Regiodivergent Organocatalytic Reactions

: Organocatalysts are abundantly used for various transformations, particularly to obtain highly enantio- and diastereomeric pure products by controlling the stereochemistry. These applications of organocatalysts have been the topic of several reviews. Organocatalysts have emerged as one of the very essential areas of research due to their mild reaction conditions, cost-effective nature, non-toxicity, and environmentally benign approach that obviates the need for transition metal catalysts and other toxic reagents. Various types of organocatalysts including amine catalysts, Brønsted acids, and Lewis bases such as N-heterocyclic carbene (NHC) catalysts, cinchona alkaloids, 4-dimethylaminopyridine (DMAP), and hydrogen bond-donating catalysts, have gained renewed interest because of their regioselectivity. In this review, we present recent advances in regiodivergent reactions that are governed by organocatalysts. Additionally, we brieﬂy discuss the reaction pathways of achieving regiodivergent products by changes in conditions such as solvents, additives, or the temperature.


Lewis Base Catalysts
Lewis base catalysts, including various tertiary amines (1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), of water, affording an oxocarbenium ion, which results in both of the cyclic hemiorthoesters (INT and ent-INT) having excellent diastereoselectivity. At this stage, chiral phosphoric acid then collapses these intermediates for regiodivergent RRM (reaction of a racemic mixture) to afford both constitutional isomers. The authors expected that the catalyst would activate different oxygen atoms to form the respective enantiomers. INT may collapse via pathway C which results in ent-5-3, which may be the reason for the lower enantioselectivity of the 5-3 isomer. Scheme 11. Proposed mechanism for the synthesis of enantioenriched bromohydrins.
The proposed mechanistic pathway involves the formation of zwitterionic intermediate A by the addition of catalyst 6-6c to 6-1c, which then abstracts the C-4-proton of 2-phenyl-4-methyloxazol-5(4H)-one 6-2a' (Scheme 13). Further oxazolide C1 reacts with phosphonium B at the C-4 position of C1 via the transition state TS-C4, followed by a hydride shift to generate addition product 6-3a' by the elimination of the catalyst. In contrast, the use of 2-methyl-4-phenyloxazol-5(4H)-one 6-4a generates the oxazolide C2, which favors the C-2-selective addition to eventually lead to the formation of C-2-selective product 6-5a, via a key transition state, TS-C2. Theoretical studies (DFT calculations) suggested that the origin of the observed regioselectivity was the distortion energy that resulted from the interaction between the nucleophilic oxazolones and the electrophilic phosphonium intermediate. Recently, in 2020, Lin's group developed a regiodivergent cascade reaction between 3-homoacylcoumarin (7-1) and the 1,3-indanedione-derived 1,6-acceptor  to construct spirocyclohexene indane-1,3-diones (7-3) and coumarin-fused cyclopentanes  catalyzed by bases such as DMAP or Et 3 N, respectively (Scheme 14) [73]. In the presence of DMAP as the base, the reaction afforded spirocyclohexene indane-1,3-diones (7-3) via 1,6-addition followed by a regio-and chemoselective aldol cascade reaction. Electronic factors did not influence the yields when 3-homoacylcoumarin containing various group such as 6-Cl, 6-Br, and 6-methoxy was used, and all derivatives afforded the expected products in good yields. In the case of the indanedione-derived acceptors, EWGs provided the products in better yields than the methoxy group regardless of its position. Fused cyclopentanes  were obtained via 1,6-addition followed by a regio-and chemoselective vinylogous Michael addition by using Et 3 N. The presence of an EWG on coumarins ensured good yields compared with an EDG irrespective of its position. This is because the EDG on coumarin enhanced the electron density at the reactive site to prevent an intramolecular Michael addition. Moreover, in the case of indanedione, sterically bulky EWGs afforded the products in good yields, whereas no product formed in the case of an EDG (OMe).
Based on the experimental results, the authors proposed a plausible mechanistic pathway (Scheme 15). Initially, in the presence of organocatalytic bases (DMAP or Et 3 N), 1,6-addition occurs between 3-homoacylcoumarin 7-1 and the indanedione 7-2 to provide a common intermediate, Shi and co-workers developed regioselective trifluoromethylthiolation between Morita-Baylis-Hillman (MBH) carbonates  and Zard's trifluoromethylthiolation reagent (8-1a) in the presence of DABCO (Scheme 16) [74]. A primary allylic trifluoromethylthiolate (SCF 3 ) was obtained as the favored product  when the authors used tetrahydrofuran as the solvent at room temperature, whereas when using chloroform at 0 • C, this produced a secondary allylic trifluoromethylthiolate as a major product . The optimized reaction conditions with THF enabled the reaction to smoothly proceed with various MBH carbonates containing 4-Cl, 4-CN, 4-Br, and heterocyclic compounds such as 2-thienyl, 2-furyl, and 2-pyridyl to afford the primary allylic trifluoromethylthiolation products in good yields with good regioselectivities. Similarly, MBH carbonates containing 4-MeO, 3-Me, 4-NO 2 , and 2-pyridyl produced a secondary allylic trifluoromethylthiolate in the CHCl 3 solvent with good yields and high selectivities. In the mechanism depicted in Scheme 17, this reaction proceeded with an initial nucleophilic addition of DABCO to 8-1a and 8-2a, forming the ammonium salt intermediates A and B, respectively. Then, the exchange of SCF 3 -and t BuO-afforded the other intermediates C and D. The secondary allylic trifluoromethylthiolation product 8-4a was obtained by an intermolecular S N 2' reaction of intermediate D.
