Organocatalysts iminium

Proline as an Asymmetric Organocatalyst Iminium-Activation of dienophile... 

Pyrrolidinium tetrafluoroborate (105) serves as an organocatalyst for the reaction of benzaldehyde with A-methyl pyrrole, to give the corresponding dipyrromethanes (106) under mild conditions.301 Initial formation of an iminium ion by condensation of the aldehyde with the catalyst is proposed. 

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

The first highly regio-, chemo-, diastereo-, and enantio-selective vinylogous Michael addition of oqa-dicyanoalkenes to oq/S-unsaturated aldehydes employs salts of a,a-diarylprolinol (103) (20 mol%) as organocatalysts. The reaction presumably involves the formation of an iminium species from the aldehyde as the first step of the cascade.153... 

A reasonable variation of the mechanism, in which piperidine acts as organocatalyst, involves the corresponding iminium intermediate as the acceptor ... 

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. 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

A limitation of MacMillan s approach towards iminium-activated Diels-Alder reactions has been the use of a-substituted a,/ -unsaturated aldehydes as dieno-philes. Recently, Ishihara and Nakano [31] succeeded in partially overcoming this problem by identifying a novel primary amine organocatalyst for this type of... 

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. 

The asymmetric reduction of imines and iminium species can be achieved using organocatalysts. The transfer hydrogenation of imines is catalysed by acids and this has led to the development of biomimetic asymmetric reductions using enan-tioselective Bronsted acids in combination with Hantzsch esters as a hydride... 

Notably, 2-substitution on the indole moiety led to enhaneed selectivity, indicative of beneficial steric effects [e.g. when is H, only 11% enantiomeric excess is observed). Additionally, as solvent polarity decreased, increases in both rate and stereoselectivity were observed. Screening other organocatalysts and other proline derivatives identified L-proline as the optimal catalyst this was suggestive of the important role of proline s carbojylate moiety in generating the iminium-like indole carbocation. It was postulated that proline s carbo>ylate moiety could interact via electrostatic interactions with the carbocation intermediate, which was thought to explain solvent effects. ... 

The iminium strategy, elegantly illustrated by MacMillan, using chiral imidazolidinones as organocatalysts in a Diels-Alder reaction was then... 

A new approach to stereoselective transfer hydrogenation of imines was the application of chiral phosphoric acid esters as organocatalysts [50-52]. The mechanism is based on the assumption that the imine is protonated by a chiral Bronsted acid, which acts as the catalyst. The resulting diastereomeric iminium ion pairs, which may be stabilized by hydrogen bonding, react with the Hantzsch dihydropyridine at different rates to give an enantiomerically enriched amine and a pyridine derivative [50-52]. The exact mechanism is still under discussion however computational density functional theory (DFT) studies ]53, 54] suggest a three-point contact model. ... 

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