Tetrapyrrole synthesis

Most of the subsequent steps of tetrapyrrole synthesis are identical in plants, animals, and bacteria. The pathway includes synthesis of the monopyrrole porphobilinogen from two molecules of ALA by the action of ALA dehydratase with the elimination of two molecules of water, followed by the assembling of a linear tetrapyrrole hydroxymethylbilane from fonr molecnles of porphobilinogen, ring closure and two modification reactions of side chains. This produces the first tetrapyrrole macrocycle, uroporphyrinogen HI. Therefore, eight molecules of ALA are necessary to form one tetrapyrrole. 

The pyrrole monomer porphobilinogen arises from the condensation of two molecules of S-aminolevulinate with the ions of two water molecules. This reaction is catalyzed by S-aminolevulinate dehydrase. Condensation of four porphobilinogen molecules yields the branchpoint compound in tetrapyrrole synthesis, uroporphyrinogen III. This is a complex reaction requiring two enzymes Uroporphyrinogen I synthase, which catalyzes a head-to-tail condensation... 

Biosynthesis of In animals, fungi and some bacteria, the first step in tetrapyrrole synthesis is... 

Lascelles (1968) had earlier postulated that Bchl synthesis in Rhodobacter might require a carrier protein, and Richards, first working with Lascelles and later with his own students, showed that Bchl precursors are complexed with a 9 kDa pol)q>eptide in mutants that are blocked in Bchl synthesis. Before the existence of the 9 kDa protein was known, the reasons for suggesting a carrier protein were that exogenous protoporphyrin IX seemed to be incorporated by cells into heme but not into Bchl and that concurrent protein s)mthesis was required for Bchl synthesis. Furthermore, although Lascelles could demonstrate feedback inhibition of tetrapyrrole synthesis by heme, no similar effect by Bchl or its precursors could be demonstrated. 

A number of ALA analogues are known as competitive inhibitors of ALA dehydratase (Figure 5.7). These contain the succinyl residue of ALA and are believed to form Schiff bases with the enzyme, causing ALA to accumulate in treated tissues. Potentially, such a target for herbicides should be effective, resulting in inhibition of all tetrapyrrole synthesis. However, toxicological problems may be associated with the use of such compounds as herbicides owing to the universal occurrence of ALA dehydratase. 

With the catalysis of strong Lewis acids, such as tin(IV) chloride, dipyrromethenes may aiso be alkylated. A very successful porphyrin synthesis involves 5-bromo-S -bromomethyl and 5 -unsubstituted 5-methyl-dipyrromethenes. In the first alkylation step a tetrapyrrolic intermediate is formed which cyclizes to produce the porphyrin in DMSO in the presence of pyridine. This reaction sequence is useful for the synthesis of completely unsymmetrical porphyrins (K.M. Smith, 1975). 

The extremely high sensitivity of bacteriochlorins to various reactions makes their chemistry very difficult. This might also be one reason why methods for the total synthesis of bacteriochlorins had not, until very recently, been developed.13 Total synthesis of a tolyporphin model was reported by Kishi et al.13 using an approach that is very closely related to Eschenmoser s syntheses of hexahydroporphyrins from reduced linear tetrapyrroles by cyclization (see Section 1.5.1). 

The synthesis of hexahydroporphyrins has been achieved using two principal routes. The first route makes use of cyclizations of linear tetrapyrroles which are alkylated at the /i-positions to block the corphin-porphyrinogcn tautomerization after cyclization has been performed. In the second route the metal-induced tautomerization of porphyrinogens is utilized to obtain conjugated hexahydroporphyrins. 

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

A simple and rapid synthesis of tetrapyrrolic macrocycle has been achieved under dry media conditions with microwave activation. Pyrrole and benzaldehyde adsorbed on silica gel afford tetraphenylporphyrin within 10 min (Scheme 8.26), whereas with conventional methods (e. g. acetic acid in the presence of pyridine) 24 h were necessary. 

Coordination compounds composed of tetrapyrrole macrocyclic ligands encompassing a large metal ion in a sandwich-like fashion have been known since 1936 when Linstead and co-workers (67) reported the first synthesis of Sn(IV) bis(phthalocyanine). Numerous homoleptic and heteroleptic sandwich-type or double-decker metal complexes with phthalocyanines (68-70) and porphyrins (71-75) have been studied and structurally characterized. The electrochromic properties of the lanthanide pc sandwich complexes (76) have been investigated and the stable radical bis(phthalocyaninato)lutetium has been found to be the first example of an intrinsic molecular semiconductor (77). In contrast to the wealth of literature describing porphyrin and pc sandwich complexes, re-... 

A few examples to render tetrapyrrolic compounds less phototoxic can be found in the hterature. In one approach, carotenoid structures were employed for the synthesis of some carotenoporphyrin derivatives [92-94]. Figure 8 shows two stuctures by way of example. Due to similar photophysical properties of the two structural components, the excited triplet state of the porphyrin is quenched by the carotenoid moiety, thus inhibiting the formation of singlet oxygen, while its fluorescence capabilities are still preserved. Biodistribution studies revealed enhanced uptake into tumour tissue [39,93,95]. However, microscopy studies have shown that such compounds are associated with connective tissues in the tumors rather than with cancerous cells indicating low specificities for mahgnant transformation [96]. 

Another approach to minimize phototoxicity involved the synthesis of het-erodimeric conjugates of two chlorine tetrapyrroles [97]. 

Heme, an iron-containing tetrapyrrole pigment, is a component of 02-binding proteins (see p. 106) and a coenzyme of various oxi-doreductases (see p. 32). Around 85% of heme biosynthesis occurs in the bone marrow, and a much smaller percentage is formed in the liver. Both mitochondria and cytoplasm are involved in heme synthesis. 

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