In the presence of the catalyst DABCO, the secondary product was readily converted to the primary product in THF, whereas the conversion in chloroform was difficult. This is attributed to electrostatic interaction between¯SCF 3 and CHCl 3 , weakening the nucleophilicity of the SCF 3 anion. The catalyst DABCO was regenerated by the nucleophilic addition of water to intermediate C.
A divergent strategy was developed by Liu and Chen et al. for the modular synthesis of various enantioenriched phenylthio-substituted lactones from the thiolation of homoallylic acids via regiodivergent cyclization (Scheme 18) [75]. The authors developed Lewis base/Brønsted acid co-catalyst-controlled regio-and enantioselective thiolactonizations of a variety of homoallylic acid derivatives with different electrophilic SAr reagents (6-endo vs. 5-exo). The homoallylic acid (9-1) underwent 6-endo cyclization using N-phenyl thiosaccharin (9-2) as the sulfenylating agent, and chiral BINOL-derived selenide ((S)-9-5a) as the Lewis base. Various styrene-based carboxylic acids afforded the products (9-3) in excellent yields with high enantioselectivity, which was affected by the position of the substrate. For instance, a fluorine substituent in the para position resulted in high enantioselectivity compared with the meta or ortho positions. Moreover, 2-naphthyl, 2-thienyl, 3-furyl, and various substituted ethynylbenzenes underwent this reaction to afford δ-valerolactones in good yield with good enantioselectivity. In the presence of 1.0 equivalent of EtSO 3 H using N-phenylthiotphthalimide as the sulfenylating agent, and chiral BINOL-derived selenide as the Lewis base, homoallylic acids afforded various γ-butyrolactones . Styrene derivatives with various functional groups, irrespective of their position, underwent 5exo cyclization to yield the corresponding five-membered ring products in good yields with high enantioselectivities. 2-Naphthyl and various unbiased alkyl-substituted alkenes proceeded smoothly to afford the products in good yields with high enantioselectivities, whereas an ethynylbenzene-substituted alkene afforded the product in poor yield with moderate enantioselectivity.
A and B, respectively. Then, the exchange of SCF3-and t BuO-afforded the other intermediates C and D. The secondary allylic trifluoromethylthiolation product 8-4a was obtained by an intermolecular SN2' reaction of intermediate D.
In the presence of the catalyst DABCO, the secondary product was readily converted to the primary product in THF, whereas the conversion in chloroform was difficult. This is attributed to electrostatic interaction between ¯SCF3 and CHCl3, weakening the nucleophilicity of the SCF3 anion. The catalyst DABCO was regenerated by the nucleophilic addition of water to intermediate C. Scheme 17. Plausible reaction mechanism for trifluoromethylthiolation.
A divergent strategy was developed by Liu and Chen et al. for the modular synthesis of various enantioenriched phenylthio-substituted lactones from the thiolation of homoallylic acids via regiodivergent cyclization (Scheme 18) [75]. The authors developed Lewis base/Brønsted acid co-catalyst-controlled regio-and enantioselective thiolactonizations of a variety of homoallylic acid derivatives with different electrophilic SAr reagents (6-endo vs. 5-exo). The homoallylic acid (9-1) underwent 6-endo cyclization using N-phenyl thiosaccharin (9-2) as the sulfenylating agent, and chiral BINOL-derived selenide ((S)-9-5a) as the Lewis base. Various styrene-based carboxylic acids afforded the products (9-3) in excellent yields with high enantioselectivity, which was affected by the position of the substrate. For instance, a fluorine substituent in the para position resulted in high enantioselectivity compared with the meta or ortho positions. Moreover, 2-naphthyl, 2-thienyl, 3furyl, and various substituted ethynylbenzenes underwent this reaction to afford δvalerolactones in good yield with good enantioselectivity. In the presence of 1.0 equivalent of EtSO3H using N-phenylthiotphthalimide as the sulfenylating agent, and chiral BINOL-derived selenide as the Lewis base, homoallylic acids afforded various γ-butyrolactones . Styrene derivatives with various functional groups, irrespective of their position, underwent 5-exo cyclization to yield the corresponding five-membered ring products in good yields with high enantioselectivities. 2-Naphthyl and various unbiased alkyl-Scheme 17. Plausible reaction mechanism for trifluoromethylthiolation. These researchers conducted experimental and computational studies to elucidate the origins of the regio-and enantioselectivity. The results of kinetic control experiments to acquire mechanistic information suggested that the 6-endo product (9-3a) could isomerize into a thermodynamic 5-exo product (9-4a) via the configurationally stable thiiranium intermediate under strongly acidic conditions (Scheme 19), which was further supported by the reaction between 6-endo and 5-exo with 100 mol% of EtSO 3 H to afford a 5-exo product with retention of ee. The combination of DFT calculation results suggested that C-O and C-S bond formation might occur simultaneously, without formation of a commonly supposed catalyst-coordinated thiiranium ion intermediate. The potential π-π stacking between the substrate and SPh is an important factor in the enantio-determining step.  [76]. The use of the L-thr-D-thr-derived chiral phosphine catalyst 10-5g in an ether in an annulation reaction produced the α-isomer 10-3 in moderate to good yield with excellent enantioselectivities. On the other hand, the L-thr-L-thr-derived chiral phosphine catalyst 10-5b yielded the γ-isomer 10-4 in good yield with high enantioselectivities (96-99%). Under the optimized reaction conditions, various substituted aurones afforded αor γ-selective spiro benzofuranones with excellent enantio-and regioselectivities depending on the catalyst present. Mechanistic studies suggested that the phosphine catalyst attacked the allene (10-2) to form zwitterionic intermediate B, in which the negative charge may be delocalized either on the α-carbon or the γ-carbon (Scheme 21). Then, the aurone (10-1a) underwent [3+2] annulation with the putative intermediates, delivering intermediates E or I. Proton transfer followed by elimination of the phosphine catalyst furnished the αand γ-selective products.
