An
efficient approach to synthesis of previously unavailable 2-substituted
difluorocyclobutane building blocks was developed and applied on a
multigram scale. The key step of the synthetic sequence included deoxofluorination
of O-protected 2-(hydroxylmethyl)cyclobutanone. Dissociation
constants (pK
a) and log P values for 2,2-difluorocyclobutaneamine and 2,2-difluorocyclobutanecarboxylic
acid or their derivatives were measured and compared with the values
obtained for the corresponding 3,3-difluorocyclobutane derivatives
and nonfluorinated counterparts. Three-dimensional structures of 2,2-
and 3,3-difluorocyclobutanamines were compared using exit vector plot
analysis of X-ray crystallographic data.
Four
3-((hetera)cyclobutyl)azetidine-based isosteres of piperidine,
piperazine, and morpholine were designed and synthesized on up to
gram scale. The key step of the synthetic sequence included cyclization
of N-protected 2-(azetidin-3-yl)propane-1,3-diol
or the corresponding 1,3-dibromide. X-ray diffraction studies of the
products obtained, followed by exit vector plot analysis of their
molecular geometry, demonstrated their larger size and increased conformational
flexibility as compared to the parent heterocycles and confirmed their
potential utility as building blocks for lead optimization programs.
Hitherto unknown cis‐ and trans‐3‐alkyl‐ and 3‐aryl‐3‐fluorocycobutylamines have been synthesised selectively from 3‐oxocyclobutane carboxylic acid in six or seven steps. Comparison of their pKa and log D values with those of the fluorine‐free parent compounds showed acidification by about 0.8 units, irrespective of the stereochemistry. This indicates that there are no through‐space interactions between fluorine and the amino function – a conclusion that was supported by the results of X‐ray analysis. Fluorinated trans‐compounds were found to be more lipophilic (Δ log P ≈ 1) compared with the non‐fluorinated analogues, whereas the difference was marginal for cis isomers.
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