Replacement of the Cobalt Center of Vitamin B₁₂ by Nickel: Nibalamin and Nibyric Acid Prepared from Metal‐Free B₁₂ Ligands Hydrogenobalamin and Hydrogenobyric Acid

Abstract

The (formal) replacement of Co in cobalamin (Cbl) by Ni II generates nibalamin (Nibl), an ew transition-metal analogue of vitamin B 12 .Described here is Nibl,synthesized by incorporation of aN i II ion into the metal-free B 12 ligand hydrogenobalamin (Hbl), itself prepared from hydrogenobyric acid (Hby). The related Ni II corrin nibyricacid (Niby)was similarly synthesized from Hby,t he metal-free cobyric acid ligand. The solution structures of Hbl,a nd Niby and Nibl, were characterized by spectroscopic studies. Hbl features two inner protons bound at N2 and N4 of the corrin ligand, as discovered in Hby.X-rayanalysis of Niby shows the structural adaptation of the corrin ligand to Ni II ions and the coordination behavior of Ni II .T he diamagnetic Niby and Nibl,a nd corresponding isoelectronic Co I corrins,w ere deduced to be isostructural. Nibl is as tructural mimic of four-coordinate base-off Cbls,a sv erified by its ability to act as as trong inhibitor of bacterial adenosyltransferase.

Synthesis, Spectral Characterization and Crystal Structure of Chlororhodibalamin: A Synthesis Platform for Rhodium Analogues of Vitamin B12 and for Rh-Based Antivitamins B12

“…-Dichloro-tetracarbonyldirhodium(I) ([Rh(CO) 2 Cl] 2 6.89 mg, 17.7 mol) was dissolved in 1.5 mL ethylene glycol under a carbon monoxide atmosphere. Hbl (6.2 mg, 5.1 mol) 17 was dissolved in ethylene glycol (3.5 mL) and the solution was degassed three times by freezepump-thaw with argon. After addition of the solution of [Rh(CO) 2 Cl] 2 to the Hbl solution under protection from air, the stirred red-orange reaction mixture was heated to 100 °C and stirring was continued for one hour.…”

“…So far, we have used such semisynthetic Hbl for the synthesis of the previously unknown Ni-analogue of vitamin B 12 , named nibalamin. 17 As described herein, the semisynthetic metal-free corrin Hbl 17 also served as the starting material in a high yielding, one-step synthesis of ClRhbl. The orange-yellow Rh IIIcorrin ClRhbl was prepared by the reaction of Hbl with an excess of -dichloro-tetracarbonyl-dirhodium(I) ([Rh(CO) 2 Cl] 2 ).…”

Antivitamins B12—Some Inaugural Milestones

“…This work has led to fruitful research collaborations, discovering new organometallic Cbl‐chemistry, photochemistry and biochemistry [22, 24, 68] . It has, likewise, opened up new avenues in the field of the fascinating transition metal analogues of the Cbls and of other natural corrinoids [34, 36, 39, 42] . The helical, ring‐contracted natural corrin ligand has been characterized as an exceptional ‘Procrustean Bed’ for bound transition metal ions, important for tightly binding and specifically activating the bound cobalt‐ions in their low‐spin states [35] .…”

“…[22,24,68] It has, likewise, opened up new avenues in the field of the fascinating transition metal analogues of the Cbls and of other natural corrinoids. [34,36,39,42] The helical, ringcontracted natural corrinl igand has been characterized as an exceptional 'Procrustean Bed' for bound transition metal ions, important for tightly binding and specifically activating the bound cobalt-ions in their low-spins tates. [35] As discovered with synthetic Ni II -corrins, [69] the naturalc orrin ligand also imposes the diamagnetic low-spins tate on bound Ni II -ions, [36] contrasting with the situation in related porphyrin-type Ni II -corphinoids.…”

“…Mechanistic insights into the exceptional biochemistry of the involved B 12 ‐dependent enzyme reactions or means of the B 12 ‐based control of essential cellular processes are areas of continuous interest. Studies with antivitamins B 12 and other structurally characterized Metbls may potentially contribute to this subject, [36] relying on two key structure‐based factors: (i) By imitating the structures of the B 12 ‐cofactors or of reactive intermediate B 12 ‐species in the course of enzyme reactions, suitably structured (inactive) B 12 ‐mimics have an excellent capacity to inhibit the corresponding enzymatic steps. Hence, for example, the Ni II ‐analogue of the cryptic intermediate Co I ‐form cob(I)alamin inhibits an AdoCbl‐generating Ado‐transferase in an in vitro study [36] (see above for corresponding pertinent findings with the alkynyl‐Cbl F2PhEtyCbl [26b] and with AdoRhbl [34] ).…”