Cahard et al. reported the synthesis of primary and secondary allylic SCF 3 compounds in the presence of DABCO with Morita-Baylis-Hillman (MBH) carbonates (Scheme 22) [77]. The combination of CF 3 SiMe 3 /S 8 /KF in DMF as the solvent afforded the primary product . Regardless of whether an EWG or EDG was present on the MBH carbonate, the primary allylic SCF 3 products formed in excellent yields. Sterically bulky groups such as 1-and 2-naphthyls and 2-thienyl were well tolerated in this trifluoromethyl thiolation reaction, furnishing the equivalent products in good yields. On the other hand, Zard's reagent (CF 3 SCO 2 C 18 H 37 ) afforded the secondary allylic SCF 3 product (11-3i) when the reaction was conducted in the THF solvent at room temperature. The authors expected that the base DABCO would activate both Zard's reagent and the MBH carbonate and provide the secondary allylic trifluoromethyl thiolation product 11-3i (kinetic product) within 5 min. Upon extension of the reaction time to 30 min, the kinetic product (secondary) was rapidly isomerized into a thermodynamic product (11-2i, primary allylic trifluoromethyl thiolation product), as monitored by 19 F NMR. Ye's group established sultam-fused azetidines and dihydropyrroles via two different cycloadditions ([2+2] and [3+2]) from cyclic sulfonamide ketimines (12-1) and allenoates (1-2). These compounds are formed by involving Lewis bases in the reaction (Scheme 23) [78]. In the toluene solvent at room temperature, PPh 3 , as a catalyst, underwent a [3+2] cycloaddition to produce 12-4 as the product via α-addition. The regioselectivity was switched in the case of PBu 3 , which led to a γ-cycloadduct (12-3). A completely different cycloaddition product was formed with the DABCO catalyst, delivering a [2+2] cycloadduct . Ketimines with an EDG or EDG worked well. Similarly, various allenoates were also found to be suitable under optimized conditions. The authors also proposed a reaction mechanism (Scheme 24). They suggested that the reaction was initiated by adding Lewis bases to the allenoate (1-2) to generate two zwitterionic intermediates, A and A', which react with the cyclicimines (12-1) to form intermediate B or B'. The carbanion A' was stabilized by the electron-poor nucleophile PPh 3 which then produced the thermodynamically favored α-addition intermediate B', and elimination of the catalyst delivered 12-4. In the case of DABCO and PBu 3 , which are relatively electron-rich nucleophiles, they provided kinetically favored intermediate B via γ-addition. Later, these intermediates underwent ring closure, followed by the release of the catalysts, to afford the expected cycloaddition products (12-2 and 12-3).
Zhong and co-workers reported [3+2] annulation between γ-substituted allenoates (13-1) and unsaturated pyrazolones (13-2) to furnish spirocyclopentene-pyrazolones (13-3) when the reaction was performed in PPh 3 and K 2 CO 3 (Scheme 25) [79]. In terms of the scope of the substrates, pyrazolones with an aryl ring bearing an EDG at the para position afforded higher yields than those bearing EWGs. Similarly, halogens such as Cl and Br, and 1-and 2-naphthalenes were compatible with the substrate to afford products. Allenoates containing tert-butyl instead of ethyl delivered spirocyclopentene-pyrazolones in lower yield owing to the steric hindrance.
