Cobalamin Derivative Research Articles

Redox-Linked Coordination Chemistry Directs Vitamin B12 Trafficking.

Metals are partners for an estimated one-third of the proteome and vary in complexity from mononuclear centers to organometallic cofactors. Vitamin B12 or cobalamin represents the epitome of this complexity and is the product of an assembly line comprising some 30 enzymes. Unable to biosynthesize cobalamin, mammals rely on dietary provision of this essential cofactor, which is needed by just two enzymes, one each in the cytoplasm (methionine synthase) and the mitochondrion (methylmalonyl-CoA mutase). Brilliant clinical genetics studies on patients with inborn errors of cobalamin metabolism spanning several decades had identified at least seven genetic loci in addition to the two encoding B12 enzymes. While cells are known to house a cadre of chaperones dedicated to metal trafficking pathways that contain metal reactivity and confer targeting specificity, the seemingly supernumerary chaperones in the B12 pathway had raised obvious questions as to the rationale for their existence.With the discovery of the genes underlying cobalamin disorders, our laboratory has been at the forefront of ascribing functions to B12 chaperones and elucidating the intricate redox-linked coordination chemistry and protein-linked cofactor conformational dynamics that orchestrate the processing and translocation of cargo along the trafficking pathway. These studies have uncovered novel chemistry that exploits the innate chemical versatility of alkylcobalamins, i.e., the ability to form and dismantle the cobalt-carbon bond using homolytic or heterolytic chemistry. In addition, they have revealed the practical utility of the dimethylbenzimidazole tail, an appendage unique to cobalamins and absent in the structural cousins, porphyrin, chlorin, and corphin, as an instrument for facilitating cofactor transfer between active sites.In this Account, we navigate the chemistry of the B12 trafficking pathway from its point of entry into cells, through lysosomes, and into the cytoplasm, where incoming cobalamin derivatives with a diversity of upper ligands are denuded by the β-ligand transferase activity of CblC to the common cob(II)alamin intermediate. The broad reaction and lax substrate specificity of CblC also enables conversion of cyanocobalamin (technically, vitamin B12, i.e., the form of the cofactor in one-a-day supplements), to cob(II)alamin. CblD then hitches up with CblC via a unique Co-sulfur bond to cob(II)alamin at a bifurcation point, leading to the cytoplasmic methylcobalamin or mitochondrial 5'-deoxyadenosylcobalamin branch. Mutations at loci upstream of the junction point typically affect both branches, leading to homocystinuria and methylmalonic aciduria, whereas mutations in downstream loci lead to one or the other disease. Elucidation of the biochemical penalties associated with individual mutations is providing molecular insights into the clinical data and, in some instances, identifying which cobalamin derivative(s) might be therapeutically beneficial.Our studies on B12 trafficking are revealing strategies for cofactor sequestration and mobilization from low- to high-affinity and low- to high-coordination-number sites, which in turn are regulated by protein dynamics that constructs ergonomic cofactor binding pockets. While these B12 lessons might be broadly relevant to other metal trafficking pathways, much remains to be learned. This Account concludes by identifying some of the major gaps and challenges that are needed to complete our understanding of B12 trafficking.

Resonance Raman Optical Activity Shows Unusual Structural Sensitivity for Systems in Resonance with Multiple Excited States: Vitamin B12 Case.

In this work, cobalamins with different upper axial substituents and a cobalamin derivative with a ring modification were studied using chiroptical spectroscopies, in particular resonance Raman optical activity (RROA), to shed light on the influence of structural modifications on RROA spectra in these strongly chiral systems in resonance with multiple excited states at 532 nm excitation. We have demonstrated that for these unique systems RROA possesses augmented structural specificity, surpassing resonance Raman spectroscopy and enabling at the same time measurement of cobalamins at fairy low concentrations of ∼10–5 mol dm–3. The enhanced structural specificity of RROA is a result of bisignate spectra due to resonance via more than one electronic state. The observation of increased structural capability of RROA for cobalamins opens a new perspective for studying chiral properties of other biological systems incorporating d-metal ions.

