Recycling in Asymmetric Catalysis - Accounts of Chemical Research

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Recycling in Asymmetric Catalysis Christina Moberg* Department of Chemistry, Organic Chemistry, KTH Royal Institute of Technology, SE 10044 Stockholm, Sweden CONSPECTUS: Cyclic reaction networks consisting of an enantioselective productforming step and a reverse reaction of the undesired enantiomer back to starting reactant are important for the generation of compounds with high enantiomeric purity. In order to avoid an equilibrium racemic state, a unidirectional cyclic process where product formation and regeneration of starting reactant proceed through different mechanistic pathways is required. Such processes must necessarily include a thermodynamically unfavorable step, since the product of the forward reaction is the reactant of the reverse reaction and vice versa. Thermodynamically uphill processes are ubiquitous to the function of living systems. Such systems gain the required energy by coupling to thermodynamically downhill reactions. In the same way, artificial cyclic reaction networks can be realized in systems open to mass or energy flow, and an out-of equilibrium nonracemic steady state can be maintained as long as the system is supplied with energy. In contrast to a kinetic resolution, a recycling process where the minor enantiomer is converted to starting reactant can result in a quantitative yield, but the enantiomeric purity of the product is limited by the selectivity of the catalysts used for the reactions. On the other hand, in a kinetic resolution, the slowly reacting enantiomer can always be obtained in an enantiomerically pure state, although the yield will suffer. In cyclic reaction systems which use chiral catalysts for both the forward and the reverse processes, a reinforcing effect results, and selectivities higher than those achieved by a single chiral catalyst are observed. A dynamic kinetic resolution can in principle also lead to a quantitative yield, but lacks the reinforcing effect of two chiral catalysts. Most examples of cyclic reaction networks reported in the literature are deracemizations of racemic mixtures, which proceed via oxidation of one enantiomer followed by reduction to the opposite enantiomer. We have developed cyclic reaction networks comprising a carbon−carbon bond formation. In these processes, the product is generated by the addition of a cyanide reagent to a prochiral aldehyde. This is followed by hydrolysis of the minor enantiomer of the product to generate the starting aldehyde. A unidirectional cycle is maintained by coupling to the exergonic transformation of the high potential cyanide reagent to a low potential compound, either a carboxylate or carbon dioxide. The products, which are obtained with high enantiomeric purity, serve as valuable starting materials for a variety of biologically and pharmaceutically active compounds.

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INTRODUCTION Autocatalytic reactions have been suggested to be responsible for the evolution of biological homochirality by amplifying an originally insignificant enantiomeric imbalance,1 resulting from a spontaneous process or caused by for example circularly polarized light or quartz. In order to explain the complete selection of chirality observed in biomolecules, recycling has been proposed as a mechanism for destruction of the minor enantiomer.2,3 Recycling of one enantiomer to achiral reactant has also been suggested to play a role in the spontaneous symmetry breaking observed in some synthetic processes in the absence of chiral reagents or catalysts.4,5 Although the models proposed are not feasible in closed system,6,7 such scenarios may be appropriate in systems open to mass or energy flow.8 Cyclic reaction networks are of interest not only for explaining the occurrence of biological homochirality. Recycling of the “wrong” enantiomer to reactant in an enantioselective chemical reaction is also an attractive approach for improving the outcome of chemical reactions with imperfect selectivity. In this Account, the requirements and characteristics of cyclic reaction systems are discussed. Only a few examples of such processes are known so far, and most of them are cyclic © XXXX American Chemical Society

deracemizations employing whole cells or designed artificial systems. The emphasis here will be on enantioselective cyanation of prochiral aldehydes. By using a minor enantiomer recycling (MER) method, selectivities higher than those observed using alternative methods can be achieved. The synthetic versatility of the processes will be highlighted.

