4‐(Di‐/Trifluoromethyl)‐2‐heterabicyclo[2.1.1]hexanes: Advanced Fluorinated Phenyl Isosteres and Proline analogues

Abstract

A gram-scale synthesis, physico-chemical characterization, and lead-likeness assessment of 4-di/trifluoromethyl-2-heterabicyclo [2.1.1]hexanes as fluorinated bicyclic proline analogues and phenyl isosteres are disclosed. The key step of the synthesis included iodocyclization of fluorinated 3-hydroxy-/3aminomethyl methylenecyclobutanes; with the amino derivatives, the reaction was accompanied with carboxylation and further cyclization. Apart from the corresponding 4-di/ trifluoromethyl-2,4-methanoprolines, a series of fluorinated oxabicyclo[2.1.1]hexane-derived building blocks relevant to medicinal chemistry (i. e. primary iodides, carboxylic acids, alcohols, azides, primary amines, sulfonyl chlorides, and alkynes) were prepared. For representative derivatives of the resulting fluorinated 2-oxabicyclo[2.1.1]hexanes, pK a and logP values were measured to clarify their potential as the possible phenyl isosteres. Apart from the somewhat increased acidity, finetuned lipophilicity intermediate between that of non-fluorinated or aromatic counterparts was observed. Finally, the potential of the title building blocks was demonstrated by generation of virtual compound libraries using the LLAMA software. The resulting libraries fitted perfectly the lead-like chemical space, had higher three-dimensionality, and showed lower mean lead-likeness penalty as compared to those obtained from either non-fluorinated or aromatic derivatives.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[33] In the latter one, iodocyclization of alkenols 93 was applied. [428,429] In both cases, physicochemical and biological characterization of the designed scaffolds was performed, which confirmed their geometric similarity with the corresponding benzene derivatives and higher aqueous solubility.…”

[2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes

“…Despite successful exemplification of this isostere, the angle between substituents (ϕ), and hence exit vectors, are deviated from the parent compound. It should be noted that recent efforts have shown that oxa-21 and aza-variants 22 are useful in increasing water solubility of this scaffold. In addition, a recent study described the introduction of 1,2-disubstituted-[1.1.1]-bicyclopentanes to serve as metaand ortho-substituted aromatic ring replacements (Fig.…”

Synthesis of novel α-trifluoromethyl cyclobutane-containing building blocks

“…Both compounds 1 and 2 are convenient intermediates for further transformations and were applied for the preparation of various promising building blocks. Continuing our research in this area [4][5][6][7][8][9], in this paper we further demonstrate the synthetic potential of compounds 1 and 2 and present synthesis of novel building blocks 3-6 that combine the 1,3-substituted cyclobutane motifs and the CF3 moiety near the functional group in their structure.…”

“…Recently, [2+2] cycloaddition reaction between allene and α-CF3-acrylonitrile was described [3]. Resulting methylene-containing nitrile 1 was used for the preparation of carboxylic acid 2 on a multigram scale [3,4]. Both compounds 1 and 2 are convenient intermediates for further transformations and were applied for the preparation of various promising building blocks.…”