Visible Light-Driven Cross Coupling Reactions Catalyzed By B12 Complex with Photosensitizer

Organometallic B12 compounds are unique metal complexes having a cobalt-carbon σ-bond present in biological systems [1]. Cleavage of the metal-organic σ-bond initiates many B12-dependent enzymatic reactions. The alkylated cobalt complex is generally formed by the reaction of the Co(I) state of the complex with electrophiles such as an organic halide in vivo. Therefore, the reductive formation of the Co(I) species followed by formal oxidative addition of the organic halide to form the alkylated cobalt complex are key steps for the development of the B12 catalyzed enzymatic reactions. Our group has been reported the photosensitizing formation of the Co(I) species of the B12 derivative, heptamethyl cobyrinate perchlorate, using various photosensitizers (PSs) such as, [Ru(bpy)3]Cl2 or cyclometalated iridium(III) complexes and performed various B12 model reactions such as 1,2-migration of functional groups, dechlorination and so on [2,3]. Here, a visible light driven Heck-type coupling reaction of alkyl halides with styrene and its derivatives catalyzed by the cobalamin derivative (B12) with the [Ru(bpy)3]Cl2 photosensitizer at room temperature is reported. The catalytic efficiencies of the B12 catalyst were compared to that of other cobalt complexes such as cobaloxime. Various control experiments supported a radical-based mechanism similar to those for typical B12 model reactions. An unique coupling reaction combined with 1,2-migration of the functional group is also reported. Mild reaction conditions using an environmentally benign cobalt catalyst derived from the natural B12 provided a practical protocol for the synthetic organic chemistry of the B12 catalyzed reaction system. [1] Reviews: a) H. Shimakoshi, Y. Hisaeda, Current Opinion in Electrochem. 2018, 8, 24; b) H. Shimakoshi, Y. Hisaeda, ChemPlusChem. 2017, 82, 17 (Back cover). [2] H. Tian, H. Shimakoshi, T. Ono, Y. Hisaeda, ChemPlusChem 2019, in press (Front cover). [3] H. Shimakoshi, Y. You, Y. Hisaeda et al, Dalton Trans. 2018, 47, 675 (Front cover).

Visible Light‐Driven, Room Temperature Heck‐Type Reaction of Alkyl Halides with Styrene Derivatives Catalyzed by B12 Complex

AbstractA visible light driven Heck‐type coupling reaction of alkyl halides with styrene and its derivatives catalyzed by the cobalamin derivative (B12) with the [Ru(bpy)3]Cl2 photosensitizer at room temperature is reported. The catalytic efficiencies of the B12 catalyst were compared to that of other cobalt complexes such as cobaloxime. Various control experiments supported a radical‐based mechanism similar to those for typical B12 model reactions. A unique coupling reaction combined with 1,2‐migration of the functional group is also reported. Mild reaction conditions using an environmentally benign cobalt catalyst derived from the natural B12 provided a practical protocol for the synthetic organic chemistry of the B12 catalyzed reaction system.magnified image

Visible light-driven cross-coupling reactions of alkyl halides with phenylacetylene derivatives for C(sp3)-C(sp) bond formation catalyzed by a B12 complex.

Visible light-driven cross-coupling reactions of alkyl halides with phenylacetylene and its derivatives catalyzed by the cobalamin derivative (B12) with the [Ir(dtbbpy)(ppy)2]PF6 photocatalyst at room temperature are reported. The robust B12 catalyst and Ir photocatalyst provided high turnover numbers of over 33 000 for the reactions.

Photocatalytic function of the B12 complex with the cyclometalated iridium(iii) complex as a photosensitizer under visible light irradiation.

A visible light induced three-component catalytic system with the cobalamin derivative (B12) as a catalyst, the cyclometalated iridium(iii) complex (Irdfppy, Irppy, Irpbt and [Ir{dF(CF3)ppy}2(dtbpy)]PF6) as a photosensitizer and triethanolamine as an electron source under N2 was developed. This catalytic system showed a much higher catalytic efficiency than the previous catalytic system using [Ru(ii)(bpy)3]Cl2 as the photosensitizer for the dechlorination reaction of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT). Noteworthy is the fact that the remarkable high turnover number (over ten thousand) based on B12, which ranks at the top among the reported studies, was obtained when Irdfppy was used as a photosensitizer. This photocatalytic system was also successfully applied to the B12 enzyme-mimic reaction, i.e., the 1,2-migration of the phenyl group of 2-bromomethyl-2-phenylmalonate. The plausible reaction mechanism was proposed, which involved two quenching pathways, an oxidative quenching pathway and a reductive quenching pathway, to be responsible for the initial electron transfer of the excited-state photosensitizers during the DDT dechlorination reaction. Transient photoluminescence experiments revealed that the oxidative quenching of the photosensitizer dominated over the reductive quenching pathway.

