Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

Abstract

Physico‐chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem‐difluorinated cycloalkanes and compared to those of non‐fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem‐difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.

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

“…[34] All other pK a (H), log P, and S w values were measured as described previously. [30] Melting points were measured on MPA100 OptiMelt automated melting point system. Column chromatography was performed using Kieselgel Merck 60 (230-400 mesh) as the stationary phase.…”

“…[26][27][28][29] In a different paper, our group scanned the impact of introduction of gem-CF 2 group in β-δ positions of 3 to 7 carbocyclic rings on pK a , log P, and aqueous solubility (Figure 1, D). [30,31] In this work, we focus on the impact of introducing the fluoroalkyl substituents into saturated cyclic amines E1 on the compound's physicochemical properties. Several representatives of chemotype E1 have already found their applications in drug development.…”

“…This property was masterly used by the O'Hagan group to design and synthesize polarized “Janus face“ derivatives of 1,2,3‐trifluorocyclopropane ( C1 – 2 ), all‐ cis tetra‐, and all‐ cis pentafluorocyclohexanes ( C3 – 4 ) that exhibit lowered lipophilicity (Figure 1C) [26–29] . In a different paper, our group scanned the impact of introduction of gem ‐CF 2 group in β–δ positions of 3 to 7 carbocyclic rings on p K a , log P , and aqueous solubility (Figure 1, D ) [30,31] …”

Solvent-Controlled Switchable Synthesis of gem-Difluoro Compounds from Anhydrides under Photoredox Catalysis

“…Remarkably, terminal alkene was found to be more reactive than internal one (46), whereas alkyne remains completely unmarked (45), demonstrating extraordinary site selectivity. We have also successfully exposed the protocol's versatility by obtaining cyclic gem-difluoro compounds using various nitriles as solvents (35,36). However, the scope was limited to aryl substituted olefins and could not be expanded to aliphatic compounds.…”

Solvent-Controlled Switchable Synthesis of gem-Difluoro Compounds from Anhydrides under Photoredox Catalysis

“…31,32 In particular, the difluoromethylene group (CF2) has recently received a great attention 33 because of its relevance to bioisostere design, 34 physicochemical and pharmacological features. 35 It is also present in many biologically active molecules, namely dipeptidyl peptidase IV inhibitor Gosogliptin, 36 chemotherapy medication Gemcitabine, 37 while the difluoro analog of γ-lactam KMN-159 is five-folds more active than its nonfluorine analog (Fig 1B). 38 For decades, perfluorocarboxylic anhydrides, such as trifluoroacetic anhydride (TFAA) and chlorodifluoroacetic anhydride (CDFAA), have been employed as efficient protecting groups as well as electrophilic acylating reagents of nitrogen, oxygen, sulfur and carbon centers in organic synthesis (Fig 1C).…”