Recent Advances in Selected Asymmetric Reactions Promoted by Chiral Catalysts: Cyclopropanations, Friedel–Crafts, Mannich, Michael and Other Zinc-Mediated Processes—An Update

: The main purpose of this review article is to present selected asymmetric synthesis reactions in which chemical and stereochemical outcomes are dependent on the use of an appropriate chiral catalyst. Optically pure or enantiomerically enriched products of such transformations may ﬁnd further applications in various ﬁelds. Among an extremely wide variety of asymmetric reactions catalyzed by chiral systems, we are interested in: asymmetric cyclopropanation, Friedel–Crafts reaction, Mannich and Michael reaction, and other stereoselective processes conducted in the presence of zinc ions. This paper describes the achievements of the above-mentioned asymmetric transformations in the last three years. The choice of reactions is related to the research that has been carried out in our laboratory for many years.


Introduction
The synthesis of optically pure or enantiomerically enriched compounds has become one of the most important areas of interest in recent decades in modern synthetic organic chemistry [1].Substances of high optical purity are still used in many industrial sectors, including the pharmaceutical and food industries.Chemists working in both academia and industry must agree with the fact that single chirality plays a huge role in nature and that biological properties are closely related to the absolute configuration of the product [2].The opposite enantiomers act differently on living organisms and may exhibit different activities.Some of the differences are huge, ranging from different tastes and smells to even teratogenic (fetal-damaging) effects [3].Between 1958 and 1962, thalidomideracemic sedative drug, taken by pregnant women, damaged more than 10,000 fetuses worldwide [4].This drastic example seems to be sufficient proof that the synthesis of optically pure substances used especially in the pharmaceutical and food industries is still gaining more and more importance.
There are three main strategies for the synthesis of enantiomerically pure substances: the first one is a methodology based on the use of naturally occurring substances with defined absolute configuration, the second resolution of racemic mixtures (kinetic resolution and deracemization techniques) [5], and finally, asymmetric synthesis in which one or more chiral centers are generated in the substrate.The subject of this review article is closely related to the last methodology, i.e., asymmetric synthesis.There are several approaches used in asymmetric synthesis; however, we focused on the use of chiral catalysts.The large number of asymmetric reactions studied and the dynamically developing synthesis of new chiral catalysts made the preparation of this review article quite difficult.However, we have used the knowledge derived from the research conducted in our laboratory.Thanks to our previous experience with asymmetric cyclopropanation reactions [6], Friedel-Crafts alkylation [7], Mannich [8,9] and Michael [10] reactions, and other asymmetric transformations performed in the presence of zinc ions [11], we decided to describe recent achievements in the field of these asymmetric transformations.

Asymmetric Cyclopropanation Reactions
Asymmetric cyclopropanation is currently one of the most used methods for creating new C-C bonds, as a cyclopropane ring having a unique steric and electronic properties is a structural motif present in many biologically active molecules, e.g., Cabozantinib, Simeprevir, Lumacaftor, etc. [12].Some synthetic approaches with or without transition metals to achieve cyclopropyl ring have been reviewed in 2018 [13].Moreover, some examples illustrating relationships between pharmacological activity and structure of various cyclopropyl derivatives have also been reported in 2018 [14].
Dictyopterenes are chemical compounds occurring in marine and freshwater environments and being sexual attractants or pheromones [15].The asymmetric synthesis of Dictyopterene C' 5 and its derivatives was performed using asymmetric cyclopropanation as one of the steps.α,β-Unsaturated aldehydes 1 and α-substituted α-diazoesters 2 took part in the reaction promoted by a chiral oxazaborolidinium ion catalyst (COBI) 3 (Scheme 1) [16].Further transformations of cyclopropyl derivatives of type 4 including Julia-Kocienski reaction and Sonogashira and Suzuki coupling led to the corresponding dictyopterenes 5 [16].Asymmetric Simmons-Smith cyclopropanation using diiodomethane and diethylzinc was applied in multi-step synthesis of the core of solanoeclepin A 7 (Scheme 2) which is a hatching agent of potato cyst nematodes [17].Tricyclo [5.2.1.0]decane skeleton of solanoeclepin A was constructed starting from (R)-seudenol 6 (Scheme 2) [17].Two further literature reports on the asymmetric cyclopropanation reaction include both experimental and theoretical studies [18,19].In the first one, α-fluoroacrylates 8 were subjected to enantioselective cyclopropanation promoted by chiral rhodium catalysts 9 (Scheme 3) [18].The corresponding cyclopropyl junctions 10 were formed with excellent enantio-and diastereoselectivities [18].Monofluorinated cyclopropane derivatives have inter alia, antiviral (anti-herpetic) and antibacterial properties; the presence of fluorine and cyclopropane increases the bioavailability, selectivity and similarity to the respective receptors.

