Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis

The π-stacking interaction is one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry. It plays an important role in stabilizing some structures and transition states in certain reactions via both intramolecular and intermolecular interactions, facilitating different selectivities, such as chemo-, regio-, and stereoselectivities. This minireview focuses on the recent examples of the π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution, asymmetric synthesis of helicenes and heterohelicenes, and multilayer 3D chiral molecules.


Introduction
Attractive π-stacking interactions between π-systems (both aromatic ring and other conjugated systems, even double and triple bonds) play various important roles in diverse phenomena, including the stabilization of biological macromolecules, such as the helical structures of DNA and tertiary structures of proteins, even the complexation of biomolecules and small organic compounds [1][2][3]; the stabilization of the complexation in host-guest systems [4,5]; and controlling selectivities in organic reactions [6][7][8][9].They can not only control chemoselectivity [10][11][12][13][14] and regioselectivity [15][16][17][18][19] but also stereoselectivities, including diastereoselectivity and enantioselectivity, in diverse organic reactions [20,21].In 1995, Jones and Chapman wrote a comprehensive review on the π-stacking effect in asymmetric synthesis [20].π-stacking effects in chiral auxiliary-controlled asymmetric synthesis have been summarized.The auxiliaries include cyclohexane-based arenecarbonyl, arylacetyl, N-arylcarboxamide, and aryl carboxylate auxiliaries; 4-aryl/ arylmethyloxazolidinone-based auxiliaries; axial chirality auxiliaries; natural productbased auxiliaries; and so on [20].In 2007, Yamada summarized the intramolecular cation-π interaction in organic synthesis in his perspective [22].In 2010, Xu collected the most important examples of the influence of the electronic effect of catalysts on the enantioselectivity in asymmetric catalytic organic reactions [21].Attractive noncovalent interactions, especially hydrogen bonding between the ligand and substrate in enantioselective transition metal catalysis, were reviewed in 2020 [23].Since 1995, some new chiral auxiliaries have been developed and applied in the π-stacking interaction-controlled asymmetric synthesis.Particularly, during the last two decades, the π-stacking interaction has also been applied in the preparation of optically active (hetero)helicenes and multilayer three-dimensional (3D) chiral molecules as potential materials.This minireview focuses on new developments in the π-stacking interaction-controlled asymmetric synthesis, including several newly developed auxiliary-induced asymmetric syntheses, kinetic resolution for the asymmetric syntheses, and asymmetric syntheses of (hetero)helicenes and multilayer 3D chiral molecules as potential organic materials from 1995 to now.All

collected examples in this
Molecules 2024, 29, 1454 2 of 27 minireview are mentioned or verified by experimental or theoretical calculational results or on the basis of X-ray crystal diffraction analysis.

