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Syntheses and Studies of Vitamin B12 Derivatives Containing Nickel, Cobalt and Zinc – From Cofactor F430-Inspired Chemistry to Potential Antibiotics


Brenig, Christopher. Syntheses and Studies of Vitamin B12 Derivatives Containing Nickel, Cobalt and Zinc – From Cofactor F430-Inspired Chemistry to Potential Antibiotics. 2021, University of Zurich, Faculty of Science.

Abstract

From the isolation of heme more than 100 years ago to the manifold structures and interconnected biosynthetic pathways we encounter today, the porphyrinoid cofactors termed ‘pigments of life’ have endured to fascinate researchers with unscathed curiosity. Two outstandingly complex cofactors of this family are clearly vitamin B12 (‘B12’), the fascinating cobalt-containing ‘anti-pernicious-anemia factor’ discovered almost 80 years ago, and a rare nickel-containing hydroporhyrin termed cofactor F430 (‘F430’). While the B12 cofactors play important roles in the metabolism of methionine and folate, nucleotide synthesis and breakdown of odd fatty acids in almost all domains of life, the latter is found only in methanogenic bacteria where it catalyses the formation – as well as the oxidation – of methane.
With the total synthesis of B12 accomplished in a 12 years-enduring endeavor by the groups of Woodward and Eschenmoser, a milestone was achieved not only in porphyrinoid chemistry but in natural product synthesis in general. However, a major goal remained unattained: The partial chemical synthesis of metal-free corrins from B12, ultimately connected to the accessibility of metal analogues of the vitamin. The availability of metal analogues of B12, especially those containing Ni(II), are ultimately intertwined with the answer to the question of the molecular origin of porphyrinoid cofactors and the unique pairing of Co with the corrin and Ni with the corphin ligand. Furthermore, metal-analogues of vitamin B12 represent a class of compounds empowered for a broad range of applications ranging from structural models of reduced states of B12 to non-functional B12 surrogates that antagonize biological functions of the natural vitamin.
In this thesis, an improved synthetic route towards 5,6-dihydroxycorrins starting from B12 is presented. This unprecedented type of corrin ligand entails a non-natural constitution of its π-electronic system, reminiscent of the one found in the natural corphin ligand of F430. Within three steps, a Ni(II)-containing 5,6-dihydroxynibalamin was synthesized in 27% overall yield. Although structurally similar to F430, the novel Ni(II) corrin sustained its square-planar, diamagnetic constitution under all conditions, corroborating earlier findings in the groups of Eschenmoser and Thauer concerning fundamental differences between Ni(II) complexes of the corrinic and corphinic ligand system. Subsequent investigations on the kinetic and thermodynamic parameters of incorporation of Ni(II) and Co(II) into 5,6-dihydroxycorrins revealed a striking kinetic preference for Co(II) insertion (Δ log k = 10), whereas the Ni(II) complexes displayed a slightly larger thermodynamic stability (Δ log Ka = 0.04). In order to explore the electrochemical properties of Ni(II)-5,6-dihydroxycorrins in detail, two synthetic routes towards a hydrophobic descendant of the novel nibalamin were developed within this thesis. A ring-opened Ni(II)-precursor complex, derived from an oxidatively opened hydrophobic heptamethylcobyrinate in quant. yields, could be cyclized under McMurry coupling conditions in 33% yield. (Spectro-)electrochemical and EPR studies of the resulting corrin-based functional model of F430, presented in this thesis, strikingly revealed that the vast differences in chemical behavior of Ni(II)-corrins and corphins are not paralleled in the Ni(I) oxidation state, enabling metal-centered reduction to a catalytically active Ni(I) species in Ni-corrins. A comparison with a ring-opened secocorrin complex revealed in a so far unparalleled study, that fundamental differences exist regarding the site of reduction in Ni(II)-corrin and secocorrin complexes, the latter being a result of complex electronic interactions between the ligand and the central nickel ion that allow for relocation of a single electron into a metal-centered orbital subsequent to the initial electron transfer. This convincingly demonstrates that the combination of Ni(II) with a corphin ligand is not a prerequisite for a catalytically active Ni(I) state and was presumably preferred by Nature due to other reasons. Furthermore, a biological relevance of secocorrins can possibly be ruled out on the basis of a preference of the latter for ligand-centered redox processes.
Within this thesis, synthetic access to a substance library of chemically modified vitamin B12 derivatives, derived semi-synthetically from natural B12, was established, and the structural and physico-chemical properties of these derivatives were thoroughly investigated with a plethora of bio-inorganic, electrochemical and biological methods regarding important factors that contribute to questions related to 1) the molecular origin of corrins and related corphins within the family of porphyrinoid cofactors termed the ‘pigments of life’, 2) the suitability of Ni(II)-containing corrins as functional models of F430 and their implication on mechanistical factors regarding the unique biocatalysis of F430, and 3) the effect of chemical alterations on the bioactivity of Cbls, connected to the distinct aim to develop efficient counteractors of B12 metabolism. The presented results clearly provide further insight into possible answers to these questions and are of relevance not only to the elucidation of the origin of important porphyrinoid biomolecules, but also allow to envisage new roles for chemically modified Cbls in catalysis and medicinal sciences.

