Novel practical deprotection of nboc compounds using. Learn tfa chapter 14 with free interactive flashcards. Intermediate intermediate diamine 7 was obtained as a yellow oil 22 mg, quant. An interesting example of selective deprotection of the tertbutyl esters in the presence of nboc protecting groups of several amino acids using ceriumiii chloride as a lewis acid is reported. Ntertbutyloxycarbonyl boc groups can be removed from peptides supported on rinks amide resin by treatment with trimethylsilyl triflate2,6lutidine. This protocol proceeds from the premise that dotatristbe has been conjugated to a molecule of interest e. Consider the solubility of starting material the choice of solvent. Deprotection akin to protection, the deprotection proceeds through pentacoodinated intermediates.
Thus, deprotection using tfa is now the final step to be accomplished. This protocol outlines the use of tfa to remove tertbutyl ester groups from dotatristbe. Tfa infused intravenously to the mother reached higher levels in amniotic fluid after long survival times, than in maternal plasma. The boc group can be added to the amine under aqueous conditions using di tert butyl dicarbonate in the presence of a base such as sodium bicarbonate. Suspend the resin in 50% vv tfadichloromethane dcm, using 1 ml of tfadcm per gram of resin. Comparison of 55% tfach2cl2 and 100% tfa for boc group. Aggregation, racemization and side reactions in peptide. Specifically, we disclose onresin deblocking using trifluoroacetic acid tfatriisopropylsilane tis in etoacmecn used in a synthesis of a melanocortin receptor agonist comprising i 1d green spps ii 2d green spps by an onresin tfatis in etoacmecn deprotection of lysmtt and aspo2phipr followed by a lactamization using pybopdiea.
Mild, selective deprotection of pmb ethers with triflic. Peptide synthesis most often occurs by coupling the carboxyl group of the incoming amino acid to the nterminus of the growing peptide chain. The crude was purified by semipreparative hplcms using a linear gradient from 25 to 30% of mecn in 12 min of mecn containing 0. Deprotection reaction an overview sciencedirect topics. Kinetic studies show comparable reaction rates with thiophenol as scavenger. A selective, catalytic and practical method for removing a boc group from several n,n. A eight residue peptide containing phosphotyrosine was synthesized with boctyropo 3 bzl 2. The driving force of fluoridebased deprotection is the formation of sif bond, which is about 30 kcalmol stronger than sio bond. Study on the process of synthesizing methylenedinitramine by a novel method. Lewis acids such as znbr 2, ticl 4, me 2bbr 2 meoch 2ch 2och 2cl, ch 2cl 2, ipr 2etn stable to base and mild acid roh roch2och2ch2ome. Tunable acidsensitive ester protecting groups in oligosaccharide. After the reaction of phenylalanine boc deprotection used tfa dcm1. The two sets of peptides were deprotected with either 55% tfa dcm for 30 min or 100% tfa for 5 min.
The phosphoamino acid was double coupled, the peptide cleaved and extracted using the tfmsa tfa procedure outlined in materials and methods. In bocbased synthesis, diketopiperazine formation can be suppressed by utilizing in situ neutralization protocols. Any suggestion on boc deprotection without using acid. Protecting groups in solidphase organic synthesis acs. I have done bocdeprotection by tfa, and reaction was monitored by tlc, even by nmr but atr does not showing any nh2 peak. The major impurity obtained during synthesis when 100% tfa was used for boc removal corresponded to the omission of the second aminoacid residue added. I have seen some procedures of pmb deprotection of amine using trifluro acetic acid. A novel series of 3,6bis4hdroxyphenyl1,2,4,5tetrazine alkanoate esters were. General procedure for the deprotection of the bocgroup. Deprotection of s10undecenyl thioacetate figure 2 dissolve s10undecenyl thioacetate 1 2. Another attempt of deprotection of 6a,b was performed by hydrogenolysis in thf using pdc 5 h, rt, which gave the deprotected derivatives 1a,b with excellent yields xzo. Protic acids such as trifluoroacetic acid tfa, commonly used for. Myers protective groups siliconbased protection of the. The deprotection of nboc amines was rapidly accomplished using 5 equivalents of tfa in methylene chloride in a focused microwave instrument with irradiation at 60.
