKR method by the Zwanenburg group (4a-d, Figure 3) [17]. It was found that methyl groups had negative effects on the reaction rate, and that slightly higher temperature could accelerate the enzymatic reaction. In the end, good ee’s (up to 86%) of the products were obtained when the reactions reached full conversions. Moreover, besides these five-membered ring structures, a six-membered pyrone derivative (compound 5, Figure 3) was obtained in a fair ee by applying lipase-catalyzed acylation on a reversible intramolecular hemiacetal process [18].

Figure 3.

Scheme Caption. Lipase-catalyzed DCKR to substituted furanones and pyrone derivative 5 [17–18].

Peroxyhemiacetal formation shows similar reversibility as typical hemiacetal formation, the main difference arising from the hydroperoxide nucleophile. Both processes are generally spontaneous, providing fast racemization rates to the intermediates without any catalysts. Using this reversible bond type, Rovis and coworkers developed an asymmetric synthesis protocol to 1,2,4-trioxane products [19]. The authors first applied p-peroxyquinol 6a and aldehyde 7a as starting materials, and involved a Brønsted acid-catalyzed oxa-Michael reaction for the subsequent asymmetric transformation (Scheme 2). The chiral biindane Brønsted acid cat A was chosen as resolution catalyst due to its high enantioselectivity, and thiourea cat B was added to the system to restore cat A. A good yield (78%) and very good ee (94%) for product 9a were detected, while peroxyhemiacetal intermediate 8a remained racemic during the whole process. Further studies showed that this DCKR system had a large substrate scope, where structural variations of both the aldehyde and p-peroxyquinol parts worked well, resulting in products with up to excellent ee’s (> 97%).

Scheme 2.

Brønsted acid-catalyzed DCKR to 1,2,4-trioxanes [19].

2.2. DCKR based on reversible hemiaminal formation

Compared to the fast equilibrium formation of the hemiacetal reaction, the equilibration between an N-acylhemiaminal and its corresponding reactants normally requires higher temperature to proceed at a sufficient rate. Based on this reaction type, Kellogg and coworkers synthesized enantioenriched pyrrolinone compounds (Scheme 3) [16], in which case the racemization process was accelerated by heating (69 °C). Under these conditions, racemization was faster than the rate of the subsequent enzyme-catalyzed acylation, and under the catalysis of the lipase CAL, pyrrolinone 12 was produced in > 99% ee at 99% conversion.

Scheme 3.

Lipase-catalyzed DCKR of pyrrolinone structure 12 [16].

N-substituted pyrrolinones with different ester groups were also studied by Feringa and coworkers (13a-k, Figure 4) [20]. Most of the tested N-acyl-substituted pyrrolinones could be obtained in > 99% ee’s and complete conversions. However, for substrates with no substituents or with only a methyl group attached, very low enantiomeric selectivities were recorded. Furthermore, different esterification agents such as methyl acetate, ethyl acetate and unsaturated acetates, could be converted to the corresponding products in excellent yields and very good ee’s. A similar process was also used in the synthesis of isoindolines by Kaga and coworkers (14a-f, Figure 4) [21]. Again, various N-acyl-substituted substrates displayed high reaction efficiencies in this DCKR system, generally leading to chiral isoindolines with excellent ee’s under full conversion.

Figure 4.

Lipase-catalyzed DCKR of various pyrrolinone and isoindoline compounds [21].

Instead of using lipases and acyl donors for enantioselective acylation of the N-acylhemiaminal intermediates, the Yamada group developed chiral twisted amides (cat C-F) as acylating reagents (Scheme 4) [22]. At elevated temperature (80 °C), to ensure fast, reversible N-acylhemiaminal formation, the DCKR protocol was applied to a range of isoindolines. Although various optimizations of the reaction conditions were applied, products of relatively low enantiopurity were obtained. However, upon screening of bases applied to accelerate the reaction rates, it was remarkably noted that addition of 4-dimethylaminopyridine (DMAP) reversed the enantioselectivity, giving the S-isomer instead of its antipode as the major product. A few years later, the same system was evaluated with a series of chiral DMAP-based catalysts (cat G-J, Scheme 5) [23]. With the assistance of acyl donors, such as isobutyric anhydride, most substrates (17) were acylated in more than 80% ee while the reactions reached full conversion. Substituted pyrrolinones (18) were furthermore evaluated, albeit resulting in lower ee’s.