Abstract

From the isolation of heme more than 100 years ago to the manifold structures and interconnected biosynthetic pathways we encounter today, the porphyrinoid cofactors termed ‘pigments of life’ have endured to fascinate researchers with unscathed curiosity. Two outstandingly complex cofactors of this family are clearly vitamin B12 (‘B12’), the fascinating cobalt-containing ‘anti-pernicious-anemia factor’ discovered almost 80 years ago, and a rare nickel-containing hydroporhyrin termed cofactor F430 (‘F430’). While the B12 cofactors play important roles in the metabolism of methionine and folate, nucleotide synthesis and breakdown of odd fatty acids in almost all domains of life, the latter is found only in methanogenic bacteria where it catalyses the formation – as well as the oxidation – of methane.
With the total synthesis of B12 accomplished in a 12 years-enduring endeavor by the groups of Woodward and Eschenmoser, a milestone was achieved not only in porphyrinoid chemistry but in natural product synthesis in general. However, a major goal remained unattained: The partial chemical synthesis of metal-free corrins from B12, ultimately connected to the accessibility of metal analogues of the vitamin. The availability of metal analogues of B12, especially those containing Ni(II), are ultimately intertwined with the answer to the question of the molecular origin of porphyrinoid cofactors and the unique pairing of Co with the corrin and Ni with the corphin ligand. Furthermore, metal-analogues of vitamin B12 represent a class of compounds empowered for a broad range of applications ranging from structural models of reduced states of B12 to non-functional B12 surrogates that antagonize biological functions of the natural vitamin.
In this thesis, an improved synthetic route towards 5,6-dihydroxycorrins starting from B12 is presented. This unprecedented type of corrin ligand entails a non-natural constitution of its π-electronic system, reminiscent of the one found in the natural corphin ligand of F430. Within three steps, a Ni(II)-containing 5,6-dihydroxynibalamin was synthesized in 27% overall yield. Although structurally similar to F430, the novel Ni(II) corrin sustained its square-planar, diamagnetic constitution under all conditions, corroborating earlier findings in the groups of Eschenmoser and Thauer concerning fundamental differences between Ni(II) complexes of the corrinic and corphinic ligand system. Subsequent investigations on the kinetic and thermodynamic parameters of incorporation of Ni(II) and Co(II) into 5,6-dihydroxycorrins revealed a striking kinetic preference for Co(II) insertion (Δ log k = 10), whereas the Ni(II) complexes displayed a slightly larger thermodynamic stability (Δ log Ka = 0.04). In order to explore the electrochemical properties of Ni(II)-5,6-dihydroxycorrins in detail, two synthetic routes towards a hydrophobic descendant of the novel nibalamin were developed within this thesis. A ring-opened Ni(II)-precursor complex, derived from an oxidatively opened hydrophobic heptamethylcobyrinate in quant. yields, could be cyclized under McMurry coupling conditions in 33% yield. (Spectro-)electrochemical and EPR studies of the resulting corrin-based functional model of F430, presented in this thesis, strikingly revealed that the vast differences in chemical behavior of Ni(II)-corrins and corphins are not paralleled in the Ni(I) oxidation state, enabling metal-centered reduction to a catalytically active Ni(I) species in Ni-corrins. A comparison with a ring-opened secocorrin complex revealed in a so far unparalleled study, that fundamental differences exist regarding the site of reduction in Ni(II)-corrin and secocorrin complexes, the latter being a result of complex electronic interactions between the ligand and the central nickel ion that allow for relocation of a single electron into a metal-centered orbital subsequent to the initial electron transfer. This convincingly demonstrates that the combination of Ni(II) with a corphin ligand is not a prerequisite for a catalytically active Ni(I) state and was presumably preferred by Nature due to other reasons. Furthermore, a biological relevance of secocorrins can possibly be ruled out on the basis of a preference of the latter for ligand-centered redox processes.
Within this thesis, synthetic access to a substance library of chemically modified vitamin B12 derivatives, derived semi-synthetically from natural B12, was established, and the structural and physico-chemical properties of these derivatives were thoroughly investigated with a plethora of bio-inorganic, electrochemical and biological methods regarding important factors that contribute to questions related to 1) the molecular origin of corrins and related corphins within the family of porphyrinoid cofactors termed the ‘pigments of life’, 2) the suitability of Ni(II)-containing corrins as functional models of F430 and their implication on mechanistical factors regarding the unique biocatalysis of F430, and 3) the effect of chemical alterations on the bioactivity of Cbls, connected to the distinct aim to develop efficient counteractors of B12 metabolism. The presented results clearly provide further insight into possible answers to these questions and are of relevance not only to the elucidation of the origin of important porphyrinoid biomolecules, but also allow to envisage new roles for chemically modified Cbls in catalysis and medicinal sciences.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Zelder Felix Hubertus, Alberto Roger, Tilley David, Zobi Fabio
Communities & Collections:07 Faculty of Science > Department of Chemistry
UZH Dissertations
Dewey Decimal Classification:540 Chemistry
Language:English
Place of Publication:Zurich
Date:2021
Deposited On:09 Feb 2022 07:10
Last Modified:19 Dec 2023 16:18
OA Status:Closed
Project Information:
  • : FunderUZH Forschungskredit
  • : Grant IDFK-17-088
  • : Project Title