The safety catch principle in solid phase peptide synthesis

Diels–Alder Ligation of Peptides and Proteins

“…Better results for the production of longer diene peptide segments were achieved by carrying out the complete synthesis on solid-phase using the sulfonamide-based safety-catch resin strategy. Initially introduced by Kenner et al, [96] the sulfonamide linker resin has been widely applied in SPPS for the preparation of carboxylic acid peptide derivatives. In this approach the linkage between the C-terminal residue and the resin linker is highly stable to the conditions of SPPS, but can be finally activated after peptide assembly by a mild chemical The diene-modified peptides were built on the sulfamylbutyryl linker resin (a modification of Kenner´s linker developed by Ellman and co-workers [97] ) using Fmoc, trityl (Trt), 4-methyltrityl (Mtt) or tert-butylthiol (StBu) for protecting N-terminal and reactive sidechain groups of the amino acid residues during peptide chain growing and activation/cleavage steps (Scheme 9).…”

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

“…Amination at C6 followed by in situ hydrazine-mediated cleavage of the phthalimide group yields the respective N 6 -(1-naphthalenemethyl)-5′-deoxy-5′-(phthalimido)adenosine (39) and N 6 -(1-naphthalenemethyl)-5′-deoxy-5′-aminoadenosine (40) intermediates. EDCI-mediated acylation or polymer-assisted acylation with the appropriately acylated safety-catch resin 29,30 is chemoselective and gives the desired products N 6 -(1-naphthalenemethyl)-5′-deoxy-5′-(cyclohexylacetamido)adenosine (41) and N 6 -(1-naphthalenemethyl)-5′-deoxy-5′-(diphenylacetamido)adenosine (42) in high yield (Scheme 2). Despite the additional steps needed to prepare the resin, employing the safety-catch acylating agent has the added benefit of merely filtering off the solid support to obtain the desired product in nearly quantitative yield and in greater than 95% purity as determined by HPLC.…”

“…The acylation step of route 3 is attractive because the desired end-product can simply be washed cleanly from the resin; however, the resin adds two additional steps to the synthesis because it also needs to be prepared. 29,30 To more thoroughly explore N 6 ,2′-disubstituted adenosine analogues, we needed to develop an economically robust route to a difunctionalized intermediate that would allow for the incorporation of a wide variety of substituents at both the N 6 and C2′ positions.…”

“…These resins were prepared from sulfonamidobutyryl-AM resin as per the methodology of Kenner et al 29 and Backes et al 30 General Procedure for the Synthesis of Naphthalene-methylamines from Naphthylnitriles LiAlH 4 (2.7 mmol) was added to naphthylnitrile (2.7 mmol) in anhydrous THF (10.0 mL) at 0 °C, and the mixture was stirred for 1 h. The reaction was quenched with MeOH and then washed with H 2 O (2 × 10 mL). The organic layer was then extracted with 1 N HCl (2 × 10 mL), and the combined extracts were left to stand for 24 h at 4 °C to yield crystals of the desired amine hydrochloride in 60-80% yield.…”

Solid Phase Synthesis

“…This concept was utilised in peptide synthesis 21 and a recent example is shown in scheme 9 where an aryl thioether is activated by oxidation to a sulfone prior to nucleophilic cleavage with a secondary amine. 22…”