RESUMEN
Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative1-4 or linear processes5-9, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide10, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon-nitrogen cross-couplings11 in a photochemical module-all without instrument reconfiguration.
Asunto(s)
Técnicas de Química Sintética/instrumentación , Técnicas de Química Sintética/métodos , Triazoles/síntesis química , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Automatización/instrumentación , Automatización/métodos , Carbono/química , Indicadores y Reactivos/química , Nitrógeno/química , Oxidación-Reducción , Procesos Fotoquímicos , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Programas Informáticos , Soluciones/química , Triazoles/químicaRESUMEN
BACKGROUND: Traditional medicines based on herbal extracts have been proposed as affordable treatments for patients suffering from coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Teas and drinks containing extracts of Artemisia annua and Artemisia afra have been widely used in Africa in efforts to prevent SARS-CoV-2 infection and fight COVID-19. METHODS: The plant extracts and Covid-Organics drink produced in Madagascar were tested for plaque reduction using both feline coronavirus and SARS-CoV-2 in vitro. Their cytotoxicities were also investigated. RESULTS: Several extracts as well as Covid-Organics inhibited SARS-CoV-2 and FCoV infection at concentrations that did not affect cell viability. CONCLUSIONS: Some plant extracts show inhibitory activity against FCoV and SARS-CoV-2. However, it remains unclear whether peak plasma concentrations in humans can reach levels needed to inhibit viral infection following consumption of teas or Covid-Organics. Clinical studies are required to evaluate the utility of these drinks for COVID-19 prevention or treatment of patients.
Asunto(s)
Antivirales/farmacología , Artemisia/química , Extractos Vegetales/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Coronavirus Felino/efectos de los fármacos , Coronavirus Felino/crecimiento & desarrollo , Extractos Vegetales/química , SARS-CoV-2/crecimiento & desarrollo , Ensayo de Placa ViralRESUMEN
Flow chemistry is a widely explored technology whose intrinsic features both facilitate and provide reproducible access to a broad range of chemical processes that are otherwise inefficient or problematic. At its core, a flow chemistry module is a stable set of conditions - traditionally thought of as an externally applied means of activation/control (e.g. heat or light) - through which reagents are passed. In an attempt to simplify the teaching and dissemination of this field, we envisioned that the key advantages of the technique, such as reproducibility and the correlation between reaction time and position within the reactor, allow for the redefinition of a flow module to a more synthetically relevant one based on the overall induced effect. We suggest a rethinking of the approach to flow modules, distributing them in two subclasses: transformers and generators, which can be described respectively as a set of conditions for either performing a specific transformation or for generating a reactive intermediate. The chemistry achieved by transformers and generators is (ideally) independent of the substrate introduced, meaning that they must be robust to small adjustments necessary for the adaptation to different starting materials and reagents while ensuring the same chemical outcome. These redefined modules can be used for single-step reactions or in multistep processes, where modules can be connected to each other in reconfigurable combinations to create chemical assembly systems (CAS) targeting compounds and libraries sharing structural cores. With this tutorial review, we provide a guide to the overall approach to flow chemistry, discussing the key parameters for the design of transformers and generators as well as the development of chemical assembly systems.
RESUMEN
It has been reported that fragments produced by glycosidic bond breakage in mass spectrometry-based experiments can retain a memory of their anomeric configuration, which has major implications for glycan sequencing. Herein, we use cryogenic vibrational spectroscopy and ion mobility-mass spectrometry to study the structure of B-type fragments of protected galactosides. Cationic fragments were generated from glycosyl donors carrying trichloroacetimidate or thioethyl leaving groups of different anomeric configuration. The obtained infrared signatures indicate that the investigated fragments exhibit an identical structure, which suggests that there is no anomeric memory in B-type ions of fully protected monosaccharides.
RESUMEN
The stereoselective formation of 1,2-cis-glycosidic bonds is challenging. However, 1,2-cis-selectivity can be induced by remote participation of C4 or C6 ester groups. Reactions involving remote participation are believed to proceed via a key ionic intermediate, the glycosyl cation. Although mechanistic pathways were postulated many years ago, the structure of the reaction intermediates remained elusive owing to their short-lived nature. Herein, we unravel the structure of glycosyl cations involved in remote participation reactions via cryogenic vibrational spectroscopy and first principles theory. Acetyl groups at C4 ensure α-selective galactosylations by forming a covalent bond to the anomeric carbon in dioxolenium-type ions. Unexpectedly, also benzyl ether protecting groups can engage in remote participation and promote the stereoselective formation of 1,2-cis-glycosidic bonds.
RESUMEN
Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions. This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, "Should we do this in flow?" has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts.
