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

syntheses exist for the functionaiization (Scheme 4.1 where R=dkyl, allyl, acyl.
hydroxyl. amino, halo, etc.) of the y-position of glutamate by a broad range of reagents.
4.1.3 Synthesis of Racemic ~Substituted Glutamic Acidr
Many of the general synthetic methods described in chapter one can be used to
synthesize y-substituted glutamic acids. The synthetic challenge arises when attempting
to induce stereoselectivity in the remote y-position in glutamic acid and although there
are exceptions, these methods generally fail to give hi@ selectivity.
4.1.3.1 Synthesis of ~Substituted Glutantic Acids: General Racemic Merhods
Michael reactions have been used extensively to synthesize racemic y-substituted
glutamates due to the well characterized nature of the reaction and availability of starting
materials. The racernic synthesis of ~methylglutamic was first reported in 1952 by two
independent groups. Done and Fowden reacted diethyl acetamidomalonate 4.18
(R'=CO~E~) and methyl methacrylate 4.19 (R~,R~=M~) in a Michael reaction followed
by hydrolysis and decarboxylation to give racernic ymethylglutamate in 45% overall
y ield? In a similar reaction. Fillman and Al bertson used eth y1 acetarnidoc yanoacetic
ester 4.18 (R'=cN) and methyl methacrylate 4.19 (R',R~=M~) followed by acid
hydrolysis and recrystallization to give an unidentified stemisomer of y-methylglutamic
acid in 1746 yield (Scheme 4.4)? This procedure was also used to synthesize other
racernic yalkylsubstituted gl~tamates.~
A similar method was used to synthesize y-hydroxyglutarnic acid d4 by reacting
ethyl acetarnidocyanacetate with ethyl-a-acetoxy-f5chloropropionate. Acid hydrolysis
gave ~hydroxyglutamic acid in 50-6096 yield as 1 : 1 mixture of diastereomers?
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