Scheme 4.

DCKR of isoindolines catalyzed by chiral twisted amides [22].

Scheme 5.

DCKR of various pyrrolinone and isoindoline structures catalyzed by chiral DMAP derivatives [23].

Besides pyrrolinone and isoindolinone core structures, 2,5-disubstituted tetrazoles, important elements in medicinal chemistry development [24], have been targeted using the DCKR method. The general synthetic strategy was in this case based on the fast, reversible reaction between 5-substituted tetrazoles and aldehydes, and the obtained hemiaminal subsequently subjected to Lewis base-catalyzed asymmetric acylation (Scheme 6). For this purpose, Piotrowski et al. designed several chiral DMAP catalysts, and applied them to the regio- and enantioselective synthesis of azole hemiaminal esters, among which cat K gave the best performance with an enantiomeric ratio (er) of 90:10 for product 22 together with a yield of 82% [25]. A multikilogram scale synthesis of a tetrazole prodrug fragment was furthermore successfully accomplished, in this case in quantitative yield. Later, Kinens et al. surveyed a series of similar chiral DMAP catalysts and found cat M to improve the yield of product 22 to > 99% with an er of 97:3 (Figure 5). Moreover, by expanding the structural variation in the 2-position (23) the tetrazole core structure (24), or the acyl donor part (25), the newly developed chiral catalysts could be used in the asymmetric synthesis of a range of products [26].

Scheme 6.

DCKR to 2,5-disubstituted tetrazoles catalyzed by chiral DMAP derivatives [25].

Figure 5.

Improved DCKR to imidazole, pyrazole, and tetrazole products catalyzed by chiral DMAP derivatives [26].

2.3. DCKR based on reversible hemithioacetal formation

Hemithioacetals can be reversibly formed from aldehydes and thiols under acid or base catalysis, and usually serve as intermediates in organic synthesis. Without additional stabilization mechanisms, the equilibrium position generally tends to be on the aldehyde side, which sometimes is an undesired property for their application. However, coupled with secondary, irreversible processes, such as O-acylation, efficient DCKR protocols can be devised.

Rayner and co-workers have pioneered DCKR systems using reversible hemithioacetal formation [27]. In their initial study, methyl glyoxalate 26 and thiol 27 were mixed in tert-butyl methyl ether (TBME), together with a lipase from Pseudomonas fluorescens and an acyl donor. Owing to the uncatalyzed hemithioacetal reaction, this protocol resulted in a typical KR process in which the maximum yield was limited to 50%. However, in the presence of catalyst SiO₂, the reaction proceeded to 90% conversion with high enantioselectivity, demonstrating the fast racemization of the hemithioacetal enantiomers under mild acidic condition. The reaction scope was subsequently explored with a range of substituents (Scheme 7), for which most substrates led to products in good to excellent ee’s and more than 50% yields.

Scheme 7.

Lipase-catalyzed DCKR of hemithioacetal acetates [27].

Zhang et al. applied reversible hemithioacetal formation for the lipase-catalyzed asymmetric synthesis of 1,3-oxathiolan-5-ones, and further construction of oxathiolane nucleoside skeletons [28]. In these cases, methyl 2-sulfanylacetate (30) was applied in the reaction with aldehydes for its double roles in the process (Scheme 8): hemithioacetal substrate and acyl donor. Candida antarctica lipase B (CAL-B) was then adopted for the subsequent intramolecular cyclization of the formed hemithioacetal intermediates. Since methanol was formed as the side product from methyl 2-sulfanylacetate, showing inhibition activity toward CAL-B, excess amount of molecular sieves was added to remove methanol from the reaction mixture. The previously used equilibration catalyst SiO₂ provided the dithiane side-product in this case. On the other hand, screening of basic additives showed that better results could be obtained by addition of 4-methylmorpholine. Using this DCKR protocol at an optimized temperature of −25 °C in toluene, various aldehydes were tested (Scheme 8), generally leading to good conversions and up to very good enantiopurities (32a-d).

