Asymmetric organocatalytic reactions by bifunctional amine-thioureas

Abstract

The development of organocatalysts has greatly changed the art of organic transformation in the chemical synthesis community for the past decades. Nature's work underpins the success of hydrogen-bonding catalysis were obviously shown in a myriad of enzymatic reactions. More recently, the emergence of bifunctional organocatalysts which work complementarily in activating two components of a chemical reaction has emerged as a frontier of research in asymmetric synthesis. In this particular review, works on asymmetric reactions catalyzed by bifunctional amine-thioureas are examined.

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Woon-Yew Siau

Woon-Yew Siau was born in Johor Bahru, Malaysia, in 1988. He earned his BASc (Honours) from National University of Singapore (NUS) in 2011. In the same year, he joined NUS chemistry department as a PhD student. His research interests lie in the discovery of new catalytic reactions.

Jian Wang

Jian Wang obtained his BSc from An Hui Normal University in China and completed in PhD study in University of New Mexico in the United States. He carried out his postdoctorial studies at Scripps Research Institute and joined National University of Singapore (NUS) as an assistant professor to embark on his career on asymmetric organocatalysis, novel synthetic method, and natural product synthesis.

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Introduction

Synthetic methodologies that manipulate the stereochemical outcome of the organic molecules have progressively gained awareness in organic synthesis. Hence, asymmetric synthesis is desirable, and if possible, a catalytic method. Organocatalysis is considered to be the most convenient and easy way to tackle this problem.¹ In particular, hydrogen-bonding mediated catalysis has gained recognition and is widely employed in enantioselective transformations.² Small organic molecules with hydrogen-bond donor capability were known to activate substrates through LUMO lowering and thiourea-based organocatalyst evolved as a prominent class due to its dual hydrogen-bonding donor characteristic. Various research groups have demonstrated that catalysts with bifunctional motif could promote enantioselective reactions in an excellent manner. In this context, the term “bifunctionality” was realised when a Lewis basic functionality was incorporated into the catalytic system in addition to hydrogen bond donors (Fig. 1).³ These two functional groups work synergistically to bring about the activation of both nucleophilic and electrophilic components in a reaction. In addition, cinchona alkaloids and their thiourea-modified frameworks are also widely seen in asymmetric reactions as the basic tertiary amine group present in the quinuclidine ring is a versatile nucleophilic base in the context of asymmetric reactions.⁴

Fig. 1 A bifunctional amine thiourea catalyst (Takemoto's catalyst, left), and general scaffold of bifunctional amine thioureas (right).

With the emergence of this new catalytic system, bifunctional mode catalysis with hydrogen bonding capability has broadened the scope of work in asymmetric reactions in recent year. To the benefit of reading and ease of understanding, asymmetric reactions catalyzed by bifunctional amine thioureas will be discussed between 2003 and 2011.

2. Hydrogen bonding catalysis: underlying principle of biological processes⁵

Activation of electrophiles by hydrogen bonding is commonly seen in biological pathway, especially enzymatic hydrolysis of amide bonds.⁶ The most notable example is serine protease.⁷ The mechanistic study has shed light on the importance of hydrogen bonding moiety embedded in the catalytic site and suggested that amide hydrolysis takes place when both electrophile and nucleophile are activated (Scheme 1). In 2003, Takemoto and co-workers has successfully elaborated the fundamental principle of hydrogen bonding catalysis through the design of a bifunctional thiourea: thiourea moiety mimicks “oxyanion hole” and Lewis basic site (usually a tertiary amine group) functions as histidine/aspartate proton shuttle system (Fig. 2).^8a

Scheme 1 Serine protease: Biological process of amide hydrolysis with the assistance of hydrogen bonding and bifunctional catalysis.

Fig. 2 Comparison between H-bond biocatalysis and chemical catalysis.

3. Michael addition

Michael addition is a highly versatile synthetic tool to join two chemical entities together during the course of reaction. Asymmetric Michael addition is particular useful as selective C–C or C–X bonds could be formed in a stereocontrolled manner with the use of bifunctional amine-thioureas.

