Description

Fmoc-N-Me-Glu(OtBu)-OH (CAS 200334-97-0): Advanced SPPS Reagent & Technical Guide

In custom peptide synthesis, medicinal chemistry, and rational drug design, controlling peptide backbone conformation and enzymatic susceptibility represents a core chemical challenge. Utilizing specialized Fmoc N-methylated glutamic acid derivatives allows synthetic chemists to eliminate amide hydrogen bond donors, disrupt interchain self-assembly, and stabilize specific bioactive secondary structures. Among these specialized reagents, Fmoc-N-Me-Glu(OtBu)-OH (CAS 200334-97-0) serves as a premier orthogonal building block for incorporating backbone-modified glutamic acid residues during Solid-Phase Peptide Synthesis (SPPS).

Glutamic acid contains a reactive side-chain $\gamma$-carboxylic acid group prone to intra-molecular side reactions if left unshielded. For synthesis laboratories seeking a reliable Fmoc-N-Me-Glu(OtBu)-OH supplier, acquiring analytical-grade reagents from amino asylum ensures optimal coupling efficiency, structural integrity, and reproducible batch-to-batch yields.

What is Fmoc-N-Me-Glu(OtBu)-OH (Fmoc-N-methyl-L-glutamic acid 5-t-butyl ester)?

Fmoc-N-Me-Glu(OtBu)-OH, chemically known as Fmoc-N-alpha-methyl-L-glutamic acid gamma-t-butyl ester or Fmoc-N-methyl-L-glutamic acid 5-t-butyl ester, is an $N^\alpha$-methylated, side-chain protected amino acid derivative engineered specifically for standard Fmoc/tBu SPPS chemistries.

By introducing a methyl substituent on the $\alpha$-amino nitrogen, Fmoc-MeGlu(OtBu)-OH converts a standard secondary amide linkage in the peptide backbone into a tertiary amide. This single modification alters the steric landscape, removes hydrogen-bonding capability at that residue, and significantly shifts the cis/trans amide bond equilibrium.

                 [ Fmoc-N-Me-Glu(OtBu)-OH Chemical Structure ]
                                       │
        ┌──────────────────────────────┼──────────────────────────────┐
        ▼                              ▼                              ▼
[ Base-Labile Fmoc ]          [ N-Methylated Nitrogen ]      [ Acid-Labile OtBu Ester ]
(Alpha-Amine Shielding)       (Eliminates H-Bond Donor)      (Gamma-Carboxyl Shielding)
        │                              │                              │
        ▼                              ▼                              ▼
 Deprotects via 20%            Prevents Beta-Sheets &         Cleaves via TFA to Yield
 Piperidine in DMF             Resin Aggregation              Free Gamma-COOH

Chemical Identity & Molecular Architecture of CAS 200334-97-0

The chemical specifications of CAS 200334-97-0 establish its technical profile as a key building block for protected amino acid sequences:

Chemical Specifications Reference:
• Full IUPAC Name: Fmoc-N-alpha-methyl-L-glutamic acid gamma-t-butyl ester
• CAS Registry Number: 200334-97-0
• Common Nomenclature: Fmoc-N-methyl-L-glutamic acid 5-t-butyl ester
• Abbreviated Name: Fmoc-MeGlu(OtBu)-OH / Fmoc-N-Me-Glu(OtBu)-OH
• Molecular Formula: C25H29NO6
• Molecular Weight: 439.50 g/mol
• Protect Group Matrix: N-alpha (Fmoc, base-labile), Gamma-Carboxyl (OtBu ester, acid-labile)
• Physical Form: White to off-white powder
• Storage Parameters: Refrigerated (-20°C to 4°C), desiccated, protected from light

The Mechanics of Orthogonal Protection: Fmoc and tert-Butyl (OtBu) Groups

Base-Labile N-alpha Protection and Deprotection Kinetics

The 9-Fluorenylmethyloxycarbonyl (Fmoc) group shields the $N^\alpha$-methylated amine during storage and coupling steps. Deprotection proceeds rapidly via base-catalyzed $E1cB$ elimination using $20\%$ piperidine in DMF, yielding a secondary $N^\alpha$-methylamine ready for subsequent coupling cycles without disturbing acid-sensitive side-chain esters.