Scheme 8.

Lipase-catalyzed DCKR of 1,3-oxathiolan-5-ones [28].

Ramström and coworkers also explored the combination of hemithioacetal and hemiacetal formations for a three-step asymmetric synthesis of lamivudine [29]. The equilibration of the hemithioacetal formation was in this work catalyzed by Et₃N, while the hemiacetal intermediate could be spontaneously and reversibly formed. For these reasons, benzoyl protected aldehyde 34 was chosen as the starting material to react with 1,4-dithiane-2,5-diol 33 under rapid equilibration (Scheme 9). Initially, the lipase CAL-B was applied as catalyst for the subsequent enantioselective esterification step, however favoring the formation of the undesired stereoisomer (35a). A range of other lipases were also explored, showing similar enantioselectivities as CAL-B. However, switching to the surfactant-treated protease subtilisin Carlsberg (STS), the desired stereoisomer 35b could be selectively obtained and further transformed to lamivudine but in two additional steps.

Scheme 9.

Lipase-catalyzed DCKR to lamivudine precursor [29].

A mechanistic study for the enzyme-catalyzed asymmetric formation of 1,3-oxathiolane derivative was also performed. Using chiral HPLC and NMR experiments, the absolute configuration of the cyclic C-5 hemiacetal could be elucidated. The S-product was thus formed with CAL-B, whereas the R-isomer was produced using STS catalysis, in both cases in the form of the trans-1,3-oxathiolane heterocycle [5b].

A similar cascade reaction process, coupled with crystallization-driven separation, was used by Whitehead and coworkers [30]. Starting from chiral aldehyde 36 and compound 37, four different diastereomers were formed through a two-step reversible reaction scheme (Scheme 10). With racemization at C-2 as the key process, evaluation of different bases revealed Et₃N as suitable for fast interconversion. Very good yields and enantiopurities were recorded.

Scheme 10.

Crystalline-driven DCKR of lamivudine precursor 39d [30].

2.4. DCKR based on reversible cyanohydrin formation

Cyanohydrin formation is one of the first reactions explored for enzyme-catalyzed asymmetric synthesis, and already in 1908, Rosenthaler applied emulsin to the formation of enantioenriched mandelonitrile from benzaldehyde and hydrocyanic acid [31]. Similar to other nucleophilic reactions, addition of HCN to a carbonyl group is known to undergo straightforward equilibration under basic conditions leading to a transhydrocyanation process. Considering the toxicity of HCN, however, acetone cyanohydrin has generally been used as an alternative hydrogen cyanide source.

In an early example, Oda and coworkers studied reversible transhydrocyanation as racemization method in the lipase-catalyzed asymmetric synthesis of chiral cyanohydrin acetates [32]. In the study, a lipase from Pseudomonas cepacia was used as catalyst and isopropenyl acetate as acyl donor, and ¹H NMR was used to monitor the formation of the corresponding cyanohydrin acetates. To ensure fast equilibration of the transhydrocyanation process, screening of base catalysts was initially conducted, where anion exchange resins like Amberlite IRA-904 (OH⁻ form) prove to be suitable to efficiently catalyze the transhydrocyanation process. Following optimization of the reaction conditions, this DCKR protocol was subsequently applied to a range of substrates (Scheme 11). Especially, benzaldehydes (40a-g) and naphthaldehydes (40h-i) were converted into corresponding cyanohydrin acetates in up to 91% ee and fair to excellent yields. In contrast, cyanohydrin acetates derived from 2-furaldehyde (40j) and simple aliphatic aldehydes (40k-l) were produced in lower yields and ee’s.

Scheme 11.

Lipase-catalyzed DCKR to cyanohydrin acetates [32].

Compared to other cyanide addition strategies, for example, catalysis by commercially available oxynitrilases, this DCKR protocol also provided an easy approach to achieve the opposite enantiomer of cyanohydrin acetates with high yields [32–33]. Therefore, as an alternative method, it has demonstrated great value in asymmetric synthesis.

