TBADT-Mediated Photocatalytic Stereoselective Radical Alkylation of Chiral N-Sulfinyl Imines: Towards Efficient Synthesis of Diverse Chiral Amines.

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.

C-H Functionalization of Heterocycles with Triplet Carbenes by means of an Unexpected 1,2-Alkyl Radical Migration.

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.

Vitamin B12-peptide nucleic acids use the BtuB receptor to pass through the Escherichia coli outer membrane.

Short modified oligonucleotides that bind in a sequence-specific way to messenger RNA essential for bacterial growth could be useful to fight bacterial infections. One such promising oligonucleotide is peptide nucleic acid (PNA), a synthetic DNA analog with a peptide-like backbone. However, the limitation precluding the use of oligonucleotides, including PNA, is that bacteria do not import them from the environment. We have shown that vitamin B12, which most bacteria need to take up for growth, delivers PNAs to Escherichia coli cells when covalently linked with PNAs. Vitamin B12 enters E. coli via a TonB-dependent transport system and is recognized by the outer-membrane vitamin B12-specific BtuB receptor. We engineered the E. coli ΔbtuB mutant and found that transport of the vitamin B12-PNA conjugate requires BtuB. Thus, the conjugate follows the same route through the outer membrane as taken by free vitamin B12. From enhanced sampling all-atom molecular dynamics simulations, we determined the mechanism of conjugate permeation through BtuB. BtuB is a ß-barrel occluded by its luminal domain. The potential of mean force shows that conjugate passage is unidirectional and its movement into the BtuB ß-barrel is energetically favorable upon luminal domain unfolding. Inside BtuB, PNA extends making its permeation mechanically feasible. BtuB extracellular loops are actively involved in transport through an induced-fit mechanism. We prove that the vitamin B12 transport system can be hijacked to enable PNA delivery to E. coli cells.

Cobalt Catalyst Determines Regioselectivity in Ring Opening of Epoxides with Aryl Halides.

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.

Recognition of the True and False Resonance Raman Optical Activity.

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.

Polarity-Reversal Strategy for the Functionalization of Electrophilic Strained Molecules via Light-Driven Cobalt Catalysis.

Strain-release-driven methodology is a powerful tool for accessing structural motifs, highly desirable by the pharmaceutical industry. The reactivity of spring-loaded cyclic reagents is dominated by transformations relying on their inherent electrophilic reactivity. Herein, we present a polarity-reversal strategy based on light-driven cobalt catalysis, which enables the generation of nucleophilic radicals through strain release. The applicability of this methodology is demonstrated by the design of two distinct types of reactions: Giese-type addition and Co/Ni-catalyzed cross-coupling. Moreover, a series of electrochemical, spectroscopic, and kinetic experiments as well as X-ray structural analysis of the intermediate alkylcobalt(III) complex give deeper insight into the mechanism of the reaction.

A multicolor riboswitch-based platform for imaging of RNA in live mammalian cells.

RNAs directly regulate a vast array of cellular processes, emphasizing the need for robust approaches to fluorescently label and track RNAs in living cells. Here, we develop an RNA imaging platform using the cobalamin riboswitch as an RNA tag and a series of probes containing cobalamin as a fluorescence quencher. This highly modular 'Riboglow' platform leverages different colored fluorescent dyes, linkers and riboswitch RNA tags to elicit fluorescence turn-on upon binding RNA. We demonstrate the ability of two different Riboglow probes to track mRNA and small noncoding RNA in live mammalian cells. A side-by-side comparison revealed that Riboglow outperformed the dye-binding aptamer Broccoli and performed on par with the gold standard RNA imaging system, the MS2-fluorescent protein system, while featuring a much smaller RNA tag. Together, the versatility of the Riboglow platform and ability to track diverse RNAs suggest broad applicability for a variety of imaging approaches.

Rhodols - synthesis, photophysical properties and applications as fluorescent probes.