Acid-Labile Side-Chain Ester Shielding and Suppression of Side-Reactions

The $\gamma$-carboxyl group of glutamic acid is protected as a tert-Butyl ($\text{OtBu}$) ester. This orthogonal protection prevents unwanted side reactions—such as intramolecular glutarimide formation or unwanted side-chain coupling—during chain elongation. The $\text{OtBu}$ group remains intact throughout all Fmoc deprotection cycles and is removed only during final TFA cleavage.

Applications of Fmoc N-Methylated Glutamic Acid in Solid-Phase Peptide Synthesis (SPPS)

                            [ SPPS Assembly Dynamics ]
                                        │
        ┌───────────────────────────────┴───────────────────────────────┐
        ▼                                                               ▼
[ Unmodified Sequence Assembly ]                             [ N-Methylated Insertion ]
        │                                                               │
        ▼                                                               ▼
[ Hydrogen-Bonded Beta-Sheets ]                              [ Steric Backbone Disruption ]
        │                                                               │
        ▼                                                               ▼
[ Incomplete Coupling / Low Yield ]                          [ Extended Solvated Chains / High Yield ]

Backbone Methylation Mechanics and Disruption of Secondary Beta-Sheet Aggregation

During SPPS, growing peptide chains often form interchain hydrogen bonds between backbone amide protons ($\text{-NH-}$) and carbonyl oxygens ($\text{-C=O}$). This leads to hydrophobic $\beta$-sheet aggregation on the resin support, shrinking resin pore size and limiting reagent access to the terminal amine.

Incorporating Fmoc N-methylated glutamic acid removes the amide hydrogen at that position, breaking up $\beta$-sheet structures. Utilizing Fmoc-MeGlu(OtBu)-OH in aggregation-prone regions ensures resin swelling and improves overall sequence assembly.

Peptide Pharmacokinetics: Enhancing Proteolytic Resistance and Membrane Permeability

Backbone methylation serves as an effective modification in medicinal chemistry:

• Proteolytic Shielding: Placing an $N^\alpha$-methyl group sterically hinders cleavage by serum peptidases, extending the biological half-life of target peptides.

• Membrane Permeability: Removing a polar hydrogen bond donor increases lipophilicity, facilitating passive trans-epithelial and trans-mucosal diffusion across cellular membranes.

Synthetic Protocols for Protected N-Methyl Amino Acids SPPS

Overcoming Steric Hindrance During N-Methylated Glutamate Coupling

Coupling an incoming amino acid onto the exposed $N^\alpha$-methylamine of a deprotected Fmoc-N-methyl-L-glutamic acid 5-t-butyl ester residue requires optimized activation conditions due to steric crowding.

Recommended Activation Protocols for N-Me Coupling:
1. Coupling Reagents: HATU / HOAt or COMU with DIPEA.
2. Alternative System: DIC / Oxyma Pure for temperature-controlled microwave coupling.
3. Extended Reaction Times: Double coupling (2 x 60 min) at 50°C to ensure quantitative yield.
4. Solvent Optimization: DMF/NMP mixtures to maximize resin solvation.

Preventing Aspartimide/Glutarimide Formation and Side-Chain Cleavage

During repeated piperidine treatments, unprotected or improperly protected acidic amino acid side chains can undergo base-catalyzed cyclization. The $\text{OtBu}$ ester on CAS 200334-97-0 provides bulk steric protection, preventing the $\gamma$-carboxyl group from attacking the peptide backbone and eliminating glutarimide side-product formation.

Comparative Analysis & Catalog Integration

Comparing N-Methyl Glutamic Acid Building Blocks with Fmoc-N-Me-His(Trt)-OH and Standard Derivatives

Utilizing protected N-methyl amino acids SPPS reagents allows chemical synthesis labs to engineer stabilized peptides with high target affinity. Comparing building blocks like Fmoc-N-Me-Glu(OtBu)-OH with other backbone-modified derivatives—such as Fmoc-N-Me-His(Trt)-OH—provides synthetic chemists with a full suite of tools to manipulate both acidic and basic positions within custom sequences.

                      [ Reagent Sourcing to Finished Research ]
                                         │
     ┌───────────────────────────────────┼───────────────────────────────────┐
     ▼                                   ▼                                   ▼
[ Chemical Synthesis Blocks ]   [ Stabilized Neuropeptides ]        [ Metabolic & Repair Compounds ]
 • Fmoc-N-Me-Glu(OtBu)-OH       • N-Acetyl-Semax Spray               • Buy Noopept
 • Fmoc-N-Me-His(Trt)-OH        • N-Acetyl-Selank Spray              • NAD+ Spray
                                • PT-141 Spray / MT-II Spray         • glutathione spray
                                                                     • BPC-157 Spray / AOD-9604 Spray

From Synthesis Reagents to Finished Bioactive Formulations

Laboratory workflows bridge raw reagent synthesis and post-synthesis research. Chemical strategies designed during solid-phase assembly directly inform evaluations of finished research products:

• Cognitive & Nootropic Protocols: Custom peptide synthesis data often complement evaluations of established central dipeptides like Buy Noopept.

