The N-heterocyclic carbene (NHC)-catalyzed enantioselective cycloaddition reactions of ketenes are powerful methods for the synthesis of chiral heterocycles. Followed by the previous reported NHC-catalyzed [2+2] and [4+2] cycloaddtion of ketenes with imines, ketones and various heterodienes, the NHC-catalyzed enantioselective [4+2] cycloaddition of ketenes with α-cyanochalcones was investigated in this paper. In the presence of the bulky N-heterocyclic carbene derived from L-pyrogutamic acid, the reaction of ketenes with α-cyanochalcones went smoothly, giving the corresponding chiral multisubstituted dihydropyranones in good yields with good diastereoselectivities and high enantioselectivities. Initially, several NHCs derived from L-pyrogultamic acids were screened for the reaction. The NHC 4b with bulkyl dimethyl(tert-butyl)silyl group and N-isopropylphenyl performed better than others. The reaction catalyzed by NHCs 4c～4d with a free hydroxyl group gave the dihydropyranones with reversed diastereoselectivity but decreased enantioselectivity. The reaction went well in THF, toluene, dichloromethane or ether, while the one in toluene showed best results. Better yield was reached when the reaction was carried out at 0 or -20 ℃. Under optimized reaction conditions, a variety of aryl(alkyl)ketenes were investigated for the reaction. It was found that both electron-donating and electron-withdrawing groups in the aryl(alkyl)ketene are tolerable for the reaction. The one with electron-withdrawing substituent gave the product in better yield and diastereoselectivity, while the one with electron-donating substituent resulted in better enantioselectivity. The alkyl chain of the ketenes could be ethyl, n-propyl and n-butyl. All the α-cyanochalcones with para-, meta- or ortho-substitutent went well for the reaction. The absolute configuration of resulted dihydropyranone 3e was established by the X-ray analysis of its crystal. The reaction is proposed to initialize with the addition of NHC to ketenes to give the enolate I. The adduct Ⅱ is formed from enolate I and α-cyanochalcone via stepwise Michael addition and cyclization or simultaneous Diels-Alder reaction. The elimination of NHC from adduct Ⅱ gives final dihydropyranone 3.

Chiral sulfonyl compounds have great versatility in organic synthesis, and they are also important as biologically active substances in medicinal chemistry. Among various methods developed for their synthesis, rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated sulfonyl compounds represents one of the most practical methods due to the stability and availability of the boronic acid used as a nucleophile. Although several Rh(I) complexes of bidentate ligands have been discovered for asymmetric conjugation addition of α,β-unsaturated sulfonyl compounds, some challenging issues still remain in terms of efficiency, enantioselectivity and substrate scope. Therefore, the development of an efficient catalytic system for the synthesis of chiral sulfonyl compounds is an important goal in extending the current methodology. Here, a general and mild method for the rhodium-catalyzed enantioselective catalytic conjugate addition of arylboronic acids to β-aryl-α,β-unsaturated sulfonate is described. The success of the process relies on the use of extraordinary simple chiral phosphite-olefin ligands as bidentate ligands which offer notable synthetic and economic advantages. Optimum reaction condition was determined to run the reaction at 50 ℃ using dioxane as the solvent, in the presence of 2.5 mol% of [Rh(coe)₂Cl]₂ and 5 mol% of chiral P/olefin ligand L7. This Rh(I) catalyst containing chiral P/olefin ligand has a broad substrate scope, a wide range of arylboronic acids with varying electronic and steric demands were successfully examined with α,β-unsaturated sulfonate (1). Notably, all transformations proceed efficiently to give the desired products in good yields (84%～95%) and excellent selectivities (92%～99% ee). The electronic properties of the arylboronic acids did not appear to affect the reactivity of the reaction. Besides, α,β-unsaturated sulfonate 1 with either an electron-donating or electron-withdrawing group on any aromatic carbon readily underwent the asymmetric arylation with arylboronic acids, affording chiral sulfonates in high yields and enantioselectivities. The current reaction provides a practical approach to the synthesis of diverse highly enantioenriched gem-diaryl substituted sulfonates.

