Resins and solid phase anchors in the organic chemistry

Resins and solid phase anchors in the organic chemistry

Overview

1963: 1. Resins Merrifield used chloromethylated-nitrated copolymer of styrene and divinylbenene 1 st cross-linked polystyrene resinds bead used for organic synthesis today: only little changes in resins characteristics: insoluble supports cross-linked (5%) for mechanical stability gel-type structure

Polystyrene support: 1. Resins cheap chem., thermal, mechan. stability normally poor swelling? active sites inaccessible Polyamide resins: very polar resins excellent swelling in some solvants (DMSO, H 2 O), but not in inpolar solv. long durability Chloromethylpolystyrene Hydroxymethylpolystyrene Aminomethylpolystyrene Pepsyne polyamide, a copolymer of:

1. Resins PS/PEG graft copolymers: lower mechanical and thermal stability than PS much better solvent spectrum resins swell in almost everython except hexane A couple of other resins for different applications controlled pore glass for continous flow SSP and oligonucleotide synthesis PEGA * : polar material with unparalleled swelling properties enabling access for a variety of large macromolecules, e.g. enzymes * PEGA: poly(ethylene glycol)(dimethylacrylamide copolymer

2. Spacers A group can be attached to the solid support to act as a spacer unit. The use of the spacer is optional, but may often be advantageous Role: distance chemistry from the solid support reduce steric hindrance modify features such as hydrophilicity/hydrophobicity tailors the swelling properties of the resin materials modifies compatibility with the solvant during the cleavage of the final product, the spacer remains attached to resin

2. Spacer Typical examples: PEG-chains as spacers extra methylene units

3. Linker bifunctional molecule bound irreversibly to the resin offers a reversible binding site for the coupling of desired molecules normally the linker remains attached to the carrier, so that the resin can be reused Anchor: resin-immobilized functional group forms an cleavable coupling to the first building block used in the synthesis a linker becomes an anchor after it is immobilized on a resin Some anchors are synthesized directly on the reisin and not a soluble bi- functional linker

3. Linker Depending on the chemical structure of the anchor and chemistry of its attachment to the resin, the product can be cleaved at the end of the synthesis by: acid base nucleophilic hydrogenolysis enzymatic cleavage methods catalytic palladium-catalyzed photochemical oxidative reductive

Acid-Labile Anchors: 3. Linker acid-labile acetal group by addition of an alcohol to a 2,3-dihydro-4H-pyran ability to form stable cations by substitution of different aromatic substuituents

3. Linker Anchors cleaved by Nucleophiles: base-labile anchor beta-eliminierung hydrolysis re-esterification aminolysis

3. Linker Photolysis-Labile Anchors: 320 365 nm For products with functional groups as: carboxylic acids carbamides amidines hydroxy

3. Linker Safety-Catch Anchors: Linker can be partially or even completely release the compound during the combinatorial synthesis of the desired product! 2 independent, separate reactions are required in order to liberate the product from the solid-phase carrier: 1 st reaction: like a switch; converts the anchor in a cleavable form 2 nd reaction: results in the release of the product mcpba

Traceless Anchors: 3. Linker Traceless Anchors do not yield a functional group in the final product after cleavage Normally these linkers are based on: Syilylfunctionalisation: cleavage of the Si-C bond by flurides or Acides Olfefin Metathesis Decarboxylation

Multifunctional Linkers: offer multiple cleavage sites different cleavage stragegies generation of various end-grups result in diverse final products 3. Linker

Literature Warras, R.: Solid Phase Anchors in Organic Chemistry in Combinatorial Chemistry Synthesis, Analysis, Screening, Ch. 5, Jung, G. (ed.), Wiley VCH, Weinheim, 1999 Bannworth, W.: Linkers for Solid-Phase Organic Synthesis in Combinatorial Chemistry A Practical Approach, Ch. 3, Bannworth, Felder (eds.), Wiley VCH, Weinheim, 2000 Winter, M: Supports for Solid-Phase Organic Chemistry in Combinatorial Peptide and Nonpeptide Libraries A Handbook, Ch. 17, Jung (ed.), Wiley VCH, Weinheim, 1996 Guillier, Orain, Bradley : Linkers and Cleavage Strategies in Solid Phase Organic Synthesis and Combinatorial Chemistry. Chem. Rev. (2000), 100, 2091-2157