RESUMEN
The installation of fluorine and fluorinated functional groups into drug-like scaffolds can perturb the physicochemical, pharmacokinetic, and pharmacodynamic properties of compounds. However, some potentially useful fluorinated substructures reside predominantly outside the realm of the current synthetic methodologies. One such substructure, the α,α-difluorophosphine oxide, might be convergently prepared by the reaction of a gem-difluorinated alkene with a P-H bond, though such nucleophilic reactions instead proceed through a C-F substitution pathway that delivers monofluorovinyl products. In contrast, we report a peroxide-initiated hydrophosphinylation reaction of gem-difluoroalkenes that avoids C-F substitution and produces a wide range of α,α-difluorophosphine oxides and functions using readily available reagents and green solvents.
RESUMEN
Regioselective functionalization of gem-difluoroalkenes enables convergent late-stage access to fluorinated functional groups, though most functionalization reactions proceed through defluorinative functionalization processes that deliver mono-fluorovinyl products. In contrast, fewer reactions undergo net hydrofunctionalization to generate difluorinated products. Herein, we report a photocatalytic hydrothiolation of gem-difluoroalkenes that enables access to a broad spectrum of α,α-difluoroalkylthioethers. Notably, the reaction successfully couples nonactivated substrates, which expands the scope of accessible molecules relative to previously reported reactions involving organo- or photocatalytic strategies. Further, this reaction successfully couples biologically relevant molecules under aqueous conditions, highlighting potential applications in both late-stage and biorthogonal functionalizations.
Asunto(s)
CatálisisRESUMEN
A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone's sp3-hybridized hydrate form is energetically favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.
Asunto(s)
Cetonas , CatálisisRESUMEN
The substitution of hydrogen atoms with fluorine in bioactive molecules can greatly impact physicochemical, pharmacokinetic, and pharmacodynamic properties. However, current synthetic methods cannot readily access many fluorinated motifs, which impedes utilization of these groups. Thus, the development of new methods to introduce fluorinated functional groups is critical for developing the next generation of biological probes and therapeutic agents. The synthesis of one such substructure, the α,α-difluoroalkylthioether, typically requires specialized conditions that necessitate early-stage installation. A late-stage and convergent approach to access α,α-difluoroalkylthioethers could involve nucleophilic addition of thiols across gem-difluorostyrenes. Unfortunately, under basic conditions, nucleophilic addition to gem-difluorostyrenes generates an anionic intermediate that can undergo facile elimination of fluoride to generate α-fluorovinylthioethers. To overcome this decomposition, we herein exploit an acid-based catalyst system to facilitate simultaneous nucleophilic addition and protonation of the unstable intermediate. Ultimately, the optimized mild conditions afford the desired α,α-difluoroalkylthioethers in high selectivity and moderate to excellent yields. These α,α-difluoroalkylthioethers are less nucleophilic and more oxidatively stable relative to nonfluorinated thioethers, suggesting the potential application of this unexplored functional group in biological probes and therapeutic agents.
Asunto(s)
Fluoruros , Flúor , Catálisis , SulfurosRESUMEN
We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.
Asunto(s)
Productos Biológicos , Éteres Metílicos , FenolesRESUMEN
gem-Difluoroalkenes represent valuable synthetic handles for organofluorine chemistry; however, most reactions of this substructure proceed through reactive intermediates prone to eliminate a fluorine atom and generate monofluorinated products. Taking advantage of the distinct reactivity of gem-difluoroalkenes, we present a cobalt-catalyzed regioselective unsymmetrical dioxygenation of gem-difluoroalkenes using phenols and molecular oxygen, which retains both fluorine atoms and provides ß-phenoxy-ß,ß-difluorobenzyl alcohols. Mechanistic studies suggest that the reaction operates through a radical chain process initiated by Co(II)/O2/phenol and quenched by the Co-based catalyst. This mechanism enables the retention of both fluorine atoms, which contrasts most transition-metal-catalyzed reactions of gem-difluoroalkenes that typically involve defluorination.
