A New Approach for the Total Synthesis of L-γ-Carboxyglutamic Acid : Utility of Ruthenium Tetroxide Oxidation

Abstract

A new and convenient synthesis of optically pure L-γ-carboxyglutamic acid (L-Gla) (1) from L-proline as a chiral source was developed. Protection of N-tert-butyloxycarbonyl (Boc) prolinol (4) with a tert-butyldimethylsilyl group followed by oxidation with ruthenium tetroxide (RuO₄) afforded the corresponding lactam compound (6), which was carboxylated with lithium diisopropylamide and benzyloxycarbonylimidazole to afford the 4-benzyloxycarbonyl lactam derivative (7). Selective removal of the silyl group from 7, followed by oxidation of the resulting alcohol (8) with pyridinium dichromate gave the carboxylic acid, which was converted into the ester derivatives (10b-d). Cleavage of the lactam bond of 10b with excess benzyl alcohol in the presence of triethylamine gave γ, γ, α-tribenzyl N-Boc-L-γ-carboxyglutamate (11). Finally, 11 was hydrogenated over Pd on charcoal and deprotected with trifluoroacetic acid to produce L-γ-carboxyglutamic acid (1).