Effective methods for the synthesis of N-methyl β-amino acids from all twenty common α-amino acids using 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones

N-Methyl beta-amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxazolidin-5-ones to synthesise N-methyl alpha-amino acids. Starting from alpha-amino acids, two approaches were used to prepare the corresponding N-methyl beta-amino acids. First, alpha-amino acids were converted to N-methyl alpha-amino acids by the so-called '1,3-oxazolidin-5-one strategy', and these were then homologated by the Arndt-Eistert procedure to afford N-protected N-methyl beta-amino acids derived from the 20 common alpha-amino acids. These compounds were prepared in yields of 23-57% (relative to N-methyl alpha-amino acid). In a second approach, twelve N-protected alpha-amino acids could be directly homologated by the Arndt-Eistert procedure, and the resulting beta-amino acids were converted to the 1,3-oxazinan-6-ones in 30-45% yield. Finally, reductive cleavage afforded the desired N-methyl beta-amino acids in 41-63% yield. One sterically congested beta-amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%) of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived N-methyl beta-amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N-methyl beta-amino acids derived from the 20 proteinogenic alpha-amino acids.