A Selective Synthesis of 2,2-Difluorobicyclo[1.1.1]pentane Analogues: “BCP-F₂”

Abstract

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments in order to improve physicochemical properties. However, bceause of the difficulty of synthesis, most BCP analogues prepared only bear 1,3-"para"-substituents. We report the first selective synthesis of 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on synthesis of other "ortho/meta-substituted" BCPs via similar mechanisms.

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.…”

“…25 Gram scale lithiation of 8c/cross-coupling delivered BCP 40 in 90% yield (1.35 g), treatment of which with diuorocarbene 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 diuorocarbene 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.…”

“…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).…”

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.…”

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

“…Earlier this year, our lab reported the selective synthesis of 2,2‐difluorobicyclo[1.1.1]pentane (BCP‐F 2 ) analogues 104 by difluorocarbene insertion into 1,3‐disubstituted bicyclo[1.1.0]butanes 103 (Scheme B) . This is the first reported synthetic procedure to access BCP analogues with controlled fluorinations on the methylene positions.…”