Next Article in Journal
Soft-Templating of Sulfur and Iron Dual-Doped Mesoporous Carbons: Lead Adsorption in Mixtures
Next Article in Special Issue
Trityl-Containing Alcohols—An Efficient Chirality Transmission Process from Inductor to the Stereodynamic Propeller and their Solid-State Structural Diversity
Previous Article in Journal
Biodegradability of Dental Care Antimicrobial Agents Chlorhexidine and Octenidine by Ligninolytic Fungi
Previous Article in Special Issue
Heteroaromatic N-Oxides in Asymmetric Catalysis: A Review
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry

Franz Steppeler
Dominika Iwan
Elżbieta Wojaczyńska
1,* and
Jacek Wojaczyński
Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50 370 Wrocław, Poland
Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50 383 Wrocław, Poland
Author to whom correspondence should be addressed.
Molecules 2020, 25(2), 401;
Submission received: 29 December 2019 / Revised: 14 January 2020 / Accepted: 16 January 2020 / Published: 18 January 2020
(This article belongs to the Special Issue Stereochemistry in Action)


For almost 20 years, thioureas have been experiencing a renaissance of interest with the emerged development of asymmetric organocatalysts. Due to their relatively high acidity and strong hydrogen bond donor capability, they differ significantly from ureas and offer, appropriately modified, great potential as organocatalysts, chelators, drug candidates, etc. The review focuses on the family of chiral thioureas, presenting an overview of the current state of knowledge on their synthesis and selected applications in stereoselective synthesis and drug development.

1. Introduction

The replacement of the electronegative oxygen atom of urea by sulfur (with electronegativity comparable to carbon) results in a significant change of properties. Thioureas (thiocarbamides) exhibit higher acidity and are stronger hydrogen bond donors [1,2,3]. This ability to participate in hydrogen bonding, which can be further modified by the appropriate substitution of nitrogen atoms, is essential for numerous applications of this class of organic compounds, mainly in organocatalysis and molecular recognition. Thioureas are also widely applied in agriculture and medicine [4,5,6,7], and as corrosion inhibitors [8,9,10,11]. For almost 20 years they have been used as catalysts in organic synthesis, especially in stereoselective reactions [12,13,14]. They also serve as valuable starting materials for the synthesis of heterocycles [15,16,17], and are used as ligands in coordination chemistry (particularly when additional donors are present in their molecules) [18,19,20,21,22], as well as in the field of anion binding and recognition [2,23].
Structurally thioureas can be classified depending on the number of substituents of nitrogen atom (Figure 1) [6,7]. Not surprisingly, derivatives with one and two organic groups (either 1,1 or 1,3-disubstituted) are most common, though trisubstituted (with limited, but still preserved possibility to act as hydrogen bond donors) and fully substituted (mainly cyclic) thioureas are also prepared and used for various purposes. The first thiocarbamides were prepared ca. 150 years ago [24,25], and their chiral derivatives have been long known [26,27], but a great interest in the latter has arisen with the development of enantioselective organocatalysis.

2. Synthesis of Chiral Thioureas

Since the thiourea skeleton is not intrinsically chiral, the existence of enantiomers typically originates from its substituents. Examples of various groups bearing stereogenic centers will be presented in the subsequent section. Desymmetrisation resulting from less common axial (biphenyl or binaphthyl derivatives) [28,29,30] or planar chirality [31,32,33] is also worth mentioning. Consequently, the methods of synthesis of chiral thioureas are essentially the same as for their achiral counterparts, but, typically, the reactants from a chiral pool are used in enantiomerically pure form. However, the preparation of the desired product as racemic mixture followed by separation of enantiomers was reported in selected cases, e.g., bis-thiourea derivatives of Tröger’s base were obtained as racemates and resolved on a chiral stationary phase [34]. Similarly, enantiomers of norbornane thiocarbamide formed as 1:1 mixture in a two-step protocol from norbornene were separated either by chiral HPLC or by crystallization of diastereomeric salts of the amine intermediates [35]. The advantage of this approach lays in the fact that both optical antipodes of chiral thiourea can be isolated and used as organocatalysts or for chiral recognition.
The choice of a particular method of preparation of the desired stereoisomer depends mainly on its structure (number and type of substituents) and availability of necessary starting materials. Certainly, one should also consider possible inconveniences (both for the person conducting the synthesis and for the environment) connected with the use of certain reactants: their limited stability, toxicity, flammability, or simply an unpleasant odor. In most preparations, reactants containing C=S bond are used—mainly isothiocyanates, but also dithiocarbamates, carbon disulfide, thiophosgene and their equivalents. Less frequently, inorganic sources of sulfur are useful for a given transformation—P4S10 or Lawesson’s reagent to convert urea into thiourea [36,37] sulfides or elemental sulfur. Amines are the most usual source of thiourea nitrogen atoms; however, isocyanides and azides are also found in various protocols. An alternative route involves modification of already constructed achiral thiourea with optically active groups.

2.1. Reaction of Isothiocyanates with Amines

For many years, the most common method of preparation of thiourea, including chiral derivatives, has been based on the reaction of alkyl or aryl isothiocyanate with amine or ammonia (Scheme 1) [1]. This way, unsymmetrical mono-, di- or trisubstituted products are formed, depending on the amine (which can be either aliphatic or aromatic). This substrate typically serves as a source of chirality in most preparations of chiral thioureas, while the isocyanate is chosen to enhance the desired properties of the designed catalyst, ligand, or receptor (most frequently trifluoromethyl-substituted aryl derivatives are used). However, chiral isothiocynates are used as well, as they can be easily obtained from the respective primary amine and CS2 [38].
The method is versatile and convenient from the point of view of atom economy. Only one C–N bond has to be formed in the course of the reaction. Among drawbacks, limited long-term stability of isothiocyanate reactants and the possibility of formation of side products (e.g., uretanes in case when alcohols are used as solvents) are often mentioned.
Recent examples of the application of this route to synthesize enantiomerically pure thioureas include the paper by Sureshbabu et al., who prepared 25 new N-urethane-protected amino alkyl isothiocyanates [39]. A CS2/trimethylamine/tosyl chloride combination was found to be the most efficient for the conversion of mono-N-protected chiral diamines, which in turn were obtained from the corresponding amino acids. The coupling of the isothiocyanates with amino acid esters in the presence of N,N-diisopropylethylamine resulted in formation of dithioureidopeptides in 65–74% yield. Liu et al. described a preparation of five new chiral thiourea organocatalysts using amines obtained in four steps from d-mannitol and isocyanates (mainly those derived from Cinchona alkaloids, Scheme 2) [40]. Isothiocyanates were also reacted with sulfoximines [41] and phosphoramides [42] to give the respective thioureas.
Modifications of typical reaction conditions have been recently proposed. Possible application of solvent-free protocols, with reactants in a gas- and/or solid state, and mechanochemical synthesis were explored [43,44,45,46]. As an example, neat grinding and liquid-assisted grinding were applied to the preparation of six (already known) chiral bis-thioureas in quantitative yields by Štrukil et al. (Scheme 3) [47]. Bhattacharjee et al. demonstrated the utility of phosphinoselenoicamide-supported titanium(IV) complex as a pre-catalyst for the addition of amines to carbodiimides, isocyanates, and isothiocyanates [48]. 1,3-Disubstituted derivatives were prepared in 75–99% yield. Arafa et al. reported on the ultrasound-assisted synthesis of bis-thioureas from isocyanates and diamines; medium and high reaction yield were observed after several minutes of sonication [49].
Methods involving inorganic isothiocyanates are less commonly used, but can be treated as an interesting option when the required organic isothiocyanate is not available. Herr and co-workers showed that monosubstituted and symmetrical 1,3-disubstituted thioureas can be prepared in high yields from amine hydrohalides (including chiral ones) and KSCN [50]. Once prepared thiourea can be easily modified as discussed in Section 2.5, to achieve the necessary substitution pattern.
An interesting example of stereoselective preparation of chiral cyclic thioureas in the reaction of organic isothiocyanates with N-tosylimines was demonstrated by Wang and co-workers [51]. The reaction was efficiently catalyzed by another chiral, rosin-derived thiourea (see Section 3.7).

2.2. Reaction of Amines with Dithiocarbamates

Preparation of thioureas from dithiocarbamate derivatives and amines (Scheme 4) can serve as alternative to the route involving isothiocyanates (which are, in fact, formed in the course of the reaction). However, only in certain protocols isolated, stable dithiocarbamates are used, and in most cases, they are prepared in situ from CS2 and amines (see Section 2.3). In the recent years, several reports of efficient preparations of diverse dithiocarbamates have been published. A reaction in water involving also α,β-unsaturated compounds, and solvent- and catalyst-free protocol with alkyl halides both furnished appropriately substituted dithiocarbamates as reported by Azizi et al. [52,53]. Similarly, hydroxylated derivatives were prepared by Ziyaei-Halimjani and Saidi from amines, CS2 and epoxides [54]. Vinyl pyridines and vinyl pyrazine served as Michael acceptors in another protocol for efficient synthesis of dithiocarbamates [55]. In turn, the use of DEAD or DIAD resulted in products bearing a sulfur-nitrogen bond, which were found to be efficient intermediates in the synthesis of thioureas, isothiocyanates and thiocarbamates [56].
The majority of publications concerning transformations of dithiocarbamates into thioureas focus on the synthesis of achiral derivatives. For example, various di- and trisubstituted thioureas were obtained in 63–92% yield via the reaction of trimethylamine or DABCO salts of dithiocarbamates and primary or secondary amines [57]. Cerium ammonium nitrate was used as a catalyst, and the condensation was carried out in acetonitrile at room temperature for 2–24 h. A series of 1-aryl-3,3-dimethylthioureas were prepared in 70–92% yield from aryl amines which were first treated with sodium hydride in DMSO and then heated with S-aryl-N,N-dimethyldithiocarbamates for 3–5 h at 90 °C, with the release of thiophenol byproduct [58].
Recently published methods show that the reaction can be performed in water under mild conditions. For example, thiazolidine-2-thiones and secondary amines stirred in aqueous solution at 80 °C for 3–5 h without a catalyst yielded trisubstituted thioureas in 60–90% yield [59]. In another preparation, unsymmetrical thioureas were formed when primary or secondary amines, either aliphatic or aromatic, were heated with dithiocarbamates (derived from primary amines) at 50–60 °C and under solvent-free conditions (Scheme 5) [60]. Yields ranged from 64% to 100%. Among various derivatives obtained, three inherited chirality from the amine, and five from the dithiocarbamate.
The reaction can be also mediated by metals that are complexed with dithiocarbamate ligands. Dirksen et al. reported on the preparation of a mixture of 1,3-disubstituted and trisubstituted thioureas from bis(dimethyldithiocarbamato) zinc(II) and primary amines [61]. Maddani and Prabhu used dioxomolybdenum dialkyl dithiocarbamates and primary amines to prepare eleven thioureas in 51–85% yield (Scheme 6) [62]. The reaction was conducted in refluxing toluene under nitrogen for 0.5–3 h. Four chiral derivatives were prepared starting from methyl esters of l-phenylalanine, l-tyrosine, and l-leucine.
The formation of thioureas upon self-condensation of trialkylammonium dithiocarbamates was reported as well [63].

2.3. The Use of Carbon Disulfide

Reactions of amines with carbon disulfide serve as a simple method for the preparation of symmetrical, 1,3-disubstituted thioureas. Using a modified protocol with two different amines opens the route to unsymmetrical, mono-, di- or trisubstituted products (Scheme 7). Transient formation of dithiocarbamates and isothiocyanates was suggested as a key step in the mechanism of the process [1]. Like other C=S transfer reagents, carbon disulfide is not free of drawbacks: it is flammable, volatile (which requires an excess to be used), and has an unpleasant smell. Atom economy suffers from the formation of sulfur-containing by-product, usually hydrogen sulfide. The reaction is typically performed in organic solvents at elevated temperature and is relatively slow; it can be accelerated by addition of bases or oxidants to remove H2S [1]. Furthermore, CBr4 was shown by Liang et al. to efficiently promote the reaction [64].
Most recent modifications involve the use of water, a convenient and green solvent, as reaction medium [65]. A simple condensation between amines and carbon disulfide in refluxing water was described by Maddani and Prabhu as a route to symmetrical and unsymmetrical di- and trisubstituted thiourea derivatives [66]. The method worked well with aliphatic amines: in the first step, a secondary or primary amine was treated with CS2 in aqueous NaOH under ambient conditions and thus prepared dithiocarbamates were heated under reflux with primary amines for 3–12 h; after acidic work-up the desired thioureas were isolated in good to high yields (19 examples, 40–93%, Scheme 8). The use of racemic 1-phenylethylamine and (1R,2R)-1,2-diaminocyclohexane illustrates the possibility of using the protocol to the synthesis of chiral derivatives (Scheme 9).
Two chiral and twenty-three achiral symmetrical disubstituted thioureas were prepared in 70–97% yield by Azizi et al. from various primary amines and CS2; the reaction was carried out in water at 60 °C for 1–12 h (aromatic amines required a longer reaction time) and purification involved only filtration, washing with water and recrystallization from ethanol or diethyl ether [67]. Six years later, the same group described an ultrasound-assisted synthesis of 1,3-disubstituted, but also trisubstituted thiourea derivatives (Scheme 10) [68]. The reaction was performed in water or polyethylene glycol, and in the latter yields were higher in most cases (60–97% after 3–6 min of sonication at 30–35 °C). Among 27 products, two enantiomers of 1,3-bis(1-phenylethyl)thiourea were prepared, both in 97% yield.
Seventeen N-sulfonylcyclothioureas, including 1 chiral derivative, were prepared in 60–87% yield by Wan et al. in the reaction of corresponding amines with carbon disulfide in water catalyzed by silica [69]. An efficient (90–99% yield), green (water used as solvent), catalyst- and chromatography-free protocol for symmetrical, bis-aliphatic thioureas was also developed by Jangale et al. [70]. Milosavljević et al. described the environmentally friendly methodology involving the use of oxidants (sodium percarbonate + EDTA system was most efficient, but also H2O2 and air were tested) and solvent recycling [71]. Other modifications of reaction conditions for the reaction of amines with CS2 have been proposed, including green variants: the use of solar energy [72], microwaves [73,74], ionic liquid media [75,76].
Ten chiral thioureas were prepared by Vázquez et al. in the reaction of enantiopure primary amines (including four pairs of enantiomers) with carbon disulfide under either solvent-free conditions or using microwave irradiation in ethanol (Scheme 11) [77]. Simple mixing of liquid reactants resulted in immediate and high yielding (91–97%) reaction, though product isolation and purification was required. Slightly lower yields (81–95%) were noted for 5 min of MW irradiation, however, pure products crystallized from ethanol used as solvent. Conventional heating was found time-consuming and less efficient (75–88% yield).
In 2019, a route to unsymmetrical thioureas was proposed by Dutta et al. involving the reaction of dithiocarbamate anions, generated in situ from secondary or primary amines and carbon disulfide at low temperature, with aromatic nitro compounds (Scheme 12) [78]. DMF as solvent, potassium carbonate as a base, and temperature of 100 °C were established as optimal conditions for the second step of the reaction. Among 22 derivatives obtained in 77–93% yield after 4–6 h one was chiral, but apparently racemic (Scheme 13). The postulated reaction mechanism involved the formation of nitrosoaryl intermediate and release of SO2 (consumed by K2CO3) as a by-product resulting from dithiocarbamate oxidation by nitroarene.
Organic azides were also converted to the corresponding thioureas. Kumar et al. reported on the synthesis of thioureido peptidomimetics using N-protected amino alkyl azides and dithiocarbamoic acids formed in situ from carbon disulfide and primary or secondary amines (Scheme 14) [79]. The reaction proceeded with the liberation of N2 and sulfur; it was performed in THF in the presence of pyridine at 0 °C to room temperature under inert atmosphere for 6 h. Fifteen enantiomerically pure derivatives were isolated in 72–85% yield.

2.4. Application of Other Compounds Containing C=S Bond

Less frequently, other thioorganic compounds find their application in the synthesis of thioureas, both chiral and achiral derivatives. In the past, a reaction of thiophosgene with primary or secondary amines was used in such preparations, though this source of C=S fragment has not gained popularity due to its corrosive and toxic properties [80]. However, its reaction with diamines was a key step in the synthesis of chiral cyclic thiourea ligands for palladium-catalyzed reactions by Yang and co-workers (Scheme 15) [81,82]. 1-(Methyldithiocarbonyl)imidazole and its quaternary N-methylated salt were found by Mohanta et al. to be effective thiocarbonyl transfer agents which allowed preparation of mono-, di- and trisubstituted thioureas (though not chiral) under mild conditions [83].
Furthermore, achiral derivatives were prepared in the reaction of amines with thiuram disulfides (Scheme 16) or monosulfides (in turn obtained from dithiocarbamates) [84]. Li et al. developed a protocol utilizing phenyl chlorothionoformate [85,86]. Its reaction with primary amines (either aliphatic or aromatic) in refluxing water carried out for 2–12 h (though 2–3 h were sufficient in most cases) afforded a series of 17 symmetrical, 1,3-disubstituted thioureas in 60–99% yield (Scheme 17) [85]. Among them, two enantiomerically pure derivatives were prepared. The protocol was also used to obtain thione heterocycles, however, it failed in the attempts with a mixture of two amines aimed to yield unsymmetrically substituted products. Such compounds could be formed using a two-step route: amines were first reacted with chloroformate in water for 1 h at room temperature [86]. Then, the resulting thiocarbamate was converted into the desired thiourea by heating with another (more reactive) amine for 20–80 min at 100 °C (Scheme 18). The yields were high (87–95% for the first step, 75–97% for the second one), products (none of them were chiral) were isolated by filtration and washed with water, without the need of further purification. The reaction could be performed on a gram scale.

2.5. Preparation of Chiral Thioureas from Other Thioureas

The thiocarbonyl moiety of chiral thiourea can also originate from achiral ones, subjected to an appropriate modification. In principle, it is possible to preserve the original skeleton and replace groups attached to the nitrogen atom(s), changing the substitution pattern. For example, the thiazolidine motif was introduced via the reaction of mono-aryl-substituted thioureas and the appropriate carboxylic acids with boronic acid catalyst (Scheme 19) [87]. Various prepared N-acyl derivatives included chiral ones and were found to exhibit antioxidant activity. Appropriate modifications of substituents of thiourea derived from 1,2-phenylenediamine were described by Liang et al. resulting in the introduction of chirality, and, finally, isolation of atropoisomeric N,S-donating ligands bearing oxazoline moiety [88].
Quite frequently, a reaction at thiocarbonyl carbon atom of thiourea is performed, resulting in C–N bond cleavage and attachment of an amine nucleophile. Yin et al. reported on the application of readily available and stable 1,3-bis-Boc-substituted thiourea as thioacylating agent of nucleophiles (amines, but also alcohols, thiols, thiophenolates, sodium malonates, Scheme 20) [89]. Thiocarbonyl compounds were formed in reasonable yields (78–94% in case of thioureas) under mild conditions (sodium hydride as a base, trifluoroacetic acid anhydride (TFAA) as an activator, THF solvent, 0 °C to RT). Amines bearing additional functional groups could be converted into desired products as well, including two enantiomerically pure derivatives for which no epimerization was observed. However, for hindered acyclic secondary amines, the procedure did not work. Bis-Boc thiourea was also utilized by Cohrt and Nielsen in their synthesis of N-terminally modified α-thiourea peptides that were further converted into the respective thiazoles, which in turn were incorporated into 15- to 17-membered macrocycles bearing up to three stereocenters [90].
Thiourea derivatives bearing heterocyclic substituents were also found to be useful thioacylating agents. 1-(Alkyl/Arylthiocarbamoyl)benzotriazoles were applied by Katritzky et al. as stable isothiocyanate equivalents (Scheme 21) [91]. Among di- and trisubstituted thioureas, three (R)-1-phenylethyl derivatives were formed in 92–99% yield (Scheme 22). Kang et al. used 1,1′-thiocarbonyldiimidazole (Figure 2) for C=S transfer, and converted it into desired monosubstituted (achiral) thioureas in two subsequent reactions with primary amines (mainly fluorene derivatives) and NH3 [92].

2.6. C=S Bond Formation

Less frequently, thioureas have been prepared via multi-component reactions in which elementary sulfur or other sulfur-transfer agents are used to form the C=S bond. Hydrogen sulfide was used by Katritzky et al. as the source of sulfur and reacted with 1-cyanobenzotriazole and amines or with carboximidamides to give thioureas in reasonable to high yields (54–99%, with two exceptions, Scheme 23) [93]. Thioureas (and selenoureas) were also prepared from cyanamides as described by Koketsu et al. [94]. The reaction with HCl in Et2O and then with LiAlHSH afforded 1,1-disubstituted products in 52–89% yield (Scheme 24). Unfortunately, chiral derivatives were not prepared by these two groups.
Tan et al. described an application of chloroform and elementary sulfur acting as thiocarbonyl surrogate (Scheme 25) [95]. Various primary amines were treated with chloroform in the presence of a base followed by addition of sulfur and a second primary amine. Optimal reaction conditions comprised t-BuOK used as a base, tert-butanol/1,4-dioxane (1:1 mixture) solvent, 55 °C, and reaction times varied from 6 to 15 h. Yields ranged from 51% to 96%, and among 35 thioureas ten chiral derivatives were obtained with a complete preservation of optical purity of the starting amines.
Sulfuration of azoles connected with N-difluoromethylation yielding a family of appropriately substituted cyclic thioureas was reported by Tang and co-workers [96]. The optimum reaction conditions were established as 24 h at 100 °C in DMA solvent with sodium hydroxymethylsulfite additive; elementary sulfur and ethyl 2-bromo-2,2-difluoroacetate were used as inexpensive reagents. Two products—derivatives of Econazole (48%) and Ketoconazole (43%)—were chiral, and the latter was obtained as a single enantiomer (Figure 3).
A relatively low explored synthetic strategy is based on the use of isocyanides. Zhu et al. described a Co(II)-catalyzed insertion of isocyanides into active N-H bonds of amines under ultrasound irradiation; the amino methylidyneaminium intermediates reacted readily with various nucleophiles including sulfur (to give thioureas) or water (yielding ureas) [97]. A series of aniline derivatives were tested with tert-butyl isocyanide to give 37–53% yield, and tryptamine with 4 different isocyanides gave products in 53–67%. The optimal reaction conditions included 20 mol% of Co(acac)2 catalyst, two equivalents of Na2CO3 and one equivalent of TBHP in 1,4-dioxane and ultrasound irradiation at 75 °C. Chiral thioureas were not prepared, however, two enantiomers of urea were obtained from enantiopure 1-phenylethylamines and tert-butyl isocyanide with a complete retention of configuration, suggesting a similar possibility for the synthesis of chiral thiourea. An efficient, three-component reaction of isocyanides, aliphatic amines and elemental sulfur under mild conditions (RT to 40 °C, solvent-free or toluene) was also reported by Nguyen et al. (Scheme 26) [98].
A three-component reaction of isocyanides, in situ formed N-chlorinated secondary amines and water or sodium sulfide was reported on by Angyal et al. [99]. Sodium dichloroisocyanurate (NaDCC) was used as a chlorinating agent. The reactions were performed in isopropanol under microwave-assisted conditions (100 °C, 10 min, 250 W, Scheme 27). Eight thioureas were prepared in 27–68% yield, including an enantiopure proline derivative (30%). Singh and Sharma developed a multicomponent protocol of thiourea preparation utilizing aromatic isocyanides, amines and 1,2-di(tert-butyl)disulfide under solvent- and catalyst-free conditions (Scheme 28) [100]. Isocyanides were obtained by formylation of aromatic amines followed by dehydration using POCl3. All the reactions were heated for 5 h at 120 °C and 1 h at 60 °C after the addition of amines. Twenty-seven thioureas were prepared in 56–99% yield, including an optically active derivative obtained from phenyl isocyanide Cinchonamine (57%).

