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α‐Alkylation of Amino Acids without Racemization. Preparation of Either ( S )‐ or ( R )‐α‐Methyldopa from ( S )‐Alanine
Author(s) -
Seebach Dieter,
Aebi Johannes D.,
Naef Reto,
Weber Theodor
Publication year - 1985
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19850680118
Subject(s) - chemistry , racemization , alkylation , alkyl , stereochemistry , amino acid , chiral auxiliary , deprotonation , alanine , hydrolysis , walden inversion , chirality (physics) , methionine , organic chemistry , medicinal chemistry , enantioselective synthesis , catalysis , ion , biochemistry , nambu–jona lasinio model , chiral symmetry breaking , physics , quantum mechanics , quark
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 1 H‐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 pivaladehyde 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 occurring 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.