Recent Advances in Multicatalyst Promoted Asymmetric Tandem Reactions



Multicatalyst promoted asymmetric tandem reactions have emerged as a powerful strategy to improve the synthetic efficiency. It enables the synthesis of complex molecules with high selectivity from simple starting materials in an almost biomimetic-like way. The use of multiple catalyst systems can enlarge the substrate and reaction scope for the reaction design, improve the reactivity, and benefit the control of selectivity. In this Focus Review, the current achievement of this promising field is discussed, including the advantages and difficulties of this research, and the strategies applied to address these problems.

1. Introduction

Nature created multienzymatic systems to accomplish extremely efficient one-pot tandem catalysis. As in an assembly line, tens of enzymes are well organized to transform simple materials to complex molecules with perfect control of selectivity by a series of coupled reactions in the cell. It has long been chemists’ endeavour to extend such coordinated catalytic action to artificial processes to make synthetic chemistry more sustainable. Nowadays, owing to the resource-intensive nature of the current synthetic industry, the development of tandem reactions has become especially important and valuable because society is confronted with bottle-neck problems such as energy shortage and environmental pollution.

Tandem catalysis refers to the synthetic strategies of modular combination of catalytic reactions into one synthetic operation with minimum workup or change in conditions.1 Compared with stepwise synthesis, tandem catalysis is able to reduce the usage of chemicals and circumvent the yield losses associated with the purification of intermediates, save time, energy, labour, and other resources, alleviate the generation of waste, and hopefully maximize synthetic efficiency. Furthermore, tandem reactions help lower the risk in the storage, transportation, and the handling of toxic, unstable, or explosive intermediates, and promote equilibrium reactions to full conversion by directly coupling them in the following reaction cycle.

Catalytic asymmetric tandem reactions could provide a practical and efficient strategy for the enantioselective preparation of chiral compounds from simple substrates in a simple process. However, the development of catalytic asymmetric tandem reactions is a big challenge because one must take into account the compatibility of the chiral catalyst with residual material (solvent, substrates, other catalyst, and intermediates generated in situ). Chiral metal complexes, in general, are sensitive to species with coordinating ability in the reaction system, while organocatalysts are relatively robust and have high compatibility, and some organocatalysts can promote several types of reactions through different activating models. In light of this, organocatalytic asymmetric tandem reactions have recently become a fast-growing field.2

During the past several years, many asymmetric cascade reactions have been developed and found wide application in the enantioselective synthesis of natural products or bioactive compounds. However, most of them rely on the employment of a single chiral catalyst, especially, the use of secondary amines and their salts. Since only one catalyst is used, the substrates and reactions coupled in one cascade reaction are limited. As a consequence, most of the currently developed cascade reactions only involve limited steps (two steps in most cases), and usually the first step is intermolecular and the rest are intramolecular. To achieve biomimetic-like, fully intermolecular tandem reactions capable of synthesizing complex molecules from simple starting materials through multi-step syntheses, the development of multicatalyst promoted asymmetric tandem reaction, as occurs in the cell, now becomes the challenging task.

As can be expected, besides the general advantages a tandem reaction should have, multicatalyst mediated asymmetric cascade reactions have some special characteristics from an academic point of view: 1) the substrates and reactions which could be coupled in one tandem reaction are obviously expanded. The cascade reaction will be truly multi-step from simple starting materials, instead of from pre-organized multifunctional substrates. 2) The cooperative effect of multicatalyst might be expected to improve the reactivity and selectivity. 3) The stereochemical control can be realized by one chiral catalyst or more, and thus the control of diastereoselectivity and enantioselectivity should be easier, or in some cases become tunable. 4) The combination of a reaction cycle into a cascade can suppress some side reactions by coupling the intermediate into the next step with a faster reaction rate than the side reactions.

In spite of the aforementioned advantages, the development of multicatalyst promoted asymmetric tandem reactions (MPATR) is still in its infancy, possibly as a result of the two main difficulties: 1) catalyst compatibility: each catalyst must be compatible with each other, and with other reaction species (substrates, solvent, additives, intermediates, and so on); 2) reaction selectivity: every step of a tandem reaction should strictly follow the designed sequence to avoid the generation of side products or termination of the tandem reaction. Furthermore, each step should have high regioselectivity, diastereoselectivity, and enantioselectivity. Otherwise, the cascade reaction will produce many isomers that are difficult to purify.

