Bifunctional catalysis organocatalysts

The concept of bifunctional catalysis as advanced for the natural cinchona alkaloids and cuprei(di)nes has resulted in the design and synthesis of a range of new cinchona derivatives. The major part of these novel organocatalysts are urea and thiourea cinchona derivatives together with cinchona alkaloids modified with, for example, a sulfonamide, squaramide, or guanidine group (Figure 6.8). 

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. 

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

Oxazole-containing molecules found several applications in catalysis and materials chemistry. Pyrrolidinyl-oxazole-carboxamide catalysts 140 were reported as new chiral bifunctional organocatalysts effective in the asymmetric Michael addition of ketones to nitroolefins (140BC8008). Compound 141 exhibits different spectral properties (both in absorption and emission) in response to external stimuli, such as pressure and protonation, and it is therefore promising for the realization of piezofluorochromic materials (14CC2569). 

Kokotos and coworkers investigated the use of prolinamide-based thioureas as bifunctional organocatalysts for the direct aldol reaction. The amide and the thiourea functionalities, tethered by a chiral diamine motif, offered multiple hydrogen bonding sites for electrophile activation, while the pyrrolidine skeleton served to activate the nucleophile via enamine catalysis. Thiourea 61 proved to provide the best catalyst in the presence of 4-nitrobenzoic acid as cocatalyst at low temperature and delivered the anti-aXAoX products in moderate to high yields and in high to excellent... 

Due to the unique bivalent carbene and diversity of the N-heterocyclic motif, NHCs have been demonstrated to be efficient organocatalysts for various enantioselective reactions. In addition to the traditional thioazolium and imidazolium NHCs, triazolium NHCs have become the most successful organocatalysts. Recently, NHC/Lewis acid cocatalysis and bifunctional NHCs have shown a very promising future. Beyond the classic NHC-catalysed umpolung of aldehydes, the extended umpolung of functionalised aldehydes are extremely successful. A series of NHC-catalysed reactions of ketenes have been developed for the synthesis of various enantioriched heterocycles. Esters, anhydrides, carboxylic acids and even Michael acceptors are useful alternative substrates for NHC-catalysed reactions. With increasing interest and rapid development of NHC catalysis, new structures of the catalysts, new reaction modes, and synthetic applications can be expected in the near future. 

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

Over the past decade, rapid growth has been achieved in organocatalytic asymmetric Diels-Alder and hetero-Diels-Alder reactions. Numerous organocatalysts such as chiral amines, guanidines, N-heterocyclic carbenes, Bronsted acids, and bifunctional catalysts have been successfully developed. The activation modes for these catalysts, such as imine-catalysis, enamine-catalysis, dienamine catalysis. 

Connon SJ. Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea organocatalysts. Chem. Commun. 2008 22 2499-2510. 

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