Resins and solid phaseanchors in the organic

chemistry

Overview

1. Resins1963:

• Merrifield used chloromethylated-nitrated copolymer of styrene anddivinylbenene• 1st 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

1. ResinsPolystyrene support:

• Chloromethylpolystyrene• Hydroxymethylpolystyrene• Aminomethylpolystyrene

Polyamide resins:

Pepsyne polyamide, a copolymer of:

• cheap• chem., thermal, mechan.stability• normally poor swelling? active sites inaccessible

• very polar resins• excellent swelling in somesolvants (DMSO, H2O), but notin inpolar solv.• long durability

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 oligonucleotidesynthesis• PEGA*: polar material with unparalleled swelling properties enablingaccess 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

• PEG-chains as spacers• extra methylene units

Typical examples:

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 canbe reused

Anchor:

• resin-immobilized functional group• forms an cleavable coupling to the first building block used in thesynthesis• a linker becomes an anchor after it is immobilized on a resin• Some anchors are synthesized directly on the reisin and not a solublebi- functional linker

3. Linker

Depending on the chemical structure of the anchor and chemistry of itsattachment to the resin, the product can be cleaved at the end of thesynthesis by:

• acid• base• nucleophilic • hydrogenolysis• enzymatic • catalytic • palladium-catalyzed• photochemical• oxidative• reductive

cleavage methods

3. Linker

Acid-Labile Anchors:

• 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 compoundduring the combinatorial synthesis of the desired product!2 independent, separate reactions are required in order to liberate theproduct from the solid-phase carrier:

• 1st reaction: like a switch; converts the anchor in a cleavable form • 2nd reaction: results in the release of the product

mCPBA

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

3. LinkerMultifunctional Linkers:

• offer multiple cleavage sites• different cleavage stragegies• generation of various end-grups• result in diverse final products

Literature

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