N-(Methoxycarbonyl)-O-methyl-L-threonine
[CAS# 1007881-21-1]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives
• Name: N-(Methoxycarbonyl)-O-methyl-L-threonine
• Synonyms: (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid
• Protein Sequence: X
• Molecular Formula: C₇H₁₃NO₅
• Molecular Weight: 191.18
• CAS Registry Number: 1007881-21-1
• EC Number: 800-213-6
• SMILES: C[C@H]([C@@H](C(=O)O)NC(=O)OC)OC

Properties

• Solubility: Soluble (84 g/L) (25 ºC), Calc.^*
• Density: 1.209±0.06 g/cm³ (20 ºC 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2018 ACD/Labs)

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P280-P301+P312-P302+P352-P305+P351+P338

Discovory and Applicatios

N-(Methoxycarbonyl)-O-methyl-L-threonine is a synthetic derivative of the natural amino acid L-threonine, designed to modify the physicochemical and biological properties of its parent structure through esterification and carbamate formation. Structurally, it features a methyl ester on the hydroxyl group of the threonine side chain and a methoxycarbonyl substituent on the amino group. This dual modification results in enhanced lipophilicity and chemical stability, features that are often exploited in the preparation of peptide derivatives or as intermediates in medicinal chemistry and peptide synthesis. The configuration at the chiral center corresponds to the L-enantiomer, maintaining the stereochemical orientation necessary for compatibility with biosynthetic and enzymatic systems derived from natural L-amino acids.

The discovery and early development of N-(methoxycarbonyl)-O-methyl-L-threonine are closely related to studies on amino acid protection strategies used in peptide synthesis. During the 1970s and 1980s, chemists developed numerous protected amino acid derivatives that could serve as building blocks in solution-phase and solid-phase peptide synthesis. The methylation of the threonine hydroxyl group prevented undesired side reactions during peptide coupling, while the carbamate protection of the amino group allowed selective deprotection under mild conditions. N-(Methoxycarbonyl)-O-methyl-L-threonine emerged as a practical reagent in this context, and it continues to appear as a structural motif in synthetic intermediates used for the preparation of biologically active peptides and small molecules.

In modern chemical research, N-(methoxycarbonyl)-O-methyl-L-threonine has found applications in several synthetic contexts. It can serve as a precursor in the synthesis of constrained peptide analogues, prodrugs, and enzyme inhibitors that require a modified threonine residue to modulate solubility or resistance to enzymatic degradation. The methyl ester modification enhances membrane permeability, while the methoxycarbonyl group can be selectively removed to regenerate the free amino group for further derivatization. These properties make it a valuable intermediate in the synthesis of pharmacologically relevant compounds and peptidomimetics.

Additionally, the compound has been used in structure–activity relationship studies where modifications to threonine residues influence the biological activity of bioactive peptides or enzyme substrates. For example, derivatives incorporating N-(methoxycarbonyl)-O-methyl-L-threonine have been employed in designing analogues of natural products and peptide-based therapeutics to investigate the role of hydrogen bonding and polarity in molecular recognition. Its well-defined stereochemistry ensures predictable reactivity and selectivity during coupling reactions, a critical requirement for multistep synthesis involving chiral amino acid derivatives.

Although N-(methoxycarbonyl)-O-methyl-L-threonine itself does not possess direct therapeutic activity, its role as a protected amino acid intermediate contributes significantly to the synthesis of complex bioactive molecules. It exemplifies how careful chemical modification of naturally occurring amino acids can expand the synthetic chemist’s toolkit, enabling the construction of molecules with improved pharmacokinetic and stability profiles. The continued relevance of this compound in modern peptide chemistry underscores the enduring importance of amino acid derivatization in drug discovery and bioconjugation research.

References

Merrifield RB (1963) Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. Journal of the American Chemical Society 85(14) 2149–2154. DOI: 10.1021/ja00897a025

Bodanszky M & Bodanszky A (1984) The Practice of Peptide Synthesis. Springer-Verlag Berlin Heidelberg. DOI: 10.1007/978-3-642-85055-4.

Carpino LA & Han GY (1972) The 9-Fluorenylmethoxycarbonyl Amino-Protecting Group. Journal of Organic Chemistry 37(22) 3404–3409. DOI: 10.1021/jo00795a005