The formal replacement of one dialkylamino group in rhodamines with a hydroxyl group transforms them into rhodols. This apparently minor difference is not as small as one may think; rhodamines belong to the cyanine family whereas rhodols belong to merocyanines. Discovered in the late 19th century, rhodols have only very recently begun to gain momentum in the field of advanced fluorescence imaging. This is in part due to the increased understanding of their photophysical properties, and new methods of synthesis. Rationalization of how the nature and arrangement of polar substituents around the core affect the photophysical properties of rhodols is now possible. The emergence of so-called π-expanded and heteroatom-modified rhodols has also allowed their fluorescence to be bathochromically shifted into regions applicable for biological imaging. This review serves to outline applicable synthetic strategies for the synthesis of rhodols, and to highlight important structure-property relationships. In the first part of this Review, various synthetic methods leading to rhodols are presented, followed by structural considerations and an overview of photophysical properties. The second part of this review is entirely devoted to the applications of rhodols as fluorescent reporters in biological imaging.

Resonance Raman Optical Activity Spectroscopy in Probing Structural Changes Invisible to Circular Dichroism Spectroscopy: A Study on Truncated Vitamin B12 Derivatives.

This work demonstrates resonance Raman optical activity (RROA) spectra of three truncated vitamin B12 derivatives modified within the nucleotide loop. Since truncated cobalamins possess sufficiently high rotational strength in the range of ROA excitation (532 nm), it was possible to record their spectra in the resonance condition. They showed several distinct spectral features allowing for the distinguishing of studied compounds, in contrast to other methods, i.e., UV-Vis absorption, electronic circular dichroism, and resonance Raman spectroscopy. The improved capacity of the RROA method is based here on the excitation of molecules via more than two electronic states, giving rise to the bisignate RROA spectrum, significantly distinct from a parent Raman spectrum. This observation is an important step in the dissemination of using RROA spectroscopy in studying the complex structure of corrinoids which may prove crucial for a better understanding of their biological role.

Visible-Light-Mediated Amination of π-Nucleophiles with N-Aminopyridinium Salts.

N-Aminopyridinium salts generate nitrogen-centered radicals by means of photoredox catalysis. Herein, we report that they can be trapped by enol equivalents to give α-amino carbonyl compounds in excellent yields. The broad synthetic utility of this method is demonstrated by functionalization of ketones, aldehydes, esters enol equivalents, vinyl ethers, and 1,3-diketones without the need for prior conversion to enol derivatives. The developed method is easily scalable, offers broad substrate scope, high chemoselectivity.

Recent developments in photochemical reactions of diazo compounds.

Diazo compounds are among the most important building blocks in organic synthesis. Generally, their photoinitiated, thermal, or transition metal catalyzed decomposition yields the corresponding carbenes or metal carbenoids, which subsequently undergo various transformations. Modern chemistry of diazo compounds is dominated by transition metal catalysis, leaving both catalyzed and non-catalyzed phototransformations of these reagents behind. Recently, photoinitiated reactions of diazo compounds have experienced a revival of interest due to the increased understanding of modern photochemistry. This mini-review covers recently published (year >2000) reports on the reactivity of diazo compounds under light irradiation.

Synthesis of Corroles and Their Heteroanalogs.

Corroles have come a long way from being a curiosity to being a mainstream research topic. They are now regularly synthesized in numerous research laboratories worldwide with diverse specific aims in mind. In this review we present a comprehensive description of corroles' synthesis, developed both before and after 1999. To aid the investigator in developing synthetic strategies, some of the sections culminate in tables containing comparisons of various methodologies leading to meso-substituted corroles. The remaining challenges are delineated. In the second part of this review, we also describe the syntheses of isocorroles and heteroanalogs of corroles such as triazacorroles (corrolazines), 10-heterocorroles, 21-heterocorroles, 22-heterocorroles, N-confused corroles, as well as norcorroles. The review is complemented with a short outlook.

α-Photooxygenation of chiral aldehydes with singlet oxygen.

Organocatalytic α-oxygenation of chiral aldehydes with photochemically generated singlet oxygen allows synthesizing chiral 3-substituted 1,2-diols. Stereochemical results indicate that the reaction in the presence of diarylprolinol silyl ethers is highly diastereoselective and that the configuration of a newly created stereocenter at the α-position depends predominantly on the catalyst structure. The absolute configuration of chiral 1,2-diols has been unambiguously established based on electronic circular dichroism (ECD) and TD-DFT methods.