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REQUIREMENTS FOR A CYCLIC PROCESS As stated by Onsager, in a monomolecular triangle reaction interconverting A, B, and C, at equilibrium transformation of A to B, for example, occurs as often as transformation of B to A.9 This is a consequence of the principle of detailed balance and implies that kAB, kBC, and kCA cannot have nonzero values at the same time as the rate constants for the reverse reactions are zero; under equilibrium conditions, there is thus no possibility for net cycling (Figure 1a). Thermodynamically unfavorable reactions can be driven by coupling to energetically favorable processes. In the cell, chemical energy stored in ATP is used to drive chemical Received: August 1, 2016

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DOI: 10.1021/acs.accounts.6b00396 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Scheme 1. Deracemization Catalyzed by Two Selective Enzymatic Systems

Figure 1. (a) Onsager’s triangle. (b) Unidirectional cyclic process.

processes requiring energy. In the first steps of cellular respiration, glucose is broken down through the process of glycolysis. In this process, initial phosphorylation of glucose is required to increase its reactivity. To achieve this, the endergonic reaction is coupled to the exergonic reaction of ATP hydrolysis to ADP: glucose + HPO4 2 − → glucose‐6‐phosphate + H 2O

ATP + H 2O → ADP + HPO4 2 −

ΔG > 0 (1)

ΔG < 0

glucose + ATP → glucose‐6‐phosphate + ADP

an imine reductase in combination with NADPH instead of the achiral reducing agent required fewer reaction cycles and thus resulted in shorter reaction times, since reduction of the intermediate imine led directly to the desired enantiomer.21 A whole cell catalytic system, consisting of a combination of a monoamine oxidase (MAO) from genetically engineered Escherichia coli and nanoscale bioreduced Pd(0) for the cyclic oxidation/reduction provided (R)-1-methyltetrahydroisoquinoline with 96% ee after five cycles. Reductions and oxidations could be run as a one-pot procedure, but needed to be performed in separate cycles to avoid a hazardous mixture of air and hydrogen.22 The same group also used a combination of a chiral iridium complex as an artificial hydrogen transferase (ATH-ase) and a monoamino oxidase. To avoid mutual inactivation of the catalysts, the metal complex was incorporated into streptavidin via a terminal biotin function.23 Hydrogen peroxide produced during the process was decomposed by a catalase (Scheme 2). This system was employed for the deracemization of several amines, among other things, rac-1-methyltetrahydroisoquinoline.

(2)

ΔG < 0 (1+2)

In case transformation of A to B in Figure 1 is thermodynamically favorable, the back reaction, via C, must necessarily be unfavorable, but can be accomplished by coupling to the exergonic transformation of X to Y (Figure 1b). Thus, by supplying a chemical system with energy, transfer of chemical energy permits low potential C to be transferred to high potential A, thereby allowing a unidirectional cyclic network.10 A nonracemic, nonequilibrium steady state can thus be maintained, provided there is an influx of energy into the system. An attractive option is to take advantage of this circumstance and transform achiral or racemic compounds into an enantiomerically pure state.

Scheme 2. Cyclic Deracemization by MAO and a Chiral Iridium Complex

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DERACEMIZATION Cellular processes have also been exploited for synthetic purposes. By using whole cells, racemic mixtures of compounds have been transformed into single enantiomers. Nakamura and co-workers, for example, used Geotrichum candidum IFO 5767 for the deracemization of arylethanols,11 and Chadha and coworkers used whole cells of Candida parapsilosis ATCC 7330 for deracemization of hydroxy esters12 and allylic alcohols.13 The processes comprise oxidation of the alcohol function of one enantiomer followed by reduction to the opposite enantiomer. In order to avoid the establishment of an equilibrium racemic mixture, the two reactions must proceed via different pathways. Synthetic processes mimicking cellular processes have also been developed. Kroutil and co-workers employed a system comprising enantioselective oxidation as well as enantioselective reduction.14 An efficient artificial deracemization system for a variety of secondary alcohols was designed by Kroutil and Faber by combining a NADPH-dependent enzyme for the oxidation and a NADH-dependent enzyme for the reduction (Scheme 1).15 Turner and co-workers developed processes for cyclic deracemization of amino acids16 as well as primary,17 secondary,18 and tertiary amines,19 which included selective oxidation by an amino acid oxidase or amine oxidase and nonselective reduction; a mathematical treatment of the kinetics of such processes has been presented by Kroutil and Faber.20 In the deracemization of nitrogen heterocycles, use of

A nonenzymatic system for deracemization of secondary amines, comprising a chemical oxidant and a chemical reductant, was designed by Toste and co-workers. A triphase system where the oxidant and reductant were separated by a nonpolar organic solvent prevented inactivation of the reagents.24 A chiral phosphate was used as catalyst together with Hantzsch ester for enantioselective reduction of the imine, in combination with an achiral oxopiperidinium salt as oxidant. The required energy was supplied by the transformation of the dihydropyridine to a pyridine derivative (Scheme 3).

