Organic amine-catalyzed aldol reaction

Although aminocatalysis of the aldol reaction via enamine intermediates is an important enzymatic strategy and several bioorganic studies of the subject have appeared, applications in preparative organic synthesis, particularly in intermolecular aldol addition reactions, have been published only sporadically. Despite the often-used Mukaiyama-aldol reaction of enol ethers and Stork s vell-developed enamine chemistry [37, 38], aldolizations of preformed enamines are rare. One report describes Le vis acid-catalyzed aldolizations of preformed enamines vith aldehydes that furnish aldol addition products [39]. Aldol condensation reactions of preformed enamines vith aldehydes have also been described [40]. Only enamine-catalytic aldolizations, vhich are primary and secondary amine-catalyzed aldol reactions, vill be discussed in this chapter, ho vever. 

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

Despite these mechanistic and theoretical studies, intermolecular amine-catalyzed aldolizations have only rarely been used on a preparative scale. A few note vorthy exceptions in vhich aldehydes are used as donors are sho vn in Scheme 4.6 [51-55]. These reactions are often performed neat or in the presence of small amounts of an organic solvent. The catalyst usually used is either a primary or secondary amine, a combination of an amine vith a carboxylic acid, or simply an amino acid. These catalyst systems have previously been used in the Knoevenagel condensation and it is apparent that synthetic amine-catalyzed aldolizations originate from Knoevenagel s chemistry [56]. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

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