Authors: Shi Cao | Ziqi Ye | Yuehua Chen | Yu‐Mei Lin | Jia-Hua Fang | Yuejiao Wang | Boxuan Yang | Lei Gong
Source: CCS Chemistry (article, 2021-10-28)
Field: Chemistry — Organic Chemistry

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds Open AccessCCS ChemistryRESEARCH ARTICLE5 Sep 2022Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds Shi Cao, Ziqi Ye, Yuehua Chen, Yu-Mei Lin, Jiahua Fang, Yuejiao Wang, Boxuan Yang and Lei Gong Shi Cao Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author , Ziqi Ye Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author , Yuehua Chen Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author , Yu-Mei Lin Google Scholar More articles by this author , Jiahua Fang Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author , Yuejiao Wang Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author , Boxuan Yang Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author and Lei Gong *Corresponding author: E-mail Address: [email protected] Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101465 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Regiodivergent asymmetric cycloadditions from the same set of starting materials offer interesting opportunities for rapid construction of optically active cyclic molecules with structural diversity. However, this remains a challenging task due to the difficulty of simultaneously controlling the regio-, diastereo-, and enantioselectivity in the ring formation processes. To address this long-standing problem, we have developed a convenient strategy relying on the different reactivity of nickel-activated α,β-unsaturated carbonyl compounds under photochemical or thermal conditions, as well as their ability to react with electron-donating alkenes in an inverse-electron-demand manner. Through switching the reaction conditions from light irradiation to darkness, or adjusting the electronic features of the reaction partners, regiodiverse diastereo- and enantioselective [2+2], [2+4], and [4+2] cycloadditions have been accessed using the same chiral nickel catalyst. Of them, the photochemical [2+2] reaction does not require the addition of other photosensitizers, since the nickel intermediate complexes upon exposure to visible light can serve as the active components. A wide variety of chiral cyclic products have been obtained in good yields, with high diastereo- and enantioselectivity (51 examples, 48–92% yield, up to >20∶1 dr, 50–97% ee), including synthetically and biologically interesting cyclobutanes, cyclohexenes, and dihydropyrane derivatives as well as bicyclic and spirocyclic compounds. Download figure Download PowerPoint Introduction Catalytic asymmetric cycloadditions of unsaturated compounds provide rapid and straightforward access to optically active cyclic molecules, which are common structural motifs in natural products and pharmaceuticals.1,2 For instance, Rumphellaone A, a caryophyllane-related derivative from the gorgonian coral rumphella antipathies, exhibits cytotoxicity against human T-cell acute lymphoblastic leukemia tumor cells.3 Artochamin H is a natural product isolated from the stems of Artocarpus chama, showing moderate cytotoxicity against HepG2 cells (Scheme 1a).4 A large number of stereoselective [4+2], [3+2], [3+3], [2+2], and other annulation reactions have been developed through transition metal catalysis or organocatalysis.5–17 Regiodivergent diastereo- and enantioselective cycloadditions from the same starting materials, in which the reactivity and selectivity can be switched by changing the catalysts or conditions, is an appealing strategy for diversity-oriented synthesis of optically active molecules, but is underdeveloped.18–26 One reason for this is the difficulty of controlling the regioselectivity so as to give exclusive cycloadducts while