Deprotection reagent

KM Sivanandiaih, VV Suresh Babu, SC Shrankarama. Solid-phase synthesis of oxytocin using iodotrichlorosilane as Boc deprotecting reagent. Int J Pept Prot Res 45, 377, 1995. 

N Fujii, A Otaka, O Ikemura, K Akiji, S Funakoshi, Y Hayashi, Y Kuroda, H Yajima. Trimethylsilyl trifluoromethylsulfonate as a useful deprotecting reagent in both solution and solid phase peptide syntheses. J Chem Soc Chem Commun 274, 1987. 

The major side reaction associated with the use of mixed anhydrides is aminolysis at the carbonyl of the carbonate moiety (Figure 7.4, path B). The product is a urethane that resembles the desired protected peptide in properties, except that the amino-terminal substituent is not cleaved by the usual deprotecting reagents. Hence, its removal from the target product is not straightforward. The problem is serious when the residues activated are hindered (Val, lie, MeXaa), where the amounts can be as high as 10%. Other residues generate much less, but the reaction cannot be avoided completely, with the possible exception of activated proline (see Section 7.22). This is one reason why mixed anhydrides are not employed for solid-phase synthesis. 

JD Wade, J Bedford, RC Sheppard, GW Tregear. DBU as an V -deprotecting reagent for the fluorenylmethoxycarbonyl group in continuous flow solid-phase peptide synthesis. Pept Res 4, 194, 1991. 

It then remains to remove protecting groups and release the product from the support. All of these tasks, except for the removal of the dimethoxytrityl group, are achieved by use of a single deprotection reagent, aqueous base (ammonia). The cyanoethyl groups are lost from the phosphates by base-catalysed elimination, and amide protection of the bases is removed by base-catalysed hydrolysis. The latter process also achieves hydrolysis of the succinate ester link to the support. 

HF-pyridine reagent, however, can also be used for the hy-drofluorination of alkenes,7 alkynes,7 cyclopropanes,7 and diazo compounds,8 the halofluonnation of alkenes,9 the preparation of fluoroformates from carbamates,10 the preparation of a-fluorocarboxylic acids from a-amino acids,11 and as a deprotecting reagent in peptide chemistry.12 Examples of the hydrofluonnation of alkenes with HF-pyridine are given in Table II. 

Alkylsilanes have been shown to be versatile deprotection reagents for the benzyloxycarbonyl group. This is achieved by treatment with Et3SiH/PdCl2,f or by reaction with tert-butyldimethylsilane/Pd(OAc)2 which allows the corresponding tert-butyldimethylsiloxy-carbonyl-protected amino acids to be isolated.t l... 

Step 3 [deprotection with TFA/CH2CI2 (15 mL)] Add a fresh batch of deprotection reagent and agitate for 30 min. CO2 is formed from decomposition of the Boc group, and should be vented in closed systems. With 50% TFA/CH2Q2, use 15 min deprotection time. 

A stronger and more rapid deprotection reagent for Boc groups is made by adding a very low concentration of methanesulfonic acid (MsOH) to TFA.t ... 

Fluoride ions are applicable deprotecting reagents for the cleavage of silyl ethers. Several fluoride sources are available The widely used tetrabutylammonium fluoride (TBAF), which is a basic agent and can cause several undesired side reactions, the acidic HF acetonitrile complex and the HF-pyridine complex. In this case only the benzylic TBS ether is cleaved, because the reaction is carried out at room temperature. ... 

Tetrabutylammonium fluoride (TBAF) is a deprotecting reagent. Which functional group is labile to nucleophilic attack by fluoride ions ... 

Add 5 mL of 20% piperidine in DMF as a deprotection reagent to remove Fmoc protecting groups from the resin. Flush with nitrogen for 10 min. Drain off reagent. Repeat twice. 

This is the reason why peptide chemists, to decrease the problems of purification prefer for long peptides to use protecting groups (tert-butyloxycarbonyl (t-Boc), benzyloxycarbonyl (Z), fluorenylmethyloxycarbonyl (FMOC).) and classical reagents such as T.B.T.U. (0-lH-benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate), B.O.P.(benzotriazol-l-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate and so on in polar solvents such as N,N-dimethylformamide or N-methylpyrrolidone. But this solvents are not compatible with the acidic deprotection reagents such as trifluoroacetic acid and... 

Dahl BH, Bjergarde K, Henriksen L, Dahl O. A highly reactive odourless substitute for thiophenol/triethylamine as a deprotection reagent in the synthesis of oligonucleotides and their analogues. Acta Chem Scand 44 639-641, 1990. 

Fig. 14. Preparation of basic polymeric deprotecting reagents via active ester synthesis...

Fig. 16. Schematic presentation ofpeptide synthesis by inverse solid phase method based on the use of polymer-bound amino acid active esters (coupling reagent) and polymer-bound jnperazine (deprotecting reagent)...

Tab. 20.2. Effect of deprotection reagent on aspartimide formation of VKDGYI. ...

The synthesis was performed at the 0.1 mmol level using 5% piperazine in DMF as the deprotection reagent and HBTU activation with a fivefold excess of reagents and was complete in 12.5 h [36]. 

The 20-mer peptide prepared also contained an Asp-Gly sequence, this potentially leading to aspartamide formation, another well documented potential side reaction when performing peptide synthesis. This sequence-dependent side reaction occurs during the Fmoc deprotection step of Asp-containing peptides where the adjacent residue is Gly, Asn, Ser, or Ala. Each subsequent deprotection after the inclusion of Asp will result in an iterative decrease in the peptide purity. In the initial synthesis of the test peptide, deprotection with 20% piperidine at 80 °C led to considerable amounts of aspartimide formation. Addition of 0.1 M HOBt to the deprotection mixture together with piperidine reduced the aspartimide formation and resulted in a 10% increase in crude purity. The use of piperazine in place of piperidine resulted in an even further decrease in the aspartimide formation, and no deletion products were observed despite the decreased pKa of the deprotection reagent. 

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