By now, chemists have developed the following four strategies to address the aformentioned problems, and an array of multicatalyst promoted tandem reactions has been successfully developed and demonstrates high reactivity and excellent selectivity. Even tandem reactions using obviously incompatible catalysts worked well in one pot to afford the desired product in good yield and enantioselectivity.

1) Use of compatible catalysts system. For example, fine tuning the hardness and softness of the catalysts by the use of soft metal Lewis acid and hard organic Lewis base catalyst.

2) Use of site-isolated techniques. For example, the use of a microencapsulated multicatalyst system to avoid catalyst interference.

3) Use of phase-separation techniques. For example, taking advantage of the hydrophobic property of the substrates with similar reactivity, using aqueous and organic biphasic system to accomplish the desired reaction sequence.

4) Sequential addition of catalyst and substrates.

This Focus Review illustrates the recent development of multicatalyst promoted asymmetric tandem reactions, and briefly discusses the strategies involved to overcome the difficulties mentioned above. The reactions are classified by the combination of types of catalysts. Since Bazan et al. have already published an excellent review on concurrent tandem catalysis in 2005,1b this review focuses on truly catalytic asymmetric multicatalyst promoted tandem reactions since then.

2. Tandem Reactions Catalyzed by Multiple Catalysts from the Same Discipline

The field of asymmetric catalysis was built on three pillars, namely metal catalysis, biocatalysis and organocatalysis. Each discipline can be divided into different types of catalysts. For example, organocatalysts mainly include four types, Lewis acids, Lewis bases, Brønsted acids, and Brønsted bases. Each division can be further subdivided into different types of catalysts according to the activation model. In light of this, the combination of multiple catalysts to promote a tandem reaction, not only means the combination of different catalysts from different disciplines (biocatalysis, metal catalysis, or organocatalysis), but means the combination of catalysts from the same discipline. In the following chapter, we summarize the tandem reactions catalyzed by different catalysts from the same discipline.

2.1. By Multiple Metal Catalysts

Since Nozaki and Noyori developed the first example of asymmetric catalysis using a chiral metal complex,3 asymmetric metal catalysis has attracted great research attention, and has been thriving for tens of years. Tremendous chiral metal complexes have been synthesized and applied to many types of catalytic asymmetric reactions. However, the combination of different metal catalysts for catalytic asymmetric reactions is rather limited, probably owing to the fact that the presence of multiple metal catalysts will lead to the competitive coordination of metals to the chiral ligand used, which makes the chiral environmental unpredictable and unsuitable for a given reaction. Nevertheless, there have some examples to elucidate the power of this concept.

In 2004, B. L. Feringa reported a short, catalytic asymmetric synthesis of (−)-pumiliotoxin C,4 the key step of which is a Cu/Pd catalyzed tandem asymmetric conjugate addition–allylic substitution reaction (Scheme 1). To prevent the possible catalyst interference, the palladium catalyst was added after the completion of the catalytic asymmetric Michael addition of Me2Zn to cyclohexenone 1. The advantage of this tandem reaction is demonstrated by the fact that allylic substitution exclusively took place at the 2-position of the 3-methylcyclohexanone, while it is difficult to control the regioselectivity if using enantiopure 3-methylcyclohexanone to prepare the enolate.

Scheme 1.

Combination of copper catalysis and palladium catalysis.

Also in 2004, Buchwald et al. reported a one-pot tandem copper catalyzed asymmetric conjugate reduction and palladium catalyzed arylation reaction, providing a facile access of enantiomerically enriched α-arylated β-substituted cycloalkanones 8 in excellent diastereoselectivity and enantioselectivity (Scheme 2).5 The solvent was found to be crucial in this transformation. The initial reduction step was carried out in a mixed solvent of THF/n-pentane (1:1) to maintain the excellent ee (95–97 %) in this step. After the reduction was completed, n-pentane was easily removed in vacuum, leaving the intermediate silyl enol ethers in THF, followed by the addition of Pd(OAc)2, ligand 7, and arylbromide for the coupling reaction.

Scheme 2.

Combination of copper catalysis and palladium catalysis.

In 2006, Trost et al. reported a one-pot synthesis of enantiopure N-and O-heterocyclic compounds using the combination of Ru catalyst and chiral palladium complex.6 After the completion of ruthenium catalyzed alkene/alkyne cross-coupling reaction of 9 and 10, the chiral ligand 12 and palladium catalyst was added to furnish the enantioselective intramolecular heterocyclization reaction. This tandem reaction was employed for the concise synthesis of ring B of bryostatin, a potent antitumor agent (Scheme 3).