simultaneously achieving a high level of asymmetric induction.27,28 In this context, Chen’s group18 reported the diversified asymmetric cycloadditions of α′-alkylidene-2-cyclopentenones with different reaction partners catalyzed by cinchona-derived chiral amines. Subsequently, they developed palladium-catalyzed regiodivergent asymmetric [5+2] and [3+2] annulations of vinyl indoloxazolidones through a ligand-controlled strategy.19 Trost and Zuo20 reported a regio- and enantioselective [3+2] spiroannulation reaction in which the regioselectivity was dominated by the fine-tuning structure of the Pd-π-allyl intermediates. Zhang and co-workers21 developed the enantioselective regiodivergent synthesis of chiral pyrrolidines through ligand-controlled copper-catalyzed asymmetric 1,3-dipolar cycloadditions. Deng et al.22 reported regiodivergent and stereoselective [3+2] and [3+3] annulations of 2-indolyl allyl carbonates with enals by cooperative N-heterocylic carbene and iridium catalysis. Notwithstanding these advances, the development of practical and economic methods for regiodiverse asymmetric cycloadditions is of general interest and in high demand. Scheme 1 | (a) Pharmaceutical candidates bearing chiral cyclobutane, cyclohexene, or dihydropyrane fragments. (b) The development of Ni-catalyzed regiodiverse diastereo- and enantioselective cycloadditions for the synthesis of optically active cyclobutane, cyclohexene, dihydropyrane derivatives, chiral bicyclic, and spirocyclic compounds. Download figure Download PowerPoint Photocatalytic asymmetric [2+2] cycloaddition is a straightforward strategy to synthesize cyclobutane derivatives with multiple stereocenters,29–33 which are important building blocks in synthetic chemistry and valuable scaffolds in drug design.34–37 The reported methods often rely on the use of photocatalysis combined with transition metal catalysis,38–41 or well-tailored bifunctional chiral photocatalysts.42–45 Recently, we found that chiral bisoxazoline complexes of nickel or copper could show unique reactivity and selectivity in asymmetric photochemical transformations.46–52 These reactions proceed smoothly upon irradiation with visible light in the absence of additional photosensitizers, thus leading to practical protocols for asymmetric photocatalytic reactions. We assumed that such chiral complexes of nickel or copper can function as bifunctional catalysts in photochemical [2+2] cycloaddition reactions, providing photoactivation of unsaturated compounds and governing the stereoselective transformations of the excited states. Under thermal conditions, reactivity and selectivity of the same set of starting materials at the ground states might be different. This could lead to switchable regioselectivity and construction of structurally diverse chiral cyclic products, and allow us to develop a convenient approach to regiodiverse asymmetric cycloaddition reactions (Scheme 1b). Experimental Methods Preparation of a 20 or 40 mM solution of nickel catalyst [L4-Ni] in acetonitrile A solution of Ni(ClO4)2·6H2O (73.0 mg, 0.20 mmol) and chiral ligand L4 (110.0 mg, 0.24 mmol) in CH3CN [10 mL (20 mM solution) or 5.0 mL (40 mM solution)] was stirred at 25 °C for 1 h, which was used freshly for the catalytic reactions. General procedure for the photochemical asymmetric [2+2] cycloaddition reaction A dried 10 mL Schlenk tube was charged with an α,β-unsaturated 2-acyl imidazole or benzimidazole ( 1c– 1i, 0.20 mmol), an alkene substrate ( 2a– 2m, 0.60 or 3.0 mmol), the chiral nickel catalyst [ L4- Ni] (1.0 mL taken from a 20 or 40 mM solution in CH3CN) and CH3CN (3.0 mL). The mixture was degassed via three freeze–pump–thaw cycles. The Schlenk tube was positioned approximately 5 cm away from a 40 W Kessil lamp (λmax = 456 nm). After being stirred at 5 °C or −20 °C for