Asymmetric Organocatalyzed Intermolecular Functionalization of Cyclohexanone‐Derived Dienones

Over the past decades, the advent of asymmetric organocatalysis has changed the way chemists think about creating or breaking chemical bonds, enabling new enantioselective strategies for functionalized molecules. The success of asymmetric organocatalysis is notably based on the existence of various activation modes, leading to countless transformations, and on the vast array of available chiral organic catalysts. Breakthroughs in this area have also been driven by selective functionalization of compounds with multiple activation sites such as cyclohexanone‐derived dienones. These platforms can undergo diverse transformations such as Michael addition, Friedel‐Crafts alkylation or Diels‐Alder cycloaddition that offer new opportunities for reaching natural products and biologically relevant compounds. Amongst cyclohexanone‐derived dienones, the 2,5‐cyclohexadienone motif has received a great deal of attention due to its reactivity pattern and recently, (cross)‐conjugated cyclohexanone‐derived substrates have also been considered. In this review, we discuss the intermolecular functionalization of (cross)‐conjugated cyclohexanone‐derived compounds employing asymmetric organocatalysis.


Introduction
The preparation of enantioenriched compounds is at the heart of concern for a large part of the research dedicated to organic synthesis. In the synthetic toolbox now available to chemists, asymmetric organocatalysis is a powerful strategy to transform achiral substrates into enantioenriched products through the action of chiral organic molecules. This research field has experienced a spectacular boom since 2000 thanks to the trailblazing works of Nobel laureates List and MacMillan in enamine and iminium catalysis, respectively. [1] Following these pioneering works, the field of asymmetric organocatalysis has grown at a brisk pace, and organocatalysis is now considered one of the three pillars of asymmetric catalysis with metal catalysis and biocatalysis. [2] Amongst the reasons for the success of asymmetric catalysis is the existence of various activation modes that can trigger a myriad of transformations. Activation modes are generally classified in covalent and non-covalent modes of activation. [3] The first mode involves the formation of transient intermediates through the formation of covalent bonds between the organocatalyst and the substrate. The covalent activation mode includes the use of aminocatalysts to promote enamine, [4] iminium [5] or SOMO (singly occupied molecular orbital) activations, [6] Lewis base catalysts such as tertiary phosphines [7] or tertiary amines, [8] and N-heterocyclic carbenes (NHC) [9] to cite only a few. The non-covalent activation mode is based on weaker interactions such as hydrogen, [10] halogen and chalcogen bonding, [11] π-stacking [12] or ion pairing. [13] Since the emergence of asymmetric organocatalysis, countless catalytic systems have been reported in the literature leading to privileged catalytic platforms (i. e. pyrrolidine-derived aminocatalysts, [14] phosphoric acids derived from Binol, [15] Cinchona alkaloid derivatives, [16] aminoacidderived phosphines) [17] able to promote efficiently diverse reactions with high levels of enantioselective control. [18] Amongst the applications of these privileged catalysts, the enantioselective functionalization of cyclohexadienone scaffolds has attracted considerable attention in the past decades owing to the importance of these motifs in biologically relevant molecules and natural products. [19] In addition, these architectures show a diverse pattern of reactivity making them attractive substrates for asymmetric organocatalysis. The cyclohexadienone backbone is generally associated with the 2,5cyclohexadienone motif owing to its synthetic potential and the number of studies devoted to its transformation. Therefore, the asymmetric functionalization of achiral 2,5-cyclohexadienones using transition metal catalysts and/or organocatalysts has been previously discussed in excellent reviews. [20] Nevertheless, recent discoveries in the functionalization of cyclohexadienones have also been driven by the investigation of new (cross)-conjugated cyclohexanone-derived substrates demonstrating the synthetic potential of asymmetric organocatalysis to reach enantioenriched products. The present contribution is deliberately focusing on the intermolecular functionalization of 2,5-cyclohexadienones, 3-alkenylcyclohexenones, 2,6-dialkylidenecyclohexanones and 6-alkylidenecyclohex-2-ones as representative examples of the functional and structural diversity of the cyclohexadienone architecture (Scheme 1). This review does not claim to cover all asymmetric organocatalyzed functionalization of (cross)-conjugated cyclo-hexanone-derived substrates but aims at demonstrating the synthetic interest of this strategy.

Catalysis with Binol-Derived Phosphoric Acids
Since the seminal works of Akiyama [21] and Terada, [22] chiral phosphoric acids have been applied in numerous asymmetric processes and the functionalization of cyclohexa-2,5-dienones did not escape this trend. In 2012, Rovis and co-workers reported an asymmetric organocatalyzed desymmetrization of para-peroxyquinols 1 to form 1,2,4-trioxanes 4 (Scheme 2). [23] A series of Brønsted phosphoric acid catalysts cat-1 and cat-2 was tested and the best results were obtained with the bis(2,4,6-triisopropylphenyl)spirobiindane phosphoric acid cat-1 a. The use of thiourea 3 as a co-catalyst was crucial to get high yields when 5 mol% of cat-1 a was used. The reaction was extended to a series of para-peroxyquinols 1 and aldehydes 2. Paraformaldehyde and sterically hindered aliphatic aldehydes gave the desired products with good yields and excellent enantioselectivities. Regarding the para-peroxyquinol partners, Corinne Coutant studied chemistry at Université Paris-Saclay (France) where she received her M.Sc degree in 2020. She is currently carrying out her Ph. D. work at Nantes Université under the supervision of Dr. Vincent Coeffard and Dr. Pierrick Nun on the development of new photosensitizers for applications in antimicrobial photodynamic therapy.
Paul de Bonfils was born in Nancy (France)  1,2,4-trioxanes 4 can be obtained from substituted paraperoxyquinols 1 bearing an ethyl group or an ester (e. g. 4 g and 4 h). Experiments were carried out to shed light on the mechanism and the results showed the reaction proceeds through a dynamic kinetic resolution of the peroxy hemiacetal intermediate formed by reaction of 1 with 2. The oxa-Michael step is not reversible and is the enantiodetermining step.
Different chiral phosphoric acid catalysts, solvents, additives were investigated in the optimization process. After a careful examination of the reaction conditions, it turned out that the best results were obtained with the catalyst cat-3 and sodium sulfate in a mixture of o-xylene and dichloromethane (5 : 1) at -10°C. A suitable solvent system was required to ensure the solubility of the catalyst and high levels of reaction yields. The substrate scope analysis showed that yields and enantioselectivities were better with an ester functional group while low enantioselectivities were observed with a methoxy or a cyano group as the C4-substituent. DFT (Density Functional Theory) calculations were carried out and the proposed transition states were based on the bifunctional activity of the catalyst containing both a Lewis basic site and a Brønsted acidic moiety interacting with the carbonyl group of 5. In particular, the interaction of the Lewis basic site of the phosphoric acid with one of the hydrogen atoms of the cyclopentadiene 6 is important to explain the high level of enantioselectivity.
Binol-derived phosphoric acid catalysts were used in 2016 by Carreño, Álvarez, Ribagorda and co-workers for the intermolecular Friedel-Crafts alkylation of indoles 9 with para-Scheme 1. Structures covered in this review and privileged catalytic systems.