The authors screened a wide range of base catalysts and identified t BuOK and DABCO as the optimal catalysts to promote the formation of αor γ-allylated products, respectively. In DABCO, the optimized conditions were compatible with a broad range of MBH carbonates having various EWGs and EDGs either at the ortho or para position of the phenyl ring and were tolerated. Similarly, NAHs having various functional groups in their aryl ring including Me, Cl, MeO, and F all afforded γ-allylated products  in good to excellent yields. On the other hand, due to the strong electron-withdrawing nature of the nitro group, it afforded the product, albeit in a lower yield. In a similar fashion, the substrate scope of t BuOK-catalyzed α-allylation was explored . Various electron-donating and withdrawing groups were incorporated in both MBH carbonates and NAHs. The electronic effect or the bulkiness of the substituents did not affect the efficiency of the α-allylation, affording the products in good to excellent yields. However, an MBH carbonate derived from aliphatic aldehydes afforded the corresponding allylated product in the DABCO base, whereas this failed to occur in t BuOK. In the proposed mechanism, the regiodivergent allylation proceeds through the key step involving deprotonation of N-Acylhydrazone (14-1) by t BuO− to produce nucleophilic intermediate II (Scheme 28). Intermediate II participates in the further reaction divergently in the presence of different catalysts to yield either αor γ-allylated products. In path a, the attack of the DABCO catalyst on the α-position of the MBH carbonate
Cheng et al. developed a Lewis base-catalyzed cycloaddition between allene ketones or α-methyl allene ketones and pyrazolones to produce tetrahydropyrano [2,3-c] pyrazoles in moderate to good yields via a [4+2] cycloaddition (Scheme 29) [101]. The annulation of benzylidenepyrazolones (15-2) with allene ketones (15-1) proceeded smoothly via either an αor γ-selective pathway, and the desired products were obtained in good yields with high regioselectivities. The use of quinine as the catalyst favored the formation of an αadduct (15-3) with high regioselectivity in a 99% yield. After optimizing the conditions, the authors examined various substrates (neutral groups, EWGs, and EDGs as substituents at the ortho, meta, or para position on benzylidene pyrazolones) and found that they are capable of delivering the expected products in good yields with excellent regioselectivities. Interestingly, pyrazolone containing α-naphthyl, β-naphthyl, and 2-furyl groups reacted smoothly and furnished the anticipated product in good yield with high regioselectivity. On the other hand, DMAP produced the γ-selective cycloaddition products as the major regioisomers in good yield . This γ-selective [4+2] annulation of various substrates with DMAP was then investigated. Pyrazolone with α-naphthyl-, β-naphthyl-, 2-thienyl-, and 2-furyl-containing substrates efficiently reacted under the standard conditions to produce the expected products in good yield with high regioselectivity.
According to the proposed reaction mechanism (Scheme 30), first, the Lewis bases undergo addition with the allene ketones (15-1) to generate zwitterionic intermediates, which then undergo nucleophilic addition with the unsaturated pyrazolones  to form intermediates C and D via αor γ-addition. An electron-poor nucleophile such as quinine may stabilize carbanion A and lead to a thermodynamically feasible α-addition, whereas a kinetically favored γ-addition could occur at carbanion B in the case of the electron-rich nucleophile DMAP. Further, a proton shift and subsequent ring closure of the intermediates via an oxygen anion or in reverse mode would then generate the cyclic adducts F and H, respectively. These adducts result in the formation of regiodivergent products after elimination of the Lewis bases from the cyclic adducts. . The (3+2) cycloaddition, which involved the reversal of the nucleophilic site in azomethine ylides, was controlled by choosing suitable base catalysts, DMAP and 1,1,3,3-tetramethylguanidine (TMG), which subsequently resulted in two different cascade processes to generate the diverse chromenopyrrolidines 16-3 and 16-4, respectively. The azomethine ylide was stabilized by the conjugate acids of the bases in two different conformations via hydrogen bonding, which afforded regiodivergent (3+2) cycloadditions. Subsequent cyclization delivered the above products in moderate to good yields (as high as 84%) and with excellent diastereo-and enantioselectivity (as high as 96%). According to the plausible mechanistic pathway (Scheme 32), initially, the iminodiester (16-1a) is deprotonated in the presence of bases to form the equivalent conjugate acids, which then subsequently participate in hydrogen bonding with the azomethine ylide. The use of the electrophile 2-hydroxybenzylidene indan-1,3-dione (16-2a) introduces steric hindrance and leads to two different transition states. In the presence of DMAP as the base, a [3+2] cycloaddition followed by cascade lactonization affords the expected product, chromeno [3,4-b]pyrrolidines (16-3a). The unanticipated chromeno [3,4-c]pyrrolidine adduct 16-4a is obtained when TMG is used as the base. This is the consequence of the opposite regioselectivity during the initial (3+2) cycloaddition, subsequent acetalization, and lactonization. Both the regiodivergent adducts 16-3a and 16-4a were further confirmed by X-ray diffraction analysis. The steric hindrance on the azomethine ylide resulting from TMG exceeded that introduced by DMAP, which led to the regioselective reversal in the (3+2) cycloaddition. The control experiments and NMR studies of the deprotonation of the iminodiester (16-1) by DMAP and TMG were in alignment with the proposed mechanism. Scheme 32. Possible reaction mechanism for base-controlled regiodivergent [3+2] cycloaddition.

Scheme 33. NHC-linked intermediates.
