Heterocyclic rings are important structural scaffolds encountered in both natural and synthetic compounds, and their biological activity often depends on these motifs. They are predominantly accessible via cycloaddition reactions, realized by either thermal, photochemical, or catalytic means. Various starting materials are utilized for this purpose, and, among them, diazo compounds are often encountered, especially vinyldiazo compounds that give access to donor-acceptor cyclopropenes which engage in [2+n] cycloaddition reactions. Herein, we describe the development of photochemical processes that produce diverse heterocyclic scaffolds from multisubstituted oximidovinyldiazo compounds. High chemoselectivity, good functional group tolerance, and excellent scalability characterize this methodology, thus predisposing it for broader applications. Experimental and computational studies reveal that under light irradiation these diazo reagents selectively transform into cyclopropenes which engage in cycloaddition reactions with various dipoles, while under thermal conditions the formation of pyrazole from vinyldiazo compounds is favored.
While in nature, reactions occur in water-based confined compartments, for a long time, water has been often regarded as an unsuitable medium for organic reactions. We have, however, found that photochemical cyclopropanation of styrenes with diazo compounds or their precursors can be performed in micellar systems. COSMO-RS studies revealed that the reactivity correlates with the predicted critical micelle concentration (CMC), with higher CMC values delivering higher yields.
Herein we describe a sustainable and efficient photocatalytic method for the stereoselective radical alkylation of chiral sulfinyl imines. By employing readily available non-prefunctionalized radical precursors and the cost-effective TBADT as a direct HAT photocatalyst, we successfully obtain diverse chiral amines with high yields and excellent diastereoselectivity under mild conditions. This method provides an efficient approach for accessing a diverse array of medicinally relevant compounds, including both natural and synthetic α-amino acids, aryl ethyl amines, and other structural motifs commonly found in approved pharmaceuticals and natural product.
Structurally diversified diazoalkanes can be activated under red light irradiation relying on direct photolysis, photosensitization or photoredox catalysis.
A versatile Co-catalyst-vitamin B12 (cobalamin)-can be photochemically reduced to its catalytically active Co(I) form under visible light irradiation, in the presence of MIL-125-NH2(Ti) as a photocatalyst and utilized for the generation of alkyl radicals. The prior reduction of cobalamin to the Co(II) form is not required in this method.
Diazo compounds with redox-active leaving groups are versatile reagents for orthogonal functionalizations, previously utilized in the Rh-catalyzed synthesis of highly substituted cyclopropanes. Photochemical activation of aryl-substituted diazoacetates generates carbenes, whereas redox-active esters can furnish C-radicals via the photoexcitation of EDA complexes. However, the photochemical behavior of these two functionalities, while present in one molecule, remains to be defined. We demonstrate that under light irradiation, reactions occur only on the diazo moiety, leaving the NHPI functionality intact. Not only aryl- but also alkyl-substituted NHPI diazoacetates are activated by blue light; either C-H insertion or the hydrogen/carbon 1,2-rearrangement occurs depending on the aryl/alkyl group.
RNA-targeting small-molecule therapeutics is an emerging field hindered by an incomplete understanding of the basic principles governing RNA-ligand interactions. One way to advance our knowledge in this area is to study model systems where these interactions are better understood, such as riboswitches. Riboswitches bind a wide array of small molecules with high affinity and selectivity, providing a wealth of information on how RNA recognizes ligands through diverse structures. The cobalamin-sensing riboswitch is a particularly useful model system, as similar sequences show highly specialized binding preferences for different biological forms of cobalamin. This riboswitch is also widely dispersed across bacteria and therefore holds strong potential as an antibiotic target. Many synthetic cobalamin forms have been developed for various purposes including therapeutics, but their interaction with cobalamin riboswitches is yet to be explored. In this study, we characterize the interactions of 11 cobalamin derivatives with three representative cobalamin riboswitches using in vitro binding experiments (both chemical footprinting and a fluorescence-based assay) and a cell-based reporter assay. The derivatives show productive interactions with two of the three riboswitches, demonstrating simultaneous plasticity and selectivity within these RNAs. The observed plasticity is partially achieved through a novel structural rearrangement within the ligand binding pocket, providing insight into how similar RNA structures can be targeted. As the derivatives also show in vivo functionality, they serve as several potential lead compounds for further drug development.
