Fmoc-Thr[psi(Me,Me)Pro]-OH

Fmoc-Thr[psi(Me,Me)Pro]-OH

           
Product Catalog # SizePrice (USD) Quantity
$50.00
$150.00
$450.00
$1,350.00
CAS #: 2023823-19-8
Molecular Formula: C22H23NO5
Molecular Weight: 381.4
Fmoc-Thr[psi(Me,Me)Pro]-OH (CAS #: 2023823-19-8) is a highly specialized pseudoproline monomer used in Fmoc solid-phase peptide synthesis (SPPS) to improve the synthesis of aggregation-prone and structurally difficult peptides. This reagent belongs to the pseudoproline family of temporary backbone-modifying amino acid derivatives that disrupt intermolecular hydrogen bonding and suppress peptide-chain aggregation during synthesis.
Among pseudoproline derivatives, threonine-based analogs are particularly important because the β-branched structure of threonine often contributes significantly to steric hindrance and secondary structure formation in growing peptide chains. The incorporation of Fmoc-Thr[psi(Me,Me)Pro]-OH can dramatically improve coupling efficiency, resin swelling, and crude peptide purity in challenging SPPS projects.
1. Structural Characteristics
The defining feature of Fmoc-Thr[psi(Me,Me)Pro]-OH is the formation of a dimethyl-substituted oxazolidine ring generated from the threonine side-chain hydroxyl group and the backbone amide nitrogen. This cyclic structure behaves conformationally like proline, giving rise to the term “pseudoproline.”
The reagent contains:
An N-terminal Fmoc protecting group compatible with standard Fmoc/tBu SPPS
A masked threonine residue in pseudoproline form
A free carboxylic acid available for peptide coupling
The ψ(Me,Me)Pro ring is acid-labile and undergoes hydrolysis during final TFA cleavage, regenerating native threonine in the final peptide sequence.
2. Mechanism of Action in SPPS
2.1 Suppression of Peptide Aggregation
One of the principal challenges in peptide synthesis is aggregation of resin-bound peptide chains through intermolecular hydrogen bonding and β-sheet formation. These interactions decrease solvent accessibility and reduce coupling efficiency.
Pseudoproline incorporation temporarily eliminates a backbone amide hydrogen-bond donor while simultaneously introducing conformational distortion. This combination significantly disrupts peptide self-association.
Benefits include:
Reduced β-sheet formation
Improved resin swelling
Enhanced solvent penetration
Increased accessibility of reactive amino groups
Higher coupling efficiency
These effects are particularly valuable in sequences containing:
β-branched amino acids
Hydrophobic motifs
Long peptide chains
Amyloidogenic regions
Membrane-active domains
2.2 Improved Coupling of Difficult Sequences
Threonine-derived pseudoprolines are especially useful because threonine residues themselves are sterically hindered due to β-branching. The monomeric pseudoproline derivative temporarily alters peptide conformation and improves accessibility for subsequent coupling reactions.
Recent studies demonstrated that Fmoc-Thr[psi(Me,Me)Pro]-OH can facilitate synthesis of difficult peptides previously considered highly challenging by conventional stepwise SPPS.
3. Monomer Versus Dipeptide Strategy
Historically, pseudoproline residues were incorporated mainly as preformed dipeptides because direct acylation of pseudoproline monomers was considered difficult. However, modern studies have shown that monomeric Fmoc-Thr[psi(Me,Me)Pro]-OH can be effectively coupled using contemporary activation systems.
Advantages of the monomer strategy include:
Greater flexibility in sequence design
Easier incorporation near noncanonical amino acids
Reduced inventory requirements
Simplified synthetic planning
Improved customization for difficult peptides
This development significantly expanded the utility of pseudoproline chemistry in modern peptide manufacturing.
4. Compatibility with Coupling Reagents
Fmoc-Thr[psi(Me,Me)Pro]-OH is generally compatible with standard peptide coupling systems including:
HATU/DIPEA
COMU
HBTU
PyBOP
DIC/Oxyma
Modern SPPS protocols, including microwave-assisted synthesis, commonly employ these reagents successfully with pseudoproline monomers.
5. Cleavage and Deprotection
The pseudoproline oxazolidine ring is removed during standard TFA cleavage conditions used in Fmoc SPPS. Acid-mediated hydrolysis restores the native threonine residue quantitatively.
This temporary modification strategy provides several advantages:
No additional deprotection step required
Compatibility with standard cleavage cocktails
Regeneration of native peptide sequence
Operational simplicity
Thus, the pseudoproline functions as a traceless backbone-protecting group.
6. Applications
Fmoc-Thr[psi(Me,Me)Pro]-OH has become valuable in several areas of peptide science:
Therapeutic Peptide Synthesis: Useful for manufacturing long and aggregation-prone peptide APIs.
Difficult Sequence Assembly: Particularly effective in peptides rich in β-branched or hydrophobic residues.
Cyclic Peptide Precursors: Improves synthesis efficiency of linear precursors intended for cyclization.
Peptidomimetic Chemistry: Enables synthesis of structurally constrained peptide analogs.
Automated and Microwave SPPS: Compatible with modern automated peptide synthesizers and high-temperature coupling protocols.
7. Advantages
Major advantages include:
Enhanced Crude Purity: Aggregation suppression reduces deletion sequences and incomplete couplings.
Improved Synthetic Yield: Higher coupling efficiency improves overall peptide recovery.
Better Solvation: Peptide-resin swelling is significantly enhanced.
Flexibility: Monomeric incorporation allows customized pseudoproline placement.
Compatibility with Modern SPPS: Suitable for automated, microwave-assisted, and large-scale synthesis.
8. Limitations
Despite its advantages, several limitations should be considered:
Higher Cost: Pseudoproline monomers are considerably more expensive than conventional amino acid derivatives.
Steric Hindrance: Thr[ψ(Me,Me)Pro] derivatives remain sterically demanding and may require optimized coupling conditions.
Sequence Dependency: Benefits vary depending on peptide sequence and pseudoproline placement.
Acid Sensitivity: The oxazolidine ring is unstable under prolonged acidic conditions.
Fmoc-Thr[psi(Me,Me)Pro]-OH is a highly effective pseudoproline monomer designed to improve difficult peptide synthesis in Fmoc SPPS. By temporarily converting threonine into a conformationally constrained oxazolidine derivative, the reagent disrupts peptide aggregation, improves coupling efficiency, and enhances overall synthetic performance.
Its compatibility with standard peptide synthesis protocols, traceless deprotection behavior, and demonstrated effectiveness in difficult sequences make it an important tool in modern peptide chemistry. As peptide therapeutics continue to expand in complexity and pharmaceutical relevance, pseudoproline monomers such as Fmoc-Thr[psi(Me,Me)Pro]-OH are expected to remain valuable enabling technologies for advanced SPPS workflows.

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

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