RESUMEN
The sun is the most sustainable light source available on our planet, therefore the direct use of sunlight for photochemistry is extremely appealing. Demonstrated here, for the first time, is that a diverse set of photon-driven transformations can be efficiently powered by solar irradiation with the use of solvent-resistant and cheap luminescent solar concentrator based photomicroreactors. Blue, green, and red reactors can accommodate both homogeneous and multiphase reaction conditions, including photochemical oxidations, photocatalytic trifluoromethylation chemistry, and metallaphotoredox transformations, thus spanning applications over the entire visible-light spectrum. To further illustrate the efficacy of these novel solar reactors, medicinally relevant molecules, such as ascaridole and an intermediate of artemisinin, were prepared as well.
RESUMEN
Reliable glycosylation reactions that allow for the stereo- and regioselective installation of glycosidic linkages are paramount to the chemical synthesis of glycan chains. The stereoselectivity of glycosylations is exceedingly difficult to control due to the reaction's high degree of sensitivity and its shifting, simultaneous mechanistic pathways that are controlled by variables of unknown degree of influence, dominance, or interdependency. An automated platform was devised to quickly, reproducibly, and systematically screen glycosylations and thereby address this fundamental problem. Thirteen variables were investigated in as isolated a manner as possible, to identify and quantify inherent preferences of electrophilic glycosylating agents (glycosyl donors) and nucleophiles (glycosyl acceptors). Ways to enhance, suppress, or even override these preferences using judicious environmental conditions were discovered. Glycosylations involving two specific partners can be tuned to produce either 11:1 selectivity of one stereoisomer or 9:1 of the other by merely changing the reaction conditions.
RESUMEN
Solid reagents, leaching catalysts, and heterogeneous photocatalysts are commonly employed in batch processes but are ill-suited for continuous-flow chemistry. Heterogeneous catalysts for thermal reactions are typically used in packed-bed reactors, which cannot be penetrated by light and thus are not suitable for photocatalytic reactions involving solids. We demonstrate that serial micro-batch reactors (SMBRs) allow for the continuous utilization of solid materials together with liquids and gases in flow. This technology was utilized to develop selective and efficient fluorination reactions using a modified graphitic carbon nitride heterogeneous catalyst instead of costly homogeneous metal polypyridyl complexes. The merger of this inexpensive, recyclable catalyst and the SMBR approach enables sustainable and scalable photocatalysis.
RESUMEN
Active pharmaceutical ingredients are either extracted from biological sources-where they are synthesized in complex, dynamic environments-or prepared in stepwise chemical syntheses by reacting pure reagents and catalysts under controlled conditions. A combination of these two approaches, where plant extracts containing reagents and catalysts are utilized in intensified chemical syntheses, creates expedient and sustainable processes. We illustrate this principle by reacting crude plant extract, oxygen, acid, and light to produce artemisinin, a key active pharmaceutical ingredient of the most powerful antimalarial drugs. The traditionally discarded extract of Artemisia annua plants contains dihydroartemisinic acid-the final biosynthetic precursor-as well as chlorophyll, which acts as a photosensitizer. Efficient irradiation with visible light in a continuous-flow setup produces artemisinin in high yield, and the artificial biosynthetic process outperforms syntheses with pure reagents.
Asunto(s)
Antimaláricos/síntesis química , Artemisia annua/química , Artemisininas/síntesis química , Extractos Vegetales/química , Antimaláricos/química , Antimaláricos/metabolismo , Artemisininas/química , Artemisininas/metabolismo , Estructura MolecularRESUMEN
Hydantoins are an important class of heterocycles with applications in pharmacy, agriculture, and as intermediates in organic synthesis. Traditional synthetic procedures to access hydantoins are target oriented with multiple synthetic steps and often use reagents that are not commercially available or sustainable. Herein, an efficient process is described for accessing hydantoins starting from commercially available amines using consecutive gas-liquid transformations (oxygen, carbon dioxide). This semi-continuous process produced ten benzylic/aliphatic hydantoins in good overall yields (52-84 %).
RESUMEN
Reported is a safe, rapid method for the synthesis of α-nitro esters via the trapping of nitronium ions. The two-stage nitration and subsequent deacetylation of readily available 1,3-dicarbonyl compounds was achieved using a biphasic semicontinuous approach. α-Nitro esters and amides were obtained in good overall yields (53-84%). Some of the α-nitro-1,3-dicarbonyl intermediates exhibit enhanced reactivity and undergo an acid-catalyzed Nef-type reaction to α-oxo-carbonyls.
