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Cleavage of Side-Chain Protecting Groups
Some amino acids (e.g., Asp, Glu, Cys,Arg, Lys, His, Ser, Thr, SelenoCys) usually require protection; Side reactions may occur during both synthesis and deprotection, but with a judicial choice of side-chain protecting groups, many known side reactions can be suppressed or avoided totally.
Here we introduce some cleavage methodds related to cyclic peptide synthesis and special peptide synthetic technique.


The Dde group is cleaved with 2% hydrazine in DMF When removing Dde in the presence of allyl-based protecting groups, allyl alcohol should be included in the deprotection solution to prevent reduction of the allyl group.
Representative amino acid:
Fmoc-Lys(Dde)-OH; Fmoc-Dab(Dde)-OH; Fmoc-Dap(Dde)-OH
Dde-Lys(Fmoc)-OH; Dde-Dab(Fmoc)-OH; Dde-Dap(Fmoc)-OH

It has very similar chemical properties to Dde, except that the side-chain ivDde group is considerably more stable to piperidine than Dde, and is less prone to migrate from protected to unprotected side-chains .
When removing ivDde in the presence of allyl based protecting groups, allyl alcohol should be included in the deprotection solution to prevent reduction of the allyl group.
Representative amino acid:
Fmoc-Lys(ivDde)-OH; Fmoc-Dab(ivDde)-OH; Fmoc-Dap(ivDde)-OH

The side-chain Mtt group can be selectively removed with 1% TFA in DCM or DCM/HFIP/TFE/TES (6.5:2:1:0.5) making this an excellent derivative for the synthesis of branched peptides, peptides modified at the lysine side-chain for the construction of templates and multifunctionalized resins for combinatorial synthesis.
Representative amino acid:
Fmoc-Lys(Mtt)-OH; Fmoc-Dab(Mtt)-OH; Fmoc-Dap(Mtt)-OH
The side-chain Mmt group can be selectively removed in the same manner as Mtt with 1% TFA in DCM or DCM/HFIP/TFE/TES (6.5:2:1:0.5) . Alternatively, it can be removed under milder conditions with AcOH/TFE/DCM (1:2:7) , leaving Mtt intact.
Representative amino acid:


Fmoc SPPS, the 2-phenyl isopropyl (OPp) moiety, which can be selectively cleaved with dilute TFA (l-2%) in the presence of tBu protecting groups, provides a viable alternative to allyl protection it is an extremely useful tool for the preparation of cyclic peptides by Fmoc SPPS or for library synthesis. For the on-resin synthesis of side-chain to side-chain lactam bridged peptides, the combination of Lys(Mtt) and Asp(O-2-PhiPr) is particularly advantageous since both side-chains can be simultaneously unmasked in a single step. This derivative has also been used in solution to prepare bicyclic helix initiating peptides .

Representative amino acid:
Fmoc-Asp(O-2-PhiPr)-OH; Fmoc-Glu(O-2-PhiPr)-OH; Fmoc-Asp-(O-2-PhiPr); Fmoc-Glu-(O-2-PhiPr)

ODmab group has been reported as a quasiorthogonal protecting group for the production of cyclic peptides for Fmoc SPPS. The ODmab group should be particularly useful in conjunction with (Mtt) protection for Lys because both moieties are removed with 2% hydrazine in DMF, allowing facile on-resin lactam formation.

Representative amino acid:
Fmoc-Asp(ODmab)-OH; Fmoc-Glu(ODmab)-OH; Fmoc-Asp-(ODmab); Fmoc-Glu-(ODmab)



It can be removed by 20% TFA in DCM. The cleavage condition is more milder than Pbf. So, some cases the yield and peptide appearance is better than other guanidino protecting groups. It is an excellent derivative for Fmoc SPPS of guanidino peptides. Coupling of this derivative can be effected using standard activation methods, such as PyBOP or TBTU, although longer reaction times may be necessary due to the bulkiness of the side-chain protection.

Representative amino acid:
Fmoc-Arg(Boc)2-OH; Fmoc-norArg(Boc)2-OH; Fmoc-Alg(Boc)2-OH


(CBZ)2 is also an excellent derivative for Fmoc SPPS of guanidino peptides. Di Cbz is be removed by hydrogenation. It is very useful when a peptide contained guanidino can't be treated with acid.
Representative amino acid:
Fmoc-Arg(Z)2-OH; Fmoc-norArg(Z)2-OH; Fmoc-Alg(Z)2-OH ;Boc-Arg(Z)2-OH

Seleno amino acid

The Mob group can either be removed in TFA in the presence of strong Lewis acids such as trimethyltrifluoromethane sulfonate or with I2 in acetic acid, which can cause complications and low yields if other intramolecular Sec or Cys residues are present, due to selenolanthionine formation.The most applicable method to date is deprotection in TFA in presence of DMSO, which leads directly to diselenide or selenylsulfide formation. Deprotection of Sec(Mob) can also be achieved under milder conditions via the addition of sub-stoichiometric amounts of 2,2-dithiobis(5-nitropyridine) (DTNP) in TFA, where the Mob group is converted to the 5-nitropyridyl selenylsulfide which can subsequently be cleaved by thiolysis . This method can be used for desired selenylsulfide bond formation and was also shown to produce vicinal selenylsulfide bonds.

Representative amino acid:
Fmoc-Sec(Mob)-OH; Fmoc-S-4-methoxybenzyl Homoselenocysteine

In the Boc/Bzl strategy Sec(MeBzl) is deprotected by standard hydrogen fluoride methods at 0 C within 1 h and with no observed difficulties A very interesting feature is that upon deprotection, the Sec residues are found to be already fully oxidised to the corresponding diselenide or mixed selenylsulfide bonds even in strong acid environments. This is probably due to the high reactivity and low pKA of the selenol.

Representative amino acid:
Boc-Sec(pMeBzl)-OH; Boc-S-4-methylbenzyl Homoselenocysteine