ASYMMETRIC-SYNTHESIS BASED ON ENOLATE CHEMISTRY - BETA-LACTAM SYNTHESIS AND MEMORY OF CHIRALITY

Two topics are described concerning asymmetric synthesis utilizing enolate chemistry. The first one is stereoselective beta-lactam synthesis through oxidative coupling of dienolates generated from acyclic tertiary amides. Amides 4 were converted into dienolates by treatment with two equivalents of n-butyllithium or t-butyllithium, and the dienolates were oxidized with N-iodosuccinimide (NIS) or Cu(II) acetate to form beta-lactams 5 stereoselectively. The stereochemistry of beta-lactam formation depends on the oxidant: NIS is cis-selective, whereas Cu(II) acetate is slightly trans-selective, By the use of optically active 1-phenylethylamine as a chiral auxiliary, asymmetric induction of 90% de is achieved. The product 11 was transformed to an intermediate for the synthesis of monobactam antibiotic carmonam. Chemoselective epimerization of cis-beta-lactam 13 was accomplished with trifluoroacetic acid, and the resulting trans-isomer 14 was converted into an intermediate of monobactam antibiotic aztreonam. The second topic is asymmetric alkylation of enolates based on a new concept, memory of chirality. An optically active ketone 20 was treated with potassium hydride and a series of alkyl halides in the presence of 18-crown-6 to furnish optically active alkylated ketones 21 in 48-73% ee without any external chiral source. These findings contravene the accepted view that chirality at the alpha-carbon to carbonyl groups is lost in the corresponding enolates because the enolates themselves are achiral. To explain this phenomenon, we propose a novel concept that chirality at the alpha-carbon to the carbonyl group is memorized as dynamic axial chirality in the intermediate enolate, and is then regenerated as central chirality in the reaction products (memory of chirality). This mechanism was supported by trapping the enolate as methyl enol ether 27 of 65% ee. The present concept was successfully applied to the development of the asymmetric alpha-alkylation reactions of a-amino acid derivatives. Thus, phenylalanine derivative 33 was found to undergo asymmetric alpha-alkylation in up to 88% ee when treated with lithium 2,2,6,6-tetramethylpiperidide followed by alkyl halides.