Chiral Auxiliary-Induced Asymmetric Synthesis 2.1. Chiral Arylsulfinyl-Based Auxiliaries in Asymmetric Synthesis
Enantiomerically pure aryl methyl sulfoxides and diaryl sulfoxides are a class of readily available optically active compounds and have been applied as chiral auxiliary starting materials in various asymmetric syntheses, such as syntheses of optically active fluorinated structurally diverse amines, fluorinated α-amino acids and β-amino alcohols [24], and fluorinated and non-fluorinated heterocyclic compounds [25].The orthosubstituted 2-alkylphenyl 4-methylphenyl sulfoxides were first used as precursors of orthoarylsulfinylbenzylcarbanions in the nucleophilic addition with N-(4-methylphenylsulfinyl) or N-(4-methylphenylsulfonyl) (tosyl) aldimines and ketimines, thereby affording 4-methylphenylsulfinamides and 4-methylphenylsulfonamides as direct addition products [26,27].The removal of the N-tosyl group was actually not a readily available process and was even inefficient in some cases.To make the synthetic strategy more practical and useful in synthetic organic chemistry, both enantiomerically pure aryl methyl sulfoxides and diaryl sulfoxides as readily available optically active compounds have been further applied in various nucleophilic additions of N-(4-methoxyphenyl) aldimines and ketimines, giving rise to N-(4-methoxyphenyl)-derived amine derivatives, which are readily and efficiently removed via oxidation.Thus, the nucleophilic addition of both enantiomerically pure aryl methyl sulfoxides and diaryl sulfoxides with N-(4-methoxyphenyl) aldimines and ketimines has been well investigated and applied in diverse asymmetric syntheses, such as the synthesis of optically active fluorinated structurally diverse amines, fluorinated α-amino acids and β-amino alcohols [24], and fluorinated and non-fluorinated heterocyclic compounds [25].
Peptides have a very wide range of functions in the human body and are a class of widely applied macromolecular medicines.However, they generally survive biodegradation in the human body.To circumvent this biodegradation problem, some structurally similar unnatural peptide analogues are prepared instead of naturally occurring amino acids with non-naturally occurring ones.Fluorinated α-amino acids are one of the choices because fluoro-organic compounds have unique properties, such as lipophilicity, membrane permeability, metabolic stability, and bioavailability.Enantiopure aryl methyl sulfoxides were used in the synthesis of both fluorinated α-amino acids and β-amino alcohols.Enantiomerically pure aryl methyl sulfoxides 1 were first treated with LDA and reacted with fluorinated imidoyl chlorides 2 to form fluorinated chiral arylsulfinyl-derived imines 3, which were further reduced with tetrabutylammonium borohydride (Bu 4 BH 4 ) in MeOH, affording chiral arylsulfinyl-derived amines 4 in almost quantitative yields with excellent diastereoselectivity.In the reduction step, Bu 4 BH 4 nucleophilically attacked the imines 3 from their Si-face due to the existence of the π-stacking interaction between the N-aryl group of imines and the S-aryl group of sulfoxides.The Re-face was shielded by the S-aryl group of sulfoxides.After the non-oxidative Pummerer reaction, the obtained optically active fluorinated arylsulfinyl-derived amines 4 were further converted into the corresponding fluorinated β-amino alcohols 5, which were finally transformed into the desired fluorinated α-amino acids 6 in 65-70% yields via the Ru-catalyzed oxidation with NaIO 4 as the oxidant (Scheme 1) [24].The current route is a convenient and useful method for the synthesis of 3,3-difluoro-, 3,3,3-trifluoro-, and 3-chloro-3,3-difluoro-derived alanines.
Enantiomerically pure (S)-4-methylphenyl 2-methylphenyl sulfoxide (7) was developed as a chiral auxiliary.It was first treated with LDA and reacted with fluorinated aldimines 8 with the N-(4-methoxyphenyl) group to form fluorinated chiral arylsulfinyl derived amines (S,S)-9 and (S,R)-9 in good yields (74-80%) with moderate stereoselectivities (69:31 to 70:30) after workup.The π-stacking interaction between the N-(4-methoxyphenyl) group of aldimines 8 and the S-aryl group of sulfoxide 7 in both transition states TS1 and intermediates A played a crucial role in controlling the stereoselectivity.However, when (S)-4-methylphenyl 2-methylphenyl sulfoxide (7) was treated with LDA and then reacted with fluorinated ketimines 10 with the N-(4-methoxyphenyl) group to generate the corresponding fluorinated chiral arylsulfinyl derived amines (S,S)-11 as major products in satisfactory yields (60-77%) with excellent stereoselectivities ((S,S)-11:(S,R)-11 = 90:10 to 96:4).The π-stacking interaction between the N-(4-methoxyphenyl) group of ketimines 10 and the S-aryl group of sulfoxide 7 in both transition states TS2 and intermediates B also played a key role in controlling the stereoselectivity.The results indicated that ketimines showed better stereoselectivities than aldimines (Scheme 2) [24].The ortho-substituted benzylcarbanion with chiral arylsulfinyl auxiliary improved the stereoselectivity efficiently.To further extend the application of ortho-substituted benzylcarbanions with chiral arylsulfinyl auxiliary in the stereoselective nucleophilic addition of various imines, enantiomerically pure (S)-4-methylphenyl 2-alkylaryl sulfoxides 12 were also developed as chiral auxiliaries.After the treatment with LDA, they reacted with both fluorinated aldimines 8 and ketimines 10 to give rise to the corresponding fluorinated chiral arylsulfinyl-derived amines (S,S)-13 in moderate to good yields (40−86%) with excellent stereoselectivities (>98%) after workup.The similar π-stacking interaction in both transition states TS3 and intermediates C controlled the stereoselectivity almost completely.If fluorinated arylsulfinyl-derived amines (S,S)-13 were further treated with KHMDS in THF at 0 °C, they underwent an intramolecular aromatic nucleophilic substitution with arylsulfinyl groups as the leaving groups, affording the corresponding fluorinated indoline derivatives 14 in 60−83% yields.Only trifluoromethyl-derived products (S,S)-13 (RF = CF3) were tested.The results illustrated that indoline derivatives 14 could be generated in one pot.The tandem reaction was attempted.After the nucleophilic addition of 2-(4-methylphenylsulfinyl)benzylcarbanions and aldimines 8 or ketimines 10 at −78 °C, the reaction mixture was warmed to −30 °C and continually stirred for 30 min.Further intramolecular aromatic nucleophilic substitution occurred, producing the desired fluorinated indoline derivatives 14 in 35−71% yields via tandem nucleophilic addition and intramolecular aromatic nucleophilic substitution in one pot, exhibiting high step-economy.In comparison with the step-wise synthetic method, the yields in the tandem fashion were similar to the total yields for two steps in the stepwise route.Furthermore, the one-pot tandem reaction of (S)-4-methylphenyl 4-cyano-2methylphenyl sulfoxide (16) with a cyano functional substituent and trifluoromethyl ketimine 10a was performed with LDA as a base in THF at −78 °C; the desired indoline derivative 16 was obtained in 45% yield after stirring for 30 min.The cyano group survived in the tandem reaction in the presence of ortho-arylsulfinylbenzylcarbanion as the strong nucleophile, showing good functional group tolerance (Scheme 3) [25].To further extend the application of ortho-substituted benzylcarbanions with chiral arylsulfinyl auxiliary in the stereoselective nucleophilic addition of various imines, enantiomerically pure (S)-4-methylphenyl 2-alkylaryl sulfoxides 12 were also developed as chiral auxiliaries.After the treatment with LDA, they reacted with both fluorinated aldimines 8 and ketimines 10 to give rise to the corresponding fluorinated chiral arylsulfinyl-derived amines (S,S)-13 in moderate to good yields (40-86%) with excellent stereoselectivities (>98%) after workup.The similar π-stacking interaction in both transition states TS3 and intermediates C controlled the stereoselectivity almost completely.If fluorinated arylsulfinyl-derived amines (S,S)-13 were further treated with KHMDS in THF at 0 • C, they underwent an intramolecular aromatic nucleophilic substitution with arylsulfinyl groups as the leaving groups, affording the corresponding fluorinated indoline derivatives 14 in 60-83% yields.Only trifluoromethyl-derived products (S,S)-13 (R F = CF 3 ) were tested.The results illustrated that indoline derivatives 14 could be generated in one pot.The tandem reaction was attempted.After the nucleophilic addition of 2-(4-methylphenylsulfinyl)benzylcarbanions and aldimines 8 or ketimines 10 at −78 • C, the reaction mixture was warmed to −30 • C and continually stirred for 30 min.Further intramolecular aromatic nucleophilic substitution occurred, producing the desired fluorinated indoline derivatives 14 in 35-71% yields via tandem nucleophilic addition and intramolecular aromatic nucleophilic substitution in one pot, exhibiting high step-economy.In comparison with the step-wise synthetic method, the yields in the tandem fashion were similar to the total yields for two steps in the step-wise route.Furthermore, the one-pot tandem reaction of (S)-4-methylphenyl 4-cyano-2-methylphenyl sulfoxide (16) with a cyano functional substituent and trifluoromethyl ketimine 10a was performed with LDA as a base in THF at −78 • C; the desired indoline derivative 16 was obtained in 45% yield after stirring for 30 min.The cyano group survived in the tandem reaction in the presence of ortho-arylsulfinylbenzylcarbanion as the strong nucleophile, showing good functional group tolerance (Scheme 3) [25].The indoline skeleton is a ubiquitous moiety in the structures of many alkaloids and natural products.Indolines are generally considered to be key privileged structures for their diverse biological activities.To develop a step-economic and efficient asymmetric synthetic method of biologically important and optically active indoline derivatives, the above developed strategy was extended to the synthesis of non-fluorinated indoline derivatives via tandem nucleophilic addition and intramolecular aromatic nucleophilic substitution with the 4-methylphenylsulfinyl group as the leaving group.When fluorinated aldimines 8 and ketimines 10 were displaced with aromatic imines 17 generated from aromatic aldehydes and aromatic amines, the reaction of (S)-(2-ethylphenyl) 4methylphenyl sulfoxide (12a) and aromatic imines 17 generated (2S,3S)-2,3-diaryl-4-methylindolines 18 in moderate to satisfactory yields of 25−62% with LDA as a base.When LHDMS or KHMDS was used as the base instead of LDA, the reaction was conducted at room temperature or at 70 °C to give the corresponding products 18 in higher yields than those with LDA as the base.The aromatic imines with electron-withdrawing substituents generally required longer reaction times and higher reaction temperatures than those with electron-donating groups.The reaction of electron-rich (S)-1-ethyl-4,5-dimethoxy-2-(4-tolylsulfinyl)benzene (19) and (E)-N-(4-methoxyphenyl)-1-phenylmethanimine (17b) stopped at the nucleophilic addition step in the presence of LDA as the base, generating the corresponding amine 20 as the final product after workup, rather than the desired The indoline skeleton is a ubiquitous moiety in the structures of many alkaloids and natural products.Indolines are generally considered to be key privileged structures for their diverse biological activities.To develop a step-economic and efficient asymmetric synthetic method of biologically important and optically active indoline derivatives, the above developed strategy was extended to the synthesis of non-fluorinated indoline derivatives via tandem nucleophilic addition and intramolecular aromatic nucleophilic substitution with the 4-methylphenylsulfinyl group as the leaving group.When fluorinated aldimines 8 and ketimines 10 were displaced with aromatic imines 17 generated from aromatic aldehydes and aromatic amines, the reaction of (S)-(2-ethylphenyl) 4-methylphenyl sulfoxide (12a) and aromatic imines 17 generated (2S,3S)-2,3-diaryl-4-methylindolines 18 in moderate to satisfactory yields of 25-62% with LDA as a base.When LHDMS or KHMDS was used as the base instead of LDA, the reaction was conducted at room temperature or at 70 • C to give the corresponding products 18 in higher yields than those with LDA as the base.The aromatic imines with electron-withdrawing substituents generally required longer reaction times and higher reaction temperatures than those with electron-donating groups.The reaction of electron-rich (S)-1-ethyl-4,5-dimethoxy-2-(4-tolylsulfinyl)benzene (19) and (E)-N-(4-methoxyphenyl)-1-phenylmethanimine (17b) stopped at the nucleophilic addition step in the presence of LDA as the base, generating the corresponding amine 20 as the final product after workup, rather than the desired indoline derivative because the electron-rich arylsulfinyl with two strong electron-donating methoxy groups could not undergo the intramolecular aromatic nucleophilic substitution.Upon further treatment of the amine 20 with LHMDS, no reaction occurred as well, indicating that the electron-rich substrate indeed hardly underwent the intramolecular aromatic nucleophilic substitution even in a step-wise fashion.For each of these cases, the π-stacking interaction between the N-aryl group of imines and the S-aryl group of sulfoxides in both the transition state TS4 and intermediate state D played an important role in controlling the stereoselectivity (Scheme 4) [28].
Molecules 2024, 29, 1454 5 of 27 indoline derivative because the electron-rich arylsulfinyl with two strong electron-donating methoxy groups could not undergo the intramolecular aromatic nucleophilic substitution.Upon further treatment of the amine 20 with LHMDS, no reaction occurred as well, indicating that the electron-rich substrate indeed hardly underwent the intramolecular aromatic nucleophilic substitution even in a step-wise fashion.For each of these cases, the π-stacking interaction between the N-aryl group of imines and the S-aryl group of sulfoxides in both the transition state TS4 and intermediate state D played an important role in controlling the stereoselectivity (Scheme 4) [28].