Scheme 3. Enantioselective cyclopropanation of α-fluoroacrylates.
Chiral rhodium catalysts were also applied in stereoselective cyclopropanation of N-phenoxylsulfonamides 11 with cyclopropenyl secondary alcohols 12 (Scheme 4) [19].A very wide spectrum of substrates was tested and, in most cases, the desired products were obtained in high chemical yields with excellent enantioselectivities and diastereoselectivity [19].This type of cyclopropane moiety is the structural basis of drugs such as milnacipran and (+)-Tranylcypromine.An original and interesting approach to the cyclopropanation process was reported by Breinbauer et al.The enzymes ene reductases were used as catalysts in the reaction of reduction in carbon-carbon double bonds in α,β-unsaturated compounds 13 with electronwithdrawing group [20].It turned out that this type of enzyme also catalyzes the process of creating carbon-carbon bonds; thus, the aforementioned α,β-unsaturated systems underwent reductive cyclization.This new enzymatic transformation allows access to chiral cyclopropyl derivatives with excellent ee (up to 99%) (Scheme 5) [20].

Asymmetric Friedel-Crafts Reactions
Asymmetric Friedel-Crafts reaction is another widely used method for the enantioselective construction of carbon-carbon bonds [21].The title transformation is often used in the synthesis of biologically active compounds [22] and some organocatalytic approaches have been compiled in a review article in 2019 [23].Among the extremely wide variety of chiral sources used in asymmetric Friedel-Crafts reaction, in this review, special attention is paid to systems such as chiral derivatives of urea [24], thiourea [24], squaramide, chiral phosphoric acids and various complexes of N-heterocycles with metals.
Herrera et al. studied the activation of urea-and thiourea-derived catalysts in an asymmetric Friedel-Crafts reaction of indole 14 and nitrostyrene 15 as model substrates (Scheme 6) [25,26].Scheme 6. Reaction of indole and nitrostyrene promoted by urea or thiourea catalysts.
In the first contribution authors showed that the addition of an external Brönsted acid (rac-mandelic acid) enhanced the catalytic activity of the urea 16 system, increasing the enantioselectivity to 68% ee [25].In the second study, chiral thiourea derivatives were activated with metals, leading to the best results in terms of enantioselectivity for the gold (I) complex of thiourea 17 [26].
An asymmetric alkylation of sulfonylindoles of type 18 with naphthol and its derivatives was performed by Han and co-workers using bifunctional catalysts bearing urea or a thiourea motif [27].The corresponding products of type 20 were formed in the highest yields and enantiomeric excesses using thiourea 19 (Scheme 7).Additionally, among many solvents tested, the authors showed that the two-phase water-toluene system is the best one [27].Taking into account the structure of compound 18, the proposed method may be useful in the synthesis of such natural compounds as (+)-gliocladin C, (+)-bionectin A or leptosin D. A similar Friedel-Crafts transformation consisting in arylation of 1-azadienes of type 21 was reported in 2020 [28].The desired product 22 was obtained in very high chemical yield (95%), and with an excellent enantiomeric ratio (97:3), when the urea-analog of system 19 (19a) was applied as catalyst (Scheme 8) [28].The same reaction was investigated using thiourea bifunctional catalyst 19 