Problem 14 - Basic Principles of Organic Chemistry

Question

Show how the following amino acids may be prepared from the indicated method and starting materials: a. glutamic acid from 2 -oxopentanedioic acid ( \(\alpha\) -ketoglutaric acid) by the Strecker method b. leucine from 2 -methyl-1-propanol by the phthalimidomalonic ester synthesis c. aspartic acid from ethyl chloroethanoate by the \(\mathrm{N}\) -formylaminomalonic ester synthesis

Step-by-Step Solution

Answer

Glutamic acid is prepared by the Strecker method, leucine by the phthalimidomalonic ester synthesis, and aspartic acid by the N-formylaminomalonic ester synthesis.

Step 1: Preparing Glutamic Acid

Glutamic acid can be prepared from 2-oxopentanedioic acid (α-ketoglutaric acid) using the Strecker method. First, react α-ketoglutaric acid with ammonia and hydrogen cyanide. This forms an α-aminonitrile intermediate. Then, hydrolyze the cyanide group to the carboxyl group while maintaining the amino group to obtain glutamic acid.

Step 2: Preparing Leucine

To synthesize leucine from 2-methyl-1-propanol using the phthalimidomalonic ester synthesis, start by converting 2-methyl-1-propanol to the corresponding alkyl halide, 2-methylpropyl bromide. Then react it with potassium phthalimide to form the phthalimide derivative. Subsequently, treat this compound with diethyl malonate to yield an acylated product. Next, perform hydrolysis and decarboxylation to finally obtain leucine.

Step 3: Preparing Aspartic Acid

To prepare aspartic acid from ethyl chloroethanoate via the N-formylaminomalonic ester synthesis, begin by forming the malonic ester with the N-formylamino group. React ethyl chloroethanoate with potassium phthalimide to attach the amine group. Hydrolyze and decarboxylate this intermediate to yield aspartic acid.

Key Concepts

Strecker Synthesis

One of the classic methods for synthesizing amino acids is the Strecker Synthesis, which is particularly well-suited for converting simple carbonyl compounds into amino acids. The Strecker synthesis involves two main steps. First, an aldehyde or ketone reacts with ammonia and hydrogen cyanide to form an intermediate known as an α-aminonitrile. This process is straightforward and primarily relies on these key reagents to transform starting materials like

• α-ketoglutaric acid (2-oxopentanedioic acid) into α-aminonitriles

Next, the nitrile group is hydrolyzed to a carboxylic acid in acidic or basic conditions, converting the α-aminonitrile into an amino acid. For instance,

• to synthesize glutamic acid, the nitrile group attached to the α-aminonitrile must be hydrolyzed, forming the carboxylic counterpart while retaining the amine group.

Strecker synthesis is highly effective due to its straightforward approach, providing a robust method for producing amino acids from relatively simple starting materials.

Phthalimidomalonic Ester Synthesis

The phthalimidomalonic ester synthesis is a versatile method used to produce α-amino acids. It involves the reaction of an alkyl halide with potassium phthalimide to introduce the amine functional group via the formation of a phthalimide derivative. Starting with a primary alcohol, such as

• 2-methyl-1-propanol, the step involves convering the alcohol into an alkyl halide, such as 2-methylpropyl bromide.

This reacts with potassium phthalimide, resulting in a phthalimide derivative. The subsequent reaction involves the use of

• diethyl malonate to perform alkylation, linking the phthalimide to a malonic ester compound, which introduces the carbon framework necessary for the amino acid.

Finally, the phthalimidomalonic ester undergoes hydrolysis to remove the phthalimide group, followed by decarboxylation, to release the desired amino acid, such as leucine. This method excels in its ability to allow for the introduction of various side chains, offering flexibility and versatility in amino acid synthesis.

N-formylaminomalonic Ester Synthesis

The N-formylaminomalonic ester synthesis is a powerful technique in the toolkit for producing amino acids, especially leveraging ethyl chloroethanoate as a starting compound. This synthesis involves forming a malonic ester that possesses the N-formylamino group using a primary reaction setup with potassium phthalimide. In this versatile method,

• ethyl chloroethanoate is first reacted with potassium phthalimide to attach an amine group.

Upon creating the N-formyl derivative, the next steps involve hydrolysis and subsequent decarboxylation, transforming this compound into the targeted amino acid. For example,

• aspartic acid can be produced from the initial N-formylamino derivative.

The method's strength lies in its straightforward nature and the ability to control the introduction and removal of functional groups, allowing for successful transformation of simple esters into complex amino acids.