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Solid-Phase Peptide Synthesis: The Merrifield Method

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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  1. Solid-Phase Peptide Synthesis:The Merrifield Method

  2. 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.

  3. 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.

  4. 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.

  5. 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).

  6. 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.

  7. CH2 CH2 CH2 CH2 CH CH CH CH O CH2Cl – BocNHCHCO R The Merrifield Procedure

  8. CH2 CH2 CH2 CH2 CH CH CH CH O CH2 BocNHCHCO R The Merrifield Procedure • Next, the Boc protecting group is removed with HCl.

  9. CH2 CH2 CH2 CH2 CH CH CH CH O CH2 H2NCHCO R The Merrifield Procedure • DCCI-promoted coupling adds the second amino acid

  10. CH2 CH2 CH2 CH2 CH CH CH CH O O CH2 BocNHCHC NHCHCO R' R The Merrifield Procedure • Remove the Boc protecting group.

  11. 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.

  12. 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

  13. CH2 CH2 CH2 CH2 CH CH CH CH CH2Br O O O + peptide NHCHC NHCHCO C H3N R' R The Merrifield Procedure –

  14. 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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