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MINOR ENANTIOMER RECYCLING Base-catalyzed addition of acyl cyanides to aldehydes has been known since more than 65 years to afford O-acylated B


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Accounts of Chemical Research Scheme 3. Cyclic Deracemization Using Chemical Oxidant and Reductant

Scheme 5. High-Throughput Analysis of Scalemic OAcylated Cyanohydrins

remaining enantiomer. The cyanohydrins obtained by the enzymatic hydrolyses were in equilibrium with the corresponding aldehyde, which was reduced by NADH present in the reaction mixture. After each step, the decrease in extinction of NADH was measured, thereby giving information about conversion and enantiomeric ratio. The analyses were conveniently performed in a high-throughput manner using microtiter plates. The second step, the stereoselective reduction of the Sproduct enantiomer, thus restored the starting aldehyde, leaving the R-enantiomer untouched. It occurred to us, that in case product formation and regeneration of starting material could be performed as a one-pot procedure, this would result in a minor enantiomer recycling process consisting of the acylcyanation of an aldehyde with formation of the Renantiomer as the major product and conversion of the minor S-enantiomer back to starting reactant - which then again could undergo reaction to produce the R-enantiomer as the major product. Under proper reaction conditions, a one-pot cyclic reaction system was indeed possible to accomplish. A two-phase solvent system consisting of toluene and a buffered aqueous phase and slow addition of the acyl cyanide into the organic phase, to avoid undesired hydrolysis, allowed the cyclic process to proceed smoothly using the titanium dimer (S,S)-1 for the forward reaction and CALB for selective regeneration of the starting aldehyde from the S-enantiomer (Scheme 6). The

cyanohydrins.25 We found that use of a catalytic system consisting of a chiral Lewis acid, such as the chiral titanium salen dimer 1, and a chiral or achiral Lewis base provides an efficient route to nonracemic products. Thus, the addition of acetyl cyanide to benzaldehyde catalyzed by 1 and triethylamine gave O-acetyl mandelonitrile with high enantiomeric purity (Scheme 4).26 The reaction conditions tolerated a combination of a wide range of aldehydes, aliphatic as well as aromatic, and acyl cyanides. Scheme 4. Lewis Acid−Lewis Base Catalyzed Acetylcyanation of Benzaldehyde

Scheme 6. Minor Enantiomer Recycling

In order to simplify the analysis of reaction mixtures resulting from screening of reaction conditions using micro reactor technology, we developed an enzymatic high throughput procedure for determination of conversion of starting material and product enantiomeric ratio.27 In this procedure the reaction mixture, consisting of remaining starting aldehyde and the two product enantiomers, was first treated with NADH/horse liver dehydrogenase (HLADH), which caused reduction of the aldehyde (Scheme 5). The reduction was monitored by the decrease in extinction of NADH, which thus served as a readout of unreacted starting material. This step was followed by addition of Candida Antarctica lipase B (CALB), which catalyzed selective hydrolysis of the S-enantiomer of the product, and finally addition of a nonselective enzyme, pig liver esterase (PLE), which caused nonselective hydrolysis of the C


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Accounts of Chemical Research mistakes made by the catalyst for the forward reaction were thus corrected by the second catalyst. Under these conditions the presence of a Lewis base was not required, a circumstance which turned out to be of importance for the preparation of base-sensitive compounds. Two to three equivalents of the acyl cyanide were usually added. By proper choice of titanium complex and biocatalyst, the desired enantiomer of the product could be obtained in high yield and in most cases in high to excellent enantiomeric ratio, from aromatic as well as aliphatic aldehydes. By instead starting from racemic acylated cyanohydrins, the procedure constitutes a deracemization, but since focus is on the carbon−carbon forming process, and thus the preparation of the O-protected cyanohydrins, we found minor enantiomer recycling to be a more appropriate term for the process.28

