Electronic Effects in a Green Protocol for (Hetero)Aryl-S Coupling.

Aryl and heteroaryl iodides have been efficiently converted into the corresponding thioacetates in cyclopentyl methyl ether (CPME), a green solvent, under Cu catalysis. The chemoselectivity of the reaction is mainly controlled by electronic factors, enabling the conversion of both electron-rich and electron-deficient substrates into the corresponding thioacetates in good to excellent yields. The products can be easily deprotected to the corresponding thiolates to carry out additional synthetic transformations in situ. Surprisingly, despite CPME's relatively low dielectric constant, the reaction rate significantly increased when conducted under microwave irradiation conditions. This synthetic methodology exhibits a remarkable tolerance to functional groups, mild reaction conditions, and a wide substrate scope, utilizing a safe and inexpensive CuI pre-catalyst in the green solvent CPME. A non-aqueous workup allowing for the complete recovery of both catalyst and solvent makes this approach an environmentally sustainable protocol for C(sp2) sulfur functionalization. Additionally, the reaction shows selective cross-coupling with iodides in competition with chlorides and bromides, allowing its use in multistep syntheses. To demonstrate the potential of this methodology, it was applied to the high-yield synthesis of a photochromic dithienylethene, where a selective synthesis had not been reported before.

Base-mediated homologative rearrangement of nitrogen-oxygen bonds of N-methyl-N-oxyamides.

Due to the well known reactivity of C(O)-N functionalities towards canonical C1-homologating agents (e.g. carbenoids, diazomethane, ylides), resulting in the extrusion of the N-centered fragment en route to carbonyl compounds, formal C1-insertions within N-O bonds still remain obscure. Herein, we document the homologative transformation of N-methyl-N-oxyamides - with high tolerance for diverse O-substituents - into N-acyl-N,O-acetals. Under controlled basic conditions, the N-methyl group of the same starting materials acts as a competent precursor of the methylene synthon required for the homologation. The logic is levered on the formation of an electrophilic iminium ion (via N-O heterolysis) susceptible to nucleophilic attack by the alkoxide previously expulsed. The procedure documents genuine chemocontrol and flexibility, as judged by the diversity of substituents placed on both amide and nitrogen linchpins. The mechanistic rationale was validated through experiments conducted on D-labeled materials which unambiguously attributed the origin of the methylene fragment to the N-methyl group of the starting compounds.

Highly chemoselective homologative assembly of the α-substituted methylsulfinamide motif from N-sulfinylamines.

α-Substituted methylsulfinamide are prepared through the homologation of electrophilic N-sulfinylamines with Li-CHXY reagents. The transformation takes place under full chemocontrol and exhibits good flexibility for preparing both N-aryl and N-alkyl analogues. Various sensitive functionalities can be accommodated on the starting materials, thus documenting a wide reaction scope.

Leveraging the 3-Chloro-4-fluorophenyl Motif to Identify Inhibitors of Tyrosinase from Agaricus bisporus.

Tyrosinase (EC 1.14.18.1) is implicated in melanin production in various organisms. There is a growing body of evidence suggesting that the overproduction of melanin might be related to several skin pigmentation disorders as well as neurodegenerative processes in Parkinson's disease. Based on this consideration, the development of tyrosinase inhibitors represents a new challenge to identify new agents in pharmaceutical and cosmetic applications. With the goal of identifying tyrosinase inhibitors from a synthetic source, we employed a cheap and facile preliminary assay using tyrosinase from Agaricus bisporus (AbTYR). We have previously demonstrated that the 4-fluorobenzyl moiety might be effective in interactions with the catalytic site of AbTYR; moreover, the additional chlorine atom exerted beneficial effects in enhancing inhibitory activity. Therefore, we planned the synthesis of new small compounds in which we incorporated the 3-chloro-4-fluorophenyl fragment into distinct chemotypes that revealed the ability to establish profitable contact with the AbTYR catalytic site. Our results confirmed that the presence of this fragment is an important structural feature to improve the AbTYR inhibition in these new chemotypes as well. Furthermore, docking analysis supported the best activity of the selected studied compounds, possessing higher potency when compared with reference compounds.

Selective noncovalent proteasome inhibiting activity of trifluoromethyl-containing gem-quaternary aziridines.

The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well-known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis-homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.

Application of Biobased Solvents in Asymmetric Catalysis.