3.1 Michael addition for C–C bond formation

First enantioselective Michael addition was reported by Takemoto's group in 2003 with the use of a bifunctional amine thiourea-organocatalyst (Scheme 2).⁸ The bifunctional organocatalyst I which was shown to promote enantioselective Michael reaction between malonates 2 and nitroolefins 1 has marked the breakthrough in organocatalysis as excellent stereochemical information was observed in the study.⁹ The mechanistic insight of the reaction was later elucidated by Pápai et al. using in silico study.¹⁰ Despite different substrate activation mode (Fig. 3) was proposed, same stereochemistry was predicted for the reaction. To further expand the scope of work on bifunctional thiourea catalyst, Takemoto and co-workers demonstrated the first asymmetric Michael addition reaction of malononitrile 5 to α,β-unsaturated imides 4 without the use of metal catalysis¹¹ (Scheme 3).

Scheme 2 Takemoto's bifunctional organocatalyst-catalyzed Michael reaction of malonates to nitroolefins.

Fig. 3 DFT-calculated dual activation mode of bifunctional thiourea.

Scheme 3 Asymmetric Michael addition of malononitrile to α,β-unsaturated imide.

Cinchona alkaloids are example of naturally occurring bifunctional organocatalysts. However, no much attention was paid to their application for asymmetric induction, and it was until 1980, Wynberg and co-workers reported a detailed investigation of base-catalyzed Michael addition of thiols to α,β-unsaturated ketones in the presence of a catalytic amount of cinchona alkaloids.¹² Later on, given that they are readily available and tunable, transformation of the initially existing hydroxyl group to “privileged” thiourea moiety has made them better hydrogen bond donor (Fig. 4). In view of the great synthetic applications of 1,4-addition Michael adducts of nitroalkanes,¹³ Soós et al. had reported an enantioselective reaction between chalcones 7 and nitromethane 8 using a cinchona alkaloid derived thiourea organocatalyst (Table 1).¹⁴ In the particular study, (R)-Baclofen was obtained in high enantioselectivity (Table 1, entry 1) and thereby, offering a better route to other biologically important γ-amino acids.¹⁵ The conformation adopted by cinchona derivatives was important for the observed catalytic activity.

Fig. 4 Bifunctional cinchona organocatalysts.

Table 1 Bifunctional cinchona organocatalyst V catalyzed enantioselective conjugate addition of nitromethane 8 to chalcones 7

Entry		R^1	R^2	Yield (%)	ee (%)
a Reactions were carried out in toluene in capped vials.
1	7a	H	p-Cl	94	95 (R)
2	7b	H	p-F	94	98^a
3	7c	H	o-Me	93	89^a
4	7d	p-OMe	H	80	96^a
5	7e	H	H	94	96

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Inspired by the binapthyl moiety, Wang et al. developed a novel bifunctional amine-thiourea VIII for asymmetric reaction between 1,3-diketone 10 and nitroolefins 1 (Scheme 4).¹⁶ Due to poor performance of Takemoto's catalyst I and cinchona modified thiourea IV, catalyst VIII turned out to be a superior bifunctional bifunctional organocatalyst in the reaction. Subsequently, synthesis of valuable α-substituted-β-amino acids¹⁷ was also highlighted in the study using Michael adduct 12. Research has been on going to explore the synthesis of enantiopure β-amino acids as these are important chemical entity in both academia and industry.¹⁸ As a result, synthesis of β-amino acids becomes a synthetic challenging issue for organic chemists. To address this issue, Chen et al. conducted an asymmetric Michael reaction between α-substituted cyanoacetates 15 and vinyl ketones 16 in a non-polar solvent (Scheme 5).¹⁹ Unlike the 1,3-dicarbonyl analogues, α-substituted cyanoacetates²⁰ are good starting material for the conversion to β^2,2-amino acid in spite of their incapability of two-point binding with the catalyst.

Scheme 4 Michael addition of 1,3-diketone 10 to nitroolefins 1 catalyzed by binaphthyl-derived thiourea organocatalyst VIII and the synthesis of α-phenyl-β-alanine 12.

