Mild, orthogonal solid-phase peptide synthesis: use of N alpha-dithiasuccinoyl (Dts) amino acids and N-(iso-propyldithio)carbonylproline, together with p-alkoxybenzyl ester anchoring linkages.
Several N alpha-dithiasuccinoyl (Dts) amino acids (1) have been esterified without racemization 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 degrees. Model experiments established that quantitative thiolytic removal (greater than 99.8%) of the Dts group occurs with (i) beta-mercaptoethanol (0.5 M)-N,N-diisopropylethylamine (0.5 M) in dichloromethane, 2 X 2 min; (ii) N-methylmercaptoacetamide (0.5 M)-N-methylmorpholine (0.5 M) in dichloromethane, 2 X 2 min; and (iii) N-methylmercaptoacetamide (0.5 M)-1-hydroxybenzotriazole (0.1 M) in N,N-dimethylformamide, 2 X 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.
Albericio
F
F
Department of Chemistry, University of Minnesota, Minneapolis.
Barany
G
G
D000596:Amino Acids; D001593:Benzyl Compounds; D002851:Chromatography, High Pressure Liquid; D004952:Esters; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis*; D011392:Proline / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D013386:Succinates
D000596:Amino Acids; D001593:Benzyl Compounds; D004952:Esters; D007202:Indicators and Reagents; D009842:Oligopeptides; D013386:Succinates; D011392:Proline