The necessity of more sustainable conditions that follow the twelve principles of Green Chemistry have pushed researchers to the development of novel reagents, catalysts and solvents for greener asymmetric methodologies. Solvents are in general a fundamental part for developing organic processes, as well as for the separation and purification of the reaction products. By this reason, in the last years, the application of the so-called green solvents has emerged as a useful alternative to the classical organic solvents. These solvents must present some properties, such as a low vapor pressure and toxicity, high boiling point and biodegradability, and must be obtained from renewable sources. In the present revision, the recent application of these biobased solvents in the synthesis of optically active compounds employing different catalytic methodologies, including biocatalysis, organocatalysis and metal catalysis, will be analyzed to provide a novel tool for carrying out more ecofriendly organic processes.

Novel alpha6 preferring GABA-A receptor ligands based on loreclezole.

The family of GABA-A receptors contains nineteen mammalian subunits from which pentameric, GABA gated anion channels are assembled. The subunit encoded by the GABRA6 gene is highly expressed in the cerebellum and the receptors to which it contributes have recently been demonstrated to be a promising candidate as a novel drug target. Here we examined a series of loreclezole derivatives for potentially selective action at α6ß3γ2 receptors with the help of computational methods and functional testing with the two-electrode voltage clamp technique. The synthetic routes to some previously published ligands were improved, and a new derivative was synthesized based on computational docking results. This new loreclezole derivative, [3-(2-chloro-4-methylphenyl)-3-methylbutanenitrile (40)], was shown to display stronger modulatory action in concatenated α6ß3γ2 receptors compared to their α1ß3γ2 counterpart. The hypothetical bound state structure provides valuable guidance for future design of selective therapeutics.

Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines.

The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed against cancer. However, to the best of our knowledge, aziridine derivatives showing inhibitory activity towards proteasome have never been described before. Herein we report a new class of selective and nonPIs bearing an aziridine ring as a core structure. In vitro cell-based assays (two leukemia cell lines) also displayed anti-proliferative activity for some compounds. In silico studies indicated non-covalent binding mode and drug-likeness for these derivatives. Taken together, these results are promising for developing more potent PIs.

Synthesis, computational investigation and biological evaluation of α,α-difluoromethyl ketones embodying pyrazole and isoxazole nuclei as COX inhibitors.

α,α-Difluoromethyl ketones (DFMKs) have emerged as currently investigated agents benefiting from the merging of chemico-physical features conferred by the constitutive elements (-CHF2 and carbonyl moietites). With a view to biological applications, the additional incorporation of heterocycles is a desirable property enabling the tuning of critical factors encompassing the pharmaco-dynamic and kinetic profiles. The underexplored assembling of α,α-difluoromethyl-heteroaromatic ketones is herein implemented via a conceptually intuitive Weinreb amide acylative transfer of a putative difluoromethyl-carbanion. To make the strategy productive, we adopted the commercially available TMSCHF2 pronucleophile - characterized by robust chemical stability and manipulability (bp 65 °C) - which upon Lewis-base mediated activation delivers the competent CHF2-nucleophile. The synthetic protocol was carried out on pyrazole- and isoxazole-based scaffolds, and a panel of heteroaryl-DFMKs was consequently developed as potential COX-inhibitors. In this sense, the bioisosterism deducted through docking studies between the widely expressed carboxylic group (in several clinically used COX inhibitors) and the -COCHF2 motif introduced herein supports this rationale. To confirm the docking results, all compounds were tested against both COX-1 and COX-2 enzyme isoforms showing activity in the micromolar range and a good selectivity index (SI). They were also evaluated for their biocompatibility using NIH/3T3 cells to which they did not show any significant toxicity.

Straightforward synthesis of bench-stable heteroatom-centered difluoromethylated entities via controlled nucleophilic transfer from activated TMSCHF2.

The commercially available and experimentally convenient (bp 65 °C) difluoromethyltrimethylsilane (TMSCHF2) is proposed as a valuable difluoromethylating transfer reagent for delivering the CHF2 moiety to various heteroatom-based electrophiles. Upon activation with an alkoxide, a conceptually intuitive nucleophilic displacement directly furnishes in high yields the bench-stable analogues.

Consecutive and Selective Double Methylene Insertion of Lithium Carbenoids to Isothiocyanates: A Direct Assembly of Four-Membered Sulfur-Containing Cycles.

