Hydroxylation of C-H bonds

The hydroxylation of C-H bonds by radicals, in contrast to the case of electrophilic oxidants, leads to alcohols without retention of stereochemical configuration. H202, activated by strong acids (superacids (277), HF-BF3 (272), A1C13 (213), and CF3COOH (214)) have been used for the hydroxylation of aromatic compounds. These acid-catalyzed hydroxylations cannot be applied for aliphatic reactants because the hydroxylated products are more reactive than the starting compounds and, hence, they are oxidized further. 

Of all of the molybdenum enzymes, mammalian xanthine oxidase/dehydrogenase has been the most studied (Figure 15). These studies, along with those of other members of this relatively large class of hydroxylases (Table la-c), suggest that all molybdenum enzymes that catalyze hydroxylation of C—H bonds contain a common structural motif. This motif is unique in high-valent molybdenum chem-... 

The active oxygen species of cytochromes P-450 is reactive enough to transfer its oxygen atom to most organic compounds. However, the most frequently encountered reactions are (1) the hydroxylation of C—H bonds, (2) the epoxidation of double bonds, (3) the hydroxylation of aromatic rings, and (4) the transfer of an oxygen atom to compounds containing an N, S, or P heteroatom. 

Terminal epoxides of high enantiopurity are among the most important chiral building blocks in enantioselective synthesis, because they are easily opened through nucleophilic substitution reactions. Furthermore, this procedure can be scaled to industrial levels with low catalyst loading. Chiral metal salen complexes have also been successfully applied to the asymmetric hydroxylation of C H bonds, asymmetric oxidation of sulfides, asymmetric aziridination of alkenes, and the asymmetric alkylation of keto esters to name a few. 

Research on aromatic hydroxylation by cytochrome P450 provides an example of how quantum chemical calculations on small models can help in developing structure-reactivity relationships. Hydroxylation of C-H bonds is a particularly important class of reaction in drug metabolism,185 which can activate pro-drugs, or affect the bioavailability of pharmaceuticals. For the reliable prediction of pharmaceutical metabolism and toxicology (ADME/ TOX) properties, a key aim is the development of structure-activity relationships to predict conversions of drugs. Earlier work has shown that structure-activity relationships based on the structures and properties of substrates alone are of limited utility. There is a need for more detailed models, which can include effects of the reaction mechanism and specificity of different cytochrome P450 isozymes. 

Only partial solutions have been provided thus far to many of the most important transformations amenable to asymmetric catalysis. For example, no generally effective methods exist yet for enantioselective epoxidation or aziridination of terminal olefins, or for hydroxylation of C-H bonds of any type. Despite the enormous advances in asymmetric hydrogenation catalysis, highly enantioselective reduction of dialkyl ketones remains elusive [9]. And as far as asymmetric C-C bond-forming reactions are concerned, the list of successful systems is certainly shorter than the list of reactions waiting to be developed. 

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. 

Since the development of a handy, even large-scale method for the generation of dime-thyldioxirane (9a), [16] it has become known best as a reagent for the epoxidation of double bonds. [17] Its application for the selective hydroxylation of C-H bonds at tertiary C atoms is less well known. For example, the reaction of 1 with 9a as the oxidizing agent provides 4 with only minor amounts (< 3 %) of side products. [18]... 

Hydroxylation of C-H bonds on tertiary C atoms can be conducted with solutions of fluorine in aqueous acetonitrile. [24] This... 

Fig. 6. Mechanism for the cleavage of DNA or DNA models after hydroxylation of C-H bonds on the 1 and 5 positions of deoxyribose by Cu(phen)2/H202 (route A) or Mn-TMPyP/KHSOs (routes A and B) (A = thermal step, B = base, BE = /3 elimination).

Hydroxylation of C-H Bonds. The only peroxidase known to effect the hydroxyl-ation of C-H bonds is chloroperoxidase (CPO) from the marine fungus Caldariomyces fumago. Its large-scale production is facilitated by the fact that it is an extracellular enzyme, which is excreted into the fermentation medium [1322-1324]. ° In order to become susceptible towards hydroxylation by CPO, the C-H bonds have to be activated by a 7i-electron system. In the allylic position, hydroxylation is not very efficient and it is doubtful whether this procedure will be of practical use [1325]. By contrast, benzylic hydroxylation is readily effected and the corresponding sec-alcohols were isolated in high e.e. (Scheme 2.177)... 

Lippard SJ. 2005. Hydroxylation of C-H bonds at carboxylate-bridged diiron centres. Phil Trans R Soc A 363 861-877. 

The recent literature has much disambiguated the reaction of hydroxylation of C-H bonds with dioxiranes, mostly contradicting previous beliefs. The present paper confirms the basic mechanism of the reaction in its first stage, i.e. attack of dioxirane oxygen to the hydrogen atom even for the case of diketopiper-azines [11]. We have also conducted studies about the successive stages of the reaction, but the presence of many interactions with the complicated substrate makes very difficult to rationalize and present the results. 

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