In 2014, Smith and co-workers described a regiodivergent Oto Cor N-carboxyl transfer of pyrazolyl carbonates (17-1) by the choice of catalyst (Scheme 34) [114]. Specifically, DMAP in dichloromethane delivered kinetically favored Oto N-carboxyl transfer with good regioselectivity (as high as 99%) and low to good yields (17-2, 10-80%), whereas triazolinylidene NHC in toluene afforded thermodynamically favored Oto C-carboxyl transfer with good regioselectivity (as much as 99%) and low to good yields (17-3, 12-84%). In addition to that, the chiral triazolium NHC catalyst promoted enantioselective (as high as 92%) and regioselective (as high as 99%) Oto C-carboxyl transfer products in good to excellent yields . Further mechanistic experiments led to the conclusion that Oto Cor N-carboxyl transfer in pyrazolyl carbonates with DMAP was irreversible because the formation of the N-carboxylation product is kinetically favored. Contrary to this, Nto C-carboxyl transfer is not possible with DMAP. The Oto Cor N-carboxyl transfer with triazolinylidene NHCs is reversible because the formation of the C-carboxylation product is thermodynamically favored, and Nto C-carboxyl transfer is also considered to be feasible. On the other hand, Oto Cor N-carboxyl transfer is irreversible, with the chiral NHC catalyst exercising good enantiocontrol, although Nto C-carboxyl transfer is allowed with high enantiocontrol. Further, DFT studies supported the proposed mechanistic pathway shown in Scheme 35. Initially, the catalyst attacks the O-carboxylate to form the tetrahedral intermediate TS (IV). Then, consecutive collapse of TS(IV) produces two common intermediates, enolate and a carboxylated catalyst, after which the carboxylated catalyst could be recaptured by the enolate either at C(4) or N(1) to produce (TS-VII). Finally, regeneration of the catalyst from the tetrahedral intermediate (TS-VIII) affords the two regiodivergent products (17-2, 17-3). Scheme 35. Proposed reaction mechanism for Oto Cand N-carboxylation.
In 2015, Smith et al. reported regioselective carboxylation either at the γ-or α-position depending on the Lewis base involved (Scheme 36) [115]. Treatment of a furanyl carbonate (18-1) with the triazolinylidene NHC catalyst produced a γ-isomer with regioselectivity as high as 99:1 . Under optimal conditions, phenyl, trichloro ethyl, and certain sterically hindered substrates were well tolerated to afford the corresponding γ-C(5) carboxylation product in good to high yields. In contrast, the α-isomer product was generated by changing the catalyst to DMAP with moderate regiocontrol (60:40) to produce the α-C(3)carboxylate as the major product . Individual treatment of the α-and γ-isomers with DMAP did not result in transformation, and the starting material was recovered even though the reaction time was prolonged. The α-carboxyl product underwent regioisomeric exchange in the presence of the NHC catalyst to afford the α/γ products in a 16:84 ratio, with the γ derivative as the major product. Similar results were obtained when the γregioisomer was reacted in the presence of the NHC catalyst to afford a 14:86 ratio of α/γ. These results revealed that C-carboxylation with DMAP is irreversible to preferentially yield the α-regioisomer. However, in the case of the NHC catalyst, C-carboxylation resulted in the formation of the γ-isomer as the major product followed by subsequent equilibration to form a mixture of α/γ products.   in the presence of a base (Scheme 37) [116]. A regioselective methodology was devised by carefully adjusting the NHC catalysts, i.e., the imidazolium NHC precursor produced the 1,5disubstituted 3-pyrazolidinone (19-3), whereas the triazolium NHC precatalyst was able to drive the reaction to completion to furnish the 2,5-difunctionalized isomer . Specifically, the regioselective Michael addition of the key intermediate to phenylhydrazine followed by subsequent lactamization afforded the regiodivergent products (19-3, 19-4). This protocol was an attractive strategy for the assembly of biologically significant 3pyrazolidinones in moderate to high yields (as high as 84%), under mild reaction conditions, and with good regioselectivity. According to the proposed reaction mechanism (Scheme 40), the chiral NHC catalyst initially undergoes addition to the enal cinnamaldehyde (20-1) to form two Breslow intermediates (II and V). The structure of the NHC is suggested to play a crucial role in determining the reaction pathways to form either a haloenolate or acyl anion. Specifically Glorius and co-workers also reported the NHC-catalyzed regiodivergent synthesis of pyridazino [ [118]. The reaction between enals (21-1) and N-iminoisoquinolinium ylides (21-2) produced the above products in good to high yields with high enantiomeric excess. The formation of regiodivergent products was governed by the NHC precatalyst, base, and solvent of the reaction. Initially, the homoenolate intermediate formed by the reaction between α,β-unsaturated aldehydes and the NHC catalyst was converted into an enol intermediate by subsequent protonation at the β-position. The conjugate acid of the catalytic base was generated from the azolium salt by deprotonation, depending on whether this was sufficiently acidic to protonate the homoenolate, to afford the

Amine Catalysts
In the past two decades, L -proline and its derivatives have found rapidly growing application in various transformations to yield products with excellent ee and dr [119][120][121][122][123][124][125][126]. Remarkable advances have been made after the seminal work of List [127,128], Córdova [129,130], Barbas [131,132], and many other research groups. The discovery that a simple and effective catalyst such as L -proline could be put to effective use was a landmark achievement in this century and opened a new avenue for asymmetric synthesis. Despite the development of several modified proline catalysts, proline is still placed at the top of the list in terms of its performance. An enormous number of chemical transformations have been conducted by using derivatives of chiral organocatalysts including Aldol, Mannich, Michael addition, and Diels-Alder reaction, and if required, these catalysts are able to induce remarkable stereoselectivity. Importantly, several natural products and drugs have been synthesized by using these L -proline-derived catalysts [133][134][135][136][137][138][139][140][141][142].
