Resins and solid phase anchors in the organic chemistry

Transcription

1 Resins and solid phase anchors in the organic chemistry

2 Overview

3 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

4 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:

5 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

6 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

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

8 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

9 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

10 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

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

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

13 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

14 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

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

16 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,