Electrochemical Reduction of Alkenes Mediated By Vitamin B12 Model Complex

Naturally-occurring B12(cobalamin)-dependent enzymes catalyze various molecular transformations that are of particular interest from the viewpoint of biological chemistry as well as synthetic organic chemistry and catalytic chemistry. The CoI species of B12 derivative is widely known as a supernucleophile that forms an alkylated complex by reaction with an alkyl halide.1 The alkylated complex is a useful reagent for forming radical species as the cobalt-carbon bond is readily cleaved homolytically by photolysis. Recently, application of CoI complex for proton reduction was extensively studied and electrochemical hydrogen evolutions by cobalt complex have been reported.2 In these studies, Co-H complex is thought to be an intermediate for hydrogen evolution. These results prompted us to investigate application of cobalamin derivative for new bio-isnpired reaction.3 The electrochemically generated CoI species of B12 derivative may reacts with proton (CF3COOH, CH3COOH etc..) to form Co-H complex, and can utilize for alkene reduction (Figure 1). Scope of substrate, detailed reaction mechanism, comparison to catalysis of other cobalt complex will be reported. References (1) a) M. Giedyk, H. Shimakoshi, K. Goliszewska, D. Gryko, Y. Hisaeda, Dalton Trans., 2016, in press (Inside cover); b) H. Shimakoshi, Z. Luo, T. Inaba, Y. Hisaeda, Dalton Trans., 2016, in press (Back cover). (2) a) V. Artero, M. Chavarot-Kerlidou, and M. Fontecave, Angew. Chem. Int. Ed., 50, 7238 (2011), b) W. T. Eckenhoff, R. Eisenberg, Dalton Trans, 41, 13004 (2011). (3) H. Shimakoshi and Y. Hisaeda, ChemPlusChem, 79, 1250 (2014) (Back cover). Figure 1

ChemInform Abstract: Oxygen‐Controlled Catalysis by Vitamin B12‐TiO2: Formation of Esters and Amides from Trichlorinated Organic Compounds by Photoirradiation.

An oxygen switch in catalysis of the cobalamin derivative (B12 )-TiO2 hybrid catalyst for the dechlorination of trichlorinated organic compounds has been developed. The covalently bound B12 on the TiO2 surface transformed trichlorinated organic compounds into an ester and amide by UV light irradiation under mild conditions (in air at room temperature), while dichlorostilbenes (E and Z forms) were formed in nitrogen from benzotrichloride. A benzoyl chloride was formed as an intermediate of the ester and amide, which was detected by GC-MS. The substrate scope of the synthetic strategy is demonstrated with a range of various trichlorinated organic compounds. A photo-duet reaction utilizing the hole and conduction band electron of TiO2 in B12 -TiO2 for the amide formation was also developed.

Oxygen-Controlled Catalysis by Vitamin B12 -TiO2 : Formation of Esters and Amides from Trichlorinated Organic Compounds by Photoirradiation.

An oxygen switch in catalysis of the cobalamin derivative (B12 )-TiO2 hybrid catalyst for the dechlorination of trichlorinated organic compounds has been developed. The covalently bound B12 on the TiO2 surface transformed trichlorinated organic compounds into an ester and amide by UV light irradiation under mild conditions (in air at room temperature), while dichlorostilbenes (E and Z forms) were formed in nitrogen from benzotrichloride. A benzoyl chloride was formed as an intermediate of the ester and amide, which was detected by GC-MS. The substrate scope of the synthetic strategy is demonstrated with a range of various trichlorinated organic compounds. A photo-duet reaction utilizing the hole and conduction band electron of TiO2 in B12 -TiO2 for the amide formation was also developed.

Oxygen‐Controlled Catalysis by Vitamin B12‐TiO2: Formation of Esters and Amides from Trichlorinated Organic Compounds by Photoirradiation

AbstractAn oxygen switch in catalysis of the cobalamin derivative (B12)‐TiO2 hybrid catalyst for the dechlorination of trichlorinated organic compounds has been developed. The covalently bound B12 on the TiO2 surface transformed trichlorinated organic compounds into an ester and amide by UV light irradiation under mild conditions (in air at room temperature), while dichlorostilbenes (E and Z forms) were formed in nitrogen from benzotrichloride. A benzoyl chloride was formed as an intermediate of the ester and amide, which was detected by GC‐MS. The substrate scope of the synthetic strategy is demonstrated with a range of various trichlorinated organic compounds. A photo‐duet reaction utilizing the hole and conduction band electron of TiO2 in B12‐TiO2 for the amide formation was also developed.

