Nickel-Catalyzed Enantioselective Access to Carbon, Boron, and Germanium Spiro Stereocenters​

Research Background​

In the field of asymmetric catalysis, expanding substrate generality remains a core scientific objective and a key challenge, particularly pronounced in the construction of quaternary stereocenters and their main-group heteroatom analogues. Chiral spirocenters of elements like carbon, boron, and germanium are highly sought-after due to their wide applications in ligand design, bioactive compounds, and materials. However, existing synthetic methods face several limitations: distinct strategies are often required for different chiral central elements; methods for constructing boron and germanium stereocenters are underdeveloped due to synthetic challenges, such as structural distortion in tetracoordinated boron compounds and bond instability in organogermanium compounds, rendering many strategies for carbon or sulfur stereocenters inapplicable. Furthermore, constructing chiral spiro skeletons is difficult, with a particular lack of general or enantioselective strategies. Existing methods for carbon centers have limited scope, routes to complex skeletons are lengthy, and the unique reactivity of boron and germanium hinders the extension of developed strategies. Recently, the team of Prof. Nicolai Cramer at the Swiss Federal Institute of Technology Lausanne (EPFL) reported a nickel/N-heterocyclic carbene (NHC)-catalyzed enantioselective hetero-[2+2+2] cycloaddition of diynes with nitriles. This reaction combines spirocycle formation with pyridine formation to construct a series of chiral spiro skeletons centered on carbon, boron, and germanium (Figure 1).

Condition Screening​

The authors selected fluorene-derived diyne substrate 1a​ and benzonitrile as model substrates for the hetero-[2+2+2] cycloaddition (Figure 2). Initial studies using 3 mol% of chiral catalyst Ni1​ yielded product 7​ in excellent yield but with low enantioselectivity. Switching to the acenaphthylene-based catalyst Ni2​ improved the enantiomeric ratio (e.r.) to 70:30. Further modification by introducing fluorine atoms into the chiral sidearm of Ni3​ afforded product 7​ in 95% yield with an optimized e.r. of 92:8. Single-crystal X-ray analysis revealed that the chiral sidearm in Ni1​ is highly flexible with a small buried volume in its chiral pocket. While the chiral pockets of Ni2​ and Ni3​ showed no significant difference, the flexibility of Ni2's sidearm is restricted by weak π-π stacking with the acenaphthylene backbone. In Ni3, the 3,5-difluoro substitution reduces the electron density of the sidearm, enhancing π-π stacking with the backbone and leading to a more rigid and well-defined chiral environment. This indicates that the rigidity and stability of the chiral sidearm are key to achieving high enantiocontrol.

Substrate Scope​

Following the establishment of optimal conditions, the authors systematically investigated the reactivity and selectivity with various aromatic nitriles (Figure 3). The reaction demonstrated good tolerance towards both electron-donating (e.g., -OMe, -NMe₂) and electron-withdrawing groups (e.g., -CF₃, -F), affording the corresponding pyridine derivatives (8a–e) in high yields and with excellent enantioselectivity. The mild conditions and strong functional group compatibility allowed for nitriles bearing ester, pinacol boronyl, chloro, and vinyl substituents (8f–i). Aliphatic nitriles, including acetonitrile, phenylacetonitrile, valeronitrile, cyclopropanecarbonitrile, and 3-methoxypropionitrile, also participated effectively, yielding the target pyridines (8j–n) with high enantioselectivity. Furthermore, electron-rich heteroaromatic nitriles (e.g., 3-cyanothiophene, N-Me-2-cyanopyrrole), electron-deficient 2-cyanopyridine, and specialized substrates like cyanocyclopentadienyl iron reacted successfully. Regarding alkyne substrates, diynes with ethyl substituents, terminal diynes, functionalized bis(1,4-enynes), and bis(1,3-enynes) all reacted smoothly. The resulting pyridine derivatives containing diene moieties (8v–w) are suitable for further polymerization reactions. The authors extended this system to the synthesis of chiral tetracoordinated boron compounds. Catalyst Ni3​ exhibited excellent catalytic activity, delivering pyridine derivatives with boron stereocenters (9a–j) in high yields and with excellent enantioselectivity, demonstrating good compatibility with various nitriles and boron-based substrates. For constructing chiral germanium spirocenters, optimizing substituents (e.g., tert-butyl, trityl) afforded the target products (10b–c) in high yield and with moderate to good enantioselectivity. In contrast, a silicon analogue underwent substrate decomposition under the reaction conditions, failing to yield the expected pyridine product.

