Construction of Chiral Cyclic Compounds Enabled by Enantioselective Photocatalysis

Chiral cyclic molecules are some of the most important compounds in nature, and are widely used in the fields of drugs, materials, synthesis, etc. Enantioselective photocatalysis has become a powerful tool for organic synthesis of chiral cyclic molecules. Herein, this review summarized the research progress in the synthesis of chiral cyclic compounds by photocatalytic cycloaddition reaction in the past 5 years, and expounded the reaction conditions, characters, and corresponding proposed mechanism, hoping to guide and promote the development of this field.


Introduction
In recent years, enantioselective photocatalysis has been successfully applied to extensive practical work of organic synthesis [1][2][3], providing an alternative method for the production of valuable chiral molecules. In this regard, many chemists such as Yoon, MacMillan, Bach, etc., made great contributions to the development of milder and more efficient enantioselective cycloaddition reaction through the organic photocatalysis. List and MacMillan were awarded the 2021 Nobel prize in chemistry for their "development in asymmetric organocatalysis". This review mainly discusses the research progress of enantioselective photocatalysis for constructing chiral cyclic compounds by photo-induced asymmetric cycloaddition reaction in the past 5 years, though some comprehensive contents regarding this topic were reported by the pioneers [4][5][6][7][8]. This paper is divided into seven parts according to the structural types of rings: the construction of 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, macroring, and multi-rings. In contrast, there are significantly more reports about the construction of 4-membered rings via enantioselective photocatalysis. In these transformations, the use of chiral catalyst could furnish an appropriate chiral environment and improve the photocycloaddition enantioselectivity; some of them have become the representative chiral photocatalyst for enantioselective photocatalysis, such as chiral oxazaborolidine Lewis acid, chiral thioxones, ruthenium catalysts, iridium catalysts, chiral amine catalysts, and chiral phosphoric acids. Especially in recent years, chiral organocatalysts are more and more widely used in enantioselective photocatalysis [9]. In addition, the catalytic system had also been developed from the original single catalysis system to the current double catalysis, or even triple catalysis, system. struction of 3-membered ring by enantioselective photocatalysis in the past five years. In 2019, Bach et al. reported a simple, efficient, and enantioselective route to obtain the cyclopropyl substituted quinolone compounds [10]. Under the irradiation of visible light (λ = 420 nm), the 3-allyl-substituted quinolones (1) underwent a triplet sensitized di-πmethane rearrangement reaction to form 3-cyclopropylquinolones (3) in the presence of a chiral hydrogen bonding sensitizer thioxanthone (2) (Scheme 1). The reaction showed excellent yields in most cases and moderate enantioselectivity (88-96% yield, 32-55% ee). The author proposed a mechanism as follows: (1) was associated with a chiral hydrogen bonding sensitizer (2) to form the 1,3-diradical intermediate (1a), which further closed the ring to form the complex (ent-4) or complex (4). Owing to the geometric constraints in complex (1a), generating (ent-4) is expected to decay preferentially. In other words, this process favours formation of (4) while the latter process shows a preference for ent-3a (higher association constant Ka than [3a]), thus reducing the enantioselectivity of the deracemization process. Finally, the major enantiomer 3-cyclopropyl-quinolones (3) were obtained. Scheme 1. Enantioselective formation of 3-cyclopropyl-quinolones.

Enantioselective Formation of 4-Membered Ring by Visible Light Catalysis
The technology for the construction of chiral 4-membered ring compounds by enantioselective photocatalysis has become more mature, and [2+2] photocycloaddition is the most common synthesis method. In 2017, an effective and enantioselectivie chiral iridium catalyzed [2+2] photocycloaddition was reported by Yoon et al. [11], who used structurally related 3-alkoxyquinolones (5) irradiated by blue LED light with Ir(III) photosensitizer (6) to synthesize products (7) in good yields and enantioselectivitiy (up to 98% yield, up to 91% ee) (Scheme 2). Chloro-and bromo-substituted quinolones performed well but iodinated substrate displayed lower enantioselectivity. The excellent performance is still capable of modified alkene moiety with small enantioselective decline.