R e v i e w T H E C H E M I C A L R E C O R D
quinols 8 (Scheme 4). [25] Diversely functionalized phosphoric acids were screened and the best results were obtained with 9anthracenyl phosphoric acid cat-4. The influence of solvents, temperature and additives was also tested to determine the best reaction conditions using 10 mol% of catalyst cat-4. Interestingly, the use of molecular sieves induced a decrease in the yield and the enantioselectivity, demonstrating the influence of water in the reaction (17 % yield, 44 % ee with 4 Å molecular sieves versus 72 % yield, 72 % ee under standard conditions). Different substrates were tested and experimental results showed that electron-rich indoles gave similar results with a longer reaction time and electron-withdrawing substituted indoles gave moderate-togood yields. Reaction with N-methyl indole under standard conditions afforded the desired product 10 e in 50 % yield but low enantioselectivity (8 %). This result suggests that the NH of indole plays a key role in the mechanism. Furthermore, 4methoxy-para-quinol did not react under the optimized conditions which proves the necessity of the free OH group on cyclohexadienone 8. To confirm the importance of water, NH and free OH groups in the reaction mechanism, DFT calculations were carried out and the results confirmed the crucial role of water in the transition state.
Following the work of Takagi and Nishi about cyclohexadienone Diels-Alder cycloadditions (Scheme 3), the group of List reported the use of Binol-derived imidodiphosphorimidate catalysts for an enantioselective Diels-Alder reaction with 2,5-cyclohexadienones (Scheme 5). [26] Initial attempts were made with phosphoric acid and disulfonimide catalysts but only trace products were obtained. Work was then directed towards imidodiphosphorimidate catalysts cat-5 with a variation on the 3,3'-substitution of the binaphthyl moiety and on the nitrogen. The optimum catalyst was identified as cat-5 d.
Reducing the temperature from À 20°C to À 80°C improved both the diastereoselectivity and the enantioselectivity. Different substituents at the 4-position of cyclohexadienone were evaluated to see the influence of the substituents next to the methyl group. Aliphatic, allylic and aromatic substituents all gave good yields, diastereoselectivities and enantioselectivities. The results also showed that increasing the steric hindrance of the substituent next to the methyl induces an improvement in diastereoselectivity. Computational modelling was also carried  out to get a better understanding of the reaction mechanism. The synthesized tricyclic compounds were engaged in several common reactions such as [2 + 2] photocycloaddition and Robinson-annulation with no erosion of the enantiomeric excesses.
In 2020, Toste and co-workers developed an acid-catalyzed kinetic resolution and asymmetric desymmetrization of paraquinols by an oxa-Michael addition in the presence of a chiral phosphoric acid catalyst (Scheme 6). [27] The authors started their investigations by determining the best catalyst which was the (R)-TCYP phosphoric acid cat-6. A screening of diverse arylboronic acids and boroxine reagents showed that the replacement of the 1-naphthylboronic acid This trend was confirmed with other pairs of boronic acids/ boroxine reagents. With the best conditions in hand, the authors extended the reaction to diversely functionalized quinols bearing substituents such as alkyl, alkenyl and heteroaromatic moieties, leading to the desired products 16 with moderate-to-excellent yields (20 to 56%) and enantioselectivities (65 to 89%). Based on experimental data and DFT calculations, the proposed mechanism would involve several possible transition states including the lowest-energy transition state I which would afford the desired enantiomer through an oxa-Michael addition.

R e v i e w T H E C H E M I C A L R E C O R D
Para-quinamines have also been integrated in chiral phosphoric acid catalysis as shown by the report of Sun, Xu, Lai and co-workers in 2021 (Scheme 7). [28] An enantioselective desymmetrization of para-quinamines 17 with isocyanates 18 was developed to produce functionalized imidazolidin-2-ones 19. After the optimization studies, good-to-excellent enantioselectivities were obtained with the chiral phosphoric acid catalyst cat-7 thanks to its large πsystem. Carbon tetrachloride was identified as the best solvent (for 19 b at 0°C: 78 % ee in dichloromethane versus 94 % ee in carbon tetrachloride). The addition of 5 Å molecular sieves and the reduction of the catalyst loading to 5 mol% improved the enantioselectivity to 98 % for compound 19 b. Various isocyanates were screened to see the robustness of the developed reaction. Good-to-excellent enantioselectivities were obtained with electron-rich or electron-deficient aryl substituents, regardless of the aromatic substitution, but also with alkyl substituents and allylic or benzyl isocyanates. Secondly, about the side chain R 1 of para-quinamines, the reaction can be carried out from methyl to n-hexyl but also with 3-butenyl or 1-propynyl with excellent yields and selectivities. The addition of R 1 phenyl groups caused a slight decrease in selectivities. For the R 2 substituent of the para-quinamines, the enantioselectivity was high with an arylmethyl group but low with a methyl group (19 e) indicating the importance of the nitrogen protecting group. To shed light on the mechanism, a series of controlled experiments was carried out and the results showed that the aza-Michael addition is an irreversible and fast step. The authors proposed an activation mode based on the simultaneous activation of the amine and the carbonyl group by hydrogen bonding interactions with the catalyst cat-7.

