Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

of p-methylaspartate 5.1 to glutamate.= Molecular biology techniques have been used to
replaced aspartic acid with threo- or eryfhro-$-methylaspartic acid in the active site of
the enzymes dihydrofolate reductase," asparagine synthetase Bn and HIV-1 proteaseg in
order to elucidate the mechanism of action of these enzymes.
Erythro-p-hydroxyaspartate 5.5 has ken used as an inhibitor and CO-crystallized
with aspartate aminotransferase?
5.1.3 Synthesis of &%bstituted Aspartic Acids
Most of the generai synthetic methods described in chapter one can be used to
synthesize B-substihited aspartic acids. These include Scholkopf s bis-lactim ether
1.33,m Williams' oxazinones l.M3' and various expoxide based methods (vide in fru).
However, as described previously, the synthetic challenge arises whilst attempting to
stereospecificaily introduce f3-substituents by 1,2-induction. Although there are
exceptions most of the general methods for the synthesis of a-amino acids fail in this
regard and therefore specific methodologies have been developed for B-substituted
aspartic acids.
5.1.3.1 Synthesis of PSubstituted Aspurtic Acids: General Rucemic Methods
P-Methylaspartic acid 5.1 was first prepared in 1941 by Dakin who condensed
ethyl a-bromopropionate with diethyl benzamidomalonate (Scheme 5.2)?2 Subsequent
racemic syntheses have also been described using diethyl a~etarnidomalonate~~ and ethyl
a~etamidocyanoafetate.~ Fractionai crystallization and ionexchange chromatography
have ken used to resolve threo- and erythro-DL-$-methylaspartate.
25 1