Dynamic systems based on reversible cyanohydrin formation reactions were furthermore generated and used for in situ evaluation of lipase performances by Sakulsombat et al [5a]. From a pool of cyanohydrin constituents, the selectivity of lipase from Burkholderia (Pseudomonas) cepacia, immobilized on a porous ceramic support (PS-CI) was evaluated at different temperatures and lipase loading. In all cases, compound 45d was obtained as the optimal product from the lipase-catalyzed transesterification, while the best ee (83%) was recorded for structure 45e in chloroform (Scheme 12).

Scheme 12.

Lipase-catalyzed DSR approach for asymmetric acylation of cyanohydrin constituents [5a].

The Kanerva group subsequently expanded the aldehyde scope to include furan and phenothiazin structures, for which the transhydrocyanation equilibrium could be reached in ca. 2 h. Based on the reversible transhydrocyanation process catalyzed by the basic Amberlite IRA-904 resin, a series of enantiopure furylbenzothiazol- (46) [34], phenylfuran- (47) [35] and phenothiazin-based (48) [36] cyanohydrin esters, could be synthesized (Figure 6). Commercially available lipases, such as a lipase from Pseudomonas cepacia or lipase A from Candida antarctica (CAL-A), showed good enantioselectivity toward most of the cyanohydrin intermediates, giving high ee’s and full conversions of the products. Vinyl acetate or vinyl butanoate were used as the acyl donor for the enzyme-catalyzed acylation, and similar to the previous protocol the amount of basic resin was critical for the process since it could be neutralized by the acid released from the acyl donors. However, control experiments showed that the basic resin was still active at the end of the reactions.

Figure 6.

Lipase-catalyzed DCKR to furylbenzotiazol-, phenylfuran- and phenothiazin-based cyanohydrin acetates [34].

In the above illustrated examples, the reversible transhydrocyanation processes were all catalyzed by the Amberlite IRA-904 basic resin. However, the stability of this anion-exchange resin proved to be unsatisfactory, leading to gradual decomposition over time. For this reason, Sakai et al. employed readily available, and more stable, silica-supported benzyltrimethylammonium hydroxide (BTAH) to accelerate the equilibration of transhydrocyanation process [37]. In combination with a lipase from Burkholderia (Pseudomonas) cepacia, immobilized on a porous ceramic support (PS-CII), a variety of enantioenriched cyanohydrin derivatives were synthesized (79–91% ee, Scheme 13). By using benzyltrimethylammonium acetate instead of BTAH in a slightly modified protocol, some of the less stable products, such as aromatic cyanohydrin acetates substituted with electron-withdrawing groups (51d-e) were also successfully synthesized in good yields and fair ee’s.

Scheme 13.

Lipase-catalyzed DCKR to cyanohydrin acetates [37].

2.5. DCKR based on reversible nitroaldol reaction

The nitroaldol (Henry) reaction proceeds through the addition of a nitronate to an aldehyde or ketone under basic conditions. The reversibility of the reaction is often deemed disadvantageous for organic synthesis, but Ramström and coworkers utilized the dynamic features in a DCKR protocol [38]. In order to control the equilibration rate of the reaction, different organic bases were first screened, of which Et₃N showed a high acceleration effect on the reaction rate and good compatibility with the enzyme. After optimization of the reaction conditions, lipase preparation PS-CI (B. cepacia) was used for enantioselective esterification of the nitroaldol intermediates at 40 °C, using p-chlorophenyl acetate as the acyl donor. A range of aromatic aldehydes (52a-j) were evaluated for the one-pot transformation, leading to up to excellent ee’s and yields of corresponding products (Scheme 14). For aromatic groups with electron-releasing substituents (52k-l), lower conversions were recorded, but the excellent enantioselectivities were retained.

Scheme 14.

Lipase-catalyzed DCKR to β-nitroalkanol derivatives [38].

The group furthermore utilized this feature to establish dynamic systems (Scheme 15) [9c]. By connecting lipase-catalyzed asymmetric esterification, a series of nitroaldol adducts from different aldehydes (55a-e) and 2-nitropropane (53) were screened. As a result, only R enantiomer of 57c was preferably synthesized, while (R)-57a was selected as the minor product, both obtained with excellent ee’s (99% and 98% respectively).

