Solid phase synthesis

Question 1

Main advantages of solid phase synthesis

Answer 1

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

Question 2

Linker

Answer 2

Links the solid support (i.e. the polymer) to the reagents/products

Question 3

Ideal properties of a linker

Answer 3

Easily formed and attached to the polymer resin
Stable to reaction conditions
Selectively cleaved
Reusable (although this property is often not achieved)

Question 4

Solid support

Answer 4

Cross-linked polymer

Question 5

Ideal properties of a solid support

Answer 5

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

Question 6

Merrifield synthesis of polypeptides

Answer 6

Draw

Question 7

Disadvantage of carbodiimide reagents

Answer 7

Acyl transfer is a problem if the amine is not very nucleophilic
Results in termination of the amide coupling reaction

Question 8

Disadvantage of Boc protecting group

Answer 8

Requires strong acid (TFA in DCM)

Question 9

Disadvantages of Merrifield resin

Answer 9

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

Question 10

Examples of more polar polymer beads

Answer 10

Wang
Sasrin
Rink

Question 11

Cleavage methods of linkers

Answer 11

1. Monofunctional cleavage
2. Cyclisation-assisted cleavage
3. Multifunctional cleavage

Question 12

Monofunctional cleavage

Answer 12

= bond breaks to give one particular functional group e.g. carboxylic acids, amines, alcohols, amides, sulphonamides, hydroxamic acids

Question 13

Examples of resins that undergo monofunctional cleavage to give carboxylic acids

Answer 13

Merrifield
Wang
Sasrin
Rink
Trityl
Photo

Question 14

Merrifield resin cleavage conditions

Answer 14

HF, CF3SO3H

Question 15

Wang resin cleavage conditions

Answer 15

95 % TFA

Question 16

Sasrin cleavage conditions

Answer 16

1 % TFA

Question 17

Rink resin cleavage conditions

Answer 17

1 % TFA

Question 18

Trityl resin cleavage conditions

Answer 18

1 % TFA/AcOH

Question 19

Photo resin cleavage conditions

Answer 19

350 nm wavelength light

Question 20

Cyclisation-assisted cleavage

Answer 20

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

Question 21

Disadvantage of cyclisation-assisted cleavage

Answer 21

Requires a lot of thought to produce a compound that will cyclise at the end of the reaction

Question 22

Multifunctional/multidirectional cleavage

Answer 22

e.g.
Direct cleavage by nucleophilic substitution
Direct cleavage by electrophilic substitution
Traceless linkers
Activation of the linker prior to cleavage (“safety catch”)

Question 23

Traceless linker

Answer 23

When no element of the linker remains in the product

Question 24

Safety catch linker

Answer 24

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

Question 25

Types of solid support

Answer 25

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

Question 26

Polystyrene (Merrifield) resin beads

Answer 26

Chemically inert alkyl backbone
Easily functionalised
High-loading
Polystyrene is cheap

Question 27

TentaGel

Answer 27

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