Scheme 2. Enantioselective photocycloaddition of 3-alkoxyquinolones.
Earlier, Yoon et al. developed a new strategy to achieve enantioselective [2+2] photocycloaddition of 2 -hydroxychalcones via Lewis acid-catalyzed triplet energy transfer [12]. Subsequently, they reported a chiral Lewis acid catalyzed triplet sensitization for enantioselective crossed photocycloaddition to synthesize highly enantioenriched cyclobutanes in 2017 [13]. In this work, 2 -hydroxychalcones (8) could couple with styrenes (9) to construct diarylcyclobutanes (10) in the presence of Sc(OTf) 3 , t-BuPybox, and Ru(bpy) 3 2+ upon the irradiation of 23 W CFL (Scheme 3). The transformations showed excellent yields and high enantioselectivity (up to 97% yield, up to 99% ee). The styrene ring could be substituted by a variety of electron-donating groups or electron-withdrawing groups, and the styryl double bond was also modified by some substituents with high ee. This method also provided a direct approach to the synthesis of diarylcyclobutane natural products, such as norlignan 3. The proposed mechanism was conducted as follows. 2 -hydroxychalcones (8) initially cooperated with Lewis acid to form the Lewis-acid-bound substrates (11), which could be transform into (11*) via triplet energy transfer by Ru(bpy) 3 2+ under the irradiation of 23 W CFL, then styrenes (9) captured with 1,4-diradical intermediates (12) to produce diarylcyclobutanes (10).
Yoon et al. reported a highly enantioselective intermolecular [2+2] photocycloaddition reaction catalyzed by chiral hydrogen bond ion iridium photosensitizer (49). 3-Hydroxyquinolones (50) reacted with maleimide (51) to generate cycloaddition products (52) under the irradiation of blue LED light in excellent yields and enantioselectivity (up to 99% yield, up to 99% ee) (Scheme 12) [22]. The reaction has high enantioselectivity when the substitutions at the 6-position of 3-hydroxyquinolones are alkyl, halogen, and alkoxy groups, and the substituted 3-hydroxyquinolones at 5-and 7-positions also have good tolerance. However, the substitution at the 8-position has a great influence in enantioselectivity. Furthermore, the reaction is also applicable to alkyl, propyl, allyl, and carbamoyl substituted maleimide. In this reaction, the quinolone substrates (50) partially combined with the pyrazole of the iridium complex to afford complex (53), which was then transformed into an excited state (53a) under the irradiation of blue LED light. The excited state (53a) reacted with maleimide (51) by bimolecular energy transfer to obtain the complex (53b) and provided cycloaddition products (52) from (53c). Recently, Bach et al. reported an enantioselective photoaddition reaction catalyzed by chiral thioxone (54). Under the irradiation of visible light (λ = 420 nm), intramolecular cyclization of 3-alkylquinolones (55) with 4-O-tethered alkenes or allenes occurred to form cycloaddition products (56) in good yields and enantioselectivity (72-99% yield, 81-99% ee) (Scheme 13) [23]. The benzo ring of quinolones substituted by methyl, chloro, cyano, methoxy, and fluoro groups has good tolerance. In the study of olefins, propylene diene and trifluoroolefins were also suitable for this reaction. The reaction mechanism shows that alkylquinolones (55c) could react with thioxanthraquinones (54) to deliver the complex (57) which gave the quinolone triplet (57a) by energy transfer, then the internal carbon atom of olefin was added to form 1,4-diradical (57b), which underwent intersystem crossing (ISC) to produce (57c) and further gave desired product (56c).
In 2020, Bach et al. reported a photocyclic addition reaction in which heterocyclic compounds (58) could be synthesized, using thioxanthone (59) as a chiral catalyst. Under the irradiation of visible light (λ = 420 nm), 3-substituted quinoxalin-2 (1H)-ones (60) and olefins (61), could occur an intermolecular aza Paternó-Büchi reaction in good yields and enantioselectivity (50-99% yield, 86-98% ee) (Scheme 14) [24]. The para-position of olefin aromatic ring could be substituted by some groups such as methyl, tert-butyl, and halogen substituents. Ethyl and trifluorocarbons at the C3 of quinoxalinones were also well tolerated. The reaction mechanism is similar to the previously mentioned mechanism (Scheme 13). In 2020, Takagi et al. reported an enantioselective intramolecular [2+2] photocycloaddition of 4-bishomoally-2-quinolones (62). When phosphoric acid (63) was used as a photocatalyst, cycloaddition products (64) were obtained with good yields and enantioselectivity (up to 88% yield, up to 92% ee) under the irradiation of visible light (λ > 290 nm) (Scheme 15) [25]. Methyl groups at the 6-and 8-positions of the substrates were well tolerated, while oxygen atoms could reduce the enantioselectivity of the products. The reaction occurred from a complex (65) formed by substrate (62b) and phosphoric acid (63) through dual hydrogen bonding, then the olefin moiety on the complex reacted with the enone moiety to form cycloadduct (64b) via photocycloaddition. The para-substituents on the phenyl ring, such as methyl, bromine, chloro, methoxy, and borate group, were well tolerated. In different olefins, styrenes, 1,3-enynes and 1,3-dienes could produce products with good enantioselectivity. The author's study shows that the reaction could be carried out due to the formation of the complex intermediates (70), which were combined by the substrates (67) and the catalyst (66). . The reaction was catalyzed by amines (72) which could easily convert into iminium ions. Under the irradiation of blue light (λ = 459 nm), the modified salicylaldehydes (73) could be successfully obtained in good yields and enantioselectivity (38-63% yield, 65-91% er) [27]. The enantioselectivity of the products could be improved if there are strong electron-donating groups at the aryl group of the salicylaldehyde core. Different aryl groups in the styrene chain, such as methyl and fluoryl, could facilitate a smooth reaction. The proposed mechanism was conducted as follows. First, the substrates (73a) combined with the catalysts (72) to furnish iminium ion intermediates (74). The excited complex (74a) was formed by SET under the irradiation of blue light LED, then the excited complex (74a) could transform into biradical intermediates (74b), which underwent [2+2] photocycloaddition to give the cyclobutyl iminium ions (74c). Finally, the cyclobutyl iminium ions (74c) produced the desired product, (71a).