Scheme 7. Minor Enantiomer Recycling Powered by Evolution of CO2

The Need for a Coupled Process

In the minor enantiomer recycling procedure shown in Scheme 6, an out-of-equilibrium nonracemic product mixture is maintained at a steady state as long as acetyl cyanide is added. The energy needed for recycling is provided by the coupled process consisting of the transformation of acetyl cyanide to HCN and acetate ion. An analogous process, where acetyl cyanide is replaced by an alkyl cyanoformate, is known to be catalyzed by the same titanium complex 1.29 The hydrolysis of the product from methyl cyanoformate and benzaldehyde, which gives monomethyl carbonic acid and mandelonitrile, is catalyzed by porcine pancreas lipase (PPL), with a preference for the S-enantiomer. Our assumption was that either deprotonation of the acid formed by hydrolysis of the product or evolution of CO2, which would promote the reversible hydrolysis, would serve as the required thermodynamic driving force for a cyclic process analogous to that shown in Scheme 6. However, the pKa of methyl carbonic acid was found to be too high for any significant deprotonation to occur under the reaction conditions, and decarboxylation of methyl carbonic acid is a slow process. As a result, recycling was found to be inefficient, and the enantiomeric ratio of the product increased only slowly (Figure 2, top).30 To our satisfaction, the presence of carbonic anhydrase, a zinc-containing enzyme which catalyzes the decarboxylation, resulted in an efficient cyclic process (Figure 2, bottom, Scheme 7).31 The evolution of the two enantiomers over time is illustrated in Figure 3. In this

process a chiral metal catalyst and two enzymes thus work in concert to constitute a cyclic reaction network.

Figure 3. Evolution of the R- (blue) and S- (red) enantiomers over time.

Characteristics of a Minor Enantiomer Recycling Process

The minor enantiomer recycling processes consist of an enantioselective product-forming step, which converts achiral starting material to nonracemic product. This is followed by an enantioenrichment step, consisting of a kinetic resolution (KR) of the product in favor of the minor enantiomer, which restores the starting material. A characteristic of minor enantiomer recycling procedures as well as cyclic deracemizations, is that the yield as well as the enantiomeric excess of the product increase over time (see Figure 2). The enantiomeric ratio, er, in an asymmetric reaction using a single chiral catalyst is equal to the selectivity of the catalyst, E. In a recycling procedure using two chiral catalysts, both catalysts contribute to the overall selectivity, which is equal to the product of the two selectivities, that is, E1 × E2.28 A reinforcing effect will thus result since the selectivities of the two catalysts contribute to the enantiomeric purity of the product.32 This follows from the definition of ee, but has also been shown experimentally. When the chiral titanium dimer was used in the acylcyanation of hexanal together with CALB, the product was, as expected, obtained with the same yield as in a reaction using a racemic titanium complex and CALB (Figure 4, top). The ee was, however, considerably lower in the second case (Figure 4, bottom), thus demonstrating experimentally the reinforcing effect of the two chiral catalysts. As long as the products of the selectivities of the two catalysts (E1 × E2) are the same, independent of how the they are distributed between the catalysts, the enantiomeric ratio at steady state will be the same, but the higher the selectivity of

Figure 2. Progress of yield (blue) and ee (green) over time in reactions with CO2 evolution switched off (top) and on (bottom). D


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Figure 5. Effect of variation of relative amounts of the two catalysts on ee (top) and yield (bottom). Blue, 1:1; red, 1:3; yellow, 1:4 ratio.

Figure 4. Progress of yield (top) and ee (bottom) over time in reactions using (S,S)-1 and CALB (blue) and rac-1 and CALB (turquoise).

enantioselective catalytic reaction, the yield of the slowly reacting enantiomer will benefit from the selectivities of both catalysts, and can evidently exceed 50% (B, Scheme 8). If, for example, a product with 80% ee is treated with a catalyst with a selectivity factor of 10 (i.e., k1/k2 = 10 where k1 and k2 are the rate constants for transformation of the two enantiomers), ca. 47% conversion is sufficient in order to obtain the slowly reaction enantiomer with 99.8% ee, whereas ca. 77% conversion is required to obtain the compound with the same purity starting from a racemate. In a minor enantiomer procedure, 100% yield can in principle be reached, but the enantiomeric excess is limited to (E1E2 − 1)/(E1E2 + 1), where E1 and E2 are the selectivities of the two catalysts (C, Scheme 8). However, in case the enantiopurity is not sufficiently high, the reaction mixture can be left after completed addition of the sacrificial reagent to allow the kinetic resolution of the product to continue. In his way an enantiopure product can be obtained, but again at the expense of the yield. Deracemizations are analogous to minor enantiomer recycling procedures, but start with a racemate instead of an achiral substrate. The selectivity in a dynamic kinetic resolution (DKR) is devoid of a reinforcing effect of two chiral catalysts and relies on the selectivity of a single catalyst and the enntiomeric excess is thus equal to (E − 1)/(E + 1) (D, Scheme 8). A requirement for a successful process is that a racemization is rapid in comparison to transformation of one of the enantiomers to the desired product. A quantitative yield can in principle be obtained, but the ee is limited by the selectivity of a single catalyst.