3. Types of Chiral Thioureas and Selected Applications in Asymmetric Synthesis

Chiral thioureas can be classified taking into account a moiety introduced to its structure in order to induce chirality. Most structures contain a stereogenic center attached to a nitrogen atom of thiourea which typically derives from amine used as one of the reactants. In many cases, also additional elements of chirality are present, as well as functional groups designed to participate in desired interactions with target molecules (e.g., substrates of catalyzed reaction) or ions (metal ions in coordination compounds, anions bound by thiourea-based receptors). In particular, derivatives based on chiral diamines have attracted attention due to their possible application as bifunctional catalysts, with thiourea moiety acting as hydrogen bond donor and an amino group as a Brønsted base/Lewis base/nucleophile. Alternatively, systems consisting of an achiral thiourea together with components responsible for asymmetric induction are tested as well [101].
Several extensive reviews have been published on asymmetric organocatalysis and, in particular, the use of chiral ureas and thioureas in various stereoselective reactions [3,12,13,14,102,103,104,105,106,107,108,109,110,111,112,113,114]. Consequently, the following part is focused on the presentation of selected examples of compounds with only a short mention about their applications in the synthesis and functionalization of one particular system, i.e., chroman scaffold and its derivatives (Figure 4). As an example for a versatile structure with various pharmaceutically active derivatives [115], it has various possible medicinal usages [116,117]. Prochiral carbon atoms can be substituted, yielding structures with several stereogenic centers, e.g., flavonoids (Figure 4) [118,119]. Preparation of various chroman derivatives with a defined stereochemistry challenged organic chemists. Versatile, general methods for their asymmetric synthesis have been found in recent years [117,120,121,122].

3.1. Thioureas Containing trans-1,2-diaminocyclohexane (DACH) Skeleton and Other Chiral Diamines

Pioneering works on application of chiral thioureas in enantioselective organocatalysis came from the laboratory of Jacobsen. Three libraries of polystyrene-supported enantiopure ligands containing amino acid residues, urea or thiourea moiety, and Schiff bases (the last two subunits linked with (R,R)-1,2-diamines) were evaluated as organocatalysts for asymmetric Strecker reactions (Figure 5) [123,124,125]. The optimized catalyst and its soluble analogues showed a broad substrate scope. Similar, appropriately modified Schiff base catalysts were found optimal in other asymmetric reactions, including hydrophosphonylation of imines [126], intermolecular addition of indoles to cyclic N-acyl iminium ions [127], hydro- and acylcyanation of imines [128,129,130]. Furthermore, imidazole derivatives of Schiff bases were applied in Strecker reaction by Tsogoeva et al. [131].
Later on, Jacobsen and co-workers developed other DACH-based thiourea organocatalysts (Figure 6) [132,133,134]. For example, pyrrole derivative appeared most efficient in acyl Pictet-Spengler reaction [133], and Cope-type hydroamination [134]. This type of catalyst was also applied by Bui et al. in asymmetric additions of oxoindoles to nitroolefins [135].
DACH-based bisfunctional thiourea organocatalysts containing a tertiary amine function were developed by Takemoto and co-workers (Figure 7). A dimethylamine derivative appeared to be a versatile promoter, active in various asymmetric transformations: Michael reaction of nitroolefins and malonates [136] or 1,3-dicarbonyl compounds [137], active methylene compounds with α,β-unsaturated imides [138,139], aza-Henry [140], Neber reaction (synthesis of azirine derivatives) [141], aldol reaction [142], and others [110,111,112].
Now commercially available (in both (R,R)- and (S,S) forms), Takemoto’s organocatalyst was also used by other groups, mainly to catalyze various stereoselective additions [135,143,144,145,146,147,148,149,150], and to control the ring-opening polymerization of racemic lactide leading to highly isotactic polylactide [151].
Diverse modifications of Takemoto’s compound have been introduced, both in the parent group and by others (Figure 8). A PEG-immobilized catalyst was efficient in the enantioselective Michael and tandem Michael reactions [152], while a hydroxylated derivative catalyzed a Petasis-type reaction of quinolones and boronic acids [153]. A hybrid catalyst containing arylboronic acid was evaluated for asymmetric hetero-Michael addition to unsaturated carboxylic acids [154,155]. Various modified derivatives of Takemoto’s catalyst were tested in the enantioselective reduction of ketones with borane; a benzyl-substituted catalyst led to the best outcomes [156]. A piperidine derivative showed the optimal performance among diamine-derived catalysts tested in inverse-electron-demand Diels-Alder cycloaddition [157], Mannich reaction of 2-substituted indolin-3-ones [158], and pyrrolidine-substituted thiourea, in conjugated addition of nitroacetates to unsaturated ketoesters [159], and in double Michael reaction used for the construction of a spiro-fused cyclohexanone-5-oxazolone system [160]. Schreiner and co-workers chose an imidazole-based catalyst (in cooperation with Brønsted acids) as the best one for cyanosilylation of various aldehydes [161]. An axially-chiral binaphthyl-derived amine was used for the synthesis of thioureas which catalyzed stereoselective Michael addition of 2,4-pentanodione and malononitrile to nitroolefins [162,163].
A variety of thiourea organocatalysts based on chiral diaminocyclohexane skeleton have been prepared. Selected examples include thioureas bearing primary amine functionalities that were tested in Michael addition of active methylene compounds to enones [164,165,166,167] and of ketones or dioxindoles to nitroolefins (Figure 9) [168,169,170,171].
Introduction of additional chiral electron-withdrawing group in place of aryl moiety of Takemoto’s catalyst allowed an additional stereocontrol in Michael addition reaction (Figure 10) [172].
The presence of two amino groups in 1,2-diaminocyclohexane opens the possibility to design and prepare dimeric structures. Nagasawa’s group developed a chiral bis-thiourea organocatalyst efficient in enantioselective Morita-Baylis-Hillman reaction (Figure 11) [173], and its analogues based on other diamines [174]. The DACH-based bis-thiourea was used in other asymmetric transformations, e.g., in photochemical intramolecular [2+2] cycloaddition of 2,3-dihydropiridone-5-carboxylates described by Mayr et al. [175].
Other chiral diamines have been converted to thioureas as well. Organocatalysts bearing multiple hydrogen bond donors—chiral diaminocyclohexane and 1,2-diphenylethylenediamine fragments (Figure 12), the latter converted into sulfonamide, were prepared by Wang and co-workers and appeared highly efficient in asymmetric Michael addition as well as nitro-Mannich reaction [176,177]. Among chiral thioureas containing tertiary amines tested in Michael additions of 3-substituted oxindoles to maleimides, and cyanoacetates to vinyl sulfones, 1,2-diphenylethylenediamine derivatives led to the highest yields and stereoselectivities (Figure 12) [178,179]. In turn, primary amines of this kind (Figure 12) were found most efficient in asymmetric additions to unsaturated ketones [180,181] and a stereoselective construction of α,α-disubstituted cycloalkanones [182]. A catalyst bearing two 1,2-diphenylethylenediamine fragments (Figure 12) was used in a tandem asymmetric Michael/cyclization reaction of 4-hydroxycoumarin and nitroalkanes, albeit with moderate yields [183].
1,2-Dinaphthylethylenediamine derivatives were applied by Tius and co-workers in asymmetric Nazorov cyclization of diketones (Figure 13) [184,185]. Berkessel and co-workers converted chiral isophoronediamine into bis-thioureas and bis-ureas (Figure 13) [186]. The derivative containing trifluoromethyl groups appeared the optimum catalyst for asymmetric Morita-Baylis-Hillman reaction of aldehydes with enones or acrylates.
Other chiral thioureas bearing additional amino functionalities have been described as well (Figure 14). Ephedrine-based thioureas were obtained in Bolm’s group and tested in Michael additions [187]. Indane scaffold introduced into a structure of a catalyst resulted in good yields and stereochemical outcome of cascade Michael-oxa-Michael-tautomerization process [188]. A bifunctional pyrrolidine-thiourea was applied by Tang and co-workers to the diastereo- and enantioselective Michael additions of cyclohexanone to alkyl and aryl nitroolefins [189]. In a study by Enders and co-workers, tertiary amines (piperidine and pyrrolidine derivatives) were found the best option for domino Michael–Mannich cycloadditions [190]. Chen’s group prepared a series of chiral catalysts, including thioureas, using a chloramphenicol base skeleton, and used them in asymmetric transformations [191,192,193].
Chromans can be easily substituted using the Michael addition approach. Various chiral organocatalysts have been used in asymmetric reactions of nitroalkenes with malonates [194,195,196]. Thiourea-based ones bearing diamine functions were tested in the Michael addition by Yan and co-workers (Scheme 29) [197]. Tang’s group prepared chroman derivatives by addition of malonate to the appropriate nitroolefins in high yield and enantiomeric excess [189].
Zhu and co-workers proposed a versatile method using vinylindols as dienophiles in an inverse electron demand Diels-Alder reaction (Scheme 30) [157,198]. This appeared an efficient method of preparation of new biochemically active flavonoids containing additional privileged structures such as pyran and indole [199].
Over recent years, asymmetric cascade reactions [200,201,202,203,204,205] have been developed into a powerful tool in asymmetric synthesis of such compounds; stereogenic quaternary all-carbon centers are especially challenging [206]. Spiro-substituted structures can be found in biologically active natural and synthetic compounds [207,208]. The study on the asymmetric synthesis of spiro centers has been recently intensified [209,210], and various asymmetric routes to chromans bearing this structural feature have been found [208,211]. Thiourea-based multivalent organocatalysts offer a great opportunity for preparation of substituted spiro-chroman structures, as exemplified by Michael-acetylation-cascade reaction of 2-oxocyclohexanecarbaldehyde derivatives (Scheme 31) [212].
A non-spiro stereogenic quaternary all-carbon center was formed in an oxa-Michael addition followed by an intramolecular Michael addition as reported by Lu and co-workers (Scheme 32) [213].

3.2. Thioureas Containing Cinchona Alkaloids

Cinchona alkaloids, a privileged motif of various structures useful in asymmetric synthesis [214,215], were also combined with thioureas, typically by conversion of hydroxyl group at C9 position into amine and its reaction with an appropriate isothiocyanate [17]. Such derivatives, introduced by the groups of Connon and Soós (Figure 15), were first applied in enantioselective addition of malonates to nitroalkenes [216] and nitroalkanes to chalcones [217]. Later on, these bifunctional organocatalysts were found efficient in a variety of asymmetric transformations, including Michael and combined Michael–Henry reaction [218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238], sulfa-Michael and retro-sulfa-Michael reaction [239,240], aldol reaction [241], Mannich reaction [242], Strecker reaction [243,244], hydrophosphonylation [245,246], decarboxylative protonation [247], fluorination of ketoesters [248], arylation of cyclic ketoamides with quinone monoamine [249] and others.
Thiourea was also introduced in place of methoxy group of quinine by Hiemstra and co-workers (Figure 16), and the resulting catalysts used in enantioselective Henry reaction [250], though they were less efficient in other asymmetric transformations [221,243,244,245]. Bis-alkaloid thioureas were prepared by Song and co-workers and were shown to exhibit high enantioselectivity in a dynamic kinetic resolution of racemic azlactone derived from valine (Figure 16) [251].
One can choose among stereoisomers (quinine/quinidine, cinchonidine/cinchonine and their epimers), and their modified derivatives, which often allows obtaining both optical antipodes of the product of the catalytical reaction [228,232,238,252]. However, other bisfunctional catalysts seem to offer more possibilities of fine tuning of catalytic properties. Certain problems are connected with limited thermal stability [217] and dimerization of alkaloid-thiourea conjugates in solution through intermolecular hydrogen bonds which can limit their activity [253,254].
Gu and co-workers prepared a series of chroman derivatives in a double Michael reaction of commercially available starting materials, chalcone enolates and nitromethane, using Cinchona-alkaloid thioureas as catalysts (Scheme 33) [255]. Three stereogenic centers were formed with high stereoselectivity. In a proposed mechanism, both Si (not observed) and Re face approaches were included, which would result in a completely diverse hydrogen bonding interactions in a transient state.
Cinchona alkaloid-based organocatalysts were also applied by Singh and co-workers in their synthesis of chiral chroman derivatives from chalcones and α,β-unsaturated nitroalkenes (Scheme 34) [256]. Reasonable yields were accompanied by a modest diastereoselectivity and high enantioselectivity, and the reaction was completed in 8–48 h.

3.3. Thioureas Derived from Amino Acids and Peptides

As already demonstrated by Jacobsen’s catalyst (described in part 3.2.) [123], naturally occurring amino acids and their derivatives can serve as chirality source in the construction of chiral thioureas [62,257,258,259,260]. Jacobsen’s group described the application of amide-thiourea catalyst obtained in three steps from valine and N-methylbenzylamine in Pictet-Spengler reaction [261,262], and tert-leucine-derived amides in iso-Pictet-Spengler reaction (both reactions were co-catalyzed with benzoic acid; Figure 17) [263]. Thioureas bearing t-leucine arylpyrrolidino amide component catalyzed the stereoselective indole addition to γ-pyrone derivatives [264]. t-Leucine-derived thioureas were also efficient in the enantioselective dearomatization of isoquinolines [265], and the synthesis of furan derivatives with a trifluoromethyl at a stereogenic center [266]. Valine derivative prepared by Pedrosa and co-workers was applied in nitro-Michael additions; a supported catalyst was also prepared [267,268,269]. Fullerene was also introduced into chiral thioureas derived from valine, phenylalanine and tert-leucine, and the resulting hybrids appeared efficient, recyclable catalysts for stereoselective nitro-Michael reaction [270].
Thioureas derived from l-proline were reported by various groups (Figure 18) [271,272,273]. These derivatives were applied in asymmetric direct aldol reaction of cyclohexanone and aldehydes or enantioselective Michael addition of 1,3-diones to nitroolefins, both proceeding in high yields and with excellent stereoselectivity [271,273].
A series of thioureas was obtained by Bolm and co-workers starting from l-aspartic acid and l-glutamic acid which were converted into cyclic amines and reacted with organic isothiocyanates (Figure 19) [274]. The resulting compounds provided excellent yields and stereoselectivities of Michael additions.
In 2007, Lattanzi prepared thioureas from commercially available enantiopure aminoalcohols and used them in stereoselective Morita–Baylis–Hillman reaction of cyclohexanone and aldehydes [275]. Various peptidomimetics containing thiourea fragment were prepared as well [39,79,90]. Peptidic derivatives containing adamantyl moiety were found efficient catalysts of Morita–Baylis–Hillman reactions (Figure 20) [276].
Amino acid-derived thiourea organocatalysts were used by Zhao’s group in a tandem thia/oxa Michael-Michael reaction yielding optically pure chromans containing the pharmaceutically important oxindole scaffold (Scheme 35) [277]. Spiro products were isolated in high yields and good up to very high enantiomeric excess.
Excellent yield, diastereomeric and enantiomeric excess were reported in a domino reaction of oxa-Michael and 1,6-addition by Enders et al. (Scheme 36) [278]. As privileged substrates ortho-hydroxyphenyl derivatives were used [279], introducing a nucleophilic group para-quinone methides that became suitable donor-Michael acceptors [280,281,282,283,284,285,286,287].

3.4. Carbohydrate-Based Chiral Thioureas

Chiral thioureas can bear enantiopure carbohydrates. Quite frequently, they are combined with other functionalities. For example, Liu et al. prepared five novel d-mannitol-derived thiourea organocatalysts containing Cinchona alkaloids as well and used them for asymmetric Henry reaction [40].
Ma and co-workers introduced bifunctional organocatalysts containing multiple stereogenic centers in both primary amine derived from DACH and various carbohydrate moieties (Figure 21) [288]. With these promoters, Michael addition of ketones to nitroalkenes proceeded with high yields and stereoselectivities. Similar catalysts (also containing 1,2-phenylenediamine) were applied in other Michael additions [194,289], Mannich reaction [290,291], and conjugate addition/dearomative fluorination [292,293]. Thioureas containing a glycosyl scaffold were also applied in aza-Henry reaction between N-Boc imines and nitromethane [294].
Asymmetric tandem Michael–Michael additions of ketones and nitroalkenes were optimized by Miao and co-workers (Scheme 37) [295]. A carbohydrate-based chiral thiourea organocatalyst used together with benzenesulfonic acid (BSA) afforded high yields, excellent enantiomeric excess and high diastereoselectivity. The resulting spiro-compounds are not only interesting due to possible biological activities [296], but also as enantiopure multi-functionalized pyrazole derivatives for further synthesis [211,212,297,298,299].

3.5. Chiral Phosphine-Bearing Thioureas

Bifunctional catalysts containing thiourea moiety (hydrogen bond donor, Brønsted acid) and nucleophilic/basic phosphine functionality, both attached to a chiral skeleton, have already found a variety of applications in stereoselective reactions [113]. The first report on their synthesis was published by Shi and Shi in 2007 who prepared three binaphthyl-based derivatives (Figure 22) [300]. A N-phenyl-substituted catalyst was most efficient in aza-Morita-Baylis-Hillman reaction of N-sulfonated imines and vinyl ketones or acrolein: (S)-products were formed in moderate to high yield and stereoselectivities. Shi and co-workers used modified thioureas belonging to the same class in the reaction of MBH adducts with oxazolones [301].
An active catalyst bearing a diphenylphosphine moiety was introduced by Wu and co-workers and tested for the Morita–Baylis–Hillman reaction of aromatic aldehydes with methyl vinyl ketone and acrylates (Figure 23) [302,303]. Slightly higher (and opposite) enantioselectivities were noted for valine-derived phosphinothiourea, however, the reaction required more time [304].
Phosphinothiourea, described by Mita and Jacobsen, catalyzed enantioselective opening of aziridines with hydrogen chloride to yield β-chloroamine derivatives (Figure 24) [305]. Chiral thiourea bearing a phosphine moiety was also efficient in 1,6-conjugate addition of para-quinone methides with dicyanoolefins [306]. An interesting example of thioureas bearing a stereogenic phosphorus atom, prepared by a stereoselective reduction of the corresponding aminophosphine oxides and their reaction with isothiocyanates, was described by Su and Taylor (Figure 24) [307]. Epimeric catalysts exhibited different activity and stereoselectivity in Morita-Baylis-Hillman reactions of methyl acrylate and aromatic aldehydes.
In a 2019 paper, amino acid-derived thiourea-phosphonium salts were explored as phase-transfer catalysts for asymmetric Mannich reaction (Figure 24) [308].
A novel chiral ferrocenyl bis-phosphine thiourea was introduced by Zhang and co-workers who described its use in Rh-catalyzed hydrogenation of nitroalkenes with high yields and enantioselectivities, even at low catalyst loading (Figure 25) [309,310]. This ligand, named ZhaoPhos, easily prepared from Ugi’s amine, showed high efficiency in various hydrogen bond-assisted catalytic hydrogenations with rhodium and iridium complexes [311,312,313,314,315,316,317,318]. The system exemplified the idea of synergistic activation via cooperating transition metal-catalyst and organocatalyst joined in one bifunctional structure [319].
Other chiral phosphorus derivatives of thioureas are also worth mentioning. Two phosphorylamide derivatives were prepared by Juaristi and co-workers and utilized in stereoselective Michael addition of cyclohexanone to nitrostyrenes and chalcones [42]. Chiral thioureas containing an aminophosphonate moiety were investigated in context of their antiviral activity as well [320].
In a chiral phosphine thiourea-mediated reaction of para-quinone methides with dicyanoolefins described by Yao et al. excellent diastereomeric excess in combination with good yield and enantioselectivity were observed (Scheme 38) [306].

3.6. Thioureas and Bis-Thioureas with Axial, Planar or Helical Chirality

Chirality of majority enantiopure thioureas used in asymmetric organocatalysis origins from the presence of stereogenic center(s). However, one cannot neglect a group of derivatives which are characterized by the presence of other stereogenic elements. Some notable representatives include efficient organocatalysts and exciting examples of molecular motors from Feringa’s laboratory.
Most compounds belonging to this class exhibit axial chirality/helicity connected with the presence of biaryl fragment characterized by a restricted rotation around the Caryl–Caryl bond. First examples come from 2005, when, looking for optimal organocatalyst for the asymmetric Morita-Baylis-Hillman reaction of cyclohexanone with aldehydes, Wang and co-workers decided to combine thiourea moiety with binaphthylamine (Figure 26) [28]. An axially chiral binaphthyl bis-thiourea was prepared by Connon and co-workers and proved useful in promotion of asymmetric Friedel–Crafts type addition of indole derivatives to nitroalkenes (Figure 26) [29]. Modified catalysts belonging to this class obtained in Shi’s group were also efficient in the asymmetric Henry [30] and Morita-Baylis-Hillman reactions [300,301,321]. A multifunctional organocatalyst containing quinine, thiourea and binaphthylamine moieties, capable of stereoselective formation of three stereocenters in a domino Michael-aldol reaction was constructed by Barbas III and co-workers [322]. Novel bis-thioureas prepared by Rampalakos and Wulff from commercially available enantiomerically pure 1,1′-binaphthyl-2,2′-diamine were tested in aza-Henry reactions (Figure 26) [323]. A series of binaphthyl-derived thiourea catalysts were applied by Kim and co-workers in asymmetric Mannich-type reactions of fluorinated ketoesters [324]. For the asymmetric Henry reaction, bis-thioureas were prepared connected with 4,4′-bisindanyl [325], and substituted biphenyl- and bianthryl-based linkers (Figure 26) [326,327,328]. High yields and stereoselectivities were observed for certain derivatives.
A combined point chirality and axial chirality resulting from the restricted rotation was observed for thiourea-oxazoline ligands used for palladium-catalyzed asymmetric reactions (Figure 27) [82,88]. A series of enantiopure atropisomeric thioxothiazol-substituted derivatives prepared by Roussel et al. were tested as enantioselective anion receptors (Figure 27) [329].
Bisfunctional, photoswitchable, dual stereoselective catalysts based on the idea of unidirectional molecular motors were designed by Feringa and co-workers (Figure 28) [330,331]. The cooperation of thiourea and tertiary amine in cis states was found a key factor for stereoselectivity of Henry reaction of nitromethane and fluorinated ketones and Michael reaction of bromonitrostyrene and pentanedione.
Enantiomerically pure planar-chiral thiourea derivatives based on [2.2]cyclophane were first prepared by Paradies and co-workers and showed rather limited efficiency in stereoselective Friedel–Crafts alkylation of indole and transfer hydrogenation of nitroolefin (Figure 29) [31]. However, the performance of cyclophane bis-thioureas in asymmetric Henry reaction was much improved and also led to high induction of chirality (Figure 29) [32]. Other modifications of the system (the introduction of amino group) were found useful for the catalysis of aldol reaction of isatines and ketones (Figure 29) [33].
Thioureas were also incorporated to optically active helical polymers. Polymerized enantiopure N-propargylthioureas derived from 1-phenylethylamine formed helices in low polarity solvents and showed affinity to iron(III) ions [332]. Polyacetylenes bearing pendant thiourea groups were used as chiral catalysts for the asymmetric Michael addition of diethyl malonate to trans-β-nitrostyrene [333].

3.7. Thioureas Containing Other Functional Groups

A variety of thiourea organocatalysts have been prepared containing additional functionalities to introduce chirality or/and to actively participate in the catalytic reaction. For example, photochemically active thioxanthone was attached to thiourea moiety with various chiral linkers and the resulting catalysts were employed in the photocyclization of 2-aryloxycyclohex-2-enones (Figure 30) [334].
Wang and co-workers reported a preparation of bifunctional rosin-derived catalysts (prepared from chiral dehydroabietic amine) and used it in a doubly stereocontrolled addition reactions, including the stereoselective synthesis of chiral cyclic thioureas (Figure 31) [51,171,335,336,337,338,339,340,341]. Wang’s group modified the original structure of their catalyst with Cinchona alkaloids as well to provide a double stereocontrol [342,343,344]. Rosin-derived thioureas were also used by Reddy and co-workers in asymmetric Michael-hemiketalization of allomaltol [345].
A series of chiral bis-thioureas bearing a central guanidine motif were developed by Nagasawa’s group and applied as catalysts of Henry reaction of nitromethane and various aldehydes (Figure 32) [346]. Ricci’s group developed an indanol chiral thiourea organocatalyst for enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes (Figure 32) [347].
Thioureas can be equipped with additional sulfur functionalities. In our laboratory, chiral amino- and diaminosulfides obtained from cyclohexane-1,2-diol were converted into mono- and bisthioureas which were tested in Morita-Baylis-Hillman reaction (Figure 33) [348]. Bolm and co-workers designed the synthesis of a set of chiral sulfoximine-based thioureas (Figure 33) [41]. Interestingly, the optimum results of asymmetric Biginelli reaction were obtained for the derivative bearing only sulfur as a stereogenic center separated from thiourea moiety.
Krasonvskaya et al. described a preparation of a thiourea-modified doxorubicin as a pH-sensitive prodrug capable of releasing cytotoxic component as well as anticonvulsant albutoin in a weakly acidic medium [349]. Thioureas containing a chiral isosteviol moiety [350,351,352], terpenes [77], camphor [353] or steroid scaffold [354] have been also reported.