Enantioselective Formation of 5-Membered Ring by Visible Light Catalysis
In nature, 5-Membered ring compounds exist widely, and some five-membered heterocyclic compounds, such as furan, pyrrole, and thiophene, are widely used in organic synthesis and have a variety of physiological activities as drugs. In 2017, MacMillan et al. reported an intramolecular α-alkylation of aldehydes (79) via a co-catalytic system (amine catalyst (80), iridium photocatalyst (81) and HAT catalyst (82)) to obtain five-membered, six-membered, or seven-membered cyclic aldehydes (83) under the irradiation of blue LED light in good yields and enantioselectivity (up to 91% yield, up to 95% ee) (Scheme 19) [29]. This reaction could be used to prepare a variety of heterocyclic compounds containing nitrogen atoms and synthesize tetrahydropyran. In the scope of alkenes, trisubstituted and 1,2-disubstituted olefins were well tolerated. The proposed mechanism was conducted as follows. The substrates (79) combined with amine catalyst (80) to afford enamines (84). At the same time, under the irradiation of visible light, enamines (84) formed electrophilic radical (84a) through SET initiated by iridium photocatalyst, which was added to olefins to produce nucleophilic radical (84b). Nucleophilic radical (84b) underwent HAT to generate iminium ions (84c); finally desired products (83) were obtained by releasing amine catalyst (80) from iminium ions (84c). In 2017, Luo et al. reported a chiral ion-pair photoredox organocatalyst (85) which was used for enantioselective anti-Markovnikov hydroetherification of alkenols (86) to synthesize five-membered oxygen-containing heterocyclic adducts (87) under the irradiation of bule LED light (λ = 450 nm) in good yields and enantioselectivity (50-90% yield, up to 64% ee). The chiral ion-pair is composed of chiral BINOL-based sodium phosphate and 9-mesityl-10-methylacridinium tetrafluoroborate (Scheme 20) [30]. The aryl substitutions of hydroxyl α-position were well tolerated. Studies have shown that the reaction begins with the chiral ion-pair-catalyzed SET step, which converts the substrates (86) into radical intermediates (88), radical intermediates (88) combine with chiral phosphate anion to form complex (89), and complex (89) undergo cyclization to yield cyclic adducts (90), which through chiral phosphate anion mediated hydrogen transfer to give desired products (87). In 2017, Bach et al. reported an enantioselective photocyclization reaction which converted 2-aryloxy-cyclohex-2-enones (91) to cis-2,3,4a,9b-tetrahydro-1H-dibenzofuran-4-ones (92) in moderate yields and enantioselectivity (26-76% yield, up to 60% ee) (Scheme 21) [31]. In the presence of Cu(ClO 4 ) 2 ·6H 2 O and bisoxazoline ligand (93), the reaction could be carried out under the irradiation of visible light (λ = 368 nm), or under the irradiation of visible light (λ = 418 nm) with the addition of 50 mol% of thioxanthone. The electron-donating groups on the aryl para-position have no effect, while the electron-withdrawing groups lead to the decrease in enantioselectivity. Studies have shown that the substrate (91a) could form the complex (94) with chiral copper-bisoxazoline complex so that the β-carbon atoms of ketene could be attacked to generate cyclic adducts (92a).
In 2018, Knowles et al. reported a photocatalytic reaction to synthesize pyrroloindolines (95) from tryptamine substrates (96) under the irradiation of blue LED light in good yields and enantioselectivity (59-81% yield, 87-92% ee) (Scheme 22) [32]. Ir(ppy) 3 and 8H-TRIP BINOL phosphate (97) were used as catalysts. Some substituents on the indole core were well tolerated, such as Br-, Cl-, Methoxy-, and alkyl-substituents. Moreover, the reaction could also be applied to the synthesis of alkaloid natural products. The proposed mechanism was conducted as follows. Chiral phosphates could first form hydrogen-bonded adducts (98) with substrates (96). Under the irradiation of visible light, electron transfer occurred and reacted with stable nitroxyl TEMPO· to produce closed-shell intermediates (99); iminium ions underwent nucleophilic addition with pendant amine to obtain alkoxyaminesubstituted pyrroloindoline products (95). In 2018, Meggers et al. reported a [3+2] photocycloaddition catalyzed by chiral-atmetal rhodium complex (100). Under the irradiation of bule LED light, cyclopropanes (101) reacted with alkenes (102) or alkynes (103) to deliver chiral