Novel N^ω-xanthenyl-protecting groups for asparagine and glutamine, and applications to N^α-9-fluorenylmethyloxycarbonyl (fmoc) solid-phase peptide synthesis

The N^α-9-fluorenylmethyioxycarbonyl (Fmoc), N^ω-9H-xanthen-9-yl (Xan), N^Ω;-2-methoxy-9H-xanthen-9-yl (2-Moxan) or N^ω-3-methoxy-9H-xianthen-9-yl (3-Moxan) derivatives of asparagine and glutamine were prepared conveniently by acid-catalyzed reactions of appropriate xanthydmls with Fmoc-Asn-OH and Fmoc-Cln-OH. The Xan and 2-Moxan protected derivatives have been used in Fmoc solid-phase syntheses of several challenging peptides: a modified Riniker's peptide to probe tryptophanalkylation side reactions, Briand's peptide to assess deblocking, at the -terminus and Marshall 's ACP (65-74) to test difficult couplings. Removal of the Asn and Gin sidechain protection occurred concomitantly with release of peptide from the support, under the conditions for acidolytic cleavage of the tris(alkoxy)benzylamide (PAL) anchoring linkage by use of Irifluoroacetic acid/scavenger mixtures. For each of the model peptides, the products obtained by the new protection schemes were purer than those obtained with N^ω-2,4,6-trimethoxybenzyl (Tmob) or N^ω-triphenylmethyi (Trt) protection for Asn and Gin.