4. Biological Activity of Chiral Thioureas

Thioureas represent an important class of compounds that attracted a lot of attention due to their bioactivity, e.g., in medicinal chemistry, pharmaceutical industry, and agriculture. Derivatives were found to be efficient antiviral [72], antifungal [355], antimicrobial [356] or anticancer agents [357]. The ability of preparing thioureas containing various scaffolds allows their use as potential inhibitors against numerous molecular targets. Consequently, these compounds have become an interesting material for further investigations. In this part of the review, selected examples of chiral thiocarbamides used in biomedical studies will be presented.

4.1. Antiviral Thioureas

Aminophosphonates are structural analogues of amino acids. Likewise the aminophosphonic acids, they are able to inhibit enzymes involved in amino acids metabolism, and thus may generate various physiological responses, e.g., neuromodulatory activity [358]. Cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) are plant virus diseases which have become a serious problem in agriculture in recent years [359]. The commercially available product Ningnanmycin is commonly used against CMV and TMV, though with serious limitations resulting from its light and moisture sensitivity. Thus, the design and preparation of novel antiviral agents constitutes a significant challenge.
In 2009, Chen et al. reported the novel anti-TMV chiral thioureas and bis-thioureas bearing α-aminophosphonate moiety [320]. The evaluation of a tested series revealed that two derivatives are active against CMV and TMV comparable to Ningnanmycin (Figure 34). It was also found that the absolute configuration of isothiocyanates, used to form corresponding mono- and bis-thioureas, considerably affected the antiviral activity of tested compounds. Generally, mono-thiourea (S)-enantiomers were more effective against TMV than corresponding (R)-enantiomers [320], while the results for bis-thioureas against CMV appeared to be reversed: derivatives obtained from (R)-enantiomer of isothiocyanate were more active against the virus [359].
Liu and co-workers prepared a series of chiral thioureas bearing t-leucine and α-aminophosphonate moieties and evaluated their anti-TMV activity [360]. Two compounds were identified as the most potent antiviral agents (Figure 35). It was shown that the derivatives containing electron withdrawing groups in para position of the aromatic ring revealed better activity. Stereoisomers with l configuration were more active than their d counterparts or the racemic form.
Yan et al. synthesized also a new collection of chiral thioureas and evaluated their activity against TMV [361]. Novel compounds were prepared in ionic liquid, an eco-friendly environment. Among them, an indane derivative (Figure 36) exhibited the best antiviral properties: in vivo protection, inactivation and curative effects against TMV with inhibitory effects of 57.0%, 96.4% and 55.0%, respectively, at 500 μg/mL. Moreover, it was more active against TMV than the reference compound Ningnanmycin.
Besides the agriculture, various thiourea derivatives are important for pharmaceutical industry. Several examples of structurally diverse derivatives that act on human viruses, e.g., human immunodeficiency virus (HIV) or human cytomegalovirus (HCMV) can be found in the literature [362,363].
After extensive studies of the pharmacological influence of novel 1,3-thiazepine-based urea and thiourea derivatives on animal central nervous system (CNS), Struga and co-workers published the results of their antiviral activity assays [364]. The compounds were found useful in antiviral therapy due to their specific structure: butterfly-like conformation formed by the hydrophilic center and two hydrophobic moieties. Such a structure is characteristic for non-nucleoside reverse transcriptase inhibitors (NNRTIs), used as anti-HIV agents [364,365].
Furthermore, the 1,3-thiazepine ring is an important system considering its biological activity. It is a part of the Omapatrilat structure, an antihypertensive drug currently in stage IV of clinical trials [366,367]. Additionally, seven-membered cyclic thiourea derivatives are used as a nitric oxide synthase inhibitors [366].
The 1,3-thiazepine-based isothiourea derivatives were tested against diverse virus classes: Retrovirus (HIV-1), Hepadnavirus (HBV) and Flaviridae (YFFV and BVDV, both the single-stranded RNA+ viruses; Figure 37). In spite of the promising pharmacological action on animal CNS, only three compounds exhibited modest antiviral activity [364].
Venkatachalam et al. studied the impact of the stereochemistry of thioureas on their anti-HIV activity (Figure 38) [368]. Eleven chiral naphthyl thioureas were tested in vitro against recombinant reverse transcriptase (RT) [369]. Generally, the (R)-stereoisomers of all eleven compounds were more active than their enantiomers. Five of the most active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). While the (R)-stereoisomers were active at nanomolar concentration, their enantiomers were again inactive. Furthermore, the most active compound was much more active against various NNI-resistant HIV-1 strains, than standard NNI drugs (nevirapine, delavirdine and trovirdine). Molecular modelling studies confirmed that the (R)-isomer fits to the target NNI binding pocket on HIV-RT much better than the (S)-enantiomer [368].
In the 1990s, Bell and co-workers reported phenethylthiazolylthiourea (PETT) compounds as potent anti-HIV agents; taking the structure-activity relationship into account various substituents in their structures were analyzed [370,371]. Later, Venkatachalam’s group undertook the studies of the influence of stereochemistry on the activity of this class of compounds [372]. A new series of chiral halopyridyl- and thiazolyl-substituted thioureas were synthesized (Figure 39). Molecular modelling suggested that for both groups (R) stereoisomers fit better to the target binding pocket of HIV reverse transcriptase than their (S) counterparts. The in vitro tests confirmed this result and exhibited also that the lead compounds were several orders of magnitude more potent than the standard NNRTI Nevirapine.

4.2. Anticancer Thioureas

Since cancer constitutes the second most common cause of death globally, the quest for the new anti-tumor agents remains a continuous interest of numerous scientific teams. It has been proven that various groups of thioureas exhibit antiproliferative activity [373,374,375]. Some compounds reveal dual biological effects, e.g. anti-tumor together with anti-oxidant or anti-inflammatory activity [376]. Depending on structure and content of other biologically active fragments they act on various types of cancer cells. Herein, we present chosen, promising results of antiproliferative studies.
Chiral thioureas containing α-aminophosphonate moiety, already mentioned as potential antiviral agents, were also used by Liu et al. as pseudo-peptides to treat cancer (Figure 40) [377]. Several derivatives revealed promising activity against human tumor cells PC3 (prostate cancer), Bcap37 (breast cancer) and BGC823 (stomach cancer). In a preliminary in vitro assay the three most potent compounds emerged with IC50 values from 4.7 to 17.2 µM against the PC3 cell line; two of them exhibited a better antiproliferative activity than the reference compound—a commercially available 6,7-dimethoxy-N-(3-bromophenyl)-4-aminoquiazoline (IC50 13.7 µM). Furthermore, one derivative exhibited higher activity than the reference drug against a stomach cancer cell line (IC50 values: 4.7 µM and 6.9 µM, respectively).
Interestingly, a significant influence of the absolute configuration of tested compounds on the antiproliferative activity was observed. Generally, d-isomers revealed higher growth inhibition in comparison with l-isomer derivatives [376]. To enhance antiproliferative activity, another amino acid residue (glycine or more rigid fragment, e.g., l-proline) was introduced into the pseudo-peptide scaffold [378]. This new series of chiral thiourea derivatives was examined toward BGC-823 (human gastric cancer) and A-549 (human non-small cell lung cancer) cell lines. The basic SAR studies led to the statement that the presence of the rigid l-proline fragment in the corresponding dipeptide structure increases antiproliferative activity. Moreover, antitumor properties may be improved by introducing an electron-withdrawing group in the para position of the terminal phenyl group of the dipeptide thioureas [377].
Huang et al. demonstrated the results of anticancer activity assays of thioureas containing the α-aminophosphonate moiety based on dehydroabietic acid (DHA, Figure 41) skeleton [379]. It was found that the DHA increases antiproliferative action of drugs on various cancer cells [380]. Hence, a new series of thioureas incorporating the α-aminophosphonate moiety and DHA core was synthesized and tested in vitro against NCI-H460 (lung), A549 (lung adenocarcinoma), HepG2 (liver) and SKOV3 (ovarian) human cancer cell lines. The compounds exhibited moderate to high level of antiproliferative activity. The most active derivative revealed better results against A549 cell line than 5-fluorouracil, the medicine commonly used in cancer therapy (Figure 41). A preliminary analysis of mechanism of its action proved that the compound is capable to induce cell apoptosis [379].
The results of previous research on impact of stereochemistry of halopyridyl and thiazolyl thioureas on anti-HIV activity [372], prompted Venkatachalam’s group to extent studies toward anti-leukemic activity. They designed and synthesized five series of new chiral derivatives (Figure 42) [381]. Their anticancer activity was evaluated against human B-lineage Nalm-6 and T-lineage Molt-3 acute lymphoblastic leukemia cell lines. Preliminary studies proved that the stereochemistry indeed was the factor that determined the activity of tested compounds: (S) enantiomers performed better in the tests.

4.3. Anti-Allergic Thioureas

Venkatachalam et al. reported the synthesis and evaluation of anti-allergic activity of novel chiral heterocycle-based thioureas [382]. Referring to the fact that leukotrienes, chemical mediators released by mast cells, play an important role in pathophysiology of allergy and asthma, they became a new target for potential thiourea based anti-allergic agents [383].
The set of indolyl-, naphthyl- and phenylethyl-substituted halopyridyl, thiazolyl and benzothiazolyl thiourea derivatives were tested in vitro for the mast cell inhibitory activity (Figure 43). Among them, naphthyl-substituted thiazolyl thioureas were found most promising. Based on the results obtained for (S)- and (R)-isomer of naphthyl thioureas it was concluded that the stereochemistry of studied thioureas did not greatly influence their activity.

4.4. Antimicrobial Thioureas

Pyrazole derivatives have been recognized as versatile compounds with multiple biological properties, e.g., antibacterial, anti-inflammatory or antiproliferative activity [384,385]. Many scientific groups have been involved in the investigation and development of novel pyrazole derivatives, facing the problem of their high toxicity.
The connection of thiourea functional group with these biologically active molecules led to a discovery of new compounds with a potential pharmaceutical importance. Bildirici and co-workers synthesized novel chiral pyrazole-based thioureas (Figure 44) [383]. The compounds were examined against three Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Bacillus megaterium) and four Gram-negative bacteria (Enterobacter aerogenes, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli) and exhibited a desired activity, one of them even higher than amikacin and rifampicin and similar to penicillin. Additionally, they were evaluated as antifungal agents against three fungal strains (Candida albicans, Saccharomyces cerevisiae and Yarrovia lipolytica).
In the literature, there are several reports concerning thiourea functional group combined with heterobicyclic fused aromatic scaffolds, e.g., benzothiazole or benzimidazole rings [386,387]. Madabhushi et al. prepared two sets of chiral thioureas bearing benzimidazole ring based on natural and non-natural amino acids ((S)-alanine, (S)-phenylalanine, (S)-valine, (S)-leucine and (R)-alanine, (R)-phenylalanine, (R)-valine and (R)-leucine, respectively; Figure 45) [388]. The obtained compounds were studied as potential antimicrobial agents against the Gram-positive strains Staphylococcus aureus, Bacillus subtilis, Staphylococcus aureus and Micrococcus luteus as well as the Gram-negative strains Klebsiella planticola, Escherichia coli and Pseudomonas aeruginosa. Additionally, antiproliferative activity was examined against A549, MCF7, DU145 and HeLa cell lines.
Interestingly, the compounds derived from natural amino acids exhibited antibacterial activity, whereas their isomers turned out to be inactive against the tested Gram-positive and Gram-negative strains. Thioureas substituted with isopropyl or isobutyl and 3,5-(CF3)2C6H3 groups were the most potent among the series. It was considered that a suitable stereochemistry and the presence of lipophilic trifluoromethyl groups which may increase bioavailability and bio-efficiency, were the factors that determined antibacterial activity.
Chiral thiophosphorylated thioureas have attracted an attention due to their biological activity, and ability to form diverse complexes with transition metals. Based on literature reports Metlushka et al. synthesized new coordination polymers with chiral thiophosphorylated thioureas in both racemic and enantiopure forms and checked their antimicrobial activity against S. aureus and B. cereus [22]. They examined both enantiopure and racemic derivatives as well as their complexes with Ni(II) (Figure 46). Neither (R)- nor (S)-ligands did exhibit valuable anti-microbial activity, while the racemic mixture was surprisingly active. In case of complexes, (R)-complex was less active than (S)-complex against S. aureus while the racemate probably was not considered in the research. In turn, both isomers and the racemic mixture performed similarly against B. cereus.

5. Summary

A relatively simple, rigid skeleton of thiourea can be combined with chiral moieties, yielding a system that is capable of strong and selective interactions with a variety of chiral molecules, including compounds of biological importance. By an appropriate substitution we can suitably modify their properties, and, in principle, there are no limitations in preparation of desired mono-, di-, tri- or tetrasubstituted, aliphatic or aromatic, unsymmetrical, or symmetrical thiocarbamides. Recently published synthetic methods extend the palette of possible reactants, and often focus on the modification of conditions: the reaction can be performed in water, with ultrasound-assistance, and even without any solvent and catalyst.
Chiral thioureas have already proven their utility in various stereoselective reactions, mainly as efficient organocatalysts and chiral ligands. As shown by numerous examples, a proper choice of a chiral component present in the structure of thiourea and its configuration can also result in a desired biological activity. This is manifested in a considerable interest in the use of these compounds as pharmaceuticals and in agriculture, and biomedical applications of chiral thioureas should become an important and growing area.


This research was supported by a grant Harmonia, funded by the National Science Centre, Poland (grant number: 2018/30/M/ST5/00401).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.


