Synthesis of Substituted Pentafluorosulfanylpyrazoles Under Flow Conditions.

The development of flow conditions for the synthesis of pentafluorosulfanylpyrazoles is reported. A range of alkyl- and aryl-substituted SF5-alkynes were used in combination with different diazoacetates for this transformation. The corresponding substituted SF5-pyrazoles were obtained in up to 90% yield (average of 74% for 21 examples) as a mixture of isomers (up to 73:27 ratio). Synthetic transformations starting from an SF5-containing pyrazole were also demonstrated.

Hydrofluorination of Alkynes: From (E) to (Z).

The hydrofluorination of alkynes is an efficient synthetic route to monofluoroalkenes or difluoroalkanes. Both fluorinated motifs have found applications in medicinal chemistry and beyond. This review explores the recent advances in the hydrofluorination of diverse alkynes through various activation methods, from classical coinage metal catalysis to metal-free conditions. The range of alkynes goes from the simplest unactivated alkynes to activated ones (ynones and derivatives, ynamides, alkynyl sulfides and sulfones as much as haloalkynes). Regio- and stereoselective methods exists, but there is still room for improvement depending on the type of alkyne.

Synthesis of Tertiary Fluorides through an Acid-Mediated Deoxyfluorination of Tertiary Alcohols.

The combination of methanesulfonic acid and potassium bifluoride is reported for the deoxyfluorination of tertiary alcohols. Under metal-free conditions that use readily available, cheap, and easy-to-handle reagents, a range of tertiary alcohols could be converted into the corresponding fluorides in excellent yields (average yields of 85% for 23 examples). Mechanistic investigation showed that the reaction proceeds at 0 °C, in part, through an elimination/hydrofluorination pathway, but no residual alkenes are observed. The application of these conditions for the fluorination of ether and ester is also demonstrated.

Room temperature deoxofluorination of aromatic aldehydes with XtalFluor-E under highly concentrated conditions.

The synthesis of difluoromethyl-containing compounds exploiting the deoxofluorination reaction of aromatic aldehydes using XtalFluor-E is described. This transformation occurs at room temperature under highly concentrated conditions, i.e., with no added solvent. A wide range of difluoromethyl-containing compounds was obtained in 21 to 87% isolated yields.

Gold N-Heterocyclic Carbene Catalysts for the Hydrofluorination of Alkynes Using Hydrofluoric Acid: Reaction Scope, Mechanistic Studies and the Tracking of Elusive Intermediates.

An efficient and chemoselective methodology deploying gold-N-heterocyclic carbene (NHC) complexes as catalysts in the hydrofluorination of terminal alkynes using aqueous HF has been developed. Mechanistic studies shed light on an in situ generated catalyst, formed by the reaction of Brønsted basic gold pre-catalysts with HF in water, which exhibits the highest reactivity and chemoselectivity. The catalytic system has a wide alkyl substituted-substrate scope, and stoichiometric as well as catalytic reactions with tailor-designed gold pre-catalysts enable the identification of various gold species involved along the catalytic cycle. Computational studies aid in understanding the chemoselectivity observed through examination of key mechanistic steps for phosphine- and NHC-coordinated gold species bearing the triflate counterion and the elusive key complex bearing a bifluoride counterion.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.

Photoinitiated anti-Hydropentafluorosulfanylation of Terminal Alkynes.

A photoinitiated anti-hydropentafluorosulfanylation of terminal alkynes using SF5 Cl and (TMS)3 SiH as the hydrogen atom donor is reported. This transformation generates selectively (Z)-(1-alken-1-yl)pentafluoro-λ6 -sulfanes (Z:E : >85:15), thus allowing the preparation of this previously unknown geometrical isomer. DFT calculations highlight that the selectivity is due to the intrinsic preference of SF5 -substituted vinylic radicals to adopt a cis geometry, and to increased steric contacts during the transition structures leading to the minor (E)-products.

Correction: Amine-borane complex-initiated SF5Cl radical addition on alkenes and alkynes.

[This corrects the article DOI: 10.3762/bjoc.16.256.].

Thiourea-Catalyzed C-F Bond Activation: Amination of Benzylic Fluorides.