which led to the appropriate chiral product with a moderate yield (72%) and enantioselectivity (62% of ee) [29].It should be stressed that chiral triarylmethanes are the structural skeleton of many systems that exhibit antiviral and antibacterial effects, as well as a drug for tuberculosis or skin diseases.Friedel-Crafts alkylation/cyclization of 4-hydroxyindole 23 promoted by bifunctional tertiary amine-urea catalyst 24 was reported by Lin and Duan et al. [30].The corresponding spirooxindole-pyranoindole products of type 25 were formed very efficiently in terms of yield and enantioselectivity (Scheme 9) [30].Indole derivatives are found in many drugs, while systems structurally similar to compound 25 have predominantly anti-malarial activity (e.g., NID609).Scheme 9. Alkylation/cyclization of 4-hydroxyindole in the presence of urea system 24.
Friedel-Crafts functionalization of 4-hydroxyindole 23 with (E)-2-nitroallylic acetate 26 was successfully carried out using bifunctional squaramide catalyst 27 (Scheme 10) [31].Chiral product 28 was formed in 86% yield, with over 99% of ee and diastereomeric ratio over 20:1 when system 27 was applied in DCM at 50 • C in the presence of dipotassium hydrogen phosphate and 4 Å molecular sieves [31].It should be mentioned that thiourea catalysts showed weaker catalytic activity in this process [31].As with other indole systems, it is present in many drugs and natural compounds.Furo [2,3-b] benzofuranones were synthesized via efficient asymmetric Friedel-Crafts alkylation/hemiketalization/lactonization cascade reaction [32].The search for new methods of the synthesis of chiral furo [2,3-b] benzofuranones is desirable due to the high biological (e.g., antibacterial, anti-thrombotic) activity of such systems.In the model reaction, 3-ylidene oxindole 29 was treated by 2-naphthol.The corresponding product 31 was obtained in the highest yield (83%) and enantioselectivity (90% of ee) in toluene when squaramide 30 was used as chiral promoter (Scheme 11).Thiourea derivatives were also tested but the results were not as significant as for squaramide [32].Porous carbon nanosheet-supported squaramide 30 catalysts were successfully used for highly enantioselective Friedel-Crafts reaction between isatin ketimine 32 and pyrazolone 33 (Scheme 12) [33].The best results in terms of yield (94%) and ee (up to 99%) were achieved after 15 min in DCM in the presence of potassium carbonate and Nfluorobenzenesulfonimide (NFSI) [33].Chiral phosphoric acids acted as catalysts in asymmetric Friedel-Crafts alkylation of indoles with trifluoromethyl ketone hydrates 34 bearing a benzothiazole moiety (Scheme 13) [34].The most successful transformation was achieved in case of the use of 35 as the chiral catalyst [34].In this synthesis, special emphasis was placed on the chiral α-trifluoromethyl tertiary alcohol, which is present in many Anti-HIV drugs.
Similar catalysts were examined in the asymmetric Friedel-Crafts reaction of indoles with in situ generated N-acyl imines from alanine-derived N-(acyloxy) phthalimide 36 (Scheme 14) [35].Reactions were performed under blue LED light in the presence of ruthenium or iridium photocatalysts [35].The most efficient model reaction (86% yield, 90% ee) was carried out in the presence lithium salt 37. Scheme 14. Friedel-Crafts reaction of indoles with in situ generated N-acyl imines.
