Cobalt corrinoids structures

Scheme 1 outlines the retrosynthetic analysis of the Woodward-Eschenmoser A-B variant of the vitamin B12 (1) synthesis. The analysis begins with cobyric acid (4) because it was demonstrated in 1960 that this compound can be smoothly converted to vitamin B12.5 In two exploratory corrin model syntheses to both approaches to the synthesis of cobyric acid,6 the ability of secocorrinoid structures (e. g. 5) to bind metal atoms was found to be central to the success of the macrocyclization reaction to give intact corrinoid structures. In the Woodward-Eschenmoser synthesis of cobyric acid, the cobalt atom situated in the center of intermediate 5 organizes the structure of the secocorrin, and promotes the cyclization... 

Although the cobalt corrinoids have been studied extensively in. the last two decades (J), the significance of corrin as an equatorial ligand is not well understood. To characterize coenzyme B12 as an organocobalt derivative, a search for model cobalt complexes that can form a Co-C bond axial to a planar equatorial ligand has been stimulated. Studies on model systems (2-13), particularly on the cobaloxime derivatives (2-7), characterized their respective chemistry, but it is still not easy to establish a general correlation between the structure of an equatorial ligand and the properties of cobalt complex... 

So far, for the highly oxygen-sensitive Co -forms of cobalt-corrinoids (such as Co -cobalamin, (6)), information from X-ray analysis on their three-dimensional structure is not available. However, in these strongly nucleophihc, highly reduced cobalt complexes, the diamagnetic Co -center (a d metal ion, isoelectronic with a Ni"-ion) presumably is ligated by the corrin ligand only, in a tetracoordinated, nearly square-planar fashion. As a consequence, the Co -forms of complete corrins would have to be base-off, that is, the nucleotide function would not be attached to the central cobalt ion. 

Our knowledge of the stereochemistry of porphyrins and related tetrapyrrole macrocycles has expanded rapidly since the first reported x-ray structure determination in 1959 The structures of metallotetrapyrrole complexes are of interest because of the common occurrence of this type of macrocycle in biological systems. As is well known, foremost among these are the heme proteins (iron derivatives), the various photosynthetic pigments (magnesium complexes), the vitamin Bn coenzyme (cobalt corrinoids), and coenzyme F430 (nickel corphinoids) of the methanogenic bacteria. 

Most living organisms depend on catalysis by the transition element cobalt (1). The biological relevance of cobalt is due, mainly, to vitamin B12 derivatives (2,3), also known as cobalt corrinoids (4). In exceptional cases, enzymes may contain natural noncorrinoid cobalt ions (5), and structural Zn centers have been reconstituted with Co (and other divalent metal) ions, without significant loss of activity (1,4). Only some microorganisms are able to produce B12 derivatives naturally (6,7). Cobalt complexes similar to vitamin B12 (1) may have had fundamental roles in early forms of life on earth (1,8). 

Fig. 4. Attachment of the deoxyadenosyl group to the cobalt of the corrinoid structure.

The corrinoids involved in methyl group transfer do not possess the organo-ligand 5 -deoxyadenosyl [see structure (II), Section I,B] and the reaction probably proceeds via the intermediate formation of the methyl cobalt complex, but no mechanistic details have yet been established. 

The structures of the biologically active forms of B12 were solved relatively recently (1961) (78) and were shown to contain a cobalt atom surrounded by a corrin ring as shown in Fig. 16 (80). The crystal structure also showed a cobalt-carbon a bond which was quite surprising since the few compounds with cobalt-carbon a- bonds known at that time were quite unstable (79). The corrin ring is similar to the porphyrin ring, but its greater saturation imports less rigidity than the porphyrin. Corrinoids with the axial 5,6-dimethylbenzimidazole substituent are called cobalamins. Vitamin B12 with Co(III) and CN in the top axial position is... 

In these compounds the cobalt atom is enclosed in a highly conjugated cobalamin structure and linked to an alkyl group via a metal-carbon bond. The B12 coenzymes are diamagnetic and can be regarded as complexes of cobalt(III) with a carbanion as a ligand (2). As this review will be limited to cases of direct metal-protein interactions the corrinoids will not be discussed further. 

Another structural variation operated in these compounds is the substitution at the angular 1,19-positions with methyl groups in natural corrinoids only the 1 postion is substituted. Such alteration is necessary on one hand because the cobalt complex of 1-methyl-octadehydrocorrin is unstable and, on the other hand, the related [Co(A2TDC)]+ is prepared by reduction of [Co(A2ODC)] + [2]. 