the catalyst for the forward reaction, the shorter the time needed to reach steady state will be. A high initial ee will therefore be observed when the selectivity of the catalyst for the forward reaction is high. The progress of ee also depends on the kinetic parameters, but at steady state the ee is always the same. On the other hand, the yield will be affected by which of the two steps is most selective, and a lower yield will be observed in a reaction where E1 > E2 than in one where E2 > E1, even when their products (E1 × E2) are equal.32 The ratio, that is, the relative amounts, of the two catalysts has an influence on the outcome of the reaction. This ratio will not affect the ee at steady state, but it will influence the time it takes to reach steady state (Figure 5). In contrast, the yield of the product varies with this ratio; as expected, a high relative amount of the catalyst for the product-forming reaction leads to a higher yield. The yield is also dependent on the total selectivity E1xE2, the kinetic parameters, and the initial substrate concentration. For this reason, the yield usually needs to be optimized, most conveniently by variation of the relative amounts of the two catalysts and the initial substrate concentration.

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COMPARISON OF KR, DKR, AND MER In a kinetic resolution, one of the enantiomers in a racemic or scalemic mixture is selectively transformed into another chiral or achiral product with the help of a chiral catalyst. The yields of pure starting material and product are dependent on the selectivity of the catalyst, but are limited to a maximum of 50%. Whereas the enantiopurity of the product (in case it is chiral) decreases over time, that of the slowly reacting enantiomer increases as the reaction proceeds, and this isomer can, even with a catalyst which is not completely selective, be obtained in enantiopure form, albeit at the expense of the yield (A, Scheme 8).33 Starting from a scalemic mixture resulting from an

Opposite Enantiomers

The outcomes of the different methods were studied experimentally using the acetylcyanation of crotonaldehyde as a suitable model system.34 Lewis acid/Lewis base catalyzed acetylcyanation gave the product with reasonable ee, 94%, but E


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Accounts of Chemical Research Scheme 8. Comparison of KR, DKR, and MER

as a result of the presence of base and the rather acidic αproton, the ee deteriorated during workup. By sequential asymmetric catalysis and kinetic resolution an enantiopure product can be obtained, without limiting the maximum yield to 50%. Thus, by treating the primarily obtained product with CALB, the ee improved to 98%, at 69% yield (by GC, Scheme 9). This should be compared to a minor enantiomer recycling

higher but the product suffered from partial racemization due to the presence of base. CALB selectively acetylates the Senantiomer and since the same enantiomer is selectively hydrolyzed in the first two processes, the enantiomer opposite to that resulting from the reactions above was obtained. Thus, in case a catalyst is not available for the preparation of the desired enantiomer, an appropriate method, either dynamic kinetic resolution or minor enantiomer recycling, can instead be selected. The combined use of two chiral catalysts results in a reinforcing effect, in sequential as well as cyclic processes. Whereas a cyclic procedure results in higher yield, enantiopure product is guaranteed only in a sequential process. In the example in Scheme 9, the highest ee and at the same time highest yield were, however, obtained from the cyclic procedure. The free cyanohydrin is an intermediate in the cyclic process, but not in the direct LA/LB-catalyzed addition of an acyl cyanide to an aldehyde.35 Thus, in case the cyanohydrin is prone to undergo some undesired reaction, a sequential process is preferred.36

Scheme 9. Preparation of 2-Acetoxy-3-pentenenitrile by (a) Combined Enantioselective Synthesis and Kinetic Resolution, (b) Minor Enantiomer Recycling, and (c) Dynamic Kinetic Resolution