• Cellular Energy & Redox Studies: Synthetic design projects frequently run alongside investigations into cellular energy catalysts like NAD+ Spray and endogenous antioxidants like glutathione spray.

• Tissue Repair & Metabolic Signaling: Advanced peptide research pairs custom-synthesized chains with functional reference compounds like BPC-157 Spray and lipolytic fragments such as AOD-9604 Spray.

• Melanocortin & Neuropeptide Pathways: Structural stabilization techniques mirror protocols used in specialized research products, including melanocortin agonists like PT-141 Spray and MT-II Spray, as well as stabilized intranasal neuropeptides like N-Acetyl-Semax Spray and N-Acetyl-Selank Spray.

Sourcing Premium Reagents from a Verified Fmoc-N-Me-Glu(OtBu)-OH Supplier

When executing multi-step SPPS, raw material quality dictates final crude purity. Sourcing from a validated Fmoc-N-Me-Glu(OtBu)-OH supplier ensures consistent synthesis outcomes.

Certificate of Analysis (COA) & HPLC Purity Verification

Every batch of Fmoc-N-Me-Glu(OtBu)-OH (CAS 200334-97-0) supplied by Amino Asylum undergoes full analytical verification:

• High-Performance Liquid Chromatography (HPLC): Confirms chemical purity ($\ge 98.0\%$).

• Proton Nuclear Magnetic Resonance ($^1\text{H-NMR}$): Confirms structural assignment of the Fmoc group, $N^\alpha$-methyl group, and $\text{OtBu}$ ester without unassigned impurities.

• Mass Spectrometry (MS): Validates precise molecular weight ($439.50\text{ g/mol}$).

Quality Assurance: Laboratories sourcing chemical reagents through amino asylum receive high-purity, batch-verified synthesis building blocks backed by comprehensive analytical testing.

Storage, Handling, and Stability Protocols for CAS 200334-97-0

• Temperature Control: Store dry powder long-term at $-20^\circ\text{C}$ to maintain compound stability.

• Moisture Protection: Allow the vial to warm to room temperature in a desiccator before opening to prevent water condensation, which can lead to slow hydrolysis.

Frequently Asked Questions (FAQ)

What Is the Full Chemical Designation for Fmoc-N-alpha-methyl-L-glutamic acid gamma-t-butyl ester?

The full chemical IUPAC name is Fmoc-N-alpha-methyl-L-glutamic acid gamma-t-butyl ester, indexed under CAS 200334-97-0 and commonly abbreviated as Fmoc-N-Me-Glu(OtBu)-OH or Fmoc-MeGlu(OtBu)-OH.

Why Is Side-Chain OtBu Protection Necessary During Fmoc Deprotection Steps?

The $\gamma$-tert-Butyl ester ($\text{OtBu}$) protects the side-chain carboxylic acid from participating in base-catalyzed side reactions during piperidine deprotection steps, preventing unwanted cyclization and branching.

How Does Fmoc-MeGlu(OtBu)-OH Differ From Unmethylated Glutamic Acid Building Blocks?

Fmoc-MeGlu(OtBu)-OH contains an $N^\alpha$-methyl group on the backbone nitrogen, which removes the amide hydrogen donor, prevents interchain $\beta$-sheet formation during synthesis, and enhances enzymatic stability in target peptides.

Final Verdict: Selecting a Trusted Fmoc-N-Me-Glu(OtBu)-OH Supplier for Research

Optimizing peptide assembly, overcoming structural aggregation, and engineering proteolytic resistance require analytical-grade chemical reagents. Fmoc-N-Me-Glu(OtBu)-OH (CAS 200334-97-0) provides the precise structural control required for incorporating backbone-modified glutamic acid residues into custom SPPS sequences.

When choosing a reliable Fmoc-N-Me-Glu(OtBu)-OH supplier for your laboratory, amino asylum delivers batch-verified purity, detailed analytical documentation, and consistent fulfillment to support your custom synthesis protocols.