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Solid Phase Synthesis of a Functionalized Bis-Peptide Using "Safety Catch" Methodology
Published on: May 15, 2012
An improved procedure for N- to C-directed (Inverse) solid-phase peptide synthesis
A Johansson1, E Akerblom, K Ersmark
1Department of Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Journal of Combinatorial Chemistry
|October 13, 2000
Summary
This study presents an optimized solid-phase peptide synthesis method using amino acid tri-tert-butoxysilyl (Sil) esters and HATU coupling reagent. The new approach achieves good yields and low epimerization for synthesizing short peptides.
Area of Science:
- Organic Chemistry
- Biochemistry
- Synthetic Chemistry
Background:
- Solid-phase peptide synthesis (SPPS) is crucial for producing peptides.
- Minimizing epimerization and maximizing coupling efficiency are key challenges in SPPS.
- Amino acid protecting groups and coupling reagents significantly impact SPPS outcomes.
Purpose of the Study:
- To develop an optimized N- to C-direction solid-phase peptide synthesis method.
- To achieve high coupling yields and low epimerization using specific reagents.
- To improve the synthesis of amino acid tri-tert-butoxysilyl (Sil) ester building blocks.
Main Methods:
- Coupling of resin-bound C-terminal amino acids with excess amino acid tri-tert-butoxysilyl (Sil) esters.
- Utilizing HATU as the coupling reagent and 2,4,6-trimethylpyridine (TMP) as the base.
- Investigating various combinations of activating agents, bases, solvents, and epimerization suppressants like cupric chloride.
Main Results:
- The optimized method yielded good coupling efficiency with typically 5% epimerization for most amino acids.
- Serine derivatives showed higher epimerization (ca. 20%).
- Cupric chloride reduced epimerization but also decreased resin loading and caused cleavage.
Conclusions:
- The developed method offers an attractive alternative for solid-phase synthesis of short peptides (≤6 residues).
- Amino acid Sil esters are stable as hydrochlorides, facilitating their use as building blocks.
- The procedure is suitable for applications like peptide library synthesis.
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