The use of unsymmetrical ketones as nucleophilic partners, depending on the solvent, enabled different regioselective products to be obtained. Subsequently, highly enantioselective linear isomers were obtained as major products when the reaction was performed in chloroform . This may also proceed via the formation of the a less substituted enamine intermediate (TS1). On the other hand, we found that the polar solvent DMSO furnished the branch isomer as the major product, and that this reaction was highly enantioand diastereoselective . The role of the solvent in the reaction remained unclear. However, other researchers also reportedly observed a similar transition state (TS2) when they utilized DMSO as the solvent. The XRD analysis (X-ray diffraction analysis) revealed that the obtained branch isomer was in fact an anti-Mannich adduct, suggesting that the enamine approaches the Re face of the benzoxazinone imine (Scheme 46).  [145]. The enolizable dicyanodienes (24-1) reacted with cinnamaldehyde  in the presence of an amine/NHC catalyst in a one-pot reaction to afford the spirodecanone (24-3) via a [3+2] cycloaddition reaction. On the other hand, the addition of 4-nitrophenol as a co-catalyst switched the reactivity to produce bicyclooctane carbaldehydes (24-4) by a [4+2] cycloaddition. A sequential C-ε regioselective bis-vinylogous Michael addition in the presence of a bulky TBS protected the prolinol catalyst, followed by an NHCcatalyzed 1,6-Stetter reaction involving C-δ [3+2] spiroannulation, producing ε,δ-bonded spiro [4.5]decanones in the presence of potassium acetate as the base. Substrates of different sizes (including both EWGs and EDGs on the benzene ring) were well tolerated with complete diastereoselectivity (>20:1 dr) along with complete regioselectivity and a high enantiomeric excess. A two-step domino reaction sequence was utilized to synthesize bicyclo[2.2.2]octane carbaldehydes via a formal [4+2] cycloaddition reaction. Initially, γ' enolate was formed from the enolizable dicyanodienes and the enal, activated by the prolinol catalyst following which the subsequent intramolecular 1,6-Michael addition at the δ region afforded the expected product. The use of 10 mol% 4-nitrophenol as an additive in chloroform at room temperature afforded the product in good yields with 17:1 site selectivity along with high ee (96%) and dr (>20:1).

Scheme 47. Regioselective synthesis of enantioenriched carbocyclic compounds.
The reaction mechanism that was proposed (Scheme 48) involves the initial activation of the cinnamaldehyde (24-2) by the organocatalyst prolinol silyl ether by lowering the LUMO. Subsequently, the hydroxide ion deprotonates the cyclohexenylidene malononitriles at ε,δ' to yield both of the enolates II and IV, respectively. Coulombic interaction between the enal nitrogen atom and the nitrogen atoms of the cyano group initiates enantioselective attack of the Si face of the enal acceptor by the bis-vinylogous enolate II. Hydrolysis of enamine intermediate III produces 24-5 and, ultimately, the final product 24-3, and this is accompanied by the regeneration of the organocatalysts. For the [4+2] cycloaddition reaction, the δ'-enolate is not stabilized by the enal nitrogen; instead, it is stabilized by the addition of p-nitrophenol, which acts as a hydrogen bond donor. Under these circumstances, the attack of IV (from its Re face) to the Si face of the enal is more favorable, producing bicyclooctane carbaldehydes (24-4) upon hydrolysis of intermediate VI along with the regeneration of the catalyst. Scheme 48. Proposed reaction mechanism for regiodivergent εand γ',δ-pathways.

Phosphoric Acid Catalysts
In recent years, the activation of carbonyl compounds by utilizing chiral Brønsted acids has received an enormous amount of attention, i.e., the activation of reactants by way of a hydrogen bonding connection, which is one of the fastest growing research areas. Chiral phosphoric acids have proven to be highly efficient catalysts for a wide range of asymmetric transformations under mild reaction conditions. In general, binaphthyl is used to synthesize chiral phosphoric acid derivatives. These catalysts have been involved in several reactions including the Diels-Alder, Nazarov, Mukaiyama Aldol, Mannich, Henry, Morita-Baylis-Hillman reactions, and 1,3-dipolar cycloadditions [146][147][148][149][150][151][152][153][154].
Tay and co-workers reported an efficient method for the regioselective synthesis of glycosides in macrolactone (Scheme 49) [155]. Chiral phosphoric acid-catalyzed selective glycosylation of complex phenols was achieved with excellent regiodivergence. Glycosylation of 6-dEB (25-6-DEB) with 6-deoxyglucose  in the presence of BINOL-based chiral phosphoric acids led to glycosylation at the C5 position of the macrolactone with a high r.r. (regiomeric ratio) (99:01) in toluene. However, the use of SPINOL as a chiral phosphoric acid in DCM resulted in glycosylation at the C3 alcohol of the macrolactone with a 73:27 r.r. The C11 hydroxyl was also selectively glycosylated in the presence of phenylboronic acid in toluene as the solvent. The C3 and C5 hydroxyls were present in a 1,3-syn relationship, which was masked by the formation of the boronic acid ester to allow formation of the glycoside at the C11 position. The hydroxyl groups at C3 and C5 were regenerated after the boronate was cleaved during the subsequent workup with peroxide.
