Combinatorial Chemistry. Advanced Medicinal Chemistry ( Pharm 5219): Section A. Md. Saifuzzaman Assoc. Professor [email protected] Ref.: An Introduction to Medicinal Chemistry , 3 rd ed. 2005, G.L.Patrick , Oxford University press. The Solid support.
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Earliest form of resin (used by Merrifield) – polystyrene beads – styrene cross-linked with 1% divinylbenzene.
Derivatized with a chloromethyl group (anchor/linker) – amino acids can be coupled via an ester group.
This ester group is stable to reaction conditions but cleaved at end of synthesis using acids (e.g., HF).
Disadvantages of polystyrene beads
Growing peptide chain is hydrophobic, so not solvated and folds itself & forms internal H bonds
thus, hinders access of further amino acids to growing chain
Therefore, more polar solid phages – developed e.g., Sheppard’s polyamide.
For non-peptides, Tentagel resin
80% polyethylene glycol grafted to cross-linked polystyrene
Provides ether or tetrahydrofuran like environment.
Beads should be capable of swelling in solvent
Most reactions in solid phase synthesis take place in interior of beads rather than surface.
Each bead - a polymer and swelling involves unfolding of the polymer chains so that solvent and reagents can move between the chains into the core of polymer.
Besides bead, pins – designed to maximize surface area, maximize amount of compounds linked to solid support.
Functionalized glass surfaces – suitable for oligoneucleotide synthesis.
A molecular unit covalently attached to polymer chain making up solid support
Contains a reactive functional group with which starting material can react and attach to the resin
Resulting link – stable to reaction conditions but cleavable to release final product
Most linkers – in interior of polymer beads, so swelling is important.
Choice of linkers depends on…..
Functional group present on starting material
Functional group to be present on final product upon release
Resins of different linkers have different names
Wang resin – has a linker suitable for attachment and release of carboxylic acids
Rink resin – for attachment of carboxylic acids and release of carboxamides
Dihydropyran-derivatized resin – suitable for attachment and release of alcohols
Wang resin –
Used in peptide synthesis where N-protected amino acid – linked to resin by means of ester link.
Ester link – remains stable to coupling and deprotection steps in synthesis and cleaved using trifluoroacetic acid (TFA) to release final product.
Rink resin –
Attach starting material (with carboxylic acid) via amide link
When reaction is complete, treatment with TFA releases final product with primary amide group.
Attach primary & secondary alcohols in presence of pyridinium 4-toluenesulfonate (PPts) in dichloromethane.
Upon completion of reaction, cleavage using TFA.
Combinatorial synthesis with aDihydropyran-derivatized resin
Important functional groups (not involved in reaction) – should be protected
Selection is extremely important
Should be stable in reaction condition but capable of being removed under mild conditions after synthesis
N-terminus of each amino acid – protected by a tert-butyloxycarbonyl (Boc) group
After adding a.a. with growing peptide chain, Boc group is removed with TFA to free up amino group
Next protected a.a. = coupled on to the chain
Bond connecting new peptide to linker – stable to TFA, so remains unaffected by synthesis; but susceptible to strong acid and after synthesis, HF – used to release peptide
Functional groups on a.a. residues – to be protected during synthesis (that protecting group has to be stable to TFA)
Benzyl-type groups – stable to TFA but susceptible to HF
So, HF both releases final peptide & deprotects residues
Disadvantage of using HF:
so use Teflon equipment
too harsh condition – decomposition of peptide
serious health risk (HF on skin!!!!)
9-fluorenylmethoxycarbonyl (Fmoc) group – for terminal amino group – removed using mild base (e.g., piperidine)
Functional groups on a.a. residues – to be protected with t-butyl group – can be removed by TFA
Orthogonal strategy – base for removing Fmoc & acid for t-butyl
Link to resin – susceptible to TFA, no need to use HF
Both peptide cleavage & functional group deprotection simultaneously