Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis

Abstract

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.

1. 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 product-based 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 minireview are mentioned or verified by experimental or theoretical calculational results or on the basis of X-ray crystal diffraction analysis.

2. 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 ortho-substituted 2-alkylphenyl 4-methylphenyl sulfoxides were first used as precursors of ortho-arylsulfinylbenzylcarbanions 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 (Bu₄BH₄) in MeOH, affording chiral arylsulfinyl-derived amines 4 in almost quantitative yields with excellent diastereoselectivity. In the reduction step, Bu₄BH₄ 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 NaIO₄ 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 (R_F = 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 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) 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].

2.2. 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].

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).

2.3. 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.

3. Acyl 2,3-Dihydroimidazo[1,2-a]pyridine and 1,2-Dihydroimidazo[1,2-a]quinolines in Kinetic Resolution

Although the asymmetric catalytic borane reduction of ketones is one of the most efficient methods for the preparation of enantiopure secondary alcohols [32,33,34], chemical resolution has been widely utilized in the industrial manufacturing of secondary alcohols as well [35,36]. Kinetic resolution is also an alternative choice for obtaining enantiopure secondary alcohols via selected reactions, for instance, acylation [37,38].

Birman’s group first developed 6-substituted (R)-2-phenyl-2,3-dihydroimidazo[1,2-a]pyridines 38 as enantioselective acylation catalysts. In the resolution, the catalysts first were acylated with acetic or propanoic anhydrides in the presence of DIPEA. The acylated 2,3-dihydro-1H-imidazo[1,2-a]pyridin-4-iums 41 predominantly reacted with (R)-alcohols (R)-39 due to less steric hindrance in the π-stacking attractive interaction. Generally, non-substituted and 6-bromo-2,3-dihydroimidazo[1,2-a]pyridines (38a and 38b) exhibited lower selectivities than 6-nitro- and 6-trifloromethyl-2,3-dihydroimidazo[1,2-a]pyridines (38c and 38d). Bulky alcohols (R = CHMe₂ and CMe₃) generally required long reaction times (30–52 h) to reach a similar conversion. However, aliphatic 1-cyclohexylethan-1-ol showed only less than 4% conversion for 50 h due to the absence of the π-stacking interaction. Although indan-1-ol was converted in 16% for 50 h, no selectivity was observed because of the nonexistence of the π-stacking interaction. These results support the function of the π-stacking attractive interaction in the kinetic resolution. The C=C double bond containing substrate 1-(cyclohexen-1-yl)ethan-1-ol (42) was resoluted in a moderate selectivity of 11 in 40% conversion (Scheme 8) [37].

To realize the kinetic resolution of conjugated cinnamyl alcohols and their derivatives 45, they further developed new (R)-7-chloro-2-phenyl-1,2-dihydroimidazo[1,2-a]quinoline (44) with an additional fused benzene ring as the enantioselective acylation catalyst. In comparison with 2,3-dihydroimidazo[1,2-a]pyridines 38, 1,2-dihydroimidazo[1,2-a]quinoline 44 extended the conjugative system and achieved efficient a kinetic resolution of both conjugated cinnamyl alcohols 45 with selectivities of 17–57 in conversions of 32–56% and non-conjugated 1-arylethan-1-ols 48 with selectivities of 33–117 in conversions of 42–56%; even the C=C double bond containing substrate 1-(cyclohexen-1-yl)ethan-1-ol (42) with a selectivity of 17 in a conversion of 47% with propanoyl anhydride was applied as the acylating reagent. In each of the cases, (R)-alcohols were acylated to the corresponding propanoates and (S)-alcohols remained (Scheme 9) [38]. All of these three classes of substrates were efficiently resoluted with (R)-7-chloro-2-phenyl-1,2-dihydroimidazo[1,2-a]quinoline (44) as the catalyst and propanoyl anhydride as the acylating reagent. However, bulky alcohols generally presented high selectivities. For example, 2,2-dimethyl-1-phenylpropan-1-ol was resoluted with the selectivity of 117. The results revealed that 1,2-dihydroimidazo[1,2-a]quinoline 44 with an extended conjugative system showed better behavior than 2,3-dihydroimidazo[1,2-a]pyridines 38 in the kinetic resolution of alcohols.

4. 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 an important role in the diastereocontrol in disubstituted ketene-participating Staudinger cycloaddition [45].

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-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.

