Improved approach for anchoring Nα‐9‐fluorenylmethyloxycarbonylamino acids as p‐alkoxybenzyl esters in solid‐phase peptide synthesis

Abstract

Several Fmoc[9-fluorenylmethyloxycarbonyl]-amino acids were esterified by use of N,N-dimethylformamide dineopentyl acetal to 2, 4, 5-trichlorophenyl 3''-(4"-hydroxymethylphenoxy)propionate and the resultant handle derivatives were purified and then quantitatively coupled onto aninomethyl supports. Compared to literature methodology, the present procedure is preferred because: (i) extra steps to selectively protect and liberate the carboxyl of the handle are circumvented; and (ii) the additional methylene group spacer reflecting substitution of a propionyl group for an acetyl group in the handle changes the electronic parameters of the resultant p-alkoxybenzyl ester sufficiently so that the rates of acidolytic cleavage of the anchoring linkage are 2- to 3-fold increased and useful improvements in yields can be achieved.