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SYNTHETIC APPLICATIONS Cyanohydrins serve as versatile starting materials for the preparation of various types of compounds.37 Acylated cyanohydrins, which have found use in a variety of applications and which serve as valuable starting materials in organic synthesis, are of particular importance since the acyl group not only serves as a protecting group, but also can form part of the product.38 Among the known methods for the preparation of O-acylated cyanohydrins, which include direct addition of acyl cyanides to aldehydes,26 addition of KCN to aldehydes in the presence of acetic anhydride,39 and acylation of enantioenriched trimethylsilyl-protected cyanohydrins with acetic anhydride catalyzed by Sc(OTf)3,40 minor enantiomer recycling using 1 in combination with a biocatalyst is that which gives the highest yield and at the same time the highest enantiomeric purity of the product. The method is particularly useful for base-sensitive compounds34 since in contrast to the direct addition of an acyl cyanide to an aldehyde, the presence of base is not required. Several types of compounds which have proven to serve as useful starting materials for a variety of biologically active compounds, and which are not accessible by the LA/LB-

procedure, which resulted in 90% isolated yield of a product (100% by GC) with >99% ee. By dynamic kinetic resolution, which employed acetone cyanohydrin for the formation of the racemic cyanohydrin in rapid equilibrium with the aldehyde, and isopropenyl acetate in the presence of CALB for enantioselective acetylation of the cyanohydrin, the product was obtained in 67% yield and with 86% ee; the initial ee was F


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Accounts of Chemical Research Scheme 10. Synthesis of Beta Blockers

Scheme 13. Substitution with Aniline Derivatives

Scheme 14. Catalytic Hydrogenation

Scheme 11. Reduction of Acylated Cyanohydrin Accompanied by Acyl Transfer Scheme 15. Synthesis of Solabegron

Scheme 12. Preparation and Applications of O-αBromoacetyl Protected Cyanohydrins

functionalized cyanohydrins are obtained with low enantiopurity. We therefore decided to apply our minor enantiomer recycling procedure to the preparation of the required cyanohydrins. By this method, the acylated cyanohydrin required for the preparation of (S)-propranolol was obtained with high enantiopurity, 97.6% ee, as compared to 15% ee by direct addition to the aldehyde, and 35% ee by addition of TMSCN. The yield was however moderate, as a result of decomposition of the aldehyde (Scheme 10).41 Further functional group manipulations gave the desired β-amino alcohol with 97% ee. Using the same method, (R)-dichloroisoproterenol and (R)-pronethalol were obtained with 99 and 96% ee, respectively. Reduction of the cyano group of acylated cyanohydrins, accompanied by acyl transfer, provides a structural motif, which is present in a number of natural products and biologically active compounds (Scheme 11).

Figure 6. Pharmaceutically active compounds.

catalyzed reaction, at least not in a highly enantiopure form, have been obtained via the cyclic process. The synthesis of β-amino alcohols serving as beta blockers has been extensively studied and several enantioselective methods are known. Surprisingly, procedures starting from enantioenriched cyanohydrins do not seem to have been explored. The reason for this is probably that the required OG


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Accounts of Chemical Research Scheme 16. Suzuki Coupling

bromide with cyanide, were used as reactants. From the achiral reagent the desired products were obtained in high yields and with high ee, whereas the racemic ketonitrile resulted in a mixture of two out of the four possible diastereomers. The corresponding direct LA/LB-catalyzed addition failed due to destructive reaction between the tertiary amine present in the catalytic system and the bromide. Further synthetic elaboration of the products included substitution with aniline derivatives and Suzuki couplings, and subsequent reduction provided access to a range of N-acylated or N-alkylated β-amino alcohols (Scheme 12). An advantage with the present procedure is that it is highly divergent, providing access to a variety of products from a single intermediate. Examples of pharmaceutically active compounds with these basic structures include Midodrine, Solabegron, Denopamine, and Mirabegron (Figure 6). Substitution with aniline derivatives proceeded smoothly without any significant deterioration of ee (Scheme 13),42 and catalytic hydrogenation provided the target compounds, although in moderate yields (Scheme 14). Reaction of an acylated cyanohydrin with an aniline derivative was used as a key step in the preparation of Solabegron, which acts as a selective agonist for the β3adrenergic receptor and was developed for the treatment of overactive bladder and irritable bowel syndrome.42 Thus, reaction of 3-chlorobenzaldehyde with α-bromoacetyl cyanide in the presence of titanium complex 1 and CALB using the minor enantiomer recycling procedure gave the expected acylated cyanohydrin (Scheme 15). Reaction with the appropriate aniline derivative followed by reduction gave, after functional group modifications, the desired compound with 95% ee. For successful Suzuki couplings mild conditions, employing KF as a base, were required in order to avoid racemization (Scheme 16). N-Acylated amino alcohols were accessible by subsequent reduction with acyl transfer (Scheme 17).43 The 2(5H)-furanone structural unit is found in a range of compounds, many of which exhibit interesting biological function. 4-Amino-2-(5H)-furanones proved to be accessible via our minor enantiomer recycling procedure, by reaction of

