Amino acids Gabriel synthesis

Working with the Concepts Practicing Variants of the Gabriel Amino Acid 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. 

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. 

An important laboratory use involves the Gabriel synthesis of a-amino-acids. 

The modified procedure involves refluxing the N-substituted phthaUmide in alcohol with an equivalent quantity of hydrazine hydrate, followed by removal of the alcohol and heating the residue with hydrochloric acid on a steam bath the phthalyl hydtazide produced is filtered off, leaving the amine hydrochloride in solution. The Gabriel synthesis has been employed in the preparation of a wide variety of amino compounds, including aliphatic amines and amino acids it provides an unequivocal synthesis of a pure primary amine. 

The hydrazinolysis is usually conducted in refluxing ethanol, and is a fast process in many cases. Functional groups, that would be affected under hydrolytic conditions, may be stable under hydrazinolysis conditions. The primary amine is often obtained in high yield. The Gabriel synthesis is for example recommended for the synthesis of isotopically labeled amines and amino acids. a-Amino acids 9 can be prepared by the Gabriel route, if a halomalonic ester—e.g. diethyl bromomalonate 7—is employed as the starting material instead of the alkyl halide ... 

The stereochemical control of the Gabriel reaction by chiral catalysts can be further enhanced in the synthesis of optically active a-amino acids when optically pure (-)-bornyl a-bromo esters are used (Table 12.8) [4]. 

Examples of the effect of double asymmetric induction on the Gabriel synthesis of optically active a-amino acids... 

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. 

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... 

In Gabriel s synthesis of primary amines, potassium phthalimide is reacted with an alkyl halide and the resulting A-alkylphthalimide is hydrolysed to release the amine and phthalic acid (Scheme 5.12). This route is also used in the synthesis of amino acids. 

The unsubstituted catalyst (3) was also used in an asymmetric Gabriel synthesis of a-amino acids via solid-liquid chiral phase-transfer alkylation of potassium phthalimide with 2-bromocarboxylates. ... 

Identify the lettered intermediates in the following reaction scheme. This is an alternative method to synthesize amino acids, based on the Gabriel synthesis of 1 ° amines (Section 25.7A). 

The N -phthaloyl group (Phth), well known for the preparation of primary amines in the Gabriel synthesis,P was used more extensively as a temporary backbone amine protecting group in the early period of amino acid and peptide chemistry.t The resulting phthalimides ensure exhaustive substitution of the primary amine, i.e. removal of both acidic hydrogens, thus, moderating the nucleophilic character. 

The most convenient method of making a-aminoaldehydes is by reduction of a-amino acid esters using sodium amalgam [5, 6] by what has come to be known as the Akabori method. Alternatively, an a-halogenocarbonyl compound can be converted via the Gabriel synthesis into the aminocarbonyl... 

The limitations of this approach can be seen in the reaction of a saturated solution of ammonia in 90% ethanol with ethyl bromide in a 16 1 molar ratio, under which conditions the yield of primary amine was 34.2% (at a 1 1 ratio the yield was 11.3%). Alkyl amines can be one type of substrate that does give reasonable yields of primary amine (provided a large excess of NH3 is used) are a-halo acids, which are converted to amino acids. A-Chloromethyl lactams also react with amines to give good yields to the A-aminomethyl lactam. Primary amines can be prepared from alkyl halides by 10-43, followed by reduction of the azide (19-32), or by the Gabriel synthesis (10-41). 

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... 

A dynamic kinetic resolution was utilized for the highly stereoselective Gabriel synthesis of -amino acids by K. Nunami and co-workers. The substrate, f-butyl-(4S)-1-methyl-3-2-(bromoalkanoyl)-2-oxoimidazolidine-4-carboxylate, smoothly reacted with potassium phthalimide at room temperature to give only one diastereomer in good yield. The removal of the chiral auxiliary afforded an A/-phthaloyl-L- -amino acid. 

Kubo, A., Kubota, H., Takahashi, M., Nunami, K.-i. Dynamic kinetic resolution utilizing 2-oxoimidazolidine-4-carboxylate as a chiral auxiliary stereoselective synthesis of a-amino acids by Gabriel reaction. Tetrahedron Lett. 1996, 37, 4957-4960. 

A commonly used modification of the Gabriel synthesis is the Ing-Manske procedure.10 Instead of removal of the phthaloyl group with aqueous base or acid, the Ing-Manske modification utilizes hydrazinolysis. It has been used in the synthesis of optically active a-amino acids 17, as illustrated by Guifa and Lingchong.11... 

Sorensen456 has built on the basis of Gabriel s method a synthesis of a-amino acids whose first step is the preparation of diethyl phthalimido-malonate 456,457... 

Liberation of amines. A modification of the classical Gabriel synthesis to gain access to a-amino acids using chiral a-bromoalkanoic esters to react with potassium phthalimide catalyzed by a chiral phase transfer agent has been reported. Unfortunately, the results are not very satisfactory. 

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