Enantioselective Friedel-Crafts reaction of cyclic N-sulfimines 38 with 2-methoxyfurane 39 catalyzed by chiral BINOL-derived phosphoric acids was described in 2019 (Scheme 15) [36].The application of chiral derivative 40 in o-xylene at room temperature gave the best results in terms of chemical yield and enantiomeric ratio [36].The asymmetric FC reaction in which furan is the substrate is less understood as compared to indole.The furan ring is present in many natural compounds: (-)-furodysinin, fraxinellone (can be used as a pesticide but is non-toxic to mammals) or lophotoxin (it is an antagonist of the nicotinic acetylcholine receptor).BINOL-derived chiral phosphoric acids are among the most widely used phosphorus derivatives to catalyze the asymmetric Friedel-Crafts reaction [37].In addition to the reaction cited above, other selected examples of application of such catalysts are: alkylation of indoles with β-substituted cyclopenteneimines leading to β-indolyl cyclopentanones [38], asymmetric arylation of 2,2,2-trifluoroacetophenones [39], reaction of indoles with αiminophosphonates [40], tandem three-component reaction of indole with aldehydes and p-toluenesulfonamide [41] and reaction of indoles with 3-indolylsulfamidates [42].
Beletskaya et al. described asymmetric Friedel-Crafts reactions of indoles with arylidene malonates 41 in the presence of magnesium iodide [43] and with phthaloyl-protected aminomethylenemalonate 43 in the presence of Cu(OTf) 2 [44].The processes were catalyzed by PyBox [43] or iPrBox [44], respectively (Scheme 16).The asymmetric reaction of indoles with α,β-unsaturated carbonyl compounds 45 (enones) was carried out using three similar catalytic systems (Scheme 17) [45][46][47].In the first contribution, reaction was promoted by imidazoline-oxazoline 46 complex with Cu(OTf) 2 (acetonitrile, room temperature), leading to indole derivatives acting as novel α-glucosidase inhibitors in vitro [45].The second approach comprises a utilization of chiral N,N-dioxide 47-scandium(III) complexes in dichloromethane at 35 • C [46], and finally, the third work relies on the application of cationic aqua complex of 2,2 -bypiridine 48 with palladium(II) in water at room temperature [47].Chiral bis (3-indolyl) methanes 51 were synthesized in high yields and in a highly enantioselective manner via asymmetric Friedel-Crafts alkylation of indoles with trifluoromethylated nitroalkenes 49 (Scheme 18) [48].Reactions were promoted by a nickel(II) complex of imidazoline oxazoline 50.Systems of type 51 have antibacterial and antifungal properties, inhibit the growth of cancer cells, and are also colorimetric sensors.Asymmetric Friedel-Crafts reactions of indoles with trifluoromethyl pyruvate 52 were independently described in 2018 [49,50] Similar dinuclear zinc catalytic systems were also used in the synthesis of 2,5-pyrrolidinyl dispirooxindoles [51] and tetrahydrofuran spirooxindoles [52] via cascade reactions, where one of the steps is a Friedel-Crafts process.Moreover, this type of chiral catalyst was successfully utilized for Friedel-Crafts reaction of pyrrole with chalcones [53].
The organocatalytic Friedel-Crafts alkylation of phloroglucinol derivatives 55 with enals 56 was described by Zu et al. [54].The corresponding chiral products were afforded in high yields and enantioselectivities (Scheme 20) when diphenylprolinol TMS ether 57 was applied as the catalyst.This reaction opens up access to total synthesis of (+)-aflatoxin B 2 [54].