Biochemical Phenomena , Riboswitch , Vitamin B 12/metabolism , Ligands , RNA , Nucleic Acid Conformation
The C-H functionalization of indole heterocycles constitutes a key strategy to leverage the synthesis of endogenous signaling molecules such as tryptamine or tryptophol. Herein, we report on the photocatalytic reaction of ethyl diazoacetate with indole, which shows an unusual solvent dependency. While C2-functionalization occurs under protic conditions, the use of aprotic solvents leads to a complete reversal of selectivity and exclusive C3-functionalization occurs. To rationalize for this unexpected reactivity switch, we have conducted detailed theoretical and experimental studies, which suggest the participation of a triplet carbene intermediate that undergoes initial C2-functionalization. A distinct cationic [1,2]-alkyl radical migration then leads to formation of C3-functionalized indole. We conclude with the application of this photocatalytic reaction to access oxidized tryptophol derivatives including gram-scale synthesis and derivatization reactions.
Despite the broad interest in organic compounds possessing a γ-aminocarbonyl motif, limited strategies for their synthesis have been reported. Herein, we describe a mild and efficient method for the site-selective amidation of unsaturated enones with electrophilic N-centered radicals as a key intermediate. The photocatalytic vinylogous reaction of dienolates with N-amino pyridinium salts affords γ-amido carbonyl compounds. This process is high-yielding, scalable, and tolerates a broad range of unsaturated α,ß-unsaturated carbonyls, including biologically relevant compounds, as starting materials.
Pyridine N-oxides have only recently marked their presence in the photocatalysis field, mainly serving as oxypyridinium salt precursors. Herein, their unique reactivity as a hydrogen atom transfer reagent in photochemical, Minisci-type alkylation of electron-deficient heteroarenes is unveiled. The formation of an EDA complex between a heterocyclic substrate and N-oxide precludes the need for a photocatalyst. The developed method allows for a broad range of radical precursors to be used, namely alkanes, alkenes, amides, and ethers, for efficient alkylation of azines.
The intracellular microsporidian parasite Nosema ceranae is known to compromise bee health by induction of energetic stress and downregulation of the immune system. Porphyrins are candidate therapeutic agents for controlling Nosema infection without adverse effects on honeybees. In the present work, the impact of two protoporphyrin IX derivatives, i.e. PP[Asp]2 and PP[Lys]2, on Apis mellifera humoral immune response has been investigated in laboratory conditions in non-infected and N. ceranae-infected honeybees. Fluorescence spectroscopy analysis of hemolymph showed for the first time that porphyrin molecules penetrate into the hemocoel of honeybees. Phenoloxidase (PO) activity and the expression of genes encoding antimicrobial peptides (AMPs: abaecin, defensin, and hymenoptaecin) were assessed. Porphyrins significantly increased the phenoloxidase activity in healthy honeybees but did not increase the expression of AMP genes. Compared with the control bees, the hemolymph of non-infected bees treated with porphyrins had an 11.3- and 6.1-fold higher level of PO activity after the 24- and 48-h porphyrin administration, respectively. Notably, there was a significant inverse correlation between the PO activity and the AMP gene expression level (r = - 0.61696, p = 0.0143). The PO activity profile in the infected bees was completely opposite to that in the healthy bees (r = - 0.5118, p = 0.000), which was related to the changing load of N. ceranae spores in the porphyrin treated-bees. On day 12 post-infection, the spore loads in the infected porphyrin-fed individuals significantly decreased by 74%, compared with the control bees. Our findings show involvement of the honeybee immune system in the porphyrin-based control of Nosema infection. This allows the infected bees to improve their lifespan considerably by choosing an optimal PO activity/AMP expression variant to cope with the varying level of N. ceranae infection.
Nosema , Protoporphyrins , Animals , Amides/pharmacology , Bees , Immunity , Monophenol Monooxygenase , Nosema/physiology , Protoporphyrins/pharmacology
Oxetanes are valuable building blocks due to their well-explored propensity to undergo ring-opening reactions with nucleophiles. However, their application as precursors of radical species is still elusive. Herein, we present a bioinspired cobalt-catalysis-based strategy to access unprecedented modes of radical reactivity via oxetane ring-opening. This powerful approach gives access to nucleophilic radicals that engage in reactions with SOMOphiles and low-valent transition metals. Importantly, the regioselectivity of these processes complements known methodologies.