Catalysis with Chiral 1,2-Diamines
Bifunctional thiourea-amine organocatalysts have found widespread applications owing to their propensity to activate both the nucleophile and the electrophilic partner. [29] Wang and coworkers took advantage of the dual role of the catalyst to develop an asymmetric enantioselective organocatalyzed desymmetrization of spiro cyclohexadienone oxindoles 20 to produce the thiol adduct 22 (Scheme 8). [30] The thioureaamine catalyst can both enhance the thiol nucleophilicity and activate the conjugate double bond of the spiro-[cyclohexadienone-oxindole] via hydrogen bonding interactions. Several catalysts were tested and the bifunctional amine-thiourea catalyst cat-8 c gave the best results. The scope of the reaction has been evaluated on a wide range of aryl thiol compounds 21, and N-benzyl and N-methyl substituted spirocyclic oxindoles 20. All the different thiols 21 tested by Wang and co-workers gave good-to-excellent yields and enantioselectivities. This demonstrates the good robustness of the asymmetric sulfa-Michael addition reported herein.
In 2014, the group of Kotsuki and co-workers described an intermolecular asymmetric desymmetrization of 4,4-disubstituted cyclohexadienones 23 by Michael addition of diethyl malonate 24 (Scheme 9). [31] The reaction conditions were optimized from 4-methyl-4-phenyl-2,5-cyclohexadienone 23 a (R = Me, Ar = Ph). Starting with 10 mol% of amine-thiourea catalyst cat-9 and 10 mol% of 4-pyrrolidinopyridine (PPY) at atmospheric pressure, the reaction of 1 equiv. of 2 a with diethyl malonate led to 25 a and 26 a with 11 % yield after 4.5 days. Working at high pressure (0.8 GPa) increased the yield to 22 % (24 h reaction time). Surprisingly, the reaction failed in tetrahydrofuran indicating the important role of hydrogen-bonding interactions in this reaction. Increasing the catalyst loading to 30 mol% and using an excess of quinol 23 a enabled the synthesis of 25 a in 82 % yield and 92 % ee at 0.8 GPa. The substrate scope was investigated on a small range of substrates using diethyl malonate as a nucleophile. Kotsuki Scheme 7. Formation of imidazolidin-2-ones 19 under phosphoric acid catalysis. and co-workers suggested a dual catalytic system composed of catalyst cat-9 and PPY which can activate the diethyl malonate 24 as a Michael donor and the cyclohexadienone 23 as a Michael acceptor.
Another example of the use of chiral 1,2-diamine-based catalysts for the functionalization of cyclohexa-2,5-dienones was reported by Fan and colleagues in 2015 (Scheme 10). [32] The asymmetric catalytic aminolysis/aza-Michael addition of para-dienoneimides 27 enabled the formation of hydrocarbazoles 29. Several catalysts were tested at 25°C on a model reaction (27, R 1 = H and R 2 = Boc; 28, benzylamine) in chlorobenzene and the best results in terms of yield and enantioselectivity were obtained with the amine thiourea cat-10 a (51 % yield and 94 % ee). This catalyst works as a bifunctional catalyst thanks to its Brønsted acid and basic activity. Various modifications on R 1 and R 2 substituents of the para-dienoneimide 27 but also on R 3 substituent of the amine 28 were tolerated and the hydrocarbazoles 29 were produced in moderate-to-good yields and high enantioselectivities. Interestingly, the organocatalytic strategy was applied to the total synthesis of molecules from the Apocynaceae alkaloids family. For example, (+)-deethylibophyllidine was obtained from 30 a after 6 steps.
Sasai, Takizawa and colleagues also focused their efforts on the synthesis of chemical platforms found in biologically active natural products. [33] To this aim, the research group reported the formation of α-methylidene-γ-lactams 33 based on the combination of an amidation and a Rauhut-Currier (RC) reaction (Scheme 11). The use of cat-11 in the presence of a base was crucial for the success of the reaction.
Without base, the loading of cat-11 must be increased to 150 mol% because the hydrogen chloride formed during the reaction reacts with the catalyst to produce an inactive catalyst.

R e v i e w T H E C H E M I C A L R E C O R D
tested and the best yields and enantioselectivities were obtained with DIPEA. In presence of the base, which acts as a catalyst restorer, catalyst loading can be decreased to 20 mol%. Experiments also showed that the catalyst cat-11 can be reused five times from an experiment to another without purification and change in yield and enantioselectivity. The proposed mechanism involves the formation of an amide bond for which the catalyst cat- 11

Catalysis with Cinchona-Derived Organocatalysts
Cinchona alkaloids and organocatalysis have a long and rich history together, dating as far back as 1912. [34] The accessibility of Cinchona alkaloids together with their modularity make them attractive platforms for asymmetric organocatalysis. [16] For instance, Enders and co-workers recognized that the squaramide catalyst cat-12 could promote the enantioselective Scheme 10. Asymmetric organocatalyzed aminolysis/aza-Michael addition. a The other enantiomer is the major compound under these conditions. Scheme 11. Amidation/Rauhut-Currier sequence towards the formation of αmethylidene-γ-lactams 33.

