Corrins

In contrast to porphyrins, corrins are characterised by complete saturation of the peripheral part of the molecule. They also have a smaller macroring, because two of the four five-membered rings are directly linked (Eq. 2.230). 

Biological compounds with the corrin structure are of particular interest, with cobyric acid and vitamin B12 occupying a special place [435-442]. The latter was first isolated in 1948 [435] and structurally characterised in 1955 (Eq. 2.231) [443]. 

The synthesis of cobyric acid is the culminating achievement in corrin chemistry. The key step in cobyric acid synthesis is transformation of the open-chain organic system into the corresponding macrocyclic corrin by means of chemically joining cycles A and B (the A/B route) as well as by secocorrin/corrin cyclisation between rings A and D (the A/D route). 

Macrocyclisation by the A/B route may be achieved in two ways [439]. One of these, designed by Woodward s group in Cambridge, consists in joining cycles A 

Photoinduced cycloisomerisation can also be carried out in the presence of other metal ions serving as templates. For example, secocorrin coordinated to metal ions such as lithiiun(I), magnesirun(II), zinc(II) or cadmium(II) readily cyclises in the absence of oxygen in almost quantitative yield at room temperature [441, 444]. Platinum(II) and palladium(II) complexes (quantum )deld 0.008 in chloroform at 20°C) also cyclise, but more slowly. However, nickel(II), cobalt(III) and copper(II) secocorrinates do not undergo such a transformation [441, 444]. If, however, the nickel(II) l-methylidene-l,19-secocorrinate is subjected to one-electron electrochemical oxidation, followed by direct reduction of the isomerised cation-radical, then such a transformation is realisable [450]. 

The C—C double bond in the cyclopentene ring can be cleaved by the osmium tetroxide-periodate procedure or by photooxygenation. The methoxalyl group on C-17 can, as a typical a-dicarbonyl system, be split off with strong base and is replaced by a proton. Since this elimination occurs with retention of the most stable configuration of the cyclization equi-hbrium, the substituents at C-17 and C-18 are located trans to one another. The critical introduction of both hydrogens was thus achieved regio- and stereoselectively. 

In principle, the direct hydride addition or catalytic hydrogenation, which did not give chlorins, was replaced by an electrocyclic intramolecular addition which is much easier with the above system. Complete regioselectivity was also achieved since electrocyclization did not occur with the resonance-stabilized ring C. 

This case history presents only a simple account of one of R.B. Woodward s adventures based on ingenious undentanding of structural features and experimental findings described in the literature. The hydrogenation of porphyrins is still one of the most active subjects in heterocyclic natural products chemistry, and the interested reader may find some modem developments in the publications of A. Eschenmoser (C.Angst, 1980 J.E. Johansen, 1980). 

It is conceivable that related ligands, e.g. dehydrocorrins, could be obtained from pyrrolic units using pathways similar to those used for porphyrins and could be hydrogenated to corrins. This has indeed been achieved (I.D. Dicker, 1971), but it is, of course, impossible to introduce the nine chiral centres of cobyrinic acid by such procedures. 

Later it turned out that activation of enamine components could not only be achieved by deprotonation of the nitrogen atom but also by connecting it with certain metals, e.g. Ni(II), Pd(II), or Co(II), and subsequent treatment with base. 

The scheme below shows how the eastern and western parts of a corrin chromo-phore can be combined regioselectively. The western part has a more acidic enamine than the eastern part, whereas the imidic ester of the eastern part is more electrophilic. 

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A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

Porphyrins and chlorophylls are the most widespread natural pigments. They are associated with the energy-converting processes of respiration and photosynthesis in living organisms, and the synthesis of specific porphyrin derivatives is often motivated by the desire to perform similar processes in the test tube. The structurally and biosynthetically related corrins (e.g. vitamin B,j) catalyze alkylations and rearrangements of carbon skeletons via organocobalt intermediates. The biosyntheses of these chromophores are also of topical interest. 

Corrin is the porphyrinoid chromophore of the vitamin parent compound cobyrinic acid. Corrin itself has not yet been synthesized, but routes to cobyrinic acid and several other synthetic corrins have been described by A. Eschenmoser (1970, 1974) and R.B. Woodward (1967). 

Introduction of the cobalt atom into the corrin ring is preceeded by conversion of hydrogenobyrinic acid to the diamide (34). The resultant cobalt(II) complex (35) is reduced to the cobalt(I) complex (36) prior to adenosylation to adenosylcobyrinic acid i7,i -diamide (37). Four of the six remaining carboxyhc acids are converted to primary amides (adenosylcobyric acid) (38) and the other amidated with (R)-l-amino-2-propanol to provide adenosylcobinamide (39). Completion of the nucleotide loop involves conversion to the monophosphate followed by reaction with guanosyl triphosphate to give diphosphate (40). Reaction with a-ribazole 5 -phosphate, derived biosyntheticaHy in several steps from riboflavin, and dephosphorylation completes the synthesis. 

The structure of the diamagnetic, cherry-red vitamin B12 is shown in Fig. 26.6 and it can be seen that the coordination sphere of the cobalt has many similarities with that of iron in haem (see Fig. 25.7). In both cases the metal is coordinated to 4 nitrogen atoms of an unsaturated macrocycle (in this case part of a corrin ring which is less symmetrical and not so unsaturated as the porphyrin in haem) with an imidazole nitrogen in the fifth position. A major... 

Figure 26.6 Vitamin B12 (a) a corrin ring showing a square-planar set of N atoms and a replaceable H, and (b) simplified stmcture of B12. In view of the H displaced from the corrin ring, the Co-C bond, and the charge on the ribose phosphate, the cobalt is formally in the - -3 oxidation state. This and related molecules are conveniently represented as r...

Incorporation of cobalt into the corrin ring system modifies the reduction potentials of... 

When the Woodward-Eschenmoser synthesis began, it was known from the work of Bernhauer et al.5 that cobyric acid (4), a naturally occurring substance, could be converted directly into vitamin B12. Thus, the synthetic problem was reduced to the preparation of cobyric acid, a molecule whose seventh side chain terminates in a carboxylic acid group and is different from the other side chains. Two strategically distinct and elegant syntheses of the cobyric acid molecule evolved from the combined efforts of the Woodward and Eschenmoser groups and both will be presented. Although there is naturally some overlap, the two variants differ principally in the way in which the corrin nucleus is assembled. 

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... 

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