  1. Schroeder, D.C. Thioureas. Chem. Rev. 1955, 55, 181–228. [Google Scholar] [CrossRef]
  2. Gómez, D.E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. Urea vs. thiourea in anion recognition. Org. Biomol. Chem. 2005, 3, 1495–1500. [Google Scholar] [CrossRef] [PubMed]
  3. Yu, X.; Wang, W. Hydrogen-bond-mediated asymmetric catalysis. Chem. Asian J. 2008, 3, 516–532. [Google Scholar] [CrossRef] [PubMed]
  4. Ruder, F.J.; Guyer, W.; Benson, J.A.; Kayser, H. The thiourea insecticide/acaricide diafenthiuron has a novel mode of action: Inhibition of mitochondrial respiration by its carbodiimide product. Pestic. Biochem. Physiol. 1991, 41, 207–219. [Google Scholar] [CrossRef]
  5. Xiao, S.; Wei, L.; Hong, Z.; Rao, L.; Ren, Y.; Wan, J.; Feng, L. Design, synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors. Bioorg. Med. Chem. 2019, 27, 805–812. [Google Scholar] [CrossRef]
  6. Shakeel, A.; Altaf, A.A.; Qureshi, A.M.; Badshah, A. Thiourea derivatives in drug design and medicinal chemistry: A short review. J. Drug Des. Med. Chem. 2016, 2, 10–20. [Google Scholar] [CrossRef] [Green Version]
  7. Choi, J.; Jee, J.-G. Repositioning of thiourea-containing drugs as tyrosinase inhibitors. Int. J. Mol. Sci. 2015, 16, 28534–28548. [Google Scholar] [CrossRef] [Green Version]
  8. Subramanyam, N.C.; Sheshadri, B.S.; Mayanna, S.M. Thiourea and substituted thioureas as corrosion inhibitors for aluminium in sodium nitrite solution. Corros. Sci. 1993, 34, 563–571. [Google Scholar] [CrossRef]
  9. Edrah, S.; Hasan, S. Studies on thiourea derivatives as corrosion inhibitor for aluminum in sodium hydroxide solution. J. Appl. Sci. Res. 2010, 6, 1045–1049. [Google Scholar]
  10. Loto, R.T.; Loto, C.A.; Popoola, A.P.I. Corrosion inhibition of thiourea and thiadiazole derivatives: A Review. J. Mater. Environ. Sci 2012, 3, 885–894. [Google Scholar]
  11. Fatima, S.; Sharma, R.; Asghar, F.; Kamal, A.; Badshah, A.; Kraatz, H.-B.B. Study of new amphiphiles based on ferrocene containing thioureas as efficient corrosion inhibitors: Gravimetric, electrochemical, SEM and DFT studies. J. Ind. Eng. Chem. 2019, 76, 374–387. [Google Scholar] [CrossRef]
  12. Kotke, M.; Schreiner, P.R. Organocatalysts. In Hydrogen Bonding in Organic Synthesis; Pihko, P.M., Ed.; Wiley-VCH: Hoboken, NJ, USA, 2009; pp. 141–251. [Google Scholar]
  13. Takemoto, Y. Recognition and activation by ureas and thioureas: Stereoselective reactions using ureas and thioureas as hydrogen-bonding donors. Org. Biomol. Chem. 2005, 3, 4299–4306. [Google Scholar] [CrossRef] [PubMed]
  14. Connon, S.J. Asymmetric catalysis with bifunctional Cinchona alkaloid-based urea and thiourea organocatalysts. Chem. Commun. 2008, 2499–2510. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Yuan, W.-K.; Liu, Y.F.; Lan, Z.; Wen, L.-R.; Li, M. Nickle catalysis enables access to thiazolidines from thioureas via oxidative double isocyanide insertion reactions. Org. Lett. 2018, 20, 7158–7162. [Google Scholar] [CrossRef] [PubMed]
  16. Pandey, G.; Bhowmik, S.; Batra, S. Synthesis of 4-substituted imino-4H-benzo[d][1,3] thiazin-2-amines via palladium-catalysed isocyanide insertion in 2-bromophenylthioureas. RSC Adv. 2014, 4, 41433–41436. [Google Scholar] [CrossRef]
  17. Goncalves, I.L.; de Azambuja, G.O.; Kawano, D.F.; Eifler-Lima, V.L. Thioureas as building blocks for the generation of heterocycles and compounds with pharmacological activity: An overview. Mini. Rev. Org. Chem. 2018, 15, 28–35. [Google Scholar] [CrossRef]
  18. Koch, K.R. New chemistry with old ligands: N-alkyl- and N,N-dialkyl-N′-acyl(aroyl)thioureas in co-ordination, analytical and process chemistry of the platinum group metals. Coord. Chem. Rev. 2001, 216–217, 473–488. [Google Scholar] [CrossRef]
  19. Mingji, D.; Liang, B.; Wang, C.; You, Z.; Xiang, J.; Dong, G.; Chen, J.; Yang, Z. A novel thiourea ligand applied in the Pd-catalyzed Heck, Suzuki and Suzuki carbonylative reactions. Adv. Synth. Catal. 2004, 346, 1669–1673. [Google Scholar] [CrossRef]
  20. Li, J.; Shi, L.-L.; Chen, J.; Gong, J.; Yang, Z. Thioureas as ligands in organometallic reactions. Synthesis 2014, 46, 2007–2023. [Google Scholar] [CrossRef]
  21. Saeed, A.; Flörke, U.; Erben, M.F. A review on the chemistry, coordination, structure and biological properties of 1-(acyl/aroyl)-3-(substituted) thioureas. J. Sulfur Chem. 2014, 35, 318–355. [Google Scholar] [CrossRef]
  22. Metlushka, K.E.; Sadkova, D.N.; Shaimardanova, L.N.; Nikitina, K.A.; Ivshin, K.A.; Islamov, D.R.; Kataeva, O.N.; Alfonsov, A.V.; Kataev, V.E.; Voloshina, A.D. First coordination polymers on the bases of chiral thiophosphorylated thioureas. Inorg. Chem. Commun. 2016, 66, 11–14. [Google Scholar] [CrossRef]
  23. Blažek Bregović, V.; Basarić, N.; Mlinarić-Majerski, K. Anion binding with urea and thiourea derivatives. Coord. Chem. Rev. 2015, 295, 80–124. [Google Scholar] [CrossRef]
  24. Nencki, M. Zur Kenntniss des Sulfoharnstoffs. Ber. Dtsch. Chem. Ges. 1873, 6, 598–600. [Google Scholar] [CrossRef] [Green Version]
  25. Brückner, A. Vorläufige Mittheilung. Ber. Dtsch. Chem. Ges. 1873, 6, 1103–1104. [Google Scholar] [CrossRef]
  26. Brown, E.L.; Campbell, N. Studies in qualitative organic analysis. identification of alkyl halides, amines, and acids. J. Chem. Soc. 1937, 1699–1701. [Google Scholar] [CrossRef]
  27. Luskin, L.S.; Gantert, G.E.; Craig, W.E. t-Carbinamines, RR’R″CNH2 IV. The addition of isothiocyanic acid to olefinic compounds. J. Am. Chem. Soc. 1956, 78, 4965–4967. [Google Scholar] [CrossRef]
  28. Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Chiral binaphthyl-derived amine-thiourea organocatalyst-promoted asymmetric Morita−Baylis−Hillman reaction. Org. Lett. 2005, 7, 4293–4296. [Google Scholar] [CrossRef]
  29. Fleming, E.M.; McCabe, T.; Connon, S.J. Novel axially chiral bis-arylthiourea-based organocatalysts for asymmetric Friedel–Crafts type reactions. Tetrahedron Lett. 2006, 47, 7037–7042. [Google Scholar] [CrossRef]
  30. Liu, X.-G.G.; Jiang, J.-J.J.; Shi, M. Development of axially chiral bis(arylthiourea)-based organocatalysts and their application in the enantioselective Henry reaction. Tetrahedron: Asymmetry 2007, 18, 2773–2781. [Google Scholar] [CrossRef]
  31. Schneider, J.F.; Falk, F.C.; Fröhlich, R.; Paradies, J. Planar-chiral thioureas as hydrogen-bond catalysts. Eur. J. Org. Chem. 2010, 2265–2269. [Google Scholar] [CrossRef]
  32. Kitagaki, S.; Ueda, T.; Mukai, C. Planar chiral [2.2]paracyclophane-based bis(thiourea) catalyst: Application to asymmetric Henry reaction. Chem. Commun. 2013, 49, 4030–4032. [Google Scholar] [CrossRef] [PubMed]
  33. Lu, Y.; Ma, Y.; Yang, S.; Ma, M.; Chu, H.; Song, C. Synthesis of planar chiral [2.2]paracyclophane-based amino thioureas and their application in asymmetric aldol reactions of ketones with isatins. Tetrahedron: Asymmetry 2013, 24, 1082–1088. [Google Scholar] [CrossRef]
  34. Didier, D.; Sergeyev, S. Thiourea derivatives of Tröger’s base: Synthesis, enantioseparation and evaluation in organocatalysis of Michael addition to nitroolefins. Arkivoc 2009, 124–134. [Google Scholar] [CrossRef] [Green Version]
  35. Caille, S.; Boni, J.; Cox, G.B.; Faul, M.M.; Franco, P.; Khattabi, S.; Klingensmith, L.M.; Larrow, J.F.; Lee, J.K.; Martinelli, M.J.; et al. Comparison of large-scale routes to manufacture ciral exo -2-norbornyl thiourea. Org. Process Res. Dev. 2010, 14, 133–141. [Google Scholar] [CrossRef]
  36. Ozturk, T.; Ertas, E.; Mert, O. Use of Lawesson’s Reagent in Organic Syntheses. Chem. Rev. 2007, 107, 5210–5278. [Google Scholar] [CrossRef] [PubMed]
  37. Ozturk, T.; Ertas, E.; Mert, O. A Berzelius Reagent, Phosphorus Decasulfide (P4S10), in Organic Syntheses. Chem. Rev. 2010, 110, 3419–3478. [Google Scholar] [CrossRef] [PubMed]
  38. Hodgekins, J.E.; Ettlinger, M.G.; Hodgkins, J.E.; Ettlinger, M.G. The synthesis of isothiocyanates from amines. J. Org. Chem. 1956, 21, 404–405. [Google Scholar] [CrossRef]
  39. Sureshbabu, V.V.; Naik, S.A.; Hemantha, H.P.; Narendra, N.; Das, U.; Guru Row, T.N. N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides. J. Org. Chem. 2009, 74, 5260–5266. [Google Scholar] [CrossRef]
  40. Liu, M.; Ji, N.; Wang, L.; Liu, P.; He, W. d-Mannitol-derived novel chiral thioureas: Synthesis and application in asymmetric Henry reactions. Tetrahedron Lett. 2018, 59, 999–1004. [Google Scholar] [CrossRef]
  41. Frings, M.; Thomé, I.; Bolm, C. Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis. Beilstein J. Org. Chem. 2012, 8, 1443–1451. [Google Scholar] [CrossRef] [Green Version]
  42. Cruz-Hernández, C.; Martínez-Martínez, E.; Hernández-González, P.E.; Juaristi, E. Synthesis of a new N-diaminophosphoryl-N’-[(2S)-2-pyrrolidinylmethyl]thiourea as a chiral organocatalyst for the stereoselective Michael addition of cyclohexanone to nitrostyrenes and chalcones—Application in cascade processes for the synthesis of Polyc. Eur. J. Org. Chem. 2018, 6890–6900. [Google Scholar] [CrossRef]
  43. Kaupp, G.; Schmeyers, J.; Boy, J. Quantitative solid-state reactions of amines with carbonyl compounds and isothiocyanates. Tetrahedron 2000, 56, 6899–6911. [Google Scholar] [CrossRef]
  44. Li, J.-P.P.; Wang, Y.-L.L.; Wang, H.; Luo, Q.-F.F.; Wang, X.-Y.Y. A new and efficient solid state synthesis of diaryl thioureas. Synth. Commun. 2001, 31, 781–785. [Google Scholar] [CrossRef]
  45. Štrukil, V.; Igrc, M.D.; Fábián, L.; Eckert-Maksić, M.; Childs, S.L.; Reid, D.G.; Duer, M.J.; Halasz, I.; Mottillo, C.; Friščić, T. A model for a solvent-free synthetic organic research laboratory: Click-mechanosynthesis and structural characterization of thioureas without bulk solvents. Green Chem. 2012, 14, 2462–2473. [Google Scholar] [CrossRef]
  46. Štrukil, V. Mechanochemical synthesis of thioureas, ureas and guanidines. Beilstein J. Org. Chem. 2017, 13, 1828–1849. [Google Scholar] [CrossRef] [Green Version]
  47. Štrukil, V.; Igrc, M.D.; Eckert-Maksić, M.; Friščić, T. Click mechanochemistry: Quantitative synthesis of “ready to use” chiral organocatalysts by efficient two-fold thiourea coupling to vicinal diamines. Chem. Eur. J. 2012, 18, 8464–8473. [Google Scholar] [CrossRef]
  48. Bhattacharjee, J.; Das, S.; Kottalanka, R.K.; Panda, T.K. Hydroamination of carbodiimides, isocyanates, and isothiocyanates by a bis(phosphinoselenoic amide) supported titanium(IV) complex. Dalton Trans. 2016, 45, 17824–17832. [Google Scholar] [CrossRef]
  49. Arafa, W.A.A.; Ibrahim, H.M. A sustainable strategy for the synthesis of bis-2-iminothiazolidin-4-ones utilizing novel series of asymmetrically substituted bis-thioureas as viable precursors. RSC Adv. 2018, 8, 10516–10521. [Google Scholar] [CrossRef] [Green Version]
  50. Herr, J.R.; Kuhler, J.L.; Meckler, H.; Opalka, C.J. A convenient method for the preparation of primary and symmetrical N,N’-disubstituted thioureas. Synthesis 2000, 1569–1574. [Google Scholar] [CrossRef]
  51. Jiang, X.; Wang, Y.; Zhang, G.; Fu, D.; Zhang, F.; Kai, M.; Wang, R. Enantioselective synthesis of cyclic thioureas via mannich reaction and concise synthesis of highly optically active methylthioimidazolines: Discovery of a more potent antipyretic agent. Adv. Synth. Catal. 2011, 353, 1787–1796. [Google Scholar] [CrossRef]
  52. Azizi, N.; Aryanasab, F.; Saidi, M.R. Straightforward and highly efficient catalyst-free one-pot synthesis of dithiocarbamates under solvent-free conditions. Org. Lett. 2006, 8, 5275–5277. [Google Scholar] [CrossRef] [PubMed]
  53. Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M.R. One-pot synthesis of dithiocarbamates accelerated in water. J. Org. Chem. 2006, 71, 3634–3635. [Google Scholar] [CrossRef] [PubMed]
  54. Ziyaei-Halimjani, A.; Saidi, M.R. Synthesis of β-hydroxy dithiocarbamate derivatives via regioselective addition of dithiocarbamate anion to epoxide in water. Can. J. Chem. 2006, 84, 1515–1519. [Google Scholar] [CrossRef]
  55. Ziyaei Halimehjani, A.; Martens, J.; Schlüter, T. A one-pot three-component synthesis of dithiocarbamates starting from vinyl pyridines and vinyl pyrazine under solvent- and catalyst-free conditions. Tetrahedron 2016, 72, 3958–3965. [Google Scholar] [CrossRef]
  56. Ziyaei Halimehjani, A.; Klepetářová, B.; Beier, P. Synthesis of novel dithiocarbamates and xanthates using dialkyl azodicarboxylates: S–N bond formation. Tetrahedron 2018, 74, 1850–1858. [Google Scholar] [CrossRef]
  57. Li, T.-T.T.; Song, X.-H.H.; Wang, M.-S.S.; Ma, N. Cerium ammonium nitrate-catalyzed aerobic oxidative coupling of dithiocarbamates: Facile synthesis of thioureas and bis(aminothiocarbonyl)disulfides. RSC Adv. 2014, 4, 40054–40060. [Google Scholar] [CrossRef]
  58. Cao, Q.; Liu, F.; Wang, M.; Xu, W.; Zeng, M.-T.; Liu, M.; Li, Y.-S.; Dong, Z.-B. Facile synthesis of substituted arylthioureas in the presence of sodium hydride. J. Chem. Res. 2017, 41, 301–303. [Google Scholar] [CrossRef]
  59. Gan, S.-F.; Wan, J.-P.; Pan, Y.-J.; Sun, C.-R. Highly efficient and catalyst-free synthesis of substituted thioureas in water. Mol. Divers. 2011, 15, 809–815. [Google Scholar] [CrossRef]
  60. Ziyaei Halimehjani, A.; Pourshojaei, Y.; Saidi, M.R. Highly efficient and catalyst-free synthesis of unsymmetrical thioureas under solvent-free conditions. Tetrahedron Lett. 2009, 50, 32–34. [Google Scholar] [CrossRef]
  61. Dirksen, A.; Nieuwenhuizen, P.J.; Hoogenraad, M.; Haasnoot, J.G.; Reedijk, J. New mechanism for the reaction of amines with zinc dithiocarbamates. J. Appl. Polym. Sci. 2001, 79, 1074–1083. [Google Scholar] [CrossRef]
  62. Maddani, M.; Prabhu, K.R. A convenient method for the synthesis of substituted thioureas. Tetrahedron Lett. 2007, 48, 7151–7154. [Google Scholar] [CrossRef]
  63. Üngören, Ş.H.; Sırça, F. Novel self -condensation of ammonium dithiocarbamates leading to symmetrical substituted thioureas. Phosphorus. Sulfur. Silicon Relat. Elem. 2017, 192, 28–33. [Google Scholar] [CrossRef]
  64. Liang, F.; Tan, J.; Piao, C.; Liu, Q. Carbon tetrabromide promoted reaction of amines with carbon disulfide: Facile and efficient synthesis of thioureas and thiuram disulfides. Synthesis 2008, 3579–3584. [Google Scholar] [CrossRef]
  65. Fardpour, M.; Shafie, A.; Bahadorikhalili, S.; Larijani, B.; Mahdavi, M. Utilizing amines and carbon disulfide to obtain nitrogen- and sulfur-containing compounds under green conditions: A review. Curr. Org. Chem. 2018, 22, 2315–2380. [Google Scholar] [CrossRef]
  66. Maddani, M.R.; Prabhu, K.R. A concise synthesis of substituted thiourea derivatives in aqueous medium. J. Org. Chem. 2010, 75, 2327–2332. [Google Scholar] [CrossRef]
  67. Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M. Toward a practical and waste-free synthesis of thioureas in water. Mol. Divers. 2011, 15, 157–161. [Google Scholar] [CrossRef]
  68. Azizi, N.; Rahimzadeh-Oskooee, A.; Yadollahy, Z.; Ourimi, A.G. Ultrasound-assisted rapid sustainable synthesis of substituted thiourea. Monatsh. Chem. 2014, 145, 1675–1680. [Google Scholar] [CrossRef]
  69. Wan, G.-X.; Xu, L.; Ma, X.-S.; Ma, N. Silica gel promoted synthesis of N-sulfonylcyclothioureas in water. Tetrahedron Lett. 2011, 52, 6250–6254. [Google Scholar] [CrossRef]
  70. Jangale, A.D.; Kumavat, P.P.; Wagh, Y.B.; Tayade, Y.A.; Mahulikar, P.P.; Dalal, D.S. Green process development for the synthesis of aliphatic symmetrical N,N′-disubstituted thiourea derivatives in aqueous medium. Synth. Commun. 2015, 45, 236–244. [Google Scholar] [CrossRef]
  71. Milosavljević, M.M.; Vukićević, I.M.; Drmanić, S.Ž.; Nikolić, J.B.; Marinković, A.D.; Krstić, S.S.; Petrović, S.D. Simple one-pot synthesis of thioureas from amines, carbon disulfide and oxidants in water. J. Serb. Chem. Soc 2016, 81, 219–231. [Google Scholar] [CrossRef]
  72. Kumavat, P.P.; Jangale, A.D.; Patil, D.R.; Dalal, K.S.; Meshram, J.S.; Dalal, D.S. Green synthesis of symmetrical N,N’-disubstituted thiourea derivatives in water using solar energy. Environ. Chem. Lett. 2013, 11, 177–182. [Google Scholar] [CrossRef]
  73. Ranu, B.C.; Dey, S.S.; Bag, S. A simple and green procedure for the synthesis of symmetrical N,N’-disubstituted thioureas on the surface of alumina under microwave irradiation. Arkivoc 2003, 14–20. [Google Scholar] [CrossRef] [Green Version]
  74. Chau, C.-M.M.; Chuan, T.-J.J.; Liu, K.-M.M. A highly efficient one-pot method for the synthesis of thioureas and 2-imino-4-thiazolidinones under microwave conditions. RSC Adv. 2014, 4, 1276–1282. [Google Scholar] [CrossRef]
  75. Ziyaei Halimehjani, A.; Farahbakhsh, F. Synthesis of thioureas in ionic liquid medium. J. Sulfur Chem. 2013, 34, 284–288. [Google Scholar] [CrossRef]
  76. Azizi, N.; Farhadi, E. Rapid and highly efficient synthesis of thioureas in biocompatible basic choline hydroxide. J. Sulfur Chem. 2017, 38, 548–554. [Google Scholar] [CrossRef]
  77. Vázquez, J.; Bernès, S.; Reyes, Y.; Moya, M.; Sharma, P.; Alvarez, C.; Gutiérrez, R. Solvent-free synthesis of chiral N,N′-disubstituted thioureas by ‘just mixing’ the reagents. Synthesis 2004, 1955–1958. [Google Scholar] [CrossRef]
  78. Dutta, S.; Mondal, M.; Ghosh, T.; Saha, A. Unprecedented thiocarbamidation of nitroarenes a facile one-pot route to unsymmetrical thioureas. Org. Chem. Front. 2019, 6, 70–74. [Google Scholar] [CrossRef]
  79. Kumar, L.R.; Panduranga, V.; Vishwanatha, T.M.; Shekharappa; Sureshbabu, V.V. Synthesis of thioureido peptidomimetics employing alkyl azides and dithiocarbamates. Org. Biomol. Chem. 2018, 16, 2258–2263. [Google Scholar] [CrossRef]
  80. Sharma, S. Thiophosgene in organic synthesis. Synthesis 1978, 803–820. [Google Scholar] [CrossRef]
  81. Dai, M.; Liang, B.; Wang, C.; Chen, J.; Yang, Z. Synthesis of a novel C2-symmetric thiourea and its application in the Pd-catalyzed cross-coupling reactions with arenediazonium salts under aerobic conditions. Org. Lett. 2004, 6, 221–224. [Google Scholar] [CrossRef]
  82. Gao, Y.; Chang, L.; Shi, H.; Liang, B.; Wongkhan, K.; Chaiyaveij, D.; Batsanov, A.S.; Marder, T.B.; Li, C.; Yang, Z.; et al. A thiourea-oxazoline library with axial chirality: Ligand synthesis and studies of the palladium-catalyzed enantioselective bis(methoxycarbonylation) of terminal olefins. Adv. Synth. Catal. 2010, 352, 1955–1966. [Google Scholar] [CrossRef]
  83. Mohanta, P.K.; Dhar, S.; Samal, S.K.; Ila, H.; Junjappa, H. 1-(Methyldithiocarbonyl)imidazole: A useful thiocarbonyl transfer reagent for synthesis of substituted thioureas. Tetrahedron 2000, 56, 629–637. [Google Scholar] [CrossRef]
  84. Ramadas, K.; Srinivasan, N. A convenient route to substituted thiocarbamides. Synth. Commun. 1995, 25, 3381–3387. [Google Scholar] [CrossRef]
  85. Li, Z.; Liu, D.; Chen, Y.; Yin, Y.; Wang, Z.; Sun, X. Practical synthesis of symmetrical thioureas and heterocyclic thiones in water. J. Chem. Res. 2016, 40, 515–518. [Google Scholar] [CrossRef]
  86. Li, Z.; Chen, Y.; Yin, Y.; Wang, Z.; Sun, X. Convenient synthesis of unsymmetrical N,N′-disubstituted thioureas in water. J. Chem. Res. 2016, 40, 670–673. [Google Scholar] [CrossRef]
  87. da Silva, T.L.; Miolo, L.M.F.; Sousa, F.S.S.; Brod, L.M.P.; Savegnago, L.; Schneider, P.H. New thioureas based on thiazolidines with antioxidant potential. Tetrahedron Lett. 2015, 56, 6674–6680. [Google Scholar] [CrossRef]
  88. Liang, B.; Liu, J.; Gao, Y.X.; Wongkhan, K.; Shu, D.X.; Lan, Y.; Li, A.; Batsanov, A.S.; Howard, J.A.H.; Marder, T.B.; et al. Synthesis of thiourea-oxazolines, a new class of chiral S,N-heterobidentate ligands: Application in Pd-catalyzed asymmetric bis(methoxycarbonylation) of terminal olefins. Organometallics 2007, 26, 4756–4762. [Google Scholar] [CrossRef]
  89. Yin, B.-L.; Liu, Z.-G.; Zhang, J.-C.; Li, Z.-R. N,N-Di-Boc-substituted thiourea as a novel and mild thioacylating agent applicable for the synthesis of thiocarbonyl compounds. Synthesis 2010, 991–999. [Google Scholar] [CrossRef]
  90. Cohrt, A.E.; Nielsen, T.E. Solid-phase synthesis of peptide thioureas and thiazole-containing macrocycles through Ru-catalyzed ring-closing metathesis. ACS Comb. Sci. 2014, 16, 71–77. [Google Scholar] [CrossRef] [Green Version]
  91. Katritzky, A.R.; Ledoux, S.; Witek, R.M.; Nair, S.K. 1-(Alkyl/arylthiocarbamoyl)benzotriazoles as stable isothiocyanate equivalents: Synthesis of di- and trisubstituted thioureas. J. Org. Chem. 2004, 69, 2976–2982. [Google Scholar] [CrossRef]
  92. Kang, I.-J.; Wang, L.-W.; Yeh, T.-K.; Lee, C.-C.; Lee, Y.-C.; Hsu, S.-J.; Wu, Y.-S.; Wang, J.-C.; Chao, Y.-S.; Yueh, A.; et al. Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors. Bioorg. Med. Chem. 2010, 18, 6414–6421. [Google Scholar] [CrossRef] [PubMed]
  93. Katritzky, A.; Kirichenko, N.; Rogovoy, B.; Kister, J.; Tao, H. Synthesis of mono- and N,N-disubstituted thioureas and N-acylthioureas. Synthesis 2004, 1799–1805. [Google Scholar] [CrossRef]
  94. Koketsu, M.; Fukuta, Y.; Ishihara, H. Preparation of N,N-unsubstituted selenoureas and thioureas from cyanamides. Tetrahedron Lett. 2001, 42, 6333–6335. [Google Scholar] [CrossRef]
  95. Tan, W.; Wei, J.; Jiang, X. Thiocarbonyl surrogate via combination of sulfur and chloroform for thiocarbamide and oxazolidinethione construction. Org. Lett. 2017, 19, 2166–2169. [Google Scholar] [CrossRef] [PubMed]
  96. Deng, J.-C.C.; Gao, Y.-C.C.; Zhu, Z.; Xu, L.; Li, Z.-D.D.; Tang, R.-Y.Y. Sulfite-promoted synthesis of N-difluoromethylthioureas via the reaction of azoles with bromodifluoroacetate and elemental sulfur. Org. Lett. 2019, 21, 545–548. [Google Scholar] [CrossRef] [PubMed]
  97. Zhu, T.-H.H.; Xu, X.-P.P.; Cao, J.-J.J.; Wei, T.-Q.Q.; Wang, S.-Y.Y.; Ji, S.-J.J. Cobalt(II)-catalyzed isocyanide insertion reaction with amines under ultrasonic conditions: A divergent synthesis of ureas, thioureas and azaheterocycles. Adv. Synth. Catal. 2014, 356, 509–518. [Google Scholar] [CrossRef]
  98. Nguyen, T.B.; Ermolenko, L.; Al-Mourabit, A. Three-component reaction between isocyanides, aliphatic amines and elemental sulfur: Preparation of thioureas under mild conditions with complete atom economy. Synthesis 2014, 46, 3172–3179. [Google Scholar] [CrossRef]