R e v i e w T H E C H E M I C A L R E C O R D
Michael addition of thiols to cyclohexadienone 34 (Scheme 12). [35] A careful screening of the reaction conditions demonstrated a dramatic influence of the solvent on the yields while not impacting the enantiomeric ratios. The study of various 2,5-cyclohexadienones and thiols showed that the reaction was tolerant to electron-neutral aryl thiols, thiophenols with electron-donating or withdrawing groups, heteroaryl thiols and also to cyclohexadienones with different Nprotecting groups. From a mechanistic point of view, the formation of 36 proceeds through a desymmetrization of the cyclohexa-2,5-dienone motif involving a sulfa-Michael addition and a dynamic kinetic resolution process. Bifunctional catalysts derived from Cinchona have also been applied by Wang and co-workers to the desymmetrization of para-quinols 37 with fluoroalkylated hemiaminals 38 (Scheme 13). [36] A focus selection of quinine-based catalysts was tested in the reaction and the results showed that the thiourea motif was crucial to get high levels of enantiomeric excess. Establishing the substrate scope of the reaction proved that the position and the electronic property of the functional group R 1 had no influence on the yields and enantioselectivities. Regarding the R 2 substituent of the cyclohexadienone, decreasing the alkyl chain length had a positive impact on the enantioselectivity (92 % and 87 % ee when R 2 = Et and R 2 = Pr respectively).
Control experiments and DFT calculations would suggest that the catalyst can activate the carbonyl thanks to hydrogenbonding interactions while the nitrogen atom of the quinuclidine would guide the nucleophilic attack of 38 from the Siface.
By means of simple Cinchona catalysts, Chauhan and coworkers illustrated that cyclohexadienones 40 react with hydroperoxides 41 to produce isochromans 42, a benzenefused oxa-heterocycle often observed in natural or active products (Scheme 14). [37] The reaction with squaramide catalysts afforded the desired products with poor yields and enantioselectivities. Yields and selectivities were better with Cinchona alkaloid catalysts cat-14. In presence of the 9-O-benzyl-protected quinidine cat-14 c, the reaction time had to be increased to 240 h and isochroman 42 a was formed with a poor selectivity. Finally, quinidine cat-14 b was chosen because it gave a better yield and enantioselectivity in a shorter time. To establish the

Catalysis with Aminoacid-Derived Phosphines
In the previous examples, bifunctional catalysts used for the functionalization of cyclohexa-2,5-dienones possessed two active sites: a hydrogen-bonding donor element and a tertiary amine basic motif. Bifunctional catalysts based on a phosphine moiety found applications in a variety of asymmetric transformations and these catalysts were applied to the sulfa-Michael addition of 44 to cyclohexadienones 43 by Harned and co-workers in 2018 (Scheme 15). [38] The optimization was

R e v i e w T H E C H E M I C A L R E C O R D
performed on a model reaction using 2,4-dimethylquinol and 2-naphthalenethiol 44 . Several bifunctional thiourea catalysts were screened and the best results were obtained with catalyst cat-15 a.
Reactions failed with iminophosphorane-based catalyst cat-15 d or phosphine oxide cat-15 e, suggesting that phosphine plays a plausible role of base or hydrogen-bond acceptor. Less conformationally flexible catalysts also gave poor results. Low conversions observed with bis(thiourea) and bis(sulfonamide) catalysts demonstrate the need of a catalyst with both a Lewis basic site and a hydrogen-bond donor unit. However, thiourea-based catalysts form aggregates in solution, so a study of reactant concentrations showed that working under dilute conditions improved the selectivity. Solvents were also screened and the best results were obtained with trifluorotoluene. Studies on different para-quinols show that moving the R 1 substituent to the 3-position decreases the selectivity indicating an influence of the 2-position during the differentiation of the two enantiomers by the catalyst. On the contrary, modification of the alkyl chain in 2-position has no influence on the selectivity. Removal of the hydroxyl group from the cyclohexadienone was detrimental to the reaction. Two potential models have been suggested by the authors to explain the reaction outcome. In model A, the phosphine catalyst would deprotonate the thiol leading to a hydrogen bond between the phosphonium and the carbonyl group. Hydrogen-bonding interactions between the thiolate and both the quinol hydroxyl group and the thiourea would be involved and would guide the addition of the thiolate. In model B, no deprotonation from the phosphine would occur and the thiol would form a hydrogen bond network with the phosphine and the quinol hydroxyl group.
Another example of the use of aminoacid-derived phosphines for asymmetric reactions on cyclohexa-2,5-dienones has been reported by the group of Sasai in 2020 (Scheme 16). [39] The Rauhut-Currier (RC)-[3 + 2] annulation reaction was first optimized under batch conditions and the best catalyst was the (S)-Valine derived catalyst cat-16 a.
This sequence allowed the formation of chiral spirooxindoles 49 which are common scaffolds in natural and bioactive products. Although the yield was moderate under batch conditions, flow conditions were investigated to improve the isolated yield. Machine-learning-assisted exploration of suitable conditions was used to optimize the reaction under flow system, leading to the optimized reaction conditions shown in Scheme 16. The substrate scope of the reaction was also explored including cyclohexadienones 47 bearing aliphatic substituents (R 1 ) or methanesulfonyl group (R 2 ) and benzyl allenoate, all of which gave good-to-excellent yields and enantioselectivities.

Miscellaneous
In 2013, the group of Johnson presented an elegant enantioselective asymmetric oxa-Michael and Michael desymmetrization of para-quinols 50 in the presence of Hayashi-Jørgensen diarylprolinol ether catalyst cat-17 b (Scheme 17). [40] The optimal reaction conditions were determined starting from the para-quinol 50 a (R 1 = Me) and cinnamaldehyde 51 a (R 2 = Ph).
Experiments were carried out in dichloromethane and toluene, but better yields were obtained in toluene. 4-Nitrobenzoic acid (PNBA) was found to be the best co-catalyst to reach high yields and selectivities. A series of diarylprolinol ether catalysts cat-17 was tested. In the presence of free alcohol cat-17 a or 3,5-(CF 3 ) 2 C 6 H 3 -derived catalyst cat-17 d, no reaction occurred. Catalysts with bulkier groups such as TES or 3,5-Me 2 C 6 H 3 aromatic substituents gave the desired product with good yields but low diastereoselectivities. The best catalyst was the trimethylsilyl ether catalyst cat-17 b. The robustness of the reaction was determined starting from different quinols and aldehydes. For example, cinnamaldehyde derivatives 51 bearing electron-donating and withdrawing para-substituents on the aromatic ring gave excellent yields. For para-quinols, linear aliphatic or bulky substituents were well tolerated and gave the desired products 52 d and 52 e with good yields and moderate diastereoselective inductions.
Diarylprolinol silyl ether catalysts have also been applied to the enantioselective desymmetrization of prochiral para-quinamines 53 via an aminocatalyzed aza-Michael/intramolecular

