Enantioselective synthesis of β-hydroxy-α-methyl carbonyl compounds by aldol reaction

Abstract

The enantioselective aldol reactions of ketone lithium enolates with aldehydes mediated chiral lithium amides were extensively investigated. The chiral amino ethers 4a– 4l and diamines 16a, b were prepared from α-amino acids. The reaction conditions and the substituent effects of chiral lithium amides were examined using 4a– 4l and 16a, b in the aldol reaction of lithium enolate of 2,2-dimethyl-3-pentanone ( 17a) with benzaldehyde. When the lithium amide from 4b or 4c was used, 18a was obtained in 92–93% yield and 68% enantiomeric excess. Reactions of various ketones 17a– 17d with aldehydes afforded the β-hydroxy-α-methyl carbonyl compounds 18a– 18k in 40–95% yield and 10–77% enantiomeric excess. The best result of 77% enantiomeric excess was realized in the aldol reaction of 17a with 1-naphthaldehyde using the chiral lithium amide from 4b. The aldols 18i– 18k were easily converted to the carboxylic acid derivatives 19a– 19c of 40–60% enantiomeric excess.