  99. Angyal, A.; Demjén, A.; Wölfling, J.; Puskás, L.G.; Kanizsai, I. A green, isocyanide-based three-component reaction approach for the synthesis of multisubstituted ureas and thioureas. Tetrahedron Lett. 2018, 59, 54–57. [Google Scholar] [CrossRef]
  100. Singh, K.; Sharma, S. An isocyanide based multi-component reaction under catalyst- and solvent-free conditions for the synthesis of unsymmetrical thioureas. Tetrahedron Lett. 2017, 58, 197–201. [Google Scholar] [CrossRef]
  101. Cui, H.-L.; Chouthaiwale, P.V.; Yin, F.; Tanaka, F. Reaction-based mechanistic investigations of asymmetric hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based three-component catalyst systems. Asian J. Org. Chem. 2016, 5, 153–161. [Google Scholar] [CrossRef] [Green Version]
  102. Serdyuk, O.V.; Heckel, C.M.; Tsogoeva, S.B. Bifunctional primary amine-thioureas in asymmetric organocatalysis. Org. Biomol. Chem. 2013, 11, 7051–7071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Pellissier, H. Asymmetric organocatalysis. Tetrahedron 2007, 63, 9267–9331. [Google Scholar] [CrossRef]
  104. Gruttadauria, M.; Giacalone, F. (Eds.) Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications; John Wiley & Sons: Hoboken, NJ, USA, 2011; ISBN 9781118087992. [Google Scholar]
  105. Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42, 774–793. [Google Scholar] [CrossRef] [PubMed]
  106. Volla, C.M.R.R.; Atodiresei, I.; Rueping, M. Catalytic C–C bond-forming multi-component cascade or domino reactions: Pushing the boundaries of complexity in asymmetric organocatalysis. Chem. Rev. 2014, 114, 2390–2431. [Google Scholar] [CrossRef] [PubMed]
  107. Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Additive effects on asymmetric catalysis. Chem. Rev. 2016, 116, 4006–4123. [Google Scholar] [CrossRef]
  108. Tsogoeva, S.B. Recent advances in asymmetric organocatalytic 1,4-conjugate additions. Eur. J. Org. Chem. 2007, 1701–1716. [Google Scholar] [CrossRef]
  109. Doyle, A.G.; Jacobsen, E.N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 2007, 107, 5713–5743. [Google Scholar] [CrossRef]
  110. Takemoto, Y.; Miyabe, H. The amino thiourea-catalyzed asymmetric nucleophilic reactions. Chimia 2007, 61, 269–275. [Google Scholar] [CrossRef]
  111. Miyabe, H.; Takemoto, Y. Discovery and application of asymmetric reaction by multi-functional thioureas. Bull. Chem. Soc. Jpn. 2008, 81, 785–795. [Google Scholar] [CrossRef] [Green Version]
  112. Takemoto, Y. Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions. Chem. Pharm. Bull. 2010, 58, 593–601. [Google Scholar] [CrossRef] [Green Version]
  113. Sun, Y.L.; Wei, Y.; Shi, M. Applications of chiral thiourea-amine/phosphine organocatalysts in catalytic asymmetric reactions. Chem. Cat. Chem. 2017, 9, 718–727. [Google Scholar] [CrossRef]
  114. Ricci, P.; Khotavivattana, T.; Pfeifer, L.; Médebielle, M.; Morphy, J.R.; Gouverneur, V. The dual role of thiourea in the thiotrifluoromethylation of alkenes. Chem. Sci. 2017, 8, 1195–1199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Ellis, G.P. (Ed.) Chromenes, Chromanones, and Chromones. In Chemistry of Heterocyclic Compounds; John Wiley & Sons: Hoboken, NJ, USA, 1977. [Google Scholar] [CrossRef]
  116. Koufaki, M.; Kiziridi, C.; Alexi, X.; Alexis, M.N. Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids. Bioorg. Med. Chem. 2009, 17, 6432–6441. [Google Scholar] [CrossRef] [PubMed]
  117. Shen, H.C. Asymmetric synthesis of chiral chromans. Tetrahedron 2009, 65, 3931–3952. [Google Scholar] [CrossRef]
  118. Crozier, A.; Jaganath, I.B.; Clifford, M.N. Dietary phenolics: Chemistry, bioavailability and effects on health. Nat. Prod. Rep. 2009, 26, 1001–1043. [Google Scholar] [CrossRef] [PubMed]
  119. Crozier, A.; del Rio, D.; Clifford, M.N. Bioavailability of dietary flavonoids and phenolic compounds. Mol. Aspects Med. 2010, 31, 446–467. [Google Scholar] [CrossRef]
  120. Wang, Y.; Lu, H.; Xu, P.-F. Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules. Acounts Chem. Res. 2015, 48, 1832–1844. [Google Scholar] [CrossRef]
  121. Sonsona, I.; Marqués-López, E.; Herrera, R.P. Enantioselective organocatalyzed synthesis of 2-amino-3-cyano-4H-chromene derivatives. Symmetry 2015, 7, 1519–1535. [Google Scholar] [CrossRef] [Green Version]
  122. Núnez, M.G.; García, P.; Moro, R.F.; Díez, D. Asymmetric organocatalytic synthesis of six-membered oxygenated heterocycles. Tetrahedron 2010, 66, 2089–2109. [Google Scholar] [CrossRef]
  123. Sigman, M.S.; Jacobsen, E.N. Schiff base catalysts for the asymmetric Strecker reaction identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 1998, 120, 4901–4902. [Google Scholar] [CrossRef]
  124. Sigman, M.S.; Vachal, P.; Jacobsen, E.N. A general catalyst for the asymmetric Strecker reaction. Angew. Chem. Int. Ed. 2000, 39, 1279–1281. [Google Scholar] [CrossRef]
  125. Vachal, P.; Jacobsen, E.N. Structure-based analysis and optimization of a highly enantioselective catalyst for the Strecker reaction. J. Am. Chem. Soc. 2002, 124, 10012–10014. [Google Scholar] [CrossRef] [PubMed]
  126. Joly, G.D.; Jacobsen, E.N. Thiourea-catalyzed enantioselective hydrophosphonylation of imines: Practical access to enantiomerically enriched α-amino phosphonic acids. J. Am. Chem. Soc. 2004, 126, 4102–4103. [Google Scholar] [CrossRef] [PubMed]
  127. Peterson, E.A.; Jacobsen, E.N. Enantioselective, thiourea-catalyzed intermolecular addition of indoles to cyclic N-acyl iminium ions. Angew. Chem. Int. Ed. 2009, 48, 6328–6331. [Google Scholar] [CrossRef]
  128. Zuend, S.J.; Coughlin, M.P.; Lalonde, M.P.; Jacobsen, E.N. Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids. Nature 2009, 461, 968–970. [Google Scholar] [CrossRef]
  129. Zuend, S.J.; Jacobsen, E.N. Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: Transition state stabilization via multiple non-covalent interactions. J. Am. Chem. Soc. 2009, 131, 15358–15374. [Google Scholar] [CrossRef] [Green Version]
  130. Pan, S.C.; List, B. The catalytic acylcyanation of imines. Chem. Asian J. 2008, 3, 430–437. [Google Scholar] [CrossRef]
  131. Tsogoeva, S.B.; Yalalov, D.A.; Hateley, M.J.; Weckbecker, C.; Huthmacher, K. Asymmetric organocatalysis with novel chiral thiourea derivatives: Bifunctional catalysts for the Strecker and nitro-Michael reactions. Eur. J. Org. Chem. 2005, 19, 4995–5000. [Google Scholar] [CrossRef]
  132. Lalonde, M.P.; Chen, Y.; Jacobsen, E.N. A chiral primary amine thiourea catalyst for the highly enantioselective direct conjugate addition of α,α-disubstituted aldehydes to nitroalkenes. Angew. Chem. Int. Ed. 2006, 45, 6366–6370. [Google Scholar] [CrossRef]
  133. Taylor, M.S.; Jacobsen, E.N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558–10559. [Google Scholar] [CrossRef]
  134. Brown, A.R.; Uyeda, C.; Brotherton, C.A.; Jacobsen, E.N. Enantioselective thiourea-catalyzed intramolecular Cope-type hydroamination. J. Am. Chem. Soc. 2013, 135, 6747–6749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Bui, T.; Syed, S.; Barbas III, C.F. Thiourea-catalyzed highly enantio- and diastereoselective additions of oxindoles to nitroolefins: Application to the formal synthesis of (+)-physostigmine. J. Am. Chem. Soc. 2009, 131, 8758–8759. [Google Scholar] [CrossRef] [PubMed]
  136. Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672–12673. [Google Scholar] [CrossRef] [PubMed]
  137. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc. 2005, 127, 119–125. [Google Scholar] [CrossRef] [PubMed]
  138. Hoashi, Y.; Okino, T.; Takemoto, Y. Enantioselective Michael addition to α,β-unsaturated imides catalyzed by a bifunctional organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 4032–4035. [Google Scholar] [CrossRef] [PubMed]
  139. Inokuma, T.; Hoashi, Y.; Takemoto, Y. Thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to α,β-unsaturated imides: Dual activation of imide by intra- and intermolecular hydrogen bonding. J. Am. Chem. Soc. 2006, 128, 9413–9419. [Google Scholar] [CrossRef] [PubMed]
  140. Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Enantioselective aza-Henry reaction catalyzed by a bifunctional organocatalyst. Org. Lett. 2004, 6, 625–627. [Google Scholar] [CrossRef]
  141. Sakamoto, S.; Inokuma, T.; Takemoto, Y. Organocatalytic asymmetric Neber reaction for the synthesis of 2H-azirine carboxylic esters. Org. Lett. 2011, 13, 6374–6377. [Google Scholar] [CrossRef]
  142. Sakamoto, S.; Kazumi, N.; Kobayashi, Y.; Tsukano, C.; Takemoto, Y. Asymmetric synthesis of trisubstituted oxazolidinones by the thiourea-catalyzed aldol reaction of 2-isocyanatomalonate diester. Org. Lett. 2014, 16, 4758–4761. [Google Scholar] [CrossRef]
  143. Wang, J.-J.; Lao, J.-H.; Hu, Z.-P.; Lu, R.-J.; Nie, S.-Z.; Du, Q.-S.; Yan, M. Organocatalytic asymmetric conjugate addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-ketoesters. Arkivoc 2010, 229–243. [Google Scholar] [CrossRef] [Green Version]
  144. Zea, A.; Valero, G.; Alba, A.N.R.; Moyano, A.; Rios, R. Bifunctional thiourea-catalyzed asymmetric addition of anthrones to maleimides. Adv. Synth. Catal. 2010, 352, 1102–1106. [Google Scholar] [CrossRef]
  145. Enders, D.; Göddertz, D.P.; Beceño, C.; Raabe, G. Asymmetric synthesis of polyfunctionalized pyrrolidines via a thiourea catalyzed domino Mannich/aza-Michael reaction. Adv. Synth. Catal. 2010, 352, 2863–2868. [Google Scholar] [CrossRef]
  146. Liao, Y.H.; Liu, X.L.; Wu, Z.J.; Du, X.L.; Zhang, X.M.; Yuan, W.C. Thiourea-catalyzed highly diastereo- and enantioselective conjugate additions of α-substituted cyanoacetates to maleimides: Efficient construction of vicinal quaternary-tertiary stereocenters. Adv. Synth. Catal. 2011, 353, 1720–1728. [Google Scholar] [CrossRef]
  147. Ma, C.H.; Kang, T.R.; He, L.; Liu, Q.Z. Highly enantioselective Michael addition of malonates to β-CF3-β-(3-indolyl)nitroalkenes: Construction of trifluoromethylated all-carbon quaternary stereogenic centres. Eur. J. Org. Chem. 2014, 3981–3985. [Google Scholar] [CrossRef]
  148. Monari, M.; Montroni, E.; Nitti, A.; Lombardo, M.; Trombini, C.; Quintavalla, A. Highly Stereoselective [4+2] and [3+2] Spiroannulations of 2-(2-Oxoindolin-3-ylidene)acetic Esters Catalyzed by Bifunctional Thioureas. Chem. Eur. J. 2015, 21, 11038–11049. [Google Scholar] [CrossRef]
  149. Lutete, L.M.; Miyamoto, T.; Ikemoto, T. Tertiary amino thiourea-catalyzed asymmetric cross aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones. Tetrahedron Lett. 2016, 57, 1220–1223. [Google Scholar] [CrossRef]
  150. Yang, J.; Sun, W.; He, Z.; Yu, C.; Bao, G.; Li, Y.; Liu, Y.; Hong, L.; Wang, R. Access to α, γ-diamino diacid derivatives via organocatalytic asymmetric 1,4-addition of azlactones and dehydroalanines. Org. Lett. 2018, 20, 7080–7084. [Google Scholar] [CrossRef]
  151. Orhan, B.; Tschan, M.J.-L.; Wirotius, A.-L.; Dove, A.P.; Coulembier, O.; Taton, D. Isoselective ring-opening polymerization of rac-lactide from chiral Takemoto’s organocatalysts: Elucidation of stereocontrol. ACS Macro Lett. 2018, 7, 1413–1419. [Google Scholar] [CrossRef] [Green Version]
  152. Miyabe, H.; Tuchida, S.; Yamauchi, M.; Takemoto, Y. Reaction of nitroorganic compounds using thiourea catalysts anchored to polymer support. Synthesis 2006, 3295–3300. [Google Scholar] [CrossRef]
  153. Yamaoka, Y.; Miyabe, H.; Takemoto, Y. Catalytic enantioselective Petasis-type reaction of quinolines catalyzed by a newly designed thiourea catalyst. J. Am. Chem. Soc. 2007, 129, 6686–6687. [Google Scholar] [CrossRef]
  154. Azuma, T.; Murata, A.; Kobayashi, Y.; Inokuma, T.; Takemoto, Y. A dual arylboronic acid-aminothiourea catalytic system for the asymmetric intramolecular hetero-Michael reaction of α,β-unsaturated carboxylic acids. Org. Lett. 2014, 16, 4256–4259. [Google Scholar] [CrossRef] [PubMed]
  155. Hayama, N.; Kuramoto, R.; Földes, T.; Nishibayashi, K.; Kobayashi, Y.; Pápai, I.; Takemoto, Y. Mechanistic insight into asymmetric hetero-Michael addition of α,β-unsaturated carboxylic acids catalyzed by multifunctional thioureas. J. Am. Chem. Soc. 2018, 140, 12216–12225. [Google Scholar] [CrossRef] [PubMed]
  156. Li, D.R.; He, A.; Falck, J.R. Enantioselective, organocatalytic reduction of ketones using bifunctional thiourea-amine catalysts. Org. Lett. 2010, 12, 1756–1759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Mao, Z.; Lin, A.; Shi, Y.; Mao, H.; Li, W.; Cheng, Y.; Zhu, C. Chiral tertiary amine thiourea-catalyzed asymmetric inverse-electron-demand Diels-Alder reaction of chromone heterodienes using 3-vinylindoles as dienophiles. J. Org. Chem. 2013, 78, 10233–10239. [Google Scholar] [CrossRef] [PubMed]
  158. Ravi Kumar, G.; Ramesh, B.; Yarlagadda, S.; Sridhar, B.; Reddy, B.V.S. Organocatalytic enantioselective Mannich reaction: Direct access to chiral β-amino esters. ACS Omega 2019, 4, 2168–2177. [Google Scholar] [CrossRef] [Green Version]
  159. Lu, R.J.; Wei, W.T.; Wang, J.J.; Nie, S.Z.; Zhang, X.J.; Yan, M. Organocatalytic conjugate addition of α-nitroacetates to β,γ-unsaturated α-keto esters and subsequent decarboxylation: Synthesis of optically active δ-nitro-α-keto esters. Tetrahedron 2012, 68, 9397–9404. [Google Scholar] [CrossRef]
  160. Zhou, M.-Q.; Zuo, J.; Cui, B.-D.; Zhao, J.-Q.; You, Y.; Bai, M.; Chen, Y.-Z.; Zhang, X.-M.; Yuan, W.-C. Organocatalytic asymmetric double Michael reaction of Nazarov reagents with alkylidene azlactones for the construction of spiro-fused cyclohexanone/5-oxazolone system. Tetrahedron 2014, 70, 5787–5793. [Google Scholar] [CrossRef]
  161. Zhang, Z.; Lippert, K.M.; Hausmann, H.; Kotke, M.; Schreiner, P.R. Cooperative thiourea-Brønsted acid organocatalysis: Enantioselective cyanosilylation of aldehydes with TMSCN. J. Org. Chem. 2011, 76, 9764–9776. [Google Scholar] [CrossRef]
  162. Peng, F.-Z.; Shao, Z.-H.; Fan, B.-M.; Song, H.; Li, G.-P.; Zhang, H.-B. Addition of 2,4-pentandione to nitroalkenes promoted by bifunctional thioureas with central and axial chiral elements. J. Org. Chem. 2008, 73, 5202–5205. [Google Scholar] [CrossRef]
  163. Guo, H.-M.; Li, J.-G.; Qu, G.-R.; Zhang, X.-M.; Yuan, W.-C. Organocatalytic enantioselective Michael addition of malononitrile to nitroolefins catalyzed by bifunctional thiourea. Chirality 2011, 23, 514–518. [Google Scholar] [CrossRef]
  164. Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan, W.; Wang, W. Simple cyclohexanediamine-derived primary amine thiourea catalyzed highly enantioselective conjugate addition of nitroalkanes to enones. Org. Lett. 2009, 11, 2864–2867. [Google Scholar] [CrossRef] [PubMed]
  165. Dudziński, K.; Pakulska, A.M.; Kwiatkowski, P. An efficient organocatalytic method for highly enantioselective Michael addition of malonates to enones catalyzed by readily accessible primary amine-thiourea. Org. Lett. 2012, 14, 4222–4225. [Google Scholar] [CrossRef] [PubMed]
  166. Moritaka, M.; Miyamae, N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Highly efficient asymmetric Michael addition reaction of malonates to α,β-unsaturated ketones promoted by a chiral thiourea/PPY dual-catalyst system. Synlett 2012, 23, 2554–2558. [Google Scholar] [CrossRef]
  167. Miyamae, N.; Watanabe, N.; Moritaka, M.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Asymmetric organocatalytic desymmetrization of 4,4-disubstituted cyclohexadienones at high pressure: A new powerful strategy for the synthesis of highly congested chiral cyclohexenones. Org. Biomol. Chem 2014, 12, 5847–5855. [Google Scholar] [CrossRef] [PubMed]
  168. Zhang, X.; Liu, S.; Lao, J.; Du, G.; Yan, M.; Chan, A.S.C.C. Asymmetric conjugate addition of carbonyl compounds to nitroalkenes catalyzed by chiral bifunctional thioureas. Tetrahedron: Asymmetry 2009, 20, 1451–1458. [Google Scholar] [CrossRef]
  169. Li, B.-L.L.; Wang, Y.-F.F.; Luo, S.-P.P.; Zhong, A.-G.G.; Li, Z.-B.B.; Du, X.-H.H.; Xu, D.-Q.Q. Enantioselective Michael addition of aromatic ketones to nitroolefins catalyzed by bifunctional thioureas and mechanistic insight. Eur. J. Org. Chem. 2010, 656–662. [Google Scholar] [CrossRef]
  170. Retini, M.; Bergonzini, G.; Melchiorre, P. Dioxindole in asymmetric catalytic synthesis: Direct access to 3-substituted 3-hydroxy-2-oxindoles via 1,4-additions to nitroalkenes. Chem. Commun. 2012, 48, 3336–3338. [Google Scholar] [CrossRef]
  171. Guo, X.-T.; Sha, F.; Wu, X.-Y. Highly enantioselective Michael addition of aromatic ketones to nitrodienes and the application to the synthesis of chiral γ-aminobutyric acid. Synthesis 2017, 49, 647–656. [Google Scholar] [CrossRef] [Green Version]
  172. Jiménez, E.I.; Vallejo Narváez, W.E.; Román-Chavarría, C.A.; Vazquez-Chavez, J.; Rocha-Rinza, T.; Hernández-Rodríguez, M. Bifunctional thioureas with α-trifluoromethyl or methyl groups: Comparison of catalytic performance in Michael additions. J. Org. Chem. 2016, 81, 7419–7431. [Google Scholar] [CrossRef]
  173. Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Development of bis-thiourea-type organocatalyst for asymmetric Baylis-Hillman reaction. Tetrahedron Lett. 2004, 45, 5589–5592. [Google Scholar] [CrossRef]
  174. Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.; Nagasawa, K. Thiourea-catalyzed Morita-Baylis-Hillman reaction. Tetrahedron 2008, 64, 9423–9429. [Google Scholar] [CrossRef]
  175. Mayr, F.; Brimioulle, R.; Bach, T. A chiral thiourea as a template for enantioselective intramolecular [2 + 2] photocycloaddition reactions. J. Org. Chem. 2016, 81, 6965–6971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chiral amine-thioureas bearing multiple hydrogen bonding donors: Highly efficient organocatalysts for asymmetric Michael addition of acetylacetone to nitroolefins. Chem. Commun. 2008, 1431–1433. [Google Scholar] [CrossRef] [PubMed]
  177. Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. Highly anti-selective asymmetric nitro-mannich reactions catalyzed by bifunctional amine-thiourea-bearing multiple hydrogen-bonding donors. J. Am. Chem. Soc. 2008, 130, 8606–8607. [Google Scholar] [CrossRef]
  178. Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Highly diastereo- and enantioselective Michael additions of 3-substituted oxindoles to maleimides catalyzed by chiral bifunctional thiourea-tertiary amine. Org. Lett. 2010, 12, 2896–2899. [Google Scholar] [CrossRef]
  179. Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Enantioselective construction of quaternary carbon centre catalysed by bifunctional organocatalyst. Org. Biomol. Chem. 2006, 4, 2097–2099. [Google Scholar] [CrossRef]
  180. Dong, L.-T.; Du, Q.-S.; Lou, C.-L.; Zhang, J.-M.; Lu, R.-J.; Yan, M. Asymmetric synthesis of nitrocyclopropanes catalyzed by chiral primary amines. Synlett 2010, 266–270. [Google Scholar] [CrossRef]
  181. Mei, R.-Q.; Xu, X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X. Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011, 52, 1566–1568. [Google Scholar] [CrossRef]
  182. Kang, J.Y.; Johnston, R.C.; Snyder, K.M.; Cheong, P.H.-Y.; Carter, R.G. Construction of stereogenic α,α-disubstituted cycloalkanones via 1° amine thiourea dual catalysis: Experimental scope and computational analyses. J. Org. Chem. 2016, 81, 3629–3637. [Google Scholar] [CrossRef]
  183. Mei, R.-Q.Q.; Xu, X.-Y.Y.; Peng, L.; Wang, F.; Tian, F.; Wang, L.-X.X. Asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with β-nitroalkenes catalyzed by chiral bifunctional thioureas. Org. Biomol. Chem. 2013, 11, 1286–1289. [Google Scholar] [CrossRef]
  184. Basak, A.K.; Shimada, N.; Bow, W.F.; Vicic, D.A.; Tius, M.A. An asymmetric organocatalytic Nazarov cyclization. J. Am. Chem. Soc. 2010, 132, 8266–8267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Asari, A.H.; Lam, Y.-H.; Tius, M.A.; Houk, K.N. Origins of the stereoselectivity in a thiourea-primary amine-catalyzed Nazarov cyclization. J. Am. Chem. Soc. 2015, 137, 13191–13199. [Google Scholar] [CrossRef] [PubMed]
  186. Berkessel, A.; Roland, K.; Neudörfl, J.M. Asymmetric Morita-Baylis-Hillman reaction catalyzed by isophoronediamine-derived bis(thio)urea organocatalysts. Org. Lett. 2006, 8, 4195–4198. [Google Scholar] [CrossRef] [PubMed]
  187. Flock, A.M.; Krebs, A.; Bolm, C. Ephedrine- and pseudoephedrine-derived thioureas in asymmetric Michael additions of keto esters and diketones to nitroalkenes. Synlett 2010, 1219–1222. [Google Scholar] [CrossRef]
  188. Ren, Q.; Gao, Y.; Wang, J. Enantioselective synthesis of densely functionalized pyranochromenes via an unpredictable cascade Michael-oxa-Michael-tautomerization sequence. Chem. Eur. J. 2010, 16, 13594–13598. [Google Scholar] [CrossRef]
  189. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Pyrrolidine—Thiourea as a bifunctional organocatalyst: Highly enantioselective Michael addition of cyclohexanone to nitroolefins. Org. Lett. 2006, 8, 2901–2904. [Google Scholar] [CrossRef]
  190. Zhi, Y.; Zhao, K.; von Essen, C.; Rissanen, K.; Enders, D. Thiourea-catalyzed domino Michael-Mannich [3+2] cycloadditions: A strategy for the asymmetric synthesis of 3,3′-pyrrolidinyl-dispirooxindoles. Synlett 2017, 28, 2876–2880. [Google Scholar] [CrossRef]
  191. Yan, L.; Wang, H.; Xiong, F.; Tao, Y.; Wu, Y.; Chen, F. Chloramphenicol base chemistry. Part 11: Chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to α,β-unsaturated ketones. Tetrahedron: Asymmetry 2017, 28, 921–929. [Google Scholar] [CrossRef]
  192. Wang, S.-X.; Chen, F.-E. A novel cost-effective thiourea bifunctional organocatalyst for highly enantioselective alcoholysis of meso-cyclic anhydrides: Enhanced enantioselectivity by configuration inversion. Adv. Synth. Catal. 2009, 351, 547–552. [Google Scholar] [CrossRef]
  193. Yan, L.-J.; Wang, H.-F.; Chen, W.-X.; Tao, Y.; Jin, K.-J.; Chen, F.-E. Development of bifunctional thiourea organocatalysts derived from a chloramphenicol base scaffold and their use in the enantioselective alcoholysis of meso cyclic anhydrides. Chem. Cat. Chem. 2016, 8, 2249–2253. [Google Scholar] [CrossRef]