R e v i e w T H E C H E M I C A L R E C O R D
cyclization by Coeffard, Greck and co-workers (Scheme 18). [41] The reaction optimization revealed that catalyst cat-18 c gave the highest yield and enantioselectivity. This result can be explained by the presence of a bulky silyl group (TBS), which increases the stability and the lifetime of the catalyst. Performing the reaction under acidic or neutral conditions decreased the yields. Different solvents were also screened and toluene was identified as the optimal one. This study also reported that the tosyl nitrogen protecting group of cyclohexadienone 53 was essential to ensure efficient deprotonation under basic conditions. Once the optimized conditions were investigated, the influence of the R 1 substituent of dienones and R 2 substituent of α,β-unsaturated aldehydes were studied. For example, the influence of the aromatic position of methyl and methoxy substituents of aldehyde on reaction rate was determined as following: para > meta > ortho and could be explained by an increased steric hindrance at the β position of the enal which prevents an efficient nucleophilic addition of the dienone. For the dienone, increasing the chain length of R 1 substituent decreases yields due to steric hindrance. In 2015, Sasai and co-workers proposed the use of phosphine catalysts for β,γ-Umpolung reaction involving a Michael and a Rauhut-Currier reaction (RC) between dienones 56 and allenic esters 57 to produce tetrahydrobenzofuranones 58 (Scheme 19). [42] Non-chiral Lewis bases were first evaluated for the reaction optimization. In presence of triphenylphosphine, the desired product was obtained in 72 % yield as an E/Z mixture (1 : 1), but side products were also obtained. The use of amine catalysts such as 4-dimethylaminopyridine (DMAP), DABCO or DBU gave only traces of the desired product. The use of axially chiral phosphines such as (R)-BINAP catalyst was also unsuccessful. Promising results were obtained with bifunctional catalysts such as cat-21, but low yields and selectivities were obtained. The best results were found with C 2 -symmetric highly nucleophilic monoaryl phosphines like cat-20 and especially cat-19 catalyst. Solvents, temperature and reactant ratio were also screened and led to the optimized reaction

R e v i e w T H E C H E M I C A L R E C O R D
conditions shown in Scheme 19. The reaction would start with the nucleophilic attack of the phosphine catalyst to the βposition of the allenic ester 57 giving rise to I. Deprotonation of para-quinol 56 by I followed by addition of the alcoholate to II would produce the intermediate III.
An intramolecular Michael addition would give rise to IV which would lead to the desired product 58. This transformation was extended to alkynes by Sasai in 2018. [43] In 2019, Liu and co-workers described an asymmetric organocatalyzed desymmetrization of para-quinols catalysed by chiral bisguanidinium hemisalts (Scheme 20). [44] The best results were obtained with cat-22 b while (bis)guanidines gave the desired product with moderate enantiomeric excesses. Good yields were achieved by switching from Ar F 4 B À counter anion to Ph 4 B À .
In light of the importance of fluoro-containing compounds in pharmaceuticals and agrochemicals, the group studied the functionalization of 4-trifluoromethyl substituted para-quinols and some examples are described in Scheme 20. Based on the crystal structure of the bisguanidinium hemisalt cat-22 b, a bifunctional catalyst model was proposed to explain the diastereo-and the enantioselectivity of the reaction. It seems that the basic guanidine catalyst accelerates the azlactone enolization, while the vicinal amide interacts with an oxygen atom of the heterocycle thanks to hydrogen bonding. The guanidinium salt and the amide would interact with the paraquinol directing its approach through a Re-Re face contact.

Catalysis with Cinchona-Derived Organocatalysts
Chiral primary and secondary amines are prone to react with carbonyl compounds to give enamine and iminium intermediates which are key species in the field of aminocatalysis. The enamine concept was further extended to dienamine [45] and trienamine-based [46] activation modes expanding the field of aminocatalysis. In 2012, the group of Melchiorre elaborated a strategy based on the concept of vinylogous iminium ion catalysis to functionalize the δ-position of 3-alkenyl-cyclohex-2-enones (Scheme 21). [47] The transformation is based on an asymmetric 1,6-addition reaction which was promoted by the cinchona-based primary amine cat-23 as a catalyst and the acid 64 as a co-catalyst. The acid co-catalyst plays a crucial role in the reaction because no reaction occurred in the absence of acid and therefore a Lewis base activation of 63 can be ruled out. The optimized conditions were subsequently applied to other 3-alkenylcyclohex-2-enones bearing heteroaryl, aryl and methyl groups from which 14 products were obtained in yields ranging from 54 % to 70 % and with high enantiomeric excesses. Furthermore, the transformation also tolerated the presence of aryl and allyl moieties on the nucleophilic thiol component 63. During the development of the reaction, the products from both 1,6 and 1,4-addition were also observed in variable and low amounts. Based on this observation, the authors decided to exploit this reactivity to obtain more complex structural products 67. This strategy was successfully investigated by increasing the catalytic and co-catalytic loading and the reaction time as well as introducing the thiol derivative 63 b (R 3 = 4-MeOC 6 H 4 ) in large excess. The products 67 were obtained in moderate yields and diastereomeric ratios, while the values of enantiomeric excesses remained high.
In the previous example, the cinchona-based primary amine reacted with the substrates 62 inducing a LUMOlowering effect. In 2012, Chen and colleagues exploited the HOMO-raising amine-based dienamine activation mode to access to bicyclo[2.2.2]octane derivatives 70 (Scheme 22). [48] Amongst the α,β-unsaturated ketone derivatives used, the authors investigated the 3-alkenyl-cyclohex-2-enones 68 which led to the formation of products 70 a or 70 b depending on the Cinchona-based catalyst cat-24 or cat-25 used with the assistance of salicylic acid as a co-catalyst. The transformation displayed excellent enantioselectivities and moderate-to-good diastereomeric ratios using primary amine as a catalyst. The proposed catalytic mechanism would proceed in a stepwise Michael-Michael addition cascade and involved the formation of the intermediate I from which it is possible to rationalize the geometry of the product. Using the catalyst cat-24, intermediate I might result from an assembly formed by hydrogen bonding between the nitrile derivative and the acid as well as between the acid and the Cinchona species. This intermediate would arise from the condensation of the α,βunsaturated ketone derivative and the catalyst. The Re-face attack might be explained by the orientation of the reagent due to a π-π stacking between the quinoline moiety and the aryl group borne by the malononitrile derivative.