Adducts of Levoglucosenone and 9-(Aryloxymethyl)arthracenes as Chiral Auxiliaries in Asymmetric Synthesis
The Diels-Alder cycloaddition of alkyl acrylates and cyclopentadiene can generate both endo-adducts and exo-adducts.If chiral alkyl acrylates were utilized, asymmetric induction would occur.Acrylate derivatives 23 bearing para-trifluoromethyl and methoxyphenoxymethyl substituents as the π-stacking templets and shelter were prepared via the Diels-Alder reaction of enantiomerically pure levoglucosenone (20) and 9-(para-trifluoromethyl and methoxyphenoxymethyl)arthracenes (21), and the subsequent reduction and acrylation.There is an intramolecular vinyl-aryl π-stacking interaction between the acrylate and aryloxy groups.When they were applied in the Diels-Alder reaction with cyclopentadiene, evident π-stacking-controlled asymmetric synthesis was observed, generating endo-(S)-bicyclo [2.2.1]hept-5-ene-2-carboxylates 24 in 65% and 59% yields as major products through more the stable transition state TS5a.Cyclopentadiene would approach the C=C bond in the acrylate moiety only from its top direction in all transition states because the aryloxy group was fixed below the C=C bond due to the existence of the vinylaryl π-stacking interaction between the acrylate and aryloxy groups (Scheme 5) [29].