In 2020, Wang's group developed aza-and oxo-[3+2] cycloadditions between αenaminones (26-2) and quinones  in the presence of chiral phosphoric acids and 4Å molecular sieves (M.S.), respectively (Scheme 50) [156]. In the presence of the chiral phosphoric acid (26-(R)-CPA5), a wide range of N-substituted indoles  were obtained as the products of a formal aza-[3+2] cycloaddition. On the other hand, in the presence of bulky chiral phosphoric acid (26-(R)-CPA3) and 4Å molecular sieves as an additive, the product 2,3-dihydrobenzofuran  was produced in the highest yields with excellent enantioselectivities via an oxo-[3+2] cycloaddition. Various substituted quinones including different esters (Me, Et, and Bn), and α-enaminones containing an EDG and EWG reacted smoothly to produce the products in good yield with excellent enantioselectivities. In the absence of molecular sieves, this reaction proceeded to produce N-substituted indole derivatives in excellent yield with toluene as the solvent . Quinones containing different ester groups as well as α-enaminones bearing an EDG or EWG at the para position of the aryl ring were compatible under the optimized conditions and delivered the indole derivatives in good yield.
The role of 4Å M.S. was important to obtain benzofuran derivatives. In the absence of molecular sieves, or when they are replaced by dry MgSO 4 or freshly activated 4Å M.S. and H 2 O (2µL), this would slow down the formation of benzofuran derivatives  and slightly increase the formation of indole derivatives . These above data reveal that M.S. do not serve as a drying reagent in this reaction, and the addition of water relatively favors the indole formation. Further, the size and format of M.S. also influence the reaction outcome. In detail, for 3Å M.S. and 4Å M.S., their selectivity towards benzofuran and indole is >20:1 (26-3:26-4) According to the proposed mechanism (Scheme 51), the enamine of the α-enaminones (26-2) initially acts as a nucleophile to attack the Re face of the quinone (26-1) from the Si face to afford the intermediate int-A via TS-I. O-tautomerization from the quinone (enol/phenol) and N-tautomerization (enamine from the imine) afford int B and int C, respectively. These intermediates (int-B, int-C) are attached to the chiral phosphoric acid, as illustrated for TS-II and TS-III. The hydroxy group of TS-II then attacks the Si face of the imine to afford 2,3-dihydrobenzofuran (26-3a), whereas indole (26-4a) is obtained from TS-III via int D. Initially, the amine group attacks the Si face of the carbonyl group to afford int D, which then undergoes dehydroxylation to produce the indole derivative. As TS II is more polarized in nature than TS III, a polar solvent such as DCM stabilizes TS II, and the addition of 4Å molecular sieves (4Å M.S.) accelerates the proton transfer in TS II via absorbing/releasing a proton. Alternatively, TS-II is destabilized in the presence of toluene, a non-polar solvent, in which case the reaction preferentially proceeds via TS-III. Recently, in 2020, the group of Li and Li reported orthoand para-selective regiodivergent C-H functionalization between 1-naphthols (27-1) and 1-azadienes (27-2) via a Michael addition reaction (Scheme 52) [157]. The chiral squaramide catalyst afforded a product in which an ortho-selective C-H bond was constructed, whereas para-selective C-H bond formation occurred in the case of chiral phosphoric acid catalysts. Under the optimized reaction conditions, with the chiral squaramide catalyst (27-SA-1), 1-naphthol with different substituted 1-azadienes (F, Cl, Br, Me, and OMe) afforded the expected ortho-selective Friedel-Crafts alkylation products in good yields with high enantioselectivities . Similar results were obtained with different substituted 1-naphthols (Br, OMe) which delivered the ortho-selective products in excellent yields with good ee. The use of 27-CPA-4 (1 mol%) as the catalyst resulted in regiodivergent para-selective C-H bond functionalization . Within the scope of this substrate, 1-azadienes containing various EWGs (F, Cl, Br) and EDGs (Me, OMe) on the aromatic ring could be well tolerated to offer para-selective Friedel-Crafts alkylation products in good yields and with high ee. Control experiments showed that the free hydroxy group of 1-napththol was essential to obtain the product in this Michael addition. Both the catalysts (27-SA-1, 27-CPA-4) failed to produce the product when 1-hydroxynaphthalene was protected with methyl (1-methoxynaphthalene, 27-1c), which reacts with 1-azadiene (27-2a).

