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Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.
Assuntos
Carbono/química , Técnicas de Química Sintética , Química Farmacêutica/métodos , Éteres/síntese química , Ácidos Carboxílicos/química , EletroquímicaRESUMO
Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Nickel(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum-hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2 ]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be transitioned to large scale through an electrochemical recirculating flow process and extended to an in situ reduction protocol to generate catalytic amounts of Ni(0) for organic transformations. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low-valent organometallic complexes in academia and industry.
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A method for deoxyfluorination of aliphatic primary, secondary, and tertiary alcohols is reported, employing a nontrigonal phosphorus triamide for base-free alcohol activation in conjunction with an organic soluble fluoride donor and a triarylborane fluoride shuttling catalyst. Mechanistic experiments are consistent with a reaction that proceeds by the collapse of an oxyphosphonium fluoroborate ion pair with fluoride transfer. The substrate scope complements existing deoxyfluorination methods and enables the preparation of homochiral secondary and tertiary alkylfluorides by stereoinversion of the substrate alcohol.
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Peptide couplers (also known as amide bond-forming reagents or coupling reagents) are broadly used in organic chemical syntheses, especially in the pharmaceutical industry. Yet, occupational health hazards associated with this chemical class are largely unexplored, which is disconcerting given the intrinsic reactivity of these compounds. Several case studies involving occupational exposures reported adverse respiratory and dermal health effects, providing initial evidence of chemical sensitization. To address the paucity of toxicological data, a pharmaceutical cross-industry task force was formed to evaluate and assess the potential of these compounds to cause eye and dermal irritation as well as corrosivity and dermal sensitization. The goal of our work was to inform health and safety professionals as well as pharmaceutical and organic chemists of the occupational health hazards associated with this chemical class. To that end, 25 of the most commonly used peptide couplers and five hydrolysis products were selected for in vivo, in vitro, and in silico testing. Our findings confirmed that dermal sensitization is a concern for this chemical class with 21/25 peptide couplers testing positive for dermal sensitization and 15 of these being strong/extreme sensitizers. We also found that dermal corrosion and irritation (8/25) as well as eye irritation (9/25) were health hazards associated with peptide couplers and their hydrolysis products (4/5 were dermal irritants or corrosive and 4/5 were eye irritants). Resulting outcomes were synthesized to inform decision making in peptide coupler selection and enable data-driven hazard communication to workers. The latter includes harmonized hazard classifications, appropriate handling recommendations, and accurate safety data sheets, which support the industrial hygiene hierarchy of control strategies and risk assessment. Our study demonstrates the merits of an integrated, in vivo -in silico analysis, applied here to the skin sensitization endpoint using the Computer-Aided Discovery and REdesign (CADRE) and Derek Nexus programs. We show that experimental data can improve predictive models by filling existing data gaps while, concurrently, providing computational insights into key initiating events and elucidating the chemical structural features contributing to adverse health effects. This interactive, interdisciplinary approach is consistent with Green Chemistry principles that seek to improve the selection and design of less hazardous reagents in industrial processes and applications.
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Irritantes , Saúde Ocupacional , Humanos , Peptídeos/farmacologia , Preparações Farmacêuticas , PeleRESUMO
A new undergraduate organic laboratory experiment has been developed for amide bond formation between biorenewable 2-furoic acid and either of two substituted piperazines to prepare medicinally relevant amide products using a procedure with industrial significance. The reactions proceeded smoothly under ambient conditions using the combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) in a minimal volume of acetonitrile with a direct crystallization upon addition of water. Students successfully collected their product by filtration and then characterized it by NMR (1H, 13C, COSY, DEPT-135, HSQC), IR, MS, and melting point. Students also explored the reaction mechanism and compared green chemistry aspects of their procedure with literature routes. A virtual version of the experiment was adapted for remote instruction.
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As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.
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Benchmarking , Preparações Farmacêuticas , Catálise , PaládioRESUMO
The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.
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Compostos Heterocíclicos com 3 Anéis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Catálise , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Ligantes , Estrutura Molecular , Paládio/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/químicaRESUMO
The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)3.
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Zinc salts have been shown to promote the Buchwald-Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.
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The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a â¼7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1).
