Aldol Reactions with Preformed Enolates

The synthesis of lithium enolates and their application in aldol additions have been the subject of several reviews.^1,2,3,4,5,6These are highly reactive, their handling is easy and they can be used on a large scale—even on an industrial scale.⁷ Ideal starting compounds proved to be chiral ene components. For that reasons most published results used this route. Heathcock et al. used lithium enolates of chiral carbohydrate-derived ketones in aldol additions. By additions to aldehydes moderate diastereo selectivities were detected.^8,9,10Pioneering investigations were made by Seebach and coworkers.¹¹ Enantiomerically pure 3-methyl-2- pentanone was converted into the corresponding lithium enolate. Subsequently addition of acetaldehyde, propion aldehyde or benzal-dehyde yielded the expected β-hydroxycarbonyl compounds. Later on, Seebach and coworkers developed the concept of ‘self-reproduction of chirality’, which is based on the use of chiral lactones.¹² Aldehydes and unsymmetrical ketones were added to lithium enolates of readily available chiral acetales derived from lactic acid, mandelic acid or amino acids.^13,14,15 High stereo selectivities were achieved. Liebeskind and Davies demonstrated that optically active iron acyl complexes can serve as chiral ene components.^16,17 Thus, through a diastereoselective reaction high stereoselectivi-ties were observed. An improvement of this strategy was achieved by introducing a pentafluorophenyl containing phosphane ligand instead of triphenylphosphane.¹⁸ Due to acceptor—donor interactions of enolate oxygen and perfluorinated phenyl ring high stereoselectivities in reactions with aldehydes were observed. Yamamoto and cow-orkers applied acetates to aldol additions containing an axial chirality. The lithium enolates react with aldehydes in a highly stereoselective manner.¹⁹ Braun et al. developed a concept based on the use of hydroxy-1,1,2-triphenylethyl acetate (HYTRA).²⁰ The starting materials—both enantiomers of methyl mandelate—are inexpensive and readily available. Double deprotonation of the starting chiral acetate 1 (commercially available) and addition to aldehydes yielded aldol adducts 2 and 3 in high diastereo meric ratios.^21,22,23,24 The diastereoselectivity can be enhanced by further adding magnesium halides (see Scheme 2.1.1).

The reliability of this transformation was demonstrated by the application in the synthesis of a large number of biologically active compounds as well as natural products. This corresponds to the syntheses of γ-amino-β-hydroxybutanoic acid (GABOB),²⁵ shikonin and alkannin,²⁶ digitoxose,²⁷ detoxinine²⁸ and statin.²⁹ Even stereoselective syntheses of tetrahydrolipstatine,³⁰ compactin,³¹ epothilones,³² (23S)-hydroxyvitamin D3 derivatives³³ and synthetic inhibitors of HMG-CoA reductase³⁴ were carried out on an industrial scale with the aid of HYTRA aldol methodology.