An alternative modular strategy has been developed for hydrogen-bond-mediated supramolecular iminium catalysis (SIC). To improve the efficiency of traditional iminium ion catalysis and provide a new approach to asymmetric catalysis, we recently developed a new concept which aims to activate iminium ions. To expand the scope of SIC, we reported here a rationally designed strategy involving the dual activation of both iminium ions and the nucleophilic partner that provides new opportunities for improving the reactivity and designing new reactions. We analyzed the different reaction rates of the addition reaction of malonate to α,β-unsaturated aldehyde catalyzed by traditional iminium ion catalysis and supramolecular iminium catalysis by the means of ¹H NMR monitoring of the reaction conversions and comparison of the isolated yields. Moreover, different carboxylic acids were employed in iminium catalytic Michael addition reaction of malonate to α,β-unsaturated aldehyde to test our hypothesis. General speaking, by using this novel supramolecular iminium catalysis, the enantioselectivities of the Michael addition products are excellent (93%～95%) with moderate to good yields (61%～86%), meanwhile, all these reactions were rather slow and only 33%～57% conversions were obtained even after 7 days in the presence of traditional iminium ion catalysis. Further reducing the catalyst loading to 5 mol%, the reaction proceeded smoothly to give a >90% conversion with 94% ee after 12 h. The results revealed that the use of less acidic acid which generates lower concentration of iminium ion associated with stronger anion-binding stabilized conjugate base gives faster reaction rate. The experimental results indicate a new approach for SIC which involves an anion-exchange process between anion-binding stabilized carboxylate ion and malonate. The self-assembled supramolecular system has higher reactivity, better efficiency and greater turnover numbers. This general strategy has the potential to be applied in many iminium catalytic nucleophilic addition reactions and might provide new opportunities for designing new asymmetric reactions. The further study is currently underway in our laboratory.

Asymmetric hydrogenation of N-hetero aromatics offers a very straightforward and efficient method to obtain the corresponding chiral N-hetero cyclic saturated or partially saturated compounds. As one of the most challenging substrates, asymmetric hydrogenation of isoquinolines has met with limited success probably because of lower reactivity and the catalyst deactivation resulted from strong coordination. Considering the prevalence of the chiral 1,2,3,4-tetrahydroisoquinoline motif in natural alkaloids and drug molecules, the development of new catalyst system for asymmetric hydrogenation of isoquinolines is highly desirable and significant. Herein, a novel chiral anion metathesis strategy successfully applied for asymmetric transfer hydrogenation of isoquinolines is reported. N-Protected 1-substituted 1,2-dihydroisoquinolines were obtained with high yield and up to 79% ee in the presence of Hantzsch ester and chloroformate using chiral phosphoric acid as catalyst. The phosphate salt and the activated N-acyl isoquinolinium chloride undergo anion metathesis to form chiral contact ion pair, which leads to a highly enantioselective transfer hydrogenation of isoquinolines. After systematically investigating the effects of activating reagent, solvent, base, hydride donor and catalyst on this transfer hydrogenation reaction, the best result was achieved under the optimized condition as follows: 5 mol% H8-BINOL-derived chiral phosphoric acid as catalyst, 1.2 equivalent 2,2,2-trichloroethyl chloroformate as activator, 1.5 equivalent dimethyl 2,6-diethyl-1,4-dihydropyridine-3,5- dicarboxylate as hydride donor, 1.5 equivalent sodium carbonate as base and cyclohexane as solvent. The reaction is tolerant toward a broad range of aryl or alkyl 1-substituted isoquinoline substrates. This methodology represents one of the rare examples of asymmetric hydrogenation of this challenging substrate. The utilizing of chiral anion metathesis strategy could enable chiral phosphoric acid to catalyze more asymmetric transformation process and further researching is ongoing in our laboratory.