  194. Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Highly enantioselective Michael addition of malonates to nitroolefins catalyzed by chiral bifunctional tertiary amine-thioureas based on saccharides. Synlett 2008, 3242–3246. [Google Scholar] [CrossRef]
  195. Chen, F.-X.; Shao, C.; Liu, Q.; Gong, P.; Liu, C.-L.; Wang, R. Asymmetric Michael addition of trisubstituted carbanion to nitroalkenes catalyzed by sodium demethylquinine salt in water. Chirality 2009, 21, 600–603. [Google Scholar] [CrossRef] [PubMed]
  196. McGarraugh, P.G.; Brenner, S.E. Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition. Tetrahedron 2009, 65, 449–455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Nie, S.-Z.; Hu, Z.-P.; Xuan, Y.-N.; Wang, J.-J.; Li, X.-M.; Yan, M. Organocatalytic asymmetric conjugate addition of malonates to 3-nitro-2H-chromenes. Tetrahedron: Asymmetry 2010, 21, 2055–2059. [Google Scholar] [CrossRef]
  198. Jiang, X.; Wang, R. Recent developments in catalytic asymmetric inverse-electron-demand Diels−Alder reaction. Chem. Rev. 2013, 113, 5515–5546. [Google Scholar] [CrossRef]
  199. Johansson, H.; Jørgensen, T.B.; Gloriam, D.E.; Bräuner-Osborne, H.; Pedersen, D.S. 3-Substituted 2-phenyl-indoles: Privileged structures for medicinal chemistry. RSC Adv. 2013, 3, 945–960. [Google Scholar] [CrossRef]
  200. Guo, H.-C.; Ma, J.-A. Catalytic asymmetric tandem transformations triggered by conjugate additions. Angew. Chem. Int. Ed. 2006, 45, 354–366. [Google Scholar] [CrossRef]
  201. Pellissier, H. Asymmetric domino reactions. Part B: Reactions based on the use of chiral catalysts and biocatalysts. Tetrahedron 2006, 62, 2143–2173. [Google Scholar] [CrossRef]
  202. Alba, A.-N.; Companyo, X.; Viciano, M.; Rios, R. Organocatalytic domino reactions. Curr. Org. Chem. 2009, 13, 1432–1474. [Google Scholar] [CrossRef]
  203. Zu, L.; Zhang, S.; Xie, H.; Wang, W. Catalytic asymmetric oxa-Michael-Michael cascade for facile construction of chiral chromans via an aminal intermediate. Org. Lett. 2009, 11, 1627–1630. [Google Scholar] [CrossRef]
  204. Moyano, A.; Rios, R. Asymmetric organocatalytic cyclization and cycloaddition reactions. Chem. Rev. 2011, 111, 4703–4832. [Google Scholar] [CrossRef] [PubMed]
  205. Chanda, T.; Zhao, J.C.-G. Recent progress in organocatalytic asymmetric domino transformations. Adv. Synth. Catal. 2018, 360, 2–79. [Google Scholar] [CrossRef]
  206. Bella, M.; Gasperi, T. Organocatalytic formation of quaternary stereocenters. Synthesis 2009, 1583–1614. [Google Scholar] [CrossRef]
  207. Kumar, K.; Waldmann, H. Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. 2009, 48, 3224–3242. [Google Scholar] [CrossRef] [PubMed]
  208. Deng, Y.; Chin, Y.-W.; Chai, H.; Keller, W.J.; Kinghorn, A.D. Anthraquinones with quinone reductase-inducing activity and benzophenones from morinda citrifolia (noni) roots. J. Nat. Prod. 2007, 70, 2049–2052. [Google Scholar] [CrossRef] [PubMed]
  209. Singh, G.S.; Desta, Z.Y. Isatins as privileged molecules in design and synthesis of spiro-fused cyclic frameworks. Chem. Rev. 2012, 112, 6104–6155. [Google Scholar] [CrossRef] [PubMed]
  210. Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Recent advances in organocatalytic methods for the synthesis of disubstituted 2- and 3-indolinones. Chem. Soc. Rev. 2012, 41, 7247–7290. [Google Scholar] [CrossRef]
  211. Mao, H.; Lin, A.; Tang, Y.; Shi, Y.; Hu, H.; Cheng, Y.; Zhu, C. Organocatalytic oxa/aza-Michael–Michael cascade strategy for the construction of spiro [chroman/tetrahydroquinoline-3,3′-oxindole] scaffolds. Org. Lett. 2013, 15, 4062–4065. [Google Scholar] [CrossRef]
  212. Hong, B.-C.; Kotame, P.; Lee, G.-H. Asymmetric synthesis of 3,4-dihydrocoumarin motif with an all-carbon quaternary stereocenter via a Michael–acetalization sequence with bifunctional amine-thiourea organocatalysts. Org. Lett. 2011, 13, 5758–5761. [Google Scholar] [CrossRef]
  213. Wang, H.; Luo, J.; Han, X.; Lu, Y. Enantioselective synthesis of chromanones via a tryptophan-derived bifunctional thiourea-catalyzed oxa-Michael-Michael cascade reaction. Adv. Synth. Catal. 2011, 353, 2971–2975. [Google Scholar] [CrossRef]
  214. Yoon, T.P.; Jacobsen, E.N. Privileged chiral catalysts. Science 2003, 299, 1691–1693. [Google Scholar] [CrossRef] [PubMed]
  215. Kacprzak, K.; Gawroński, J. Cinchona alkaloids and their derivatives: Versatile catalysts and ligands in asymmetric synthesis. Synthesis 2001, 961–998. [Google Scholar] [CrossRef]
  216. McCooey, S.H.; Connon, S.J. Urea- and thiourea-substituted Cinchona alkaloid derivatives as highly efficient bifunctional organocatalysts for the asymmetric addition of malonate to nitroalkenes: Inversion of configuration at C9 dramatically improves catalyst performance. Angew. Chem. Int. Ed. 2005, 44, 6367–6370. [Google Scholar] [CrossRef] [PubMed]
  217. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly enantioselective conjugate addition of nitromethane to chalcones using bifunctional Cinchona organocatalysts. Org. Lett. 2005, 7, 1967–1969. [Google Scholar] [CrossRef] [PubMed]
  218. Vakulya, B.; Varga, S.; Soós, T. Epi -Cinchona based thiourea organocatalyst family as an efficient assymmetric Michael addition promoter: Enantioselective conjugate addition of nitroalkanes to chalcones and α,β-unsaturated N-acylpyrroles. J. Org. Chem. 2008, 73, 3475–3480. [Google Scholar] [CrossRef]
  219. Varga, S.; Jakab, G.; Drahos, L.; Holczbauer, T.; Czugler, M.; Soós, T. Double diastereocontrol in bifunctional thiourea organocatalysis: Iterative Michael-Michael-Henry sequence regulated by the configuration of chiral catalysts. Org. Lett. 2011, 13, 5416–5419. [Google Scholar] [CrossRef]
  220. Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J. Enantioselective organocatalytic Michael addition of malonates to α, β-unsaturated ketones. Org. Lett. 2009, 11, 753–756. [Google Scholar] [CrossRef]
  221. Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Organocatalytic asymmetric synthesis of chiral fluorinated quaternary carbon containing β-ketoesters. Chem. Commun. 2009, 2136–2138. [Google Scholar] [CrossRef]
  222. Han, X.; Luo, J.; Liu, C.; Lu, Y. Asymmetric generation of fluorine-containing quaternary carbons adjacent to tertiary stereocenters: Uses of fluorinated methines as nucleophiles. Chem. Commun. 2009, 2044–2046. [Google Scholar] [CrossRef]
  223. Fan, L.-P.; Li, P.; Li, X.-S.; Xu, D.-C.; Ge, M.-M.; Zhu, W.-D.; Xie, J.-W.W. Facile domino access to chiral mono-, bi-, and tricyclic 2,3-dihydrofurans. J. Org. Chem. 2010, 75, 8716–8719. [Google Scholar] [CrossRef]
  224. Pham, T.S.; Balázs, L.; Petneházy, I.; Jászay, Z. Enantioselective Michael addition of diethyl cyanomethylphosphonate to chalcones using bifunctional Cinchona-derived organocatalysts: Synthesis of chiral precursors of α-substituted β-aminophosphonates. Tetrahedron: Asymmetry 2010, 21, 346–351. [Google Scholar] [CrossRef]
  225. Mancheño, O.G.; Tangen, P.; Rohlmann, R.; Fröhlich, R.; Alemán, J. Synthesis of chiral cyclic nitrones by asymmetric addition of β-ketosulfones to nitroalkenes followed by reductive cyclization. Chem. Eur. J. 2011, 17, 984–992. [Google Scholar] [CrossRef] [PubMed]
  226. Liu, Y.-Z.Z.; Cheng, R.-L.L.; Xu, P.-F.F. Asymmetric michael addition of 1-acetylindolin-3-ones to β-nitrostyrenes catalyzed by bifunctional thioureas: A simple access to 2-functionalized indoles. J. Org. Chem. 2011, 76, 2884–2887. [Google Scholar] [CrossRef] [PubMed]
  227. Wang, J.-J.; Hu, Z.-P.; Lou, C.-L.; Liu, J.-L.; Li, X.-M.; Yan, M. Asymmetric synthesis of trifluoromethyl substituted dihydropyrans via organocatalytic cascade Michael-hemiketalization reaction. Tetrahedron 2011, 67, 4578–4583. [Google Scholar] [CrossRef]
  228. Chiarucci, M.; Lombardo, M.; Trombini, C.; Quintavalla, A. Enantioselective conjugate addition of nitroalkanes to alkylidenemalonates promoted by thiourea-based bifunctional organocatalysts. Adv. Synth. Catal. 2012, 354, 364–370. [Google Scholar] [CrossRef]
  229. Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.; Battistini, L.; Zanardi, F.; Casiraghi, G. Bifunctional Cinchona alkaloid/thiourea catalyzes direct and enantioselective vinylogous Michael addition of 3-alkylidene oxindoles to nitroolefins. Angew. Chem. Int. Ed. 2012, 51, 6200–6204. [Google Scholar] [CrossRef]
  230. Guo, Z.-W.; Li, X.-S.; Zhu, W.-D.; Xie, J.-W. Construction of chiral multi-functionalized polyheterocyclic benzopyran derivatives by using an asymmetric organocatalytic domino reaction. Eur. J. Org. Chem. 2012, 6924–6932. [Google Scholar] [CrossRef]
  231. Molleti, N.; Allu, S.; Ray, S.K.; Singh, V.K. Bifunctional chiral urea catalyzed highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to 2-enoylpyridines. Tetrahedron Lett. 2013, 54, 3241–3244. [Google Scholar] [CrossRef]
  232. Kwiatkowski, J.; Lu, Y. Highly enantioselective preparation of fluorinated phosphonates by Michael addition of α-fluoro-β-ketophosphonates to nitroalkenes. Asian J. Org. Chem. 2014, 3, 458–461. [Google Scholar] [CrossRef]
  233. Kwiatkowski, P.; Cholewiak, A.; Kasztelan, A. Efficient and highly enantioselective construction of trifluoromethylated quaternary stereogenic centers via high-pressure mediated organocatalytic conjugate addition of nitromethane to β,β-disubstituted enones. Org. Lett. 2014, 16, 5930–5933. [Google Scholar] [CrossRef]
  234. Konda, S.; Zhao, J.C.-G. High enantioselective Michael addition of malonates to β,γ-unsaturated α-ketoesters catalyzed by bifunctional thioureas. Tetrahedron Lett. 2014, 55, 5216–5218. [Google Scholar] [CrossRef]
  235. Chang, H.-H.; Chu, K.-T.; Chiang, M.-H.; Han, J.-L. Organocatalytic enantioselective Michael reaction of 1,3-dicarbonyls with α-substituted β-nitroacrylates. Tetrahedron 2017, 73, 727–734. [Google Scholar] [CrossRef]
  236. Bhagat, U.K.; Peddinti, R.K. Asymmetric organocatalytic approach to 2,4-disubstituted 1,2,3-triazoles by N2-selective aza-Michael addition. J. Org. Chem. 2018, 83, 793–804. [Google Scholar] [CrossRef]
  237. Reddy, S.N.; Reddy, V.R.; Dinda, S.; Nanubolu, J.B.; Chandra, R. Asymmetric reaction of p-quinone diimide: Organocatalyzed Michael addition of α-cyanoacetates. Org. Lett. 2018, 20, 2572–2575. [Google Scholar] [CrossRef]
  238. Yuan, J.-N.; Liu, H.-X.; Tian, Q.-Q.; Ji, N.; Shen, K.; He, W. Highly enantioselective Michael addition of dithiomalonates to nitroolefins catalyzed by new bifunctional chiral thioureas. Synthesis 2018, 50, 2577–2586. [Google Scholar] [CrossRef] [Green Version]
  239. Wang, Y.-F.; Wu, S.; Karmaker, P.G.; Sohail, M.; Wang, Q.; Chen, F.-X. Enantioselective synthesis of trifluoromethylated tertiary thioethers through organocatalytic sulfa-Michael addition of thiols to β-trifluoromethyl β,β-disubstituted enones. Synthesis 2015, 47, 1147–1153. [Google Scholar] [CrossRef]
  240. Bacsó, A.; Szigeti, M.; Varga, S.; Soós, T. Bifunctional thiourea-catalyzed stereoablative retro-sulfa-Michael reaction: Concise and diastereoselective access to chiral 2,4-diarylthietanes. Synthesis 2017, 49, 429–439. [Google Scholar] [CrossRef] [Green Version]
  241. Konda, S.; Guo, Q.-S.; Abe, M.; Huang, H.; Arman, H.; Zhao, J.C.-G. Organocatalyzed asymmetric aldol reactions of ketones and β,γ-unsaturated α-ketoesters and phenylglyoxal hydrates. J. Org. Chem. 2015, 80, 806–815. [Google Scholar] [CrossRef]
  242. Ji, S.; Alkhalil, A.E.; Su, Y.; Xia, X.; Chong, S.; Wang, K.-H.; Huang, D.; Fu, Y.; Hu, Y. Bifunctional thiourea catalyzed asymmetric Mannich reaction using trifluoromethyl aldimine as trifluoromethyl building blocks. Synlett 2015, 26, 1725–1731. [Google Scholar] [CrossRef]
  243. Liu, Y.-L.; Shi, T.-D.; Zhou, F.; Zhao, X.-L.; Wang, X.; Zhou, J. Organocatalytic asymmetric Strecker reaction of di- and trifluoromethyl ketoimines. Remarkable fluorine effect. Org. Lett. 2011, 13, 3826–3829. [Google Scholar] [CrossRef]
  244. Xie, H.; Song, A.; Song, X.; Zhang, X.; Wang, W. Organocatalytic enantioselective Strecker reaction of cyclic trifluoromethyl-ketoimines. Tetrahedron Lett. 2013, 54, 1409–1411. [Google Scholar] [CrossRef]
  245. Xie, H.; Song, A.; Zhang, X.; Chen, X.; Li, H.; Sheng, C.; Wang, W. Quinine-thiourea catalyzed enantioselective hydrophosphonylation of trifluoromethyl 2(1H)-quinazolinones. Chem. Commun. 2013, 49, 928–930. [Google Scholar] [CrossRef] [PubMed]
  246. Du, F.; Zhou, J.; Peng, Y. Asymmetric reaction of α-diazomethylphosphonates with α-ketoesters to access optically active α-diazo-β-hydroxyphosphonate derivatives. Org. Lett. 2017, 19, 1310–1313. [Google Scholar] [CrossRef] [PubMed]
  247. Amere, M.; Lasne, M.-C.; Rouden, J. Highly enantioselective decarboxylative protonation of α-aminomalonates mediated by thiourea Cinchona alkaloid derivatives: Access to both enantiomers of cyclic and acyclic α-aminoacids. Tetrahedron: Asymmetry 2007, 9, 2621–2624. [Google Scholar] [CrossRef]
  248. Xu, J.; Hu, Y.; Huang, D.; Wang, K.-H.; Xu, C.; Niu, T. Thiourea-catalyzed enantioselective fluorination of β-keto esters. Adv. Synth. Catal. 2012, 354, 515–526. [Google Scholar] [CrossRef]
  249. Hu, X.-Y.; Hu, F.-Z.; Chen, H.; Xu, X.-Y.; Yuan, W.-C.; Zhang, X.-M. Enantioselective α-arylation of cyclic β-ketoamides with a quinone monoimine. ChemistrySelect 2018, 3, 3975–3977. [Google Scholar] [CrossRef]
  250. Marcelli, T.; van Der Haas, R.N.S.; van Maarseveen, J.H.; Hiemstra, H. Asymmetric organocatalytic Henry reaction. Angew. Chem. Int. Ed. 2006, 45, 929–931. [Google Scholar] [CrossRef]
  251. Oh, J.-S.; Lee, J.-W.; Ryu, T.H.; Lee, J.H.; Song, C.E. Self-association free bifunctional thiourea organocatalysts: Synthesis of chiral α-amino acids via dynamic kinetic resolution of racemic azlactones. Org. Biomol. Chem. 2012, 10, 1052–1055. [Google Scholar] [CrossRef]
  252. Dondoni, A.; Massi, A. Asymmetric organocatalysis: From infancy to adolescence. Angew. Chem. Int. Ed. 2008, 47, 4638–4660. [Google Scholar] [CrossRef]
  253. Tárkányi, G.; Király, P.; Varga, S.; Vakulya, B.; Soós, T. Edge-to-face CH/π aromatic interaction and molecular self-recognition in epi-Cinchona-based bifunctional thiourea organocatalysis. Chem. Eur. J. 2008, 14, 6078–6086. [Google Scholar] [CrossRef]
  254. Oh, S.H.; Rho, H.S.; Lee, J.W.; Lee, J.E.; Youk, S.H.; Chin, J.; Song, C.E. A highly reactive and enantioselective bifunctional organocatalyst for the methanolytic desymmetrization of cyclic anhydrides: Prevention of catalyst aggregation. Angew. Chem. Int. Ed. 2008, 47, 7872–7875. [Google Scholar] [CrossRef] [PubMed]
  255. Jia, Z.-X.; Luo, Y.-C.; Cheng, X.-N.; Xu, P.-F.; Gu, Y.-C. Organocatalyzed Michael–Michael cascade reaction: Asymmetric synthesis of polysubstituted chromans. J. Org. Chem. 2013, 78, 6488–6494. [Google Scholar] [CrossRef] [PubMed]
  256. Saha, P.; Biswas, A.; Molleti, N.; Singh, V.K. Enantioselective synthesis of highly substituted chromans via the oxa-Michael–Michael cascade reaction with a bifunctional organocatalyst. J. Org. Chem. 2015, 80, 11115–11122. [Google Scholar] [CrossRef] [PubMed]
  257. Andrés, J.M.; Manzano, R.; Pedrosa, R. Novel bifunctional chiral urea and thiourea derivatives as organocatalysts: Enantioselective nitro-Michael reaction of malonates and diketones. Chem. Eur. J. 2008, 14, 5116–5119. [Google Scholar] [CrossRef]
  258. Chen, X.-K.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.; Cao, W.-G. Highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-keto esters. Adv. Synth. Catal. 2010, 352, 1648–1652. [Google Scholar] [CrossRef]
  259. Cui, H.-F.; Li, P.; Wang, X.-W.; Zhu, S.-Z.; Zhao, G. Asymmetric Michael addition of α-fluoro-α-phenylsulfonyl ketones to nitroolefins catalyzed by phenylalanine-based bifunctional thioureas. J. Fluor. Chem. 2012, 133, 120–126. [Google Scholar] [CrossRef]
  260. Massolo, E.; Benaglia, M.; Orlandi, M.; Rossi, S.; Celentano, G. Enantioselective organocatalytic reduction of β-trifluoromethyl nitroalkenes: An efficient strategy for the synthesis of chiral β-trifluoromethyl amines. Chem. Eur. J. 2015, 21, 3589–3595. [Google Scholar] [CrossRef]
  261. Klausen, R.S.; Jacobsen, E.N. Weak Brønsted acid-thiourea co-catalysis: Enantioselective, catalytic protio-Pictet-Spengler reactions. Org. Lett. 2009, 11, 887–890. [Google Scholar] [CrossRef] [Green Version]
  262. Klausen, R.S.; Kennedy, C.R.; Hyde, A.M.; Jacobsen, E.N. Chiral thioureas promote enantioselective Pictet-Spengler cyclization by stabilizing every intermediate and transition state in the carboxylic acid-catalyzed reaction. J. Am. Chem. Soc. 2017, 139, 12299–12309. [Google Scholar] [CrossRef] [Green Version]
  263. Lee, Y.; Klausen, R.S.; Jacobsen, E.N. Thiourea-catalyzed enantioselective iso-pictet-spengler reactions. Org. Lett. 2011, 13, 5564–5567. [Google Scholar] [CrossRef] [Green Version]
  264. Yeung, C.S.; Ziegler, R.E.; Porco, J.A.; Jacobsen, E.N. Thiourea-catalyzed enantioselective addition of indoles to pyrones: Alkaloid cores with quaternary carbons. J. Am. Chem. Soc. 2014, 136, 13614–13617. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  265. Choudhury, A.R.; Mukherjee, S. Enantioselective dearomatization of isoquinolines by anion-binding catalysis en route to cyclic a-aminophosphonates. Chem. Sci. 2016, 7, 6940–6945. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  266. Yang, G.-J.; Du, W.; Chen, Y.-C. Construction of furan derivatives with a trifluoromethyl stereogenic center: Enantioselective Friedel−Crafts alkylations via formal trienamine catalysis. J. Org. Chem. 2016, 81, 10056–10061. [Google Scholar] [CrossRef] [PubMed]
  267. Manzano, R.; Andrés, J.M.; Muruzábal, M.D.; Pedrosa, R. Stereocontrolled construction of quaternary stereocenters by inter- and intramolecular nitro-michael additions catalyzed by bifunctional thioureas. Adv. Synth. Catal. 2010, 352, 3364–3372. [Google Scholar] [CrossRef]
  268. Manzano, R.; Andrés, J.M.; Álvarez, R.; Muruzábal, M.D.; de Lera, Á.R.; Pedrosa, R. Enantioselective conjugate addition of nitro compounds to α,β-unsaturated ketones: An experimental and computational study. Chem. Eur. J. 2011, 17, 5931–5938. [Google Scholar] [CrossRef] [PubMed]
  269. Andrés, J.M.; Ceballos, M.; Maestro, A.; Sanz, I.; Pedrosa, R. Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions. Beilstein J. Org. Chem. 2016, 12, 628–635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  270. Andrés, J.M.; González, M.; Maestro, A.; Naharro, D.; Pedrosa, R. Recyclable chiral bifunctional thioureas derived from [60]fullerene and their use as highly efficient organocatalysts for the asymmetric Nitro-Michael reaction. Eur. J. Org. Chem. 2017, 2683–2691. [Google Scholar] [CrossRef]
  271. Li, Y.; Yang, Q.; Xu, X.-Y.; Zhou, Y.; Bai, J.; Wang, F.; Wang, L. A highly asymmetric direct aldol reaction catalyzed by chiral proline amide – thiourea bifunctional catalysts. Can. J. Chem. 2011, 89, 1312–1318. [Google Scholar] [CrossRef]
  272. Vargas-Caporali, J.; Cruz-Hernández, C.; Juaristi, E. Synthesis of versatile bifunctional derivatives of chiral diamines obtained through anchimerically assisted nucleophilic substitution reactions on diastereomeric phenylprolinols. Heterocylces 2012, 86, 1275–1300. [Google Scholar] [CrossRef]
  273. Vinayagam, P.; Vishwanath, M.; Kesavan, V. New class of bifunctional thioureas from l-proline: Highly enantioselective Michael addition of 1,3-dicarbonyls to nitroolefins. Tetrahedron: Asymmetry 2014, 25, 568–577. [Google Scholar] [CrossRef]
  274. Hielkema, J.U.; Ticheler, J.; Jörres, M.; Schiffers, I.; Atodiresei, I.; Bolm, C. Asymmetric Michael additions of α-nitrocyclohexanone to aryl nitroalkenes catalyzed by natural amino acid-derived bifunctional thioureas. Org. Lett. 2012, 14, 4518–4521. [Google Scholar] [CrossRef]
  275. Lattanzi, A. Asymmetric Morita-Baylis-Hillman reaction catalyzed by simple amino alcohol derived thioureas. Synlett 2007, 2106–2110. [Google Scholar] [CrossRef]
  276. Wanka, L.; Cabrele, C.; Vanejews, M.; Schreiner, P.R. γ-aminoadamantanecarboxylic acids through direct C-H bond amidations. Eur. J. Org. Chem. 2007, 1474–1490. [Google Scholar] [CrossRef]
  277. Huang, Y.; Zheng, C.; Chai, Z.; Zhao, G. Synthesis of spiro[chroman/tetrahydrothiophene-3,3′-oxindole] scaffolds via heteroatom-Michael-Michael reactions: Easily controlled enantioselectivity via bifunctional catalysts. Adv. Synth. Catal. 2014, 356, 579–583. [Google Scholar] [CrossRef]
  278. Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Organocatalytic domino oxa-Michael/1,6-addition reactions: Asymmetric synthesis of chromans bearing oxindole scaffolds. Angew. Chem. Int. Ed. 2016, 55, 12104–12108. [Google Scholar] [CrossRef]
  279. Wang, L.; Jia, Y.-X.; Zhang, J.-M.; Qian, C.; Chen, X.-Z. Improved synthesis of 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dienone and its derivatives. Monatsh. Chem. 2014, 145, 1941–1945. [Google Scholar] [CrossRef]
  280. Hughes, B.; Howat, D.; Lisle, H.; Holbrook, M.; James, T.; Gozzard, N.; Blease, K.; Hughes, P.; Kingaby, R.; Warrellow, G.; et al. The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4. Br. J. Pharmacol. 1996, 118, 1183–1191. [Google Scholar] [CrossRef] [Green Version]
  281. Rovner, E.S.; Wein, A.J. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: A review. Eur. Urol. 2002, 41, 6–14. [Google Scholar] [CrossRef]
  282. Davidson, S.J.; Barker, D. Synthesis of various lignans via the rearrangements of 1,4-diarylbutane-1,4-diols. Tetrahedron Lett. 2015, 56, 4549–4553. [Google Scholar] [CrossRef]
  283. Jiang, X.; Wu, S.; Wang, J.; Mei, G.; Shi, F. Catalytic Asymmetric [4+2] Cyclization of para-quinone methide derivatives with 3-alkyl-2-vinylindoles. Adv. Synth. Catal. 2018, 360, 4225–4235. [Google Scholar] [CrossRef]
  284. Li, W.; Yuan, H.; Liu, Z.; Zhang, Z.; Cheng, Y.; Li, P. NHC-Catalyzed enantioselective [4 + 3] cycloaddition of ortho-hydroxyphenyl substituted para -quinone methides with isatin-derived enals. Adv. Synth. Catal. 2018, 360, 2460–2464. [Google Scholar] [CrossRef]