the indicated time, the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel [eluted with petroleum ether (PE):ethyl acetate (EtOAc) = 4:1] to afford the nonracemic product ( 3c– 3u). General procedure for the asymmetric [2+4] cycloaddition reaction A dried 2.0 mL vial was charged with an α,β-unsaturated 2-acyl imidazole or benzimidazole ( 1a or 1i– 1s, 0.20 mmol), an alkene substrate ( 2a or 2n– 2q, 2.0 mmol), and the chiral nickel catalyst [ L4- Ni] (1.0 mL taken from a 20 or 40 mM solution in CH3CN). After being stirred at 25 °C for the indicated time, the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluted with PE:EtOAc = 4∶1) to afford the nonracemic product ( 4a– 4p). General procedure for the asymmetric [4+2] cycloaddition reaction A dried 2.0 mL vial was charged with an α,β-unsaturated 2-acyl imidazole or benzimidazole ( 1a or 1i– 1s, 0.20 mmol), an alkene substrate ( 2r– 2w, 1.0 mmol), and the chiral nickel catalyst [ L4- Ni] (1.0 mL taken from a 20 or 40 mM solution in CH3CN). After being stirred at 25 °C for the indicated time, the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluted with PE:EtOAc = 2∶1) to afford the nonracemic product ( 5a– 5q). Density functional theory calculation All the calculations were carried out using density functional theory (DFT) and an ultrafine grid as implemented in the Gaussian 09 program package. Geometry optimizations were conducted by SMD(Acetonitrile)-B3LYP-D3(BJ)-def2svp (see Supporting Information Figures S8 and S9 for details). Results and Discussion We began our study on the photochemical asymmetric [2+2] cycloaddition with an α,β-unsaturated 2-acyl imidazole ( 1a) as the model substrate, which can be activated by bidentate chelation with transition-metal catalysts.53–55 The reaction of 1a with a diene ( 2a) in the presence of nickel perchlorate, Ni(ClO4)2·6H2O (10 mol %), and a chiral bisoxazoline ligand, (4R,4′R)-2,2′-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) ( L1, 12 mol %), was irradiated with a 24 W blue light-emitting diodes (LEDs) lamp (λmax = 455 nm) (Table 1, entry 1). The desired cyclobutane product ( 3a) was obtained in 54% yield, with 2∶1 dr and 23% ee. However, a side cyclohexene product ( 4a) derived from the competitive Diels–Alder reaction (a [2+4] process) was isolated in 31% yield. Screening of metal salts (entries 2–4) and chiral ligands (entries 5–9) revealed that the combination of Ni(ClO4)2·6H2O and a tridentate ligand ( L4) gave the best yield of 3a (61%) with 2:1 dr and 90% ee, while the yield of 4a was reduced to 19% (entry 7). It was found that changing the N-protecting group on the imidazole substrates from methyl to benzyl ( 1c) slightly improved the yield, diastereo- and enantioselectivity (entry 11). At 5 °C and a lower concentration and upon irradiation with a 40 W Kessil lamp (λmax = 456 nm), the reaction produced 3c as the exclusive product in 85% yield with stereoselectivity of 4∶1 dr and 95% ee (entry 19). Only [2+4] adduct ( 4c) was obtained in 81% yield under the optimal conditions and without light irradiation (entry 20). This observation revealed the possibility of developing regiodivergent cycloadditions by the same nickel catalysis system while replacing photochemical with thermal conditions. Table 1 | Optimization of Reaction Conditions for the Photochemical Asymmetric [2+2] Cycloadditiona Entry Metal Salt Ligand Substrate Temp (°C) Product (Yield, %)b drb ee (%)c Byproduct (Yield, %)b 1 Ni(ClO4)2·6H2O L1 1a 25 3a (54) 2∶1 23 4a (31) 2 Cu(ClO4)2·6H2O L1 1a 25 3a (31) 5∶1 20 4a (10) 3 Co(ClO4)2·6H2O L1 1a 25 3a (6) n.d. n.d. 4a (73) 4 Fe(ClO4)2·6H2O L1 1a 25 3a (trace) n.d. n.d. 4a (12) 5 Ni(ClO4)2·6H2O L2 1a 25 3a (47) 3∶1 70 4a (28) 6 Ni(ClO4)2·6H2O L3 1a 25 3a (63) 3∶1 73 4a (21) 7 Ni(ClO4)2·6H2O L4 1a 25 3a (61) 2:1 90 4a (19) 8 Ni(ClO4)2·6H2O L5 