Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes.

Dimitri F J Caputo,Steven J Mansfield,Antonia F Stepan,Carlos Arroniz,Alexander B Dürr,James J Mousseau,Edward A Anderson

doi:10.1039/c8sc01355a

Dimitri F J Caputo, Steven J Mansfield + Show 5 more

Open Access

https://doi.org/10.1039/c8sc01355a

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Abstract

Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.

Highlights

Bioisosteres are important motifs in drug design,[1] enabling the expansion of chemical and intellectual property space[2] while improving biological pro les relative to the parent functionality
Access to carbon-substituted BCPs remains a challenge. Their synthesis typically relies on multistep sequences from a small number of available precursors,[9] or requires relatively harsh conditions,[10] necessitating early-stage introduction of the BCP and limiting functional group tolerance
The BCP system is most commonly accessed through ‘strain release’[11] reactions of tricyclo[1.1.1.01,3]pentane 4 (TCP),[12] where in addition to classical approaches,[3,13] recent work has seen the development of elegant methods for the synthesis of heteroatom-substituted BCPs.[11,14]

Summary

Introduction

Bioisosteres are important motifs in drug design,[1] enabling the expansion of chemical and intellectual property space[2] while improving biological pro les relative to the parent functionality. Bicyclo[1.1.1]pentanes (BCPs) have shown impressive results in this eld as surrogates for 1,4-disubstituted arenes, tertbutyl, and alkyne groups, imparting desirable properties such as membrane permeability, solubility and metabolic stability.[3,4] Examples include BCP analogues of the g-secretase inhibitor BMS-708, 163 (1, Fig. 1a)[5] and resveratrol (2),[6] in which the BCP serves as a bioisostere for a p-substituted arene due to its comparable positioning of substituents; and of the pulmonary arterial hypertension agent bosentan (3, Fig. 1b), where a monosubstituted BCP replaces a tert-butyl group.[7,8] Despite these favourable attributes, access to carbon-substituted BCPs remains a challenge Their synthesis typically relies on multistep sequences from a small number of available precursors,[9] or requires relatively harsh conditions,[10] necessitating early-stage introduction of the BCP and limiting functional group tolerance. The mild conditions of this chemistry allow the synthesis of bicyclopentanes that could not be accessed using other methods, and open up opportunities for the late-stage functionalization of more complex molecules

Results and discussion

Conflicts of interest

Conclusions