Phthalimidomalonic ester

The A-phthalimidomalonic ester 8 can be further alkylated at the malonic carbon center with most alkyl halides, or with an o ,/3-unsaturated carbonyl compound thus offering a general route to a-amino acids 9. 

Sorensen suggests that the same reactions might be employed for the synthesis of aspartic acid and of glutamic acid, in the case of the former condensing the sodium phthalimidomalonic ester with chlor-acctic ester and in that of the latter with -chloropropionic ester... 

Sorensen and Andersen in 1908 synthesised proline by the sodium phthalimidomalonic ester method, a yield of about 80 per cent, being obtained. Sodium phthalimidomalonic ester is condensed with trimethylene bromide,... 

Problem 21.2 Synthesize leucine, (CH,),CHCH,CH(NH,)COO, by (a) Hell-Volhard-Zelinsky reaction (Section 16.3) followed by ammonolysis. (b) Gabriel synthesis, (c) phthalimidomalonic ester synthesis, (d) reductive amination of a keto acid, (e) Strecker synthesis (addition of NH, HCN to RCH=0), (/) acetylaminomalonic ester. 

Problem 21.4 Outline the preparation of (a) methionine from acrolein by the Strecker synthesis (Problem 21.2(e)), (b) glutamic acid by the phthalimidomalonic ester synthesis (Problem 21.2(c)]. ... 

In a 6oo-cc. beaker 210 g. (0.87 mole) of ethyl bromomal-onate (p. 34) (Note 1) and 165 g. (0.89 mole) of potassium phthalimide (p. 8) are intimately stirred together. The mixture is stirred approximately every ten minutes. If no spontaneous reaction starts in half an hour (Note 1), it is necessary to initiate the reaction by heating to no-1200. The mixture then becomes liquid and can be stirred easily. It turns to a light brown color, especially near the top where it comes in contact with the air. When the temperature begins to drop, the mixture is heated in an oil bath at no0 for one hour to insure completion of the reaction. The mixture is then poured into a mortar where it solidifies to a solid mass (Note 2). When cold, the mixture is ground up with water and filtered to remove most of the potassium bromide. The precipitate is then reground with water and refiltered, finally washing the precipitate well with water. The solid material on the filter consists of some potassium bromide, some phthalimide, and the phthalimidomalonic ester. 

The Gabriel-malonic ester synthesis begins with (V-phthalimidomalonic ester. Think of (V-phthalimidomalonic ester as a molecule of glycine (aminoacetic acid) with the amino group protected as an amide (a phthalimide in this case) to keep it from acting as a nucleophile. The acid is protected as an ethyl ester, and the a position is further activated by the additional (temporary) ester group of diethyl malonate. 

Better yields are generally obtained by the Gabriel phthalimide synthesis (Problem 11, p. 744) the a-halo esters are used instead of a-halo acids (Why ). A further modification, the phthalimidomalonic ester method, is a combined malonic ester-Gabriel synthesis. 

Phthalimidomalonic ester method serine, glutamic acid, aspartic acid List the necessary starting materials in each case, and outline the entire sequence for one example from each group. 

Alkyl groups can be introduced in phthalimidomalonic esters by way of the sodio derivative. Hydrolysis then leads to <%-amino carboxylic acids through various intermediates. A good synthesis of asparagine, for example, is described in Organic Syntheses.458 Other examples are syntheses of lanthionine and ethionine,459 also of kynurenine.460... 

Since the side-chain is an isobutyl group, we must attach an amino acid root to the isobutyl alcohol. This can be accomplished via the phthalimidomalonic ester synthesis ... 

Substituent a can be attached to the n-butyl group by phthalimidomalonic ester synthesis, while substituent b can be attached by a substitution reaction with ammonia with the carboxylic acid group protected. Therefore ... 

Just as the malonic ester synthesis gives substituted acetic acids, the A/-phthalimidoma-lonic ester synthesis gives substituted aminoacetic acids a-amino acids. A-Phthalimido-malonic ester is alkylated in the same way as malonic ester. When the alkylated A-phthalimidomalonic ester is hydrolyzed, the phthalimido group is hydrolyzed along with the ester groups. The product is an alkylated aminomalonic add Decarboxylation gives a racemic a-amino add. 

Synthesis. nn-Cystine is prepared in about 23% over-all yield by the method of Wood and du Vigneaud (877). S-Benzylthiolmrthylphthali-midomalonic ester, prepared from bensylthiolmethyl chloride and sodimn phthalimidomalonic ester, is hydrolysed with NaOH to S-bensyl-DL-cysteine. The latter substance is reduced with sodium in liquid ammonia, and the resulting DL-cysteine is oxidised with (catalyzed by seep. 359. 

Amino acids can be synthesized with much better yields than those obtained by the previous two methods via an A-phthalimidomalonic ester synthesis, a method that combines the malonic ester synthesis (Section 18.18) and the Gabriel synthesis (Section 16.18). 

A proton is easily removed from the a-carbon of A-phthalimidomalonic ester because it is flanked by two carbonyl groups. (Section 18.1)... 

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

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. 

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