Mechanism of cytochrome P-450 catalysis. Mechanism of N-dealkylation and amine oxide deoxygenation

Burka, Leo T.; Guengerich, F. Peter; Willard, R. J.; Macdonald, Timothy L.

doi:10.1021/ja00294a057

Cited by 106 publications

(61 citation statements)

References 2 publications

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“…The negative slope in Fig. 10 is in good agreement with the experimentally [90] reported negative Hammett slope value. Fig.…”

Section: Amine N-dealkylationsupporting

confidence: 87%

“…The N-dealkylation reaction of amine has been the subject of several experimental and theoretical investigations [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101]. NDealkylation of amine is proposed to result from hydroxylation of a carbon adjacent to the N atom, forming the unstable carbinolamine, which decomposes subsequently to give rise to a carbonyl product and a dealkylated amine.…”

Section: Amine N-dealkylationmentioning

confidence: 99%

“…One is a hydrogen atom transfer (HAT) reaction [86][87][88][89], labeled as (i), on the carbon adjacent to the N atom, followed by oxygen rebound to form the carbinolamine, which decomposes subsequently to formaldehyde and a dealkylated amine. An alternative mechanism involves a single electron transfer (SET) on the N atom itself [90,91,98], labeled as (ii), followed by proton transfer, and then oxygen rebound to form the carbinolamine, which then decomposes as outlined above.…”

Section: Amine N-dealkylationmentioning

confidence: 99%

“…Experimental results [87][88][89]99] on N-cyclopropylamines fit the HAT mechanism as well. The SET mechanism is supported by the low KIEs of oxidative dealkylation [93,94,101], as well as the correlation of the reaction rates for N-demethylation of p-X-DMAs with the Hammett substituent constant para and the redox potential E 1/2 of the p-X-DMA substrates [90,91].…”

Section: Amine N-dealkylationmentioning

confidence: 99%

“…Experimental studies revealed a fundamental mechanistic difference between the Ndemethylation reactions of the two systems: (a) The turnover rate of DMA N-demethylation exhibits a linear relationship with the nature of the para-substituent, with a moderately negative Hammett value [90], and the reaction rates correlate with the corresponding substrate redox potentials E 1/2 . By contrast, the Ndemethylation reaction rates of DMBA are entirely insensitive to the change in the p-X substituent.…”

Section: Amide N-demethylationmentioning

confidence: 99%

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Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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“…The negative slope in Fig. 10 is in good agreement with the experimentally [90] reported negative Hammett slope value. Fig.…”

Section: Amine N-dealkylationsupporting

confidence: 87%

Section: Amine N-dealkylationmentioning

confidence: 99%

Section: Amine N-dealkylationmentioning

confidence: 99%

Section: Amine N-dealkylationmentioning

confidence: 99%

Section: Amide N-demethylationmentioning

confidence: 99%

See 3 more Smart Citations

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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Use of Synthetic Metalloporphyrins as Oxidation Catalysts

Kim

Watanabe

2002

Encyclopedia of Catalysis

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While heme enzymes use iron porphyrin (heme) as the prosthetic group, a variety of metal ions can be introduced into the porphyrin ring to produce metalloporphyrin complexes. In addition to the change of the central metal ions, we are able to synthesize the porphyrin bearing many types of substituents. Thus, the use of synthetic metalloporphyrin complexes is not limited to model reactions of heme enzymes such as peroxidase and P‐450. Although a major concern of this review is oxidations catalyzed by metalloenzymes, many oxidants such as iodosylbenzene (C 6 H 5 IO), m ‐chloroperbenzoic acid ( m CPBA), and sodium hypochlorite (NaOCl) can be used in addition to hydrogen peroxide and reductive oxygen activation as observed for P‐450. In early part of this article, the use of metalloporphyrin as synthetic model systems of heme enzymes is discussed. Preparation and characterization of high valent oxo‐metal intermediates are reviewed in detail. Then, applications of synthetic metalloporphyrins as catalysts for oxidation reactions are described. Highly efficient, robostic against the heme destruction, and stereo‐ and enantioselective reaction systems are the major concerns.

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ThePolonovski Reaction

Grierson¹

1990

Organic Reactions

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In connection with their interest in the isolation and medicinal properties of the “gen alkaloids” ( N ‐oxides), Max and Michel Polonovski reported in 1927 their discovery that the treatment of a tertiary amine N ‐oxide with acetic anhydride or acetyl chloride results in a rearrangement in which one of the alkyl groups attached to nitrogen is cleaved, and the N ‐acetyl derivative of the corresponding secondary amine and aldehyde are obtained. As the original work by the Polonovskis was mainly carried out on bicyclic tropane N ‐oxide derivatives, the products of the reaction were the demethylated amides and formaldehyde. The reaction was thus looked upon as a means of effecting N ‐demethylation of tertiary amines. As such it was, and still remains, a viable alternative to the use of cyanogen bromide, alkyl chloroformates, azocarboxylic esters, or nitrous acid for this purpose. These methods often require more drastic conditions and/or promote unwanted side reactions. The central feature of the Polonovski reaction is the transformation of an N ‐oxide to an iminium ion intermediate. Depending on the structure of the substrate and the acid anhydride or other activating reagent employed, iminium ion formation can occur through loss of an α hydrogen, or through fragmentation of a Cαcarbon bond. Again, depending on conditions, the reaction will either stop at this stage and iminium ions become the Polonovski products, or proceed to give enamines or tertiary amides and/or secondary amines and aldehydes. The often close relationship between structure and reaction conditions, which determine both product types and reaction regiochemistry, is discussed. In its initial stages the Polonovski reaction resembles other reactions in which a tertiary amine is oxidized through interaction of the pair of electrons on nitrogen with an agent X followed by elimination of the elements of HX. Reagents like lead tetraacetate, N ‐bromosuccinimide and in particular mercuric acetate have been employed for this purpose. However, the Polonovski reaction can offer certain advantages in selectivity and experimental ease. In principle, any reagent capable of activating the N ‐oxide oxygen could promote the Polonovski reaction. However, three major types of activating agents, acid anhydrides and chlorides (including chloroformate esters), iron salts and complexes, and sulfur dioxide, are usually employed. Perhaps the most important contribution to the use of the Polonovski reaction in modern organic synthesis was the discovery in the 1960s that on replacing acetic anhydride by trifluoroacetic anhydride the reaction could be stopped at the iminium ion stage. Considering the rich chemistry of iminium ions, many applications of this modified, or Polonovski–Potier, reaction have appeared in the literature, the most spectacular of which was the first successful approach to the synthesis of the indole antitumor agents of the vinblastine group. In this chapter the discussion is limited to examples of the Polonovski reaction in which the abovementioned activating reagents are employed. The coverage is restricted to tertiary amine oxides in which at least one of the substituents on nitrogen is an alkyl group. Both acyclic and cyclic amine oxides such as piperidine N ‐oxide fall into this category, whereas heteroaromatic N ‐oxides do not. With the exception of one special case, nitrones are also omitted from the discussion. The literature coverage includes articles appearing before the end of August 1988.

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Mechanism of cytochrome P-450 catalysis. Mechanism of N-dealkylation and amine oxide deoxygenation

Cited by 106 publications

References 2 publications

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Use of Synthetic Metalloporphyrins as Oxidation Catalysts

ThePolonovski Reaction

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