Metallophosphite-catalyzed asymmetric acylation of alpha,beta-unsaturated amides

Abstract

The l-menthone-derived TADDOL phosphite 6b catalyzes highly enantioselective conjugate additions of acyl silanes to alpha,beta-unsaturated amides. p-Methoxybenzoyl cyclohexyldimethylsilane adds to a variety of N,N-dimethyl acrylamide derivatives in the presence of the lithium salt of 6b. In many instances the alpha-silyl-gamma-ketoamide product undergoes facile enantioenrichment (to 97-99% ee) upon recrystallization. Desilylation with HF.pyr affords the formal Stetter addition products. Baeyer-Villiger oxidation of the desilylated gamma-ketoamides affords useful ester products. An X-ray diffraction study of 6b reveals that the isopropyl group of the menthone ketal influences the position of the syn-pseudoaxial phenyl group in the TADDOL structure. Through a crossover experiment, the silicon migration step in the reaction mechanism is shown to be strictly intramolecular.

Figure 1

TADDOL-phosphites containing the l-menthone ketal.

Figure 2

X-ray structures of phosphites 1-Ph and 6b.

Figure 3

Proposed model for anti diastereoselectivity.

Scheme 1

Alkene Acylation Catalyzed by Phosphites 1-Ar

Scheme 2

Enantioselective Acylation of N,N-Dimethylcinnamide

Scheme 3

Recrystallization and Enantiomeric Excess Upgrade of α-Silyl-γ-ketoamide 11

Scheme 4

Synthetic Operations Involving 13a

Scheme 5

Crossover Experiment to Determine Silyl Group Transfer Pathway