Transition metal catalyzed asymmetric reaction is a hot issue and a frontier of the research in current organic chemistry. The design and synthesis of new type of efficient chiral ligands and chiral catalysts, esspecially those with novel skeleton is the focus of research in asymmetric catalysis. Since 1990's, chiral ligands based on spiro skeletons have received increasing attention and gradually developed into a new type of chiral ligands with distinctive characteristics. The skeletons of the chiral spiro ligands developed from spiro[4.4]nonane with three chiral stereocenters to spirobiindane and spiro[4.4]nonadiene with only one axial chirality, as well as other types of spiro skeletons. Nowadays, the library of chiral spiro ligands contains a wide range of chiral spiro ligands with different skeletons, including chiral spiro monophosphorus ligands, diphosphine ligands, phosphine-nitrogen ligands, dinitrogen ligands, and etc. Many of these chiral spiro ligands and related catalysts not only have shown high catalytic activity and high enantioselectivity for various asymmetric reactions such as asymmetric hydrogenations, asymmetric carbon-carbon bond forming reactions, and asymmetric carbon-heteroatom bond forming reactions, but also have made the enantiocontrol of many catalytic asymmetric reactions, which are difficult in obtaining high enantioselectivities, more easily and possible. The chiral spiro skeleton has become a ‘privileged structure’, and chiral spiro ligands and catalysts have been used in the syntheses of different type of chiral compounds including chiral natural products and chiral drugs. The emergence of chiral spiro ligands increased the dynamism of research on finding new chiral ligands and catalysts, and promoted asymmetric synthesis chemistry. Henceforth, the focus of study in chiral spiro ligands will continue to be the development of new chiral spiro ligands and catalysts with high activity and high enantioselectivity. At the same time, the applications of chiral spiro ligands in the new catalytic asymmetric reactions, and in the asymmetric synthesis of bioactive chiral compounds, chiral natural products and chiral drugs will become a new focus of research.

Some important progress has been made in palladium-catalyzed asymmetric intermolecular Heck reaction in recent years. The breakthrough was achieved in the use of acyclic olefins, the aryl halide and benzylic electrophiles in asymmetric intermolecular Heck reaction with some newly developed chiral ligands by Jung, Sigman and Zhou groups. Asymmetric intermolecular oxidative Heck-type reaction of acyclic α,β-unsaturated carbonyls and boronic acids was realized by Jung group in high enantioselectivity in the presence of chiral NHC-amidate-alkoxide Pd(Ⅱ) complexes as catalyst. The Heck reaction of acyclic hydroxyl alkenes and allyl alcohol aryldiazonium salts was achieved by Sigman group with a catalyst derived from Pd₂dba₃ and chiral pyridine oxazoline by using a redox-relay strategy, affording β-, γ-, and δ-aryl carbonyl products in excellent enantioselectivity. Sigman group also reports a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids, providing direct access to diverse molecular building blocks containing an enantiomerically enriched quaternary carbon center. The first examples of asymmetric Mizoroki-Heck reaction using benzyl electrophiles was reported by Zhou group with their newly developed phosphoramidite as the optimal chiral ligand. With this strategy, a key intermediate in asymmetric synthesis of (+)-anisomycin was quickly afforded when p-methoxybenzyl trifluoroacetate was adopted as starting material. Zhou group also realized the first Heck reaction of aryl bromides and chlorides with various cyclic olefins in high enantioselectivities with (R)-Xyl-SDP(O) as the ligand. The use of alcoholic solvents and alkylammonium salts were essential to creating cationic aryl-Pd species for enantioselective olefin insertion. Zhou group has also realized desymmetrization of substituted cyclic olefins successfully via asymmetric Heck reaction and found that the use of bisphosphine mono oxide as ligand was important. The Heck reaction of substituted cyclopentenes gives almost exclusively trans isomers and establishes two stereocenters in high ee. Under the effect of some newly developed chiral ligands, fused carbo- and heterocycles are synthesized in high ee via asymmetric domino cyclizations. The method is applied to a short synthesis of chiral diamine en route to (-)-martinellic acid.

The asymmetric allylic alkylation (AAA) reaction is one of the important transformations in asymmetric synthesis, which was intensively studied in the last decade. Recently, the use of Morita-Baylis-Hillman (MBH) carbonates as electrophiles for the AAA reaction has attracted much attention. Pyrazole is an important pharmacophore, which often exhibit various biological and pharmacological activities. In the last years, the asymmetric synthesis using pyrazolones as the nucleophiles were reported by several research groups. However, the work were mainly focused on the asymmetric conjugate addition of pyrazoles to α,β-unsaturated compounds, and other types of enantioselective reactions were seldom studied. Herein, we report the first example of AAA reaction of MBH carbonates using pyrazolones as nucleophiles. In the reaction, we found that different Lewis basic catalyst, namely PPh₃ and DABCO, shown different regioselectivity: PPh₃ gave the γ-selective product whereas DABCO led to a complete β-selectivity. During the catalyst screening, cinchonine gave the best result. The enantioselectivity heavily relied on the choice of solvent: MeOH was superior compared to EtOH, CH₂Cl₂, DCE, acetone, CH₃CN, toluene, m-xylene and PhCl. In the substrate scope study, all the reactions were proceeded smoothly under mild conditions by using cinchonine as the catalyst (20 mol%) and give the β-selective allylic alkylation products with good yields (55%～91%) and high enantioselectivities (up to 93% ee). Based on our experimental results and previous reports, a preliminary mechanism of bifunctional catalysis was proposed. A representative procedure for the asymmetric allylic alkylation of MBH-carbonates with pyrazolones is as follows: to a flask equipped with a magnetic stirring bar was charged with pyrazolone 1 (0.1 mmol) and MBH-carbonate 2 (0.12 mmol) in methanol (2 mL), and then, the cinchonine catalyst (6 mg, 20 mol%) was added under air. The reaction solution was stirred at room temperature for 72 to 96 hours. Then, the mixture was concentrated and purified through a flash chromatography (silica gel, PE/EtOAc, V:V=7:1) to give the corresponding products 3.