Asunto(s)
Cobalto , Flúor , Catálisis , FluorurosRESUMEN
gem-Difluorinated alkenes are readily accessible building blocks that can undergo functionalization to provide a broad spectrum of fluorinated and non-fluorinated products. Herein, we review recent (since 2017) transition metal-catalyzed transformations of these specialized alkenes and summarize general reactivity patterns of these reactions. Many transition metal-catalyzed reactions undergo net C-F bond functionalization reactions to deliver monofluorinated products. These reactions typically proceed through ß-fluoro alkylmetal intermediates that readily eliminate a ß-fluoride to deliver monofluoroalkene products. A second series of reactions exploit coinage metal fluorides to add F- to the gem-difluorinated alkene, and further functionalization delivers trifluoromethyl-containing products. In stark contrast, few transition metal-catalyzed reactions proceed in net "fluorine-retentive processes" to deliver difluoromethylene-based products.
RESUMEN
A new bench-stable trifluoromethylation reagent, phenyl bromodifluoroacetate, converts readily available alcohols to trifluoromethanes in a Cu-catalyzed deoxytrifluoromethylation reaction. This reaction streamlines access to target biologically active molecules, and should be useful for a variety of medicinal, agricultural, and materials chemists.
Asunto(s)
Alcoholes/síntesis química , Cobre/química , Hidrocarburos Fluorados/química , Alcoholes/química , CatálisisRESUMEN
Herein, we report a practical synthesis of 2-D-L-tryptophan via sequential Ir-catalyzed C-H borylation, and Ir-catalyzed C-2-deborylative deuteration steps. In this synthetic sequence, deprotection of the Boc and methyl ester groups proved challenging, due to replacement of deuterium with hydrogen. However, mild deprotection conditions were developed to avoid this D/H scrambling. Further, 2-D-L-Tryptophan is stable in many buffers used for biological studies.
RESUMEN
Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful intermediate for elaborating into more complex fluorinated compounds. Currently, most functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or monofluorinated products, respectively. In contrast, we present a complementary "fluorine-retentive" reaction that exploits an organocatalytic strategy to add phenols across gem-difluoroalkenes to deliver ß,ß-difluorophenethyl arylethers. The products are produced in good to moderate yields and selectivities, thus providing a range of compounds that are underrepresented in the synthetic and medicinal chemistry literature.
RESUMEN
Fluorinated peptidomimetics are valuable substrates for exploring peptide backbone conformations and for perturbing physicochemical properties of probe compounds. However, in some cases synthetic limitations restrict installation of the fluorinated peptidomimetics into the desired probe compounds. For instance, trifluoromethylalkenes have served as amide isopolar mimics, but are rarely utilized, because many standard peptide-coupling conditions promote the isomerization of the alkene to thermodynamically favored positions. To address this challenge, we report the conversion of a naturally occurring amino acid to a Tyr1-ψ/[CF3C=CH]-Gly2 dipeptide mimetic, and notably, successful peptide coupling reactions that avoid alkene isomerization. Using this strategy, we generated trifluoromethylalkene-containing Leu-enkephalin peptidomimetics in high purity and good yield. This sequence suggests that the trifluoromethylalkene peptidomimetics can be incorporated into other target molecules with appropriate optimization.
RESUMEN
As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR's protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit ß-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.
Asunto(s)
Encefalina Leucina/farmacología , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Células CHO , Cricetulus , Encefalina Leucina/genética , Humanos , Fenilalanina , Receptores Opioides delta/agonistas , Receptores Opioides delta/genética , Receptores Opioides mu/agonistas , Receptores Opioides mu/genética , Transducción de Señal/genéticaRESUMEN
Heme-based tryptophan dioxygenases are established immunosuppressive metalloproteins with significant biomedical interest. Here, we synthesized two mechanistic probes to specifically test if the α-amino group of the substrate directly participates in a critical step of the O atom transfer during catalysis in human tryptophan 2,3-dioxygenase (TDO). Substitution of the nitrogen atom of the substrate to a carbon (probe 1) or oxygen (probe 2) slowed the catalytic step following the first O atom transfer such that transferring the second O atom becomes less likely to occur, although the dioxygenated products were observed with both probes. A monooxygenated product was also produced from probe 2 in a significant quantity. Analysis of this new product by HPLC coupled UV-vis spectroscopy, high-resolution mass spectrometry, 1H NMR, 13C NMR, HSQC, HMBC, and infrared (IR) spectroscopies concluded that this monooxygenated product is a furoindoline compound derived from an unstable epoxyindole intermediate. These results prove that small molecules can manipulate the stepwise O atom transfer reaction of TDO and provide a showcase for a tunable mechanism by synthetic compounds. The product analysis results corroborate the presence of a substrate-based epoxyindole intermediate during catalysis and provide the first substantial experimental evidence for the involvement of the substrate α-amino group in the epoxide ring-opening step during catalysis. This combined synthetic, biochemical, and biophysical study establishes the catalytic role of the α-amino group of the substrate during the O atom transfer reactions and thus represents a substantial advance to the mechanistic comprehension of the heme-based tryptophan dioxygenases.
