Protective groups, removal peptides

The triphenylmethyl function, also known as trytil (Trt), is a valuable bulky protecting group for peptide chemistry. Trytil groups confer acid-labile protection onto amines, but effective removal can also be achieved by catalytic hydrogenolysis. 

GM Anantharamaiah, KM Sivanandaiah. Transfer hydrogenation. A convenient method for the removal of commonly used protecting groups in peptide synthesis, (formic acid) J Chem Soc Perk Trans 1 490, 1977. 

To overcome the chain fragmentation of sensitive peptides that contain /V-alkyl amino acids caused by acids as described vide supra, the following measures are recommended (1) in solution synthesis the exploitation of protecting groups removed by acids should be minimized (e.g., apply Fmoc chemistry, use acid-labile side-chain protection as little as possible) (2) if the peptides must be subjected to acid use low temperatures (—20 °C) for the shortest time possible (monitor the reaction by HPLC ) (3) in SPPS if the peptide does not contain functionalized side chains, prepare the peptide by Fmoc chemistry on Trt resin and remove the peptide from the resin with HFIP (see Section 10.1.1.2.2). If the peptides have functionalized side chains see point (1). 

For removal of the Fmoc protecting group, the peptide T4-(4a14,4COCH2ONHFmoc) (13 mg, 1.56 pmol) was dissolved in 10% piperidine/DMF (200 pL) and stirred at rt for 30 min. After precipitation with cold Et20, the product was isolated by centrifugation (5 min, 4000 rpm), lyophilized from MeCN/H20 and purified by HPLC (gradient 5—95% MeCN) yield 10.3mg (90%). 

Cys(StBu) was coupled to the side chain. After removal of the Fmoc protecting group, the peptide was cleaved from the resin with TFA to give the linear peptide 76. The Ser moiety attached to the first Lys served as a masked aldehyde, which was oxidized to aldehyde 77 by sodium periodate. The cyclic peptide 78 was formed by utilizing the intramolecular oxime formation from the reaction between the Lys-side-chain-tethered O-alkylhydroxylamine and the aldehyde. 

Transfer hydrogenation. Hydrazine is apparently superior to cyclohexene for transfer hydrogenation with palladium black as catalyst for hydrogenolysis of various protective groups of peptides. It can be used for cleavage of CBZ groups, benzyl esters, and benzyl ethers it is particularly useful for removal of nitro groups. 

Remove the formyl- and benzyl-type protective groups from peptide side chains by using the low TFMSA method. Treat the resin with a mixture of TFMS A/TFA/ p-cresol/dimercaptoethane (10/50/30/8/2 v/v). Mix all the components on ice carefully adding TMFSA as the last step. Take 1 mL of mixture per 50 mg of peptide resin and mix on ice for 2 h. 

Approximately 100 mg of resin was distributed to each of the reaetion bloek wells (of an ACT block or a Bohdan block) by pipetting a slurry of the resin in DMF/DCM (3 1) or as dry resin into each IRORI kan. The peptides were then assembled by the combinatorial chemistry apparatus suited for parallel or split-and pool-synthesis (34) using in situ neutralization/HBTU activation protocols for BOC chemistry. The resin was initially washed with DCM and the BOC protecting group removed by washing twice with a 40% solution of TFA in DCM. 

Removal of protective groups in peptide synthesis. The reagent, dis.solved in tri-fluoroacetiu acid, removes various acid-Iabiie N-protecting groups (Cb, BOC, etc.) at 0°. It also removes nitro, tosyl, or p-methoxybenzyl groups used for protection of side-chain groups. 

In the synthesis of sulfur-free peptides, protecting groups removable by catalytic hydrogenation, such as Arg(N02), Asp(OBzl), or Glu(OBzl), can be used. Boissonnas et al. employed this procedure for the synthesis of bradykinin in 1960,and Arakawa and Bumpus utilized this method in the synthesis of angiotensin II in 1961.0 ... 

A more useful application of the electron-attracting effect of aryl subtituents is found in the cleavage of 4-picolyl derivatives of protected cysteine and tyrosine in peptide synthesis (Scheme 14).Catalytic cleavage of these derivatives is usually unattractive for SProtecting groups removable also include 3- and 4-picolyl esters. ... 

Hep),14-9, 31, 32, 98-1001 the 2-bromoethyl (EtBr) I4-6, 31, 32, 1011 and the p-nitrobenzyl (PNB) esters11021 as carboxy protecting groups for peptide synthesis which can be enzymatically removed by means of lipases or esterases, respectively (Fig. 18-11). 

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