Advances in ultra‐high load polymer‐supported peptide synthesis with phenolic supports: 1. A selectively‐labile c‐terminal spacer group for use with a base‐mediated n‐terminal deprotection strategy and fmoc amino acids

Abstract

Crosslinked poly(N‐[2‐(4‐hydroxphenyl)ethyl]‐acrylamide) has been modified by conversion of each pendant 4‐hydroxyphenyl group to its 2‐(4‐hydroxymethyl‐phenoxy)ethanoyl‐L‐prolyl ester. This provides a spacer group which makes the polymer matrix suitable for solid (gel) phase peptide synthesis with Fmoc amino acids at ultra‐high load (2.2 mmol g−1 of spacer‐modified support). The selectively labile linkages incorporated in the spacer group provide for peptide detachment by either mild acidolysis or hydrazinolysis. The products of hydrazinolysis of intermediate and final peptide‐matrix assemblies are amenable to analysis by high‐pressure liquid chromatography (HPLC).

Amino Acid-Protecting Groups

“…It is not completely stable to the catalytic hydrogenolysis treatment required to remove benzyl esters when Pd/C or PtO 2 are used as catalysts The most selective catalyst is Pd/BaSO 4 . 51 Solution removal: liquid NH 3 (10 h) and morpholine or piperidine (within minutes), 10% diethylamine (DEA), dimethylacetamide (DMA) (2 h), 52 polymeric (silica gel or polystyrene) secondary amines (i.e. piperazine, piperidine) in organic solvents.…”

“…The most selective catalyst is Pd/BaSO 4 . 52 Solution removal is done by liquid NH 3 (10 h) and morpholine or piperidine (within minutes), 10% diethylamine (DEA), dimethylacetamide (DMA) (2 h), 53 and polymeric (silica gel or polystyrene) secondary amines (i.e., piperazine, piperidine) in organic solvents. 54,55 This was applied for the first time for SPPS by two different laboratories independently.…”

“…The most selective catalyst is Pd/BaSO 4 . Solution removal is done by liquid NH 3 (10 h) and morpholine or piperidine (within minutes), 10% diethylamine (DEA), dimethylacetamide (DMA) (2 h), and polymeric (silica gel or polystyrene) secondary amines (i.e., piperazine, piperidine) in organic solvents. , This was applied for the first time for SPPS by two different laboratories independently. , Since then, several optimized removal conditions for SPS have been described, with the most relevant being 20% piperidine in DMF, which is the most common; 1−5% DBU in DMF; , morpholine−DMF (1:1) or 2% HOBt; 2% hexamethyleneimine; and 25% N -methylpyrrolidine in DMSO−NMP (1:1), with the latter method leaving thioesters intact. The addition of a relatively small amount of HOBt to the piperidine solution [0.1 M HOBt in piperidine−DMF (2:8)] reduces the formation of aspartimide in the sequences prone to this side reaction. , …”