Adducts of Levoglucosenone and 9-(Aryloxymethyl)arthracenes as Chiral Auxiliaries in Asymmetric Synthesis
The Diels-Alder cycloaddition of alkyl acrylates and cyclopentadiene can generate both endo-adducts and exo-adducts.If chiral alkyl acrylates were utilized, asymmetric induction would occur.Acrylate derivatives 23 bearing para-trifluoromethyl and methoxyphenoxymethyl substituents as the π-stacking templets and shelter were prepared via the Diels-Alder reaction of enantiomerically pure levoglucosenone (20) and 9-(para-trifluoromethyl and methoxyphenoxymethyl)arthracenes (21), and the subsequent reduction and acrylation.There is an intramolecular vinyl-aryl π-stacking interaction between the acrylate and aryloxy groups.When they were applied in the Diels-Alder reaction with cyclopentadiene, evident π-stacking-controlled asymmetric synthesis was observed, generating endo-(S)-bicyclo [2.2.1]hept-5-ene-2-carboxylates 24 in 65% and 59% yields as major products through more the stable transition state TS5a.Cyclopentadiene would approach the C=C bond in the acrylate moiety only from its top direction in all transition states because the aryloxy group was fixed below the C=C bond due to the existence of the vinyl-aryl π-stacking interaction between the acrylate and aryloxy groups (Scheme 5) [29].

