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Anchor‐linked intermediates in peptide amide synthesis are caused by dimeric anchors on the solid supports
Author(s) -
Flechsler Insa,
BeckSickinger Annette G.,
Stephan Holger,
Sheppard Robert,
Jung Günther
Publication year - 1995
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.310010306
Subject(s) - trifluoroacetic acid , chemistry , amide , cleavage (geology) , dichloromethane , peptide , cleave , peptide bond , stereochemistry , organic chemistry , enzyme , solvent , biochemistry , geotechnical engineering , fracture (geology) , engineering
Cleavage and kinetic studies have been carried out using commercially obtained H‐Tyr( t Bu)‐5‐(4′‐aminomethyl‐3′,5′‐dimethoxyphenoxy)valeric acid‐TentaGelS (H‐Tyr( t Bu)‐4‐ADPV‐TentaGelS) and H‐Tyr ( t Bu)‐4‐ADPV‐Ala‐aminomethyl‐resin (H‐Tyr( t Bu)‐4‐ADPV‐AM‐resin) prepared from commercially available resin and loaded with commercially available Fmoc‐4‐ADPV‐OH amide anchor. Cleavage with pure trifluoroacetic acid (TFA) gave the intermediate H‐Tyr‐4‐ADPV‐NH 2 , which was then degraded to H‐Tyr‐NH 2 , and cleavage with TFA/dichloromethane (1:9) yielded H‐Tyr‐4‐ADPV‐NH 2 which could be isolated in preparative amounts. Cleavage reactions with 15 N‐labelled H‐Ala‐4‐ADPV‐[ 15 N]‐Gly‐AM‐resin yielded the intermediate H‐Ala‐4‐ADPV‐NH 2 , which contained no 15 N as demonstrated by 1 H‐NMR. The analysis of the commercial Fmoc‐4‐ADPV‐OH amide anchor showed the presence of Fmoc‐4‐ADPV‐4‐ADPV‐OH as an impurity in high amounts. This dimeric anchor molecule is the cause of formation of the anchor‐linked peptide intermediate obtained during the cleavage from the resin. The particularly high acid‐lability of the amide bond between the two ADPV moieties was utilized to synthesize sidechain and C‐terminally 4‐ADPV protected pentagastrin on a double‐anchor resin, and to cleave it using 5% trifluoroacetic acid in dichloromethane. This method may offer a new way for the synthesis of protected peptide amides with improved solubility to be used in fragment condensation.