Scheme 3.

Combination of ruthenium catalysis with palladium catalysis.

In 2006, Nishibayashi et al. demonstrated that iridium catalyst can be compatible with ruthenium catalyst in the same medium to promote a tandem asymmetric α-alkylative reduction of ketones with alcohols (Scheme 4).7

Scheme 4.

Combination of iridium catalysis and ruthenium catalysis.

This cascade possibly began with the catalytic dehydrogenation of primary alcohol 15 by the iridium complex to form the corresponding aldehyde 16, which underwent a base catalyzed aldol condensation to afford an α,β-unsaturated ketone 17. The following iridium catalyzed hydrogenation gave α-alkylated ketone 18, which was transferred to chiral alcohol 20 by an enantioselective transfer hydrogenation. The chiral transfer hydrogenation catalyst 19 and reagents were added after the completion of α-alkylation of ketone to avoid the hydrogenation of the substrate ketone.

To overcome the problem that iridium catalysts are powerful for the allylic substitution of linear allylic electrophiles but ineffective for branched ones, and to provide a general method for the highly regio- and enantioselective allylic substitution reaction, Hartwig et al. developed a sequential palladium-catalyzed isomerization and iridium-catalyzed asymmetric allylic substitution reaction in 2006 (Scheme 5).8 This tandem reaction allows the conversion of easily synthesized branched aromatic esters 21 to branched allylic products 24 in good yield and excellent regio- and enantioselectivity. To prevent the interference of palladium with chiral iridium catalyst to secure high yield and ee of the final product 24, it needed simple filtration of the crude isomerization product 22 through silica to remove the bulk of palladium catalyst before the addition of chiral ligand 23, iridium catalyst, and nucleophile.

Scheme 5.

Combination of palladium catalysis and iridium catalysis.

In 2007, Nishibayashi et al. reported the deracemization of secondary benzylic alcohols by a two-step process with the combination of two different chiral ruthenium catalyst (Scheme 6).9 The initial step of this sequential process was a kinetic resolution of the alcohol by the selective oxidation of the S-alcohol to the corresponding ketone 27 catalyzed by chiral ruthenium complex 26. The ketone intermediate 27 was then selectively reduced to R-alcohol by chiral ruthenium catalyst 28. As compared with kinetic resolution, this two chiral ruthenium catalyst system provided a convenient and efficient approach for the synthesis of chiral alcohols in high yields and excellent enantioselectivity.

Scheme 6.

Combination of two different ruthenium complexes.

In contrast to the above multicatalyst system, where a different metal catalyst mediated a catalytic cycle independently, two metal cations might cooperate in each cycle of a tandem reaction, as reported in 2007 by the Shibasaki group.10 This novel three component tandem reaction involves the addition of dialkylzinc 31 to allenic ester 30, aldolization to ketone, and a lactonization reaction. Initially, the CuII was reduced to CuI in the presence of alkylzinc to produce an alkylcopper–phosphine complex. Because the use of Cu(OAc)2 afforded significantly higher enantioselectivity and yield than CuBr and CuCl, the authors proposed that the acetate might act as a bridging ligand between ZnII and CuI, and thus ZnII might serve as Lewis acid to activate carbonyl groups, stabilize the oxygen anion intermediate, and direct the substrate (Scheme 7). As such, copper and zinc cooperate efficiently to afford the desired product in excellent yield and enantioselectivity.

Scheme 7.

Cooperative effect of zinc and copper catalysis.

2.2. By Multiple Organocatalysts

Organocatalysts are usually readily available, easy to handle, and robust, and a significant advantage is their high compatibility.11 For example, the most commonly used organocatalyst, secondary amines, are usually used in combination with a certain acid cocatalyst.12 Furthermore, many organocatalysts can promote several types of reactions through different activation models. These attributes make it versatile to combine different organocatalyst to design new tandem reactions.

In 2005, MacMillan et al. disclosed the concept of cycle-specific catalysis, wherein each cycle in a tandem reaction is moderated by a different chiral amine catalyst, which allows selective synthesis of any product enantiomer or diastereomer by choosing an appropriate catalyst.13 They demonstrated the versatility of this idea by the control of diastereoselectivity in the asymmetric addition of HF across the 3-phenyl-but-2-enal 36 by using two different chiral amine catalysts. Amine catalyst 37 acted as iminium catalyst for the asymmetric transfer hydrogenation of the enal, and the other amine catalyst served as enamine catalyst for the α-fluorination of the aldehyde intermediate. To ensure high yield, the enamine catalyst and the electrophile was added after the consumption of the Huntzsch ester 38.

