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

4.1.4 Synthesis of Optically Active ~Substihted Glutamic Ac*
Synthetic methodologies designed spcificaily for the generation of glutamic acid
derivatives center around four main concepts with varying degrees of success: glycine
enolate equivalents. enzymatic methods, asymmetric hydrogenation and y-anion
chemistry (including the use of pyroglutamate). Surprisingly few diastereoselective
syntheses for psubstituted glutamic acids exist.
4.1.4.1 Glycine Enolates
The Ni@) glycine Schiff base enolate 1.39 of Belekon et dm (Scheme 1.3.3.1)
was reacted in a Michael addition with methyl methacrylate to give 2: 1 mixture of 2S:4R
4.2 and 2S:4S methylglutamic acid 4.1 in 75% yield. However, only the methyl adduct
was teported.
1 &Addition of Schollkopf s bis-lactim ether 1.33 (Scheme 1.3.3.1) with meth y1
methacrylate 4.19 (lt2,It3=~e) resulted in a 1: 1 ratio of 2R:4R and 2R:4S methylglutamic
acid to the exclusion of any of the 2s isomer.)'
4.1.4.2 Enzymntic Methods
Enzyrnatic methods have ken used to prepare asymmetric molecules due to the
inherent nature of enzymes to differentiate between chiral centers. Both of the methods
reported to synthesize yglutarnate denvatives have used appropriately substitutea 2-
ketoglutaric acids as the substrate. rii 1984, Righini-Tapie and Azeraà incubated
glutamate dehydrogenase (GDH, EC 1.4.1.2) in ammonium phosphate buffer with
racernic methyl ketoglutarate 4.22 (R = Me) to give ymethylglutarnate Al in 60 1 yield
(Scheme 4.6, lefbhand side). Surprisingly, no differentiation between the two