Optically active 3-aryl-2-hydroxymethylpropionoic acids are highly useful chiral building blocks for the preparation of some drugs, but so far their asymmetric syntheses are still plagued by modest enantioselectivity and/or limited substrate scope. In the present study, the SpinPHOX/Ir(I) complexes (S,S)-1c and (R,S)-1e have been demonstrated to be highly effective for the asymmetric hydrogenation of (E)-2-(hydroxymethyl)-3-arylacrylic acids, affording the corresponding optically active 3-aryl-2-hydroxymethylpropionoic acids in good to excellent enantiopurities (ee up to 95%). Catalyst screening and reaction optimization with (E)-2-(hydroxymethyl)-3-phenylacrylic acid 2a as the model substrate, revealed that the asymmetric hydrogenation was best conducted in dichloromethane at r.t. under 10 atm of hydrogen with (S,S)-1c as the catalyst, and the presence of 1 equiv. of a suitable organic base (such as triethylamine) was essential for full substrate conversion and excellent product enantioselectivity (94% ee). Evaluation of the substrate scope of the protocol was performed using various 2-hydroxymethyl cinnamic acid derivatives 2a～2n with various substituents on the phenyl group. Full conversions and good to high ee values were obtained in most cases, irrespective of the electron-withdrawing or -donating nature of the substituent. Using complex (R,S)-1e as the catalyst under a slightly modified reaction conditions (50 atm H₂, 40 ℃), several substrates were hydrogenated in excellent ee values but with the sense of chiral induction opposite to those obtained by using (S,S)-1c. The reaction can be readily scaled up to gram-scale with retention of enantioselectivity. Among the optically enriched hydrogenation products obtained from this procedure, (S)-3a, (R)-3a and (-)-3n can be used as chiral building blocks for the asymmetric synthesis of pharmaceuticals Alvimopan, Ecadotril, and Fasidotril, respectively. Using this protocol, various (E)-2-(hydroxymethyl)-3-arylacrylic acids could be readily hydrogenated in high optical purities, thus providing a facile access to both enantiomers of the chiral 3-aryl-2-hydroxymethylpropionoic acids as well as the relevant chiral drugs.

We report a highly enantioselective aza-Henry reaction of nitroalkanes with N-Boc isatin ketimines 1. A cinchona alkaloid derived bifunctional catalyst C5, featuring a C6 hydroxy group, is identified as a powerful catalyst for this reaction. Accordingly, under an atmosphere of nitrogen, to a 10 mL Schlenk tube are added C5 (0.03 mmol, 14.6 mg), MS5Å (120 mg), nitromethane (4.5 mmol, 244 μL) and 3.0 mL of toluene successively, followed by the addition of N-Boc isatin ketimine 1 (0.3 mmol). The resulting mixture is stirred at 20 ℃ till the full consumption of the ketimine, monitored by TLC analysis. After the solvent is removed under reduced pressure, the residue is directly subjected to column chromatography, using an eluent of dichloromethane and acetone (10:1, V/V), to afford the desired product 3. Under this condition, a variety of differently substituted N-Boc isatin ketimines work well with MeNO₂ to provide the Mannich adduct in up to 91% ee. A 1.0 mmol scale reaction of 1a and MeNO₂ is examined, giving adduct 3a in 87% yield and 90% ee. Unfortunately, unprotected isatin derived N-Boc isatin ketimine 1j provides the corresponding product in only 66% ee, suggesting the importance of the N-protecting group of isatin in securing high enantioselectivity. Nitroethane and nitropropane are also viable for this reaction, affording the corresponding products in high yield and excellent ee value, albeit with moderate diastereoselectivity.

