Asymmetric Synthesis of 1,5-Bicyclo[2.1.1]hexanes via [2+2]-Photocycloaddition Approach

Keywords

1,5-bicyclo[2.1.1]hexanes - bioisosteres - ortho-disubstituted phenyl - asymmetric synthesis - photocatalysis

Significance

Increasing the three-dimensionality of molecules by replacing aromatic rings with saturated motifs is an effective strategy for enhancing biological and physiochemical properties. Among such motifs, 1,5-disubstituted bicyclo[2.1.1]hexanes (1,5-BCHs) have gained popularity as bioisosteres for ortho-disubstituted phenyl rings in modern medicinal chemistry. The bridged scaffold of 1,5-BCHs increases molecular rigidity and Fsp³ (fraction sp³) compared to their phenyl analogues. This article describes the asymmetric synthesis of 1,5-BCHs via a Lewis acid catalyzed [2 + 2] photocycloaddition of 1,5-dienes bearing an acyl pyrazole group. The acyl pyrazole plays a crucial role in forming a bidentate complex with the Lewis acid, which governs enantioselectivity. Furthermore, the application of the strategy to well-known drugs highlights its versatility and adaptability. This approach serves as a valuable tool for improving drug-likeness, particularly when an increase of Fsp³ is desired.

 

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Comment

The reaction proceeds via a photocatalytic intramolecular [2 + 2] cycloaddition of 1,5-diene derivatives containing an acyl pyrazole group. The enantioselectivity of the reaction is attributed to the complex formation between the acyl pyrazole group and the chiral Lewis acid, Λ-RhS, as shown in A. The reaction is tolerant of phenyl analogues bearing various functional groups including halides, carbamates, ketones, nitriles, and nitro groups. Additionally, heteroaromatics such as quinoline and pyrazole afford the corresponding products, albeit with compromised yields and enantioselectivities. To demonstrate its value in drug discovery, this approach was applied to the synthesis and biological evaluation of a blood-pressure drug, Telmisartan analogue, among others. Overall, 1,5-BCHs serve as effective bioisosteres of the ortho-disubstituted phenyl motif, and this approach will enhance their value in medicinal chemistry.

 

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Publikationsverlauf

Artikel online veröffentlicht:
22. Mai 2025