The beginning of peptide chemistry can be attributed to Emil Fischer for the preparation of glycine glycine dipeptide (Gly-Gly).
He synthesized the corresponding peptide through the hydrolysis of diketopiperazine. Although Curtius had synthesized the first N-protected dipeptide, benzoylglycylglycine, twenty years earlier during his doctoral studies with H. Kolbe. Theodor Curtius’ intensive research on diazo compounds paved the way for the development of the first practical method of peptide synthesis. The coupling method of azides was successfully used in the synthesis of benzoylglycines. On the other hand, Fischer presented a method for coupling amino acids using acyl chlorides, which is based on the use of the corresponding amino acid, acetyl chloride and phosphorus pentachloride. One of the limitations and problems of both methods at that time was the lack of a protective group that could be easily removed.

Emil fischer and Theodor curtius

In 1931, Bergman solved some of the problems by introducing the carbobenzoxy group (Cbz) as a protector of the amino group of peptides and created a new era in peptide synthesis. Therefore, many small peptides such as glutathione and carnosine were synthesized. Du Vigneault and his colleagues synthesized the active hormone oxytocin two years later and received the Nobel Prize two years later. It should be mentioned here that Bergmann showed during the synthesis of glutathione that the use of Cbz protecting group prevents racemization. They later found that this configurational stability is a general property of urethane protecting groups. In 1957, Carpino and his co-workers introduced a protecting group for amines called (tert-butyloxycarbonyl) which was unstable in acidic environment and stable in hydrogenation, bridge reduction and alkaline conditions. After that, the combination of Cbz and BOC protecting groups was used to synthesize several peptides.

Vincent du vigneaud

One of the most important achievements of that time is the introduction of carbodiimides as activators of the carboxylic acid group in 1955 by Sheehan and his colleagues. However, the activation of the acidic group by carbodiimide, due to the high reactivity of O-acylisourea, can lead to the formation of oxazolone through an intramolecular cyclization reaction and increase the possibility of racemization. However, adding reagents such as 1-hydroxybenzotriazole (HOBt) to the reaction mixture minimizes racemization. With the passage of time, many other reagents were also discovered.

John clark sheehan

The next major advance in peptide chemistry came in 1963 when Merrifield published a paper on the principles and applications of solid-phase peptide synthesis (SPPS), for which he won the Nobel Prize. In the solid phase method, the amino acid is placed on a non-soluble substrate (resin) and the addition of other amino acids is performed cyclically and automatically due to the repetitive nature of the peptide synthesis process. The discovery and expansion of the use of different resins gradually led to many developments in peptide chemistry.

Robert bruce merrifield

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