A formal CH2 -CH2 homologation conducted with C1 carbenoids on a carbon electrophile for the obtainment of a four-membered cycle is reported. The logic proposes the consecutive delivery of two single nucleophilic CH2 units to an isothiocyanate-as competent electrophilic partner-resulting in the assembling of a rare imino-thietane cluster. The single synthetic operation procedure documents genuine chemocontrol, as indicated by the tolerance to various reactive elements decorating the starting materials. Significantly, the double homologation protocol is accomplished directly on a carbon electrophile, thus not requiring the installation of heteroatom-centered manifolds (e.g. boron).

Direct and straightforward transfer of C1 functionalized synthons to phosphorous electrophiles for accessing gem-P-containing methanes.

The direct transfer of different α-substituted methyllithium reagents to chlorinated phosphorous electrophiles of diverse oxidation state (phosphates, phosphine oxides and phosphines) is proposed as an effective strategy to synthesize geminal P-containing methanes. The methodology relies on the efficient nucleophilic substitution conducted on the P-chlorine linkage. Uniformly high yields are observed regardless the specific nature of the carbanion employed: once established the conditions for generating the competent nucleophile (LiCH2Hal, LiCHHal2, LiCH2CN, LiCH2SeR etc.) the homologated compounds are obtained via a single operation. Some P-containing formal carbanions have been evaluated in transferring processes, including the carbonyl-difluoromethylation of the opioid agent Hydrocodone.

Taking advantage of lithium monohalocarbenoid intrinsic α-elimination in 2-MeTHF: controlled epoxide ring-opening en route to halohydrins.

The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding ß-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses.

The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.

Straightforward chemoselective access to unsymmetrical dithioacetals through a thiosulfonate homologation-nucleophilic substitution sequence.

A sequential C1-homologation-nucleophilic substitution tactic is presented for the preparation of rare unsymmetrical dithioacetals. The judicious selection of thiosulfonates as convenient sulfur electrophilic sources - upon the homologation event conducted on an intermediate α-halothioether - guarantees the release of the non-reactive sulfonate group, thus enabling the subsequent nucleophilic displacement with an external added thiol [(hetero)aromatic and/or aliphatic]. Uniform high yields and excellent chemocontrol were deduced during the extensive scope study, thus documenting the versatility of the direct technique for the preparation of these unique and manipulable materials.

Chemoselective Homologation-Deoxygenation Strategy Enabling the Direct Conversion of Carbonyls into (n+1)-Halomethyl-Alkanes.

The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp3-type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-like species can act as nucleophiles, thus making it of general applicability.

Electrophilicity Scale of Activated Amides: 17 O†NMR and 15 N†NMR Chemical Shifts of Acyclic Twisted Amides in N-C(O) Cross-Coupling.

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to nN →π*C=O conjugation. In this study, we report electrophilicity scale by exploiting 17 O NMR and 15 N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.

Direct and Chemoselective Electrophilic Monofluoromethylation of Heteroatoms (O-, S-, N-, P-, Se-) with Fluoroiodomethane.

The commercially available fluoroiodomethane represents a valuable and effective electrophilic source for transferring the CH2F unit to a series of heteroatom-centered nucleophiles under mild basic conditions. The excellent manipulability offered by its liquid physical state (bp 53.4 °C) enables practical and straightforward one-step nucleophilic substitutions to retain the chiral information embodied, thus allowing it to overcome de facto the requirement for fluoromethylating agents with no immediate access. The high-yielding methodology was successfully applied to a variety of nucleophiles including a series of drugs currently in the market.

Halogen-Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis-Trifluoromethyl-ß-Diketiminates and the Dual Role of LiCH2I.

The selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation-metalation-acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated ß-diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCH2Cl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent. The mechanistic rationale grounded on experimental evidences supports the hypothesized proposal and, the structural analysis gathers key aspects of this class of valuable ligands in catalysis.

A Combination of Pharmacophore and Docking-based Virtual Screening to Discover new Tyrosinase Inhibitors.

Melanogenesis controls the formation of melanin pigment whose overproduction is related to various hyperpigmentary disorders in humans. Tyrosinase is a type-3 copper enzyme involved in the rate limiting step of melanin synthesis, therefore its inhibition could represent an efficient way for the development of depigmenting agents. In this work, a combination of pharmacophore and docking-based studies has been employed to screen two in-house 3D compound databases containing about 2,000 molecules from natural and synthetic sources. As result we selected two "hit compounds" which proved to inhibit tyrosinase activity showing IC50 values in the micromolar range.