Resin Selection Based on the Lability of Peptidyl-Resin Linkage towards HF and TFA Steps : Dependence on the C-Terminal Amino Acid and Peptide Length

• Published in: Chemical & pharmaceutical bulletin Vol. 47; no. 11; pp. 1560 - 1563
• Main Authors: JUBILUT, Guita N., MIRANDA, Maria Teresa, TOMINAGA, Mineko, OKADA, Yoshio, MIRANDA, Antonio, NAKAIE, Clovis R.
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1999; Pharmaceutical Soc Japan; Maruzen
• Subjects: benzhydrylamine-resin; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Exact sciences and technology; Life Sciences & Biomedicine; methylbenzhydrylamine-resin; Organic chemistry; peptide synthesis; Peptides; peptidyl-resin cleavage; Pharmacology & Pharmacy; Physical Sciences; Preparations and properties; Science & Technology; SUPPORT; methylbenzhydrylamine-resin; peptidyl-resin cleavage; SOLVATION; peptide synthesis; benzhydrylamine-resin; C terminal aminoacid; Acidolysis; Chain length; Hydrofluoric acid; Peptide synthesis; Peptide chain; Solid phase; Reaction support; Resins; Chemical synthesis; Scission
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.47.1560

Ideally, the solid support used for tert-butyloxycarbonyl (Boc)-peptide synthesis method must allow sufficient stability of the peptide linkage towards TFA-α-amino deprotection but adequate lability to final HF cleavage. Due to these conflicting characteristics, the choice of the correct resin for peptide synthesis is complex and dependent upon many factors. Aiming to clarify this issue, a time-course study of the trifluoroacetic acid (TFA) and HF steps using model peptidyl-resins was developed. The peptidyl-resin bond stability was strongly dependent upon the resin and the carboxy-terminus residue. The decreasing order of acid stability for resins was : benzhydrylamine-resin (BHAR)>p-methylbenzhydrylamine-resin (MBHAR)≅4-(oxymethyl)-phenylacetamidomethyl-resin (PAMR)>chloromethyl-resin (CMR) and Phe>Gly≅His≅Asp for C-terminal amino acids. HF-cleavage times of near 6 h (BHAR) and 2-3 h (MBHAR and PAMR) were necessary for quantitative cleavage of hydrophobic Phe residue-containing sequence at its C-terminal portion. When premature chain loss in TFA and incomplete cleavage in HF values were both quantitatively considered, a significant decrease in the overall yield (up to 35%) was observed in some resins. Moreover, MBHAR was more suitable than BHAR only when the peptide C-terminal residue is hydrophobic. The data also allow the prediction that due to more significant chain loss in TFA when MBHAR is used, BHAR will be the resin of choice for much longer than 40-mer peptide sequences containing C-terminal hydrophilic residues. Otherwise PAMR is the best resin for the synthesis of free carboxyl peptides but significantly low HF cleavage was observed when the C-terminal amino acid is of the hydrophobic-type.