Direct Conjugate Additions via Enamine Activation

Small chiral organic molecules may catalyze the asymmetric addition of ketones, and aldehydes to electron-deficient olefins, such as vinylidene acetones, nitroole-fins, enones, and vinyl sulfones. In this chapter we will describe the inter- and intramolecular reactions in which activation of the carbonyl compound takes place via enamine formation. 

Although asymmetric conjugate additions have over the years been dominated by the application of chiral Lewis acids as catalysts [1, 2], more recently organo-catalysts have been added as efficient tools [3, 4]. 

Chiral organic molecules may promote conjugate additions in numerous ways (see also Chapters 3, 4 and 6). An important part of this chemistry is related to aminocatalytic reactions [5], that is, when activation takes place either via imi-nium intermediates (see Chapter 3) or, by activating the donors by forming enam-ines (this Chapter). 

Factors Determining the Stereoselectivity of the Organocatalytic Conjugate Additions 

The partial steps of the conjugate addition in aminocatalytic reactions are in dynamic equilibrium, and thus products are formed under thermodynamic control. This fact is translated also in the geometry of the enamine intermediates, leading to the product, which can be either E or Z (Fig. 2.9). The geometry of the enamine depends on the catalyst structure and also on the substrate. Whilst proline-catalyzed reactions form preferentially, with a-alkyl substituted ketones, the. E-isomer, enamines derived from pipecolic acid afford an approximate 1 1 mixture of the E and Z isomers [6], In turn, small- and medium-sized cyclic ketones afford the E isomer. 

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