Scheme 15.

Lipase-catalyzed DSR approach for asymmetric esterification of nitroaldol constituents [9c].

A crystallization-driven asymmetric synthesis of pyridine-β-nitroalcohols was discovered from a similar nitroaldol reaction based dynamic system. With the presence of two chiral centers in the potentials product pools, only (R,R)/(S,S) diastereomers of4-pyridin substituted products (60h) were selectively synthesized and crystalized (Scheme 16a) [39]. By using the same crystallization strategy, when 2-cyanobenzaldehyde (61b) was included in the dynamic system, isoindolinone (63) was unexpectedly and diastereoselectively formed with the crystal state (Scheme 16b) [40], while the iminolactone intermediates being confirmed after mechanism investigations [3e]. Furthermore, this strategy was successfully applied for facile synthesis of other isoindolinones, with high yields and diastereomer ratios.

Scheme 16.

Crystallization-driven DSR to nitroalcohols and isoindolinones [39].

2.6. DCKR based on reversible nitrone addition

Similar to aldehydes and imines, nitrones constitute a class of electrophilic compounds that are sufficiently reactive towards addition by thiols. The reversibility of this reaction was more recently explored, and its application in DCKR demonstrated [41]. By reversible nitrone addition coupled with lipase-catalyzed lactonization, different oxathiazinanones could be synthesized in up to very good ee’s and excellent yields (Scheme 17). During evaluation of the equilibration rate, a virtual dynamic character of the system was observed under basic conditions, where no intermediates were visibly expressed but transiently formed in low amounts. Candida antarctica lipase B was identified as optimal catalyst for the cyclization process, however potentially inhibited by the methanol released from methyl 2-sulfanylacetate (65). This effect could be circumvented by using isopropenyl acetate as an efficient methanol scavenger through a proposed double catalytic pathway (Scheme 18). Of the substrates explored, aliphatic nitrones with short chains, such as isopropyl and n-propyl groups (64a-b), could be successfully transformed, whereas aromatic groups or longer aliphatic chains (64c-e) resulted in lower conversions and enantioselectivity.

Scheme 17.

Lipase-catalyzed DCKR to oxathiazinanones [41].

Scheme 18.

Proposed double catalytic pathway of CAL-B catalysis [41].

2.7. DCKR based on reversible N,O-acetal formation

Addition of alcohol nucleophiles to imines leads to N,O-acetal bonds, a reaction that can display reversibility. With this in mind, Akiyama and coworkers recently proposed an atroposelective DCKR strategy to chiral biaryls based on transfer hydrogenation with Hantzsch’ ester and a binaphthol-based phosphoric acid (Scheme 19). Lactol 55 was chosen as starting compound, reacting with aniline 68 to form the corresponding imine/N,O-acetal. With catalyst cat N, enantioenriched biaryl amines could be produced in yields up to 98% and ee’s up to 94% [42]. A proposed mechanism involved a racemization step based on the ring-opening/closing equilibrium between the biaryl N,O-acetal and the imine (Scheme 20). Subsequent kinetic resolution of the generated imines (71 and ent-71) through asymmetric transfer hydrogenation, resulted in high enantiopurities.

Scheme 19.

DCKR to chiral biaryl amines catalyzed by binaphtol-based phosphoric acids [42].

Scheme 20.

Proposed racemization mechanism through N,O-acetal intermediates [42].

2.8. DCKR based on reversible N,S-acetal formation

Similarly, thiol addition to imines can result in reversible N,S-acetal formation. Capaccio et al. used this racemization strategy to obtain chiral 3-thio-indolin-1-imines (Scheme 21) [43]. The reversibility was evaluated by ¹H NMR spectroscopy, from which fast, spontaneous formation of the acyclic N,S-acetal (75) was recorded. For the kinetic resolution step, a series of cinchona alkaloid-based catalysts was screened, of which cat O and cat P resulted in the highest conversions and enantioselectivities. In conjunction with the reversible N,S-acetal formation, the asymmetric heterocyclization process could be achieved. The structural scope of the thiol compounds was also evaluated, resulting in a best performance with substituted aryl thiols carrying electron-donating and relatively electron-neutral groups (up to 80% yield and 90% ee).

