Peptide chain elongation scheme

PREPARATION OF BAL-ANCHORED PEPTIDE RESINS BY ON-RESIN REDUCTIVE AMINATION, FOLLOWED BY STEPWISE CHAIN ELONGATION (SCHEME B)... 

The acyl oxazolidinone stracture 25 was reported as another active structure, in which an NS acyl shift reaction can be performed under neutral conditions, and ligation with cysteinyl peptide 7 can then proceed [59]. Although the synthesis of hBNP32-NH2 was successfully performed, the acyl oxazolidinone was partially decomposed by piperidine treatment and was potentially racemized during peptide chain elongation by Fmoc SPPS (Scheme 7). 

A CPE peptide can be easily prepared by the Fmoc SPPS procedure (Scheme 19). In order to prevent DKP formatiOTi during peptide chain elongation, the dipeptide, Fmoc-Xaa-Cys(Trt)-OH (60), must be introduced onto the Pro-OCHaNH-resin. Standard Fmoc SPPS is then applied to peptide chain elongation, and the usual TFA treatment, followed by RP-HPLC purification, gives the CPE peptide. 

For the synthesis of methionine-containing peptides the Fmoc group is recommendable for temporary protection in the chain elongation steps as shown in Scheme 15. 

The method was also applied to 4, which requires elongation of the peptide chain at both termini (Scheme 1). Thus, after the A-terminal elongation to get 5, its C-terminus was deprotected with 50% TFA in dichloromethane (DCM). The free carboxyl group was thereby activated by selective reaction with 1-hydroxy-... 

The 2-hydroxy-2,2-diphenylethyl ester represents a dual-function group which ensures suitable carboxy protection during chain elongation in peptide synthesis while being readily converted into the active 2,2-diphenylvinyl ester using TEA (Scheme 3). ... 

Besides the use of Z-Arg(HX)-OH (X = Q, Br),fi5] Boc-Arg(HCl)-OH,ti and Z-Arg(HC104)-0HP l for incorporation of the arginine residue, Z-Arg(N02)-OH (see Section 2.6.1.2) and Z-Arg(Z)2-OH (see Section 2.6.1.3.3) are useful for this purpose. After N -deprotection or, in the case of the two latter arginine derivatives, N -deprotection, subsequent chain-elongation steps are performed with the protonated arginine residues, as shown in Scheme 4 for the synthesis of a subfragment of somatostatin-28.t l This protonated arginine approach is well-suited for peptide synthesis in solution and has been successfully... 

The first reported solid-phase synthesis of head-to-tail cyclic peptides was based on the intramolecular aminolysis of resin-bound o-nitrophenyl esters. The cyclization proceeds concurrently to cleave the peptide from the resin, after deprotection and neutralization of the AT-terminal residue (Scheme 2A). Accordingly, Fridkin et al. [3] reported the preparation of several simple, unhindered cyclopeptides, such as cyc/o(Ala-Gly-Ala-Ala). Similarly, Flanigan and Marshall [4] obtained activation of the resin-bound peptide ester, after elongation of the peptide chain, by oxidation of the 4-(methyl-thio)phenyl (MTP) linker to a sulfonyl ester. Subsquent deblocking of the A-terminal residue and intramolecular condensation yielded the desired cyclic peptide. However, this method was found not to be suitable for the synthesis of longer and more hindered cyclic peptides [5]. 

Boc-Asp(OH)-OFm was attached to a methylbenzhydrylamine (MBHA)-resin, maintaining a low substitution level (0.4 mmol/g) in order to respect the pseudodilution principle unreacted amino groups were capped by acetylation. After elongation of the peptide chain by standard methods on an automatic synthesizer using the Boc/Bzl strategy and deprotection of the C-and A-termini with TFA and piperidine, respectively, cyclization was obtained by treatment with BOP (3 equiv.) and DIEA (6 equiv.) in NMP (2 h at room temperature, twice). HF cleavage yielded the desired cyclic product with an overall 10% yield after HPLC purification (Scheme 3). 

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