Scheme 5 Organocatalytic approach to multifunctional compounds with an all-carbon-substituted quaternary stereocenter and its possible active intermediate calculated by PM3 (semi-empirical method).

3.2 Michael addition for C–O, C–N and C–S bond formation

Oxo-, aza- and sulfa-Michael addition are particular useful for the construction of heteroatom compounds. β-hydroxylation reaction²¹ employing oxime as the oxygen source was illustrated by Jørgensen's group (Table 2).²² This enantioselective oxa-Michael addition²³ was the first documented protocol to access optically active aliphatic nitro- or aminoalcohols 18 with the use of nitroalkenes 16 and ethyl glyoxylate oximes 17. Subsequently, selective cleavage of O–N bond was also shown using adduct 18d under hydrogenation conditions (H₂/Pd/C; (Boc)₂O) or using ZrCl₄ and NaBH₄.²⁴

Table 2 Enantioselective β-hydroxylation of nitroalkenes 1 catalyzed by cinchona alkolide amine-thiourea IV

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Great attention has also been focused on the enantioselective synthesis of nitrogen-containing compounds due to their broad utility and application in organic synthesis and medicinal chemistry.^25,26 Aza-Michael addition is the most direct and easiest way to access such valuable organic molecules. Using N-heterocycle 20 as a nucleophilic source, the enantioselective conjugate addition was accomplished in the presence of a bifuntional cinchona alkaloid based thiourea IV (Table 3).²⁷ This protocol was applicable to a broad scope of α,β-unsaturated ketones, furnishing the desired products 22 in good yields and with moderate to good enantioselectivities. On the other hand, organosulfur compounds are sparsely reported in asymmetric Michael reaction, particular with the use of bifunctional amine-thioureas.^28,29 In this instance, Wu et al. envisioned an asymmetric reaction between arylthiols 23 and α,β-unsaturated carbonyl compounds (24 and 25, Scheme 6).³⁰ Stabilization of the thiolate and activation of the electrophilic α,β-unsaturated system via hydrogen bonding is the fundamental aspect of this conjugate reaction.

Table 3 Scope of asymmetric conjugate addition reaction of 1H-benzotriazole (20) with enones (21a–g)

Entry	Product	Ar	R	Yield (%)	ee (%)
1	22a	p-ClC6H4	Ph	79	61
2	22b	o-ClC6H4	Ph	69	63
3	22c	p-NO2C6H4	Ph	85	63
4	22d	p-MeOC6H4	Ph	62	57
5	22e	Ph	Ph	67	64
6	22f	Ph	p-ClC6H4	78	62
7	22g	2-Thiophenyl	2-Thiophenyl	69	56

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Scheme 6 Conjugate addition of arythiols 23 to α,β-unsaturated carbonyl compounds 24 and 25.

Besides, a weakly nucleophilic thioacetic acid 28 was reported to react with α,β-unsaturated ketones 21 to afford the oxo-thiolate products 29 in diethyl ether at room temperature. The reaction was facilitated in the presence of catalyst I and lower enantioselectivities were observed with electron-withdrawing groups and alkyl substituents. After all, the products could be obtained in an excellent yields (95–100%) and with moderate enantioselectivities (up to 65% ee, Scheme 7).³¹

Scheme 7 Bifunctional organocatalysis of thioacetic acid 28 to enones 21.

4. 1,2-Addition

1,2-addition reaction is not uncommon in organic synthesis and it often provides a better route to nitrogen-containing compounds. Electrophilic acceptors like imines play an important role for this kind of organic transformation and could be easily generated through the formation of Schiff base.³² Often, electron-withdrawing groups like tert-butyl-carbonate group (t-Boc), carbobenzyloxy group (Cbz), and fluorenylmethyloxycarbonyl group (Fmoc) are installed in the molecular scaffold for the purpose of establishing hydrogen bonding with the thiourea moiety, thus activating imine moiety.

