Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

Das, Kousik; Pedada, Abhilash; Singha, Tushar; Hari, Durga Prasad

doi:10.1039/d3sc05700c

Cited by 6 publications

(3 citation statements)

References 88 publications

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“…In recent years, bicyclo[1.1.0]-butanes (BCBs) have garnered attention as intriguing synthons capable of engaging in diverse ring-opening reactions, thanks to the significant strain present in BCBs (Fig. 1c) 6,[37][38][39][40][41][42][43][44][45][46][47] . Of particular interest is their involvement in cycloaddition reactions, where the selective cleavage of the bridgehead C-C bond facilitates the assembly of ring-enlarged, yet conformationally restricted bridged bicycles.…”

Section: Introductionmentioning

confidence: 99%

Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Wang,

Liu,

Lin

et al. 2024

Preprint

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The exploration of C(sp3)-rich three-dimensional (3D) scaffolds as bioisosteres for planar aromatics has garnered increasing attention. While the bioisosterism of benzenes has been extensively studied, the bioisosterism of pyridines, the second most prevalent aromatic compounds in pharmaceuticals, faces additional challenges and has encountered surprisingly limited success. In this study, we propose unprecedented 2-azabicyclo[3.1.1]heptenes as effective bioisosteres of 1,3,5-trisubstituted pyridines in terms of not only 3D conformation but also basicity. We develop a pyridine-boryl radical-catalyzed [3π + 2σ] cycloaddition reaction of vinyl azides with bicyclo[1.1.0]butanes (BCBs) as an efficient synthetic approach. Synthetic manipulation of the products reveals valuable synthetic handles, allowing for the modular synthesis of various pyridine bioisosteres.

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Section: Introductionmentioning

confidence: 99%

Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Wang,

Liu,

Lin

et al. 2024

Preprint

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“…In particular, motifs that have a bridge between opposite carbon atoms, such as bicyclo[1.1.0]butanes (BCBs) (63.9 kcal/mol of strain energy) and [1.1.1]propellane (98 kcal/mol of strain energy), have garnered significant attention since they are often used to install the cyclobutane and bicyclo[1.1.1]pentane derivatives that serve as high-value bioisosteres in medicinal chemistry and drug discovery . Several groups have explored the reactivity of strained carbon–carbon σ bond of BCB derivatives in various difunctionlizations, cycloadditions, carbene insertions, and fragmentations (Scheme B). However, the developments in the field of strain-release functionalizations of BCB derivatives rely primarily on the inherent electrophilic reactivity of the strained carbon–carbon σ bond.…”

Section: Introductionmentioning

confidence: 99%

Rhodium(II)-Catalyzed Strain-Enabled Stereoselective Synthesis of Skipped Dienes

Kadam,

Singha,

Rawat

et al. 2024

ACS Catal.

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Skipped dienes are not only present in fatty acid primary metabolites and natural products but also serve as reactive intermediates in diverse chemical synthesis. Despite this, the regioselective and stereoselective synthesis of skipped dienes remains a challenging goal. Strain release in organic molecules is a powerful tool for creating chemical complexity under mild conditions. The reactivity of strained bicyclo[1.1.0]butane (BCB) systems is mainly dominated by transformations relying on their innate electrophilic reactivity. Herein, we report a rare example of the carbene-type reactivity of the BCB system based on rhodium−carbene chemistry, which enables the highly stereoselective synthesis of skipped dienes through strain release. The reaction is compatible with a diverse range of functional groups on both diazo compounds and BCBs and could be applied successfully to complex structures, providing highly valuable and functionalizable skipped dienes. The functional groups introduced during the reaction served as synthetic handles for downstream manipulations. The high stereoselectivity observed has been rationalized based on DFT calculations, which suggests that the reaction is likely proceeding via a concerted mechanism, and noncovalent interactions between the metallocarbene and BCB mainly control the observed exclusive selectivity.

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“…In particular, bicyclo[1.1.0]butane (BCB) derivatives have enormous synthetic potential and have attracted considerable attention among synthetic chemists not only due to their unique structural features but also for their ability to give efficient access to synthetically challenging scaffolds at ambient conditions . The strained C–C σ-bond of BCB derivatives was reported to participate in various cycloadditions, difunctionalizations, carbene insertions, and cascade reactions under photochemical and Lewis acid-catalyzed conditions. In the past decade, photocatalytic strategies that depend on the ability of photocatalysts to absorb light and participate in either electron transfer or energy transfer processes with organic molecules have evolved into efficient synthetic tools for chemical synthesis.…”

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confidence: 99%

Photoredox-Catalyzed Strain-Release-Driven Synthesis of Functionalized Spirocyclobutyl Oxindoles

Singha,

Bapat,

Mishra

et al. 2024

Org. Lett.

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Spirocyclobutyl oxindoles have garnered substantial attention in drug discovery and pharmaceuticals owing to their wide range of biological activities. Strain-release in small-ring compounds is a powerful strategy to enable efficient access to complex molecules. In this study, we successfully realized a photoredox-catalyzed strain-release radical spirocyclization approach to attain functionalized spirocyclobutyl oxindoles. A diverse array of radicals, such as sulfonyl, phosphonyl, and trifluoromethyl, were added efficiently to the strained C−C σ-bond of bicyclobutanes (BCBs) to afford a library of spirocyclobutyl oxindoles. Furthermore, the obtained products could be transformed into valuable building blocks. The observed reactivity and selectivity have been rationalized based on density functional theory calculations.

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Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

Abstract: Spirocyclobutane derivatives have gained significant attention in drug discovery programs due to their broad spectrum of biological activities and clinical applications. Ring-strain in organic molecules is a powerful tool to...

Cited by 6 publications

References 88 publications

Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Rhodium(II)-Catalyzed Strain-Enabled Stereoselective Synthesis of Skipped Dienes

Photoredox-Catalyzed Strain-Release-Driven Synthesis of Functionalized Spirocyclobutyl Oxindoles

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