RESUMEN
Aerobic amine oxidation is an attractive and elegant process for the α functionalization of amines. However, there are still several mechanistic uncertainties, particularly the factors governing the regioselectivity of the oxidation of asymmetric secondary amines and the oxidation rates of mixed primary amines. Herein, it is reported that singlet-oxygen-mediated oxidation of 1° and 2° amines is sensitive to the strength of the α-C-H bond and steric factors. Estimation of the relative bond dissociation energy by natural bond order analysis or by means of one-bond C-H coupling constants allowed the regioselectivity of secondary amine oxidations to be explained and predicted. In addition, the findings were utilized to synthesize highly regioselective substrates and perform selective amine cross-couplings to produce imines.
RESUMEN
While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels--choice of starting material, reagent, or order of reaction modules--enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, ß-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).
Asunto(s)
Preparaciones Farmacéuticas/síntesis químicaRESUMEN
Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45%. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed formation of an aryl isocyanate and a subsequent intramolecular cyclization to install the carbamate core of Efavirenz in one step. The three-step method represents the shortest synthesis of this life-saving drug to date.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Benzoxazinas/síntesis química , Alquinos , Fármacos Anti-VIH/química , Benzoxazinas/química , Carbamatos/química , Catálisis , Cobre/química , Ciclización , Ciclopropanos , Isocianatos/químicaRESUMEN
Due to the narrow width of tubing/reactors used, photochemistry performed in micro- and mesoflow systems is significantly more efficient than when performed in batch due to the Beer-Lambert Law. Owing to the constant removal of product and facility of flow chemical scalability, the degree of degradation observed is generally decreased and the productivity of photochemical processes is increased. In this Personal Account, we describe a wide range of photochemical transformations we have examined using both visible and UV light, covering cyclizations, intermolecular couplings, radical polymerizations, as well as singlet oxygen oxygenations.
Asunto(s)
Luz , Fotoquímica/métodos , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/química , Alquenos/química , Artemisininas/química , Catálisis , Ciclización , Compuestos Organometálicos/química , Oxidación-Reducción , Fotoquímica/instrumentación , Polimerizacion , Polímeros/química , Oxígeno Singlete/químicaRESUMEN
Primary and secondary amines can be rapidly and quantitatively oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temperature continuous-flow LED-photoreactor with a catalytic amount of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an inâ situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addition and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50 °C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.
Asunto(s)
Aminas/química , Cianuros/química , Iminas/química , Nitrilos/síntesis química , Oxígeno Singlete/química , Estructura Molecular , Nitrilos/química , Oxidación-Reducción , Fotoquímica , Porfirinas/químicaRESUMEN
The development of cell printing is vital for establishing biofabrication approaches as clinically relevant tools. Achieving this requires bio-inks which must not only be easily printable, but also allow controllable and reproducible printing of cells. This review outlines the general principles and current progress and compares the advantages and challenges for the most widely used biofabrication techniques for printing cells: extrusion, laser, microvalve, inkjet and tissue fragment printing. It is expected that significant advances in cell printing will result from synergistic combinations of these techniques and lead to optimised resolution, throughput and the overall complexity of printed constructs.
Asunto(s)
Células , Impresión , Rayos Láser , Ingeniería de Tejidos/métodosRESUMEN
The transition states (TSs) of 5-endo-dig and 5-endo-trig anionic ring closures are the first unambiguous examples of nonpericyclic reactions with TSs stabilized by aromaticity. Their five-center, six-electron in-plane aromaticity is revealed by the diatropic dissected nucleus-independent chemical shifts, -24.1 and -13.7 ppm, respectively, resulting from the delocalization of the lone pair at the nucleophilic center, a σ CC bond, and an in-plane alkyne (or alkene) π bond. Other seemingly analogous exo and endo cyclization TSs do not have these features. A symmetry-enhanced combination of through-space and through-bond interactions explains the anomalous geometric, energetic, and electronic features of the 5-endo ring closure transition state. Anionic 5-endo cyclizations can be considered to be "aborted" [2,3]-sigmatropic shifts. The connection between anionic cyclizations and sigmatropic shifts offers new possibilities for the design and electronic control of anionic isomerizations.
RESUMEN
The on-demand printing of living cells using inkjet technologies has recently been demonstrated and allows for the controlled deposition of cells in microarrays. Here, we show that such arrays can be interrogated directly by robot-controlled liquid microextraction coupled with chip-based nanoelectospray mass spectrometry. Such automated analyses generate a profile of abundant membrane lipids that are characteristic of cell type. Significantly, the spatial control in both deposition and extraction steps combined with the sensitivity of the mass spectrometric detection allows for robust molecular profiling of individual cells.