1a 25 3a (41) 2∶1 53 4a (39) 9 Ni(ClO4)2·6H2O L6 1a 25 3a (50) 2∶1 49 4a (23) 10 Ni(ClO4)2·6H2O L4 1b 25 3b (59) 3∶1 71 4b (23) 11 Ni(ClO4)2·6H2O L4 1c 25 3c (70) 3∶1 93 4c (21) 12 Ni(ClO4)2·6H2O L4 1c 15 3c (74) 3∶1 93 4c (15) 13 Ni(ClO4)2·6H2O L4 1c 5 3c (77) 4∶1 94 4c (11) 14 Ni(ClO4)2·6H2O L4 1c 0 3c (75) 4∶1 94 4c (9) 15 Ni(ClO4)2·6H2O L4 1c −5 3c (72) 3∶1 94 4c (5) 16 Ni(ClO4)2·6H2O L4 1c −10 3c (68) 3∶1 94 4c (trace) 17d Ni(ClO4)2·6H2O L4 1c 5 3c (78) 4∶1 94 4c (9) 18e Ni(ClO4)2·6H2O L4 1c 5 3c (82) 4∶1 95 4c (trace) 19f Ni(ClO4)2·6H2O L4 1c 5 3c (85) 4∶1 95 4c (0) 20g Ni(ClO4)2·6H2O L4 1c 25 3c (0) n.a. n.a. 4c (81) aReaction conditions: 1a (0.10 mmol), 2a (1.5 mmol, 15 equiv), metal salt (0.010 mmol, 10 mol %), ligand (0.012 mmol, 12 mol %), CH3CN (0.50 mL), indicated temperature, 24 W blue LEDs lamp (λmax = 455 nm), under argon (see Supporting Information Table S1 for details). bIsolated yield, dr determined by 1H NMR. cee value determined by chiral HPLC. dIrradiation with a 40 W Kessil lamp (λmax = 456 nm), CH3CN (0.50 mL), 10 h. eIrradiation with a 40 W Kessil lamp (λmax = 456 nm), CH3CN (1.0 mL), 15 h. fIrradiation with a 40 W Kessil lamp (λmax = 456 nm), CH3CN (2.0 mL), 20 h. gReaction in the dark. n.a. = not applicable. n.d. = not determined. With the optimal conditions in hand, we next evaluated the generality of the nickel-catalyzed photochemical asymmetric [2+2] cycloaddition reaction (Scheme 2). First, a range of α,β-unsaturated 2-acyl imidazoles bearing a different substituent at the β-position were examined. The reaction proceeded smoothly and afforded the cyclobutane products ( 3c– 3h) in good yield (82–90%) and with high stereoselectivity (4:1 dr, 90–95% ee), with the exception of the β-methyl substituted substrate (product 3i, 0% yield). Amongst the alkene reaction partners, an enyne was tolerated under the standard conditions, and gave the product ( 3j) in 54% yield and with 2:1 dr and 62/66% ee. Styrene and its derivatives were also compatible, furnishing the products ( 3k– 3p) in 65–92% yield, with 1:1–>20:1 dr and 62–95% ee. A 1,1-dialkyl substituted alkene, 2-ethyl-1-butene, was found to be an excellent substrate, furnishing the product ( 3q) in 61% yield, with >20:1 dr and 94% ee. Optically active spirocyclic moieties are important scaffold products in many bioactive molecules and natural products.56,57 Under the standard conditions, chiral spirocyclic products ( 3r– 3t) were obtained in 63–81% yield, with 1:1–>20:1 dr and 85–91% ee from exocyclic alkenes ( 2j– 2l). The absolute configuration of the [2+2] cycloadducts were assigned as (1R,2R,3S) by comparison of their high-performance liquid chromatography (HPLC) data and optical rotations with published data.42 This method was subsequently applied to the synthesis of an estrone derivative ( 3u), demonstrating its potential in late-stage modification of complex molecules. Scheme 2 | Reaction scope of the photochemical asymmetric [2+2] cycloaddition. a Reaction with 3.0 equiv of the alkene (2f or 2m). b Reaction with Ni(ClO4)2·6H2O (20 mol %), L4 (24 mol %) at −20 °C. Download figure Download PowerPoint In an effort to understand the mechanism of the photochemical [2+2] cycloaddition reaction, the UV–vis spectra of the reaction components were recorded (Scheme 3a). The substrates ( 1c, 2a), the product ( 3c), the chiral ligand ( L4), and the nickel catalyst ([ L4- Ni]) all failed to exhibit visible light absorption in CH3CN. A mixture of 1c and 2a did not show any enhancement of absorption, with the exception of electron–donor–acceptor (EDA) pathways. The spectra of potential intermediate complexes such as [ Ni- 1c] and [ L4- Ni- 1c] exhibited an obvious red shift and absorption enhancement in the range of 400–450 nm. These results suggest that the nickel intermediates could be the photoactive