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

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

           
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CAS #: 1201651-31-1
Molecular Formula: C21H21NO5
Molecular Weight: 367.4
Fmoc-Ser[psi(Me,Me)Pro]-OH (CAS #: 1201651-31-1) is a serine-derived pseudoproline (oxazolidine) monomer carrying an Fmoc (9-fluorenylmethyloxycarbonyl) protecting group on the ring nitrogen. The compound is formed by condensation of L-serine with acetone (a ketone), creating a 5-membered 2,2-dimethyloxazolidine ring. This ring simultaneously protects the hydroxyl side chain of serine and converts the free amine into a tertiary, proline-like nitrogen, yielding a bicyclic Fmoc-amino acid building block.
1. Pseudoproline Concept
The term pseudoproline (ψPro), introduced by Mutter and co-workers at EPFL Lausanne, describes oxazolidine and thiazolidine heterocycles derived from serine/threonine (oxazolidines) or cysteine (thiazolidines). Because the ring nitrogen in these structures mimics that of proline, the amide bond preceding a pseudoproline residue acquires a strong preference for the cis-configuration. This backbone kink disrupts both β-sheet and α-helix formation, thereby preventing on-resin aggregation during Fmoc solid-phase peptide synthesis (SPPS).
The isopropylidene (2,2-dimethyl) substituent at the 2-position of the oxazolidine ring is the preferred choice for Fmoc-SPPS: it renders the ring sufficiently acid-labile to be cleaved cleanly by trifluoroacetic acid (TFA) during the standard global deprotection / cleavage step, regenerating the free serine residue in the final peptide without the need for additional conditions.
2. Key Functional Groups
• Ring nitrogen (tertiary, N-Fmoc) — provides base-labile N-protection
• Oxazolidine ring oxygen — acts as temporary side-chain protection for Ser-OH
• Free carboxylic acid — activated during coupling to the resin-bound peptide
• Isopropylidene gem-dimethyl — confers TFA lability to the oxazolidine ring
3. Role in Solid-Phase Peptide Synthesis
3.1 Background: The Aggregation Problem
Stepwise Fmoc-SPPS can fail when resin-bound peptide chains aggregate through inter- and intramolecular hydrogen bonding, forming β-sheet-like structures. This leads to incomplete Fmoc deprotection, poor coupling efficiency, deletion sequences, and low overall yield and purity. Aggregation is especially severe for hydrophobic or β-sheet-prone sequences, long peptides, and sequences containing multiple consecutive serine or threonine residues.
3.2 Dual Function of Fmoc-Ser[psi(Me,Me)Pro]-OH
When incorporated into a growing peptide chain, this building block simultaneously serves two roles:
• Side-chain protection of serine — the oxazolidine ring replaces the conventional acid-labile tBu ether protecting group; the ring is removed by TFA during cleavage.
• Structure-disrupting element — the tertiary ring nitrogen induces a cis-amide bond with the preceding residue, introducing a proline-like kink that breaks β-sheet aggregation and improves solvation of the growing chain.
On final treatment with TFA (typically 95:5 TFA/H₂O or standard cocktails), the oxazolidine ring opens quantitatively to restore the native serine residue, so no trace of the pseudoproline modification remains in the final product.
3.3 Monomer vs. Dipeptide Format
Traditionally, pseudoprolines were incorporated exclusively as preformed dipeptides (Fmoc-AA-Ser[Ψ(Me,Me)Pro]-OH) because acylation of the hindered oxazolidine nitrogen was considered too inefficient for practical use. Dipeptides bypass this issue by presenting the incoming amino acid already coupled and ready to extend the chain by two residues in one step.
However, Senko et al. (Amino Acids, 2021, 53: 665–671) demonstrated that Fmoc-Ser[psi(Me,Me)Pro]-OH and the corresponding Thr analogue can be used successfully as individual monomers in SPPS. Their study showed that modern activation reagents (HATU, HBTU, and others, excluding BOP/DIPEA) achieve acceptable coupling, allowing introduction of pseudoprolines at any sequence position regardless of whether the required dipeptide is commercially available. This is particularly valuable when the preceding amino acid is non-natural or rare, for which no commercial dipeptide building block exists.
3.4 Coupling Efficiency Considerations
Because the oxazolidine nitrogen is tertiary and sterically hindered, acylation proceeds more slowly than with standard Fmoc amino acids. Coupling efficiency varies with the nature of the incoming amino acid:
• More efficient: Amino acids with small aliphatic or polar side chains (Ala, Leu, Asp, Glu, Ser, Thr)
• Less efficient: Amino acids with bulky aromatic or large side-protecting groups (Phe, Trp, Arg, His, Asn, Gln)
Recommended strategies include the use of HATU or HBTU activation, extended coupling times, double coupling, and elevated reagent equivalents. Automated synthesizers can be programmed with customized coupling cycles for this building block.
4. Handling and Practical Usage
4.1 Compatibility
Fmoc-Ser[psi(Me,Me)Pro]-OH is compatible with:
• Standard Fmoc-SPPS resins (Wang, Rink amide, TCP, ChemMatrix, etc.)
• Common SPPS solvents: DMF, NMP, DCM
• Standard coupling reagents: HATU, HBTU, HCTU, PyBOP, DIC/Oxyma
• Standard Fmoc deprotection: 20% piperidine in DMF
• Standard global cleavage/deprotection: TFA-based cocktails
4.2 Fmoc Deprotection
The Fmoc group is removed under standard conditions (20% piperidine/DMF, 5–20 min) to expose the secondary nitrogen of the oxazolidine ring. The subsequent coupling step must account for the reduced nucleophilicity of this nitrogen relative to primary amines.
4.3 Oxazolidine Ring Cleavage
The 2,2-dimethyloxazolidine ring is stable under the basic conditions of Fmoc deprotection but is cleaved under acidic conditions. It opens readily and completely with TFA (standard cleavage cocktails, room temperature), regenerating the free serine hydroxyl and α-amino group in the target peptide. No special conditions or additional steps are required.
4.4 Storage
Store at 2–8 °C in a tightly sealed container under dry conditions. Protect from moisture and light. The compound is stable for extended periods under recommended storage conditions.
5. Applications
• Synthesis of aggregation-prone or ‘difficult’ peptide sequences where standard Fmoc-SPPS fails
• Introduction of pseudoproline at sequence positions where no commercial pseudoproline dipeptide is available (e.g., adjacent to non-natural or rare amino acids)
• Long peptide synthesis where cumulative aggregation is a concern
• Peptide library synthesis (combinatorial / HTS), where aggregation reduces library diversity and quality
• Conformational and folding studies: exploring the effect of cis-amide bond induction on peptide backbone geometry
• Macrocyclization: the kink induced by the pseudoproline pre-organizes the peptide chain, which can enhance macrolactamization yields
References
1. Senko, D.A.; Timofeev, N.D.; Kasheverov, I.E.; Ivanov, I.A. Scope and limitations of pseudoprolines as individual amino acids in peptide synthesis. Amino Acids 2021, 53, 665–671. https://doi.org/10.1007/s00726-021-02973-1
2. Wöhr, T.; Wahl, F.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X.; Mutter, M. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J. Am. Chem. Soc. 1996, 118, 9218–9227.
3. Dumy, P.; Keller, M.; Ryan, D.E.; Rohwedder, B.; Wöhr, T.; Mutter, M. Pseudo-prolines as a molecular hinge: reversible induction of cis amide bonds into peptide backbones. J. Am. Chem. Soc. 1997, 119, 918–925.

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

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