Solid phase synthesis Flashcards
Main advantages of solid phase synthesis
Reactions can be purified by just washing and filtration
Can use an excess of reagents
Can use a high concentration of reagents
Reaction, washing and filtration are easily automated
Linker
Links the solid support (i.e. the polymer) to the reagents/products
Ideal properties of a linker
Easily formed and attached to the polymer resin
Stable to reaction conditions
Selectively cleaved
Reusable (although this property is often not achieved)
Solid support
Cross-linked polymer
Ideal properties of a solid support
Insoluble (at the point of filtration)
Solvent swellable - to allow the reagents to reach the polymer and react
Have an easy method for linkage and cleavage
Overall synthetic procedure must be compatible with the linker and the solid phase
Merrifield synthesis of polypeptides
Draw
Disadvantage of carbodiimide reagents
Acyl transfer is a problem if the amine is not very nucleophilic
Results in termination of the amide coupling reaction
Disadvantage of Boc protecting group
Requires strong acid (TFA in DCM)
Disadvantages of Merrifield resin
Require liquid HF to cleave the linker
Very hydrophobic but growing peptide is hydrophilic - this leads to peptide folding around the polymer bead and therefore hinders peptide bond formation
Examples of more polar polymer beads
Wang
Sasrin
Rink
Cleavage methods of linkers
- Monofunctional cleavage
- Cyclisation-assisted cleavage
- Multifunctional cleavage
Monofunctional cleavage
= bond breaks to give one particular functional group e.g. carboxylic acids, amines, alcohols, amides, sulphonamides, hydroxamic acids
Examples of resins that undergo monofunctional cleavage to give carboxylic acids
Merrifield Wang Sasrin Rink Trityl Photo
Merrifield resin cleavage conditions
HF, CF3SO3H
Wang resin cleavage conditions
95 % TFA
Sasrin cleavage conditions
1 % TFA
Rink resin cleavage conditions
1 % TFA
Trityl resin cleavage conditions
1 % TFA/AcOH
Photo resin cleavage conditions
350 nm wavelength light
Cyclisation-assisted cleavage
Only molecules that have gone through the whole reaction sequence will be cleaved - i.e. only the final product can cyclise onto the linker and be cleaved
Therefore improves purity
Even if each step isn’t quantitative - cyclisation will lead to pure products
Independent of the nature of the linker
Depends on the synthesis required to create the precursor
Disadvantage of cyclisation-assisted cleavage
Requires a lot of thought to produce a compound that will cyclise at the end of the reaction
Multifunctional/multidirectional cleavage
e.g.
Direct cleavage by nucleophilic substitution
Direct cleavage by electrophilic substitution
Traceless linkers
Activation of the linker prior to cleavage (“safety catch”)
Traceless linker
When no element of the linker remains in the product
Safety catch linker
Linker is inert during whole synthesis - stable to a wide range of reaction conditions
Linker activated at the end of the synthesis and can be cleaved under mild conditions
Leads to multidirectional cleavage - so generates a structurally and functionally diverse library
Types of solid support
Cross-linked organic polymers (insoluble in organic solvents, allowing for filtration)
Linear organic polymers (usually soluble in organic solvents but can be precipitated)
Dendrimers (solubility depends on size and shape)
Inorganic supports e.g. porous glass, SiO2, Al2O3, clays, graphite
Polystyrene (Merrifield) resin beads
Chemically inert alkyl backbone
Easily functionalised
High-loading
Polystyrene is cheap
TentaGel
PEG attached to cross-linked polystyrene through an ether linker
Less hydrophobic than Merrifield-type polymers (so better for making peptides)
Swell better in aqueous solutions
Less mechanically stable
Lower loading than Merrifield-type polymers
Expensive
