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

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

           
Product Catalog # SizePrice (USD) Quantity
$300.00
$850.00
$2,400.00
Synonym: Fmoc-Tyr(tBu)-Ser(psiMe,Mepro)-OH
CAS #: 878797-09-2
Molecular Formula: C34H38N2O7
Molecular Weight: 586.7
Fmoc-Tyr(tBu)-Ser[psi(Me,Me)pro]-OH is a specialized, protected dipeptide derivative used primarily as a building block in solid-phase peptide synthesis (SPPS), particularly for the synthesis of “difficult” or aggregation-prone peptide sequences. Its key feature is the incorporation of a dimethylated pseudoproline (ψ(Me,Me)pro) moiety derived from the Serine residue. This modification temporarily alters the peptide backbone conformation, offering significant advantages during chain assembly.
1. Key Application: Solid-Phase Peptide Synthesis (SPPS)
The primary utility of this compound lies in overcoming challenges associated with “difficult sequences” during SPPS. These sequences often contain hydrophobic residues or segments prone to forming secondary structures (like β-sheets) on the resin, leading to:
• Inter-chain Aggregation: Peptide chains clump together, hindering reagent access.
• Intra-chain Folding: Individual chains fold back on themselves.
• Poor Solubility: The growing peptide-resin complex becomes poorly solvated by synthesis solvents.
• Incomplete Reactions: Both deprotection and coupling steps become inefficient, leading to deletion sequences and low purity/yield.
2. Role and Advantages of the Ser[psi(Me,Me)pro] Moiety
The incorporation of the pseudoproline unit at a Ser (or Thr) residue preceding the problematic sequence provides several benefits:
• Disruption of Aggregation: The oxazolidine ring structure restricts backbone flexibility and disrupts the hydrogen bonding patterns necessary for β-sheet formation, thereby preventing aggregation.
• Increased Solubility/Solvation: By breaking up secondary structures, the peptide-resin becomes better solvated, improving reagent diffusion and accessibility.
• Enhanced Coupling Efficiency: Preventing aggregation allows subsequent coupling reactions to proceed more efficiently and completely.
• Induction of Cis-like Conformation: The pseudoproline moiety favors a specific backbone dihedral angle (ω ≈ 0° or 180°, often mimicking cis-Pro), introducing a kink or turn structure. While temporary, this conformational constraint helps keep the peptide chain extended and accessible during synthesis.
• Reversibility: The pseudoproline (oxazolidine ring) is acid-labile. During the final cleavage and deprotection step using strong acid (typically TFA-based cocktails), the ring is hydrolyzed, regenerating the original Serine residue and the native peptide backbone structure.
3. Usage in SPPS
Fmoc-Tyr(tBu)-Ser[psi(Me,Me)pro]-OH is used like any other Fmoc-dipeptide building block in SPPS:
1. The N-terminal Fmoc group of the preceding residue on the resin is removed (deprotection).
2. Fmoc-Tyr(tBu)-Ser[psi(Me,Me)pro]-OH is activated (e.g., using HATU/DIPEA or DIC/Oxyma) and coupled to the free N-terminus on the resin.
3. The cycle continues: the Fmoc group of the newly added Tyr(tBu) is removed for the next coupling step.
The strategic placement of the pseudoproline unit (often every 6-8 residues within a problematic region, or specifically at Ser/Thr residues predicted to be involved in aggregation) is crucial for its effectiveness.
4. Deprotection
• Fmoc Group: Removed under standard basic conditions (e.g., 20% piperidine in DMF).
• tert-Butyl (tBu) Group & Pseudoproline Ring: Both are removed simultaneously during the final cleavage from the resin using strong acidic conditions, typically a TFA cocktail (e.g., TFA/H 2 O/TIPS 95:2.5:2.5). The acid hydrolyzes the tBu ether protecting the Tyr side chain and opens the oxazolidine ring, regenerating the native Serine residue.
5. Properties
• Solubility: Soluble in common SPPS solvents like DMF, NMP, and DCM (dichloromethane), often used in combination with coupling reagents.
• Stability: Reasonably stable when stored correctly (cool, dry, protected from light and moisture). Sensitive to strong bases (Fmoc cleavage) and strong acids (tBu cleavage, ring opening). The oxazolidine ring itself is relatively stable under the basic Fmoc deprotection conditions and neutral coupling conditions used during SPPS.
• Chirality: Contains chiral centers derived from L-Tyrosine and L-Serine. Synthesis methods aim to preserve the stereochemical integrity.
6. Limitations and Considerations
• Ring Opening: While designed to open during final cleavage, incomplete ring opening under certain conditions could potentially lead to a minor side product, although standard TFA cleavage is usually effective.
• Strategic Placement: Requires careful sequence analysis to determine the optimal position for insertion to maximize its aggregation-disrupting effect.
Fmoc-Tyr(tBu)-Ser[psi(Me,Me)pro]-OH is a valuable and powerful tool in modern peptide synthesis. By temporarily introducing a specific conformational constraint via the reversible dimethylpseudoproline modification at a Serine residue, it effectively mitigates peptide aggregation and improves solvation during SPPS. This leads to higher coupling efficiencies, reduced side-product formation (e.g., deletions), and ultimately facilitates the successful synthesis of challenging peptide sequences that would otherwise be difficult or impossible to assemble using standard protocols. Its use, while requiring strategic planning and incurring higher reagent costs, often proves essential for accessing complex peptide targets.
References
1. Overview of Pseudoproline Dipeptides
2. Pseudoproline
3. Incorporation of pseudoproline monomer (Fmoc-Thr[ψMe,Mepro]–OH) facilitates efficient solid-phase synthesis of difficult peptides
4. Pseudo-prolines in peptide synthesis: Direct insertion of serine and threonine derived oxazolidines in dipeptides
5. Mutter, M. et al. (1995) “Pseudo-prolines (psi Pro) for accessing ‘inaccessible’ peptides.” Peptide Research 8, 145-153.
6. Wohr, T. et al. (1996) “Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis.” Journal of the American Chemical Society 118, 9218-9227.
7. Haack, T. and Mutter, M. (1992) “Serine derived oxazolidines as secondary structure disrupting, solubilizing building blocks in peptide synthesis.” Tetrahedron Letters 33, 1589-1592.
8. White, P. et al. (2004) “Expediting the Fmoc solid phase synthesis of long peptides through the application of dimethyloxazolidine dipeptides.” Journal of Peptide Science 10, 18-26.

For Research & Development use only. Not for testing and/or use on humans.

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