Abstract:Mechanistic studies with 5-ethyl-3-methyllumiflavinium (Fl + )p erchlorate, ab iomimetic model for flavoenzyme monoamine oxidase B( MAO-B) catalysis, and the tertiary, allyl amine 1-methyl-4-(1-methyl-1 H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP) revealt hat proton-coupled electron transfer (PCET) may be an important pathway for MAO catalysis. The first step involves as ingle-electron transfer (SET) leading to the free radicals FlC and MMTPC,t he latter produced by deprotonation of the initially formed an… Show more
“…A first irreversible oxidation wave appeared at a slightly lower oxidation potential than the oxidation event of the amine alone. This shift of potential relative to the cyclic voltammogram in the absence of base is attributed to an oxidation event of the amine interacting with cesium pivalate, possibly a proton-coupled electron transfer process 64 , 65 . The second wave, whose potential corresponds to the oxidation event observed in the absence of base, becomes less reversible in presence of cesium pivalate.…”
Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. These bicyclic aniline derivatives are hardly accessible via the classical Robinson tropane synthesis and represent a particularly attractive scaffold for medicinal chemistry. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.
“…A first irreversible oxidation wave appeared at a slightly lower oxidation potential than the oxidation event of the amine alone. This shift of potential relative to the cyclic voltammogram in the absence of base is attributed to an oxidation event of the amine interacting with cesium pivalate, possibly a proton-coupled electron transfer process 64 , 65 . The second wave, whose potential corresponds to the oxidation event observed in the absence of base, becomes less reversible in presence of cesium pivalate.…”
Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. These bicyclic aniline derivatives are hardly accessible via the classical Robinson tropane synthesis and represent a particularly attractive scaffold for medicinal chemistry. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.
“…Both reactions, MPTP activation to MPP + and its deactivation by N -demethylation, are catalyzed by MAO B and P450s (Fig. 26 ) (Bajpai et al 2013 ; Hanna et al 2001 ; Herraiz et al 2006 ; Nakamura et al 2020 ; Trevor et al 1987a ; Uehara et al 2015 ). Fig.…”
Section: Examples Of Metabolic Reactions Of Mao Substratesmentioning
This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, “general chemicals,” natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10–15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.
“…This shift of potential relative to the cyclic voltammogram in the absence of base is attributed to an oxidation event of the amine interacting with cesium pivalate, possibly a proton-coupled electron transfer (PCET) process. 54,55 The second wave, The hypothesis that the reactions stop at the bicyclic stage due to inefficient deprotonation of the bicyclic radical cations offers the opportunity to run a more complex reaction process involving a bisannulation process starting from a tertiary acyclic aniline derivative and ending with an oxidationresistant bicyclic system. This assumption was tested with N,N-dimethyl aniline.…”
Section: Scheme 10 Thermodynamic Epimerization Of Tropane and Homotropane Derivativesmentioning
A mild and simple protocol for the synthesis of 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives is described. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.
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