It should be noted that the structure of the enamine catalyst significantly influenced the reaction diastereoselectivity. Using the same catalyst 37 as both the iminium and enamine catalyst only afforded moderate ratio of syn to anti (3:1). Amine (R)-41 as enamine catalyst could improve the diastereoselectivity to 9:1. More, the opposite enantiomer of (S)-41 afforded anti product as the major in 16:1 dr (Scheme 8). This interesting result demonstrated MPATR enables tunable control of diastereoselectivity.

Scheme 8.

Combination of two chiral amine catalysts.

In 2007, List et al. reported a novel one-pot tandem reaction which for the first time combined chiral Brønsted acid catalysis with enamime and iminium catalysis.14 By control experiments and ESI-MS/MS analysis,15 a reasonable reaction mechanism was proposed as in Scheme 9. The initial step of this cascade reaction was mediated by achiral p-ethoxyaniline (PEP-NH2) and chiral phosphoric acid TRIP, either reagent alone is inefficient in promoting this aldol condensation to afford intermediate 46. The following step is a conjugate reduction which was also Brønsted acid and amine co-catalyzed, and no further conversion took place in the absence of either catalyst. The final step is an acid catalyzed reductive amination.

Scheme 9.

Combination of Brønsted acid catalysis with enamine and iminium catalysis.

This tandem reaction demonstrated the power of combining amino-catalysis and Brønsted acid catalysis, providing a convenient method for the highly enantioselective synthesis of pharmaceutically active chiral cis-3-substituted cyclohexyl or heterocyclohexyl amines 49, which is difficult to obtain by other methods. It should be noted that the stereocontrol of the conjugate reduction and reductive amination step was accomplished by the chiral phosphoric acid TRIP, as is demonstrated by the control experiments (Table 1).

Table 1. Control experiments. inline image
Catalyst systemYieldcis/trans
1) TsOH (10 mol %), HE 47 (1.2 eq), c-hexane/MS 5 Å89 %1.0/3.6
2) (S)-TRIP (10 mol %), HE 47 (1.2 eq), c-hexane/MS 5 Å91 %6.0/1.0
3) (R)-TRIP (10 mol %), HE 47 (1.2 eq), c-hexane/MS 5 Å82 %1.2/1.0
4) NaBH(OAc)3, HOAc/CH2Cl2, RT.94 %1.0/3.7

Recently, Jørgensen et al. reported a novel one-pot efficient synthesis of 4,5-disubstituted isoxazoline-N-oxides from simple commercially available starting materials using the combination of iminium catalyst 52 and chiral PTC catalyst 54.16 This cascade was initiated by the asymmetric epoxidation of α,β-unsaturated aldehyde, followed by chiral ammonium salt 54 catalyzed Henry reaction under phase-transfer-catalysis conditions. It should be noted that the use of chiral ammonium salt 54 was essential for achieving high selectivity in the addition of a nitro compound to the aldehyde. The following base mediated intramolecular O-alkylation afforded the desired isoxazoline-N-oxides 58 in excellent enantioselectivity, good yield, and dr. The product could be easily transformed to the β,γ,δ-trihydroxylated α-amino acid derivative (Scheme 10).

Scheme 10.

Combination of iminium, PTC and Brønsted base catalysis.

Most recently, Fréchet reported an elegant water/organic biphasic one-pot tandem reaction enabling the selective formation of a major cross coupling product (Scheme 11).17 The success of this tandem reaction is based on the following prerequisites: 1) The proline dissolves well in aqueous phase, but poor in organic phase. Furthermore, proline could efficiently catalyze the condensation of aldehyde with nitromethane under aqueous conditions, but was a poor catalyst for the Michael addition of aldehyde to the nitroalkene intermediate 61. 2) The other amine catalyst diphenylprolinol TMS ether 52, dissolves well in organic phase rather than in water. It is a poor catalyst for condensation, but an efficient and highly enantioselective catalyst for the Michael addition.

Scheme 11.

Combination of two different chiral amine catalysts.