species.58–61 Scheme 3 | (a) UV–vis spectra of the reaction components. (b) Control experiments. (c) A proposed reaction mechanism for the photochemical [2+2] cycloaddition. (d) Left: a reported crystal structure of chiral nickel complex [L4-Ni] (CCDC no.119941).63 Middle: a transition state ([L4-Ni-1c] with 2a), simulated by Gaussian 09, and drawn by CYLview 1.0. Right: a modeled structure of product (1R,2R,3S)-3c based on a reported crystal structure of the enantiomer of an N-phenyl derivative of 3g (CCDC no. 1536749).42 Download figure Download PowerPoint Control experiments were conducted to establish the possibility of a mechanism involving light excitation of the metal complex followed by the cyclization of its T1 state with the alkene substrate (Scheme 3b).39,43 In the absence of the nickel salt [Ni(ClO4)2·6H2O] and the chiral ligand ( L4), the reaction of 1c + 2a → 3c afforded the [2+2] adduct ( 3c) in significantly reduced yield (17%), but in the presence of Ni(ClO4)2·6H2O it gave a similar yield (85%) as the standard reaction. It was revealed that the nickel salt is essential for the photochemical process, and the chiral ligand only exerts stereocontrol. The addition of (E)-1,2-diphenylethylene, a triplet quencher,62 to the reaction led to a greatly reduced yield (27%). Upon replacement of the chiral nickel catalyst with benzil, a triplet sensitizer, the reaction still afforded 3c in 82% yield.42 Introduction of one-electron chemical reductants such as tetrakis(dimethylamino)ethylene (TDAE) and SmI2, or oxidants [ceric ammonium nitrate (CAN), Fe(acac)3] to the reaction, failed to produce any obvious trace of 3c.39 All of these results support the hypothesis that the reaction proceeds through a triplet energy transfer process rather than an electron transfer mechanism. On the basis of these mechanistic studies, a plausible cyclic cycle is proposed and shown in Scheme 3c. Initially, fast ligand exchange between the nickel catalyst [ L4- Ni] and α,β-unsaturated 2-acyl imidazole ( 1) delivers an intermediate complex ( A), which upon irradiation with blue LEDs is excited to its singlet state ( B). The subsequent intersystem crossing (ISC) of intermediate B results in a T1 state ( C). The reaction of C with the alkene substrate ( 2) gives rise to an intermediate ( D), and is followed by cyclization to afford a nickel-coordinated product ( E). The final ligand exchange of E with substrate 1 leads to the formation of the product ( 3) and regeneration of the nickel intermediate ( A). Scheme 3d shows a published crystal structure of nickel catalyst [ L4- Ni] (left),63 a transition state ([ L4- Ni- 1c] + 2a) simulated by Gaussian 09 (middle), and a modeled structure of a [2+2] adduct ((1R,2R,3S)- 3c) (right), which clearly demonstrates the asymmetric induction during the cycloaddition process. During the investigation of the photochemical [2+2] cycloaddition reaction, a regular Diels–Alder product, the [2+4] adduct 4c, was obtained exclusively in the absence of irradiation starting from the same set of starting materials and the identical catalyst (Table 1, entry 20). To evaluate the generality of this divergent transformation, a variety of dienophiles, α,β-unsaturated 2-acyl imidazoles ( 1a, 1i), and 2-acyl benzimidazoles ( 1j– 1s) were examined (Scheme 4). The reaction delivered cyclohexene compounds bearing adjacent tertiary carbon stereocenters ( 4a– 4l) as single diastereomers (all >20∶1 dr) in 48–87% yield and with 85–96% ee. The β-methyl substituent on the substrates tolerated this thermal process, giving rise to the products ( 4b, 4d) in good yields (75%, 82%) and with high enantioselectivity (96%, 91% ee). Typically, the reactions of 2-acyl benzimidazoles ( 1j– 1s) proceeded more rapidly than those of the 2-acyl imidazoles ( 1a, 1i), revealing the influence