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Peptide synthesis – chemistry and modifications
Peptides and proteins exhibit the largest structural and functional variation of all classes of biologically active macromolecules. Biological functions as diverse as sexual maturation and reproduction, enzyme inhibition, blood pressure regulation, glucose metabolism, thermal control, analgesia and learning and memory are now thought to be regulated by peptides.

Peptide synthesis chemistry
Synthetic peptides are valuable tools in analysis of naturally occurring peptides or proteins. Since Emil Fischer’s pioneering work in the early 1900’s, synthesis methods have improved continually – especially with Merrifield’s development of solid-phase syntheses. Besides the classical synthesis in solution, solid-support synthesis is now the most widely used method to prepare synthetic peptides. The advantages of solid-support synthesis are its speed, versatility, ease of automation and low costs.

However, peptide chemistry still remains a difficult and exacting science. Solid-phase synthesis is usually carried out as follows:
1.
2.
3.
4.
5.

loading of C-terminal amino acid to resin (not shown below)
deprotection: removal of N-terminal protecting group (PG) at amino residue activation of next amino acid at carboxy residue
coupling reaction
start synthesis cycle 2-4 again or cleave fully-synthesised peptide off resin

R

H
N

C

PG

H

C

H

R

N
OH

PG

activation

N
PG

C

C

O
C
O

H

deprotection
R

H

O
C

N
OH

H

R

H

O

H

C
H

O

etc.

C
O

coupling

R

H
N
PG

O

C

C

H

R
N

C

H

H

O

O

removal H

R

H

C

N

O

C

C

H

R
N

C

H

H

O
C
OH

1

Protecting groups (PGs)
One of the demanding parts in peptide synthesis is the necessity to block those functional groups that must not participate in peptide bond formation. Such “protecting groups” are needed for all specific side chain functions of DNA-encoded amino acids (p.e. the amino group of the amino acid that lends its activated carboxyl group to the coupling reaction and for the carboxyl group of the amino acid that will be acylated in its amine group).

In order to elongate the resulting dipeptide, one protecting group has to be removed. This has to be done under such conditions that the peptide bond itself is not harmed and transient protecting groups still stay on, too.

Solid phase synthesis requires two types of protecting groups: a) Transient protecting groups for amino groups that form the peptide bond. b) Permanent protecting groups for functional groups within the amino acid side chains. These PGs have to be stable enough to sustain chemicals used to remove transient PGs.

Transient PGs for amino acids
Such PGs should be easily removable but still stable enough to survive the conditions of coupling reactions and other manipulations. Two commonly used amino protecting groups are:

deprotection

t-Boc (t-Butoxycarbonyl)
under mild acidic conditions
with TFA (50% TFA in DCM)

advantage

stable towards catalytic hydrogenation,
can be used with Z group for side chain
protection
disadvantage final workup with HF necessary

Fmoc (9-fluorenylmethyloxycarbonyl)
mild basic, non-hydrolytic conditions
with primary or secondary amines:
20% piperidine in DMF
deprotection does not affect amide or t-butyl
protected side-chain esters,
stable towards tertiary amines

CH3

Fmoc
CH2

H3C

HF

O

tBoc

C

CH3
H3C

C

O
O

C

C

O

CH2
NH CH C

CH3

O

C

CH3

TFA

O

O
H

CH2 O

C

O

CH2
NH CH C

NH

NH

O

Piperidine

TFA

Permanent PGs for side chains
Since the different side chains of the DNA-encoded amino acids encompass the majority of the common functional groups in organic chemistry, several different types of side chain protecting groups are required for peptide synthesis.

These PGs...
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