Oxiranecarbonnitriles are very important synthetic intermediates and have been applied in several transformations [46,47,48,49,50]. During the transformation of 3-substituted trans-oxiranecarbonnitriles 58 to 3-substituted (Z)-propenonitriles 60 through the thiourea-mediated stereospecific deoxygenation, trans-oxiranecarbonnitriles 58 generated (Z)-propenonitriles 60 stereospecifically due to the π-stacking interaction in intermediates G and 61. N,N,N′,N′-Tetramethylthiourea (59) first nucleophilically attacked the cyano-attached ring carbon atom to form intermediates G via an S_N2 ring opening. Intermediates G rotated 180° to generate intermediates H, which further underwent an intramolecularly nucleophilic addition to produce 1,3-oxathiolane derivatives 61. In an amine-induced fragmentation, they transformed into intermediates I, which rotated 180° to yield intermediates J. Intermediates J further underwent an intramolecularly nucleophilic substitution, resulting in the formation of trans-thiiranecarbonitriles 62 stereospecifically. Trans-Thiiranecarbonitriles 62 lost their sulfur atom to lead to (Z)-propenonitriles 60 stereospecifically (Scheme 11) [51].

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].

5. Asymmetric Synthesis of Optically Active Helicenes

Helicenes are a class of important carbon-rich materials. Helical supramolecular structures are important in chemistry and materials science. Helical structures that are derived from conjugated ortho-annelated arenes or heteroarenes are known as [n]helicenes. The n presents the number of the ortho-annelated arene or heteroarene ring. Helicenes are 3-dimensional polycyclic aromatic systems, which consist of all ortho-fused aromatic or heteroaromatic rings and are inherently chiral, presenting helical conformation. Different from fullerenes, carbon nanotubes, and graphene, helicenes are chiral organic compounds and exist in left-hand or right-hand helical structures. Different racemic [11]helicenes consisting of all ortho-fused benzene rings or ortho-fused benzene and conjugated cyclohexadiene rings were prepared successfully from 4,6-bis((2-(4-(triisopropylsilyl)but-3-yn-1-yl)naphthalen-1-yl)ethynyl)isophthalaldehyde (67), which was synthesized from 4,6-diformyl-1,3-phenylene bis(trifluoromethanesulfonate) and (4-(1-ethynylnaphthalen-2-yl)but-1-yn-1-yl)triisopropylsilane via the CuI-catalyzed coupling. The dialdehyde 67 reacted with n-butyl lithium-treated prop-1-yn-1-yltripropylsilane, generating a pair of enantiomeric double addition products and a meso-double addition product in an equivalent amount. After a series of transformations, they were converted into diacetates rel-(R,R)-68 and meso-68 as precursors for the next [2 + 2 + 2] annulation. The [2 + 2 + 2] annulations were conducted under three different conditions. For precursor rel-(R,R)-68, it asymmetrically produced double-annulated product [11]helicene-like derivatives rel-(M,R,R)-69 and rel-(P,R,R)-69 through intermediates rel-(M,R,R)-69 and rel-(P,R,R)-69. The CpCo(CO)₂-catalyzed annulation preferred the formation of rel-(P,R,R)-70 with a diastereoselectivity of 17:83 for rel-(M,R,R)-70:rel-(P,R,R)-70, while the Ni(COD)₂-catalyzed annulation predominately generated rel-(M,R,R)-70 with a diastereoselectivity of 72:28 for rel-(M,R,R)-70:rel-(P,R,R)-70. However, only very low diastereoselectivity was observed in the CpCo(C₂H₄)₂-catalyzed annulation, with a slightly favorable formation of rel-(M,R,R)-70 with a diastereoselectivity of 57:43 for rel-(M,R,R)-70:rel-(P,R,R)-70. For the double [2 + 2 + 2] annulation of meso-68, the Co-catalyzed double [2 + 2 + 2] annulations gave rise to the annulated product [11]helicene-like derivative rel-(M,R,R)-70 in higher yields (40% and 30%) than those in the Ni-catalyzed annulation. The [11]helicene-like derivative rel-(M,R,R)-63 was further converted to racemic [11]helicene rac-70 in excellent yield via the elimination of acetate and dehydrogenation. In all [2 + 2 + 2] annulations, the edge-to-face π-stacking interaction plays a key role in controlling the diastereoselectivity (Scheme 13) [56]. Interestingly, the CpCo(CO)₂- and Ni(COD)₂-catalyzed double [2 + 2 + 2] annulations exhibit different diastereoinduction in the stereoselective synthesis of [11]helicene-like molecules.