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Amidas/química , Nucleosídeos/síntese química , Ácidos Fosfóricos/química , Pró-Fármacos/síntese química , Anisóis/química , Cristalização , Cinética , Estrutura Molecular , Nucleosídeos/química , Fosforilação , Pró-Fármacos/química , EstereoisomerismoRESUMO
The Achmatowicz rearrangement is a powerful method for the construction of pyranones from simple furan derivatives. Here, we describe the development of improved reaction conditions and an interrogation into the fate of the metal center during this interesting transformation. The reaction to form the synthetically important lactol, 6-hydroxy-2H-pyran-3(6H)-one (3), proceeds cleanly in the presence of tert-butyl hydroperoxide (TBHP, 2) using low loadings of VO(O(i)Pr)3 as catalyst. The nonaqueous conditions developed herein allow for easy isolation of product 3 and synthetically important derivatives, a key advantage of this new protocol. Detailed experimental, spectroscopic, and kinetic studies along with kinetic modeling of the catalytic cycle support a positive-order dependence in both furfurol and TBHP concentrations, first-order dependence in catalyst (VO(O(i)Pr)3), and a negative dependence on the 2-methyl-2-propanol (4) concentration. (51)V-NMR spectroscopic studies revealed that 2-methyl-2-propanol (4) competes with substrates for binding to the metal center, rationalizing its inhibitory effect.
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Furanos/química , Compostos Organometálicos/química , Vanádio/química , terc-Butil Hidroperóxido/química , Catálise , Cristalografia por Raios X , Cinética , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Described herein is the synthesis of BMS-986001 by employing two novel organocatalytic transformations: 1)â a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate, and 2)â an unprecedented small-molecule-mediated dynamic kinetic resolution to access a variety of enantiopure pyranones, one of which served as a versatile building block for the multigram, stereoselective, and chromatography-free synthesis of BMS-986001. The synthesis required five chemical transformations and resulted in a 44% overall yield.
Assuntos
Fármacos Anti-HIV/síntese química , Timidina/análogos & derivados , Fármacos Anti-HIV/química , Catálise , Levamisol/química , Estereoisomerismo , Timidina/síntese química , Timidina/químicaRESUMO
In this Communication, an investigation of the combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) for the synthesis of esters and thioesters is described. This work revealed the unique challenges of the reactions of less nucleophilic alcohols and more reactive thiols with the N-acyl imidazolium intermediate and led to the identification of general enabling conditions that provide high yields and selectivity for a range of alcohols and thiols.
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Since the landmark publications of the first directed aldol addition reaction in 1973, the site, diastereo-, and enantioselective aldol reaction has been elevated to the rarefied status of being both a named and a strategy-level reaction (the Mukaiyama directed aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed aldol addition reactions. The evolution of this process is chronicled from the authors' laboratories as well as in those of Professor Teruaki Mukaiyama.
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Aldeídos/síntese química , Bases de Lewis/química , Aldeídos/química , Catálise , Estrutura MolecularRESUMO
A Rapid Injection NMR (RINMR) apparatus has been designed and constructed to allow the observation of fast chemical reactions in real time by NMR spectroscopy. The instrument was designed to allow the rapid (<2 s) injection and mixing of a metered volume of a reagent into a spinning NMR tube followed by rapid acquisition of the data resulting from the evolution of the chemical process. The various design criteria for this universal system included the ability to deliver any chemical reagent at any temperature and allow for the observation of any nucleus. The various challenges associated with the construction and implementation of this instrument are documented along with the validation of the accuracy of the apparatus with respect to volume and temperature. Finally, the ultimate validation and reproducibility of the technique is presented in the form of three case studies that used the instrument to elucidate various aspects of organic reaction mechanisms. The authors urge interested parties to not embark on the construction of their own instrument and invite those whose research problems might be amenable to this kind of analysis to contact the corresponding author for access to the apparatus described herein.
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Espectroscopia de Ressonância Magnética/instrumentação , Espectroscopia de Ressonância Magnética/métodos , Calibragem , Desenho de Equipamento , Éteres/síntese química , Éteres/química , Estrutura Molecular , Silanos/química , Estereoisomerismo , TemperaturaRESUMO
An effective strategy has been developed for the preparation of 3-alkoxymethyl-pyrazolo[3,4-b]pyridines, compounds that are currently not readily accessible by existing synthetic methods. Further manipulation of these compounds allows for access to 3-alkoxymethyl-pyrazolo[3,4-b]pyridines with a variety of substitution patterns as well as 3-aminomethyl-pyrazolo[3,4-b]pyridines.
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Pirazóis/síntese química , Piridinas/síntese química , Cinética , Pirazóis/química , Piridinas/químicaRESUMO
The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Brønsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.
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Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent stereogenic centers using the combination of N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.
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A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
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A nickel(0)-catalyzed method for the synthesis of quinazolinediones from isatoic anhydrides and isocyanates is described. High-throughput ligand screening revealed that XANTPHOS was the optimal ligand for this transformation. Subsequent optimization studies, supported by kinetic analysis, significantly expanded the reaction scope. The reaction exhibits a case of substrate inhibition kinetics with respect to the isocyanate. Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.