Difluoro-Substituted Bicyclo[1.1.1]pentanes for Medicinal Chemistry: Design, Synthesis, and Characterization

Abstract

A practical synthetic approach to the difluoro-substituted bicyclo[1.1.1]­pentanes was developed. The key step was an addition of difluorocarbene (:CF2) to electron-rich bicyclo[1.1.0]­butanes by the CF3TMS/NaI system. The obtained difluoro-bicyclo[1.1.1]­pentanes are suggested to be used as saturated bioisosteres of benzene rings for the purpose of drug discovery projects.

Synthesis of 1,3-disubstituted bicyclo[1.1.0]butanes via directed bridgehead functionalization

“…45 Many of these aryl-BCBs are hard to access via traditional routes, in particular for ortho -substituted aryl BCB products. 26,29 The scalability of the chemistry was demonstrated through the successful synthesis of BCB 11 on >gram scale, with no decrease in yield (1.89 g, 96%). These disubstituted BCB products were found to be relatively stable, with resistance to rearrangement increasing with electron withdrawing character of the coupled aryl group; as noted above, little to no isomerization took place under the reaction conditions.…”

“… 25 Gram scale lithiation of 8c /cross-coupling delivered BCP 40 in 90% yield (1.35 g), treatment of which with difluorocarbene source 55 afforded the desired BCP-F 2 56 in 33% yield (60% brsm) along with 40% of the undesired rearrangement product 57 . Notably, other difluorocarbene sources 26,29 failed to deliver 56 . The N , N -diisopropylamide group in 56 could be transformed to the corresponding BCP-F 2 acid 58 via a two step reduction/oxidation sequence; 48 the BCP analogue of this compound has been converted to BCP-darapladib in previous work.…”

“…1,3-disubstituted BCBs are attractive precursors to bicyclo[1.1.1]pentanes (BCPs, 5 ), which are valuable motifs in drug design, 24–26 via a formal carbene insertion into the C1–C3 bond. 26–30 However, access to 1,3-disubstituted BCBs is more challenging than their monosubstituted counterparts: the predominant routes consist of transannular 1,3-cyclization of a cyclobutyl carbanion onto a tertiary halide ( 6 , Fig. 1b ), 25,28,31–33 which can suffer from competing elimination to a cyclobutene, or 3- exo-tet cyclization of a cyclopropyl carbanion onto a halomethyl substituent ( 7 ).…”

The Powerful Symbiosis Between Synthetic and Medicinal Chemistry

“…The Baran group, in collaboration with scientists at Pfizer, developed the synthesis of 1,2-disubstituted BCP building blocks bearing two synthetic handles for further derivatization [12], whereas scientists at Merck Sharp & Dohme (Merck & Co., Inc.) reported on the synthesis of 1-amino-2-alkyl BCPs [13]. Even more highly substituted BCPs are becoming synthetically accessible (e.g., 1,3-disubstituted 2,2difluoro-BCP building blocks [14,15] and 1,2,3-trisubstituted BCPs [16]). However, more straightforward methods for accessing different substitution patterns for cubanes still need to be developed.…”

Water‐Soluble Non‐Classical Benzene Mimetics

“…[8,9] For example, recently, Merck chemists and our group developed difluoro-substituted BCPs (Figure 1). [10] The obtained molecules retained the planar collinearity of exit vectors, but had lower solubility in water than BCPs, unfortunately. Herein, we have therefore designed, synthesized, and characterized a new generation of saturated benzene mimetics with improved solubility in water and reduced lipophilicity: 2-oxabicyclo[2.1.1]hexanes ( Figure 1).…”