Peptides -- Sequencing and Synthesis

When a sequence has been obtained for a peptide, attention can be turned to its synthesis. There are two issues to resolve in synthesizing a peptide. One is to develop a method for making the peptide bond which does not damage anything else in the peptide. This is called "coupling" the two amino acids. The other is to be sure that the amino acids are added to the peptide in the proper sequence.

The key to the first issue is to convert the O- an amino acid's carboxylate group into a better leaving group. We've seen something similar when we've converted an OH into a Cl as we made the reactive acyl chlorides. This is done by the use of a reagent called dicyclohexyl carbodiimide, or DCC for short. DCC works by bonding to the O- and converting it to a good leaving group -- good because it has many electronegative atoms which can help stabilize the negative charge as it leaves. An amino acid which has a good leaving group is said to be "activated."

The actual coupling reaction occurs when the amino group of the amino acid "to the right" in the sequence attacks the carbonyl carbon of the "activated" amino acid and the DCC leaves with the oxygen it is bonded to. As usual, there are some proton shifts needed to tidy things up.

The second issue, adding amino acids in desired sequence, can be illustrated by considering the synthesis of a dipeptide such as Ala-Gly. If we simply mix equal quantities of glycine and alanine and run a DDC coupling reaction, we will get glycines reacting with glycines to give Gly-Gly, alanines reacting with alanines to give Ala-Ala, and glycines reacting with alanines in two ways to give Ala-Gly and Gly-Ala. This is a mess and it would be better to develop a more specific approach.