Scheme 21.

DCKR to 3-thio-indolin-1-imines catalyzed by cinchona alkaloid derivatives [43].

2.9. DCKR based on reversible imine reactions

Reversible imine formation is one of the most frequently used reactions in dynamic systems, however rarely used in DCKR processes due to the lack of suitable stereogenic centers. Nevertheless, the α-position of aldehydes can be racemized through transient enamine formation in consequence of imine formation. Based on this principle, Kroutil and coworkers developed a DCKR strategy to chiral amines using asymmetric transaminase (TA) catalysis (Scheme 22). After screening of various wild-type TAs, both the R- and S-isomers of Brivaracetam and Pregablin precursors (79) could be obtained with fair to very good ee’s (> 90% for the R-isomer, 80% for the S-isomer). The racemization was found not to be caused by the enzyme, but instead proposed to go through imine formation in the presence of amines, such as isopropyl amine (Scheme 23). However, the enzyme itself, as well as added pyridoxamine phosphate, caused higher racemization rate [44].

Scheme 22.

DCKR to lactam structures catalyzed by transaminase [44].

Scheme 23.

Proposed racemization mechanism through imine-enamine equilibration [44].

2.10. DCKR based on reversible Strecker reactions

The Strecker reaction, traditionally composed of consecutive imine formation and hydrocyanation reactions, is analogous to cyanohydrin formation and can be applied to DCKR since both steps can be reversible. The second cyanation step requires special consideration, and Ramström and coworkers identified conditions using acidic catalysts for faster equilibrium of the overall Strecker reaction (Scheme 24) [10c]. Among the tested Lewis acids, zinc bromide proved the most efficient, using which a double dynamic system containing multiple aromatic groups and various amine substituents could be generated. By coupling to the reaction system to lipase-catalyzed asymmetric amidation, high chemo- and enantio-selectivity were observed, providing N-acyl-α-aminonitriles as final products, with a very good (90%) ee for selected compound 84.

Scheme 24.

Lipase-catalyzed DSR to N-acyl-α-aminonitriles [10c].

Instead of acidic conditions, Chaplin et al. evaluated eight different organic bases for acceleration of the racemization process, however in this case likely proceeding through the nitrile anion, in combination with nitrilase-catalyzed hydrolysis [45]. Of these, only 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) showed enhancement of the racemization rate, although not suitable for the biphasic conditions devised for the enzyme. However, by increasing the pH of the reaction solutions to > 10, racemization occurred producing (R)-(4-fluoro)-phenylglycine in fair-to-good yields and excellent ee’s.

2.11. DCKR based on reversible aza-Henry reactions

Similar to the nitroaldol reaction, the aza-Henry reaction involves reversible addition of nitronate species to imine groups, a reaction type that has also been applied to DCKR. However, in this case the aza-Henry adducts could not be easily observed unless an excess amount of nitroalkanes, or bases, such as tetramethylguanidine (TMG) or DBU, were added. Zhang et al. combined this type of aza-Henry addition with a range of other reversible reactions, generating dynamic systems with high degrees of complexity (Scheme 25) [11]. By connecting a subsequent lipase-catalyzed acylation/cyclization, only two products (85 and 86) were selectively resolved from the system.

Scheme 25.

Lipase-catalyzed complex DSR form networks of eight reversible reaction types [11].

More recently, Cheng et al. developed a cascade aza-Henry and aza-Michael reaction to enantioenriched pyrrolidines [46]. It was initially found that the aza-Henry reaction proceeded smoothly for enoate substrates (88) in the presence of DBU, however leading to modest diastereoselectivities (Scheme 26). From screening of different organocatalysts, Cinchona alkaloid-derived Cat Q was identified as especially effective for the overall process, affording substituted pyrrolidine products carrying multiple stereogenic centers in up to excellent yields and ee’s.

Scheme 26.

Cinchona alkaloid derivatives catalyzed DCKR of polysubstituted pyrrolidines [46].

