Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages

FERNANDO ALBERICIO, George Barany

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Several Nα‐dithiasuccinoyl (Dts) amino acids (1) have been esterified without race‐mization by use of either N,N'‐dicyclohexylcarbodiimide or 1‐(3‐dimethylamino‐propyl)‐3‐ethylcarbodiimide hydrochloride, each in the presence of 4‐dimethylaminopyridine (0.1 equiv.), to 2, 4, 5‐trichlorophenyl 4′‐hydroxymethylphenoxyacetate (10) or the corresponding propionate (11). The resultant handle derivatives (8,9) were purified and then quantitatively attached onto aminomethyl supports by couplings using as solvent N,N‐dimethylformamide containing 1‐hydroxybenzotriazole (0.1 M). This methodology facilitates anchoring of Dts‐amino acids as p‐alkoxybenzyl esters, which can be cleaved in good yields by trifluoroacetic acid‐dichloromethane (1:1) at 25°. Model experiments established that quantitative thiolytic removal (>99.8%) of the Dts group occurs with (i) β‐mercaptoethanol (0.5M)‐N,N‐diisopropylethylamine (0.5M) in dichloromethane, 2 times 2min; (ii) N‐methylmercaptoacetamide (0.5M)‐N‐methylmorpholine (0.5M) in dichloromethane, 2 times 2min; and (iii) N‐methylmercaptoacetamide (0.5M)‐1‐hydroxybenzotriazole (0.1M) in N,N‐dimethylformamide, 2 times 2 min. The susceptibility of the Dts functionality to nucleophiles was also defined, including demonstration of tertiary amine‐catalyzed hydantoin formation from Dts‐dipeptidyl units, but side reactions from these processes are entirely avoided under appropriate conditions relevant to peptide synthesis. These observations were exploited to devise efficient, racemization‐free solid‐phase syntheses of a number of model peptides in high yields and purities, including L‐leucyl‐L‐alanylglycyl‐L‐valine, H‐Gly6‐Val‐OH, H‐Met‐Ala‐Gly‐OH, methionine‐enkephalin, and bradykinin.

Original languageEnglish (US)
Pages (from-to)177-205
Number of pages29
JournalInternational Journal of Peptide and Protein Research
Volume30
Issue number2
DOIs
StatePublished - Aug 1987

Keywords

  • 4‐hydroxymethylphenoxyacetate and 3‐(4′‐hydroxymethylphenoxy)propionate handles
  • N‐(iso‐propyldithio)carbonylproline
  • N‐dithiasuccinoyl amino acids
  • hydantoins
  • orthogonal protection schemes
  • p‐alkoxybenzyl esters
  • solid‐phase peptide synthesis

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