Conformational rigidification is an established strategy in medicinal chemistry to improve affinity, selectivity, and metabolic stability of a parent drug molecule by presenting defined exit vectors. Small rings like, cyclobutane and cyclopropane moieties have been extensively used due to their rigid structure. A recent analysis of the most common rings found in drugs ranked cyclopentane in 18th position. However, cyclopentane is flexible due to facile interconversion between the half-chair and envelope conformations. Despite considerable progress in the conformational restriction strategy, rigidification of cyclopentane has not seen significant development. Due to the similarity in exit vectors, we sought to develop a rigidified 1,3-disubstituted cyclopentane variant in the form of a 1,3-disubtituted-bicyclo[2.1.1]hexane. In the case of syn-1,3-disubstituted cyclopentanes, rigidification can allow for disfavored conformation. For anti-1,3-disubstituted cyclopentanes, the bicyclo[2.1.1]hexane analog can lock the conformation (Figure 1A). A 2+2 cycloaddition reaction was employed to synthesize 1,3-disubstituted bicyclo[2.1.1]hexanes with synthetic handles, which can open access to a wide variety of compounds by functional group manipulation. In an orthogonal approach, a directed Pd catalyzed arylation/heteroarylation reaction was employed on the mono-substituted bicyclo[2.1.1]hexane to access the syn diastereomer whereas a photochemical chloro-carbonylation reaction afforded the anti-diastereomer (Figure 1B). To further underscore the significance of the building block, a rigidified version of FAS inhibitor BI 99179 was synthesized (Figure 1C).

Taming cyclopentane: Bicyclo[2.1.1]hexanes as rigidified variants to enable medicinal chemistry

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