Based on these observations, they developed a phase separation technique to selectively activate the two aldehydes with similar reactivity (Scheme 11). In the aqueous phase where condensation is observed, the use of a large amount of proline catalyst (40 mol %) could efficiently catalyze the condensation of nitromethane and 3-methylbutanal 59 with greater miscibility with the aqueous phase, while in organic phase where the Michael addition took place, the use of only 1 mol % of catalyst 52 could slow down the Michael addition, so that 3-methylbutanal 59 was consumed as much as possible in the condensation step to suppress the addition of 3-methylbutanal 59 to the nitroalkene intermediate 61 to afford the undesired product 63. As a result, the more hydrophobic n-decanal 60, could survive from the condensation step and readily react with the nitroalkene intermediate 61 in the organic phase. Indeed, only trace amount of side product 64 and 65 were detected.

This biphase system casts light on the selective activation of substrates with similar reactivity by using properties other than chemical reactivity, which will be a powerful strategy to solve the problem of reaction sequence selectivity in the development of multicatalyst directed tandem reaction.

In 2009, Maruoka et al. reported an enantioselective, one-pot synthesis of nitrogen containing heterocyclic compounds by the combination of chiral phase-transfer-catalysis and Brønsted acid catalysis.18 As shown in Scheme 12, the one pot reaction was realized by sequential addition of reagents and variation of reaction condition, to prevent catalyst interference. After the chiral PTC salt 68 catalyzed conjugate addition of glycine ester 67 to enone 66 finished, which took place at 0 °C in ether affording the intermediate 69 in 94 % ee, the solvent was removed in vaccum, followed by the addition of ethanol, water, and CF3COOH. The acid catalyzed acetal hydrolysis was run at room temperature for one hour, then Hantzsch ester 47 was added, and the reductive amination was run at 60 °C, furnishing the cascade in 48 % yield.

Scheme 12.

Combination of PTC and Brønsted acid catalysis.

Most recently, Rovis et al. found that amine catalyst 52 could be compatible with a carbene catalyst 74 to promote a tandem Michael addition/benzoin reaction (Scheme 13),19 enabling the synthesis of cyclic compounds 75 from readily available starting materials.

Scheme 13.

Combination of iminium and carbene catalysis.

Interestingly, they observed that the cooperation of the iminium catalyst 52 and carbene catalyst 74 is important for the high yield and enantioselectivity of this tandem reaction. If this transformation was carried out stepwise, the intermediate aldehyde 73 was isolated in diminished enantioselectivity (ca. 60 % ee), possibly owing to the retro-Michael reaction in the presence of prolinol 52 and the epimerization during purification on column chromatography, which was confirmed by control experiments. As a consequence, the desired product 75 was obtained in obviously lower yield (46 % for two steps) and enantioselectivity (58 % ee), in sharp contrast to the high yield and enantioselectivity of the one-pot tandem reaction (93 % yield, 86 % ee). When the two reactions were combined into a cascade, the carbene catalyst could concurrently promote the following benzoin reaction, preventing the pile up of the intermediate aldehyde 73 which effectively suppressed the retro-Michael addition, and achieved the high enantioselectivity (Scheme 13). This work further demonstrated an advantage of MPATR over stepwise synthesis in achieving high enantioselectivity and reactivity by suppressing side reactions.

2.3. By Multiple Enzymes

Enzyme catalysis is a powerful tool for enantioselective synthesis owing to its high selectivity and non-toxicity. Furthermore, multiple enzyme catalysts can be performed under the same mild conditions, which help the development of one-pot enzymatic cascade reactions. However, owing to the fact that enzymes often have no appropriate active sites for non-natural substrates, the suitable enzyme for each step of a cascade reaction must be carefully optimized. In light of this, there are only very limited examples of tandem biocatalysis.

In 2008, Kroutil et al. reported the first example of deracemization of secondary alcohols through a concurrent tandem bio-oxidation and bio-reduction (Scheme 14).20 They observed that the use of Alcaligenes faecalis DSM 13975 as the catalyst could use O2 as the oxidant to selectively oxidize the R-enantiomer of racemic secondary alcohols 76 to form intermediate ketone 77. The combination of this powerful R-enantioselective biooxidation reaction with S-enantioselective bio-reduction of the intermediate ketone 77 catalyzed by S-selective alcohol dehydrogenase ADA-“A” from Rhodococcus rubber DSM 44541 with cofactor recycling provides a facile method for the synthesis of enantiomerically pure S-alcohol. This tandem biocatalytic deracemization of secondary alcohols can be performed on a preparative scale, for example, 0.5 mL of racemic 4-phenyl-2-butanol can be transformed to pure (S)-4-phenyl-2-butanol in 91 % yield with >99 % ee.