Scheme 21. Asymmetric Friedel-Crafts propargylation of indoles.
At the end of this chapter, it is worth mentioning a few more non-obvious approaches to the asymmetric Friedel-Crafts reaction.They are for sure the use of N-heterocyclic carbenes as catalysts in the synthesis of indole-fused polycyclic alcohols [56], guanosinebased self-assembly as catalytic system [57], and various DNA-employing catalytic systems [58][59][60].

Asymmetric Mannich Reactions
Asymmetric Mannich reaction is another process of enantioselective formation of carbon-carbon bonds, which can result in the formation of useful building blocks and compounds exhibiting biological activity.
Bifunctional thiourea systems were employed to the reaction between 3-indolinone-2carboxylates 58 to N-Boc-benzaldimines generated in situ from α-amidosulfones 59 [61].The best results in terms of chemical yield, enantio-and diastereoselectivity were obtained with the use of thiourea 60 (Scheme 22) [61].Chiral derivatives of isatins occur in the nature; these are compounds such as (+)-isatisine A, trigonoliimine or mersicarpine.All three exhibit antiviral properties.4-Substituted isoxazolidin-5-ones 61 were reacted with isatin-derived imines in the presence of (DHQD) 2 PYR ligand 62 (Scheme 23) [62].Reactions performed in methyl tert-butyl ether (MTBE) at 0 • C gave the corresponding Mannich products in almost quantitative yields, and excellent enantioselectivity (99%) and diastereoselectivity (20:1 of d.r.).The obtained products are building blocks for the synthesis of systems with bactericidal properties.Catalytic asymmetric Mannich reaction of N-Boc-aldimines with α,β-unsaturated pyrazoleamides 63 was successfully catalyzed by the complex of copper(I)-(R)-DTBM-SEGPHOS 64 in the presence of triethylamine leading to the corresponding syn-vinylogous products in a highly enantioselective and diastereoselective manner (Scheme 24) [63].One of the most common chiral catalysts used in the asymmetric Mannich reaction, namely L-proline, was combined with the corresponding photocatalysts and used in enantioselective Mannich reaction of dihydroquinoxalinones 65 with ketones [64] and in the synthesis of C2-quaternary indolin-3-ones [65].The dihydroquinoxalinone skeleton is found in many natural and synthetic compounds, which are drugs and plant protection products.In the first work, chiral quinoxaline junctions 66 were obtained in high yields (up to 94%) and very high enantioselectivities (up to 99% of ee) (Scheme 25) [64].Dihydroquinoxalin-2-one 65 under the irradiation of visible light and in the presence of Eosin Y and oxygen is oxidized to quinoxalin-2(1H)-one (imine).In the second case, Guan and He et al. also showed excellent catalytic activity of L-proline in the presence of ruthenium-bipirydyl complex (Scheme 26) [65].

Asymmetric Michael Reactions
The Michael addition reaction constitutes one of the most powerful tools of construction of C-C bonds in modern synthetic organic chemistry.The number of different Michael donors and acceptors is large and constantly increasing; therefore, this reaction is still the subject of numerous studies.The Michael reaction in the asymmetric version is often a key step in the synthesis of many natural products [67].The search for new chiral catalysts for this asymmetric transformation is still a challenge for various research groups [68].Many recent reports inform about the use of bifunctional organocatalysts, such as thioureatertiary amine systems [69].Moreover, Michael additions performed in the presence of zinc ions also enjoy quite a lot of interest [70].Currently, target materials in the asymmetric Michael addition reaction are very often isoxazole-5-ones and isoxazolidin-5-ones [71], and pyrazolones [72].
Enantioselective 1,6-aza-Michael addition reaction of 4(H)-isoxazol-5-ones 70 to pquinone methides 71 promoted by various organocatalysts was described by Blay and Pedro et al. [73].The isoxazol-5-one ring is present in many natural compounds, and there are many examples of compounds from this group that are inhibitors of various enzymes.The properties of this ring mean that some derivatives are successfully used in photonics.The desired isoxazolin-5-one derivatives 72 were formed with the greatest efficiency in dichloroethane (DCE) at room temperature in the presence of 3Å molecular sieves under action of thiourea system 73 (Scheme 28) [73].

Asymmetric Reactions in the Presence of Zinc Ions
Among the very wide range of asymmetric reactions taking place in the presence of zinc ions, the most exploited but still valid and simple reactions are asymmetric additions of diethylzinc to carbonyl compounds, especially aldehydes.In 2018, Wang described an enantioselective analysis towards the rational design of chiral ligands efficiently catalyzing the asymmetric addition of diethylzinc to benzaldehyde [84].

Summary
This review article presented selected examples of recent achievements in the field of asymmetric synthesis with chiral catalysts.The authors' attention was focused on asymmetric transformations such as the cyclopropanation, Friedel-Crafts, Mannich, Michael reactions, and reactions in the presence of zinc ions.All the examples given relate to reactions with high chemical yields and high stereoselectivity.
The research related to asymmetric synthesis with the use of chiral organic catalysts is extremely well studied and is constantly developed by many research groups around the world.The asymmetric reactions presented in this review are well known and exploited in the literature.Our suggestion for future research directions in this field is that researchers should focus on less obvious asymmetric transformations, such as Morita-Baylis-Hillman or Rauhut-Currier reactions, whose chiral products have potential applications in many fields.Moreover, perhaps it is worth trying to design chiral catalysts taking into account new structural motifs, such as the aziridine ring.

Scheme 34 .
Scheme 34.Addition of Et 2 Zn to benzaldehyde in the presence of atropisomeric 1-phenylpyrroles.