Subsequent to the original quest for vitamin B12 (1), driven by medicinal purposes mainly, further investigations on the natural corrinoids laid bare the central roles of the Bi2-coenzymes in the metabolism of microorganisms, in particular. These primitive organisms uniquely possess the capacity to build up the complex B12 structure in nature, in which they may vary the constitution of the nucleohde ftmchon in a species-specihc way (Figure 2). The cobalt-corrins, in turn, have been proposed to be structural and functional renmants of early (primihve) forms of life, where presumably, central metabolic processes could rely considerably on organometalhc chemistry at cobalt and nickel centers. ... 

The crystal structure of DD (from Kl. oxytoca) was solved as the complex with vitamin B12 (1) and (5 )-propane-1,2-diol. It showed the corrinoid to be bound at an interdomain-interface (of the Bi2-binding jS-subunit and of the substrate-binding a-subunit) and confirmed the base-on nature of the bound corrinoid. The crystal structure showed the corrin-bound cobalt ion to be (largely) pentacoordinated, with an axial Co-Nq, bond with 2.5 A length, and the diol substrate to be ligating the potassium ion, which is situated at a distance of 11.7 A from the cobalt center of the corrinoid. The diol substrate is also bound via a tight net of H bonds to polar... 

The crystal structures of dGTP-free AdoCbl-dependent RNR in the apo-form complexed with Co -aderunylpentyl-cobalamin (a structural analog of AdoCbl (3), see e.g. ) confirmed the base-on nature of the bound corrinoid, deduced from ESR data earlier. In crystalline RNR, the cracial cysteine is at a distance of about 10 A from the cobalt(II) center of the bound corrinoid, and in a region of space that is also well conserved in the three classes of RNRs. ... 

Figure 1 In the above structure, R = CN denotes cyanocobalamin (CN-Cbl), whilst R = OH is hydroxocobalamin (OH-Cbl) R = 5 -deoxyadenosyl is coenzyme B12 (adenosylcobalamin, AdoCbl) and R = Me is methylcobalamin (MeCbl). By definition all cobalamins contain 5,6-dimethylbenzimidazole, which is the so-called 6th ligand to cobalt in the above structure. Substances containing the corrin ligand, i.e. the planar 14 electron p-system embracing cobalt in the above structure, are also called corrinoids.

Structure of the cobalamin family of compounds. A through D are the four rings in the corrinoid ring system. The B ring is important for cobalamin binding to intrinsic factor. If R = -CN, the molecule is cyanocobalamin (vitamin B12) if R = 5 -deoxyadenosine, the molecule is adenosylcobalamin if R = -CH3, the molecule is methylcobalamin. Arrows pointing toward the cobalt ion represent coordinate-covalent bonds. 

Qualitative information on the structure of the colored corrinoids in solution can be extracted rapidly from UVA7is and CD spectra most of the spectroscopic features can be rationalized nowadays by comparison with theoretically calculated spectra. For more precise constitutional information, some of the newly developed methods of mass spectrometry allow the analysis even of the involatile Bi2-derivatives. Modern one-and two-dimensional proton, carbon, nitrogen, and phosphorus NMR spectroscopy has proven a powerful instrument for the delineation of the structure of diamagnetic cobalt-corrins in solution. ESR-spectroscopy has given important information on paramagnetic corrinoid Co -complexes, whether in frozen solutions or bound in corrinoid enzymes. X-ray adsorption fine spectroscopy (EXAFS) spectroscopy and vibrational (IR and Raman) spectroscopy are other spectroscopic techniques used more frequently now in the B12 field. ... 

Crystallographic studies with GM from Cl. cochlearium have provided a detailed structural picture of the enzyme, in which the corrinoid cofactor is bound base-off/His-on again and at the interface between the subunits a and The cobalt-coordinating histidine is part of an H-bonded regulatory His-Asp-Ser triad. Detailed analysis of GM with the bound coenzyme B12 (3) revealed the position of the ribose part of the 5 -deoxyadenosyl moiety to be disordered and to be present in two conformations, related to each other by a pseudo-rotation of the furanose ring. One of these structures places the 5 -methylene group of the adenosine close to the position of the corrin-bound cobalt center, but at a distance of about 3.1 A, and thus appears to have features expected for the direct product of the homolysis of the Co-C bond of the bound cofactor (3). In the other conformation, the 5 methylene carbon is at a distance of about 4.5 A from the metal center and is displaced toward the substrate-binding site, as if in van der Waals contact with the bound substrate. In this way, GM... 

---