Lewis Base-Catalysed Aldol Additions

In 1996, Denmark et al. described an aldol reaction of trichlorosilyl enolates with aldehydes for the first time.¹ In contrast to the well-established Mukaiyama reaction, where catalytic amounts of Lewis acids were deployed in reactions with trimethylsilyl enolates, this transformation was catalysed by Lewis bases. When used with chiral Lewis bases, aldol adducts can be obtained with a high degree of enantioselectivity. For several comprehensive overviews in this field see Denmark and coworkers.^2,3,4 For a general and comprehensive overview of Lewis base catalysis in organic chemistry see Denmark and Beutner.⁵

The development of Lewis base-catalysed aldol additions was strongly connected with the development of an easy and general protocol for the synthesis of trichlorosilyl enolates and chiral Lewis bases. These problems were solved by Denmark and coworkers. They developed several useful and general procedures for the preparation of trichlorosilyl enolates of carbonyl compounds by metal exchange reactions. These are reactions between corresponding enol stannanes of ketones with SiCl₄, or metal exchange of trimethylsilyl enolethers with SiCl₄ in the presence of catalytic amounts of mercury(II) or tin(IV) salts or Pd(OAc)₂.⁶ The synthesis of trichlorosilyl enolates of aldehydes was accomplished by transmetallation of the corresponding trimethylsilyl ethers of aldehydes with SiCl₄ in the presence of catalytic amounts of Pd(OAc)₂.⁷ Trichlorosilyl enolates of ketones react at room temperature with aldehydes without any activation (Scheme 3.2.1).⁸