Scheme 14.

Combination of two different enzymes.

In 2009, Li et al. reported the preparation of chiral aryl vicinal diols through a tandem epoxidation and hydrolysis reaction with the combination of two biocatalysts (Scheme 15).21 The enantioselective epoxidation of styrene with E. coli JM101 (pSPZ10) performed efficiently to generate (S)-styrene oxide in>99 % ee, which was hydrolyzed to the corresponding (S)-diol in excellent regioselectivity catalyzed by the lyophilized cell free extract (LCFE) of Sphingomonas sp. HXN-200. This tandem reaction was carried out in a two-phase system, and styrene 78 mainly remained in the organic phase and the diol product 80 existed in the aqueous phase, which allowed a facile product separation, and reduced the inhibition of styrene 78 and styrene oxide 79 to the enzyme. As such, the utilization of tandem biocatalysts could achieve higher conversion for the epoxidation than the use of only styrene monooxygenase, and more efficient synthesis of enantiopure vicinal diols than the use of dioxygenase, which afforded mixtures of diol and cyclohexadiene-cis-diol with low to moderate yield and enantioselectivity.

Scheme 15.

Combination of two different enzymes.

3. Tandem Reactions Catalyzed by Multiple Catalysts from Different Discipline

As far as metal catalysis, organocatalysis, and biocatalysis are concerned, each discipline has its own advantages, limitations, and range of application. The combination of catalysts from different disciplines will enable unprecedented transformations not currently possible by use of any catalysis alone, or make current synthetic methods more economical and practical. As can be seen from this chapter, the combination of different type of catalysts is fruitful for the development of new synthetic methods.

3.1. By the Combination of Metal and Organocatalysts

Although the combination of transition metal catalysis with organocatalysis has become a fruitful strategy for the development of new and valuable reactions,22 it is still a challenge to develop a cascade reaction catalyzed by the combination of two types of catalysts. While organocatalysis is dominated by Lewis base catalysts, such as amines, carbenes, and tertiary phosphines, a metal catalyst usually needs to have an empty coordination site to interact and activate a given substrate to facilitate a reaction. In light of this, how to prevent the possible catalyst deactivation by Lewis acid base interaction is the key point to develop such a tandem reaction. Even if there is no catalyst poison, the presence of a Lewis base might erode the chiral environment of a chiral metal complex. To circumvent this problem, several strategies have already been employed in the reaction development: 1) fine tuning the hardness and softness of the metal catalyst and organocatalyst used to increase the catalyst compatibility; 2) the use of phase separation techniques to partition incompatible catalysts; 3) sequential addition of catalysts and substrates.

In 2006, McQuade reported a one-pot tandem reaction catalyzed by microencapsulated amine catalyst (μcap amine) and chiral Nickel complex 81,23 capable of converting aldehyde, nitromethane, and dimethylmalonate to their corresponding Michael adducts 82 (Scheme 16). Although the ee of this tandem reaction was not so high, the site-isolation of two otherwise incompatible catalysts provided by microencapsulation brought new insight into the development of amine–Lewis acid tandem reactions. The encapsulation of the amine catalyst was key for the success of this tandem reaction for the following reasons: 1) the use of soluble amine catalyst led to catalyst deactivation by complexation with nickel catalyst 81; 2) silica MCM-41 or polystyrene supported amine catalyst failed to catalyze the nitroalkene formation at room temperature, but the encapsulated poly(ethyleneimine) (PEI) can; 3) the μcap amine swollen in methanol retains their catalytic potency when in toluene, which allowed the one-pot reaction to be run in a mixture of two different solvents, and the μcap amine and nickel catalyst 81 could work under their respective ideal solvents of methanol and toluene.

Scheme 16.

Combination of iminium catalysis with nickel catalysis.

The superiority of this two catalyst one-pot system was demonstrated by the following three facts (Table 2). 1) If the reactions were run sequentially, rather than in one-pot, the dinitro compound 85 was obtained preferably; 2) the use of either μcap amine or nickel catalyst 81 alone afforded almost no Michael adduct; 3) the polyurea shells which contained the PEI amine could cooperate with the nickel catalyst in the Michael addition of malonate to nitroalkene, acting as hydrogen-bonding donor catalyst to activate nitroalkene 61. These advantages further demonstrated the versatility of multicatalyst promoted tandem reactions.