  285. Sun, M.; Ma, C.; Zhou, S.-J.; Lou, S.-F.; Xiao, J.; Jiao, Y.; Shi, F. Catalytic asymmetric (4 + 3) cyclizations of in situ generated ortho-quinone methides with 2-indolylmethanols. Angew. Chem. Int. Ed. 2019, 58, 8703–8708. [Google Scholar] [CrossRef] [PubMed]
  286. Wang, Z.-H.; Zhang, X.-Y.; You, Y.; Zhao, J.-Q.; Zhou, M.-Q.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Efficient construction of polycyclic chromans through 4-methylbenzenesulfonic acid mediated domino 1,6-addition/oxa-Mannich reaction of ortho-hydroxyphenyl substituted para-quinone methides and cyclic enamides. Tetrahedron 2019, 75, 3456–3462. [Google Scholar] [CrossRef]
  287. Cheng, Y.-C.; Wang, C.-S.; Li, T.-Z.; Gao, F.; Jiao, Y.; Shi, F. Organocatalytic [4 + 2] cyclizations of para -quinone methide derivatives with isocyanates. Org. Biomol. Chem. 2019, 17, 6662–6670. [Google Scholar] [CrossRef]
  288. Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Highly enantioselective Michael addition of aromatic ketones to nitroolefins promoted by chiral bifunctional primary amine-thiourea catalysts based on saccharides. Org. Lett. 2007, 9, 923–925. [Google Scholar] [CrossRef]
  289. Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.; Ma, J.-A. Chiral bifunctional thiourea-catalyzed enantioselective Michael addition of ketones to nitrodienes. J. Org. Chem. 2010, 75, 1402–1409. [Google Scholar] [CrossRef]
  290. Qiao, B.; Huang, Y.-J.; Nie, J.; Ma, J.-A. Highly regio-, diastereo-, and enantioselective Mannich reaction of allylic ketones and cyclic ketimines: Access to chiral benzosultam. Org. Lett. 2015, 17, 4608–4611. [Google Scholar] [CrossRef]
  291. Liu, Y.-J.; Li, J.-S.; Nie, J.; Ma, J.-A. Organocatalytic asymmetric decarboxylative Mannich reaction of β-keto acids with cyclic α-ketiminophosphonates: Access to quaternary α-aminophosphonates. Org. Lett. 2018, 20, 3643–3646. [Google Scholar] [CrossRef]
  292. Li, F.; Sun, L.; Teng, Y.; Yu, P.; Zhao, J.C.-G.; Ma, J.-A. Highly diastereo- and enantioselective organocatalytic one-pot sequential 1,4-addition/dearomative-fluorination transformation. Chem. Eur. J. 2012, 18, 14255–14260. [Google Scholar] [CrossRef]
  293. Meng, W.-T.; Zheng, Y.; Nie, J.; Xiong, H.-Y.; Ma, J.-A. Organocatalytic asymmetric one-pot sequential conjugate addition/dearomative fluorination: Synthesis of chiral fluorinated isoxazol-5(4H)-ones. J. Org. Chem. 2013, 78, 559–567. [Google Scholar] [CrossRef]
  294. Wang, C.; Zhou, Z.; Tang, C. Novel bifunctional chiral thiourea catalyzed higly enantioselective aza-Henry reaction. Org. Lett. 2008, 10, 1707–1710. [Google Scholar] [CrossRef] [PubMed]
  295. Zheng, W.; Zhang, J.; Liu, S.; Yu, C.; Miao, Z. Asymmetric synthesis of spiro[chroman-3,3′-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael–Michael cascade strategy with bifunctional amine-thiourea organocatalysts. RSC Adv. 2015, 5, 91108–91113. [Google Scholar] [CrossRef]
  296. V. Kouznetsov, V.; R. Merchan Arenas, D.; Arvelo, F.; S. Bello Forero, J.; Sojo, F.; Munoz, A. 4-Hydroxy-3-methoxyphenyl substituted 3-methyl-tetrahydroquinoline derivatives obtained through imino Diels-Alder reactions as potential antitumoral agents. Lett. Drug Des. Discov. 2010, 7, 632–639. [Google Scholar] [CrossRef]
  297. Breschi, M.C.; Calderone, V.; Martelli, A.; Minutolo, F.; Rapposelli, S.; Testai, L.; Tonelli, F.; Balsamo, A. New benzopyran-based openers of the mitochondrial ATP-sensitive potassium channel with potent anti-ischemic properties. J. Med. Chem. 2006, 49, 7600–7602. [Google Scholar] [CrossRef] [PubMed]
  298. Rapposelli, S.; Da Settimo, F.; Digiacomo, M.; La Motta, C.; Lapucci, A.; Sartini, S.; Vanni, M. Synthesis and biological evaluation of 2′-oxo-2,3-dihydro-3′H- spiro[chromene-4,5′-[1,3]oxazolidin]-3′yl]acetic acid derivatives as aldose reductase inhibitors. Arch. Pharm. 2011, 344, 372–385. [Google Scholar] [CrossRef] [PubMed]
  299. Ramachary, D.B.; Madhavachary, R.; Prasad, M.S. Observation of neighboring ortho-hydroxyl group participation in organocatalytic asymmetric sequential Michael-lactonization reactions: Synthesis of highly substituted chiral spirodihydrocoumarins. Org. Biomol. Chem. 2012, 10, 5825–5829. [Google Scholar] [CrossRef] [PubMed]
  300. Shi, Y.-L.; Shi, M. Chiral thiourea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman reaction. Adv. Synth. Catal. 2007, 349, 2129–2135. [Google Scholar] [CrossRef]
  301. Yang, Y.-L.; Pei, C.-K.; Shi, M. Multifunctional chiral phosphines-catalyzed highly diastereoselective and enantioselective substitution of Morita-Baylis-Hillman adducts with oxazolones. Org. Biomol. Chem. 2011, 9, 3349–3358. [Google Scholar] [CrossRef]
  302. Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Chiral phosphinothiourea organocatalyst in the enantioselective Morita-Baylis-Hillman reactions of aromatic aldehydes with methyl vinyl ketone. Tetrahedron Lett. 2008, 49, 6262–6264. [Google Scholar] [CrossRef]
  303. Yuan, K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Chiral phosphinothiourea-catalyzed asymmetric Morita-Baylis-Hillman reactions of acrylates with aromatic aldehydes. Tetrahedron 2009, 65, 8185–8190. [Google Scholar] [CrossRef]
  304. Gong, J.-J.; Yuan, K.; Wu, X.-Y. Valine-derived phosphinothiourea as organocatalyst in enantioselective Morita-Baylis-Hillman reactions of acrylates with aromatic aldehydes. Tetrahedron: Asymmetry 2009, 20, 2117–2120. [Google Scholar] [CrossRef]
  305. Mita, T.; Jacobsen, E. Bifunctional asymmetric catalysis with hydrogen chloride: Enantioselective ring opening of aziridines catalyzed by a phosphinothiourea. Synlett 2009, 1680–1684. [Google Scholar] [CrossRef]
  306. Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Organocatalyzed asymmetric 1,6-conjugate addition of para-quinone methides with dicyanoolefins. Org. Lett. 2016, 18, 428–431. [Google Scholar] [CrossRef] [PubMed]
  307. Su, H.Y.; Taylor, M.S. P-Stereogenic β-aminophosphines: Preparation and applications in enantioselective organocatalysis. J. Org. Chem. 2017, 82, 3173–3182. [Google Scholar] [CrossRef] [PubMed]
  308. Zhang, J.; Zhao, G. Enantioselective Mannich reaction of γ-malonate-substituted α,β-unsaturated esters with N-Boc imines catalyzed by chiral bifunctional thiourea-phosphonium salts. Tetrahedron 2019, 75, 1697–1705. [Google Scholar] [CrossRef]
  309. Zhao, Q.; Li, S.; Huang, K.; Wang, R.; Zhang, X. A novel chiral bisphosphine-thiourea ligand for asymmetric hydrogenation of β,β-disubstituted nitroalkenes. Org. Lett. 2013, 15, 4014–4017. [Google Scholar] [CrossRef]
  310. Zhao, Q.; Wen, J.; Tan, R.; Huang, K.; Metola, P.; Wang, R.; Anslyn, E.V.; Zhang, X. Rhodium-catalyzed asymmetric hydrogenation of unprotected NH imines assisted by a thiourea. Angew. Chem. Int. Ed. 2014, 53, 8467–8470. [Google Scholar] [CrossRef]
  311. Han, Z.; Li, P.; Zhang, Z.; Chen, C.; Wang, Q.; Dong, X.Q.; Zhang, X. Highly enantioselective synthesis of chiral succinimides via Rh/bisphosphine-thiourea-catalyzed asymmetric hydrogenation. ACS Catal. 2016, 6, 6214–6218. [Google Scholar] [CrossRef]
  312. Li, P.; Hu, X.; Dong, X.Q.; Zhang, X. Rhodium/bisphosphine-thiourea-catalyzed enantioselective hydrogenation of α,β-unsaturated N-acylpyrazoles. Chem. Commun. 2016, 52, 11677–11680. [Google Scholar] [CrossRef]
  313. Li, P.; Huang, Y.; Hu, X.; Dong, X.-Q.; Zhang, X. Access to chiral seven-member cyclic amines via Rh-catalyzed asymmetric hydrogenation. Org. Lett. 2017, 19, 3855–3858. [Google Scholar] [CrossRef]
  314. Han, Z.; Wang, R.; Gu, G.; Dong, X.-Q.; Zhang, X. Asymmetric hydrogenation of maleic anhydrides catalyzed by Rh/bisphosphine-thiourea: Efficient construction of chiral succinic anhydrides. Chem. Commun. 2017, 53, 4226–4229. [Google Scholar] [CrossRef] [PubMed]
  315. Huang, Y.; Li, P.; Dong, X.-Q.; Zhang, X. Synthesis of chiral seven-membered β-substituted lactams via Rh-catalyzed asymmetric hydrogenation. Org. Biomol. Chem. 2018, 16, 8819–8823. [Google Scholar] [CrossRef] [PubMed]
  316. Liu, G.; Han, Z.; Dong, X.-Q.; Zhang, X. Rh-catalyzed asymmetric hydrogenation of β-substituted-β-thio-α,β-unsaturated esters: Expeditious access to chiral organic sulfides. Org. Lett. 2018, 20, 5636–5639. [Google Scholar] [CrossRef] [PubMed]
  317. Liu, Y.; Huang, Y.; Yi, Z.; Liu, G.; Dong, X.-Q.; Zhang, X. Enantioselective access to chiral cyclic sulfamidates through iridium-catalyzed asymmetric hydrogenation. Adv. Synth. Catal. 2019, 361, 1582–1586. [Google Scholar] [CrossRef]
  318. Han, Z.; Liu, G.; Wang, R.; Dong, X.-Q.; Zhang, X. Highly efficient Ir-catalyzed asymmetric hydrogenation of benzoxazinones and derivatives with a Brønsted acid cocatalyst. Chem. Sci. 2019, 10, 4328–4333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  319. Dong, X.-Q.; Zhao, Q.; Li, P.; Chen, C.; Zhang, X. Metalorganocatalysis: Cooperating transition metal catalysis and organocatalysis through a covalent bond. Org. Chem. Front. 2015, 2, 1425–1431. [Google Scholar] [CrossRef]
  320. Chen, M.-H.; Chen, Z.; Song, B.-A.; Bhadury, P.S.; Yang, S.; Cai, X.-J.; Hu, D.-Y.; Xue, W.; Zeng, S. Synthesis and antiviral activities of chiral thiourea derivatives containing an α-aminophosphonate moiety. J. Agric. Food Chem. 2009, 57, 1383–1388. [Google Scholar] [CrossRef]
  321. Shi, M.; Liu, X.-G. Asymmetric Morita-Baylis-Hillman reaction of arylaldehydes with 2-cyclohexen-1-one catalyzed by chiral bis(thio)urea and DABCO. Org. Lett. 2008, 10, 1043–1046. [Google Scholar] [CrossRef]
  322. Tan, B.; Candeias, N.R.; Barbas, C.F. Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst. Nat. Chem. 2011, 3, 473–477. [Google Scholar] [CrossRef]
  323. Rampalakos, C.; Wulff, W.D.D. A novel bis-thiourea organocatalyst for the asymmetric aza-Henry reaction. Adv. Synth. Catal. 2008, 350, 1785–1790. [Google Scholar] [CrossRef]
  324. Kang, Y.K.; Yoon, S.J.; Kim, D.Y. Asymmetric Mannich-type reactions of fluorinated ketoesters with binaphthyl-modified thiourea catalysts. Bull. Korean Chem. Soc. 2011, 32, 1195–1200. [Google Scholar] [CrossRef] [Green Version]
  325. Nakayama, Y.; Hidaka, Y.; Ito, K. Asymmetric Henry reactions of aldehydes using chiral biaryl-based bis(thiourea) organocatalysts. Synlett 2013, 24, 883–885. [Google Scholar] [CrossRef]
  326. Otevrel, J.; Bobal, P. Biphenyl-based bis(thiourea) organocatalyst for asymmetric and syn-selective Henry reaction. Synthesis 2017, 49, 593–603. [Google Scholar] [CrossRef] [Green Version]
  327. Otevrel, J.; Bobal, P. Diamine-tethered bis(thiourea) organocatalyst for asymmetric Henry reaction. J. Org. Chem. 2017, 82, 8342–8358. [Google Scholar] [CrossRef]
  328. Otevrel, J.; Svestka, D.; Bobal, P. Bianthryl-based organocatalysts for the asymmetric Henry reaction of fluoroketones. Org. Biomol. Chem. 2019, 17, 5244–5248. [Google Scholar] [CrossRef]
  329. Roussel, C.; Roman, M.; Andreoli, F.; del Rio, A.; Faure, R.; Vanthuyne, N. Non-racemic atropisomeric (thio)ureas as neutral enantioselective anion receptors for amino-acid derivatives: Origin of smaller Kass with thiourea than urea derivatives. Chirality 2006, 18, 762–771. [Google Scholar] [CrossRef]
  330. Vlatković, M.; Bernardi, L.; Otten, E.; Feringa, B.L. Dual stereocontrol over the Henry reaction using a light- and heat-triggered organocatalyst. Chem. Commun. 2014, 50, 7773–7775. [Google Scholar] [CrossRef]
  331. Pizzolato, S.F.; Collins, B.S.L.; van Leeuwen, T.; Feringa, B.L. Bifunctional molecular photoswitches based on overcrowded alkenes for dynamic control of catalytic activity in Michael addition reactions. Chem. Eur. J. 2017, 23, 6174–6184. [Google Scholar] [CrossRef]
  332. Song, C.; Li, L.; Wang, F.; Deng, J.; Yang, W. Novel optically active helical poly(N-propargylthiourea)s: Synthesis, characterization and complexing ability toward Fe(III) ions. Polym. Chem. 2011, 2, 2825–2829. [Google Scholar] [CrossRef]
  333. Zhang, H.; Yang, W.; Deng, J. Optically active helical polymers with pendent thiourea groups: Chiral organocatalyst for asymmetric Michael addition reaction. J. Polym. Sci. Part A Polym. Chem. 2015, 53, 1816–1823. [Google Scholar] [CrossRef]
  334. Mayr, F.; Mohr, L.-M.; Rodriguez, E.; Bach, T. Synthesis of chiral thiourea-thioxanthone hybrids. Synthesis 2017, 49, 5238–5250. [Google Scholar] [CrossRef] [Green Version]
  335. Jiang, X.; Zhang, Y.; Chan, A.S.C.; Wang, R. Highly enantioselective synthesis of γ-nitro heteroaromatic ketones in a doubly stereocontrolled manner catalyzed by bifunctional thiourea catalysts based on dehydroabietic amine: A doubly stereocontrolled approach to pyrrolidine carboxylic acids. Org. Lett. 2009, 11, 153–156. [Google Scholar] [CrossRef] [PubMed]
  336. Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang, J.; Wang, R. Enantio- and diastereoselective asymmetric addition of 1,3-dicarbonyl compounds to nitroalkenes in a doubly stereocontrolled manner catalyzed by bifunctional rosin-derived amine thiourea catalysts. J. Org. Chem. 2009, 74, 5562–5567. [Google Scholar] [CrossRef] [PubMed]
  337. Jiang, X.; Zhang, Y.; Wu, L.; Zhang, G.; Liu, X.; Zhang, H.; Fu, D.; Wang, R. Doubly stereocontrolled asymmetric aza-Henry reaction with in situ generation of N-Boc-imines catalyzed by novel rosin-derived amine thiourea catalysts. Adv. Synth. Catal. 2009, 351, 2096–2100. [Google Scholar] [CrossRef]
  338. Jiang, X.; Fu, D.; Zhang, G.; Cao, Y.; Liu, L.; Song, J.; Wang, R. Highly diastereo- and enantioselective Mannich reaction of lactones with N-Boc-aldimines catalyzed by bifunctional rosin-derived amine thiourea catalysts. Chem. Commun. 2010, 46, 4294–4296. [Google Scholar] [CrossRef]
  339. Jiang, X.; Zhang, G.; Fu, D.; Cao, Y.; Shen, F.; Wang, R. Direct organocatalytic asymmetric aldol reaction of α-isothiocyanato imides to α-ketoesters under low ligand loading: A doubly stereocontrolled approach to cyclic thiocarbamates bearing chiral quaternary stereocenters. Org. Lett. 2010, 12, 1544–1547. [Google Scholar] [CrossRef]
  340. Liu, L.; Zhong, Y.; Zhang, P.; Jiang, X.; Wang, R. Core scaffold-inspired stereoselective synthesis of spiropyrazolones via an organocatalytic Michael/cyclization sequence. J. Org. Chem. 2012, 77, 10228–10234. [Google Scholar] [CrossRef]
  341. Shi, X.M.; Dong, W.P.; Zhu, L.P.; Jiang, X.X.; Wang, R. Asymmetric vinylogous Michael addition/cyclization cascade reaction for the construction of diversely structured spiro-oxindole skeletons. Adv. Synth. Catal. 2013, 355, 3119–3123. [Google Scholar] [CrossRef]
  342. Zhang, G.; Zhang, Y.; Jiang, X.; Yan, W.; Wang, R. Highly enantioslective synthesis of multisubstituted polyfunctional dihydropyrrole via an organocatalytic tandem Michael/cyclization sequence. Org. Lett. 2011, 13, 3806–3809. [Google Scholar] [CrossRef]
  343. Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang, R. One-pot enantioselective synthesis of functionalized pyranocoumarins and 2-amino-4H-chromenes: Discovery of a type of potent antibacterial agent. J. Org. Chem. 2012, 77, 878–888. [Google Scholar] [CrossRef]
  344. Jiang, X.; Wang, L.; Kai, M.; Zhu, L.; Yao, X.; Wang, R. Asymmetric inverse-electron-demand hetero-Diels-Alder reaction for the construction of bicyclic skeletons with multiple stereocenters by using a bifunctional organocatalytic strategy: An efficient approach to chiral macrolides. Chem. Eur. J. 2012, 18, 11465–11473. [Google Scholar] [CrossRef] [PubMed]
  345. Reddy, B.V.S.; Swain, M.; Reddy, S.M.; Yadav, J.S.; Sridhar, B. Asymmetric Michael/hemiketalization of 5-hydroxy-2-methyl-4H-pyran-4-one to β,γ-unsaturated α-ketoesters catalyzed by a bifunctional rosin-indane amine thiourea catalyst. RSC Adv. 2014, 4, 42299–42307. [Google Scholar] [CrossRef]
  346. Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Guanidine-thiourea bifunctional organocatalyst for the asymmetric Henry (nitroaldol) reaction. Adv. Synth. Catal. 2005, 347, 1643–1648. [Google Scholar] [CrossRef]
  347. Herrera, R.P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Catalytic enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes by using a simple thiourea organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 6576–6579. [Google Scholar] [CrossRef] [PubMed]
  348. Nowak, A.E.; Wojaczyńska, E.; Skarewski, J. Enantiopure trans-1-amino-2-(arylsulfanyl)cyclohexanes: Novel chiral motifs for ligands and organocatalysts. Tetrahedron: Asymmetry 2011, 22, 1687–1691. [Google Scholar] [CrossRef]
  349. Krasnovskaya, O.O.; Malinnikov, V.M.; Dashkova, N.S.; Gerasimov, V.M.; Grishina, I.V.; Kireev, I.I.; Lavrushkina, S.V.; Panchenko, P.A.; Zakharko, M.A.; Ignatov, P.A. Thiourea modified doxorubicin: A perspective pH-sensitive prodrug. Bioconjug. Chem. 2019, 30, 741–750. [Google Scholar] [CrossRef] [PubMed]
  350. Ma, Z.-W.; Liu, Y.-X.; Zhang, W.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Highly enantioselective Michael additions of isobutyraldehyde to nitroalkenes promoted by amphiphilic bifunctional primary amine-thioureas in organic or aqueous medium. Eur. J. Org. Chem. 2011, 6747–6754. [Google Scholar] [CrossRef]
  351. Ma, Z.-W.; Liu, Y.-X.; Huo, L.-J.; Gao, X.; Tao, J.-C. Doubly stereocontrolled asymmetric Michael addition of acetylacetone to nitroolefins promoted by an isosteviol-derived bifunctional thiourea. Tetrahedron: Asymmetry 2012, 23, 443–448. [Google Scholar] [CrossRef]
  352. Song, Z.-T.; Zhang, T.; Du, H.-L.; Ma, Z.-W.; Zhang, C.-H.; Tao, J.-C. Highly enantioselective Michael addition promoted by a new diterpene-derived bifunctional thiourea catalyst: A doubly stereocontrolled approach to chiral succinimide derivatives. Chirality 2014, 26, 121–127. [Google Scholar] [CrossRef]
  353. Grošelj, U.; Golobič, A.; Stare, K.; Svete, J.; Stanovnik, B. Synthesis and structural elucidation of novel camphor-derived thioureas. Chirality 2012, 24, 307–317. [Google Scholar] [CrossRef]
  354. Khan, S.A.; Singh, N.; Saleem, K. Synthesis, characterization and in vitro antibacterial activity of thiourea and urea derivatives of steroids. Eur. J. Med. Chem. 2008, 43, 2272–2277. [Google Scholar] [CrossRef] [PubMed]
  355. Ramadas, K.; Suresh, G.; Janarthanan, N.; Masilamani, S. Antifungal activity of 1,3-disubstituted symmetrical and unsymmetrical thioureas. Pestic. Sci. 1998, 52, 145–151. [Google Scholar] [CrossRef]
  356. Cunha, S.; Macedo, F.C.; Costa, G.A.N.; Rodrigues, M.T.; Verde, R.B.V.; de Souza Neta, L.C.; Vencato, I.; Lariucci, C.; Sá, F.P. Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatsh. Chem. 2007, 138, 511–516. [Google Scholar] [CrossRef]
  357. Omar, A.-M.M.E.; Farghaly, A.M.; Hazzai, A.A.B.; Eshba, N.H.; Sharabi, F.M.; Daabees, T.T. Thiourea and thiosemicarbazide derivatives structurally related to hexestrol: Synthesis and anticancer and other pharmacological properties. J. Pharm. Sci. 1981, 70, 1075–1079. [Google Scholar] [CrossRef] [PubMed]
  358. Kafarski, P.; Lejczak, B. Biological activity of aminophosphonic acids. Phosphorus. Sulfur. Silicon Relat. Elem. 1991, 63, 193–215. [Google Scholar] [CrossRef]
  359. Yang, X.; Song, B.; Jin, L.; Wei, X.; Bhadury, S.P.; Li, X.; Yang, S.; Hu, D. Synthesis and antiviral bioactivities of novel chiral bis-thiourea-type derivatives containing α-aminophosphonate moiety. Sci. China Chem. 2011, 54, 103–109. [Google Scholar] [CrossRef]
  360. Liu, J.; Yang, S.; Li, X.; Fan, H.; Bhadury, P.; Xu, W.; Wu, J.; Wang, Z. Synthesis and antiviral bioactivity of chiral thioureas containing leucine and phosphonate moieties. Molecules 2010, 15, 5112–5123. [Google Scholar] [CrossRef]
  361. Yan, Z.; Cai, X.; Yang, X.; Song, B.; Chen, Z.; Bhadury, S.P.; Hu, D.; Jin, L.; Xue, W.; Lu, P. Synthesis and antiviral activities of chiral thiourea derivatives. Chin. J. Chem. 2009, 27, 593–601. [Google Scholar] [CrossRef]
  362. Lewi, P.; Heeres, J.; Ariën, K.; Venkatraj, M.; Joossens, J.; Van der Veken, P.; Augustyns, K.; Vanham, G. Reverse transcriptase inhibitors as microbicides. Curr. HIV Res. 2012, 10, 27–35. [Google Scholar] [CrossRef]
  363. Jones, T.R.; Lee, S.-W.; Johann, S.V.; Razinkov, V.; Visalli, R.J.; Feld, B.; Bloom, J.D.; O’Connell, J. Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule. J. Virol. 2004, 78, 1289–1300. [Google Scholar] [CrossRef] [Green Version]
  364. Struga, M.; Kossakowski, J.; Koziol, A.E.; Kedzierska, E.; Fidecka, S.; La Colla, P.; Ibba, C.; Collu, G.; Sanna, G.; Secci, B.; et al. Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives. Eur. J. Med. Chem. 2009, 44, 4960–4969. [Google Scholar] [CrossRef] [PubMed]
  365. De Clercq, E. Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Farmaco 1999, 54, 26–45. [Google Scholar] [CrossRef]
  366. Robl, J.A.; Sun, C.-Q.; Stevenson, J.; Ryono, D.E.; Simpkins, L.M.; Cimarusti, M.P.; Dejneka, T.; Slusarchyk, W.A.; Chao, S.; Stratton, L.; et al. Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J. Med. Chem. 1997, 40, 1570–1577. [Google Scholar] [CrossRef] [PubMed]
  367. Saha, D.; Jain, G.; Sharma, A. Benzothiazepines: Chemistry of a privileged scaffold. RSC Adv. 2015, 5, 70619–70639. [Google Scholar] [CrossRef]
  368. Venkatachalam, T.K.; Sudbeck, E.A.; Mao, C.; Uckun, F.M. Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2000, 10, 2071–2074. [Google Scholar] [CrossRef]
  369. Venkatachalam, T.K.; Mao, C.; Uckun, F.M. Stereochemistry as a major determinant of the anti-HIV activity of chiral naphthyl thiourea compounds. Antivir. Chem. Chemother. 2001, 12, 213–221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  370. Bell, F.W.; Cantrell, A.S.; Hoegberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kinnick, M.D.; Lind, P.; Morin, J.M. Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J. Med. Chem. 1995, 38, 4929–4936. [Google Scholar] [CrossRef] [PubMed]
  371. Cantrell, A.S.; Engelhardt, P.; Högberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kangasmetsä, J.; Kinnick, M.D.; Lind, P.; Morin, J.M.; et al. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure−activity relationship studies of PETT analogs. J. Med. Chem. 1996, 39, 4261–4274. [Google Scholar] [CrossRef] [PubMed]