Although much work has been done for nitro-Mannich (or aza-Henry) reactions,³³ it was not until Wang et al. documented a highly enantioselective and diastereoselective protocol for the synthesis of β-nitro amines 31 (Scheme 8). The bifunctional amine-thiourea IX bearing an extra hydrogen bonding donor at the sulphonamide part³⁴ (NH₂SO₂Ar) appeared to exhibit excellent catalytic performance for the transformation at low temperature. To further expand the work on cinchona alkaloid derived amine-thiourea, Deng's group has studied an 1,2-addition approach towards biological interesting β-amino acids under a rather mild, moisture and air-compatible condition (Scheme 9).³⁵ The generality of the reaction was subsequently investigated. A wide range of alkyl and aryl substituted malonates 2 were employed as nucleophiles, and good yields (55–99%) and excellent enantioselectivities (88–99% ee) were attainable. Around the same time, Dixon and co-workers published a similar work on Mannich reaction regarding the synthesis of β-amino esters 36 (Scheme 10).³⁶ The synthesis was catalyzed by a cinchonine modified bifunctional thiourea and the decarboxylation reaction was carried out in a simple procedure.

Scheme 8 Highly enantioselective and diastereoselective nitro-Mannich reaction and activation of imines via hydrogen bonding with thiourea IX (left).

Scheme 9 Enantioselective Mannich reaction catalyzed by a thiourea-based cinchona alkaloid VII.

Scheme 10 A simple organocatalytic route to β-amino esters 36.

In 2006, Deng's group made an advance leap in organocatalysis by demonstrating an asymmetric version of Friedel–Crafts reaction³⁷ with the use of a cinchona thiourea-derived organocatalyst (Scheme 11). The indoles 37 reacted with the imines 30 in 1,2-fashion to give rise to the product 38 in both excellent yields and enantioselective controls.³⁸ It is noteworthy that both enantiomeric pair of 38 could be obtained in highly enantioselective manner via this synthetic methodology with the use of catalyst VII or quinine derived amine-thiourea. The conversion of N-Ts to N-Bs was also highlighted in the work without affecting the stereochemical information.

Scheme 11 Asymmetric Friedel–Crafts alkylation reaction catalyzed by bifunctional amine-thiourea VII.

Last but not least, the author would also want to highlight another 1,2-reaction contributed by Jacobsen and co-workers.³⁹ Valuable chiral building blocks for instance α-hydroxy acids, β-amino alcohols could be easily derived from cyanohydrins⁴⁰ from the standpoint of synthetic organic chemistry. As a result, development of cyanation chemistry is highly acknowledged.⁴¹ Jacobsen et al. presented an enantioselective cyanosilylation of ketones 39 with trimethylsilanecarbonitrile (TMSCN, 40) in the presence of a catalyst XId (Scheme 12).⁴²

Scheme 12 1,2-cyanosilylation of ketones by Jacobsen's bifunctional thiourea catalyst

Despite the challenging issue arise from the formation of a quaternary carbon center,⁴³ such synthetic protocol is of great interest of synthetic organic chemists. To probe the viability of the cyclohexane-based amine thiourea (catalyst I, namely Takemoto's catalyst), Takemoto and co-workers has identified a reaction between N-Boc benzaldimine 30 with prochiral 1,3-dicarbonyl compounds 33, furnishing quaternary-carbon containing compounds in good yield (Table 4).⁴⁴

Table 4 Stereoselective Mannich reaction for the construction of quaternary stereocenter

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5. Bifunctional mode on cascade reaction

Unlike classical chemical synthesis, cascade reaction offers a rather quick and efficient route to assemble complex molecular architecture in one-pot process.⁴⁵ The strategy underscored the fundamental principles of biosynthesis has enabled the assembly of small organic molecules in a chemical reaction without isolating the intermediates or changing the reaction conditions. As a result, cascade reaction is considered as an atom economic pathway as it requires no protecting-group chemistry during the course of reaction. Moreover, this also greatly simplifies the synthetic steps and eventually, leads to step and cost economic if it meets the need of industrial application one day. Furthermore, owing to its operationally simple and environmentally benign approach, organocatalytic cascade reaction has evolved as a powerful tool for the total synthesis of natural product-like scaffolds as well as biologically interesting compounds in recent year.⁴⁶

