Enantioselective organocatalytic Lewis bases

It should be noted that not only the Lewis base but also typical Lewis acid roles can be emulated by organocatalytic systems. The proton is arguably the most common Lewis acid found in Nature, and these exist in two forms classified by the nature of the hydrogen bond polar covalent (RX-H) and polar ionic (RX+H-Y ). In the former case, in asymmetric transformations the chiral information is dictated by the chiral anion, whilst in the latter case the anion is non-chiral and the enantioselectivity is introduced by a chiral ligand (usually an amine base), which complexates the proton. This activation is discussed more extensively in Chapter 7. 

Considerable effort has been devoted to the development of enantiocatalytic MBH reactions, either with purely organic catalysts, or with metal complexes. Paradoxically, metal complex-mediated reactions were usually found to be more efficient in terms of enantioselectivity, reaction rates and scope of the substrates, than their organocatalytic counterparts [36, 56]. However, this picture is actually changing, and during the past few years the considerable advances made in organocatalytic MBH reactions have allowed the use of viable alternatives to the metal complex-mediated reactions. Today, most of the organocatalysts developed are bifunctional catalysts in which the chiral N- and P-based Lewis base is tethered with a Bronsted acid, such as (thio)urea and phenol derivatives. Alternatively, these acid co-catalysts can be used as additives with the nucleophile base. 

Besides these organocatalytic methods, enantioselective Biginelli reactions can be induced by means of chiral Lewis acids. Indeed, the first synthesis of a highly enantioenriched dihydropyrimidine (compound 46) via Biginelli chemistry was developed by Zhu and coworkers in 2005 [46] and was based on the use of the chiral ytterbium species 47 as a Lewis acid catalyst. This reaction gave very good chemical yields and enantioselectivities and showed excellent functional group tolerance. In the proposed transition state, coordination of the catalyst with intermediate 48 leads... 

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