Question

The side-chain carboxyl groups of aspartic acid and glutamic acid are often protected as benzyl esters. CC(=O)NC(CCC(=O)OCc1ccccc1)C(=O)O (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

Answer: To selectively deprotect the side-chain carboxyl group without removing the BOC-protecting group, dissolve the amino acid benzyl ester in an appropriate solvent, such as THF or DMF, and add a catalytic amount of palladium on carbon (Pd/C). Pass a stream of hydrogen gas through the reaction mixture for several hours at room temperature, which causes the selective breakdown of the benzyl ester bond, releasing the free side-chain carboxyl group. The BOC-group remains intact, as it is stable under these conditions.

Step-by-step solution

a) Converting the side-chain carboxyl group to a benzyl ester using benzyl chloride

To convert the side-chain carboxyl group of aspartic acid or glutamic acid to a benzyl ester, we can use the following reaction: 1. Dissolve the amino acid in an appropriate solvent, such as pyridine or dimethylformamide (DMF). 2. Add a slight excess of benzyl chloride to the solution. This will react with the carboxyl group, forming the benzyl ester. 3. Stir the reaction mixture for several hours at room temperature. 4. Isolate the product by evaporating the solvent, re-dissolving the residue in a minimal amount of ethyl acetate, and slowly adding water to precipitate out the benzyl ester. The overall reaction can be shown as follows: Amino acid COOH + Benzyl chloride (Bn-Cl) → Amino acid COOBn

b) Deprotecting the side-chain carboxyl group without removing the BOC-protecting group

To selectively deprotect the side-chain carboxyl group without removing the BOC-protecting group, we can use the following method: 1. Dissolve the amino acid benzyl ester in an appropriate solvent, such as tetrahydrofuran (THF) or dimethylformamide (DMF). 2. Add a catalytic amount of palladium on carbon (Pd/C) to the reaction mixture. This will serve as a catalyst for the hydrogenolysis (hydrogen cleavage) reaction of the benzyl ester group. 3. Pass a stream of hydrogen gas through the reaction mixture for several hours at room temperature or use a hydrogen balloon or hydrogen atmosphere in a pressure vessel. This will cause the selective breakdown of the benzyl ester bond, releasing the free side-chain carboxyl group. 4. Remove the catalyst by filtration and evaporate the solvent to isolate the deprotected amino acid. The overall reaction can be shown as follows: Amino acid COOBn + H2 (hydrogen gas, presence of Pd/C catalyst) → Amino acid COOH + Bn-H This reaction selectively cleaves the benzyl ester bond, leaving the BOC-protecting group intact, as the BOC-group is stable under these conditions.