Catalytic asymmetric hydrogenation of unsaturated substrates is one of the most important transformations in organic chemistry, which provides a significant approach to produce optically active compounds both in academia and chemical industry due to its atom-economy and high efficiency. Since the original work of Knowles and Sabacky in 1960s, transition-metal-catalyzed asymmetric hydrogenation has been well developed with great achievements. However, metal-free asymmetric hydrogenation utilizing molecular hydrogen is extremely challenging, and has long been an unsolved problem. Frustrated Lewis pairs (FLPs) with a combination of sterically encumbered Lewis acids and Lewis bases preclude the formation of classical Lewis acid-base adducts via dative bonds due to the steric effects, and they therefore possess novel and interesting properties and reactivities. Since frustrated Lewis pairs was first disclosed to enable heterolytic cleavage of H₂ reversibly by Stephan and co-workers in 2006, its applications on activating various of small molecules such as H₂, CO₂, NO and catalytic hydrogenation of unsaturated compounds were reported. Asymmetric hydrogenation under H₂ by metal-free catalysts has been realized and has witnessed important progress. In this perspective, the achievements on frustrated Lewis pair catalyzed asymmetric hydrogenation are discussed from two aspects: (1) asymmetric hydrogenation induced by chiral substrates; (2) asymmetric hydrogenation catalyzed by chiral frustrated Lewis pairs.

Spirocyclic scaffolds are prevalent in numerous naturally occurring products and pharmaceuticals, which exhibit important biological and pharmacological activities. In this communication, a Sc(OTf)₃/Bis(oxazoline) complex catalyzed asymmetric Diels-Alder reaction of 2-arylidene-1,3-indanediones with 2-vinylindoles has been developed. The reaction provides a convenient and practical approach to biologically useful and synthetically important spiro-tetrahydrocarbazoles in good yields with high enantioselectivities (16 examples, up to 92% yield, 94% ee). A representative procedure for this asymmetric Diels-Alder reaction is described below: Sc(OTf)₃ (0.02 mmol) and chiral tridentate diphenyl-pybox ligand IV (0.02 mmol) were dissolved in toluene (1.5 mL) and stirred for 30 minutes at room temperature. 2-Arylidene-1,3-indanediones (0.20 mmol) was added to the above-mentioned solution and stirred at 5 ℃ for another 30 minutes. The solution of 2-vinylindoles (0.20 mmol) in toluene (0.5 mL) was then added to the reaction system and the mixture was stirred until the complete consumption of substrates (as monitored by TLC). The reaction mixture was purified directly by flash column chromatography on silica gel (petroleum ether/ethyl acetate=15:1～10:1) to give the corresponding products.

Metal/metal oxide nanoparticles for asymmetric hydrogenation and transfer hydrogenation have emerged as a frontier and evolved into a hot topic of asymmetric catalysis in recent years. Their catalytic modes resemble that of “nano-reactor”, where substrates diffuse through organic shells into catalytic active sites. Thus, high local catalyst concentration usually dramatically improves TON and TOF. In the case of nanoparticles as active sites, Orito’s platinum catalytic system received most extensive interests. Achievements have been made in chiral modifier structural modification, catalyst supports, reaction medium, nanoparticle morphology and catalytic mechanism. Moreover, other metal nanoparticles including palladium, rhodium, ruthenium, iridium and iron exhibited favorable catalytic efficiency in the asymmetric hydrogenation and transfer hydrogenation of alkenes, ketones and imines, especially for iridium and iron nanoparticles, ee values over 95% were obtained. In another case of metal/metal oxide nanoparticles as catalyst supports, comparable efficiency and enantioselectivity were observed to homogeneous catalysts, meanwhile, this protocol overcame the drawbacks of homogeneous catalysts with easier recovery and reuse. This review presents a brief overview on the recent progress in the asymmetric hydrogenation and transfer hydrogenation catalyzed by metal/metal oxide nanoparticles, as well as the related catalytic mechanism. However, there are still many challenges in this promising research field of metal/metal oxide nanoparticles for asymmetric catalysis. In addition to the continuous understanding of the catalytic mechanism, it is highly desirable to develop new types of metal/metal oxide nanoparticles with high efficiency, high enantioselectivity, and convenient recyclability.