Helicenes containing one or more nonaromatic heterocycles are also a class of important carbon-rich materials. Similar to helicenes derived from conjugated ortho-annelated arenes or heteroarenes, helicene-like molecules also present helical conformation. After the successful preparation of racemic [11]helicenes, the asymmetric synthesis of optically active (P,S,S)- and (M,S,S)-[11]helicene-like molecules (P,S,S)-74 and (M,S,S)-74 was realized from 1,1’-((4,6-bis((((S)-4-(p-tolyl)but-3-yn-2-yl)oxy)methyl)-1,3-phenylene)bis(ethyne-2,1-diyl))bis(2-(but-3-yn-1-yl)naphthalene) (−)-(S,S)-72 through the Co-catalyzed double [2 + 2 + 2] annulation. In the [2 + 2 + 2] annulation, the edge-to-face π-stacking interaction plays a crucial role in controlling the stereoselectivity. Under all the used conditions, (P,S,S)-annulated product (P,S,S)-74 was obtained as the major product. High stereoselectivity ((M,S,S)-74:(P,S,S)-74 = 10:90) was observed under photo-irradiation (in 26% yield) and microwave irradiation (in 33% yield) conditions. However, a low stereoselectivity ((M,S,S)-74:(P,S,S)-74 = 25:75) and yield (17%) were obtained at room temperature. The results indicated that a higher reaction temperature was favorable to improve both the yield and stereoselectivity (Scheme 14) [56]. The current Co-catalyzed double [2 + 2 + 2] annulation strategy is an efficient route to synthesize optically active [11]helicene-like molecules.

Heterohelical supramolecular structures are important in chemistry and materials science as well. Oligothiophenes are the most studied π-systems due to their favorable electrical and optical properties. Much attention has been paid to their preparation. Several classical oligothiophenes, such as α-sexithiophene, quasi-linear oligomer pentathienoacene, and helical oligomer [7]helicene, have been synthesized until now. The asymmetric synthesis of optically active (M,R,M)-bis[7]helicene (M,R,M)-79 was carried out from bis(β-trithiophene) 75 [57]. Bis(β-trithiophene) 75 was obtained from 3,4-dibromo-2-trimethylsilyldithieno[2,3-b:3’,2’-d]thiophene via lithiation with butyl lithium and the CuCl₂-catalyzed coupling followed with the treatment with TFA in dichloromethane. 3,4-Dibromo-2-trimethylsilyldithieno[2,3-b:3’,2’-d]thiophene was prepared from 3,4-dibromothiophene via lithiation with butyl lithium and the CuCl₂-catalyzed coupling followed by dilithiation with LDA and oxidation with bis(phenylsulfonyl)sulfide [58]. To circumvent solubility problems, bis(β’-bromo-β-trithiophene) 75 was protected with tripropylsilyl chloride with the treatment with LDA in the presence of a chiral diamine (-)sparteine, affording optically active mono-tripropylsilyl-protected (R)-tetrakis(β-trithiophene) (R)-76 and ditripropylsilyl-protected tetrakis(β-trithiophene) 77, which was hydrolyzed to starting material 75 with TFA in chloroform for reuse. The (R)-tetrakis(β-trithiophene) (R)-76 was further coupled under the catalysis of a palladium catalyst in the presence of potassium phosphate to generate tetrakis[7]helicene (R,R,R)-78 with (R,R,R) configuration. Finally, the (R,R,R)-tetrakis[7]helicene (R,R,R)-78 was transformed to optically active (M,R,M)-bis[7]helicene (M,R,M)-79 via the formation of two new thiophene rings through the sequential treatments with LDA in the presence of (−)-sparteine and oxidation with bis(benzenesulfonyl) sulfide. During the transformation, the strong noncovalent π–π stacking interaction plays an important role in stereoinduction in the formation of (M,R,M)-bis[7]helicene (M,R,M)-79, which showed a helical structure. However, the transformation from (R,R,R)-tetrakis[7]helicene (R,R,R)-78 into (M,R,M)-bis[7]helicene (M,R,M)-79 exhibited low to moderate stereoselectivity, 62–64% ee for 3–4% conversion, and 22–47% ee for 12–23% conversion. The stereoselectivity decreased evidently along with the increase in conversion (Scheme 15) [57]. Although the synthetic method is not so efficient in conversion and stereoselectivity, it is still useful for the preparation of optically active bis[7]helicene and will show further application in the preparation of other [n]helicene derivatives in the future.

6. 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].

Racemic multilayer 3D chiral molecules were first prepared from 8-arylnaphthalen-1-amines 80 and 1,2-dibromobenzene (81) via the palladium-catalyzed dual Buchwald–Hartwig couplings, generating vicinal N,N’-bis(8-arylnaphthalen-1-yl)benzene-1,2-diamines 82 and ent-82, which exist in an equilibrium of two enantiomeric conformers 82 and ent-82. However, after the treatment with phosphorus oxychloride in THF, they cyclized into 2-chloro-1,3-bis(8-arylnaphthalene-1-yl)-1,3-dihydrobenzo[d][1,3,2]diazaphosphole 2-oxides 83 and ent-83, existing in two stable enantiomers 83 and ent-83, which were resoluted. They were further converted to 2-amino-1,3-bis(8-arylnaphthalene-1-yl)-1,3-dihydrobenzo[d][1,3,2]diazaphosphole 2-oxides 84 and 85, respectively, under sequential treatments with sodium azide and hydrogenolysis in the presence of Pd/C (Scheme 16).