The Tetraarylpyrrolo[3,2-b]pyrroles-From Serendipitous Discovery to Promising Heterocyclic Optoelectronic Materials.

Progress in organic optoelectronics requires compounds possessing a suitable combination of photophysical and electronic properties. Another key constraint encompasses the availability of feasible, and hopefully scalable, synthetic procedures for preparing the molecular scaffolds of interest. A multicomponent reaction of aromatic aldehydes, aromatic amines, and butane-2,3-dione that was discovered in 2013 gives straightforward access to previously unavailable 1,2,4,5-tetraarylpyrrolo[3,2-b]pyrroles. These dyes are examples of heteropentalenes-a class of 10-π-electron aromatic compounds. The unsurpassed variety of aromatic aldehydes and primary aromatic amines, which are commercially available or easy to prepare, allows for potential routes to thousands of 1,2,4,5-tetraarylpyrrolo[3,2-b]pyrroles that are currently unknown. This synthetic procedure offers a means for preparing the pyrrolopyroles in gram quantities and isolating them by simple filtration. Typically, the construction of an aromatic core is merely the first phase in a long procedure toward multistep functionalization. Conversely, the synthesis of 1,2,4,5-tetraarylpyrrolo[3,2-b]pyrroles leads to preinstalled substituents in frames with C2 symmetry, which "opens Sesame" to a wealth of structural possibilities. In addition, steric hindrance of the aldehyde components, rather than presenting a problem, is beneficial for increasing the yields of the products. This feature provides invaluable routes for the synthesis of a broad range of π-extended systems possessing the pyrrolo[3,2-b]pyrrole core in just a few steps. Indeed, this approach has enabled the preparation of a large number of previously unknown ladder-type heteroacenes possessing additional rings based on carbon-carbon, carbon-nitrogen, and nitrogen-nitrogen double bonds as well as nitrogen-boron single bonds. This set of chromophores includes planar and curved structures bearing up to 14 conjugated rings. 1,2,4,5-Tetraarylpyrrolo[3,2-b]pyrroles manifest broad absorption bands between about 300 and 450 nm, strong violet-blue or blue fluorescence with typical quantum yields of ∼60%, significant Stokes shifts ranging between 3000 and 5800 cm-1, and emission while in the solid state. Should the two peripheral aryl groups have an electron-deficient character, the two-photon absorption cross section also becomes pronounced, i.e., ∼400 GM. Perhaps the most important feature of these dyes is their strong solvatofluorochromism, which predestines their value as environment-sensitive probes. Extension of the π-conjugation of 1,2,4,5-tetraarylpyrrolo[3,2-b]pyrroles enables further modifications of their photophysical properties, such as shifting the emission bathochromically, increasing the Stokes shift beyond 10 000 cm-1, and attaining solvatofluorochromism for curved, butterfly-shaped analogues without a decrease in emission intensity when the solvent polarity is increased. Common features of these chromophores include a significant difference between the geometries of their relaxed ground and relaxed excited states as well as strong electronic coupling through their aromatic cores. Past and future intense exploration of the wide chemical space built around the pyrrolo[3,2-b]pyrrole skeleton offers unprecedented opportunities for comprehensive elucidation of how photoexcitation increases the electronic coupling through biaryl linkages.

meso-Modified Cobalamins: Synthesis, Structure, and Properties.

Vitamin B12 and its derivatives present excellent paradigms for bioinspired catalysis. The inherent challenges for derivatizing cobalamins, such as vitamin B12 , to incorporate them in supramolecular designs and materials, limit the range of their utility and applications. Herein, we present a synthetic approach toward derivatives of vitamin B12 possessing electron-donating and -withdrawing substituents at the meso position (C10). Spectroscopic and cyclic voltammetry studies reveal that changes in the substitution pattern on the equatorial ligand have a significant impact on the electronic and optical properties of the cobalamin. These synthetic methods, therefore, provide invaluable routes not only for covalent linking to other structures, but also for attaining a wide range of functionalities for the derivatives of vitamin B12 .