Primary and secondary amines are shown to activate electrophiles (LUMO-lowering) and nucleophiles (HOMO-raising) in a sequential manner through the iminium and enamine catalytic pathway respectively.⁴⁷ However, the scope of reactions is bound to carbonyl-containing compounds. In view of the demand for a new template for activating non-carbonyl systems, such catalytic system is hoped to trigger off the cascade reaction between the reacting species at the same time. In contrast to enamine-iminium pathway, a bifunctional system with hydrogen-bonding capability could elso induce the electrophilicity of reagent through noncovalent interactions.⁴⁸

Wang et al. has disclosed a new organocatalyzed enantioselective cascade Michael-aldol reaction towards stereochemically, highly enantio- (91–99% ee) and diastereoselective (>20 : 1 dr) complex benzothiopyrans 45 (Scheme 13).⁴⁹ The reaction was accomplished with the use of 2-mercaptobenzaldehyde 43 and α,β-unsaturated oxazolidinone 44 in the presence of a cinchona-derived thiourea IV (1 mol% of catalyst loading). It is noteworthy that the desired compounds were furnished with three chiral centres in one-pot process. Highly functionalized 4-chromanones are important scaffold in medicinal chemistry.⁵⁰ Our group has made an effort to undertake the development of the asymmetric synthesis of a variety of spiro-(thio)chromans 47. In the particular work, we were envisioned that dihedral angle between amine and thiourea groups is crucial for asymmetric induction and hence, a series of C1-symmetric bifunctional amine-thiourea catalysts was synthesized for investigation (Fig. 5). The bifunctional indane amine-thiourea XIV was shown to successfully promote asymmetric cyclization reaction between 2-mercaptobenzaldehyde 43 and (E)-3-benzylidenechroman-4-one 46 in a highly concise manner (Scheme 14).⁵¹

Scheme 13 Hydrogen-bonding promoted cascade thio-Michael-aldol reaction.

Fig. 5 Wang's group developed bifunctional indane amine-thioureas.

Scheme 14 Enantioselective heterocyclic synthesis of spiro-(thio)chromans 47.

Malononitrile 5 serves as an important building block due to its two versatile nitrile groups in organic synthesis.⁵² Recently, our group has uncovered the synthetic utility of malononitrile in a Michael-oxa-Michael-tautomerization reaction by demonstrating its capability as both nucleophile and electrophile, giving rise to pyranochromenes 49 with the use of Michael acceptor 46 and malononitrile 5. It was shown that instead of the formation of simple Michael adduct 48, the reaction would favour the cascade product in the presence of an indane catalyst XIV (Scheme 15).⁵³ Further in our recent progress, β,γ-unsaturated ketoesters 51 was used to react with α-nitroketones 50 in the presence of a rigid bifunctional thiourea-organocatalyst XIII (Scheme 16).⁵⁴ The Michael adduct B was proposed to undergo hemiketalization and retro-Henry reaction to afford 5-nitro-pent-2-enoates 52, a precursor to α-ketolactams or γ-amino-α-keto acids.⁵⁵

Scheme 15 Asymmetric organocatalytic approach towards pyranochromene moiety.

Scheme 16 Organocatalytic asymmetric approach to α-ketolactams or γ-amino-α-keto acids.

Despite the aforementioned synthetic advantages, cascade reaction is also useful for the preparation of cyclised product. Organocatalytic transformation towards medicinally useful and biologically important compounds has tremendously transformed the art of organic synthesis in the field of medicinal chemistry in recent year.⁵⁶ 2-Amino-4H-chromene-3-carbonitrile is an important molecular framework due to its broad application in the field of medicinal chemistry.⁵⁷ To our delight, we successfully described an asymmetric version to synthesize this chromene system via an organocatalytic approach using α-amido sulfone amines 53 (Scheme 17).⁵⁸

Scheme 17 Enantioselective Mannich intramolecular ring cylization-tautomerization.