Asymmetric aminocatalysis provides versatile tools for the stereoselective functionalizations of cyclic enone substrates at various sites. Recently, we developed an unusual [5+3] formal cycloaddition reaction of β-substituted 2-cyclopentenones or simple 2-cyclohexenone with bis(electrophilic) 1-azadienes, 3-vinyl-1,2-benzoisothiazole-1,1-dioxides, through α'-regioselective Michael addition followed by γ-regioselective intramolecular Mannich reaction via cascade cross-conjugated dienamine-endo-dienamine catalysis of a chiral primary amine. However, a completely different reaction pathway was disclosed when other type of cyclic enones, such as β-substituted 2-cyclohexenones or simple 2-cyclopentenone, were used under the similar aminocatalytic conditions. In this case, the same 1-azadiene partners act as electron-deficient dienophiles, and α',β-regioselective [4+2] cycloadditions occurred via cross-conjugated dienamine catalysis, giving bridged [2.2.2] octane or [2.2.1] heptane architectures with densely adorned functionalities. After systematically screening a number of reaction parameters, such as catalyst, acid additive and solvent, we can successfully realize the diastereodivergence in the above mentioned [4+2] cycloadditions. The endo-selective cycloadducts were efficiently obtained in moderate to excellent stereoselectivity (5:1～>19:1 dr, 86%～98% ee) in toluene at 50 ℃, by employing a (R,R)-1,2- diphenylethanediamine derived bifunctional primary amine catalyst with a benzothiadiazine-1,1-dioxide group as hydrogen bonding donor and in combination of benzoic acid. Even exclusive endo-selectivity (>19:1 dr) was consistently observed in the reactions of simple 2-cyclopentenone. A combination of 9-amino-9-deoxyepiquinidine and salicylic acid also produced the endo-selective cycloadduct but with slightly lower diastereoselectivity. In contrast, the diastereoselective [4+2] cycloadditions of β-substituted 2-cyclohexenones and 3-vinyl-1,2-benzoisothiazole-1,1-dioxides could be pleasingly switched by using 6'-OH-9-amino-9-deoxyepiquinidine and benzoic acid in PhCF₃ at 50 ℃, providing the exo-selective cycloadducts with good results in terms of diastereo- and enantioselectivity (4:1～>19:1 dr, 83%～95% ee). 6'-OH-9-amino- 9-deoxyepiquinine could afford the exo-cycloadducts with an opposite configuration, but with less satisfactory stereoselectivity (3 examples, 5:1～9:1 dr, 62%～71% ee). Moreover, the analogous 4-styryl-1,2,3-benzoxathiazine-2,2-dioxide could be smoothly utilized as the dienophilic partner, which further enriched the functionalities of the [4+2] cycloadducts.

Effective access to both enantiomers of any targeted products from a single chiral source of catalyst is highly desirable in asymmetric catalysis. Such dual stereocontrol has normally been encountered with structural modifications on the chiral ligands or catalysts skeletons. Recently, simple variations of reactions conditions such as solvents, temperature, additive and catalytic metal center, can lead to remarkable reversal of enantioselectivity with minimum structural modifications, thus providing a modular and synthetic appealing approach in asymmetric catalysis and synthesis. Previously, we have developed asymmetric binary acid catalysis wherein chiral Brønsted acids, mostly phosphoric acids, are utilized as dual acids and ligands in concert with metal catalysts, and this type of catalysis demonstrated tunable, even switchable stereoselectivity due to the combinatorial and synergistic features. In particular, simple swap of counteranion (from F^- to Br^-) of Indium(Ⅲ) salts led to complete switch of regioselectivity (1,2- vs. 1,4- addition) in the reaction of N-methyl indole 2a' and ketoester 3a with high enantioselectivity achieved for both regioisomers. In our further studies, we have found that when indole 2a was employed instead of N-methyl indole 2a', the counter anion effect on regioselectivity was not observed and both InF₃ and InBr₃ promoted exclusively 1,4-addition reactions. Interestingly, reversal of enantioselectivity of the 1,4-conjugate adduct was observed by simple swap of counter anions of indium(Ⅲ). The obtained optimal binary-acids combination, InF₃(1c)₂ and InBr₃(1d)₂ were found to be R- and S-selective catalyst for the 1,4-addition reactions, respectively. In the presence of asymmetric binary-acid catalysts (InX₃/1, 2.5 mol%), indoles and β,γ-unsaturated α-ketoesters were stirred at -70 ℃ for 24 h to afford the various indole esters 4 in good to excellent yield (up to 98% yield ) and enantioselectivities (up to>99% ee).

