ChemInform Abstract: Safety-Catch Anchoring Linkage for Synthesis of Peptide Amides by Boc/ Fmoc Strategy.

Abstract

Summary: 2-Methoxy-4,4’-bis(methylthio)benzhydrylamine (10) and the corresponding disulfoxide were prepared and tested as a model amide protecting groups for their stability toward acidic conditions. Subsequently, the novel 4-[4,4’-bis(methylsulfinyl)-2-o~-(9-fluorenylmethylo~c~bonyl) benzhydrylami- nolbutanoic acid (SCAL) handle (9) has been prepared and applied to solid-phase peptide synthesis of C-terminal peptide amide using both 9-fluorenylmethyloxycarbonyl (Fmoc) and tert-butyloxycarbonyl (Boc) groups for Na-amino protection. A range of naturally occurring peptides, especially hormones such as oxytocin, secretin, LHRH, and calcitonin, contain a C-terminal amide function. Synthesis of peptide amides is best carried out by application of appropriate handles, which are quantitatively coupled in a single step onto amino-functionalized supports to provide ageneral starting point for peptide chain assembly. Surprisingly, the development of amide-anchor groups which can be cleaved by relatively mild procedures (e.g., TFA), were established only recently.’ Considerable attention has been focused on preparation of benzylamine1’2 and benzhydrylamine1’3 deriva- tives substituted with electron-donating alkoxy groups. Earlier we have examined some benzhydrylamines containingp-methylsulfinyl orp-methylthio groups as a model amrde protecting groups4 We have found that 4,4’-bis(methylsulfinyl)benzhydryl protecting group for amides is fully compatible with Fmoc and/or Boc protecting groups. We now describe the synthesis and application of anew type of safety-catch acid labile5 (SCAL) handle9 derived from 2-alkoxy-4,4’-bis(methyl- thio)benzhydrylamine, which extends the orthogonalit$ of currently