Corrins synthesis

Scheme 28 outlines Eschenmoser s model corrin synthesis. The enamide (310) was treated with KCN to give (311), and this gave the thiolactam (312) when treated with phosphorus pentasulfide. Benzoyl peroxide oxidation yielded the disulfide (313), and in the presence of the enamide (310) this gave the bicyclo thio-bridged compound (314). Sulfur extrusion, by this time a standard procedure (Scheme 22), provided the vinylogous amidine (315)... 

The beautiful simplicity in Eschenmoser s strategy was that, for the purposes of the seco-corrin synthesis, the required materials could all be obtained from one precursor (383),... 

An impressive example of the possibilities of metal complex photochemistry is the substantiation of the critical step in corrin synthesis reported by Eschenmoser 145> Ring closure is brought about by antara-facial cycloisomerization of a secocorrinoidic palladium complex by photochemical 1.16-hydrogen shift. 

The complex pathways of corrin synthesis have been worked out in detail. This has been possible because of extensive use of and H NMR and because the group of 20 enzymes required has been produced in the laboratory from genes cloned from Pseudomonas denitrificons. The first alterations of uroporphyrinogen are AdoMet-dependent methyla-tions on carbon atoms. Surprisingly, one of these is on the bridge atom that is later removed. The details, including the insertion of Co + by a cobaltochelatase, are described by Battersby and portrayed in Michal s Biochemical Pathways. 

Stereoselectivity. See Asymmetric induction Axial/equatorial-, Cis/trans-, Enantio-, Endo/exo- or Erythro/threo-Selectivity Inversion Retention definition (e.e.), 107 footnote Steric hindrance, overcoming of in acylations, 145 in aldol type reactions, 55-56 in corrin synthesis, 261-262 in Diels-Alder cyclizations, 86 in Michael type additions, 90 in oiefinations Barton olefination, 34-35 McMurry olefination, 41 Peterson olefination, 33 in syntheses of ce-hydrdoxy ketones, 52 Steric strain, due to bridges (Bredt s rule) effect on enolization, 276, 277, 296, 299 effect on f3-lactam stability, 311-315 —, due to crowding, release of in chlorophyll synthesis, 258-259 in metc-cyclophane rearrangement, 38, 338 in dodecahedrane synthesis, 336-337 in prismane synthesis, 330 in tetrahedrane synthesis, 330 —, due to small angles, release of, 79-80, 330-333, 337... 

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. 

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. 

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 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... 

The tautomerization of porphyrinogens to pyrrocorphins has been reported in detail in connection with the synthesis of chlorins (sec Section 1.2.1.3.), baeteriochlorins (see Section 1.3.1.) and isobacteriochlorins (see Section 1.4.1.3.). Therefore, only the porphyrinogen-pyrrocorphin tautomerization of uroporphyrinogen I octacarbonitrile 8- 96 will be described as it is of importance regarding the biosynthesis and a possible prebiotic formation of corrins.la,b-2 A major problem concerned with using this approach synthetically is the number of possible diastereomeric products (4 in a 1 1 1 1 ratio) obtained in the reaction and also the formation of isobacteriochlorin diastereomers 10. 

The tetramerization of suitable monopyrroles is one of the simplest and most effective approaches to prepare porphyrins (see Section 1.1.1.1.). This approach, which is best carried out with a-(hydroxymethyl)- or ot-(aminomethyl)pyrroles, can be designated as a biomimetic synthesis because nature also uses the x-(aminomethyl)pyrrole porphobilinogen to produce uroporphyrinogen III. the key intermediate in the biosynthesis of all kinds of naturally occurring porphyrins, hydroporphyrins and corrins. The only restriction of this tetramerization method is the fact that tnonopyrroles with different -substituents form a mixture of four constitutionally isomeric porphyrins named as porphyrins I, II, III, and IV. In the porphyrin biosynthesis starting from porphobilinogen, which has an acetic acid and a propionic acid side chain in the y6-positions, this tetramerization is enzymatically controlled so that only the type III constitutional isomer is formed. 

This procedure illustrates a broadly applicable method which is essentially that of Roth, Dubs, Gotschi, and Eschenmoser,2 for the synthesis of enolizable /1-dicarbonyl compounds. Although there are various methods for the preparation of /3-dicarbonyl systems,3 the scheme of sulfide contraction widens the spectrum of available methods. The procedure can also be utilized in the synthesis of aza and diaza analogs of /3-dicarbonyl systems. Eschenmoser2 has utilized the method to produce vinylogous amides and amidines in connection with the total synthesis of corrins and vitamin B12.4... 

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