Asymmetric Synthesis of α-Amino Acids from a Chiral Masked Form of Glyoxal

Enantiopure acyclic and cyclic α-amino acids were synthesized from glyoxal. This dialdehyde was desymmetrized by condensing it with various (R)-phenylglycinol-derived β-amino alcohols and was thus used as a chiral masked form which allows chemo and stereoselective reactions to be carried out. When the β-amino alcohol was N-methyl (R)-phenylglycinol, an amino thioether precursor affords an iminium ion whose reaction with nucleophiles led either to saturated acyclic amino esters (nucleophiles: organozinc reagents) or to unsaturated α-amino acids (nucleophiles: silyl and silyloxy derivatives). On the other hand, the use of β-amino alcohol derivatives with an olefinic chain linked to the amino moiety provides access to cyclic α-amino acids. An intramolecular ene-iminium reaction between the transient iminium ion and the ene component of the substrate eventually afforded pipecolic acid and proline derivatives. On the other hand, substituted prolines were the result of aza-Cope/ene-iminium or aza-Cope/Mannich tandem reactions. An illustrative example of the latter methodology is the enantioselective synthesis of (-)-allokainic acid.

α-amino acids - glyoxal - iminium ions - organozinc reagents - aza-Cope/Mannich reaction