We describe the first thiourea-catalyzed C-F bond activation. The use of a thiourea catalyst and Ti(OiPr)4 as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S- and O-based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.

Monofluoroalkene-Isostere as a 19 F†NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane-Bound PGLa and (KIGAKI)3.

Solid-state 19 F NMR is a powerful method to study the interactions of biologically active peptides with membranes. So far, in labelled peptides, the 19 F-reporter group has always been installed on the side chain of an amino acid. Given the fact that monofluoroalkenes are non-hydrolyzable peptide bond mimics, we have synthesized a monofluoroalkene-based dipeptide isostere, Val-Ψ[(Z)-CF=CH]-Gly, and inserted it in the sequence of two well-studied antimicrobial peptides: PGLa and (KIGAKI)3 are representatives of an α-helix and a ß-sheet. The conformations and biological activities of these labeled peptides were studied to assess the suitability of monofluoroalkenes for 19 F NMR structure analysis.

Synthesis of Acyl Fluorides from Carboxylic Acids Using NaF-Assisted Deoxofluorination with XtalFluor-E.

The synthesis of acyl fluorides using the deoxofluorination reaction of carboxylic acids using XtalFluor-E is described. This transformation, assisted by a catalytic amount of NaF, occurs at room temperature in EtOAc, where XtalFluor-E behaves as the activating agent and the fluoride source. A wide range of acyl fluorides were obtained in moderate to excellent yields (36-99%) after a simple filtration on a pad of silica gel. We also demonstrated that sequential deoxofluorination/amidation was possible.

Amine-borane complex-initiated SF5Cl radical addition on alkenes and alkynes.

The SF5Cl radical addition on unsaturated compounds was performed using an air-stable amine-borane complex as the radical initiator. This method showed to be complementary to the classic Et3B-mediated SF5Cl addition on alkenes and alkynes. A total of seven alkene and three alkyne derivatives were tested in the reaction, with yields ranging from 3% to 85%.

Incorporating a Monofluoroalkene into the Backbones of Short Peptides: Evaluating the Impact on Local Hydrophobicity.

The local hydrophobicity of an amino acid residue in a peptide sequence can be determined by measuring the hydrophobicity index (φ0 ) by reversed-phase (RP) HPLC. Herein, the impact on the local hydrophobicity of the replacement of an amide by a monofluoroalkene unit in short peptides is discussed. Monofluoroalkene-containing dipeptides and tripeptides were synthesized, as well as their natural parent compounds, and the hydrophobicity indexes of these short peptides and peptidomimetics were determined. Comparison between the natural parent peptides and their alkene-containing analogues was made, and the dependence of the peptidomimetic analogues' behaviour on the pH and the solvent was studied. It was found that the presence of a monofluoroalkene unit enhanced a peptide's hydrophobicity.

Novel approaches to probe the binding of recoverin to membranes.

Recoverin is a protein involved in the phototransduction cascade by regulating the activity of rhodopsin kinase through a calcium-dependent binding process at the surface of rod outer segment disk membranes. We have investigated the interaction of recoverin with zwitterionic phosphatidylcholine bilayers, the major lipid component of the rod outer segment disk membranes, using both 31P and 19F solid-state nuclear magnetic resonance (NMR) and infrared spectroscopy. In particular, several novel approaches have been used, such as the centerband-only detection of exchange (CODEX) technique to investigate lipid lateral diffusion and 19F NMR to probe the environment of the recoverin myristoyl group. The results reveal that the lipid bilayer organization is not disturbed by recoverin. Non-myristoylated recoverin induces a small increase in lipid hydration that appears to be correlated with an increased lipid lateral diffusion. The thermal stability of recoverin remains similar in the absence or presence of lipids and Ca2+. Fluorine atoms have been strategically introduced at positions 4 or 12 on the myristoyl moiety of recoverin to, respectively, probe its behavior in the interfacial and more hydrophobic regions of the membrane. 19F NMR results allow the observation of the calcium-myristoyl switch, the myristoyl group experiencing two different environments in the absence of Ca2+ and the immobilization of the recoverin myristoyl moiety in phosphatidylcholine membranes in the presence of Ca2+.

Use of XtalFluor-E as an Alternative to POCl3 in the Vilsmeier-Haack Formylation of C-2-Glycals.

