Deprotection solid phase peptide synthesis

Macke recently introduced a monoreactive DOTA prochelator (4,7,10-tricarboxymethyl-tert-butyl ester A, A, A", A "-tetraazacyclododecane-1 -acetate), which was coupled to Tyr3—Lys5 (BOQ-octreotide via solid-phase peptide synthesis. A one-step deprotection reaction generated the bioactive compound DOTATOC in about 65% yield.142 The 90Y and 177Lu DOTATOC complexes have shown promise for the treatment of neuroendocrine tumors in early clinical trials.143,444... 

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. 

A thiazolium amino acid (Taz) has been developed which can be utilized to mimic TDP-dependent enzyme function [52]. In this strategy, illustrated in Fig. 15, the commercially available amino acid 4-thiazolylalanine is incorporated into peptides by solid phase peptide synthesis. Prior to deprotection of the amino acid side chains and cleavage of the peptide from the resin, the thiazole amino acid is alkylated with an alkyl halide to generate the corresponding thiazolium amino acid having various N3-substituents (BzTaz = 3-benzyl-Taz, NBTaz = 3-nitrobenzyl-Taz). 

One of the very first papers reporting about endo-linkers was published by Elmore et al. (Scheme 10.4) [13]. They described a new linker containing a phos-phodiester group (19) for solid-phase peptide synthesis using a Pepsyn K (polyacrylamide) resin. After completion of coupling and deprotection cycles, the phos-phodiester (20) was cleaved with a phosphodiesterase. In this way / -casomorphin. Leu-enkephalin and a collagenase substrate (21) were synthesized in high yields. 

The ability to synthesize chemically short sequences of single-stranded DNA (oligonucleotides) is an essential part of many aspects of genetic engineering. The method most frequently employed is that of solid-phase synthesis, where the basic philosophy is the same as that in solid-phase peptide synthesis (see Section 13.6.3). In other words, the growing nucleic acid is attached to a suitable solid support, protected nucleotides are supplied in the appropriate sequence, and each addition is followed by repeated coupling and deprotection cycles. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

Esters of the PAM linker are slightly more resistant towards acids than the corresponding 4-alkylbenzyl esters [5,25-27] (Table 3.1). The PAM linker is particularly well suited for solid-phase peptide synthesis using A-Boc amino acids because less than 0.02% cleavage of the peptide from the support occurs during the acidolytic deprotection steps [27], Esters of both the 4-alkylbenzyl alcohol and PAM linkers can also be cleaved by nucleophiles (see Sections 3.1.2 and 3.3.3). 

The 9-fluorenylmethoxycarbonyl group, developed by Carpino and co-workers in 1972 [257], has become one of the most widely used protective groups for aliphatic or aromatic amines in solid-phase synthesis. For solid-phase peptide synthesis in particular, this protective group plays an important role [258] (Section 16.1). The Fmoc group is not well suited for liquid-phase synthesis because non-volatile side products are formed during deprotection. 

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

All peptides were prepared by solid-phase peptide synthesis on a peptide synthesizer. [1171 Various protection groups were used for the terminal positions and side-chain functionalities of the amino acids. The coupling mixture consisted of HBTU/HOBt/amino acid/NMM. Deprotection of the desired side chains with piperidine in NMP, followed by cyclization with HBTU/HOBt/NMM in HFIP/NMP, led to the formation of lactam bridges on the resin. 

This new approach involved alkylation of methyl 4-hydroxybenzoate with (354) using caesium bicarbonate as the acid scavenger [174]. The resulting amide ester (356) was sequentially deprotected and saponified to produce (357). Incorporation of the glutamic acid moiety was best accomplished using solid-phase peptide synthesis techniques and gave consistently better overall yields of (358) [102, 177]. 

Solid-phase peptide synthesis is based on the sequential addition of protected amino acids onto an insoluble support. Addition proceeds from carboxy terminus to amino terminus. The first amino acid is attached to a solid support by a linker and, if necessary, side-chain amino acid function is protected throughout chain assembly. The carboxy group of the in-coming, acylating amino acid is activated for coupling while its amino group is protected temporarily for each coupling step and then deprotected for the next cycle. The... 

In solid phase peptide synthesis, polypeptides are chemically synthesized by addition of free amino acids to a tethered peptide. To prevent unwanted reactions, the a-amino group and reactive side chain groups of the free amino acids are chemically protected or blocked, and then deprotected or deblocked once the amino acid is attached to the growing polypeptide chain. 

Peptide synthesis Polypeptides can be chemically synthesized by covalently linking amino acids to the end of a growing polypeptide chain. In solid phase peptide synthesis the growing polypeptide chain is covalently anchored at its C-terminus to an insoluble support such as polystyrene beads. The next amino acid in the sequence has to react with the free a-amino group on the tethered peptide, but it has a free a-amino group itself which will also react. To overcome this problem the free amino acid has its a-amino group chemically protected (blocked) so that it does not react with other molecules. Once the new amino acid is coupled, its now N-terminal a-amino group is deprotected (deblocked) so that the next... 

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