R e v i e w T H E C H E M I C A L R E C O R D
(Scheme 23). [49] Among the different reaction parameters examined such as the catalyst, additives or the solvent, it turned out that the choice and the presence of both the catalyst and the acid were decisive. Running the reaction with TFA or in the absence of an acid led to the desired product in low yields while using the catalytic system cat-26/73d allowed the formation of the product in 89% yield and high selectivities. A wide range of cyclohex-2-enones derivatives bearing substituted aromatics was used and the reaction is tolerant regardless of the substitution pattern of the aromatic group. Additionally, the reaction also allows the presence of a thiophene moiety and an aliphatic substituent such as a methyl group (R 1 ).
In the same vein, Ye and co-workers reported an enantioselective 1,6-addition/1,4-addition to generate new complex spirocyclic scaffolds (Scheme 24). [50] As observed in the previous examples, a catalytic system involving a cinchonabased amine catalyst cat-25 and an acid co-catalyst was required to promote the reaction. Switching from benzoic acid 73 a to (S)-mandelic acid (77) enhanced the stereoselectivity while the use of its (R)-enantiomer slightly decreased the enantiomeric excess. The optimized conditions were employed on several 3-alkenyl-cyclohex-2-enone derivatives leading to 24 compounds. Various substituents were allowed for the reaction, such as phenyl derivative rings or ester for R 3 , and electro-withdrawing or donating groups for R 4 . All the cyclized

R e v i e w T H E C H E M I C A L R E C O R D
products were produced in moderate-to-good yields and diastereomeric ratio, along with high enantioselectivities. For chiral HPLC separation, the nitrogen protection was carried out after the organocatalytic step. Mechanistically, the strategy is based on a 1,6-addition/ 1,4-addition cascade reaction. The exposed mechanism would start with the condensation of the catalyst cat-25 with the 3alkenyl-cyclohex-2-enone derivative to form the activated vinylogous iminium ion I, which would then undergo a 1,6addition to produce the intermediate II. From the latter, a tautomeric process would lead to the intermediate III, which would evolve through an intramolecular thia-Michael addition to give access to the spiro compounds after a hydrolysis step.
In 2017, another elegant tactic based on an hydrogen bond activation of cyclohex-2-enone derivatives, in contrast to the previously covalent bond activation, was investigated by the group of Albrecht (Scheme 25). [51] To investigate the influence of the free C-9 alcohol, the authors carried out the reaction in the presence of β-isocupreidine catalyst cat-31. The reaction conversion was extremely low suggesting that the free C-9 alcohol plays a key role in the mechanism. Further optimization of the reaction conditions showed that cinchonine cat-30 a was the best catalyst to reach high ee as well as chloroform for the solvent, which allowed to obtain 13 compounds with

R e v i e w T H E C H E M I C A L R E C O R D
yields up to 98 % and excellent selectivities. In a mechanistic viewpoint, the reaction would start by the deprotonation of the thiol which would react via a 1,6-Michael addition following the transition state I. Intramolecular cyclization would then afford the desired products.
In 2018, Ouyang, Chen and co-workers demonstrated that cross-trienamine intermediates could react through [4 + 2] cycloadditions to prepare polycyclic compounds. (Scheme 26). [52] Two activated alkenes were investigated for this reaction: α-cyano-α,β-unsaturated ketones 83 and the alkene derived from the Meldrum's acid 85. The catalytic system cat-24/thiosalicylic acid was optimal to obtain the bicyclo products 84 with moderate-to-good yields and excellent enantiomeric excesses up to 98 %. Thereafter, the authors extended the reaction to other alkenes 85 derived from Meldrum's acid, which also showed exclusive �,δ-regioselectivity in the reactions with 82. The reaction was performed with cat-32 and salicylic acid, respectively as a catalyst and a cocatalyst. The products 86 were provided with good yields and enantioselectivities, although the diastereomeric ratio was moderate-to-good.
The research group of Xia and Xu focused their studies on the addition of (nitromethyl)benzenes to the δ-position of cyclic dienone derivatives (Scheme 27). [53] Preliminary investigations showed that (nitromethyl)benzene was a suitable nucleophile for this reaction while nitromethane did not react. The identification of the optimized conditions revealed that Cinchona-based amine catalysts such as cat-33 were superior to other classic diamine catalysts and bifunctional thiourea organocatalysts. The optimum conditions were applied to a focus selection of (nitromethyl)benzenes while a range of (hetero)aryl substituents were tolerated for the R 2 group. While high levels of enantiomeric excesses were obtained, poor-to-moderate diastereoselectivity were observed owing to a probable easy racemization at the alpha site of the nitromethyl moiety.
Following the work of Ye and colleagues about the enantioselective 1,6-addition/1,4-addition cascade process (Scheme 24), the group of Pan applied the same strategy to the synthesis of spiro-dihydropyrano cyclohexanones (Scheme 28). [54] Their investigation began with the optimization of the reaction conditions realized on the dienone derivative 91 a (R 1 = Ph) and the compound 92 a (R 2 = Ph), which led to the selection of the Cinchona-based primary amine cat-32 as a catalyst. The use of diamine derivatives, such as compound cat-38 enabled the preparation of the desired compound with drastically lower enantiomeric excesses. The authors applied the optimized reaction conditions on a range of α-cyanoketones and dienone derivatives. The R 1 and R 2 groups were limited to aromatic groups and the Scheme 26. Synthesis of functionalized hydronaphthalen-2-one from 82 through an organocatalysis triggered cycloaddition.

R e v i e w T H E C H E M I C A L R E C O R D
products were obtained in good-to-excellent yields and enantioselectivities while the diastereoselectivities remained low regardless of the substitution pattern of 91 and 92.