Scheme 17. Catalytic Hydrogenation

Scheme 18. Blaise Cyclization for Preparation of 4-Amino-2(5H)-furanones

Under the conditions used for the cyclic process, the choice of acyl group is limited due to the substrate tolerance of CALB. It was therefore of interest to prepare compounds with an acyl group containing a reactive handle, which would allow subsequent synthetic manipulations. For this purpose αbromoacetyl cyanide and (rac)-α-bromoethanoyl cyanide, prepared by substitution of the appropriate α-bromoacyl H



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aromatic or aliphatic aldehydes with racemic α-bromoethanoyl cyanide followed by Blaise cyclization (Scheme 18).44 The recycling reaction catalyzed by (S,S)-1 and CALB resulted in initial formation of four stereoisomers. Two of the isomers were selectively hydrolyzed by the enzyme, resulting in final formation of two isomers, both with S-configuration at the center next to the cyano group. The acylated cyanohydrins were obtained in yields ranging from 51 to 80% and the target furanones, with a single stereocenter, were obtained in 71−98% yields and with ee’s from 91 to 98%.

ACKNOWLEDGMENTS The author is deeply grateful to the students who with great patience and skill have contributed to this work. Special thanks go to Dr. Robin Hertzberg for having read and commented the manuscript.

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CONCLUSIONS AND PERSPECTIVES Cyclic reaction networks permitting a minor product enantiomer to be transferred back to starting reactant can be generated provided a source of energy is available. Other prerequisites for a unidirectional cyclic process are that the product-forming step can be reversed, that suitable catalysts for the forward and reverse reactions are available, and that the two catalysts are compatible. Only a few types of cyclic reaction networks are known. Development of new carbon−carbon bond forming reactions, where mistakes made by one catalyst are corrected by a second selective catalyst, would be of major synthetic interest. The enzymes used for the minor enantiomer recycling processes described in this Account have a quite narrow substrate tolerance. With the emergence of new technologies for enzyme engineering and evolution, a wider scope of reactions may be available, thus leading to increased synthetic utility. Furthermore, other combinations of metal catalysts, organocatalysts, and biocatalysts could lead to the development of new processes. The possible role of recycling in processes related to the origin of homochirality is an intriguing subject. Although the processes presented here might not be compatible with prebiotic chemistry, an analogous speculative cyclic network composed of autocatalytic Strecker synthesis and degradation has been suggested as a scenario for the emergence of homochirality.45 The proposed cycle consists of addition of cyanide to an imino species, generated from the corresponding aldehyde and ammonia, followed by hydrolysis of the cyano group, and final destruction of the “wrong” amino acid to restore the reactant along with evolution of CO2. The experimental realization of such autocatalytic processes might lead to possible scenarios for the origin of homochirality and may at the same time be beneficial for synthetic chemistry.

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Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The author declares no competing financial interest. Biography Christina Moberg obtained her B.Sc. at the University of Stockholm and her Ph.D. at KTH with Martin Nilsson. She spent a few months in the group of J. Normant in Paris, and then joined the group of B. Åkermark for 2 years. She became full professor at KTH in 1997. She has held visiting professorships at Louis Pasteur University in Strasbourg, and at IRCOF, Rouen. She is presently the President of the Royal Swedish Academy of Sciences. Her research interests are in the field of asymmetric metal catalysis and concern mainly the development of selective synthetic methods. I


Article


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