Synthetic Applications​

Given the widespread use of bipyridines and 2-phenylpyridines as ligands or ligand precursors, the authors proposed that the synthesized spiro compounds could coordinate to metal centers to impart unique properties to materials. Using products 8q​ and 8b, they successfully prepared copper-based light-emitting electrochemical cells and platinum-based organic light-emitting diodes 11a​ and 11b​ (Figure 4). Photophysical characterization showed that the fluorescence lifetimes and quantum yields of 11a​ and 11b​ are comparable to literature values. To further validate the method's utility for complex chiral optical materials, a concise synthetic route was employed to prepare the highly conjugated heptacyclic, C₂-symmetric dispirobifluorene 11c. Photophysical tests revealed that 11c's emission spectrum spans 350–650 nm, with a blue shift of approximately 2820 cm⁻¹ in the solid state. Its microsecond-scale fluorescence lifetime indicates thermally activated delayed fluorescence (TADF) characteristics. The circularly polarized luminescence (CPL) dissymmetry factor (gₗᵤₘ) at 490 nm is 1.5 × 10⁻³, comparable to chiral organic dyes and helicenes.

Mechanistic Studies​

To investigate the interaction between the chiral Ni(0)-NHC complex and the substrates (Figure 5), the authors synthesized the nickel-nitrile complex Ni4​ in 90% yield from L10, Ni(COD)₂, and 4-methoxybenzonitrile. Ni4​ could replace Ni3​ as the catalyst without changing the yield or enantiomeric ratio. Since Ni3​ did not react with 4-methoxybenzonitrile alone, it was concluded that nickel has a stronger affinity for styrene, and nitrile coordination requires ligand exchange triggered by the alkyne substrate. Regarding the reaction mechanism, under a heterocoupling pathway, the enantio-determining step is the selective migratory insertion of a prochiral alkyne into a Ni(II) metallaziridine intermediate. The crystal structure of Ni4​ shows the nitrile substrate sandwiched between the chiral sidearms, which are poised to recognize the stereochemical information of the diyne substrate. In the proposed catalytic cycle, Ni3​ first undergoes ligand exchange to form intermediate I, followed by oxidative cyclization to form a metallaziridine. After migratory insertion of the coordinated alkyne, a second alkyne coordinates and undergoes another migratory insertion to form a seven-membered metallacycle. Finally, reductive elimination yields the chiral spiro pyridine and regenerates the catalyst.

Conclusion​

This study developed a nickel-catalyzed enantioselective hetero-[2+2+2] cycloaddition reaction for constructing spiro skeletons with chiral carbon, boron, and germanium centers in good to excellent yields and with moderate to good enantioselectivity. Remote stereocontrol was achieved by designing a chiral, bulky NHC-Ni(0)-styrene complex, where strong π-π stacking between the electron-deficient aryl sidearms and the ligand backbone forms a C₂-symmetric chiral pocket, which is key to the catalyst-induced selectivity. The reaction proceeds via a heterocoupling mechanism, with the migratory insertion of a prochiral alkyne into a metallaziridine species as the enantioselectivity-determining step. This method is suitable for the rapid assembly of complex compounds with promising photophysical and chiroptical properties.

Publication Details​

Authors:​ Yi-Xuan Cao, Anne-Sophie Chauvin, Shuo Tong, Layth Alama, and Nicolai Cramer*

Title:​ Accessing carbon, boron and germanium spiro stereocentres in a unified catalytic enantioselective approach

Journal:​ Nature Catalysis

DOI:​ 10.1038/s41929-025-01352-3