An Enzyme-Labile Safety Catch Linker for Synthesis on a Soluble Polymeric Support

Abstract

The development of new and broadly applicable linker groups which are stable under a variety of reaction conditions and allow release of the desired products from the solid support under very mild conditions is of great interest in organic synthesis and combinatorial chemistry. We describe an enzyme-labile safety-catch linker which releases alcohols and amines through i) enzymatic cleavage of an amino group and ii) subsequent lactam formation. The linker group was investigated on different polymeric supports: TentaGel. PEGA, CPG-beads and the soluble polymer POE-6000. From these linker-polymer conjugates 2-methoxy-5-nitrobenzyl alcohol was released by penicillin G acylase catalysed cleavage of a phenylacetamide and attack of the liberated benzylamine on the neighbouring ester group in ortho position. The model study revealed that only in the case of soluble POE-6000 conjugate high yields for the cleavage could be achieved. In the case of the other solid supports the enzyme does not have access to the interior of the polymer matrix. The application of the POE-6000 linker conjugate was investigated for various esters in Pd0-catalysed Heck-, Suzuki- and Sonogashira reactions as well as in a Mitsunobu reaction and cycloadditions. These studies proved that the linker is stable under a broad variety of reaction conditions and that the enzymatic method allows for release of the desired product alcohols under extremely mild conditions at pH 7 and 37 degrees C. In addition, the enzymatic reaction proceeds with complete chemoselectivity, that is other esters or amides are not attacked by the biocatalyst. In addition to alcohols amines can also be cleaved by means of the enzyme-initiated two-step process. In these cases the higher stability of amides as compared to esters requires warming to 60 degrees C to induce cyclization and release of the desired product.

Strategies in the Design of Small‐Molecule Fluorescent Probes for Peptidases

“…To drive the phenol‐based fluorophores feasible in the design of peptidase probes, Renard et al employed the Waldmann self‐immolative linker to secure the coumarin fluorophore and peptide sequence to synthesize a probe for determining penicillin G acylase (PGA) . Unlike its application in combinatorial chemistry, the peptide sequence–Waldmann self‐immolative linker–coumarin probe was unstable under the simulated physiological conditions due to the leaving‐group ability of the 7‐hydroxycoumarin fluorophore . The same phenomenon also occurred in the design of self‐cleavable chemiluminescent probes for PGA .…”

Enhancement of the enzymatic digestibility of sugarcane bagasse by steam pretreatment impregnated with hydrogen peroxide

“…Enzymatically‐cleavable linkers can match these requirements since enzymes work under very mild conditions (close to neutrality and room temperature) while offering high chemo‐, regio‐ and enantioselectivity. Enzymatically‐cleavable linkers for polymer‐supported synthesis have been extensively reviewed by Waldmann 12, 48…”

Cross‐Coupling of Organyl Halides with Alkenes: the Heck Reaction

“…An enzyme-labile, so-called safety catch linker 367 was used successfully in various palladium-catalyzed cross-coupling reactions [459]. The linker 367, which releases a hydroxy or an amino functionality upon enzymatic cleavage of its phenylacetamide moiety and subsequent rapid lactam formation, was attached to a soluble POE 6000 polymer, and its free phenyl acetic acid moiety was transformed to a m-iodobenzyl ester.…”

“…Starting from aryl iodides with appropriate alkenyl or, under reductive conditions, alkynyl ethers, smooth cyclizations occur under standard conditions. Intermolecular carbopalladation of a triple bond as in 372 by an in-situ formed organopalladium triflate and subsequent intramolecular nucleophilic trapping Scheme 5-75 Heck reaction of an iodoarene anchored on an enzyme-labile safety catch linker [459]. gives rise to indoles 373 (Scheme 5-77) [467].…”