We report the use of XtalFluor-E ([Et2NSF2]BF4) as an alternative to POCl3 in the Vilsmeier-Haack formylation reaction of C-2-glycals. Employing a XtalFluor-E/DMF combination allowed the desired C-2-formyl glycals to be isolated in 11-90% yield. This method was extended to the synthesis of a C-2 -formylated disaccharide glycal.

Progress in the synthesis of fluorinated phosphatidylcholines for biological applications.

The synthesis and biophysical studies of fluorinated phospholipids have attracted a lot of interest over the past 40 years. Mono- and polyfluorinated phospholipids, containing 1-4 fluorine atoms, are designed mostly with the goal of developing new model membranes. The fluorine atoms are herein used as probes, mainly in 19F-NMR spectroscopy, to study biomolecule complexes. In this case, the spectroscopic features of the fluorine atom and the preservation of the parent lipid properties are of primary importance. On the other hand, highly fluorinated phospholipids, which contain a perfluorinated segment in alkyl chains, are mainly developed as drug-delivery devices and oxygen carriers. Here, the particular chemical characteristics of fluorine are used to form more stable and less toxic lipid vesicles/emulsions. This review will focus on describing the synthetic pathways for mono-, poly- and highly fluorinated phosphatidylcholines. We will also discuss, though not thoroughly, their properties and potential applications.

Stereochemical outcomes of C-F activation reactions of benzyl fluoride.

In recent years, the highly polar C-F bond has been utilised in activation chemistry despite its low reactivity to traditional nucleophiles, when compared to other C-X halogen bonds. Paquin's group has reported extensive studies on the C-F activation of benzylic fluorides for nucleophilic substitutions and Friedel-Crafts reactions, using a range of hydrogen bond donors such as water, triols or hexafluoroisopropanol (HFIP) as the activators. This study examines the stereointegrity of the C-F activation reaction through the use of an enantiopure isotopomer of benzyl fluoride to identify whether the reaction conditions favour a dissociative (SN1) or associative (SN2) pathway. [2H]-Isotopomer ratios in the reactions were assayed using the Courtieu 2H NMR method in a chiral liquid crystal (poly-γ-benzyl-L-glutamate) matrix and demonstrated that both associative and dissociative pathways operate to varying degrees, according to the nature of the nucleophile and the hydrogen bond donor.

Influence of the Length and Charge on the Activity of α-Helical Amphipathic Antimicrobial Peptides.

Hydrophobic mismatch is important for pore-forming amphipathic antimicrobial peptides, as demonstrated recently [Grau-Campistany, A., et al. (2015) Sci. Rep. 5, 9388]. A series of different length peptides have been generated with the heptameric repeat sequence KIAGKIA, called KIA peptides, and it was found that only those helices sufficiently long to span the hydrophobic thickness of the membrane could induce leakage in lipid vesicles; there was also a clear length dependence of the antimicrobial and hemolytic activities. For the original KIA sequences, the cationic charge increased with peptide length. The goal of this work is to examine whether the charge also has an effect on activity; hence, we constructed two further series of peptides with a sequence similar to those of the KIA peptides, but with a constant charge of +7 for all lengths from 14 to 28 amino acids. For both of these new series, a clear length dependence similar to that of KIA peptides was observed, indicating that charge has only a minor influence. Both series also showed a distinct threshold length for peptides to be active, which correlates directly with the thickness of the membrane. Among the longer peptides, the new series showed activities only slightly lower than those of the original KIA peptides of the same length that had a higher charge. Shorter peptides, in which Gly was replaced with Lys, showed activities similar to those of KIA peptides of the same length, but peptides in which Ile was replaced with Lys lost their helicity and were less active.

Synthesis of novel substituted pyrimidine derivatives bearing a sulfamide group and their in vitro cancer growth inhibition activity.

The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI50<6µM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity.

Palladium-catalyzed synthesis of monofluoroalkenes from 3,3-difluoropropenes using dimethylmalonate and derivatives as nucleophiles.

The synthesis of monofluoroalkenes bearing a malonate or its derivatives at the ß position is presented. The reaction can be performed with various 3,3-difluoropropenes. A preliminary result for an enantioselective variant is also reported. Further synthetic transformations of a monofluoroalkene were also accomplished.