cyclopentanes (104) or cyclopentenes (105) in good yields and enantioselectivity (63-99% yields, up to >99% ee) (Scheme 23) [33]. Alkenes have a wide range of applicability, and the olefins substituted by Michael acceptors, styrenes, enynes, and aromatic rings were well tolerated; pyridine could also be used as a substituent group to participate in the reaction. In the scope of alkynes, various aryl substituted alkynes were well tolerated. The proposed mechanism was conducted as follows. Bidentate coordination occurred between cyclopropane substrates (101) and rhodium complex RhS (100) to generate intermediates (106), which were excited to intermediates (106a) under the irradiation of visible light. Intermediates (106a) as a strong oxidant were reduced to intermediates (106b) by tertiary amine. Intermediates (106b) were converted into radical intermediates (106c), which were added to alkenes (102) to generate ketyl radical (106d). Then ketyl radical (106d) released cycloaddition products (105) to complete catalytic cycle.
In 2019, Hyster et al. reported a photoexcitation catalyzed by flavin-dependent "ene"reductase. The methodology could convert chloroacetamides (107) to five-, six-, seven-, and eight-membered lactams (108) under the irradiation of 50 W cyan light (λ = 497 nm) in good yields and enantioselectivity (up to 99% yield, up to >99% er), GluER-T36A (109) is used as the main chiral catalyst (Scheme 24) [34]. Aromatic substituted alkenes could participate in this reaction smoothly, and a variety of alkyl substituents on the olefin were well tolerated. The proposed mechanism was conducted as follows. Substrates (108) could combine with catalyst (109) to yield complex (110), which underwent electron transfer to obtain radical intermediates (111). Intermediates (111) formed exocyclic radical (111a) via cyclization, which gave desired products (108) through hydrogen atom transfer. form cyclic adducts (115) in good yields and enantioselectivity (up to 98% yield, up to 96% er) (Scheme 25) [35]. Many kinds of substituted furoindolines and pyrroloindolines were produced by this reaction with high enantioselectivity. In addition, substituted indolo [2,3-b]quinolines could also be constructed. The proposed mechanism was conducted as follows. In the presence of an iridium photocatalyst, substrate (113d) went through first SET oxidation to form radical cation intermediate (116)   In 2020, Knowles et al. reported a kind of enantioselective intramolecular hydroamination of alkenes with sulfonamides (118) catalyzed by an iridium photocatalyst and a chiral phosphate (119). Pyrrolidines (120) were successfully obtained under the irradiation of blue LED light in good yields and enantioselectivity (up to 98% yield, up to 98% er) (Scheme 26) [36]. In the scope of sulfonamide moieties, the substituents at paraand metaposition of the sulfonamide arenes could provide products with high er; the reaction could also be suitable for benzofuran, thiophene, and thiazole heterocycles. Benzyl substitution, phenethyl chain, sulfamate ester, and sulfamide substrates were well tolerated. In addition, some complex sulfonamide substrates could also participate in this reaction. For the scope of alkenes, cyclohexyl-substituted and cyclobutyl-substituted substrates showed better enantioselectivity.
In 2021, Gao et al. reported a method for the construction of polycyclic structures (A) from substituted 2-methylbenzaldehydes (147) and dienophiles (148) via a chiral titanium (149)-mediated enantioselective photoenolization/Diels-Alder reaction [42]. The reaction has good yields and enantioselectivity (up to 98% yield, up to 99% ee) (Scheme 32), and could be used to synthesize a variety of complex natural products and drugs.
Not long before, another chiral TADDOL-type ligand (150) for exo-selective and enantioselective photoenolization/Diels-Alder reaction was found by Gao et al. [43]. Under the irradiation of visible light (λ = 366 nm), electron-rich 2-methylbenzaldehydes (151) reacted with dienophiles containing a benzoyl group at its α position (152) to form a variety of D-A addition products (B) in good yields and enantioselectivity (up to 92% yield, up to 99% ee) (Scheme 33). The process of the reaction depended on the generation of the structure of the dienophiles and the chiral ligands, and the chiral dinuclear Ti-TADDOLate species provided an excellent enantioselective environment for [4+2] cycloaddition.

