Question

The side-chain carboxyl groups of aspartic acid and glutamic acid are often protected as benzyl esters. (a) Show how to convert the side-chain carboxyl group to a benzyl ester using benzyl chloride as a source of the benzyl group. (b) How do you deprotect the side-chain carboxyl under mild conditions without removing the BOC-protecting group at the same time?

Short answer

Based on the given step-by-step solution, the short answer is as follows: To convert the side-chain carboxyl group of aspartic acid and glutamic acid to a benzyl ester, an esterification reaction with benzyl chloride is performed using DCC or EDCI as a catalyst and Et3N as the base. To deprotect the side-chain carboxyl group without removing the BOC-protecting group, hydrogenolysis with palladium on carbon (Pd/C) as a catalyst under a hydrogen atmosphere is used. This method selectively cleaves the benzyl ester without affecting the BOC-protecting group.

Step-by-step solution

Write the Reaction for Esterification with Benzyl Chloride

Write the general esterification reaction for converting a side-chain carboxyl group of either aspartic acid or glutamic acid to a benzyl ester using benzyl chloride. For simplicity, you can represent the amino acids as RCOOH, where R is the side chain of aspartic acid or glutamic acid. The reaction would be: RCOOH + ClCH2Ph ⟶ RCOOCH2Ph + HCl Here, Ph represents the phenyl (C6H5) group.

Determine the Appropriate Catalyst and Conditions

To drive this esterification forward, you need to use a suitable catalyst and reaction conditions. A commonly used catalyst for this reaction is Dicyclohexylcarbodiimide (DCC) or 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI). Additionally, you will need a base that can neutralize the HCl formed in the reaction. An appropriate base for this purpose is triethylamine (Et3N).

Write the Complete Reaction

Now, write the complete reaction for the esterification using DCC or EDCI as the catalyst and Et3N as the base. The reaction would be: RCOOH + ClCH2Ph + DCC(or EDCI) + Et3N ⟶ RCOOCH2Ph + HCl + (By-products) #Phase 2: Deprotecting the Side-Chain Carboxyl Group#

Determine Appropriate Conditions for Selective Deprotection

To selectively deprotect the side-chain carboxyl group without removing the BOC-protecting group, you need to choose mild reaction conditions. A suitable reagent for this purpose is hydrogenolysis using palladium on carbon (Pd/C) as a catalyst under a hydrogen atmosphere. This method allows the selective cleavage of the benzyl ester without affecting the BOC-protecting group.

Write the Deprotection Reaction

Write the deprotection reaction for the side-chain carboxyl group using Pd/C as the catalyst and hydrogen gas. The reaction would be: RCOOCH2Ph + H2/Pd/C ⟶ RCOOH + PhCH3 This deprotection reaction selectively cleaves the benzyl ester, leaving the BOC-protecting group intact.

Key concepts

Benzyl Ester Formation

The formation of benzyl esters from carboxylic acids is a crucial process in organic synthesis. Benzyl esters are often used as protecting groups for carboxyl functionalities.
This is particularly useful when reactions might otherwise interfere with the functional group, allowing the molecule to undergo various transformations without degradation of its crucial components.
To form a benzyl ester, we typically start with a carboxylic acid, such as the side-chain carboxyl of amino acids like aspartic acid or glutamic acid. By using benzyl chloride (ClCH2Ph) as a source of the benzyl group, the carboxylic acid reacts to form the ester. The chemical reaction is as follows:
- - RCOOH + ClCH2Ph ⟶ RCOOCH2Ph + HCl Here, "Ph" denotes a phenyl group, a part of the organic benzyl moiety. This transformation is pivotal in synthesizing compounds where the benzyl group serves as a protective and removable placeholder during multi-step synthesis processes.

DCC and EDCI Catalysts

Catalysts like DCC (Dicyclohexylcarbodiimide) and EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) play an essential role in promoting esterification reactions.
They enhance reaction efficiency by facilitating the formation of an activated intermediate.
DCC is frequently employed in peptide synthesis. However, in benzyl ester formation, both DCC and EDCI serve to activate the carboxylic acid to make it more reactive towards nucleophilic attack by benzyl chloride. Using these catalysts:

• DCC or EDCI facilitates the formation of an O-acylurea intermediate, which readily reacts with benzyl chloride to form the ester.
• These catalysts are also supported by bases like triethylamine (Et3N), which neutralizes the HCl byproduct, maintaining a favorable reaction environment.

Thus, the combination of DCC or EDCI with a base facilitates a smooth conversion to the desired ester, making them an invaluable part of the protection process in organic synthesis.

BOC-Protecting Group

The BOC (tert-butoxycarbonyl) protecting group is widely used in peptide synthesis to safeguard amine functionalities.
It offers stability under a variety of reaction conditions while being removable under mild acidic conditions.
When working with amino acids, employing a BOC group protects the amino part of the molecule, allowing focus on transforming other areas, such as esterifying carboxyl groups without unwanted reactions. The stability of the BOC group is crucial when performing reactions that might otherwise affect amine groups. Some benefits of BOC protecting groups include:

• Protection from strong acids and bases in neutral and slightly acidic environments.
• Easy removal through exposure to weak acids like trifluoroacetic acid (TFA).

The BOC group, thus, assists in multi-step synthesis protocols by preventing interference from reactive amino groups while allowing for selective deprotection.

Hydrogenolysis

Hydrogenolysis is a chemical reaction that involves breaking a chemical bond by adding hydrogen.
It is often used to remove protective groups like benzyl esters without affecting other parts of the molecule.
In the context of deprotecting benzyl esters, hydrogenolysis employs hydrogen gas and a palladium on carbon (Pd/C) catalyst. This method is particularly advantageous because it cleaves the benzyl group gently without affecting other protective groups like the BOC group. For example, during hydrogenolysis of a benzyl ester: - - RCOOCH2Ph + H2/Pd/C ⟶ RCOOH + PhCH3 This reaction demonstrates how hydrogenolysis facilitates the removal of benzyl esters, recovering the original carboxylic acid. Hydrogenolysis is favored when the selectivity of deprotection is paramount, minimizing potential side reactions.

Palladium on Carbon Catalyst

Palladium on carbon (Pd/C) is a widely used heterogeneous catalyst in hydrogenation and hydrogenolysis reactions.
Its effectiveness stems from palladium’s ability to adsorb hydrogen gas, allowing the reaction to proceed efficiently.
In the deprotection of benzyl esters, Pd/C stands out because:

• The catalyst under a hydrogen atmosphere converts benzyl esters to their corresponding acids efficiently.
• It ensures that other sensitive protecting groups, such as BOC, remain intact during the reaction.

Pd/C is advantageous due to:

• High selectivity, often necessary in organic synthesis involving complex molecules.
• Reusability and recovery from the reaction mixture make it cost-effective.

Thus, the combination of palladium on carbon with hydrogen gas serves as a versatile tool in processing intermediates in organic synthesis, particularly when sensitive functional groups are present.