Garrido-García P,
Quirós I,
Milán-Rois P,
Ortega-Gutiérrez S,
Martín-Fontecha M,
Campos LA,
Somoza Á,
Fernández I,
Rigotti T *,
Tortosa M *.
Autonomous University of Madrid and Center of Innovation in Advanced Chemistry, Madrid,
Spain
Enantioselective Photocatalytic Synthesis of Bicyclo[2.1.1]hexanes as
ortho-Disubstituted Benzene Bioisosteres with Improved Biological Activity.
Nat. Chem. 2025;
17: 734-745
DOI:
10.1038/s41557-025-01746-7
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.
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.
