Cobyric acids

A second synthesis of cobyric acid (14) involves photochemical ring closure of an A—D secocorrinoid. Thus, the Diels-Alder reaction between butadiene and /n j -3-methyl-4-oxopentenoic acid was used as starting point for all four ring A—D synthons (15—18). These were combined in the order B + C — BC + D — BCD + A — ABCD. The resultant cadmium complex (19) was photocyclized in buffered acetic acid to give the metal-free corrinoid (20). A number of steps were involved in converting this material to cobyric acid (14). 

The total syntheses have yielded cobyric acid and thence cyanocobalamin. Routes to other cobalamins, eg, methylcobalamin and adenosylcobalamin, are known (76—79). One approach to such compounds involves the oxidative addition of the appropriate alkyl haUde (eg, CH I to give methylcobalamin) or tosylate (eg, 5 -A-tosyladenosine to yield adenosylcobalamine) to cobalt(I)alamine. 

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... 

Scheme 1. Retrosynthetic analysis of the Woodward-Eschenmoser synthesis of cobyric acid (4).

Scheme 21 presents the successful sequence of reactions that solved the remaining two problems and led to the completion of the synthesis of cobyric acid. Exposure of 96 to concentrated sulfuric acid for one hour brings about a clean conversion of the nitrile grouping to the corresponding primary amide grouping. The stability of die corrin nucleus under these rather severe conditions is noteworthy. This new substance, intermediate 97, is identified as cobyrinic acid abcdeg hexamethylester f amide and it is produced along with a very similar substance which is epimeric to 97 at C-13. The action of sulfuric acid on 96 produces a diastereomeric... 

In March 1976, M.A. Wuonola and R.B. Woodward accomplished the conversion of cobyric acid (4) to vitamin B12 (1). The total synthesis of vitamin B12 can thus be claimed, see reference Id, footnote 11, p. 1420. The formal total synthesis of 1 had been accomplished in 1973. 

Fig. 37. Proton-decoupled natural-abundance carbon-13 NMR spectra. Peaks are numbered from left to right, (a) 0.064 M aqueous dicyano-cobyric acid, (b) 0.064 M aqueous aquocyanocobric acid, (compliments of A. Allerhartd)...

The initial objective of the approach was cobyric acid (334), in which the propionic substituent at the 17-position must be differentiated from all other amides in the molecule ... 

Scheme 34 shows the synthesis of the bc portion (336), which possessed three of the nine asymmetric centers present in cobyric acid. Retrosynthesis determined that (336) could be obtained, via sulfide contraction, from the two intermediates (337) and (338). Ring c was synthesized from (+)-camphor quinone (not shown). Ring b (337) was obtained from 8-methyl-j8-acetylacrylic acid (339), the two adjacent chiral centers being generated in the required relative orientation by a Diels-Alder cycloaddition with butadiene in the presence of tin(IV) chloride. Fractional crystallization served to resolve the diastereomeric a-phenethylamine salts derived from them, eventually affording the compound (340). Oxidation with chromic acid cleaved the double bond in (340) and one of the newly generated... 

ISE Based on a Hydrophobic Cobalamin. Cobalamin 4 (Figure 2) is a hydrophobic vitamin B12 derivative that retains a proximal base (an imidazole ring), which provides the molecule with a resemblance to the original vitamin (Figure 1). The selectivity pattern of electrodes prepared with ionophore 4 at pH 5.5 is shown in Figure 4. These electrodes exhibit an anion selectivity pattern that differs from that of the Hofmeister series and from that of the previously reported cobyric acid derivatives (see section above). Indeed, electrodes based on 4 are selective for... 

Vitamin B12 has been successfully synthesized (W2), but this was a major undertaking involving 100 people over 11 years. The synthesis was completed in two stages first, the corrinoid cobyric acid, which is a natural substance, was converted to vitamin B12, then work was continued on the synthesis of the cobyric acid. The procedure is complex and still not of commercial significance. However, the synthesis of such a complex molecule was a great achievement at the time. 

The methylated complex of cobyric acid is in isomer equilibrium under photolytic or thermal condition to give anti- and syn-forms at a 92 8 molar ratio (Figure 7). The anti- to syn-form ratio for the ethyl-... 

The free energy difference between the anti- and syn-forms of the methylated cobyric acid RTIn (92/8) — 1.4 kcal, CH3—CH3 repulsion energy. 

The cobyric acid was crystalline, and it was identical in all respects, most particularly in liquid chromatographic behavior, with cobyric acid derived from natural sources. (Italics are Woodward s.)... 

Eschenmoser [15] has recently alluded to the concepts of structure-directed synthesis and autochthonous reactivity — the propensity of certain systems to undergo reactions as a consequence of their intrinsic molecular structural factors — within the context of certain biomolecules, particularly the organic cofactor, vitamin B12. The formation of the AD ring junction in the corrin ligand had to be regarded as a major hurdle in any proposed chemical synthesis of cobyric acid (5) (Fig. 2), and hence of vitamin B12. However, driven initially by the desire to identify a dark, and therefore potentially biomimetic, variant of the photochemical... 

Fig. 2. The synthesis of cobyric acid (5) marked effectively the completion [15b, c, h, i, j] of the synthesis of vitamin B12 by Woodward and Eschenmoser. Extensive studies subsequently by Eschenmoser [15a—e] have revealed that many of the structural features are attainable with surprising ease from structural-ly-appropriate precursors. Most notably, the four highlighted (bold) structural features represent thermodynamically-favored arrangements...

Figure 5 Outline of the total synthesis of cobyric acid (Figure 1) on the way to vitamin B12 top the ETH approach via an A/D ring closure of the corrin ring system bottom the Harvard/ETH approach via an A/B ring closure...

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