Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Abstract

Small-ring cage hydrocarbons are common bioisosteres for para-substituted benzene rings in drug design 1 . The popularity of these structures derives from the superior pharmacokinetic properties they exhibit compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism 2,3 . A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesised by ring-opening of the inter-bridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions 4 . In contrast, scaffolds mimicking metasubstituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce substituent vectors 5 . Here we show that bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally-relevant carbon-and heteroatom-substituted BCHeps, including pharmaceutical

Rapid and Scalable Halosulfonylation of Strain‐Release Reagents**

“…[9] We recently demonstrated the suitability of [1.1.1]propellane and [3.1.1]propellane to engage in atom transfer radical addition (ATRA) reactions with carbon and nitrogen-centred radicals to afford halide-functionalized para- [10] and meta-arene bioisosteres. [11] However, equivalent methodologies to access sulfonyl BCP and bicyclo[3.1.1]heptane (BCHep) iodides and bromides are so far unknown. Here, we exploit sulfonyl halides, which can be easily generated in situ from readily available sulfinate salts, to rapidly construct difunctionalized sulfonyl arene bioisosteres via direct radical addition to strained hydrocarbon reagents (Figure 1c).…”

Photocatalyzed [3sigma + 2sigma] and [3sigma + 2pi] cycloadditions for the synthesis of bicyclo[3.1.1]heptanes and cyclopentenes.

“…Furthermore, with the addition of diphenylphosphate as a mild Brønsted acid co-catalyst, the protocol could be extended to a [3 + 2] cycloaddition with bicyclo[1.1.0]butanes (BCBs), yielding highly functionalized bicyclo[3.1.1]heptanes (BCHs). BCHs have been recently investigated as bioisosteres for meta-substituted arenes (Scheme 1C) 24,25 as part of a resurging interest in non-aromatic benzene bioisosteres. [26][27][28][29] The synthesis of BCHs is however challenging.…”

“…Most recent studies focus on functionalizing [3.1.1]propellane as a pre-formed skeleton of BCHs. 24,25 However, the poor stability of [3.1.1]propellane along with difficult handling and storage still remains a limitation for applications. In contrast, bicyclo[1.1.0]butane derivatives are stable at room temperature and easy to handle.…”

General access to cubanes: ideal bioisosteres of ortho-, meta-, and para-substituted benzenes

“…Furthermore, all cubanes in drug candidates, like most benzene bioisosteres, are either mono-substituted or bear linear exit vectors 180° apart, acting solely as substitutes for terminal or para-substituted phenyl rings. While several bicycloalkanes have recently been explored as nonlinear benzene isosteres [11][12][13][14][15][16][17][18] , their scarcity is a severe limitation for drug design given that over 170 approved drugs contain orthoor meta-substituted benzene rings. 1,2-and 1,3-disubstituted cubanes are ideally suited to bridge this gap since they most closely emulate the size and spatial arrangement of the substituents in the parent benzenes.Access to these nonlinear cubanes is hampered by protracted sequences towards the respective precursors (Fig.…”