Scheme 5. π-stacking-controlled Diels-Alder reaction with endo-(S)-products as major products.
Both enantiomerically pure levoglucosenone (20) and its dihydro derivative 28 are readily available from biomass because they are products of cellulose pyrolysis.Enantiomerically pure dihydrolevoglucosenone (28) was also applied as a chiral auxiliary in the diastereoselective Diels-Alder reaction.It was first converted to dibenzylated dihydrolevoglucosenols (29) through double benzylation with benzyl halides under basic conditions followed by a reduction with sodium borohydride.Differently, dibenzylated dihydrolevoglucosenols (29) were further acrylated and then reacted with cyclopentadiene in the presence of Lewis acids in DCM, affording endo-(R)-bicyclo [2.2.1]hept-5-ene-2-carboxylates (R)-31 as major products due to the existence of the vinyl-aryl π-stacking interaction (Scheme 6) [30].Through the utilization of both levoglucosenone (20) and its dihydro derivative 28 as auxiliaries, both enantiomeric bicyclo [2.2.1]hept-5-ene-2-carboxylates were prepared in good to high yields.Both diastereomeric monobenzylated dihydro derivatives were also attempted as auxiliaries in the diastereoselective Diels-Alder reactions.They show excellent endo/exo selectivity, but their R/S stereoselectivity is generally lower than the corresponding dibenzylated dihydrolevoglucosenone (28).Both enantiomerically pure levoglucosenone (20) and its dihydro derivative 28 are readily available from biomass because they are products of cellulose pyrolysis.Enantiomerically pure dihydrolevoglucosenone (28) was also applied as a chiral auxiliary in the diastereoselective Diels-Alder reaction.It was first converted to dibenzylated dihydrolevoglucosenols (29) through double benzylation with benzyl halides under basic conditions followed by a reduction with sodium borohydride.Differently, dibenzylated dihydrolevoglucosenols (29) were further acrylated and then reacted with cyclopentadiene in the presence of Lewis acids in DCM, affording endo-(R)-bicyclo [2.2.1]hept-5-ene-2carboxylates (R)-31 as major products due to the existence of the vinyl-aryl π-stacking interaction (Scheme 6) [30].Through the utilization of both levoglucosenone (20) and its dihydro derivative 28 as auxiliaries, both enantiomeric bicyclo [2.2.1]hept-5-ene-2-carboxylates were prepared in good to high yields.Both diastereomeric monobenzylated dihydro derivatives were also attempted as auxiliaries in the diastereoselective Diels-Alder reactions.They show excellent endo/exo selectivity, but their R/S stereoselectivity is generally lower than the corresponding dibenzylated dihydrolevoglucosenone (28).

Chiral Oxazolidinone-Based Auxiliaries in Asymmetric Synthesis
Lignin is a class of natural plant-based polymers and ranks second in abundance only after cellulose, making it a potentially valuable raw material for biorefinery.However, it is a considerable challenge to use lignin as a feedstock for the production of biobased chemicals in either catalytic or enzymatic processes due to the structural heterogeneity of lignin.The heterogeneity is the result of the biosynthesis of lignin from the radical coupling of three primary monolignols.To improve lignin's utility as a renewable carbon feedstock, it is necessary to understand the assembly, stereostructure, and reactivity of the separation of lignin and the enzymatic lignin disassembly process.To realize these purposes, it is required to synthesize lignin models with different configurations in a stereospecific manner.To enantioselectively synthesize lignin models, Njiojob and coworkers selected the Evans auxiliary as the chiral source.They first prepared N-(2-methoxyphenyloxy)acetylated (R)-4-isopropyloxazolidin-2-ones 32 as starting materials.The reaction of aryloxyacetyl-derived (R)-4-isopropyloxazolidin-2-ones 32 and 4-benzyloxybenzaldehydes 33 stereospecifically generated lignin dimer models 34 in 60−68% yields in the presence of di-n-butylboron triflate and diisopropylethylamine (DIPEA) via condensation through six-membered Zimmerman-Traxler transition states TS7, in which the π-stacking interaction between benzaldehydes and aryloxy groups plays an important role in controlling the stereoselectivity.After subsequent transformations, including reduction, protection of the hydroxyl group, and oxidation, one of the lignin dimer models 34 was converted into aldehyde 35.Following a similar strategy, the reaction of aldehyde 35 with (S)-4-isopropyl-N-(2-methoxyphenyloxy)acetyloxazolidin-2-ones 36 as the chiral starting material, a lignin trimer model 38 was synthesized in a 53% yield.(R)-and (S)-Evans auxiliaries 32 and 36 show completely opposite stereoselectivities (Scheme 7) [31].The current synthetic strategy is an efficient way to prepare enantiopure lignin dimers and trimers with different stereochemical configurations from aryloxyacetylate oxazolidin-2-ones derivatives and appropriate aromatic aldehydes.Scheme 6. π-stacking-controlled Diels-Alder reaction with endo-(R)-products as major products.

Chiral Oxazolidinone-Based Auxiliaries in Asymmetric Synthesis
Lignin is a class of natural plant-based polymers and ranks second in abundance only after cellulose, making it a potentially valuable raw material for biorefinery.However, it is a considerable challenge to use lignin as a feedstock for the production of biobased chemicals in either catalytic or enzymatic processes due to the structural heterogeneity of lignin.The heterogeneity is the result of the biosynthesis of lignin from the radical coupling of three primary monolignols.To improve lignin's utility as a renewable carbon feedstock, it is necessary to understand the assembly, stereostructure, and reactivity of the separation of lignin and the enzymatic lignin disassembly process.To realize these purposes, it is required to synthesize lignin models with different configurations in a stereospecific manner.To enantioselectively synthesize lignin models, Njiojob and coworkers selected the Evans auxiliary as the chiral source.They first prepared N-(2-methoxyphenyloxy)acetylated (R)-4-isopropyloxazolidin-2-ones 32 as starting materials.The reaction of aryloxyacetyl-derived (R)-4-isopropyloxazolidin-2-ones 32 and 4-benzyloxybenzaldehydes 33 stereospecifically generated lignin dimer models 34 in 60-68% yields in the presence of di-n-butylboron triflate and diisopropylethylamine (DI-PEA) via condensation through six-membered Zimmerman-Traxler transition states TS7, in which the π-stacking interaction between benzaldehydes and aryloxy groups plays an important role in controlling the stereoselectivity.After subsequent transformations, including reduction, protection of the hydroxyl group, and oxidation, one of the lignin dimer models 34 was converted into aldehyde 35.Following a similar strategy, the reaction of aldehyde 35 with (S)-4-isopropyl-N-(2-methoxyphenyloxy)acetyloxazolidin-2-ones 36 as the chiral starting material, a lignin trimer model 38 was synthesized in a 53% yield.(R)-and (S)-Evans auxiliaries 32 and 36 show completely opposite stereoselectivities (Scheme 7) [31].The current synthetic strategy is an efficient way to prepare enantiopure lignin dimers and trimers with different stereochemical configurations from aryloxyacetylate oxazolidin-2ones derivatives and appropriate aromatic aldehydes.

