RESUMO
The synthesis of isotopically labeled organic molecules is vital for drug and agrochemical discovery and development. Carbon isotope exchange is emerging as a leading method to generate carbon-labeled targets, which are sought over hydrogen-based labels due to their enhanced stability in biological systems. While many bioactive small molecules bear carbon-containing stereocenters, direct enantioselective carbon isotope exchange reactions have not been established. We describe the first example of an enantioselective carbon isotope exchange reaction, where (radio)labeled α-amino acids can be generated from their unlabeled precursors using a stoichiometric chiral aldehyde receptor with isotopically labeled CO2 followed by imine hydrolysis. Many proteinogenic and non-natural derivatives undergo enantioselective labeling, including the late-stage radiolabeling of complex drug targets.
RESUMO
The synthesis of a water-soluble, phosphine-pegylated iridium(I) catalyst and its application in hydrogen isotope exchange (HIE) reactions in buffer is reported. The longer polyethylene glycol side chains on the phosphine increased the water solubility independently from the pH. HIE reactions of polar substrates in protic solvents were studied. DFT calculations gave further insights into the catalytic processes. The scope and limitation of the pegylated catalyst was studied in HIE reactions of several complex compounds in borax buffer at pHâ 9 and the best conditions were applied in a tritium experiment with the drug telmisartan.
RESUMO
We have studied the photoredox-catalyzed hydrogen isotope exchange (HIE) reaction with deuterium or tritium gas as isotope sources and in situ formed transition metal nanoparticles as hydrogen atom transfer pre-catalysts. By this means we have found synergistic reactivities applying two different HIE mechanisms, namely photoredox-catalyzed and CH-functionalization HIE leading to the synthesis of highly deuterated complex molecules. Finally, we adopted these findings successfully to tritium chemistry.
RESUMO
We have studied the highly selective homogeneous iridium-catalyzed hydrogen isotope exchange (HIE) with deuterium or tritium gas as an isotope source in water and buffers. With an improved water-soluble Kerr-type catalyst, we have achieved the first insight into applying HIE reactions in aqueous media with varying pH. Density functional theory (DFT) calculations gave consistent insights in the calculated energies of transition states and coordination complexes, further explaining the observed reactivity and guidance on the scope and limitations for HIE reactions in water. Finally, we successfully adapted these findings to tritium chemistry.
RESUMO
Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatecholâ A, which is reported to have antiviral activity, particularly against influenzaâ A virus (H1N1). Through a straightforward, one-pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2-methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.
Assuntos
Antivirais/química , Antivirais/síntese química , Policetídeos , Antivirais/farmacologia , HIV/efeitos dos fármacos , Alphainfluenzavirus/efeitos dos fármacos , Estrutura Molecular , Policetídeos/síntese química , Policetídeos/químicaRESUMO
The sorbicillinoids are a large family of fungal natural products, many of which possess highly challenging molecular architectures. Depending on their individual structures they exhibit strong biological activities ranging from radical scavenging and anti-infective properties to cytotoxicity. Despite the resulting strong biomedical potential of these natural products and the interest of synthetic chemists owing to their fascinating structures, many sorbicillinoids are currently not synthetically accessible, thus hampering in-depth biological characterization and structural diversification. By using recombinant oxidoreductase SorbC and readily accessible sorbicillin-type synthetic precursors, we have developed enantioselective, one-pot chemo-enzymatic routes to a broad range of sorbicillinoids, thereby establishing total syntheses of oxosorbicillinol, sorrentanone, rezishanonesâ B and C, sorbicatecholâ A, bisvertinolone, and (+)-epoxysorbicillinol.
Assuntos
Cicloexanonas/química , Compostos de Epóxi/química , Policetídeos/química , Benzoquinonas/química , Estrutura MolecularRESUMO
Natural products are a virtually inexhaustible source of small molecules with spectacular molecular architectures and biomedical potential. Their structural complexity generates formidable challenges to total synthesis but often also precludes time- and resource-efficient, stereoselective synthetic access. Biosynthetically, nature frequently uses dimerization and oligomerization reactions to produce highly challenging frameworks from simple starting materials. Impressive examples are the bisorbicillinoids, a family of fungal natural products thought to originate from the polyketide precursor sorbicillin. Utilizing the recombinant oxidoreductase SorbC from the sorbicillin biosynthetic gene cluster, a robust, fully stereoselective synthesis of bisorbicillinoid natural products and unnatural side-chain analogues was developed.
Assuntos
Produtos Biológicos/metabolismo , Resorcinóis/metabolismo , Biocatálise , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Dimerização , Fungos/metabolismo , Oxirredução , Oxirredutases/genética , Oxirredutases/metabolismo , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Resorcinóis/química , EstereoisomerismoRESUMO
Isotopically carbon-labeled α-amino acids are valuable synthetic targets that are increasingly needed in pharmacology and medical imaging. Existing preparations rely on early stage introduction of the isotopic label, which leads to prohibitive synthetic costs and time-intensive preparations. Here we describe a protocol for the preparation of C1-labeled α-amino acids using simple aldehyde catalysts in conjunction with [*C]CO2 (* = 14, 13, 11). This late-stage labeling strategy is enabled by the one-pot carboxylate exchange of unprotected α-amino acids with [*C]CO2. The protocol consists of three separate procedures, describing the syntheses of (±)-[1-13C]phenylalanine, (±)-[1-11C]phenylalanine and (±)-[1-14C]phenylalanine from unlabeled phenylalanine. Although the delivery of [*C]CO2 is operationally distinct for each experiment, each procedure relies on the same fundamental chemistry and can be executed by heating the reaction components at 50-90 °C under basic conditions in dimethylsulfoxide. Performed on scales of up to 0.5 mmol, this methodology is amenable to C1-labeling of many proteinogenic α-amino acids and nonnatural derivatives, which is a breakthrough from existing methods. The synthesis of (±)-[1-13C]phenylalanine requires ~2 d, with product typically obtained in a 60-80% isolated yield (n = 3, µ = 71, σ = 8.3) with an isotopic incorporation of 70-88% (n = 18, µ = 72, σ = 9.0). Starting from the preformed imino acid (~3 h preparation time), rapid synthesis of (±)-[1-11C]phenylalanine can be completed in ~1 h with an isolated radiochemical yield of 13%. Finally, (±)-[1-14C]phenylalanine can be accessed in ~2 d with a 51% isolated yield and 11% radiochemical yield.