Difluoro-Substituted bicyclo[1.1.1]pentanes as Novel Motifs for Medicinal Chemistry: Design, Synthesis and Characterization

Abstract

Herein we developed a practical synthetic approach to the previously unknown difluoro-substituted bicyclo[1.1.1]pentanes. The key step was an addition of difluorocarbene to electron-rich bicyclo[1.1.0]butanes by CF<sub>3</sub>TMS/NaI system. The obtained difluoro-bicyclo[1.1.1]pentanes are a new generation of saturated bioisosteres of the benzene ring for drug discovery projects.

Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues

“…This is the first reported synthetic procedure to access BCP analogues with controlled fluorinations on the methylene positions. Soon after our original report, chemists from Enamine also reported a similar process using trimethyl(trifluoromethyl)silane (TMSCF 3 ) as the difluorocarbene source (Scheme C) …”

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 orthosubstituted 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.…”

“…Trisubstituted aryl (26) and naphthyl ( 27) iodides also served as effective coupling partners, the former of which demonstrated useful selectivity for coupling of the aryl iodide (both 82% yield). Alkenyl iodides were similarly competent substrates, using either electron-poor (28, 54%) or electron-rich alkenes (E/Z-29, 61-74%).…”

“…10,20,21 A BCB-containing natural product (4) has even been isolated and synthesised. 22, 23 1,3-disubstituted BCBs are attractive precursors to bicyclo [1.1.1]pentanes (BCPs, 5), which are valuable motifs in drug design, [24][25][26] via a formal carbene insertion into the C1-C3 bond. [26][27][28][29][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.…”

“…22, 23 1,3-disubstituted BCBs are attractive precursors to bicyclo [1.1.1]pentanes (BCPs, 5), which are valuable motifs in drug design, [24][25][26] via a formal carbene insertion into the C1-C3 bond. [26][27][28][29][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][32][33] which can suffer from competing elimination to a cyclobutene, or 3-exo-tet cyclization of a cyclopropyl carbanion onto a halomethyl substituent (7).…”