Synthesis of non-proteinogenic amino acids using Michael addition to unsaturated orthopyroglutamate derivative

Stereoselective synthesis of non-proteinogenic amino acids via Michael addition to 3.4-didehydropyroglutamate derivative in which the carboxyl function is protected as a 2,7,8-trioxabicyclo[3.2.1]octane (ABO ester) group is described. The obtained 3-substituted pyroglutamic ABO ester was directly converted to 3-substituted glutamic acids such as chlorpheg by acidic hydrolysis, whereas 3-substituted proline derivatives were obtained by chemoselective reduction of the lactam carbonyl group. A formal total synthesis of baclofen, a gamma-aminobutyric acid (GABA) analogue, is also described. (C) 2008 Elsevier Ltd. All rights reserved.