6. Miscellaneous reactions

Nucleophilic unhindered tertiary amine is well-known for its performance for the Morita–Baylis–Hillman (MBH) reaction.⁵⁹ By forming the double hydrogen bonding with the carbonyl compounds, bifunctional amine-thioureas could even act as suitable catalyst for the enantioselective Morita–Baylis–Hillman (MBH) reaction in organic synthesis. First bifunctional amine-thiourea catalyzed Morita–Baylis–Hillman reaction was described by Wang et al. (Scheme 18).⁶⁰ The reaction was carried out with the use of cylic enones 25 as α,β-unsaturated system and aldehydes 55 in the presence of a binaphthyl-derived thiourea organocatalyst VIII. The reaction was well-tolerated with a broad range of linear aliphatic and aromatic aldehydes, furnishing the allylic alcohols in moderate to good yields (55–84%) and with moderate to excellent enantioselectivities (60–94% ee). It was proposed that the reaction proceeded via the formation of enolate, which could be stabilized by the thiourea moiety (A). In the last step, deprotonation of the α-hydrogen leaded to the elimination of the catalyst for next catalytic cycle (B).

Scheme 18 Hydrogen-bonding assisted MBH reaction

Dynamic kinetic resolution (DKR) is a common strategy to access highly enantiopure compounds.⁶¹ This is particularly useful if the achiral starting materials are cheap and easily available. In addition, tedious and elaborative synthetic steps could be avoided without compromising the stereochemical outcome of the desired products. To probe the feasibility of bifunctional amine-thiourea on resolution, Berkessel and co-workers employed catalyst XV in a highly enantioselective DKR process of azlactones.⁶²N- and O-protected amino acids were obtained in good to excellent yields and with excellent enantioselectivities in the presence of allylic alcohols (Table 5).

Table 5 Substrate screening using catalyst XV

Entry	R	Time/h	Conversion (%)	ee (%)
a Yield using 1.7-fold concentration of the substrates.
1	Me	24	94	80
2	i-Pr	48	89^a	90^a
3	PhCH2	48	98	77
4	i-Bu	48	77	91

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Furthermore, inspired by the bifunctionally activated push/pull system, researchers deduced that boronic esters⁶³ could be activated to facilitate organic transformation in a stereocontrolled manner. A research group lead by Flack applied amine-thiourea to catalyze an unprecedented intramolecular oxy-Michael addition reaction (Scheme 19).⁶⁴ Under the optimized condition, various γ-hydroxy-α,β-enones 59 could be converted to the desired adduct 61 in good to excellent yields (62–95%) and enantioselectivities (87–99% ee).

Scheme 19 Organocatalytic oxa-Michael addition reaction using boronate-amine complexe as chiral hydroxyl synthons.

Another common technique used in asymmetric synthesis is desymmetrization reaction.⁶⁵ Desymmetrization is an easy and quick method to tackle enantioselective synthesis when chiral center is required to be derived from a symmetrical molecule. Quinine-derived bifunctional organocatalyst IV was demonstrated to catalyze bicyclic meso-anhydrides 62 accomplishing chiral hemiester 63 at room temperature (Scheme 20).⁶⁶

Scheme 20 Enantioselective desymmetrization of bicyclic meso-anhydrides in dioxane at room temperature.

Diels–Alder reaction is common route to the synthesis of valuable cyclic building blocks.⁶⁷ Orientation of both nucleophiles and electrophiles presents a challenging issue for Diels–Alder reaction, in particular with the use of organocatalyst.⁶⁸ Amine and thiourea groups are not only responsible for HOMO–LUMO activation, induction of the rearrangement of both nucleophiles and electrophiles also play a crucial part so that other undesired isomers could be eliminated in the reaction. Intrigued by this hypothesis, Deng and co-workers described an organocatalytic asymmetric Diels–Alder reaction of 2-pyrones 74 in the presence of a cinchona-derived amine-thiourea IV and VI (Table 6).⁶⁹ The reaction was successfully conducted at low temperature as well as ambient temperature within 20 h.