Trifluoroacetic acid tfa and bromide, formed mainly by maternal metabolism of halothane, accumulated in fetus and amniotic fluid with time, and reached plateau levels in amniotic fluid between 4 and 24 hr. Myers protective groups siliconbased protection of the hydroxyl group chem 115 general reference. The purity of the peptides obtained when deprotecting with 55% tfa dcm was, on average, 9% higher than with 100% tfa. Deprotection of glutamic acid residues during hf cleavage can result in the formation of an acylium ion from the hf protonation and dehydration of the unprotected carboxyl moiety. Reaction times of 36 h and overall yields of 7898% were achieved with the pmb group in place compared to no reaction without this protecting group. Protecting groups hydroxyl protecting groups 4 ethers 3. First the resin is separated from tfa by filtration through a mediumporosity fritted glass funnel and the resin is washed with 1 ml of tfa. The freebase amines are then obtained by scavenging the crude reaction mixture with the basic amberlyst a21 ionexchange resin. The benzyl ester linkage between the cterminal amino acid and the polystyrene can be partially cleaved in the deprotection step and important losses can occur during the construction of a long peptide chain 3. Received 29 june 2011 revised 16 august 2011 accepted 18 august 2011 available online 25. What happens to the tbutyl cation in the tfa deprotection of.
Isobutene reacts with trifluoroacetic acid and yields t. After the reaction of phenylalanine boc deprotection used tfadcm1. Selective deprotection of lysmtt cleavage with tfatisdcm. Rapid deprotection of n boc amines by tfa combined with. Though it is difficult to see nh2 nmr peak, in ir primary amines rnh2 display. Boc falls off fairly easily in some cases, but in your case you are better to use tfa. A practical, catalytic and selective deprotection of a boc.
Protection and deprotection of functional groups in organic. A method for removal of nboc protecting groups from. The process is clean, not needing a purification step. Try it first, as it can take longer then you think also you need to track your products. Deprotection of s10undecenyl thioacetate figure 2dissolve s10undecenyl thioacetate 1 2. After stirring at room temperature until starting material was.
The sacetamidomethyl acm or trityl trt protecting groups are widely used in the chemical synthesis of peptides that contain one or more disulfide bonds. Cleavage and deprotection is one of the most crucial steps in. The solvent was removed in vacuo and the crude was dissolved in 10% ipachloroform, washed with sat aq nahco3, brine, dried, and concentrated. The co2 gas that forms during the reaction should be allowed to escape. How to confirm boc deprotection by tfa researchgate. However, the excess iodine needs to be quenched or adsorbed as quickly as. Bocprotected amino groups organic chemistry portal. This procedure is suitable for the parallel deprotection of nboc amines. A necessary evil 3 note, however, that each protecting group incorporated in a multistep synthesis increases the synthesis by two nonproductive steps reducing the overall yield and efficiency of the synthesis. I know boc can easily be deprotected using strong acid like tfa and hcl, but final product is salt of tfa or hcl, my question is that, how we can avoid formation of slat and obtained free amine group. A practical, catalytic and selective deprotection of a boc group in n,n. More important, compounds that are sensitive to typical acidic conditions tfa and hcl such as 5d and 23 gave the corresponding deprotected product in. The purity of the peptides obtained when deprotecting with 55% tfadcm was, on average, 9% higher than with 100% tfa.
This cton synthesis is opposite from protein biosynthesis, during which the nterminus of the incoming amino acid is linked to the cterminus of the protein chain ntoc. How to do workup of a boc deprotection reaction by tfa. The phosphoamino acid was double coupled, the peptide cleaved and extracted using the tfmsatfa procedure outlined in materials and methods. Mild, selective deprotection of pmb ethers with tri. The tertbutyloxycarbonyl protecting group or tertbutoxycarbonyl protecting group boc group is a protecting group used in organic synthesis the boc group can be added to the amine under aqueous conditions using ditertbutyl dicarbonate in the presence of a base such as sodium bicarbonate. All synthetic steps, other than the removal of the boc group, were performed simultaneously under identical experimental conditions. The tertbutyl cation will either be quenched by a suitable trapping agent, deprotonate to form isobutylene gas, or polymerize to form isobutylene oligomers. New tfafree cleavage and final deprotection in fmoc solid. The two sets of peptides were deprotected with either 55% tfadcm for 30 min or 100% tfa for 5 min. Method g with bu 4nf in thf was found to be a very good alternative 6a. Protecting groups of hydroxyl groups consider the stability and effect of anomeric group. In addition, removal of the nde group could be followed visually and monitored. A theoretical study rationalizing the results with several metals i. I have done bocdeprotection by tfa, and reaction was monitored by tlc.