Table 2. Control experiments. inline image
EntryCatalyst systemConversion of 83Yield of 86
1μcap amine+Ni catalyst 819580.2
2μcap amine alone672.1
3Ni catalyst 81 alone618.5
4Free PEI+Ni catalyst 81965.4

In 2007 at the same time, Breit et al.24a and Eilbracht et al.24b independently reported a novel tandem hydroformylation and cross-aldol reaction catalyzed by rhodium catalyst and proline catalyst (Scheme 17). Possibly owing to the fact that proline is “hard” but Rh catalyst is “soft”, the proline can be compatible with Rh catalyst to furnish this tandem reaction, as demonstrated by the control experiments by Eilbracht et al. By fine adjustment of the hydroformylation rate to that of the proline-catalyzed aldol addition, the undesired homodimerization of the donor aldehyde 89 could be suppressed. As a result, by in situ hydroformlyation reaction, the donor aldehyde 89 of a cross-aldol reaction could be readily generated and kept in low concentration, which allows the suppression of its homo-aldolate formation. This is one of the advantages of a multicatalyst promoted tandem reaction.

Scheme 17.

Combination of rhodium catalysis with enamine catalysis.

Later, Eilbracht et al. applied the same strategy to the synthesis of optically active amine compounds from alkenes through a tandem hydroformylation/Mannich reaction (Scheme 18).25 The combination of rhodium catalyst hydroformylation with the proline catalyzed asymmetric Mannich worked well to afford the desired product in moderate yield and good enantioselectivity.

Scheme 18.

Combination of rhodium catalysis with enamine catalysis.

In 2007, List et al. reported a tandem synthesis of β-all carbon quaternary amines by a highly enantioselective α-alkylation of α-branched aldehydes,26 involving palladium catalyst and a chiral phosphoric acid. Under the catalysis of phosphoric acid, a secondary allylamine 98 reacted with aldehyde 97 to form an enammonium phosphate salt 99, which upon reaction with Pd catalyst afforded a cationic π-allyl palladium complex 100. The intermediate 100 resulted in the formation of α-allylated iminium ion 101, which might be reduced to the chiral amine 102 or be hydrolyzed to chiral aldehydes 102 with all-carbon quaternary stereogenic centers. The synthetic utility of this transformation was also demonstrated by the formal synthesis of (+)-cuparene starting from aldehyde 104 (see Scheme 19).

Scheme 19.

Combination of palladium catalysis with Brønsted acid catalysis.

In 2008, Hu and co-workers developed an enantioselective four-component reaction of aryl diazoacetates with alcohols, aldehydes, and amines by the cooperative catalysis of rhodium complex and a chiral phosphoric acid, to readily prepare β-amino-α-hydroxyl acid derivatives with excellent control of chemo-, diastereo-, and enantioselectivity.27 Under the catalysis of Brønsted acid, the aldehyde 83 reacted with p-methoxyaniline 107 (PMP-NH2) to form enamonium phosphate salt 109, which reacted with the oxonium ylide intermediates 108 generated in situ from diazoacetate 105 and alcohol 106 catalyzed by the Rh catalyst. The intermediate 108 and 109 might be organized through hydrogen bonding with the bridging chiral anion of the chiral acid to form 110, which undergoes intramolecular addition to form the desired product 111 in excellent yield, diastereoselectivity, and enantioselectivity (Scheme 20).

Scheme 20.

Combination of rhodium catalysis with Brønsted acid catalysis.

In 2009, MacMillan et al. reported another example of a cycle-specific cascade reaction blending Grubbs catalyst with iminium and enamine catalyst.28 In this case, the sequential addition of Grubbs II catalyst, iminium catalyst 41 and proline together with the respective addition of 5-hexene-2-one 112, crotonaldehyde 113, and trimethylsilyloxyfuran 114 afforded the desired diastereomer of the product in 64 % yield, 95 % ee with 5:1 dr. It is really striking that from simple starting materials 112114, the complex skeleton 117 with four stereocenters could be constructed through a one-pot multicatalyst promoted tandem reaction in a very simple operation. Based on the cascade product 117, the total synthesis of (−)-aromadendranediol was accomplished in 8 steps (see Scheme 21). This example vividly demonstrated the power of multicatalyst promoted tandem reaction in the total synthesis of complex natural products with multiple chiral centers.

Scheme 21.

Combination of ruthenium catalysis with iminium and enamine catalysis.