of the auxiliary moiety on the reaction rate. Acyclic dienes ( 2m, 2n), cyclic dienes ( 2o), and myrcene ( 2p) proved to be excellent reaction partners, providing the products ( 4m– 4q) in 67–85% yield, with >20∶1 dr and 86–94% ee. The absolute configuration of product 4b (96% ee) was assigned as (1R,6R) by comparison of its optical rotation and HPLC results with the published data.64 The configurations of other [2+4] adducts were determined by comparison with analogs. Scheme 4 | Reaction scope of the asymmetric [2+4] cycloaddition. aReaction with Ni(ClO4)2·6H2O (20 mol %), L4 (24 mol %). Download figure Download PowerPoint Asymmetric hetero-Diels–Alder reactions have attracted considerable attention due to their ability to produce optically active heterocyclic molecules.65–71 We conjectured that this nickel-catalyzed system was applicable to the inverse-electron-demand oxa-Diels–Alder ([4+2] annulation) of the α,β-unsaturated 2-acyl imidazoles once employing electron-rich alkenes as dienophiles. Indeed, under the identical conditions and in the presence of the same chiral nickel catalyst, the reaction of 2,3-dihydrofuran ( 2r) with the imidazole or benzimidazole substrates ( 1a, 1i– 1s) gave the chiral bicyclic products ( 5a– 5l) in 75–91% yields, with 11∶1–>20∶1 dr and 87–97% ee (Scheme 5). The substrates containing a β-methyl substituent provided the products ( 5b, 5d) as single diastereomers with 92% and 91% ee, respectively. The absolute configuration of product 5b (92% ee) was assigned as (3aS,4S,7aR) by comparison of its optical rotation and HPLC behavior with the published data.64 Other electron-rich alkenes with substituents such as alkoxyl and thioether groups can be used as the dienophiles, the corresponding dihydropyrane products ( 5m– 5q) being obtained in 70–82% yield, and with up to 9:1 dr and 94% ee. Scheme 5 | Reaction scope of the asymmetric hetero-Diels–Alder cycloaddition. aReaction was performed with Ni(ClO4)2·6H2O (20 mol %), L4 (24 mol %), at 25 °C. Download figure Download PowerPoint Finally, removal of the imidazole or benzimidazole moiety from the cyclized products was achieved according to a reported procedure, and led to the formation of synthetically more of a [2+2] adduct ( >20∶1 dr, 95% ee) with (2.0 followed by with (20 in the presence of (3.0 in acetonitrile gave the product ( in yield and with >20∶1 dr and 95% ee (Scheme the same the [2+4] adduct ( 4c, >20∶1 dr, 90% ee) bearing a benzimidazole moiety was the corresponding derivative ( in 92% yield and with >20∶1 dr and 90% ee (Scheme The [4+2] adduct ( >20∶1 dr, ee) failed to react in this but it can be in 90% yield a chiral cyclic bearing stereocenters ( (Scheme All the reactions proceeded with of the and absolute the synthetic of this Scheme 6 | of the cycloaddition (a) of product to an (b) of product 4c to an (c) of product to a Download figure Download PowerPoint We have developed a for regiodiverse asymmetric [2+2], [2+4], and [4+2] cycloadditions of α,β-unsaturated carbonyl compounds by a chiral nickel catalyst. The regioselectivity can be by switching the reaction conditions from light irradiation to darkness, or adjusting the electronic features of the reaction partners to an inverse-electron-demand process. A wide variety of optically active cyclic with structural including synthetically and biologically interesting cyclobutanes, cyclohexenes, as well as bicyclic and spirocyclic can be obtained in good yields, with high diastereo- and enantioselectivity (51 examples, 48–92% yield, up to >20∶1 dr, 50–97% ee). The photochemical [2+2] reaction does not require the addition of other photosensitizers, on the basis of UV–vis spectra and the nickel intermediate complexes upon exposure to visible light to be the active components. 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