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Human CblC catalyzes the elimination of the upper axial ligand in cobalamin or B12 derivatives entering the cell from circulation. This processing step is critical for assimilation of dietary cobalamin into the active cofactor forms that support the B12-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase. Using a modified nitroreductase scaffold tailored to bind cobalamin and glutathione, CblC exhibits versatility in the mechanism by which it removes cyano versus alkyl ligands in cobalamin. In this study, we have characterized the effects of two pathogenic missense mutations at the same residue, R161G and R161Q, which are associated with early and late onset of the CblC disorder, respectively. We find that the R161Q and R161G CblC mutants display lower protein stability and decreased dealkylation but not decyanation activity, suggesting that cyanocobalamin might be therapeutically useful for patients carrying mutations at Arg-161. The mutant proteins also exhibit impaired glutathione binding. In the presence of physiologically relevant glutathione concentrations, stabilization of the cob(II)alamin derivative is observed, which occurs at the expense of increased oxidation of glutathione. Futile redox cycling, which is suppressed in wild-type human CblC, explains the reported increase in oxidative stress levels associated with the CblC disorder.

Visible Light Responsive B12-TiO2 Hybrid Catalyst Composed of Interfacial Complexation

The CoI species of the cobalamin derivative (B12) is widely known as a supernucleophile that forms an alkylated complex by reaction with an alkyl halide. The alkylated complex is a useful reagent for forming radical species as the cobalt-carbon bond is readily cleaved homolytically.1 Our research interest is focused on the application of this catalytic system to various molecular transformations.2 Recently, we have reported the unique catalysis of the cobalamin derivative (B12)-titanium oxide (TiO2) hybrid catalyst in which the B12 complex, cyanoaquacobyrnic acid (CoIII oxidation state), is immobilized on the surface of TiO2 and the B12 complex is reductively activated to form the CoI species by electron transfer from TiO2 under UV-light irradiation.3 The hybrid catalyst mediated the dehalogenation of various organic halides and was applied to the radical-mediated organic reaction via an alkylated complex as a catalytic intermediate. Though the great advantage of the catalyst is the facile and efficent formation of CoI species by light irradiation, UV light irradiation was required for band gap excitation of TiO2 semiconductor. To overcome this problem, we synthesized new B12-TiO2 hybrid catalyst (B12-TiO2-Cat) composed of interfacial complexation with catechol as shown in Figure 1a. As a charge transfer band ascribed to catechol to TiO2 appear in visible region,4 this new hybrid catalyst is expected to work under visible light irradiation. Futhermore, exploiting the interparticle electron transfer process in the B12-TiO2 and Cat-TiO2 combination system as shown in Figure 1b was investigated.

Crystal Structure Dependence for Reactivities of B12-TiO2Hybrid Catalysts with Anatase and Rutile Forms

ABSTRACT : The debromination of phenethyl bromide by the B 12 - TiO 2 hybrid catalyst under UV light irradiation was investigated. The catalytic efficiency was dependent on the type of TiO 2 . The anatase form of TiO 2 was superior to the rutile form of TiO 2 . The selectivity of the product was also dependent on the crystal structure of TiO 2 , and the rutile form of TiO 2 showed a high selectivity for the formation of the coupling product, 2,3-diphenylbutane, when compared to that of the anatase form of TiO 2 . The application of titanium oxide (TiO 2 ) has increased in various areas such as organic synthesis, solar cell devices, antibiotic and environmental applications, and surface selfcleaning due to its semiconductor property. 1-4 We recently reported the preparation and catalysis of TiO 2 combined with a cobalamin derivative (B 12 ), cyanoaqua cobyrinic acid, [(CN)(H 2 O)Cob(III)7COOH]Cl. 5-10 Naturally-occurring B 12 (cobalamin)-dependent enzymes catalyze various molecular transformations that are of particular interest from the viewpoint of biological chemistry as well as synthetic organic chemistry and catalytic chemistry.

Development of metal-organic framework (MOF)-B12 system as new bio-inspired heterogeneous catalyst

A novel bimetal complex {Zn4Ru2(bpdc)4·4C2NH8·9DMF}n (1) (H2bpdc = 4,4′-biphenyldicarboxylic acid) was synthesized by the solvothermal method. The results of the X-ray crystallographic analysis revealed that 1 crystallizes in the orthorhombic Pna21 space group, which has a 3D 2-fold interpenetrated hex framework, with open channel sizes along the [010] direction of ca. 1.4 nm × 1.4 nm. The photosensitizer [Ru(bpy)3]2+ was adsorbed into the 1 to form Ru@MOF by cation exchanging. A cobalamin derivative (B12), heptamethyl cobyrinate, was also effectively immobilized on Ru@MOF, and the resulting hybrid complex, B12–Ru@MOF, exhibited a high reactivity for the dechlorination reaction of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) under an N2 atmosphere by visible light irradiation in the solid state. The catalysis of B12–Ru@MOF can still reach more than a ca. 80% conversion after third recyclings. Furthermore, the heterogeneous catalyst, B12–Ru@MOF, was useful for the cobalamin-dependent reaction, such as the 1,2-migration of the acetyl group.