Does a Conjugation Site Affect Transport of Vitamin†B12 -Peptide Nucleic Acid Conjugates into Bacterial Cells?

Gram-negative bacteria develop specific systems for the uptake of scarce nutrients, including vitamin B12 . These uptake pathways may be utilized for the delivery of biologically relevant molecules into cells. Indeed, it was recently reported that vitamin B12 transported an antisense peptide nucleic acid (PNA) into Escherichia coli and Salmonella Typhimurium cells. The present studies indicate that the conjugation site of PNA to vitamin B12 has an impact on PNA transport into bacterial cells. Toward this end, a specifically designed PNA oligomer has been tethered at various positions of vitamin B12 (central Co, R5' -OH, c and e amide chains, meso position, and at the hydroxy group of cobinamide) by using known or newly developed methodologies and tested for the uptake of the synthesized conjugates by E. coli. Compounds in which the PNA oligonucleotide was anchored at the R5' -OH position were transported more efficiently than that of other compounds tethered at the peripheral positions around the corrin ring. Of importance is the fact that, contrary to mammalian organisms, E. coli also takes up cobinamide, which is an incomplete corrinoid. This selectivity opens up ways to fight bacterial infections.

Vitamin B12 Deficiency Induces Imbalance in Melanocytes Homeostasis-A Cellular Basis of Hypocobalaminemia Pigmentary Manifestations.

Vitamin B12 deficiency causes significant changes in cellular metabolism leading to various clinical symptoms, such as hematological, psychiatric, and neurological disorders. We hypothesize that skin pigmentation disorders may be a diagnostically important manifestation of vitamin B12 deficiency, however the cellular and molecular mechanisms underlying these effects remain unknown. The aim of this study was to examine the effect of vitamin B12 deficiency on melanocytes homeostasis. Hypocobalaminemia in vitro model was developed by treating epidermal melanocytes with synthesized vitamin B12 antagonist-hydroxycobalamin(c-lactam). The cells were examined using immunoenzymatic, spectrophotometric, and fluorimetric assays as well as image cytometry. Significant melanogenesis stimulation-the increase of relative melanin content and tyrosinase activity up to 131% and 135%, respectively-has been indicated. Cobalamin-deficient cells displayed the elevation (by 120%) in reactive oxygen species level. Moreover, the redox status imbalance was stated. The study provided a scientific evidence for melanocytes homeostasis disturbance under hypocobalaminemia, thus indicating a significant element of the hyperpigmentation mechanism due to vitamin B12 deficiency. Furthermore, the implication between pigmentary and hematological and/or neuropsychiatric symptoms in cobalamin-deficient patients may be an important issue.

Vitamin B12 Catalysis: Probing the Structure/Efficacy Relationship.

Vitamin B12 is a cofactor for many enzymes, but it also functions as a catalyst in C-C bond-forming reactions. Herein, the impact of corrin structural modifications on their catalytic efficacy was examined. Derivatives with various substituents at c-, d-, and meso-positions were synthesised by using traditional and new microwave methodologies, and then tested in the model reaction of 1,1-diphenylethylene with ethyl diazoacetate. To complement the experimental data, cyclic voltammetry and DFT calculations were performed. Mainly alterations at the c- or d-positions influence both the reaction yield and selectivity.

Porphyrins as Photoredox Catalysts: Experimental and Theoretical Studies.

Metalloporphyrins not only are vital in biological systems but also are valuable catalysts in organic synthesis. On the other hand, catalytic properties of free base porphyrins have been less explored. They are mostly known as efficient photosensitizers for the generation of singlet oxygen via photoinduced energy transfer processes, but under light irradiation, they can also participate in electron transfer processes. Indeed, we have found that free base tetraphenylporphyrin (H2TPP) is an efficient photoredox catalyst for the reaction of aldehydes with diazo compounds leading to α-alkylated derivatives. The performance of a porphyrin catalyst can be optimized by tailoring various substituents at the periphery of the macrocycle at both the ß and meso positions. This allows for the fine tuning of their optical and electrochemical properties and hence their catalytic activity.