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*

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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.