Dealkylation, base catalyzed

Since the N(5)-methylflavinium cation undergoes general-base-catalyzed dealkylation (Equation 36) (31) with a deuterium kinetic isotope effect (N(5)—CH3/N(5)—CD3) of greater than 10, we chose —CD3 and more simply —CH2CH3 as the N(5)-blocking groups. The compound 4a-FlEtOOH is prepared routinely in our laboratory in... 

Okazaki O, Guengerich FP. Evidence for specific base catalysis in M-dealkylation reactions catalyzed by cytochrome P450 and chloroperoxidase. Differences in rates of deprotonation of aminium radicals as an explanation for high kinetic hydrogen isotope effects observed with peroxidases. / Biol Chem 1993 268 1546-52. 

It is generally admitted that skeletal transformations of hydrocarbons are catalyzed by protonic sites only. Indeed good correlations were obtained between the concentration of Bronsted acid sites and the rate of various reactions, e g. cumene dealkylation, xylene isomerization, toluene and ethylbenzene disproportionation and n-hexane cracking10 12 On the other hand, it was never demonstrated that isolated Lewis acid sites could be active for these reactions. However, it is well known that Lewis acid sites located in the vicinity of protonic sites can increase the strength (hence the activity) of these latter sites, this effect being comparable to the one observed in the formation of superacid solutions. Protonic sites are also active for non skeletal transformations of hydrocarbons e g. cis trans and double bond shift isomerization of alkenes and for many transformations of functional compounds e.g. rearrangement of functionalized saturated systems, of arenes, electrophilic substitution of arenes and heteroarenes (alkylation, acylation, nitration, etc ), hydration and dehydration etc. However, many of these transformations are more complex with simultaneously reactions on the acid and on the base sites of the solid... 

Silverman s studies on mechanism based MAO inactivation have provided overwhelming support for the role of electron transfer in the MAO catalyzed dealkylation of amines. It must be mentioned however that spectroscopic attempts for detecting the radical ion intermediates have hitherto been unsuccessful. Yasanobu and coworkers could not find EPR spectral evidence for radical intermediates in MAO-catalyzed oxidation of benzylamine [205]. Miller et al. failed to observe the flavin semiquinone or an amine-flavin adduct in rapid-scan-stopped flow spectroscopy [206]. The only time-dependent absorption change observed in this study was the bleaching of the oxidized flavin. Furthermore, no influence of a magnetic field up to 6500 G was observed on the rate of MAO B reduction. The reaction rates of systems with kinetically significant radical pair intermediates are known to be altered... 

Search for new mechanism based investigations for deducing the mechanism of the enzyme catalyzed activity continues to be active area of research. Mariano and coworkers have used activated flavins such as 5-ethylflavinium perchlorate, whose ground state reduction potentials are high enough to promote oxidative dealkylation of amines, as enzyme models [209]. Studies on the inactivation of the model enzymes by cyclopropylamines and a-silylamines suggest a polar mechanistic model. Silverman attributes this result to the drastically altered nature of the flavin used in these studies, which could favor a nucleophilic mechanism [16]. 

Studies using isotopic labeling as well as mechanism based on inactivation such as 4-alkyldihydropyridines and cycloalkylamines have supported the view that the first step involves an electron-transfer process (path a. Scheme 23) [18, 184-186, 211]. Deprotonation of the resultant aminium radical would yield the a-aminoalkyl radical. The formation of the dealkylated amine and carbonyl derivative has been proposed to occur via a second electron transfer to the enzyme and a nonenzymatic hydrolysis of the imine formed. In the P-450 catalyzed reaction, however this process is proposed to occur via a radical recombination process to yield a carbinolamine (99) which then decomposes to the dealkylated amine and the corresponding carbonyl derivative. Evidence for this was obtained by the incorporation of label from 02, into the carbonyl derivative [212-214]. 

Fig. S.7 Mechanistic pathways to the quasi-irreversible mechanism-based inactivation via P450-catalyzed MI-complex generation from amines. Pathway a entails P450-mediated sequential N-dealkylation of secondary and tertiary amines to the primary amine that is then oxidized to the hydroxylamine. The latter requires a further P450-mediated or autocatalytic oxidation to the nitroso...

P450 2D6 catalyzes maity of the basic kinds of oxidative reactions of P450s, e.g., aliphatic and aromatic hydroxylations, heteroatom dealkylations, etc. [887]. In early work in this laboratory [888], the observation was made that many of the substrates contained a basic nitiDgen atom situated 5 A away from the site of oxidation, possibly due to a specific anionic charge in P450 2D6. Subsequently more detailed pharmacophore models have been developed [889-892]. All of these are based on the premise that a basic nitrogen atom in the molecule interacts (coulom-bic bond) with an acidic anuno acid in P450 2D6, usually Asp-301 in most studies. (More recent work shows a role for Glu-216, however, vide infra.)... 

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