Facile synthesis of Fmoc-N-methylated α- and β-amino acids

A highly efficient and environmentally friendly synthesis of Fmoc-N-methyl α- and β-amino acids from the corresponding Fmoc-amino acid, via intermediate oxazolidinones/oxazinanones, has been developed. Microwave heating for 3 min was required for the synthesis of the oxazinanones, while their Lewis acid catalyzed reductive opening only needed 1 min for completion. Hence, Fmoc-N-methyl-amino acids, suitable for, for example, solid phase peptide synthesis, can be readily prepared from the corresponding Fmoc amino acid in less than 1 h including purification. Fmoc-β3-homophenyl alanine showed unanticipated reactivity, and provided a one-step route to the highly useful Fmoc-protected 1,2,3,4-tetrahydroisoquinolineaceticacid, that is a β-hTic analogue.