Cobalt , Catalysis
Red-light enables deeper material penetration, which is important for biological applications and has consequences for chemical synthesis. Therefore, the search for new photocatalysts that absorb in this region is crucial. Despite the undeniable utility of porphyrins in blue- and green-light-induced energy- and electron-transfer processes, they are also perfectly suited for red-light applications. Herein, we describe free-base porphyrins as photoredox catalysts for red-light-induced organic transformations. They can act as both photooxidants and photoreductants and can accomplish the synthesis of biaryls once merged with Pd-catalysis. The developed methodology holds promise for broader applications, as the heme-based protoporphyrin is used as a photocatalyst and reactions can be realized in aqueous conditions.
Reactivity of donor-acceptor cyclopropanes towards nucleophiles and electrophiles is determined by the specific philicity of the carbon atoms originating from the strong polarization of the central C-C bond. Herein, we report that vitamin B12 catalysis enables the transformation of an initially electrophilic center into a nucleophilic radical that reacts with SOMOphiles. This radical-based strategy reverses the standard regioselectivity and thus complements the classical approaches.
Vinyl azides are very reactive species and as such are useful building blocks, in particular, in the synthesis of N-heterocycles. They can also serve as precursors of ketones. These form in reactions of vinyl azides with nucleophiles or radicals. We have found, however, that under light irradiation vitamin B12 catalyzes the reaction of vinyl azides with electrophiles to afford unsymmetrical carbonyl compounds in decent yields. Mechanistic studies revealed that alkyl radicals are key intermediates in this transformation.
Ketones
Vitamin B12 (cobalamin, Cbl) is an essential nutrient for all mammals and some bacteria. From a chemical point of view, it is a highly functionalized molecule, which enables conjugation at multiple positions and attachment of various cargoes. Both mammalian and bacterial cells have developed a specific transport pathway for the uptake of vitamin B12, and as a consequence, cobalamin is an attractive candidate for the delivery of biologically relevant molecules into cells. Indeed, hybrid molecules containing vitamin B12 in their structure have found various applications in medicinal chemistry, diagnostics, and biological sciences.Herein, we describe synthetic strategies toward the synthesis of vitamin B12 conjugates with peptide nucleic acid (PNA ) oligomers. Such short-modified oligonucleotides targeted at bacterial DNA or RNA can act as antibacterial agents if efficiently taken up by bacterial cells. The uptake of such oligonucleotides is hindered by the bacterial cell envelope, but vitamin B12 was found to efficiently deliver antisense PNA into Escherichia coli and Salmonella Typhimurium cells. This paves the way to the use of vitamin B12-PNA conjugates in antibacterial and diagnostic applications.Vitamin B12-PNA conjugates can be prepared via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) that gives access to covalently linked hybrids or via connecting both building blocks by reduction-sensitive disulfide bridge. Both approaches require prior modification of vitamin B12 by incorporation of the azide moiety or via transformation of the native functional group into a moiety reactive toward thiols. Conjugation of vitamin B12 with PNA-tagged substrates efficiently furnishes designed conjugates.
Peptide Nucleic Acids/metabolism , Anti-Bacterial Agents , Azides , Bacteria , Escherichia coli/genetics , Vitamin B 12 , Vitamins
Resonance Raman optical activity (RROA) possesses all aspects of a sensitive tool for molecular detection, but its measurement remains challenging. We demonstrate that reliable recording of RROA of chiral colorful compounds is possible, but only after considering the effect of the electronic circular dichroism (ECD) on the ROA spectra induced by the dissolved chiral compound. We show RROA for a number of model vitamin B12 derivatives that are chemically similar but exhibit distinctively different spectroscopic behavior. The ECD/ROA effect is proportional to the concentration and dependent on the optical pathlength of the light propagating through the sample. It can severely alter relative band intensities and signs in the natural RROA spectra. The spectra analyses are supported by computational modeling based on density functional theory. Neglecting the ECD effect during ROA measurement can lead to misinterpretation of the recorded spectra and erroneous conclusions about the molecular structure.
Ring-opening of epoxides furnishing either linear or branched products belongs to the group of classic transformations in organic synthesis. However, the regioselective cross-electrophile coupling of aryl epoxides with aryl halides still represents a key challenge. Herein, we report that the vitamin B12/Ni dual-catalytic system allows for the selective synthesis of linear products under blue-light irradiation, thus complementing methodologies that give access to branched alcohols. Experimental and theoretical studies corroborate the proposed mechanism involving alkylcobalamin as an intermediate in this reaction.