2-Chloro-1,3-bis(8-(4-methoxyphenyl)naphthalene-1-yl)-1,3-dihydrobenzo[d][1,3,2]diazaphos-phole 2-oxide (83b) was also transformed into 2-benzylamino-1,3-bis(8-(4-methoxyphenyl)naphthalene-1-yl)-1,3-dihydrobenzo[d][1,3,2]diazaphosphole 2-oxide (86) and 2-methyl-1,3-bis(8-(4-methoxyphenyl)naphthalene-1-yl)-1,3-dihydrobenzo[d][1,3,2]diazaphosphole 2-oxide (87), respectively, through the reaction with lithium benzylamide and methyl lithium (Scheme 17) [59].

In the same year, two different strategies for the enantioselective assembly of multilayer 3D chiral compounds were exploited as well. In the first one, 4,7-bis(8-bromonaphthalen-1-yl)benzo[c][1,2,5]thiadiazole (88) as a core molecule was reacted with various (R)-4-carbamoylphenylboronic acids 89, respectively, via the palladium-catalyzed dual Suzuki–Miyaura coupling to give rise to the desired products 90 in low 16–48% yields in diastereomeric ratios of 1.49:1 to 3.00:1. To improve the yields, the second strategy was attempted. 4,7-Dibromobenzo[c][1,2,5]thiadiazole (91) as the central molecule was reacted with (R)-(8-(4-((1-phenylethyl)carbamoyl)phenyl)naphthalene-1-yl)boronic acid (92) to generate the target product 90a in 53% yield with a diastereomeric ratio of 2.09:1. Alternatively, the reaction of benzo[c][1,2,5]thiadiazole-4,7-diyldiboronic acid (93) and (R)-4-(8-bromonaphthalen-1-yl)-N-(1-phenylethyl)benzamide (94) gave rise to the expected product 90a in 60% yield with a diastereomeric ratio of 1.91:1. The yield was improved slightly, but diastereoselectivity decreased (Scheme 18) [60].

To increase the steric bulkiness, different substituted (R)-4-(1-phenylethyl)carbamoylphenylboronic acids 95 were applied in the Suzuki–Miyaura coupling with 4,7-bis(8-bromonaphthalen-1-yl)benzo[c][1,2,5]thiadiazole (88) as a core molecule, giving the desired products 96 in 20–73% yields with diastereomeric ratios of 1.64:1 to 2.17:1. The reaction of 4,9-dibromonaphtho [2,3-c][1,2,5]thiadiazole (97) and (8-phenylnaphthalen-1-yl)boronic acid (98) led to the target product 99 in 70% yield (Scheme 19) [60]. The results indicate that the synthetic strategies involving difunctionalized planar aromatic (hetero)arenes as the central molecules generally result in the formation of the desired products in high yields.

Asymmetric catalytic Suzuki–Miyaura coupling was also developed with diaryl(1-bromonaphthalene-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].

Chiral amide (R)-4-(8-bromonaphthalen-1-yl)-N-(1-phenylethyl)benzamide 94 was prepared in a 58% yield from 1,8-dibromonaphthalene (104) and (R)-(4-((1-phenylethyl)carbamoyl)phenyl)boronic acid (89a) via the Suzuki–Miyaura coupling. It further dually coupled with pinacol 2,3-dihydronaphtho[2,3-b][1,4]dioxine-5,10-diyldiboronate (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 from the previous 2,3-dihydronaphtho[2,3-b][1,4]dioxine central one, which exists at a dihedral angle of approximate 60°. Other structural features are very similar to the previous 2,3-dihydronaphtho[2,3-b][1,4]dioxine central one. The functional group amide was further transferred to nitrile, amide, and carbamate groups, sequentially (Scheme 22) [64].

Recently, a similar synthetic strategy was utilized in the synthesis of polymeric multilayer 3D chiral compounds 115–117 with pinacol (naphtho[2,3-c][1,2,5]thiadiazole-4,9-diyl)bis(8-naphthalen-1-ylboronate) and (naphtho[2,3-c][1,2,5]selenodiazole-4,9-diyl)bis(8-naphthalen-1-ylboronate) 104 with three different 1,8-dibromonaphthalene derivatives 104, 112, and 113 as monomers (Scheme 23) [65]. They are very interesting polymers and oligomers of multilayer 3D chiral compounds and show potential application in materials science.

7. 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 conformations 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.