Metalloporphyrin hydroxylation

Groves JT, Subramanian DV. Hydroxylation by cytochrome-P-450 and metalloporphyrin models—evidence for allylic rearrangement. J Am Chem Soc 1984 106(7) 2177-2181. 

A new trend in the field of oxidations catalyzed by metalloporphyrin complexes is the use of these biomimetic catalysts on various supports ion-exchange resins, silica, alumina, zeolites or clays. Efficient supported metalloporphyrin catalysts have been developed for the oxidation of peroxidase-substrates, the epoxidation of olefins or the hydroxylation of alkanes. 

The metalloporphyrin-PhIO system catalyzes the oxidation of alkanes mainly to alcohols under mild conditions. High selectivity for the hydroxylation at the tertiary carbon is observed.132 Yields up to 40% based on the oxidant consumed are obtained. Acyclic alkanes usually exhibit very poor reactivity. A large isotope effect and retention of configuration in the oxidation of ds-decalin are additional important characteristics of the process. 

Metalloporphyrins have been used for epoxidation and hydroxylation [5.53] and a phosphine-rhodium complex for isomerization and hydrogenation [5.54]. Cytochrome P-450 model systems are represented by a porphyrin-bridged cyclophane [5.55a], macrobicyclic transition metal cyclidenes [5.55b] or /3-cyclodextrin-linked porphyrin complexes [5.55c] that may bind substrates and perform oxygenation reactions on them. A cyclodextrin connected to a coenzyme B12 unit forms a potential enzyme-coenzyme mimic [5.56]. Recognition directed, specific DNA cleavage... 

Among the oxidation catalyzed by heme enzymes, alkane hydroxylation is the hardest process to mimic with synthetic metalloporphyrins (7). This finding is also true for myoglobin mutants, even though the mutants are able to afford... 

Metalloporphyrins and some related metal complexes are effective catalysts in IOB oxidations, as already discussed for alkenes, and acids (Sections 5.1.1.1 and 5.2.4). Also, sulphides have been oxidized to sulphoxides [58]. Some other substrates of various types underwent such catalysed oxidations, because these systems mimic the natural oxidant cytochrome P-450 [2]. From a synthetic point of view, only a few reactions are of importance alkanes were mainly used which underwent regio- and stereo-specific hydroxylation, for instance the methyl group of a pyrrole derivative was converted into hydroxymethyl, leading to one-pot preparation of dipyrro-methanes [59], The preparation of elaborated catalysts is, however, very demanding and precludes a wider use. 

Cytochrome P-450 can perform both intramolecular and intermolecular nitrene insertions with 106 in water solution [181]. However, the intermediate metallo-nitrene (108) also hydrolyzed to some extent so the enzyme performed a hydroxylation as well as an amidation. Although we have also performed an intermolecular amidation of a steroid, using such a metalloporphyrin reaction with 106 to form 112 [182], we have not yet extended it to the kinds of directed functionalizations described above with either benzophenones or chlorinations. 

Metalloporphyrins can catalyze the hydroxylations of solvent species such as cyclohexane. From our studies with cyclodextrin dimers, we concluded that by attaching cyclodextrin rings to metalloporphyrins we should be able to bind substrates in water and achieve selective hydroxylations directed by the geometries of the complexes. This was successful. 

The last decade has greatly increased our knowledge on how metallo-porphyrins are able to interact with hydrogen peroxide without producing the unspecific hydroxyl radical. It would therefore appear likely that in the near future, industrial applications of such metalloporphyrins with hydrogen peroxide will be started in earnest. 

Whereas important progress has been made regarding the use of metalloporphyrins as catalysts for alkene epoxidations and alkane hydroxyla-tions, work concerning the mechanism of hydroxylation of aromatic hydrocarbons has received only limited attention. In fact, the main problem encountered with the design of systems capable of performing such oxidative reactions is in the preparation of superstructured porphyrins for the selective complexation of aromatic compounds. 

An example of application of Fe(III) porphyrins is the hydroxylation of the anticancer drug cyclophosphamide to active metabolite 4-hydroxycyclophosphamide in yields similar or higher than those typically obtained by the action of liver enzymes in vivo [198]. This allows the development of novel anticancer drugs for the treatment of tumors with less toxic side effects to the patient. There are many other examples of metalloporphyrin-based systems for the synthesis of drugs or agrochemicals that mimic P450 catalyzed processes. 

D. Mansuy, J. F. Bartoli, J. C. Chottard, M. Lange, Metalloporphyrin-catalyzed hydroxylation of cyclohexane by alkyl hydroperoxides pronounced efficiency of iron-porphyrins, Angew. Chem. Int. Ed. Engl. 19 (1980) 909. 

D. Mansuy, J. F. Bartoli, M. Momenteau, Alkane hydroxylation catalyzed by metalloporphyrins-evidence for different active oxygen species with aUcylhydroperoxides and lodosobenzene as oxidants. Tetrahedron Lett. 23 (1982) 2781. 

The kinetics of product evolution in a typical reaction of adamantane hydroxylation showed an initial induction period followed by a fast, apparently zero-order phase with the maximum rate and highest efficiencies (Fig. 2). Deviation from linear behavior took place only after 90% oxygen donor and 80% of the substrate had been consumed. When Ru (TPFPP)(0)2, prepared by reaction of Ru"(TPFPP)(CO) with 3-chloroperbenzoic acid was used as the catalyst, no induction time was detected and zero-order kinetics were observed as well. The well defined and characteristic UV-vls spectra of metalloporphyrins provide an invaluable tool for the mechanistic studies. Thus, monitoring the state of the metalloporphyrin catalysts during the course of both model reactions by UV-vis spectroscopy revealed that the initial form of the catalyst remained the predominant one throughout the oxidation, i.e. in the Ru°(TPFPP)(CO) catalyzed reaction c.a. 80% of the porphyrin catalyst existed as Ru"(TPFPP)(CO) and in Ru (TPFPP)(0)2 catalyzed reaction more than 90% of... 

Although the mechanism of hydroxylation of C-H bonds by P-450 is surrounded by controversy [8], it is very likely that hydroxylation of activated C-H bonds catalyzed by synthetic metalloporphyrin complexes proceeds through radical intermediates. 

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