Impact of Fluoroalkyl Substituents on the Physicochemical Properties of Saturated Heterocyclic Amines.

The physicochemical properties (pKa (H), log P, and aqueous solubility) of fluoroalkyl-substituted heterocyclic amines were profiled to facilitate the amines' rational application in medicinal chemistry research. The features of fluorine-containing compounds were compared to those of the corresponding parent non-fluorinated heterocycles and the corresponding fluorinated n-alkylamines. Amine basicity was observed to change in a monotonic fashion depending on the fluorination pattern. Although the introduction of fluoroalkyl groups had complex effects on the lipophilicity and aqueous solubility of the compounds, possible contributions of the fluorination pattern, ring size, and conformation of the substituent in the ring were addressed for a series of derivatives. The summarized data provide a useful guideline for the application of fluorinated motifs for fine-tuning a compound's properties related to drug discovery.

Impact of ß-perfluoroalkyl substitution of proline on the proteolytic stability of its peptide derivatives.

A series of all stereoisomers of ß-CF3 or ß-C2F5 substituted prolines and their dipeptide derivatives were synthesized. Mouse plasma stability assay was carried out to study the impact of fluoroalkyl substituents on the proteolytic stability of proline-derived peptides. The effect of the (R)-/(S)-configuration at the C-2 atom in combination with electronic and steric effects imposed by fluoroalkyl groups was addressed to rationalize the difference in the half-life stability of diastereomeric ß-CF3-Pro-Gly and ß-C2F5-Pro-Gly derivatives and compared to those of parent (S)-Pro-Gly and (R)-Pro-Gly dipeptides. The steric effect was predominant when the ß-CF3 or ß-C2F5 group was placed properly to create a spatial interference within the pockets of proteases, thereby protecting the substances from degradation (e.g., for cis-isomeric derivatives). Otherwise, a smaller electronic effect accelerating proteolysis was in charge (i.e., for the (2S,3S) isomers).

Fluoroalkyl-Substituted Cyclopropane Derivatives: Synthesis and Physicochemical Properties.

A series of all 12 cis- and trans-cyclopropanecarboxylic acids and cyclopropylamines bearing CH2F, CHF2, and CF3 substituents were synthesized by different methods on a multigram scale. Dissociation constants (pKa) and log P values were measured for the obtained compounds or their derivatives to evaluate the influence of the type and relative position of fluoroalkyl substituents on the acidity and lipophilicity of monofunctionalized cyclopropanes. An analysis of the selected products by X-ray crystallography was carried out to obtain a better insight into the observed differences in physicochemical properties.

Formyl MIDA Boronate: C1 Building Block Enables Straightforward Access to α-Functionalized Organoboron Derivatives.

Formyl MIDA boronate has been known to be an elusive type of acylboronate that has not been obtained to date. In this work, an approach to the one-pot preparation and chemical transformations of formyl MIDA boronate were developed to provide new types of α-functionalized organoboron compounds. Among them are acylboronate reagents which present boron-substituted analogues of ynones and ß-dicarbonyl compounds. The developed synthetic procedures, utilizing formyl MIDA boronate, are tolerant to diverse functional groups, making this reagent an advantageous C1 building block for extending the scope of organoboron chemistry.

3-((Hetera)cyclobutyl)azetidines, "Stretched" Analogues of Piperidine, Piperazine, and Morpholine: Advanced Building Blocks for Drug Discovery.

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.

Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles.

A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.

Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks.

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 (p Ka) 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.

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles.

Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.