Direct Aldol Addition

Several aspects of C—C bond formation processes in the mid-1990s led to the beginning of the development of so-called direct aldol additions. Due to the increasing demands of the industry for environmentally clean and economic reaction conditions and atom economy¹ stoichiometric amounts of reagents should be excluded. These processes are connected with waste, salts, aqueous solutions of base or acids. For that reasons a direct and catalytic asymmetric aldol addition is strongly suggested.

Early examples of this development are the applications of catalytic amounts of Lewis acids using unactivated carbonyl components in direct aldol additions. Miyoshi and coworkers described the employment of a BiCl₃-Zn reagent.² Mahrwald and coworkers reported the use of substoichiometric amounts of titanium(IV) halides in direct aldol additions.^3,4 When used with unsymmetrical ketones in these direct aldol additions high degrees of regio- and diastereoselectivities were measured. C—C bond formation was observed at the sterically more encumbered α-position of the ketones only.⁵ Later on Tanabe and coworkers reported the in situ generation of silyl enol ethers using catalytic amounts of trimethylchlorosilane in the presence of a TiCl₄/amine reagent. Thus, the authors were able to react ketones with sterically overcrowded ketones.^6,7,8,9