Gabriel-malonic ester synthesis

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. 

The Gabriel-malonic ester synthesis is used to make many amino acids that cannot be formed by direct amination of haloacids. The following example shows the synthesis of methionine, which is formed in very poor yield by direct amination. 

Show how the Gabriel-malonic ester synthesis could be used to make (a) valine (b) phenylalanine (c) glutamic acid (d) leucine... 

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. 

Q Show how to make a given amino acid using one of the following syntheses Reductive amination, HVZ followed by ammonia, the Gabriel-malonic ester synthesis, and the Strecker synthesis. Problems 24-34, 35, 37, 38, and 39... 

Show how you would use the Gabriel-malonic ester synthesis to make histidine. What stereochemistry would you expect in your synthetic product ... 

Show how the Gabriel-malonic ester synthesis could be used to make... 

HVZ followed by ammonia Gabriel-malonic ester synthesis Strecker synthesis... 

A third amino acid synthesis begins with diethyl a-bromomalonate. First the Br is replaced by a protected amino group using the Gabriel synthesis (see Section 10.6). Then the side chain of the amino acid is added by an alkylation reaction that resembles the malonic ester synthesis (see Section 20.4). Hydrolysis of the ester and amide bonds followed by decarboxylation of the diacid produces the amino acid. An example that shows the use of this method to prepare aspartic acid is shown in the following sequence ... 

One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines (Section 19-20) with the malonic ester synthesis of carboxylic acids (Section 22-16). The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid. 

Problem 36.10 Various amino acids have been made in the following ways Direct ammonolysis glycine, alanine, valine, leucine, aspartic acid Gabriel synthesis glycine, leucine Malonic ester synthesis valine, isoleucine... 

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). 

Another synthesis of phenylalanine from malonic ester, in which Gabriel s phthalimide reaction is also made use of, is described by Sorensen, namely,... 

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. 

This method, a modification of the Gabriel synthesis of amines (Section 20.4A), uses potassium phthalimide and diethyl a-bromomalonate to prepare an imido malonic ester. The example shown is a synthesis of methionine ... 

One of the best methods for synthesizing amino acids is based on the chemistry of malonate esters (Section 22.17) and a modification of the Gabriel synthesis of amines (Section 23.7). Diethyl acetamidomalonate has a nitrogen atom bonded to the a-carbon of the malonate ester. This nitrogen eventually becomes the nitrogen of the final amino acid product. 

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