Asymmetric Synthesis of β-Lactams and Deoxygenation of Oxiranecarbonitriles via Intramolecular π-π Stacking Interaction
β-lactam has been a key structural moiety of widely applied β-lactam antibiotics all over the world since the 1940s.β-lactam antibiotics have helped millions of people.Most β-lactam antibiotics are prepared from semisynthesis.The key structures of the β-lactam ring with defined stereostructures are generally constructed by organisms.The stereoselective synthesis of β-lactam derivatives is a crucial issue in constructing the β-lactam ring in both organic and medicinal chemistry [39].The Staudinger cycloaddition is a versatile method of synthesizing β-lactams from imines and ketenes, generated from acyl chlorides or α-diazoketones [40,41].The diastereoselectivity in the Staudinger cycloaddition is controlled by the competition between the direct ring closure and isomerization of zwitterionic intermediates E generated from imines 55 and ketenes 54 (Scheme 10) [42].In contrast with other factors [43], the substituents of imines and ketenes and reaction temperature evidently impact diastereoselectivity [44].On the other hand, torquoselectivity also plays

Asymmetric Synthesis of β-Lactams and Deoxygenation of Oxiranecarbonitriles via Intramolecular π-π Stacking Interaction
β-lactam has been a key structural moiety of widely applied β-lactam antibiotics all over the world since the 1940s.β-lactam antibiotics have helped millions of people.Most βlactam antibiotics are prepared from semisynthesis.The key structures of the β-lactam ring with defined stereostructures are generally constructed by organisms.The stereoselective synthesis of β-lactam derivatives is a crucial issue in constructing the β-lactam ring in both organic and medicinal chemistry [39].The Staudinger cycloaddition is a versatile method of synthesizing β-lactams from imines and ketenes, generated from acyl chlorides or αdiazoketones [40,41].The diastereoselectivity in the Staudinger cycloaddition is controlled by the competition between the direct ring closure and isomerization of zwitterionic intermediates E generated from imines 55 and ketenes 54 (Scheme 10) [42].In contrast with other factors [43], the substituents of imines and ketenes and reaction temperature evidently impact diastereoselectivity [44].On the other hand, torquoselectivity also plays an important role in the diastereocontrol in disubstituted ketene-participating Staudinger cycloaddition [45].
withdrawing phthalimido and electron-donating 4-methoxyphenyl groups in intermediate E at low temperatures and played an important role in stabilizing the intermediate E, leading to the formation of cis-β-lactam product 52.However, the stability of the π-stacking interaction decreased along with the increase in the reaction temperature, resulting in the intermediate E converting into intermediate F, which generated trans-β-lactam product 53 (Scheme 10) [44].The intramolecular π-stacking interaction played an important role in controlling the formation of cis-β-lactam product 54 diastereoselectively at low temperatures.The nucleophilic ring expansion of saturated three-membered heterocycles has been well investigated [52].Recently, the electrophilic ring expansion of saturated three-membered heterocycles was also realized [18,53,54].In contrast with the nucleophilic ring expansion of saturated three-membered heterocycles [52], their electrophilic ring expansion is a new avenue to construct new heterocyclic compounds [18,53,54].The electrophilic ring expansion of polycyclic arylthiiranes 64 and ketenes K generated from aryloxyacetyl chlorides 63 in the presence of triethylamine is a new strategy for the synthesis of areno[d]ε-thiolactones 66 directly without catalysts or additives.In the reaction, aryloxyacetyl chlorides 63 are first eliminated in the presence of TEA to form aryloxyketenes K.
Arylthiiranes 64 and aryloxyketenes K undergo a dearomatic sulfur-shifted ene reaction to directly generate intermediates 66 through the endo transition states TS8endo due to the existence of the π-stacking interaction, which was verified by theoretical calculation.After aromatization, intermediates 65 transform into the final products 66 in 22−94% yields.The current reaction features atom and step-economic characteristics via a tandem sequence of in situ ketene generation, π-stacking-controlled dearomatic sulfur-shifted ene, and aromatization and is a novel strategy for the electrophilic ring expansions of three-membered saturated heterocycles (Scheme 12) [55].The nucleophilic ring expansion of saturated three-membered heterocycles has been well investigated [52].Recently, the electrophilic ring expansion of saturated three-membered heterocycles was also realized [18,53,54].In contrast with the nucleophilic ring expansion of saturated three-membered heterocycles [52], their electrophilic ring expansion is a new avenue to construct new heterocyclic compounds [18,53,54].The electrophilic ring expansion of polycyclic arylthiiranes 64 and ketenes K generated from aryloxyacetyl chlorides 63 in the presence of triethylamine is a new strategy for the synthesis of areno[d]ε-thiolactones 66 directly without catalysts or additives.In the reaction, aryloxyacetyl chlorides 63 are first eliminated in the presence of TEA to form aryloxyketenes K.
Arylthiiranes 64 and aryloxyketenes K undergo a dearomatic sulfur-shifted ene reaction to directly generate intermediates 66 through the endo transition states TS8endo due to the existence of the π-stacking interaction, which was verified by theoretical calculation.After aromatization, intermediates 65 transform into the final products 66 in 22-94% yields.The current reaction features atom and step-economic characteristics via a tandem sequence of in situ ketene generation, π-stacking-controlled dearomatic sulfur-shifted ene, and aromatization and is a novel strategy for the electrophilic ring expansions of three-membered saturated heterocycles (Scheme 12) [55].

