Acetamidomalonic ester

A substituted acetamidomalonic ester, tetraethyl 1 -acetamido-4-hydroxy-butane-l,l,3,3-tetracarboxylate, was used in the preparation of cis- and frans-pyrrolidine-2,4-dicarboxylic acids, cyclic analogs of glutamic acid (91TL3049). 

As shown in Scheme 86, the CHIRAPHOS-Pd-catalyzed reaction of 1,1,3- or 1,3,3-triphenyl-substituted allyl acetate and sodiomalonate results in optical yields of up to 86%. A BINAP-Pd(0) complex is effective for asymmetric synthesis of a-allyl-a-acetamidomalonate esters of high enantiomeric purity (202). 

In common with other malonate derivatives, the a-hydrogen atom in the acetamidomalonate is reactive on treatment with a base the reagent forms a meso-merically stabilised carbanion (36) from which a variety of substituted acetamidomalonic esters can be made. For example, C-alkylation ensues when the anion is allowed to react with an alkyl halide the resulting product (37) is then subjected to the hydrolytic and decarboxylative sequence shown to yield a simple a-amino acid. 

The Gabriel-malonic ester synthesis uses an aminomalonic ester with the amino group protected as a phthalimide. A variation has the amino group protected as an acetami-do group. Propose how you might use an acetamidomalonic ester synthesis to make phenylalanine. 

L-Phenylalanine has been produced continuously from ACA with the help of ACA acylase in an enzyme membrane reactor (EMR) with a space-time-yield of 277 g L 1 d1 83 . With ACL acylase, L-Ieucine was produced at 123-180 g L-1 d 1 in the same reactor set-up1821. The dehydroamino acid substrates can be prepared conveniently, either from 2-halogen carboxylic acid esters1841, or, specifically in the case of ACA, via the acetamidomalonic ester route by reaction with benzyl halogenides[851. 

As base. In the absence of solvent KF promotes the condensation of trimethyl-silylacetonitrile with aldehydes to give the /3-cyanohydrin silyl ethers. With micro-wave as energy source the reaction is complete within minutes. KF in the presence of 18-crown-6 successfully effects the Michael reaction between a-acetamidomalonic esters and propynoic esters also. 

In a second synthesis of labeled phenylalanine Battersby et al. (305, 306) used the pro-R specific enzyme horse liver alcohol dehydrogenase to reduce [ HJbenzaldehyde 306, Ha = H. The (lS)-[l- H,]benzyl alcohol 307 obtained was converted via tosylation and reaction with malonate anion to the acid 308 (Scheme 81), which, on bromination and ammonolysis, gave (2RS, 3R)-[3- Hi]phenylalanine 297, He = H. Ife and Haslam (309) used the more direct replacement of the tosylates of the alcohol 307 with acetamidomalonic ester in a similar synthesis of (3R)- and (3S)-[3- Hi]pheny-lalanines. Fermenting yeast replaced liver alcohol dehydrogenase in a further synthesis (310). 

Alternatively, the use of acetamidomalonic ester in the classical manner is exemplified by the synthesis of 2-amino-7,7-difluoro-7-(dihydroxyphosphinoyl)heptanoic acid (Scheme 32) in the search for compounds with NMDA antagonist activity, and in yet another synthesis of phosphinothricin. ... 

WORKED PROBLEM 23.10 In a simpler version of the Gabriel synthesis, acetamidomalonic ester is used rather than bromomalonic ester. Sketch out the steps in this related amino acid synthesis. 

A variation of the A-phthalimidomalonic ester synthesis uses acetamidomalonic ester in place of A-phthalimidomalonic ester. 

What alkyl halide would you use in the acetamidomalonic ester synthesis to prepare a. lysine b. phenylalanine ... 

Separation can also be done by ion-exchange chromatography employing an anion- or a cation-exchange resin. An amino acid analyzer is an instmment that automates ion-exchange chromatography. Amino acids can be synthesized by a Hell-VoUiard-Zelinski reaction (followed by reaction with excess NH3), a Strecker synthesis, reductive amination, a A-phthalimidomalonic ester synthesis, or an acetamidomalonic ester synthesis. 

A variation of the Gabriel s3mthesis uses diethyl A-acetyl-2-aminopropanedioate (acetamidomalonic ester), A. Propose a s3mthesis of racemic saine from this reagent. 

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