Asunto(s)
Compuestos de Amonio/metabolismo , Compuestos Epoxi/metabolismo , Oxígeno/metabolismo , Triptófano Oxigenasa/metabolismo , Compuestos de Amonio/química , Compuestos Epoxi/química , Humanos , Conformación Molecular , Oxígeno/química , Especificidad por Sustrato , Triptófano Oxigenasa/químicaRESUMEN
A palladium-catalyzed decarboxylative benzylation reaction of α,α-difluoroketone enolates is reported, in which the key C(α)-C(sp(3) ) bond is generated by reductive elimination from a palladium intermediate. The transformation provides convergent access to α-benzyl-α,α-difluoroketone-based products, and should be useful for accessing biological probes.
Asunto(s)
Compuestos de Bencilo/síntesis química , Cetonas/química , Cetonas/síntesis química , Paladio/química , Compuestos de Bencilo/química , Catálisis , Descarboxilación , Estructura MolecularRESUMEN
Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation.
Asunto(s)
Compuestos de Bencilo/química , Cobre/química , Fluoroacetatos/química , Hidrocarburos Fluorados/síntesis química , Catálisis , Descarboxilación , Hidrocarburos Fluorados/química , Estructura MolecularRESUMEN
α,α-Difluoroketones possess unique physicochemical properties that are useful for developing therapeutics and probes for chemical biology. To access the α-allyl-α,α-difluoroketone substructure, complementary palladium-catalyzed decarboxylative allylation reactions were developed to provide linear and branched α-allyl-α,α-difluoroketones. For these orthogonal processes, the fluorination pattern of the substrate enabled the ligands to dictate the regioselectivity of the transformations.
Asunto(s)
Cetonas/química , Ligandos , Paladio/química , Compuestos Alílicos/química , Catálisis , Halogenación , Fosfinas/química , EstereoisomerismoRESUMEN
The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl ß,ß,ß-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing ß,ß,ß-trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.
Asunto(s)
Aldehídos/química , Hidrocarburos Fluorados/síntesis química , Cetonas/química , Metales/química , Catálisis , Hidrocarburos Fluorados/química , Metilación , Estructura Molecular , EstereoisomerismoRESUMEN
Trifluoromethyl arenes (Ar-CF3) are amongst the commonly encountered fluorinated substructures in pharmaceutical, agrochemical, and material sciences. However, predominant methods to access Ar-CF3 possess several limitations, including harsh conditions, lack of availability of substrates, and poor regioselectivity, which combined restrict access to desirable highly functionalized Ar-CF3-containing compounds. To expand the scope of accessible Ar-CF3-based molecules, we present an orthogonal deoxyfluoroalkylation/aromatization approach that exploits readily accessible and programable cyclohexan(en)one substrates, which undergo a reliable 1,2-addition reaction with the Ruppert-Prakash reagent (TMSCF3) followed by aromatization to deliver highly functionalized Ar-CF3 compounds in a one/two-pot sequence. This general strategy enables access to highly substituted Ar-CF3-containing molecules that are difficult, expensive, and/or impossible to access by current synthetic methods.
RESUMEN
The installation of fluorine and fluorinated functional groups in organic molecules perturbs the physicochemical properties of those molecules and enables the development of new therapeutics, agrichemicals, biological probes and materials. However, current synthetic methodologies cannot access some fluorinated functional groups and fluorinated scaffolds. One such group, the gem-difluorobenzyl motif, might be convergently synthesized by reacting a nucleophilic aryl precursor and an electrophilic gem-difluoroalkene. Previous attempts have relied on forming unstable anionic or organometallic intermediates that rapidly decompose through a ß-F elimination process to deliver monofluorovinyl products. In contrast, we report a fluorine-retentive palladium and copper co-catalyzed chloro-arylation of gem-difluorostyrenes that takes advantage of a nitrite (NO2 -) additive to avoid the favorable ß-F elimination pathway that forms monofluorinated products, instead delivering difluorinated products.