Iminium-enamine-acid catalysis

It is possible that conjugated enamines such as enaminones hydrolyze by the mechanism shown in Scheme 2, a variation of Scheme 1 in which nucleophilic hydration occurs on an O-protonated enamine rather than on the C-protonated (iminium) ion. This mechanism has been proposed for the acidic hydrolysis of compounds 36 and 37. This mechanism cannot be considered established, however, as the experiments that would rule out C-protonation were not done. It is highly pertinent that hydrolyses of other conjugated enamines, 10,11, 25, 26,39 and 40, all obey the expectations of Scheme 1, equation 15, namely they exhibit general-acid catalysis and (for 25, 26, 39 and 40) primary kinetic solvent isotope effects. 

Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

Chen and coworkers have reported a new domino Michael-Michael addition reaction between a,a-dicyanoalkene [26] derived from cyclohexanone and benzyli-deneacetone, resulting in a stepwise [4 + 2]-type cycloaddition to afford almost enantiopure bicyclic adduct 15. In contrast to the completely inert function of secondary ammonium salt, a primary amine, 9-amino-9-deoxyepiquinine lo [27], in combination with trifluoroacetic acid, was found to be highly efficient in the activation of the a, 3-unsaturated ketone by tandem iminium-enamine catalysis (Scheme 10.21) [28],... 

In the range of the study of new processes to improve the atom efficiency, the discovering versatility of a catalyst as multifunctional catalyst in a transformation is important. On the strength of this concept. Jiao and coworkers reported an enantioselective reduction and alkylation reaction of a,p-unsaturated aldehydes with alcohols, in which the ammonium salt catalyst performed three kinds of catalytic functions, namely, iminium catalysis, enamine catalysis, and acid catalysis [90]. 

S. K. Xiang, B. Zhang, L. H. Zhang, Y. Cui, N. Jiao, Chem. Commun. 2011, 47, 5007-5009. The versatile roles of ammonium salt catalysts in enantioselective reduction and alkylation of a, 3-unsaturated aldehydes iminium catalysis, enamine catalysis and acid catalysis. 

In the same year, Zhou and List reported a novel one-pot tandem reaction which, for the first time, combined chiral Bronsted acid catalysis with enamine and iminium catalysis. Later, on the basis of control experiments and ESI-MS/MS analysis, a reasonable mechanism was proposed (Scheme 2.2). The initial step of this tandem reaction was mediated by achiral /j-ethoxyaniline (PEP-NH2) and chiral phosphoric acid (R)-TRIP either reagent alone was inefficient in promoting this aldol condensation to afford the first iminium intermediate. The following step was a conjugate reduction which was also Bronsted acid and amine co-catalysed, and no further conversion took place in the absence of either catalyst. The final step was an acid-catalysed reductive amination. This novel sequence allowed the highly enantioselective synthesis of pharmaceutically active chiral ds-3-substituted cyclohejyl or heterocyclohexyl amines in high diastereo- and... 

Nature s aldolases use combinations of acids and bases in their active sites to accomplish direct asymmetric aldolization of unmodified carbonyl compounds. Aldolases are distinguished by their enolization mode - Class I aldolases use the Lewis base catalysis of a primary amino group and Class II aldolases use the Lewis acid catalysis of a Zinc(II) cofactor. To accomplish enolization under essentially neutral, aqueous conditions, these enzymes decrease the pKa of the carbonyl donor (typically a ketone) by converting it into a cationic species, either an iminium ion (5) or an oxonium ion (8). A relatively weak Bronsted base co-catalyst then generates the nucleophilic species, an enamine- (6) or a zinc enolate (9), via deprotonation (Scheme 4.2). 

Cascade reactions triggered by the combination of chiral amines and achiral Brpnsted acid were well documented on the basis of enamine and iminium ion formation, while examples with the combination of a chiral amine catalyst and a chiral Brpnsted acid were rare, hi 2(X)7, Zhou and List reported an elegant cascade intramolecular aldol-reduction process to prepare chiral 3-substituted cyclohexyl-amines by combining achiral enamine catalysis and chiral phosphoric acid catalysis [38]. Unusually, achiral aryl primary amine was exploited as an amino catalyst to generate a transient enamine intermediate to facilitate an intramolecular aldolization-dehydration process, while chiral phosphoric acid was harnessed to accelerate the following conjugate reduction-reductive amination cascade. Starting from readily available 2,6-diketones and aryl amines, pharmaceutically relevant 3-substituted cyclohexyamine derivatives were readily produced in satisfactory yield and excellent enantioselectivity (Scheme 9.42). 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

L-Proline is perhaps the most well-known organocatalyst. Although the natural L-form is normally used, proline is available in both enantiomeric forms [57], this being somewhat of an asset when compared to enzymatic catalysis [58], Proline is the only natural amino acid to exhibit genuine secondary amine functionality thus, the nitrogen atom has a higher p Ka than other amino acids and so features an enhanced nucleophilicity compared to the other amino acids. Hence, proline is able to act as a nucleophile, in particular with carbonyl compounds or Michael acceptors, to form either an iminium ion or enamine. In these reactions, the carboxylic function of the amino acid acts as a Bronsted acid, rendering the proline a bifunctional catalyst. 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

Proline is a stable, nontoxic, cyclic, secondary pyrrolidine-based amino acid with an increased pK value. Thus, proline is a chiral bidentate compound that can form catalytically active metal complexes (Melchiorre et al. 2008). Bidentate means that proline has not only one tooth but also a second one to bite and react. The greatest difference to other amino acids is a Lewis-base type catalysis that facilitates iminium and enamine-based reactions. It is especially noteworthy that cross-aldol condensations of unprotected glycoladehyde and racemic glyceralde-hyde in the presence of catalytic amounts of the Zn-(proline)2 gave a mixture of pentoses and hexoses (Kofoed et al. 2004). Again, proline seems to play the decisive role. The conditions are prebiotic the reaction proceeded in water for seven days at room temperature. It is remarkable that the pentose products contained ribose (34%), lyxose (32%), arabinose (21%), and xylose (12%) and that all are stable under the conditions. Thus, the diastereomeric and enantiomeric selection observed support the idea that amino acids have been the source of chirality for prebiotic sugar synthesis. 

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