Nickel-Catalyzed Regioselective Hydrogen Metallation Cyclization of Alkynylcyclobutanones Enables Synthesis of Bicyclo[2.1.1]hexanes

In a groundbreaking advancement in synthetic organic chemistry, Professor Wen-Bo Liu and his research team at Wuhan University have unveiled a novel nickel-catalyzed regioselective hydrometalative cyclization methodology for the construction of bicyclo[2.1.1]hexane (BCH) frameworks. This innovative approach harnesses the reactivity of β-alkynylcyclobutanone substrates to afford multi-substituted bicyclo[2.1.1]hexanol compounds in a single synthetic operation. The resulting products can be further transformed into 1,2,4-trisubstituted bicyclo[2.1.1]hexanones, structures of significant interest due to their emerging role as bioisosteres of benzene rings. This work, recently published as an open-access article in the journal CCS Chemistry, provides a powerful new tool for medicinal chemists seeking to introduce three-dimensionality and enhanced physicochemical profiles into drug candidates.

The ubiquity of benzene rings in pharmaceuticals is undeniable; however, their planar geometry often imparts limitations such as metabolic instability and poor aqueous solubility, factors that can compromise drug efficacy and safety. Consequently, there has been an intense focus on developing non-planar, saturated bioisosteres that mimic the spatial arrangements of benzene substituents while addressing these shortcomings. Among these, bicyclo[2.1.1]hexane cores have garnered particular attention as three-dimensional surrogates that retain the geometric disposition of substituents akin to benzene derivatives yet confer improved solubility and metabolic resistance. Despite their promising attributes, synthetic access to diverse and functionalized BCH derivatives has been constrained by the lack of efficient, generalizable methods.

Historically, methods to assemble bicyclo[2.1.1]hexane skeletons have largely relied on cycloaddition approaches, including [2π+2π] cycloadditions involving 1,5-dienes and [2σ+2π] cycloadditions of bicyclo[1.1.0]butane precursors with unsaturated bonds. These strategies, while powerful, face challenges such as limited substrate scope, regio- and stereochemical control, and the need for prefunctionalized starting materials. Notably absent in the synthetic landscape until now has been a transition metal-catalyzed approach enabling direct intramolecular cyclization of β-alkynylcyclobutanone substrates—structures characterized by inherent ring strain and challenging reactivity profiles.

The key ingenuity of Liu’s team lies in their successful orchestration of a nickel-catalyzed “hydrometalation-5-exo-trig cyclization” cascade that surmounts the high strain and reactivity challenges intrinsic to the bicyclo[2.1.1]hexane formation. Utilizing (TMSO)₂MeSiH as a hydride source, the nickel catalyst generates an active Ni-H species in situ, which performs carbonyl-directed regioselective cis-hydroxynickelation of the alkyne moiety tethered to the cyclobutanone. This critical regioselectivity is guided by strong coordination between the nickel center and the carbonyl oxygen, an interaction elucidated and supported by complementary Density Functional Theory (DFT) computational studies.

Following initial hydrometalation, the resultant alkenylnickel intermediate undergoes an intramolecular nucleophilic addition into the cyclobutanone carbonyl, accompanied by ring closure to yield the strained bicyclo[2.1.1]hexane core. Subsequent protonolysis releases the bicyclic alcohol product, which serves as a versatile scaffold amenable to skeletal rearrangement under acidic or basic conditions. This rearrangement affords access to 1,2,4-trisubstituted bicyclo[2.1.1]hexanone derivatives, compounds poised for further functional elaboration and diversification.

This strategy overcomes the formidable challenges associated with such strained intermediates, particularly the propensity for β-carbon elimination or ring-opening side reactions often observed in metallacyclobutane species. Additionally, competing reduction of alkynes or carbonyl groups, common in hydride-rich reaction environments, was deftly circumvented due to precise reaction condition optimization and the directing influence of the carbonyl group. The efficiency, mildness, and regioselectivity of this nickel-catalyzed transformation position it as a paradigm-shifting approach in the synthesis of BCH-containing molecules.

The resultant bicyclo[2.1.1]hexanol and related ketone derivatives offer a high degree of structural similarity to 1,2,4-trisubstituted benzene rings, enabling their potential deployment as benzene bioisosteres in drug design. By replacing planar aromatic motifs with these saturated, three-dimensional cores, medicinal chemists can confer enhanced water solubility, improved metabolic stability, and reduced off-target reactivity to pharmaceutical candidates. Such physicochemical benefits are critical in overcoming long-standing obstacles in drug development pipelines.

Beyond their pharmaceutical potential, the synthetic accessibility of these BCH derivatives enables the exploration of novel chemical space hitherto less accessible, facilitating the preparation of complex molecular architectures for broader applications. The modularity of the synthetic procedure allows incorporation of diverse substituents, enriching the scope and enabling tailored property tuning for specific applications.

The study’s comprehensive use of DFT calculations not only corroborated the proposed reaction mechanism but also shed light on the pivotal role of carbonyl coordination in steering regioselectivity during hydrometalation. This mechanistic insight paves the way for rational design of related catalytic processes, spotlighting the integration of computational and experimental approaches as a powerful strategy in reaction development.

Published in the flagship journal of the Chinese Chemical Society, CCS Chemistry, this open-access research heralds a new frontier in organometallic catalysis and synthetic methodology. Such advances underscore the growing prominence of Chinese research institutions in contributing cutting-edge chemical science to the global community.

The work was supported by major funding bodies including the National Natural Science Foundation of China and the National Key Research and Development Program of China, further attesting to the strategic importance of this research in national scientific agendas. Professor Wen-Bo Liu led the project alongside doctoral and master’s students who contributed equally as co-first authors, symbolizing the holistic integration of mentorship and innovation.

As the method gains traction, further applications are anticipated in late-stage functionalization of drug-like molecules, enabling the rapid incorporation of BCH motifs into complex frameworks. This could foster the development of next-generation therapeutics with optimized pharmacokinetic and dynamic profiles.

In sum, the nickel-catalyzed intramolecular hydrometalative cyclization of β-alkynylcyclobutanones stands as a seminal accomplishment, deftly converting strained cyclic substrates into structurally versatile BCH derivatives under mild conditions with excellent regioselectivity. This breakthrough not only enriches synthetic toolbox but also advances the frontier of medicinal chemistry by providing robust pathways for three-dimensional benzene bioisosteres, a crucial step toward designing more effective and safer pharmaceuticals.

Subject of Research: Not applicable

Article Title: Ni-Catalyzed Regioselective Hydrometalative Cyclization of Alkynyl Cyclobutanones to Bicyclo[2.1.1]hexanes

News Publication Date: 30-Sep-2025

Web References: https://www.chinesechemsoc.org/journal/ccschem

References: DOI: 10.31635/ccschem.025.202506260

Image Credits: CCS Chemistry

Keywords

Catalysis

Tags: bicyclo[2.1.1]hexane synthesisbioisosteres of benzenedrug candidate developmentenhanced physicochemical profilesmedicinal chemistry advancementsmulti-substituted bicyclo[2.1.1]hexanolsnickel-catalyzed hydrometalationnon-planar saturated compoundsregioselective cyclization methodssynthetic organic chemistry innovationsthree-dimensional molecular structuresβ-alkynylcyclobutanones