Protective groups for amino acid raw materials for polypeptide synthesis
Amino acid protecting group
20Common amino acids can be divided into several categories according to their side chains: Aliphatic amino acids (Ala, Gly, Val, Leu, Ile), Aromatic amino acids (Phe, Tyr, Trp, His), Amide or carboxyl side chain amino acid (Asp, Glu, Asn, Gln), Basic side chain amino acids (Lys, Arg), Sulfur-containing amino acids (Cys, Met), Alcohol-containing amino acids (Ser, Thr), Imino acid (Pro).
The protection of amino acids in the chemical synthesis of peptides is very critical and directly determines the success of the synthesis. Because many of the 20 common amino acids have active side chains and need to be protected, it is generally required that these protecting groups are stable during the synthesis process, have no side reactions, and can be completely and quantitatively removed after the synthesis is completed. Amino acids that need protection during synthesis include: Cys, Asp, Glu, His, Lys, Asn, Gln, Arg, Ser, Thr, Trp, Tyr. Groups that need protection: Hydroxyl, carboxyl, mercapto, amino, amide, guanidine, indole, imidazole, etc.
In Trp There is no need to protect it because indole is relatively stable in nature. Of course, under special circumstances, some amino acids may not be protected, such as Asn, Gln , Thr, Tyr.
Table 1 Three common conditions for deamination of amino groups
| TFA | HBr/TFA | H2/Pd-C | Piperidine/DMF | |
| Boc | y | y | n | n |
| Z | n | y | y | n |
| Fmoc | n | y | n | y |
Figure 1 Three common amino protecting group structures
There are many protective groups for amino acid side chains. The same side chain has many different protective groups, which can be selectively removed under different conditions. This is of great significance in the modification of cyclic peptides and polypeptides. Moreover, the side chain protecting group is closely related to the selected synthesis method. The liquid phase and the solid phase are different. In the solid phase BOC and FMOC The strategies are also different. In a sense, peptide chemistry is the flexible use and combination of amino acid protecting groups. Regarding the use of side chain protecting groups, please refer to Wang Dexin's "Solid Phase Organic Synthesis" -- "Principles and Application Guide" Chapter 4, we mainly introduce here Cys, Lys, Asp Several protective groups and their removal methods. Cys There are three most common protecting groups: Trt, Acm, Mob, These three protecting groups can complete the synthesis of polypeptides with multiple pairs of disulfide bonds.
Lys The most common protecting groups are: Boc, Fmoc, Trt, Dde, Allyl, This provides many orthogonal protection strategies for solid-phase synthesis of cyclic peptides. Asp The most common protecting groups are: Otbu, OBzl, OMe, OAll, OFm, A variety of orthogonal protection strategies are also provided.
Table 2 Common protective groups for thiol groups
| Abbreviation | Structure | Exclusion conditions |
| Trt |  |
TFA, HCl/HOAc, I2/MeOH |
| Acm |  |
I2/MeOH, Hg2+ |
| Mob |  |
HF, TFMSA, Hg2+ |
Table 3 Common protective groups for amino groups
| Abbreviation | Structure | Exclusion conditions |
| Trt |  |
TFA, HOAc, HCOOH |
| Boc |  |
HCl/HOAc, TFA/DCM |
| Fmoc |  |
Pip/DMF, NaOH/MeOH |
| Dde |  |
H2NNH2/DMF |
| Allyl |  |
Pd (Ph3P)4, Morpholine /THF |
Table 3 Common protective groups for carboxyl groups
| Abbreviation | Structure | Exclusion conditions |
| Otbu |  |
TFA, HOAc, HCOOH |
| OBzl |  |
H2/Pd, HF, TFMSA |
| OMe |  |
NaOH/MeOH |
| OAll |  |
Pd(Ph3P)4, Morpholine /THF |
| OFm |  |
Pip/DMF, DBU/DMF |