Asymmetric Synthesis of Multilayer 3D Chiral Molecules
Multilayer 3D chiral molecules are a new class of macromolecular sandwich-shaped organic materials.They possess a new form of chirality which is different from traditional planar and helical counterparts.They are composed of both planar and axial chirality.Their middle part includes three parallel top, medium, and bottom layers of aromatic (hetero)arene systems, which fold together by an aromatic π-stacking interaction, while the medium aromatic (hetero)arene is linked generally with the top and bottom aromatic arenes, respectively, on its para-positions through two naphthalene derivatives, existing in axial chirality.They show a strong luminescence of different colors under UV irradiation and some of them display aggregation-induced emission (AIE) properties.Thus, they exhibit potential applications in chemical, medicinal, and material sciences including optoelectronic materials in the future [59,60].

Asymmetric Synthesis of Multilayer 3D Chiral Molecules
Multilayer 3D chiral molecules are a new class of macromolecular sandwich-shaped organic materials.They possess a new form of chirality which is different from traditional planar and helical counterparts.They are composed of both planar and axial chirality.Their middle part includes three parallel top, medium, and bottom layers of aromatic (hetero)arene systems, which fold together by an aromatic π-stacking interaction, while the medium aromatic (hetero)arene is linked generally with the top and bottom aromatic arenes, respectively, on its para-positions through two naphthalene derivatives, existing in axial chirality.They show a strong luminescence of different colors under UV irradiation and some of them display aggregation-induced emission (AIE) properties.Thus, they exhibit potential applications in chemical, medicinal, and material sciences including optoelectronic materials in the future [59,60].
Asymmetric catalytic Suzuki-Miyaura coupling was also developed with diaryl(1bromonaphthalene-2-yl)phosphine oxides 100 and (7-(8-arylnaphthalen-1-yl)benzo[c][1,2,5] thiadiazol-4-yl)boronic acid pinacol esters 101 as starting materials, generating the target products 103 in 40-57% yields with diastereomeric ratios of 58:42 to 87:13 with enantiopure phosphine 102 as chiral ligand (Scheme 20) [61].Similar asymmetric catalytic Suzuki-Miyaura coupling was also investigated for the synthesis of desired products 96 with a naphthyl group in the middle part instead of the aryl group by displacement of the 8-aryl group with the 8-(naphthalen-1-yl) group in substrates 101 [62].97) to generate a pair of diastereomeric products 106 and 107 in 2:1 in a 53% total yield.The XRD single crystal diffraction analysis reveals that two naphthalenes are located in opposing directions at a dihedral angle of approximately 60°.For the middle part, the top and bottom layers are nearly parallel to the central layer due to the π-stacking interaction.The phenyl group of one of the amide groups is oriented nearly parallel to the naphthalene ring.In a unit cell, the intermolecular distances between proximate aromatic rings are very similar to those of intramolecular distances due to the π-stacking interaction.The functional group amide was further transferred to nitrile, amide, carbamate, amino, and hydroxyl groups, sequentially (Scheme 21) [63].
Similarly, chiral amide (R)-4-(8-bromonaphthalen-1-yl)-N-(1-phenylethyl)benzamide (94) was dually coupled with pinacol naphtho[2,3-c][1,2,5]thiadiazole-4,9-diyldiboronate (108) to generate a pair of diastereomeric products 109 and 110 in 1.6:1 in a 45% total yield.The XRD single crystal diffraction analysis indicates that two naphthalenes are located in opposing directions nearly perpendicular to the central anphthothiadiazole ring, different  97) to generate a pair of diastereomeric products 106 and 107 in 2:1 in a 53% total yield.The XRD single crystal diffraction analysis reveals that two naphthalenes are located in opposing directions at a dihedral angle of approximately 60 • .For the middle part, the top and bottom layers are nearly parallel to the central layer due to the π-stacking interaction.The phenyl group of one of the amide groups is oriented nearly parallel to the naphthalene ring.In a unit cell, the intermolecular distances between proximate aromatic rings are very similar to those of intramolecular distances due to the π-stacking interaction.The functional group amide was further transferred to nitrile, amide, carbamate, amino, and hydroxyl groups, sequentially (Scheme 21) [63].

