Solid phase peptide synthesis the merrifield method
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Solid-Phase Peptide Synthesis: The Merrifield Method PowerPoint PPT Presentation


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Solid-Phase Peptide Synthesis: The Merrifield Method. Solid-Phase Peptide Synthesis. In solid-phase synthesis, the starting material is bonded to an inert solid support. Reactants are added in solution.

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Solid-Phase Peptide Synthesis: The Merrifield Method

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Solid-Phase Peptide Synthesis:The Merrifield Method


Solid-Phase Peptide Synthesis

  • In solid-phase synthesis, the starting material is bonded to an inert solid support.

  • Reactants are added in solution.

  • Reaction occurs at the interface between the solid and the solution. Because the starting material is bonded to the solid, any product from the starting material remains bonded as well.

  • Purification involves simply washing the byproducts from the solid support.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

The Solid Support

  • The solid support is a copolymer of styrene and divinylbenzene. It is represented above as if it were polystyrene. Cross-linking with divinylbenzene simply provides a more rigid polymer.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

The Solid Support

  • Treating the polymeric support with chloromethyl methyl ether (ClCH2OCH3) and SnCl4 places ClCH2side chains on some of the benzene rings.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

CH2Cl

The Solid Support

  • The side chain chloromethyl group is a benzylic halide, reactive toward nucleophilic substitution (SN2).


CH2

CH2

CH2

CH2

CH

CH

CH

CH

CH2Cl

The Solid Support

  • The chloromethylated resin is treated with the Boc-protected C-terminal amino acid. Nucleophilic substitution occurs, and the Boc-protected amino acid is bound to the resin as an ester.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

O

CH2Cl

BocNHCHCO

R

The Merrifield Procedure


CH2

CH2

CH2

CH2

CH

CH

CH

CH

O

CH2

BocNHCHCO

R

The Merrifield Procedure

  • Next, the Boc protecting group is removed with HCl.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

O

CH2

H2NCHCO

R

The Merrifield Procedure

  • DCCI-promoted coupling adds the second amino acid


CH2

CH2

CH2

CH2

CH

CH

CH

CH

O

O

CH2

BocNHCHC

NHCHCO

R'

R

The Merrifield Procedure

  • Remove the Boc protecting group.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

O

O

CH2

H2NCHC

NHCHCO

R'

R

The Merrifield Procedure

  • Add the next amino acid and repeat.


CH2

CH2

CH2

CH2

CH

CH

CH

CH

O

O

O

CH2

+

peptide

NHCHC

NHCHCO

C

H3N

R'

R

The Merrifield Procedure

  • Remove the peptide from the resin with HBr in CF3CO2H


CH2

CH2

CH2

CH2

CH

CH

CH

CH

CH2Br

O

O

O

+

peptide

NHCHC

NHCHCO

C

H3N

R'

R

The Merrifield Procedure


The Merrifield Method

  • Merrifield also automated his solid-phase method.

  • Synthesized a nonapeptide (bradykinin) in 1962 in 8 days in 68% yield.

  • Synthesized ribonuclease (124 amino acids) in 1969.369 reactions; 11,391 steps

  • Nobel Prize in chemistry: 1984


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