  372. Venkatachalam, T.K.; Mao, C.; Uckun, F.M. Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds. Bioorg. Med. Chem. 2004, 12, 4275–4284. [Google Scholar] [CrossRef] [PubMed]
  373. Pingaew, R.; Sinthupoom, N.; Mandi, P.; Prachayasittikul, V.V.; Cherdtrakulkiat, R.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V.V. Synthesis, biological evaluation and in silico study of bis-thiourea derivatives as anticancer, antimalarial and antimicrobial agents. Med. Chem. Res. 2017, 26, 3136–3148. [Google Scholar] [CrossRef]
  374. Rohde, J.M.; Brimacombe, K.R.; Liu, L.; Pacold, M.E.; Yasgar, A.; Cheff, D.M.; Lee, T.D.; Rai, G.; Baljinnyam, B.; Li, Z.; et al. Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors. Bioorg. Med. Chem. 2018, 26, 1727–1739. [Google Scholar] [CrossRef] [PubMed]
  375. Manjula, S.N.; Noolvi, N.M.; Vipan Parihar, K.; Reddy, S.A.M.; Ramani, V.; Gadad, A.K.; Singh, G.; Kutty, N.G.; Rao, C.M. Synthesis and antitumor activity of optically active thiourea and their 2-aminobenzothiazole derivatives: A novel class of anticancer agents. Eur. J. Med. Chem. 2009, 44, 2923–2929. [Google Scholar] [CrossRef] [PubMed]
  376. Dinakaran, V.S.; Jacob, D.; Mathew, J.E.; Seekarajapuram, V.; Divya, D.; Jessy, J.; Mathew, E. Synthesis and biological evaluation of novel pyrimidine-2(1H)-ones/thiones as potent anti-inflammatory and anticancer agents. Med. Chem. Res. 2012, 21, 3598–3606. [Google Scholar] [CrossRef]
  377. Liu, J.-Z.; Song, B.-A.; Fan, H.-T.; Bhadury, P.S.; Wan, W.-T.; Yang, S.; Xu, W.; Wu, J.; Jin, L.-H.; Wei, X.; et al. Synthesis and in vitro study of pseudo-peptide thioureas containing α-aminophosphonate moiety as potential antitumor agents. Eur. J. Med. Chem. 2010, 45, 5108–5112. [Google Scholar] [CrossRef]
  378. Liu, J.; Liao, P.; Hu, J.; Zhu, H.; Wang, Y.; Li, Y.; Li, Y.; He, B. Synthesis and Antitumor Activities of Chiral Dipeptide Thioureas Containing an Alpha-Aminophosphonate Moiety. Molecules 2017, 22, 238–248. [Google Scholar] [CrossRef] [Green Version]
  379. Huang, X.-C.; Wang, M.; Pan, Y.-M.; Yao, G.-Y.; Wang, H.-S.; Tian, X.-Y.; Qin, J.-K.; Zhang, Y. Synthesis and antitumor activities of novel thiourea α-aminophosphonates from dehydroabietic acid. Eur. J. Med. Chem. 2013, 69, 508–520. [Google Scholar] [CrossRef]
  380. Rao, X.; Song, Z.; He, L.; Jia, W. Synthesis, structure analysis and cytotoxicity studies of novel unsymmetrically N,N′-substituted ureas from dehydroabietic acid. Chem. Pharm. Bull. 2008, 56, 1575–1578. [Google Scholar] [CrossRef] [Green Version]
  381. Venkatachalam, T.K.; Vassilev, A.O.; Benyunov, A.; Grigoriants, O.O.; Tibbles, H.E.; Uckun, F.M. Stereochemistry as a determinant of the anti-leukemic potency of halopyridyl and thiazolyl thiourea compounds. Lett. Drug Des. Discov. 2007, 4, 318–326. [Google Scholar] [CrossRef]
  382. Venkatachalam, T.K.; Qazi, S.; Samuel, P.; Uckun, F.M. Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/FcεRI receptor mediated mast cell leukotriene release. Bioorg. Med. Chem. 2003, 11, 1095–1105. [Google Scholar] [CrossRef]
  383. Wasserman, S.I. Mast cell biology. J. Allergy Clin. Immunol. 1990, 86, 590–593. [Google Scholar] [CrossRef]
  384. Bildirici, I.; Cetin, A.; Menges, N.; Alan, Y. Synthesis and SAR studies of pyrazole-3-carboxamides and -3-carbonyl thioureides including chiral moiety: Novel candidates as antibacterial agents. J. Serb. Chem. Soc. 2018, 83, 795–807. [Google Scholar] [CrossRef]
  385. O’Dwyer, P.J.; King, S.A.; Plowman, J.; Grieshaber, C.K.; Hoth, D.F.; Leyland-Jones, B. Pyrazole: Preclinical reassessment. Invest. New Drugs 1988, 6, 305–310. [Google Scholar] [CrossRef] [PubMed]
  386. Saeed, S.; Rashid, N.; Jones, P.G.; Ali, M.; Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem. 2010, 45, 1323–1331. [Google Scholar] [CrossRef] [PubMed]
  387. Singh, L.P.; Tiwari, O.P. Brijog Synthesis and antimicrobial activity of some methyl 4-(1H-benzo[d] imidazol-2-yl) phenyl carbamodithioate amine derivatives. Int. J. Pharm. Sci. Res. 2018, 9, 1194–1200. [Google Scholar] [CrossRef]
  388. Madabhushi, S.; Mallu, K.K.R.; Vangipuram, V.S.; Kurva, S.; Poornachandra, Y.; Kumar, C.G. Synthesis of novel benzimidazole functionalized chiral thioureas and evaluation of their antibacterial and anticancer activities. Bioorg. Med. Chem. Lett. 2014, 24, 4822–4825. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Types of thioureas; (a) monosubstituted; (b) 1,1-disubstituted; (c) 1,3-disubstituted; (d) trisubstituted; (e) tetrasubstituted.
Figure 1. Types of thioureas; (a) monosubstituted; (b) 1,1-disubstituted; (c) 1,3-disubstituted; (d) trisubstituted; (e) tetrasubstituted.
Molecules 25 00401 g001
Scheme 1. Preparation of thioureas from isothiocyanates and amines or ammonia.
Scheme 1. Preparation of thioureas from isothiocyanates and amines or ammonia.
Molecules 25 00401 sch001
Scheme 2. Chiral thiourea organocatalysts prepared from d-mannitol derivative and Cinchona alkaloids [40].
Scheme 2. Chiral thiourea organocatalysts prepared from d-mannitol derivative and Cinchona alkaloids [40].
Molecules 25 00401 sch002
Scheme 3. Mechanochemical synthesis of axially chiral thiourea [47].
Scheme 3. Mechanochemical synthesis of axially chiral thiourea [47].
Molecules 25 00401 sch003
Scheme 4. Preparation of thioureas from diacarbamates and amines.
Scheme 4. Preparation of thioureas from diacarbamates and amines.
Molecules 25 00401 sch004
Scheme 5. Solvent-free synthesis of non-racemic thioureas from dithiocarbamates and amines [60].
Scheme 5. Solvent-free synthesis of non-racemic thioureas from dithiocarbamates and amines [60].
Molecules 25 00401 sch005
Scheme 6. The use of coordinated dithiocarabamate in the preparation of chiral thiourea [62].
Scheme 6. The use of coordinated dithiocarabamate in the preparation of chiral thiourea [62].
Molecules 25 00401 sch006
Scheme 7. Synthesis of symmetrical and unsymmetrical thioureas from carbon disulfide and amines.
Scheme 7. Synthesis of symmetrical and unsymmetrical thioureas from carbon disulfide and amines.
Molecules 25 00401 sch007
Scheme 8. Preparation of thioureas in refluxing water [66].
Scheme 8. Preparation of thioureas in refluxing water [66].
Molecules 25 00401 sch008
Scheme 9. Synthesis of a chiral, racemic thiourea from diamine and CS2 [66].
Scheme 9. Synthesis of a chiral, racemic thiourea from diamine and CS2 [66].
Molecules 25 00401 sch009
Scheme 10. Ultrasound-assisted synthesis of chiral thioureas [68].
Scheme 10. Ultrasound-assisted synthesis of chiral thioureas [68].
Molecules 25 00401 sch010
Scheme 11. Preparation of chiral, symmetrical thioureas from CS2 and amines [77].
Scheme 11. Preparation of chiral, symmetrical thioureas from CS2 and amines [77].
Molecules 25 00401 sch011
Scheme 12. Preparation of thioureas from nitro compounds, carbon disulfide and amines [78].
Scheme 12. Preparation of thioureas from nitro compounds, carbon disulfide and amines [78].
Molecules 25 00401 sch012
Scheme 13. A racemic thiourea prepared by Dutta et al [78].
Scheme 13. A racemic thiourea prepared by Dutta et al [78].
Molecules 25 00401 sch013
Scheme 14. Azides in the syntheisis of thioureas [79].
Scheme 14. Azides in the syntheisis of thioureas [79].
Molecules 25 00401 sch014
Scheme 15. The use of thiophosgene in the preparation of a chiral cyclic thiourea [81].
Scheme 15. The use of thiophosgene in the preparation of a chiral cyclic thiourea [81].
Molecules 25 00401 sch015
Scheme 16. Thiuram disulfide as a reactant in preparation of thioureas [84].
Scheme 16. Thiuram disulfide as a reactant in preparation of thioureas [84].
Molecules 25 00401 sch016
Scheme 17. Synthesis of symmetrical thioureas from phenyl chlorothionoformate and amine [85].
Scheme 17. Synthesis of symmetrical thioureas from phenyl chlorothionoformate and amine [85].
Molecules 25 00401 sch017
Scheme 18. Two-step approach to unsymmetrical thioureas from phenyl chlorothionoformate [86].
Scheme 18. Two-step approach to unsymmetrical thioureas from phenyl chlorothionoformate [86].
Molecules 25 00401 sch018
Scheme 19. Reaction of monosubstituted thiourea with a chiral carboxylic acid as a route to a chiral thiourea [87].
Scheme 19. Reaction of monosubstituted thiourea with a chiral carboxylic acid as a route to a chiral thiourea [87].
Molecules 25 00401 sch019
Scheme 20. Conversion of bis-Boc thiourea into other thioureas.[89]
Scheme 20. Conversion of bis-Boc thiourea into other thioureas.[89]
Molecules 25 00401 sch020
Scheme 21. Benzotriazole derivative in the synthesis of appropriately substituted thioureas [91].
Scheme 21. Benzotriazole derivative in the synthesis of appropriately substituted thioureas [91].
Molecules 25 00401 sch021
Scheme 22. Preparation of chiral thioureas from 1,3-bis-benzotriazole-substituted derivative [91].
Scheme 22. Preparation of chiral thioureas from 1,3-bis-benzotriazole-substituted derivative [91].
Molecules 25 00401 sch022
Figure 2. Bis-imidazole thiourea used in the synthesis of other derivatives [92].
Figure 2. Bis-imidazole thiourea used in the synthesis of other derivatives [92].
Molecules 25 00401 g002
Scheme 23. Utilization of hydrogen sulfide in the synthesis of thioureas [93].
Scheme 23. Utilization of hydrogen sulfide in the synthesis of thioureas [93].
Molecules 25 00401 sch023
Scheme 24. Cyanamide as a starting point for the preparation of thioureas [94].
Scheme 24. Cyanamide as a starting point for the preparation of thioureas [94].
Molecules 25 00401 sch024
Scheme 25. Reaction of amines with sulfur and chloroform as a route to thioureas [95].
Scheme 25. Reaction of amines with sulfur and chloroform as a route to thioureas [95].
Molecules 25 00401 sch025
Figure 3. Ketoconazole thiourea derivative prepared by Tang and co-workers [96].
Figure 3. Ketoconazole thiourea derivative prepared by Tang and co-workers [96].
Molecules 25 00401 g003
Scheme 26. Preparation of thioureas from isocyanides, amines and elementary sulfur [98].
Scheme 26. Preparation of thioureas from isocyanides, amines and elementary sulfur [98].
Molecules 25 00401 sch026
Scheme 27. Synthesis of thioureas from amines, isocyanides, and sodium sulfide [99].
Scheme 27. Synthesis of thioureas from amines, isocyanides, and sodium sulfide [99].
Molecules 25 00401 sch027
Scheme 28. Preparation of thioureas from isocyanides, amines and disulfide [100].
Scheme 28. Preparation of thioureas from isocyanides, amines and disulfide [100].
Molecules 25 00401 sch028
Figure 4. General structures of chroman and flavonoid scaffolds.
Figure 4. General structures of chroman and flavonoid scaffolds.
Molecules 25 00401 g004
Figure 5. Jacobsen’s thioureas derived from 1,2-diaminocyclohexane [123,124,125].
Figure 5. Jacobsen’s thioureas derived from 1,2-diaminocyclohexane [123,124,125].
Molecules 25 00401 g005
Figure 6. Modified Jacobsen’s organocatalysts.[132,133,134]
Figure 6. Modified Jacobsen’s organocatalysts.[132,133,134]
Molecules 25 00401 g006
Figure 7. Takemoto’s thiourea organocatalyst [110,111,112].
Figure 7. Takemoto’s thiourea organocatalyst [110,111,112].
Molecules 25 00401 g007
Figure 8. Various chiral DACH-based thioureas used as organocatalysts [153,154,155,156,157,158,159,160,161,162,163].
Figure 8. Various chiral DACH-based thioureas used as organocatalysts [153,154,155,156,157,158,159,160,161,162,163].
Molecules 25 00401 g008
Figure 9. DACH-based thioureas bearing primary amine function [164,165,166,167,168,169,170,171].
Figure 9. DACH-based thioureas bearing primary amine function [164,165,166,167,168,169,170,171].
Molecules 25 00401 g009
Figure 10. Thiourea derivative with three stereogenic centers [172].
Figure 10. Thiourea derivative with three stereogenic centers [172].
Molecules 25 00401 g010
Figure 11. A chiral bis-thiourea prepared by Nagasawa and co-workers [173].
Figure 11. A chiral bis-thiourea prepared by Nagasawa and co-workers [173].
Molecules 25 00401 g011
Figure 12. Chiral thioureas based on 1,2-diphenylethylenediamine [176,177,178,179,180,181,182,183].
Figure 12. Chiral thioureas based on 1,2-diphenylethylenediamine [176,177,178,179,180,181,182,183].
Molecules 25 00401 g012
Figure 13. Chiral thioureas preparaed by the groups of Tius (left) [184,185] and Berkessel (right) [186].
Figure 13. Chiral thioureas preparaed by the groups of Tius (left) [184,185] and Berkessel (right) [186].
Molecules 25 00401 g013
Figure 14. Chiral thioureas based on various diamines [187,188,189,190,191,192,193].
Figure 14. Chiral thioureas based on various diamines [187,188,189,190,191,192,193].
Molecules 25 00401 g014
Scheme 29. Asymmetric Michael addition and a proposed mechanism of formation of nitrochroman [197].
Scheme 29. Asymmetric Michael addition and a proposed mechanism of formation of nitrochroman [197].
Molecules 25 00401 sch029
Scheme 30. Asymmetric DA reaction and proposed interactions in a transition state [157].
Scheme 30. Asymmetric DA reaction and proposed interactions in a transition state [157].
Molecules 25 00401 sch030
Scheme 31. Asymmetric Michael-acetylation-cascade reaction and proposed reaction mechanism of spiro-center formation [212].
Scheme 31. Asymmetric Michael-acetylation-cascade reaction and proposed reaction mechanism of spiro-center formation [212].
Molecules 25 00401 sch031aMolecules 25 00401 sch031b
Scheme 32. Formation of all-carbon quarternary centers catalyzed by a chiral thiourea and its postulated interactions with the reactant [213].
Scheme 32. Formation of all-carbon quarternary centers catalyzed by a chiral thiourea and its postulated interactions with the reactant [213].
Molecules 25 00401 sch032
Figure 15. Thioureas derived from Cinchona alkaloids [216,217,250].
Figure 15. Thioureas derived from Cinchona alkaloids [216,217,250].
Molecules 25 00401 g015
Figure 16. Bis-alkaloid thioureas prepared by Song’ group [251].
Figure 16. Bis-alkaloid thioureas prepared by Song’ group [251].
Molecules 25 00401 g016
Scheme 33. Asymmetric double Michael reaction catalyzed by Cinchona alkaloid-derived thiourea and a proposed reaction mechanism [255].
Scheme 33. Asymmetric double Michael reaction catalyzed by Cinchona alkaloid-derived thiourea and a proposed reaction mechanism [255].
Molecules 25 00401 sch033aMolecules 25 00401 sch033b
Scheme 34. Synthesis of chiral chroman derivatives catalyzed by a thiourea obtained from Cinchona alkaloid [256].
Scheme 34. Synthesis of chiral chroman derivatives catalyzed by a thiourea obtained from Cinchona alkaloid [256].
Molecules 25 00401 sch034
Figure 17. Examples of chiral thioureas derived from amino acids [263,264,265,266,267,268,269].
Figure 17. Examples of chiral thioureas derived from amino acids [263,264,265,266,267,268,269].
Molecules 25 00401 g017
Figure 18. Chiral thioureas obtained from l-proline [271,272,273].
Figure 18. Chiral thioureas obtained from l-proline [271,272,273].
Molecules 25 00401 g018
Figure 19. An example of chiral thiourea prepared in Bolm’s group [274].
Figure 19. An example of chiral thiourea prepared in Bolm’s group [274].
Molecules 25 00401 g019
Figure 20. A peptide-like chiral thiourea [276].
Figure 20. A peptide-like chiral thiourea [276].
Molecules 25 00401 g020
Scheme 35. Asymmetric tandem Michael–Michael reaction reported by Zhao et al. and its proposed mechanism [277].
Scheme 35. Asymmetric tandem Michael–Michael reaction reported by Zhao et al. and its proposed mechanism [277].
Molecules 25 00401 sch035
Scheme 36. Asymmetric domino oxa-Michael-1,6-addition and the proposed interactions in the transient state [278].
Scheme 36. Asymmetric domino oxa-Michael-1,6-addition and the proposed interactions in the transient state [278].
Molecules 25 00401 sch036
Figure 21. Carbohydrate-derived chiral thiourea [288].
Figure 21. Carbohydrate-derived chiral thiourea [288].
Molecules 25 00401 g021
Scheme 37. Asymmetric synthesis of various spiro-compounds with mechanism proposed [295].
Scheme 37. Asymmetric synthesis of various spiro-compounds with mechanism proposed [295].
Molecules 25 00401 sch037
Figure 22. Axially chiral phosphine-containing thiourea [300].
Figure 22. Axially chiral phosphine-containing thiourea [300].
Molecules 25 00401 g022
Figure 23. Chiral thioureas with diphenylphosphine moiety [302,303].
Figure 23. Chiral thioureas with diphenylphosphine moiety [302,303].
Molecules 25 00401 g023
Figure 24. Examples of chiral thioureas bearing phosphine functionalities[305,307] and a phosphonium salt [308].
Figure 24. Examples of chiral thioureas bearing phosphine functionalities[305,307] and a phosphonium salt [308].
Molecules 25 00401 g024
Figure 25. ZhaoPhos, a chiral bis-phosphine thiourea organocatalyst [309,310].
Figure 25. ZhaoPhos, a chiral bis-phosphine thiourea organocatalyst [309,310].
Molecules 25 00401 g025
Scheme 38. Asymmetric reaction of para-quinone methides catalyzed by chiral phosphine thiourea catalysts and a proposed transient state [306].
Scheme 38. Asymmetric reaction of para-quinone methides catalyzed by chiral phosphine thiourea catalysts and a proposed transient state [306].
Molecules 25 00401 sch038
Figure 26. Examples of thioureas and bis-thioureas with axial chirality [28,29,323,324,325,326,327,328].
Figure 26. Examples of thioureas and bis-thioureas with axial chirality [28,29,323,324,325,326,327,328].
Molecules 25 00401 g026
Figure 27. Thioureas with axial chirality resulting from a restricted rotation [82,329].
Figure 27. Thioureas with axial chirality resulting from a restricted rotation [82,329].
Molecules 25 00401 g027
Figure 28. Molecular motors bearing thiourea moiety [330,331].
Figure 28. Molecular motors bearing thiourea moiety [330,331].
Molecules 25 00401 g028
Figure 29. Examples of thioureas with planar chirality [31,32,33].
Figure 29. Examples of thioureas with planar chirality [31,32,33].
Molecules 25 00401 g029
Figure 30. Chiral thioureas bearing thioxanthone fragment [334].
Figure 30. Chiral thioureas bearing thioxanthone fragment [334].
Molecules 25 00401 g030
Figure 31. Rosin-derived thiourea [51].
Figure 31. Rosin-derived thiourea [51].
Molecules 25 00401 g031
Figure 32. Chiral thioureas with guanidine moiety [346] and indanol derivative [347].
Figure 32. Chiral thioureas with guanidine moiety [346] and indanol derivative [347].
Molecules 25 00401 g032
Figure 33. Chiral thioureas substituted with thioether groups [348] and sulfoximine [41].
Figure 33. Chiral thioureas substituted with thioether groups [348] and sulfoximine [41].
Molecules 25 00401 g033
Figure 34. Ningnanmycin (left) and the most active bis-thiourea derivatives bearing α-aminophosphonate functional group [320,359].
Figure 34. Ningnanmycin (left) and the most active bis-thiourea derivatives bearing α-aminophosphonate functional group [320,359].
Molecules 25 00401 g034
Figure 35. The most active fluorinated thiourea derivatives containing α-aminophosphonate moiety based on leucine [361].
Figure 35. The most active fluorinated thiourea derivatives containing α-aminophosphonate moiety based on leucine [361].
Molecules 25 00401 g035
Figure 36. A set of new chiral thioureas (left) prepared by Yan et al.and the most active indane derivative (right) tested against TMV [361].
Figure 36. A set of new chiral thioureas (left) prepared by Yan et al.and the most active indane derivative (right) tested against TMV [361].
Molecules 25 00401 g036
Figure 37. 1,3-Thiazepine isothiourea derivatives [364].
Figure 37. 1,3-Thiazepine isothiourea derivatives [364].
Molecules 25 00401 g037
Figure 38. A series of chiral naphthyl thioureas tested as anti-HIV agents [368,369].
Figure 38. A series of chiral naphthyl thioureas tested as anti-HIV agents [368,369].
Molecules 25 00401 g038
Figure 39. Chiral thioureas studied by Vankatachalam and co-workers as antiviral agents [372].
Figure 39. Chiral thioureas studied by Vankatachalam and co-workers as antiviral agents [372].
Molecules 25 00401 g039
Figure 40. Potential lead compounds displaying antiproliferative activity in vitro [376,377,378].
Figure 40. Potential lead compounds displaying antiproliferative activity in vitro [376,377,378].
Molecules 25 00401 g040
Figure 41. Dehydroabietic acid and its most active thiourea derivative [379].
Figure 41. Dehydroabietic acid and its most active thiourea derivative [379].
Molecules 25 00401 g041
Figure 42. A new set of chiral halopyridyl and thiazolyl thioureas studied as antiproliferative agents [381].
Figure 42. A new set of chiral halopyridyl and thiazolyl thioureas studied as antiproliferative agents [381].
Molecules 25 00401 g042
Figure 43. Chiral naphthyl-substituted thioureas as potential anti-allergic agents [383].
Figure 43. Chiral naphthyl-substituted thioureas as potential anti-allergic agents [383].
Molecules 25 00401 g043
Figure 44. Novel chiral pyrazole-based thioureas exhibiting antibacterial activity [383].
Figure 44. Novel chiral pyrazole-based thioureas exhibiting antibacterial activity [383].
Molecules 25 00401 g044
Figure 45. Novel chiral thioureas bearing benzimidazole fragment studied by Madabhushi et al. [388].
Figure 45. Novel chiral thioureas bearing benzimidazole fragment studied by Madabhushi et al. [388].
Molecules 25 00401 g045
Figure 46. Structures of thiophosphorylated thioureas and their Ni(II) complexes forming coordination polymers studied for their antimicrobial activity [22].
Figure 46. Structures of thiophosphorylated thioureas and their Ni(II) complexes forming coordination polymers studied for their antimicrobial activity [22].
Molecules 25 00401 g046

Share and Cite

MDPI and ACS Style

Steppeler, F.; Iwan, D.; Wojaczyńska, E.; Wojaczyński, J. Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry. Molecules 2020, 25, 401.

AMA Style

Steppeler F, Iwan D, Wojaczyńska E, Wojaczyński J. Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry. Molecules. 2020; 25(2):401.

Chicago/Turabian Style

Steppeler, Franz, Dominika Iwan, Elżbieta Wojaczyńska, and Jacek Wojaczyński. 2020. "Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry" Molecules 25, no. 2: 401.

Article Metrics

Back to TopTop