Table 6 Cinchona alkoid amine-thioures IV- and VI-catalyzed stereoselective Diels–Alder reactions

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7. Flexible bifunctional thiourea catalysts and their application

Vinyl sulfones are synthetically useful and unique acceptors in conjugate addition.⁷⁰ As a result, they are applicable in catalytic asymmetric Michael addition reactions. Chen et al. has described an enantioselective synthesis towards various sulfones or sulfonyl compounds 70 with a quaternary carbon centre using α-substituted cyanoacetates 15 and vinyl sulfones 69 in the presence of a flexible bifunctional amine-thiourea XVIa (Scheme 21).⁷¹ This was the first reaction which suggested a doubly hydrogen bonding interaction between the NH of the thiourea and the sulfone functionality.

Scheme 21 Enantioselective construction of quaternary carbon compounds 70.

Functionalized coumarins exhibited a wide range of biological properties.⁷² For instance, warfarin, bromodialone and phenprocoumon are coumarin-based anticoagulant drug that are commonly found in medicinal chemistry. However, they are formulated as racemate. Synthesis to afford one of the enantiomers is highly desirable as this could avoid potential side-effect arising from the metabolism of another enantiomer.⁷³ To address this issue, our group was trying to make an effort to it. Delightfully, a flexible catalyst like XVII was developed in our group and was shown to catalyze an enantioselective reaction between 4-hydroxy-2H-chromen-2-one 71 and β,γ-unsaturated ketoesters 51 (Scheme 22).⁷⁴ Dual characteristics possessed by the reacting molecules allowed the cascade reaction to take place smoothly, affording the final product 72 in the one-pot process.

Scheme 22 Enantioselective synthesis of coumarins.

8. Immobilized bifunctional amine-thiourea catalysts

In 2006, Takemoto and co-workers reported case studies towards the immobilization of bifunctional thiourea on polymer support using an ester moiety as the linker group.^75a It was shown that soluble ester-functionalized thiourea derivative XVIII (10 mol% loading) turned out to catalyze the model Michael addition of diethyl malonate 2 to tran-β-nitrostyrene 1 in 88% yield and in 91% enantioselectivity after 48 h in toluene. The insoluble crosslinked polystyrene-bound thiourea derivatives XIX-1 and XIX-2 exhibited a drastically reduced catalytic activity and gave the desired (S)-configured Michael adduct after 6 d at room temperature in 37% and 4% yield (87% and 88% ee, respectively, Scheme 23). On the other hand, soluble poly(ethylene glycol) (PEG)-bound thiourea XIX-3 could be used in dichloromethane under homogeneous condition and able to afford Michael adduct in 71% yield and 86% ee after 6 d at room temperature. The catalyst was readily recovered by filtration after addition of diethyl ether to the reaction mixture and could be reused without further purification to give the same adduct in comparable yield (74%) and ee value (90%) in second run. PEG-bound thiourea XIX-3 also catalyzed the enantioselective double Michael addition of a γ,δ-unsaturated β-ketoester 73 to trans-β-nitrostyrene 1, resulting in the desired 4-nitrocyclohexanone derivative 82 (63% yield; 76% ee; rt, 6 d). No impact on catalytic activity of the catalyst (second run: 64% yield; 76% ee third run: 63% yield; 79% ee) even though it was reused in this reaction.^75b,c

Scheme 23 Double Michael addition catalyzed by PEG-bound amine-thiourea catalyst.

9. Summary

Asymmetric organocatalysis using bifunctional amine-thioureas has been presented in this review. The success of bifunctional catalysis which works cooperatively between double hydrogen bonding character of thiourea moiety and basic amine group has underscored the fundamental principle of biocatalysis in which both nucleophile and electrophile are activated to bring about a chemical reaction. These catalysts could also be derived from readily available privileged scaffolds. Another highlight of using bifunctional system to catalyze a chemical reaction is the cascade reaction. Complex molecules could be generated in an efficient way and environmentally friendly manner. Last but not least, case study pertaining to the use of immobilization technique of the bifunctional amine-thiourea onto polymer-support surface was also reviewed. Much has already been understood, however, other breakthrough using bifunctional amine-thioureas is anticipated in the near future.

Acknowledgements

We gratefully acknowledge the National University of Singapore for financial support of our work (Academic Research Grant: R143000408133, R143000408733 and R143000443112).

References

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