Synthesis of Enantiomerically Pure γ-Amino-β-hydroxybutyric Acid Using Malic Acid as the Chiral Precursor

Article abstract of DOI:10.1021/jo00350a007

The synthesis of enantiomerically pure γ-amino-β-hydroxybutyric acid using malic acid as the chiral precursor is described.The key step involves the regioselective carboxamidation of the β-carboxyl group (adjacent to the hydroxyl) in malic acid.This was achieved by converting (S)-malic acid to its cyclic anhydride 8, which was then treated with ammonia.Protection of the alcoholic group in the ester amide 9 as a tert-butyl ether followed by LiAlH4 reduction gave 3-(tert-butyloxy)-4-aminobutanol (11c).The amino group in 11c was protected as the tert-butyl carbamate to give (S)-3-(tert-butyloxy)-4-<((tert- butyloxy)carbonyl)amino>butanol (12c).The oxidation of the primary alcoholic group was successfully carried out with zinc permanganate to give the desired acid (S)-3-(tert-butyloxy)-4-<((tert-butyloxy)carbonyl)amino>butyric acid (13c).Removal of the protecting groups gave (S)-(+)-γ-amino-β-hydroxybutyric acid, the optical rotation measurements of which indicated no racemization during the six-step synthesis.The R isomer could be synthesized starting from (R)-malic acid.Thus a short and efficient route to chirally pure (R)- and (S)-γ-amino-β-hydroxybutyric acid is presented.Furthermore, this work also highlights zinc permanganate as a useful oxidant for the preparation of carboxylic acids.