4-Trifluoromethoxy proline: synthesis of stereoisomers and lipophilicity study.

All four stereoisomers of 4-CF3O-proline have been synthesized through a fluorodesulfurization approach using the corresponding 4-hydroxyprolines as starting materials. The investigation of their lipophilicity characteristics and comparison with those of other 4-substituted proline analogs demonstrated a similar impact of CF3 and CF3O groups on log D.

1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene.

Bicyclo[2.1.1]hexanes have been synthesized, characterized, and biologically validated as saturated bioisosteres of the ortho-substituted benzene ring. The incorporation of the 1,2-disubstituted bicyclo[2.1.1]hexane core into the structure of fungicides boscalid (BASF), bixafen (Bayer CS), and fluxapyroxad (BASF) gave saturated patent-free analogs with high antifungal activity.

General Synthesis of 3-Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres.

A general approach to 3-azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability of this transformation were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties.

General and Scalable Approach to Trifluoromethyl-Substituted Cyclopropanes.

CF3-cyclopropanes with aliphatic, aromatic, and even heteroaromatic substituents were prepared on a multigram scale by deoxyfluorination of cyclopropane carboxylic acids or their salts with sulfur tetrafluoride. For labile α-pyridine acetic acids, only the use of their potassium salts allowed to obtain the needed products. Derivatization of CF3-cyclopropanes into building blocks ready for direct use in medicinal chemistry was performed.

Fluorinated Aliphatic Diazirines: Preparation, Characterization, and Model Photolabeling Studies.

The previously unknown difluoromethyl diazirines and the previously neglected trifluoromethyl-aliphatic diazirines were synthesized and characterized. Model photolabeling experiments and biological studies showed that these compounds could indeed be used as photoaffinity labels.

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity.

A practical synthesis of 2,4-methanopyrrolidines was elaborated. The key synthetic step was an intramolecular photochemical [2 + 2]-cycloaddition of an acrylic acid derivative in flow. In spite of a higher molecular weight, 2,4-methanopyrrolidines were shown to have higher solubility in water and lower lipophilicity than pyrrolidines, important characteristics of bioactive molecules in drug design.

Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting-Group-Free Synthesis of Sulfonamides.

Cyclic saturated aminosulfonyl fluorides were synthesized as their HCl salts. The compounds were found to be stable upon storage and could be used for the protecting-group-free synthesis of sulfonamides. In the presence of the -SO2 F group, the nitrogen atom could be modified by means of acylation, arylation, or reductive amination to give products that have high potential for the synthesis of bioactive compounds.

Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery.

Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF3 /NaI. Novel fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained.