Fmoc-Ala-Ser[psi(Me,Me)pro]-OH

Fmoc-Ala-Ser[psi(Me,Me)pro]-OH

           
Product Catalog # SizePrice (USD) Quantity
$250.00
$800.00
$2,250.00
Synonym: Fmoc-Ala-Ser(psiMe,Mepro)-OH
CAS #: 252554-78-2
Molecular Formula: C24H26N2O6
Molecular Weight: 438.5
Fmoc-Ala-Ser[psi(Me,Me)pro]-OH is a specialized, protected dipeptide building block primarily utilized in Solid-Phase Peptide Synthesis (SPPS). Its key structural feature is the incorporation of a dimethylated pseudoproline (ψ(Me,Me)pro) moiety derived from the C-terminal Serine residue. This modification is strategically employed to overcome common challenges encountered during the synthesis of “difficult sequences,” particularly those prone to aggregation and poor coupling efficiencies. As the demand for complex synthetic peptides in research, diagnostics, and therapeutics continues to grow, tools like Fmoc-Ala-Ser[psi(Me,Me)pro]-OH remain indispensable for efficient and successful peptide assembly.
1. Primary Application: Solid-Phase Peptide Synthesis (SPPS)
The paramount use of Fmoc-Ala-Ser[psi(Me,Me)pro]-OH is as a strategic building block in SPPS to address “difficult sequences.” These are peptide sequences that are prone to:
• Inter-chain aggregation: Growing peptide chains on the solid support can aggregate via intermolecular hydrogen bonding, primarily forming β-sheet structures.
• Intra-chain folding: Individual peptide chains can fold back on themselves.
• Poor solvation: Aggregated or folded sequences are poorly solvated by the synthesis solvents, hindering reagent access.
• Incomplete coupling reactions: Difficulty in achieving complete acylation of the N-terminus.
• Deletion sequences and low purity/yield: As a consequence of incomplete reactions.
2. Role and Advantages of the Ser[psi(Me,Me)pro] Moiety
The incorporation of the pseudoproline unit at a Ser (or Thr, Cys) residue provides several crucial benefits during peptide chain elongation:
• Disruption of Aggregation: The oxazolidine ring structure restricts the conformational freedom of the peptide backbone and disrupts the regular hydrogen-bonding patterns required for β-sheet formation. The gem-dimethyl groups can further enhance this effect.
• Increased Solubility/Solvation: By minimizing aggregation, the peptide-resin remains better solvated, allowing improved diffusion and access for reagents.
• Enhanced Coupling Efficiency: Better solvation and reduced steric hindrance from aggregates lead to more efficient and complete subsequent coupling steps.
• Temporary “Kink”: The pseudoproline introduces a temporary Proline-like kink (favoring a cis-amide bond conformation for the Ser-Xaa bond it replaces) in the peptide backbone. This can help maintain an extended and accessible conformation for the growing chain.
• Reversibility: The pseudoproline (oxazolidine ring) is designed to be stable to the basic conditions used for Fmoc deprotection but is readily cleaved (hydrolyzed) under strong acidic conditions (e.g., standard TFA cleavage cocktails used at the end of SPPS). This regenerates the original Serine residue and the native peptide backbone amide bond.
3. Usage in SPPS
Fmoc-Ala-Ser[psi(Me,Me)pro]-OH is incorporated into a peptide sequence using standard Fmoc-SPPS protocols:
• The N-terminal Fmoc group of the preceding residue on the resin-bound peptide is removed.
• Fmoc-Ala-Ser[psi(Me,Me)pro]-OH is activated using appropriate peptide coupling reagents and coupled to the free N-terminus.
• The Fmoc group of the newly added Alanine (from the dipeptide) is then removed for the next coupling cycle.
The placement of pseudoproline dipeptides is strategic. They are typically inserted at Ser, Thr, or Cys residues within or immediately preceding a sequence known or predicted to be aggregation-prone (often every 5-7 residues in such regions).
4. Deprotection
• Fmoc Group: Removed by standard treatment with ~20% piperidine in DMF during each cycle of SPPS.
• Pseudoproline Ring: The dimethylated oxazolidine ring is stable to the basic conditions of Fmoc deprotection. It is cleaved during the final global deprotection and cleavage of the peptide from the resin using strong acidic conditions, typically a Trifluoroacetic Acid (TFA) cocktail (e.g., TFA/H₂O/TIPS 95:2.5:2.5). This acidic hydrolysis regenerates the native L-Serine residue.
5. Limitations and Considerations
• Strategic Placement: Effective use requires careful analysis of the peptide sequence to identify optimal insertion points for maximum benefit.
• Complete Ring Opening: While generally efficient, conditions must be sufficient to ensure complete hydrolysis of the oxazolidine ring during final cleavage to avoid an undesired modified Serine in the final peptide.
Fmoc-Ala-Ser[psi(Me,Me)pro]-OH is a well-established and highly valuable tool in the arsenal of peptide chemists. Its ability to act as a temporary “beta-sheet breaker” by introducing a conformational kink via the reversible dimethylpseudoproline modification makes it essential for the successful synthesis of numerous difficult peptide sequences.
References
1. Overview of Pseudoproline Dipeptides
2. Pseudoproline
3. Pseudo-prolines in peptide synthesis: Direct insertion of serine and threonine derived oxazolidines in dipeptides
4. Mutter, M. et al. (1995) “Pseudo-prolines (psi Pro) for accessing ‘inaccessible’ peptides.” Peptide Research 8, 145-153.
5. Wohr, T. and Mutter, M. (1995) “Pseudo-prolines in peptide synthesis: Direct insertion of serine and threonine derived oxazolidines in dipeptides.” Tetrahedron Letters 36, 3847-3848.
6. Dumy, P. et al. (1997) “Pseudo-prolines as a molecular hinge: Reversible induction of cis amide bonds into peptide backbones.” Journal of the American Chemical Society 119, 918-925.
7. Coin, I. et al. (2007) “Pseudoproline as a molecular hinge: Conformational effects in the β-structure breaker model peptide Boc-(Leu-Phe-Val-Thr-psiPro-Gly-Leu-Phe-Val)-OMe.” Journal of Organic Chemistry 72, 6383-6389.
8. Postma, T.M. and Albericio, F. (2013) “N-Methylation of peptides: A new perspective in medicinal chemistry.” RSC Advances 3, 14277-14280.

You may also like: