Application of carboxylic‐phosphinic mixed anhydrides in the fragment peptide synthesis of protected analogues of substance P

Abstract

Mixed carboxylic‐phosphinic anhydrides derived from peptide acids and 1‐oxo‐1‐chlorophospholane have been applied in the synthesis of the protected [Leu11]‐SP1‐11 by the fragment coupling strategy. The yields from fragment couplings were ca. 75%, the products were of high purity while the conditions of formation and coupling of the corresponding mixed phosphinic anhydrides, for optimum yields, have been evaluated.

Application of carboxylic‐phospholanic mixed anhydrides to fragment coupling in peptide synthesis

“…Evidence for maintenance of the stereochemical integrity was exhibited by the 'H NMR spectra of the products obtained by fragment condensation and stepwise synthesis. Both (4) and ( Similar results were obtained when the stability experiments were carried out at 0" and are in agreement with our previous observations on fragment couplings via mixed phospholanic anhydrides (4).…”

“…The couplings were performed at 0" while the pH of the reaction mixture was adjusted to 7-8 with the addition of NMM. The yields of the peptide products were high (87-93 %) in times compatible with those indicated by the 31P NMR studies and in agreement with our results previously reported (4). The products were homogeneous on TLC and their purity was further established by HPLC while they were identified by FAB-MS and 'H NMR spectroscopy.…”

“…Mixed carboxylic-phosphinic anhydrides have been successfully applied in the stepwise synthesis of peptides either in liquid (1) or solid phase (2), while they have been used relatively little in fragment couplings (3,4). In addition to the problems encountered in stepwise peptide synthesis, a strategy incorporating fragment condensations is likely to involve further complications.…”

“…However, such a strategy is not always available on consideration of the primary structure, thus, methods and conditions which minimise racemization are desirable. Considering the advantages of the carboxylic-phospholanic mixed anhydrides in the stepwise peptide chain elongation and our recent work (4) with fragment couplings, it was decided to use 31P NMR for investigation of the reactivity and stability of carboxylic phospholanic mixed anhydrides derived from 1-0x0-1-chlorophospholane and peptide fragments'with C-terminal carboxyl residues other than Gly or Pro in order to evaluate further the potential of these intermediates in peptide synthesis.…”

ΣΥΜΒΟΛΗ ΣΤΗ ΜΕΛΕΤΗ ΤΩΝ ΣΧΕΣΕΩΝ ΔΟΜΗΣ-ΔΡΑΣΤΙΚΟΤΗΤΑΣ ΤΗΣ ΑΓΓΕΙΟΤΕΝΣΙΝΗΣ ΙΙ :ΑΝΑΠΤΥΞΗ ΑΝΑΛΟΓΩΝ ΤΗΣ ΜΕ ΤΡΟΠΟΠΟΙΗΣΕΙΣ ΣΤΙΣ ΘΕΣΕΙΣ 13&5.

“…Το βασικό πρόβλημα που αντιμετωπίζεται κατά την εφαρμογή της μεθόδου είναι η ύπαρξη δύο σχεδόν ισοδύναμων ηλεκτρόφιλων κέντρων, τα οποία κατά την αμινόλυση μπορούν να δώσουν μίγμα προϊόντων. Cpt)[367]. Οι Cpt ανυδρίτες πλεονεκτούν έναντι των Dpp στην καθαρότητα του τελι κού προϊόντος, αφού το παραγόμενο κυκλικό φωσφινικό οξύ είναι διαλυτό στο νερό.…”