Gastrin is a hormone released from the stomach that controls the progress of digestion. Early work on the hormone showed that only the four C-terminal amino acids of the peptide (the C-terminal tetrapeptide) were necessary for its physiological activity. The synthesis starts with the coupling of two more amino acids: aspartic acid and phenyl alanine. As you would expect, the carboxylic acid group of phenylalanine is protected, this time as a methyl ester, and the NH₂ group of aspartic acid is protected as a Cbz derivative. Since aspartic acid has two carboxylic acid groups, one of these also has to be protected. Here is the method—first the Cbz group is put on; then both acids are protected as benzyl esters. Then just one of the benzyl esters is hydrolysed. It may seem surprising to you that this chemoselective hydrolysis is possible, and you could not have predicted that it would work without trying it out in the laboratory.

The protected acid is next activated as its 2,4,6-trichlorophenyl ester, ready for coupling with the phenylalanine methyl ester in base. Now you see why the benzyl ester was chosen to protect Asp’s side-chain carboxylic acid group—hydrogenolysis can be used to cleave both the Cbz group and the benzyl ester at the same time.

The next amino acid in the peptide is methionine, and it will of course need N-protecting and C-activating. The N-protecting group used this time was different—still a carbamate, although not Cbz— it was Boc, which stands for t-butyloxycarbonyl and is pronounced ‘bock’. The Boc group, t-BuOCO, is introduced with (t-BuOCO)₂O, known as Boc anhydride.

Like Cbz, the Boc group is a carbamate protecting group. But, unlike Cbz, it can be removed simply with dilute aqueous acid. Just 3M HCl will hydrolyse it, again by protonation, loss of t-butyl cation, and decarboxylation. Base, on the other hand, cannot touch the Boc group— the carbonyl group is too hindered to be attacked even by OH−, and Boc is strongly resistant to basic hydrolysis.

Meanwhile, back at the tetrapeptide synthesis, methionine (Met) has been Boc-protected, and is ready for activation—as a 2,4,6-trichlorophenyl ester (abbreviated to Ar below) this time—and coupling with the deprotected AspPhe–OMe. Aqueous acid takes off the Boc group without hydrolysing peptide or ester bonds, and a repeat of this cycle with Boc-tryptophan trichlorophenyl ester (BocHN–Trp–OAr) followed by formation of the amide with ammonia finally gives the tetrapeptide.

مواضيع ذات صلة

The Cbz protecting group—oxytocin

Peptide synthesis

A survey of protecting groups

How to react the less reactive group (II): protecting groups

Chemoselectivity in the reactions of dianions

How to react the less reactive group (I): react both then ‘unreact’ one

Competing reactivity: choosing which group reacts

How to oxidize primary alcohols to aldehydes

How to oxidize secondary alcohols to ketones

Birch reduction of arenes

Dissolving metal reductions

Getting rid of functional groups