Catalysis with Chiral 1,2-Diamines
The enantioselective functionalization of the δ-position of 3alkenyl-cyclohex-2-enone derivatives is also achievable via a chiral 1,2-diamine catalyst as described by Dixon and Ye in 2015 (Scheme 29). [55] An extensive screening of reaction conditions allowed the selection of the diamine catalyst cat-28 a and para-anisic acid 73 c. The optimized reaction conditions were subsequently investigated on different cyclohex-2-enone derivatives. A first set of compounds, bearing Boc protective group on the lactam derivative, was obtained with moderate-to-excellent yields and high levels of diastereo-and enantioselectivities. However, long reaction times were required, up to 4 days. The transformation was tolerant with the presence of (hetero)aryl rings (R 1 ), such as thienyl or phenyl derivatives and alkyl groups. The products were also accessible

R e v i e w T H E C H E M I C A L R E C O R D
with benzyloxycarbonyl or toluenesulfonyl as N-protective groups with phenyl derivatives rings for R 1 . Afterwards, this strategy was extended to the formation of fused polycycles by performing the reaction on cyclopentadienone derivatives instead of cyclohex-2-enone compounds. Nevertheless, the molecules were provided in yields ranging from 37 % to 67 % but with high enantioselectivity values up to 99 %. The previous strategy was extended to other nucleophilic partners such as 5H-oxazol-4-ones and 2-oxindoles by the group of Ye. [56] A similar catalyst system combining the diamine cat-39 and 73 a found to be relevant for the formation of 103 (Scheme 30). A vast number of products 103 were synthesized by this protocol, many with excellent diastereo-and enantioselectivities (ee: 98-99 %). The substrate scope featured the reaction of 5H-oxazol-4-ones 102 with dienones 101 containing diverse (hetero)aromatic R 1 groups such as substituted benzene rings, naphthalene or thiophene. 2-oxindoles has also been considered for the functionalization of dienones 101 (Scheme 31).
Nevertheless, more disparate results were obtained for enantiomeric excesses and diastereomeric ratios ranging from 6 : 1 to 19 : 1. While 3 days were required with 102, a longer reaction time (5 days) was required for the reaction of 101 with 104.
In 2020, Zhang, Ye and co-workers described an asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethyl isatin ketimines 107 with cyclic dienones 106 (Scheme 32). [57] Key to the success of the reaction was the use of the catalyst cat-40 which proved to be superior to other diamine organocatalysts both in terms of yields and enantioselectivities. Various parameters were evaluated during the optimization step such as the temperature or the solvent. The optimized condition reactions showed in Scheme 32 allowed the formation of 20 products with overall good levels of yields and high enantiomeric excesses up to 95 %. The authors mentioned the essential role of the N-substituent (R 4 ) for good solubilization in dichloromethane of the substrates 107 leading to the spirocycles 108 with good-to-excellent yields (26 % with

R e v i e w T H E C H E M I C A L R E C O R D
NÀ H for R 1 = R 3 = H and R 2 = Ph). Except for the abovementioned criterion, the reaction did not show relevant dependence of R 2 moiety which was mainly phenyl derivatives bearing electron-rich or poor substituents. It is interesting to note that the reaction could also be realized with an ester for R 2 , even if the diastereomeric ratio was lower.

Miscellaneous
Although amine-based catalysts have been largely described for the functionalization of 3-alkenyl-cyclohex-2-enones, the group of Melchiorre reported a LUMO-lowering activation of this family of substrates employing a readily available chiral phosphoric acid (Scheme 33). [58] The authors showed that binol-derived phosphoric acids were able to promote the reaction between 3-alkenyl-cyclohex-2-enone and indole de-rivatives. In the presence of the catalyst, the yields and the enantiomeric excesses were sensitive to the moiety flanked on the binol, unlike the diastereomeric ratio values which were mainly higher than 19 : 1 under the optimized reaction conditions. The reactions were carried out with the catalyst cat-43 a to deliver 18 compounds. The role of the catalyst was to activate both the substrate 109 and the reagent 110 by hydrogen bonding, which was confirmed with a test carried out with the N-methyl indole derivative whose reaction conversion was unsatisfactory. The substrate scope was mainly realized with various phenyl derivatives for R 1 and R 3 . The substituent R 2 was either an electro-withdrawing or donating group with no significant impact on the enantioselectivity.

R e v i e w T H E C H E M I C A L R E C O R D
However, with methoxy for R 2 , the reaction was negatively impacted to reach only a yield level of 59 %. All compounds presented good-to-excellent enantiomeric excesses, up to 99 %.

Functionalization of 2,6-Dialkylidenecyclohexanones
In 2011, Yan and co-workers reported a conjugate addition of malononitrile to dienone 112 organocatalyzed by the bifunctional catalyst cat-45 (Scheme 34). [59] The desired pyran 113 was obtained in 97 % yield and 92 % enantiomeric excess. The transformation was limited to one example of cyclohexadienone substrate but the reaction was successfully extended to diversely substituted conformationally restricted dienones producing enantioenriched piperidine derivatives 114 a-f, tetrahydropyrans 114 g or other functionalized pyrans 114 h-i. The authors demonstrated that this reaction can also be promoted by quinine as an organocatalyst. [60] Du and Gao took advantage of the bifunctional activity of the tertiary amine-squaramide catalyst in the reaction of malononitrile with the conformationally restricted dienones 115 (Scheme 35). [61] After a careful optimisation, the organocatalyst cat-46 was investigated in the reaction of malononitrile with carbocycles such as bisarylidenecyclohexanone 115

R e v i e w T H E C H E M I C A L R E C O R D
produce the dispirane 119 (Scheme 36). [62] With (S,S)-FerroPHANE cat-47 as the catalyst, the product 119 was isolated in 60 % yield with high selectivities. In their studies, other substituted conformationally restricted dienones were investigated to form spiranes and dispiranes.