Enantioselective Formation of Macroring by Visible Light Catalysis
Compared with mesocyclic molecules, chiral macrocyclic molecules are relatively rare, and the corresponding synthesis methods are not mature. In 2020, Xiao et al. reported palladium-catalyzed asymmetric [8+2] dipolar cycloadditions. In the presence of a chiral ligand (164) and Pd 2 (dba) 3 ·CHCl 3 , vinyl carbamates (165) could react with photogenerated ketenes (166) to deliver 10-membered cycloadducts (167) upon the diffraction of blue LED light in excellent yields and enantioselectivity (up to 97% yield, up to 97% ee) (Scheme 36) [46]. A variety of vinyl carbamates bearing different aryl groups could afford desired cycloadducts with high er, and unsaturated vinyl group substituted with vinyl carbamate could be well tolerated in asymmetric [8+2] cycloaddition. Electronically different substituents at the phenyl ring of α-diazoketones showed excellent applicability; α-diazoketones with alkyl groups, such as methyl, ethyl, and n-butyl are also applicable in this reaction. However, 2-aryl or alkyl-substituted vinyl carbamates and 2-aryl or alkenyl-substituted α-diazoketones cannot participate in the reaction. This method is the first visible light induced asymmetric [8+2] cycloaddition reaction.

Enantioselective Formation of Multi-Ring by Visible Light Catalysis
Compared with traditional synthesis methods, photocatalytic synthesis of chiral polycyclic compounds is new and effective. In 2018, Nicewicz et al. reported an asymmetric cation radical intramolecular Diels-Alder reaction, utilizing an oxidizing pyrilium salt bearing a chiral N-triflyl phosphoramide anion (168) to synthesize cycloaddition products with bicyclic structure (169) from trienes (170) upon the diffraction of blue LED light (λ = 470 nm) in good yields and enantioselectivity (up to 72%, up to 75% er) (Scheme 37) [47]. Moreover, this reaction could also be used to yield [2.2.1]-bicycloheptenes. The proposed mechanism was conducted as follows. Electron-rich dienophile of substrates (170) underwent the one-electron oxidation by photoredox catalyst upon the diffraction of blue LED light to transform into radical intermediates (171), which gave radical intermediates (171a) via cyclization. One-electron reduction of intermediates (171a) furnished bicyclic products (169).

Conclusions
In the past 5 years, enantioselective visible light catalysis has become an important strategy for the synthesis of chrial organic molecules. In this review, we have mainly summarized the new methods for the construction of chiral cyclic compounds via photoinduced transformation. The substrate applicability and mechanism of various methods are briefly described. It is worth noting that these photochemical synthesis methods provide a good supplement for the construction of polychiral and polycyclic compounds which are difficult, or even impossible, to synthesize with the previous methods. It can be predicted that photocatalysis will become a greener and more environmentally friendly synthesis method and will play an important role in the synthesis of a variety of corresponding chiral compounds, providing new ideas for the total synthesis of natural products and drugs.

Conflicts of Interest:
The authors declare no conflict of interest.