Electrolysis of Trichlomethylated Compound Under Aerobic Condition Catalyzed by B12 Model Complex

Reductive dehalogenation reactions are presently of great interest, primary because of their potential use in the treatment of halogenated solvent wastes as well as in remedial approaches to remove such chemicals from contaminated soils. A Co(I) species of cobalamin emerged in the active site of B12-dependent enzyme is a supernucleophile and reacts with an alkyl halide to form an alkylated complex with dehalogenation. Thus, the superior ability of cobalamin for reductive dehalogenation prompted us to investigate the catalysis of a cobalamin derivative for degradation of various halogenated compounds such as 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT), perchloroethelene (PCE), chloroform and so on. Electrolysis of such organic halides mediated by cobalt complex usually achieved in anaerobic condition to avoid loss of reactive Co(I) species by autooxidation. Carbon center radical formed by homolysis of cobalt-carbon bond in alkylated complex generally coupled to form dimerized compound or abstract hydrogen to form simply reduced product. Here we reported electrolysis of organic halide under aerobic condition and conducted the reaction of in-situ generated substrate radical with oxygen to form more valuable compound such as ester. Electrolysis of trichloromethyl benzene at -0.9 V vs. Ag/AgCl in the presence of heptamethyl cobyrinate perchlorate (1) in ethanol under anaerobic condition using undivided cell equiped with Pt mesh cathode and Zn plate anode to yield Z and E forms of 1,2-dichlorostilbene with 49% and 7%, respectively. In contrast, the same reaction was carried out in an aerobic condition, ethyl benzoate was selectively produced in 61 % yield based on initial concentartion of substrate. When the electrolysis was carried out in methanol or isopropano, methyl benzoate and isopropyl benzoate were formed, respectively. As for mechanism, primary formed radical species from homolysis of alkylated complex may reacts with oxygen to form peroxy species. Homolysis of O-O bond of peroxy species should produce oxyl radical. Following disproportionation and isomerization may produce benzoyl chloride as key intermediate in this reaction. Reactive benzoyl chloride could reacts with solvent ethanol to yield ethyl benzoate. Application of this aerobic electrolysis with colalamin derivative toward various trichloromethylated compounds will be reported.

An amphiphilic, catalytically active, vitamin B12 derivative

We performed the reaction of vitamin B12 with N,N-dimethylformamide dimethyl acetal for primary amide activation, and added MeOH as a nucleophile, to afford cobalester, the first amphiphilic cobalamin derivative. The unique combination of redox properties and solubility represents an asset for its use as a catalyst in C-C bond forming reactions.

Hydrophobic Vitamin B12 Derivatives: Unprecedented Formation of a 7‐Membered Lactam

AbstractThe synthesis of a new hydrophobic cobalamin derivative through intramolecular aminolysis is described. Under acidic conditions, (CN)2CobIII(10‐NH2)7C1‐ester formed a seven‐membered lactam between the ester and amino groups present at the C8 and C10 positions. Subsequent Boc protection of the NH group enabled ring opening with primary amines, leading to derivatives functionalized at the C8 and C10 positions.

Photosensitizing catalysis of the B12 complex without an additional photosensitizer

A cobalamin derivative, heptamethyl cobyrinate perchlorate, was activated by UV light irradiation to form a Co(I) species in the presence of triethanolamine and used for a dechlorination reaction, and this photochemical reaction was accelerated in an ionic liquid.

B12–TiO2 Hybrid Catalyst for Dehalogenation of Organic Halides

Abstract A cobalamin derivative, cobyrinic acid, was effectively immobilized on TiO2, and the hybrid TiO2 was characterized by UV–vis, XPS, MALDI-TOFMS as well as TEM analysis. The hybrid TiO2 exhibits high reactivity for dehalogenation of various organic halides such as phenethyl bromide, benzyl bromide, and 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) under irradiation with UV light at room temperature.

Sol-Gel Modified Electrode Trapped with a Cobalamin Derivative

not Available.