Functionalization of 6-Alkylidenecyclohex-2-Ones
The organocatalyst 9-amino-9-deoxy epiquinine cat-25 was employed by the research group of Chen in 2017 to access highly functionalized poly-fused cycles from 6-alkylidenecyclohex-2-one derivatives 120. [63] To achieve their goal, the methodology involved an inverse electron-demand aza-Diels-Alder reaction, which was triggered by the presence of the catalyst (Scheme 37). The condensation of the catalyst with the substrate 120 leads to the formation of a cross-conjugated trienamine intermediate, which allows the [4 + 2] cycloaddition with 121. The reaction was performed on a large panel of substrates and reagents bearing phenyl derivatives substituted with electron-withdrawing or electron-donating groups and alkyl such as methyl, propyl or pentyl groups. The different products were isolated in good-to-high yields and enantiomeric excess values. In order to shed light on the regioselectivity of the cycloaddition, DFT studies were performed on simplified cross-conjugated trienamine intermediates. The results of the DFT calculations showed that the intermediate I is thermodynamically more stable and possesses a higher HOMO energy level and therefore a greater reactivity towards the cycloaddition. These outcomes are in agreement with the reactivity of the β,γ-alkene bond. Chen and co-workers later decided to apply this strategy in the same work to other components that could perform aza-Diels-Alder reactions (Scheme 37). Reagent 123 was successfully engaged and yielded 8 adducts with still good enantioselectivities. In the same year, the same group developed an elegant strategy for the regioselective functionalization of 126 (Scheme 38). [64] This route was initially set up with malononitrile as a nucleophile and the best reaction conditions involved the chiral 1,2-diamine derivative cat-36 as a catalyst and salicylic acid as a co-catalyst. The reaction also required the presence of the nucleophilic co-catalyst 128 to obtain the desired compounds 129 in 50-93 % yields. The presence of this cocatalyst prevents the addition of malononitrile on the exoalkylidene diene. The reaction was tolerant with aryl substituents for R 1 while the presence of alkyl groups led to lower levels of yields. The transformation was also feasible with a malononitrile derivative bearing a propargyl moiety (R 2 ). The crucial role of thiol 128 is presented on the mechanism proposed in Scheme 38, whose intermediates could be detected by HRMS analyses. The thiol component allows the deactivation of the exo-alkylidene diene via a reversible 1,4-addition reaction on the dienone motif. Then, the formation of intermediate II enables the addition of the malononitrile derivative on the cyclohex-2-one ring. Further, DFT calculations showed that the presence of the thiol and the dienamine catalyst activates the β-position of the endo-cyclic diene more than a hypothetical intermediate which only includes the dienamine catalyst. A thiol release and then hydrolysis step led to the desired products. This work was extended to indole nucleophiles 131 which gave 13 compounds in 51-94 % yields.
In a work from Jørgensen, cyclohexen-2-ones 126 underwent formal [4 + 2] and [8 + 2] cycloadditions to generate polycyclic compounds 136 and 137 (Scheme 39). [65] To implement these reactions, the cinchona catalyst cat-24 was used in the presence of camphorsulfonic acid (CSA) or propanoic acid. For the compounds 136, the transformation involved dicyanoheptafulvene 134 and led only to the formal [4 + 2] cycloadducts with variable yields and enantiomeric excesses between 61-80 %. The [8 + 2] cycloadducts 137 were specifically available from the cyanoesterheptafulvene 135 with disparate yields but with a very efficient enantiocontrol. These differences about the yield and the enantiocontrol were due to the sensitivity of the reaction to the nature of R 1 when using the dicyanoheptafulvene component, for which an electronwithdrawing group induced a low yield and enantiomeric

R e v i e w T H E C H E M I C A L R E C O R D
excess, while the opposite result was reported with an electrondonating group. In order to better understand the results, the authors have conducted different experiments, which led them to suggest a mechanism described in Scheme 39. The pathway reaction would start with the formation of intermediate I, from which two ways are possible. If the reagent contains the dicyano moiety then the [8 + 2]-cycloadduct is formed after a hydrolysis step, in the other case an equilibrium gives access to a zwiterrionic species, which then evolves towards the formal [4 + 2]-cycloadduct after hydrolysis.
In the study realized in 2017 by Chen and co-workers, the functionalization of the endo-cyclic alkene was achieved by using the thiol 128 co-catalyst preventing the addition of malononitrile on the exo-cyclic part (Scheme 38). In 2020, the same group also used a thiol as co-catalyst, but to protect the β-position of the endo-cyclic alkene, which allowed the formation of the spirocyclic compounds 139 (Scheme 40). [66] Various parameters were scrutinized such as the catalyst and the acid co-catalyst, as well as the temperature and the solvent. These studies led to the optimized reaction conditions showed in Scheme 40 with the use of quinine cat-29 a. Examples of substituents borne by the compound 126 include aryl, pyridyl, furyl or ethyl groups while heterocycles 138 bearing different protecting groups were tested. All compounds were obtained with good-to-excellent yields and with high enantiomeric excesses, up to 96 % except for the compound 126 bearing an ethyl group. The one-pot formation of spiro-product 139 started with the activation of endo-cyclic alkene thanks to the hydrogen bond formed between the catalyst and the carbonyl,

Conclusions
Asymmetric organocatalysis continues to impact many aspects of organic synthesis. The wealth of catalytic systems available to the scientific community and various modes of organocatalytic activations explain, in part, why asymmetric organo-Scheme 40. Regio-and enantioselective synthesis of spirocyclic compounds 139.

R e v i e w T H E C H E M I C A L R E C O R D
catalysis is a leading method for creating or breaking chemical bonds. In this review, we discussed the intermolecular functionalization of (cross)-conjugated cyclohexanone-derived compounds employing asymmetric organocatalysis. These molecular architectures display a large palette of reactivity that offers interesting synthetic possibilities. For instance, (cross)conjugated cyclohexanone-derived compounds underwent Diels-Alder cycloadditions, Michael additions or Friedel-Crafts alkylations as representative transformations. Throughout this review, we have sought to highlight the importance of screening the catalytic system and other reaction parameters for determining the best conditions. This part is very often time-consuming and not efficient because the optimization task is traditionally based on a strategy involving the modification of one reaction parameter at a time. The recent emergence of predictive sciences for the implementation of synthetic methodologies could be an attractive tool in the near future to accelerate the discoveries of new catalytic systems. In addition, the investigations of other (cross)-conjugated cyclohexanone-derived compounds could pave the way to diversely functionalized products with applications in total synthesis of natural products or biologically relevant molecules.