Oxidative catalysis, enamines

The asymmetric a-chlorination of aldehydes has also be achieved using SOMO catalysis (Scheme 13.21) [49]. In these reactions, saturated aldehydes condensed with MacMillan s imidazolidinone organocatalyst to form enamines. The oxidant combination of Cu(TFA)2 and Na2S20g oxidized the enamine to the radical cation (inset in Scheme 13.21), the reactive intermediate in this transformation containing... 

Reaction conditions depend on the reactants and usually involve acid or base catalysis. Examples of X include sulfate, acid sulfate, alkane- or arenesulfonate, chloride, bromide, hydroxyl, alkoxide, perchlorate, etc. RX can also be an alkyl orthoformate or alkyl carboxylate. The reaction of cycHc alkylating agents, eg, epoxides and a2iridines, with sodium or potassium salts of alkyl hydroperoxides also promotes formation of dialkyl peroxides (44,66). Olefinic alkylating agents include acycHc and cycHc olefinic hydrocarbons, vinyl and isopropenyl ethers, enamines, A[-vinylamides, vinyl sulfonates, divinyl sulfone, and a, P-unsaturated compounds, eg, methyl acrylate, mesityl oxide, acrylamide, and acrylonitrile (44,66). 

Carbonyl addition reactions include hydration, reduction and oxidation, the al-dol reaction, formation of hemiacetals and acetals (ketals), cyanohydrins, imines (Schiff bases), and enamines [54]. In all these reactions, some activation of the carbonyl bond is required, despite the polar nature of the C=0 bond. A general feature in hydration and acetal formation in solution is that the reactions have a minimum rate for intermediate values of the pH, and that they are subject to general acid and general base catalysis [121-123]. There has been some discussion on how this should be interpreted mechanistically, but quantum chemical calculations have demonstrated the bifunctional catalytic activity of a chain of water molecules (also including other molecules) in formaldehyde hydration [124-128]. In this picture the idealised situation of the gas phase addition of a single water molecule to protonated formaldehyde (first step of Fig. 5) represents the extreme low pH behaviour. 

In these reactions, the C2-atom of ThDP must be deprotonated to allo v this atom to attack the carbonyl carbon of the different substrates. In all ThDP-dependent enzymes this nucleophilic attack of the deprotonated C2-atom of the coenzyme on the substrates results in the formation of a covalent adduct at the C2-atom of the thiazolium ring of the cofactor (Ila and Ilb in Scheme 16.1). This reaction requires protonation of the carbonyl oxygen of the substrate and sterical orientation of the substituents. In the next step during catalysis either CO2, as in the case of decarboxylating enzymes, or an aldo sugar, as in the case of transketo-lase, is eliminated, accompanied by the formation of an a-carbanion/enamine intermediate (Ilia and Illb in Scheme 16.1). Dependent on the enzyme this intermediate reacts either by elimination of an aldehyde, such as in pyruvate decarboxylase, or with a second substrate, such as in transketolase and acetohydroxyacid synthase. In these reaction steps proton transfer reactions are involved. Furthermore, the a-carbanion/enamine intermediate (Ilia in Scheme 16.1) can be oxidized in enzymes containing a second cofactor, such as in the a-ketoacid dehydrogenases and pyruvate oxidases. In principal, this oxidation reaction corresponds to a hydride transfer reaction. 

In the next section, the mechanism of the C2-H deprotonation of ThDP in enzymes is considered, followed by a discussion of the proton transfer reactions during catalysis. Finally, the oxidation mechanism of the a-carbanion/enamine intermediate in pyruvate oxidase is discussed. 

The use of secondary amine catalysis in combination with radical chemistry was first introduced by MacMillan in 2007 in a process he termed as organo-SOMO catalysis [32]. hi this system, the enamine that is generated in the condensation of a chiral secondary amine and a carbonyl, is oxidized via a single electron process. This generates a three-7i-electron radical cation with a singly occupied molecular orbital (SOMO) which can react asymmetrically in a variety of different processes (Scheme 1.25). 

OxidatiV0 Enamine Catalysis. The oxidative transformation of enam-ines derived from saturated aldehydes into a,(3-unsaturated iminium ions by dehydrogenation has been independently disclosed in 2011 by Li, Wang, and co-workers [108] and by Hayashi and co-workers [109]. This chemistry provides an alternative procedure to the standard iminium catalysis, which relies on the use of a,(3-unsaturated aldehydes. Both research groups used diphenylprolynol trimethylsilyl ether as the chiral amine catalyst but while Wang employs o-iodoxybenzoic acid (IBX) as the stoichiometric oxidant [108], Hayashi s procedure relies on the use of 2,3-dichloro-5,6-dicyanoquinone (DDQ) as the oxidant [109]. This oxidation can be performed in the presence of a suitable nucleophile... 

Comparing the activation mode of iminium and enamine catalysis, iminium catalysis is based on a LUMO-activation mode of the electrophile whereas enamine catalysis is based on a HOMO-activation of the nucleophile. Keeping in mind the fact that enamine and iminium species are rapidly interconverted via a two-electron redox process (proton abstraction of an iminium species results in an enamine), MacMillan and co-workers reasoned that it should be possible to interrupt this equilibrium chemically by carrying out just a one-electron oxidation of an enamine. This would then generate a three-7i-electron radical cation with a singly occupied molecular orbital (SOMO) that should be activated towards catalytic transfomiatirHis (racemic or asymmetric) not possible using classical enamine or iminium activation (Scheme 80) 316). 

An enantioselective a-alkylation of aldehydes (R-CH2CHO) gives a xanthenyl product (137, X = O) in up to 93% ee, using a simple organocatalyst (138) that activates the aldehyde via enamine catalysis, with subsequent addition of the stabilized benzyllc carbocation. This dehydrogenative alkylation uses dioxygen as oxidant and has been extended to the cases of thioxanthene and 10-methyl-9,10-dihydroacridine (i.e. 137, X = S and NMe). 29... 

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