α-Alkylation of Amino Acids without Racemization. Preparation of Either (S)- or (R)-α-Methyldopa from (S)-Alanine

Article abstract of DOI:10.1002/hlca.19850680118

Enantiomerically pure cis- and trans-5-alkyl-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-ones (1, 2, 11, 15, 16) and trans-2-(tert-butyl)-3-methyl-5-phenylimidazolidin-4-one (20), readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21).Diastereoselective alkylation of these enolates to 5,5-dialkyl- or 5-alkyl-5-arylimidazolidinones (5, 6, 9, 10, 13a-d, 17, 18, 22) and hydrolysis give α-alkyl-α-amino acids such as (R)- and (S)-α-methyldopa (7 and 8a, resp.), (S)-α-methylvaline (14), and (R)-α-methyl-methionine (19).The configuration of the products is proved by chemical correlation and by NOE 1H-NMR measurements (see 23, 24).In the overall process, a simple, enantiomerically pure α-amino acid can be α-alkylated with retention or with inversion of configuration through pivalaldehyde acetal derivatives.Since no chiral auxiliary is required, the process is coined 'self-reproduction of a center of chirality'.The method is compared with other α-alkylations of amino acids occuring without racemization.The importance of enantiomerically pure, α-branched α-amino acids as synthetic intermediates and for the preparation of biologically active compounds is discussed.