A direct and facile access to highly functionalized 5-aza-spiro[2,4]heptane derivatives is developed via Cu(CH₃CN)₄BF₄/DTBM-BIPHEP-catalyzed asymmetric exo-selective 1,3-dipolar cycloaddition of azomethine ylides with ethyl cyclopropylidene acetate for the first time. The Cu(CH₃CN)₄BF₄/DTBM-BIPHEP complex was identified as the optimal catalyst for the exo-selectivity. The reaction was carried out smoothly with wide substrate scope, and electron-deficient, electron-neutral and electron-rich aryl substituted imino esters were all compatible with the reaction, affording the 5-aza-spiro[2,4]heptane adducts containing three tertiary stereogenic centers and one spiro quaternary center in moderate to good yield (53%～83%) with excellent diastereoselectivity (>98:2, dr) and high enantioselectivity (up to 99% ee). The less reactive alkyl substituted imino ester derived from butyraldehyde was also tolerated in this annulation. The absolute configuration of the cycloadduct was unequivocally determined to be (4R,6S,7S) by X-ray analysis of N-tosylated derivative of exo-3a. Based on the relative and absolute configuration of the exo-cycloadducts, we proposed that an exo approach of ethyl 2-cyclopropylidene acetate to the copper(I) complex occurred predominantly because of the disfavored steric repulsion generated in the endo approach between the substituents of ethyl 2-cyclopropylidene acetate and the large bulky aryl group on the phosphorus atom of the chiral ligand. The produced 5-aza-spiro[2,4]heptanes fragment is widely present in many bioactive carbapenems derivatives, HSR-903 and substituted oxazolidinones. The optically active compounds with different stereoselectivities show different biological activities, therefore, it is important to develop the atom economical method for the asymmetric synthesis ofbiologically active exo-selective 5-aza-spiro[2,4]heptane derivatives.

The spiro pyrrolidin-3,3'-oxindole core is a privileged skeleton that is found in many natural products and biologically active molecules. For its construction, the [3+2] cycloaddition of 2π component 3-alkenyl-oxindoles with 3π component azomethine ylides is one of the most effective strategies. Since the pioneering work of Gong and co-workers, great effort has been devoted to the development of asymmetric [3+2] cycloadditions with azomethine ylides as the dipole synthon, and impressive progress has been achieved. In contrast, there is no report about higher-order [8+2] cycloaddition of 3-alkenyl-oxindoles with azaheptafulvenes as the 8π dipole synthons, which is an effective way to build cycloheptatriene-fused pyrrolidin-3,3'-oxindole derivatives with three contiguous stereocenters, including a spiro-quaternary chiral carbon atom. Herein, the azaheptafulvenes is developed as a new dipole synthon with 3-alkenyl-oxindoles to construct pyrrolidin-3,3'-oxindoles derivatives for the first time. In the presence of 1 mol% of chiral N,N'-dioxide L6-Ni(Ⅱ) complex, the asymmetric [8+2] cycloaddition performs well, affording functionalized cycloheptriene-fused pyrrolidin-3,3'-oxindoles derivatives in excellent yields (90%～99%), diastereoselectivities (up to 97:3 dr), and enantioselectivities (92%～99% ee) under mild conditions. A representative procedure for the asymmetric [8+2] cycloaddition is as follows: to a test tube, the catalyst solution (1 mol%, in THF) was added, and the THF was evaporated by oil pump. N-Boc-3-alkenyl-oxindole 2a and 0.5 mL of CH₂Cl₂ were added sequentially under air (N₂ atmosphere is not necessary). The reaction solution was stirred at 35 ℃ for 0.5 h, then the 8π component azaheptafulvene 1a (1.05 equiv.) was added. The mixture continued stirring at 35 ℃ until N-Boc-3-alkenyl-oxindole 2a was consumed (detected by TLC). Finally, the corresponding product 3a was purified by flash chromatography on basic Al₂O₃ [V(petroleum)/V(CH₂Cl₂)/V(EtOAc)=8:8:1].