2.12. DCKR based on reversible thia-Michael reactions

Conjugate addition of thiols to α,β-unsaturated carbonyl compounds displays reversibility and has, for example, been used to create dynamic systems for biorecognition studies. Lattanzi and coworkers coupled this reversible process with asymmetric Michael cyclization to obtain trisubstituted tetrahydrothiophenes [47]. After screening a series of chiral organocatalysts, cat R showed the best stereoselectivity. The resulting one-pot, sequential thia-Michael/carba-Michael process proved efficient in accessing a variety of tetrahydrothiophene structures in up to excellent yields and ee’s (Scheme 27). The racemization step of the DCKR system was studied by using the racemic thia-Michael adduct as starting point for the subsequent asymmetric transformation. Compared to using the enone and thiol as starting materials, the product yield and enantiopurity was identical, confirming the reversibility of the first thia-Michael step.

Scheme 27.

DCKR to trisubstituted tetrahydrothiophenes catalyzed by a chiral amino thiourea derivative [47].

Domino/tandem tansformations, such as the combination of Michael- and Henry reactions, can be used to efficiently access a variety of cyclic structures with multiple chiral centers. This was exemplified by Zhang et al. in a DCKR process yielding substituted thiolane structures carrying three contiguous chiral centers [10a]. Starting from substituted nitropropenes (95a-b) and 1,4-dithiane-2,5-diol (96), the initial thia-Michael reaction could be coupled with intramolecular nitroaldol cyclization, resulting in 16 isomeric thiolane structures (98a-b) (Scheme 28). In this case, the combination of 1,1,3,3-tetra-methylguanidine (TMG) and ZnI₂ proved important to accelerate the equilibration process of the domino reaction. Following lipase-catalyzed asymmetric transesterification, isomer 99 was selected from the dynamic system with excellent enantiopurity (98% ee).

Scheme 28.

Lipase-catalyzed DSR to multisubstituted thiolanes [10a].

3. Conclusion

Especially during the last two decades, DCKR has emerged as an increasingly useful method for asymmetric synthesis. In the current review, we have illustrated a variety of DCKR systems using different reversible covalent reactions, by which racemization of chiral intermediates can be effectuated. By combining this dynamic process with a selective kinetic resolution step, typically catalyzed by bio-, organo-, or transition metal catalysts, valuable products can be obtained in a straightforward way. In most examples, the overall DCKR process can be developed to produce good yields and high enantiopurities of the targeted products.

In relation to other DKR strategies, DCKR often offers an advantageous complement, especially in cases where other racemization processes are less straightforward and require conditions unsuitable for the subsequent step and/or the structures involved. However, since the process depend on reversible covalent processes, new and improved protocols are in demand. Some of the existing examples of DCKR were essentially discovered during other synthetic endeavors and not explicitly designed. However, with a broader range of appropriate reversible reactions becoming available and applied for asymmetric synthesis, more DCKR protocols can be developed. Together with other developments, such as complex system control and cascade reactions, the DCKR strategy can also lead to better exploration of chemical space and convenient access to complex enantioenriched compounds.

Biography

Yan Zhang received her BSc degree in 2008 from Central South University, P.R. China. In 2013, she obtained her PhD degree from the Royal Institute of Technology, Sweden, where she worked on chemoenzymatic resolution of dynamic systems under the supervision of Olof Ramström. After a postdoctoral period at the Institut Européen des Membranes (IEM), Montpellier, France, she is now Professor at Jiangnan University, School of Pharmaceutical Sciences, P.R. China.

Yang Zhang received her BSc degree in Applied Chemistry from Northwest A&F University, P.R. China, in 2010. After Master’s studies at the same university, she pursued graduate studies under the supervision of Olof Ramström at the Royal Institute of Technology, Sweden, from where she obtained her PhD degree in 2015. She is currently active at Hunan University, P.R. China.

Olof Ramström received his MSc and PhD degrees from Lund Institute of Technology/Lund University, Sweden. After a period at the Louis Pasteur University, Strasbourg, France, he returned to Sweden and the Royal Institute of Technology, Stockholm. He is currently active at University of Massachusetts, Lowell, USA, and Linnaeus University, Sweden.