p-Toluenesulfonic Acid Catalyst
Chen and co-workers reported the regiodivergent nucleophilic phosphorylation of indolylmethanols (28-1) with diaryl phosphine oxide  in the presence of a Brønsted acid catalyst (Scheme 53) [158]. The benzyl phosphorylated product  was obtained by the utilization of 10 mol% of TsOH.H 2 O (p-toluenesulfonic acid monohydrate) in nitromethane at 25 • C with moderate to good yield. A variety of 2-indolylmethanols with an EDG produced comparably higher yields than those with an EWG. Similarly, diarylphosphine oxides with an EWG at the para position produced higher yields. On the other hand, the C-3 phosphorylation product  was obtained in good yield by using 20 mol% of the TfOH catalyst at 80 • C. Indolylmethanol containing both an EDG and EWG was well tolerated to afford the products in moderate yields. Scheme 53. Brønsted acid-catalyzed regiodivergent phosphorylation of 2-indolylmethanols.
In the proposed reaction mechanism (Scheme 54), the Brønsted acids generate a partial positive charge at the benzylic position of the nitrogen atom or the C3 position of the 2indolylmethanols. Then, the diarylphosphine oxides attack the benzylic position to afford the benzylic phosphorylated product 28-3. In the presence of a strong acid such as TfOH and upon exposure to heat, the benzylic phosphorylated product may undergo a [1,3]-P migration to afford the thermodynamically stable product

Thiourea Catalyst
In recent decades, thiourea derivatives have been commonly used as organocatalysts in organic and pharmaceutical chemistry. Moreover, these derivatives are also widely used as bifunctional catalysts in combinations such as amine-thiourea and phosphine-thiourea. Along with their catalytic activity, they are also involved as a component in various reactions including guanylation, thioarylation, and C-S cross-coupling reactions [159][160][161][162][163][164][165][166].
The regiodivergent chlorination of electron-rich phenols (29-1) established by Gustafson and co-workers is demonstrated in Scheme 55 [167]. Here, ortho-chlorination of the phenol  with N-chlorosuccinimide is promoted by 10 mol% of Nagasawa's bis-thiourea catalyst . The meta-substituted phenols (F, Cl, Br, I, and t-Bu) efficiently afforded good ortho-regioselectivity in the presence of Nagasawa's catalyst. The authors also demonstrated the augmentation of the innate para-selectivity of phenols by using BINAP-derived phosphine sulfide as a catalyst . Phenols containing Ph, t-Bu, CN, and a halogen substituent afforded a para-selective chlorinated product as the major product . The authors also investigated the reaction conditions for regioselective bromination. Catalyst 29-4 afforded mainly the para-selective brominated product as the major regioisomer , whereas the presence of Nagasawa's bis-thiourea catalyst overcame the innate para-preference of the phenol to afford the ortho-brominated products  with good selectivity. The authors concluded that the regioselectivity mainly depends on the structure of the Lewis bases, and reversal of the regioselectivity by Nagasawa's bis-thiourea catalyst could promote chlorination via dual activation. That is, one of the thiourea moieties interacts with the phenol and the other activates NCS via a Lewis base or Brønsted acid manifold. Scheme 55. Catalyst-controlled regiodivergent chlorination of phenols.
In 2018, Xu and co-workers reported the organocatalytic, regiodivergent C-C bond cleavage of cyclopropenones (Scheme 56) [177]. Their efficient methodology involves a cascade cycloaddition followed by a regioselective cyclopropyl ring strain release process catalyzed by bifunctional squaramide catalysts. Aldimines (30-1) reacted with 2,3diphenylcycloprop-2-enone (30-2) with 1 mol% of the catalyst to afford tetrahydrochromeno [4,3-b]pyrroles  as products in excellent yields with excellent ee and dr ratios (20:1). In contrast, completely different cyclized products, tetrahydrobenzofuro [3,2-b]pyridines , were obtained when methylphenylcyclopropenone (30-2') was used along with 20 mol% of the catalyst. The products were obtained in excellent yields with excellent enantioselectivities. The synergistic effect of hydrogen bonding activation and controlled ring strain release played a pivotal role in the generation of the two different ring systems. The "spring-loaded" intermediate with switchable C-C bond cleavages achieved by controllable ring strain release governed the regioselectivity of the reaction (Scheme 57). Nucleophilic addition to the hydroxy group at the carbonyl carbon (30-A) produced fivemembered products, whereas six-membered cyclic products were obtained when the ring opening occurred at the α-site of the carbonyl carbon (30-B). This was substantiated by DFT studies. With this protocol, the authors were able to synthesize diverse heterocyclic frameworks with good enantioselectivity of 99% and an excellent yield (as high as 99%) for both regioisomers.

Conclusions
This review summarized the control of regiodivergent reactions by utilizing various organocatalysts. The use of several organocatalysts such as Lewis bases, amine bases, Brønsted acids, and hydrogen bond-donating catalysts that were employed to deliver the regiodivergent products was described. The reactivity of various organocatalytic systems, the scope of the substrates, and their mechanistic studies were briefly discussed.
The choice of the catalysts, additives, temperature, and solvents was found to play a crucial role in determining the regioselectivity of the reaction.
Although synthetic chemists have devoted lots of efforts to developing organocatalytic regiodivergent methods, in order to cater to the need for diverse molecules to access the chemical space, we need more regiodivergent methods by which we can synthesize a broad range of molecules easily.