Later, You et al. demonstrated that Ru catalyst can also be compatile with Brønsted acid catalyst.29 They reported a practical and economical synthesis of tetrahydropyrano[3,4-b]indols and tetrahydro-β-carbollines by the combination of Ru catalyzed olefin cross-metathesis and a chiral Brønsted acid catalyzed Friedel–Crafts alkylation reaction (see Scheme 22). This tandem reaction allows the use of readily available starting materials to highly enantioselectively construct synthetically valuable polycyclic indole frameworks.

Scheme 22.

Combination of ruthenium catalysis with Brønsted acid catalysis.

Recently, Gong et al. reported that an achiral Au complex compatibly worked with a chiral phosphoric acid to promote a tandem hydroamination/reduction reaction,30 readily transforming 2-(2-propynyl)aniline derivatives 124 into tetrahydroquinolines 126 in one operation with excellent ee (see Scheme 23). This cascade was initiated by a Au-catalyzed intermolecular hydroamination of alkynes 124, followed by a Brønsted acid catalyzed enantioselective transfer hydrogenation using Huntzsch ester.

Scheme 23.

Combination of gold catalysis with Brønsted acid catalysis.

Almost at the same time, Che et al. independently applied the same strategy to the synthesis of chiral secondary amines through tandem intermolecular hydroamination/transfer hydrogenation of alkynes 128 using a gold(I) complex-chiral Brønsted acid.31 This tandem reaction has a broad substrate scope that a wide variety of aryl, alkenyl and aliphatic alkynes can be coupled with anilines with different electronic properties to afford chiral amine in excellent ee (see Scheme 24).

Scheme 24.

Combination of gold catalysis with Brønsted acid catalysis.

3.2. By the Combination of Metal and Enzymes

The best example to demonstrate the versatility of the combination of enzymes and metal catalysts is chemoenzymatic dynamic kinetic resolution (DKR).32 To overcome the major drawback of kinetic resolution—that its maximum yield is only 50 %, the combination of a metal catalyzed racemization of the slow-reacting enantiomer with the enzyme catalyzed resolution of a racemate turned out to be a powerful strategy to accomplish dynamic kinetic resolution (DKR) processes. Since this strategy has already been well summarized, only a recent breakthrough is included in this review.

Owing to the fact that the racemization of unfunctionalized amines is much more difficult and entails harsher reaction conditions, the first example of general chemoenzymatic DKR of amines was reported in 2005.33a Bäckvall et al. reported that a broad scope of unfunctionalized primary amines could be transformed to the corresponding amide of one enantiomer in high yield and enantioselectivity by chemoenzymatic DKR. Under the catalysis of ruthenium catalyst 132, the dehydrogenation of the amine and re-addition of the hydrogen to the thus formed imine underwent efficiently at 90 °C, driving the S-enantiomer of the amine to be converted to the R-enantiomer, which readily reacted with isopropyl acetate to afford optically pure amide, under the catalysis of Candida Antarctica lipase B (CALB, Novozym 435). Based on this work, the author developed a new route for the total synthesis of norsertraline starting from the DKR of readily available 1,2,3,4-tetrahydro-1-naphthylamine (see Scheme 25).33b

Scheme 25.

Combination of ruthenium catalysis with enzyme catalysis.


Although in its infancy, multicatalyst promoted asymmetric tandem reaction has exhibited its power in maximizing synthetic efficiency by saving time, energy, labour, and chemicals, and in many cases, achieving high reactivity and selectivity that traditional methods can not reach, as the examples described in this review demonstrated. It is no exaggeration to say that this combining concept provides great opportunities to develop new exciting chemistry. Since there are so many different catalysts, the combination of different catalysts seems to be limitless.34 The development of new combinations for new tandem reactions will surely be accelerated since this concept has attracted increasing attention. Besides providing new efficient synthetic methodologies, endeavours aiming at how to improve catalyst compatibility will benefit the understanding of catalysis, will finally contribute to the development of powerful catalyst systems. As can be expected, biomimetic-like, multicatalyst promoted tandem reactions will find increasing application in drug and natural product synthesis.


The financial support from East China Normal University is highly appreciated.

Biographical Information

Jian Zhou obtained his PhD degree in 2004 from Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences, under the guidance of Prof. Yong Tang. After spending one year working as a postdoctoral fellow with Prof. Shū Kobayashi at the University of Tokyo, three years with Prof. Benjamin List at Max-Planck-Institut für Kohlenforschung, he joined East China Normal University as a Professor and began independent research from the end of 2008. His current research interests include the development of new chiral catalysts and new asymmetric reactions.

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