Even though the cleavage of the tbutylcarbamate boc group can be achieved at solvent reflux temperature, the deprotection process was significantly accelerated under microwaveassisted conditions. Its known that hexanes will form an azeotrope with acetic acid, so you could try redissolving in hexanes and spinning it down a few times. New tfafree cleavage and final deprotection in fmoc solidphase peptide synthesis. Br removal tbaf, 35% tfa pdpph 3 4, scavengers photolytic cleavage 320 nm stable basic conditions basic and acidic conditions acidic and mild basic conditions orthogonal fmoc boc, fmoc, zfmoc, boc 10. Tentagel 12 1987 rink and others introduction of various tfa labile linkers for the fmoctbu spps of peptide amides. If the fmoctbu protection strategy is utilized, performing the synthesis on 2chlorotrityl chloride resin is preferred when proline, pipecolic acid or tic is one of the first two amino acids. Catalog technical deprotection pdf, forms catalog technical deprotection pdf, reference technical deprotection pdf, forms technical deprotection pdf. In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. The acylium ion can cyclize to produce a pyroglutamine residue or it can react with scavengers such as anisole to form an aryl ketone. Fmoc protecting group, which is stable to tfa deprotection, must be removed by a 20% solution of piperidine in dmf. I need the product to be a tfa salt and not an hcl salt so i need to use tfa. Mild, selective deprotection of pmb ethers with triflic acid.
If tbutyltrifluoroacetate is the byproduct, then the catalyst is consumed. Protonation of amine under the acidic conditions provides the pdt as the tfa salt. The org layer was separated, dried mgso4, and concentrated in vacuo to provide the product as a brown solid. For an acetylated map peptide, the removal of the fmoc protecting group is followed by capping with acetic anhydride to give an acetylated map peptide. Protecting group strategies are usually necessary to prevent undesirable side reactions with the. Eventually i pass ammonia gas to remove tfasalt but unfortunate atr is not showing any primary amine nh2 peak yet. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. The pmb group was easily and selectively removed in 6898% yield using tfa in dcm.
The thermolytic deprotection of nboc compounds was accomplished using tfe 2,2,2trifluoroethanol or hfip hexafluoroisopropanol as solvents. Tfa equal amount as the solvent was added and the solution was allowed to warm to room temperature. During cleavage of peptide after solid phase synthesis. Decarboxylation of the carbamic acid results in the free amine. Tentagel 12 1987 rink and others introduction of various tfalabile linkers for the fmoctbu spps of peptide amides. Read 1 answer by scientists with 2 recommendations from their colleagues to the. The tfa filtrate could be used in two ways, depending on the size of the peptide. Loss of the tertbutyl cation results in a carbamic acid. The deprotection of nboc amines was rapidly accomplished using 5 equivalents of tfa in methylene chloride in a focused microwave instrument with irradiati.
Ive done many insitu deprotection in dcm after a coupling. The boc group has also been cleaved with conditions that do not use tfa. Consider the reactivity of different hydroxyl groups. If the beads turn orange immediately, continue shaking for another 30 minutes and retest. Treatment of peptides containing sacm protecting group with iodine results in simultaneous removal of the sulfhydryl protecting group and disulfide formation. Trimethylsilyl tms triethylsilyl tes triisopropylsilyl tips dimethylisopropylsilyl. Protecting group pg is a small molecule, to mask temporarily the a specific functional group of a molecule from undergoing reaction, allowing the rest of the functional groups present in the molecule to react without affecting the original reactivity and leave from the host molecule without affecting the rest of the functional groups. Choose from 500 different sets of tfa chapter 14 flashcards on quizlet. The reaction mechanism is unlike the s n 1 path in carbon chemistry as silyl cations are unstable. Excess 1 n naoh was added and the mixture was stirred vigorously for 15 min. Read here what the tfa file is, and what application you need to open or convert it.
The workup of the deprotection reaction consists of precipitation of the peptide product from tfa. New tfafree cleavage and final deprotection in fmoc solidphase. The purity of each fraction was verified by analytical hplc and malditof and showed that the peptides were 94% pure. Cleavage, deprotection, and isolation of peptides after fmoc. A simple protocol for the deprotection of 1,3dithianes and 1,3dithiolanes showed tolerance for a number of phenol and amino protecting groups using 30% aqueous hydrogen peroxide activated by iodine catalyst 5 mol% in water in the presence of sodium dodecyl sulfate sds under essentially neutral conditions without any detectable overoxidation. A novel method for cleaving from resin and removing acidlabile protecting groups for the fmoc solidphase peptide synthesis is described. Albr3, etsh phse ph2p me3sii o o obz ome o o obz oh albr 3, etsh tl 1987, 28, 3659 methoxymethyl ether mom roh roch2ome stable to base. In the initial step, protonation is more likely on the co oxygen. Scheme 1 efficient global removal of nap ethers in dodecyl maltoside 1 by tfa in. The usefulness of adding scavengers to trifluoroacetic acid in deblocking reactions is due to the removal of t. The deprotection cleavage of the boc group is realized using a 50% solution of tfa in dcm. A pmethoxybenzyl pmb protectiondeprotection approach. Protection of the amine can also be accomplished in acetonitrile solution using 4.
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