| Synonym: | Fmoc-Phe-Ser(psiMe,Mepro)-OH |
| CAS #: | 878797-01-4 |
| Molecular Formula: | C30H30N2O6 |
| Molecular Weight: | 514.6 |
| Fmoc-Phe-Ser[psi(Me,Me)pro]-OH is a specialized dipeptide derivative widely employed in solid-phase peptide synthesis (SPPS), particularly within the Fmoc/tBu (9-fluorenylmethoxycarbonyl/tert-butyl) strategy. Its significance lies in the incorporation of a pseudoproline (ψPro) moiety, specifically a 2,2-dimethyloxazolidine derived from serine, which offers substantial advantages in the synthesis of “difficult” or aggregation-prone peptide sequences. 1. 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. 2. Applications in Peptide Synthesis Fmoc-Phe-Ser[psi(Me,Me)pro]-OH is primarily used as a strategic building block in Fmoc-SPPS to: • Overcome Peptide Aggregation: Aggregation of the growing peptide chain on the solid support is a major hurdle in SPPS, leading to incomplete coupling reactions, low yields, and difficult purifications. The incorporation of the Phe-Ser[psi(Me,Me)pro] unit disrupts the secondary structures (primarily β-sheets) responsible for this aggregation. • Improve Coupling Yields and Kinetics: By minimizing aggregation, the N-terminus of the growing peptide chain remains more accessible and better solvated, leading to more efficient and faster coupling of subsequent amino acids. • Enhance Solubility: Peptides incorporating pseudoprolines often exhibit improved solubility in common SPPS solvents. • Facilitate Synthesis of Long or “Difficult” Peptides: Sequences rich in hydrophobic residues or those known to adopt stable secondary structures during synthesis often benefit significantly from the strategic insertion of pseudoproline dipeptides. • Improve Crude Peptide Purity: By mitigating common synthesis problems like deletion sequences (from incomplete couplings) and truncations, the use of this dipeptide can lead to a purer crude product, simplifying downstream HPLC purification. • Aid in Peptide Cyclization: The turn-inducing nature of pseudoprolines can pre-organize the linear peptide in a conformation favorable for cyclization, potentially improving the efficiency of macrocycle formation. The oxazolidine ring of the pseudoproline is stable to the mildly basic conditions used for Fmoc deprotection but is readily cleaved under strong acidic conditions typically used for final peptide cleavage from the resin and removal of side-chain protecting groups (e.g., trifluoroacetic acid (TFA)-based cocktails). This reverts the serine residue to its natural form in the final peptide product. 3. Advantages of Using Fmoc-Phe-Ser[psi(Me,Me)pro]-OH • Reversible Modification: The beneficial conformational effects are temporary; the native serine structure is restored upon final cleavage. • Compatibility: Fully compatible with standard Fmoc-SPPS protocols and common reagents. • Strategic Placement: Can be inserted at specific Xaa-Ser sites within a peptide sequence predicted or known to be prone to aggregation. 4. Considerations and Limitations While highly beneficial, some general points regarding pseudoprolines are worth noting: • Hydrolysis: The oxazolidine ring can be susceptible to premature hydrolysis under certain (e.g., very acidic) conditions if not handled properly during synthesis steps prior to final cleavage. • Mass Spectrometry Interpretation: Occasionally, the pseudoproline-containing protected peptide fragment might show a slightly different fragmentation pattern or apparent mass in MS analysis compared to the native sequence, requiring careful interpretation. • Steric Hindrance: While designed to improve coupling to the pseudoproline, the coupling of the pseudoproline dipeptide itself, or the subsequent amino acid, can sometimes be slightly slower due to the steric bulk, though this is generally outweighed by the aggregation-disrupting benefits. Recent studies also highlight that acylation of pseudoproline monomers (e.g., Fmoc-Ser(ψMe,Mepro)-OH) can be hindered, potentially making pre-formed dipeptides like Fmoc-Phe-Ser[psi(Me,Me)pro]-OH advantageous. • Side Reactions under Harsh Conditions: Some studies on pseudoprolines in general have indicated potential for side reactions (e.g., aspartimide formation catalysis or ring-opening by-products) under harsh conditions like elevated temperatures in flow peptide synthesis, though this is not specific to Fmoc-Phe-Ser[psi(Me,Me)pro]-OH and depends on the overall synthetic context. Fmoc-Phe-Ser[psi(Me,Me)pro]-OH is a valuable and well-established tool in the arsenal of peptide chemists. Its ability to disrupt peptide aggregation by temporarily introducing a cis-amide bond character at the Phe-Ser linkage significantly enhances the efficiency of solid-phase peptide synthesis, particularly for sequences that are otherwise challenging to assemble. The commercial availability and compatibility with standard Fmoc-SPPS protocols make it a practical solution for improving yields, purity, and the overall success rate in the synthesis of complex peptides for research, therapeutic, and diagnostic applications. Researchers often turn to such modified dipeptides when facing difficulties in synthesizing long or hydrophobic peptide sequences prone to aggregation. 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(3):145-153. 5. Wohr T, et al. (1996) “Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis.” Journal of the American Chemical Society, 118(39):9218-9227. 6. Haack T, Mutter M. (1992) “Serine derived oxazolidines as secondary structure disrupting, solubilizing building blocks in peptide synthesis.” Tetrahedron Letters, 33(12):1589-1592. 7. 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(1):18-26. 8. García-Martín F, et al. (2006) “ChemMatrix, a poly(ethylene glycol)-based support for the solid-phase synthesis of complex peptides.” Journal of Combinatorial Chemistry, 8(2):213-220. |
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Fmoc-Phe-Ser[psi(Me,Me)pro]-OH
For Research & Development use only. Not for testing and/or use on humans.