Conclusions
As one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry, the π-stacking interaction can exist in different fashions, for instance, in face-to-face, edge-to-face, and even T-shape interactions.It exists widely, such Scheme 23.Asymmetric catalytic synthesis of polymeric multilayer 3D chiral molecules.

Conclusions
As one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry, the π-stacking interaction can exist in different fashions, for instance, in face-to-face, edge-to-face, and even T-shape interactions.It exists widely, such as in biological macromolecules, organic materials, and organic reactions.It plays an important role not only in the stabilization of biological macromolecules and complexations of biomolecules with small organic compounds but also in the stabilization of confor-mations and transition states in organic reactions via intramolecular and intermolecular attractive interactions.This minireview summarized the recently developed examples of π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution for asymmetric synthesis, diastereoselective synthesis, the asymmetric synthesis of helicenes and heterohelicenes, and the synthesis of multilayer 3D chiral molecules.The π-stacking interaction has been applied in the stabilizations of biomacromolecules, complexations of biomacromolecules and small organic compounds, design of organic materials, organocatalysts, and chiral ligands for asymmetric catalysis.It will show wide applications in understanding the biological function of biomacromolecules and the development of medicines in the future.Before, steric hindrance was considered to be one of the most crucial issues in the design of chiral auxiliaries and catalysts.Recently, steric hindrance, electronic effect, and noncovalent interaction have been recognized as important factors in realizing high stereoselectivity in the design of chiral auxiliaries and catalysts.Recently, several highly efficient asymmetric catalytic reactions have been achieved through the π-stacking interaction between substrates with organocatalysts or chiral ligands under the catalysis of organocatalysts [66][67][68][69][70] and transition metal-chiral ligand complexes [71][72][73], respectively.The enantiomerization of [5]helicene was also successful under the catalysis of a perylene bisimide cyclophane through the π-stacking interaction [74].As one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry, the π-stacking interaction will be paid much attention to in the design of novel chiral auxiliaries for stereocontrol in asymmetric synthesis and in the design of new organocatalysts and chiral ligands for asymmetric catalysis in the preparation of biologically important organic compounds, medicines, and their intermediates in the future.

Scheme 7 .
Scheme 7. Asymmetric synthesis of dimers and trimer of lignin models.

Scheme 7 .
Scheme 7. Asymmetric synthesis of dimers and trimer of lignin models.

Scheme 8 .
Scheme 8. Synthesis of phosphonopeptides with DCC as a coupling reagent.

Scheme 10 .Scheme 11 .
Scheme 10.Diastereoselective synthesis of β-lactams.Oxiranecarbonnitriles are very important synthetic intermediates and have been applied in several transformations[46][47][48][49][50].During the transformation of 3-substituted transoxiranecarbonnitriles 58 to 3-substituted (Z)-propenonitriles 60 through the thiourea-mediated stereospecific deoxygenation, trans-oxiranecarbonnitriles 58 generated (Z)-Scheme 10.Diastereoselective synthesis of β-lactams.To illustrate the influence of different substituted ketenes and imines on diastereoselectivity in the formation of β-lactams at various reaction temperatures, the reaction of phthalimidoacetyl chloride(50) and N-(4-methoxybenzylidene)isopropylamine (51) was conducted and exhibited an evident increase in temperature on the diastereoselectivity.There was a favorable formation of trans-β-lactam product 53 at a higher temperature (150 • C) and a predominant generation of cis-β-lactam product 52 at a lower temperature (40 • C).It was rationalized that the strong π-stacking interaction existed between the electron-withdrawing phthalimido and electron-donating 4-methoxyphenyl groups in intermediate E at low temperatures and played an important role in stabilizing the intermediate E, leading to the formation of cis-β-lactam product 52.However, the stability of the π-stacking interaction decreased along with the increase in the reaction temperature, resulting in the intermediate E converting into intermediate F, which generated trans-βlactam product 53 (Scheme 10)[44].The intramolecular π-stacking interaction played an important role in controlling the formation of cis-β-lactam product 54 diastereoselectively at low temperatures.Oxiranecarbonnitriles are very important synthetic intermediates and have been applied in several transformations[46][47][48][49][50].During the transformation of 3-substituted transoxiranecarbonnitriles 58 to 3-substituted (Z)-propenonitriles 60 through the thiourea-mediated stereospecific deoxygenation, trans-oxiranecarbonnitriles 58 generated (Z)-propenonitriles
from from Scheme 21.Asymmetric synthesis of multilayer 3D chiral molecules with arenediboronate as the central moiety.Scheme 22. Asymmetric synthesis of multilayer 3D chiral molecules with heteroarenediboronate as the central moiety.