Fmoc-S-Trityl-L-penicillamine
[CAS 201531-88-6]

Identification

• Classification: Biochemical >> Amino acids and their derivatives >> FMOC-amino acid
• Name: Fmoc-S-Trityl-L-penicillamine
• Synonyms: Fmoc-Pen(Trt)-OH; Fmoc-beta,beta-Dimethyl-Cys(Trt)-OH
• Molecular Formula: C₃₉H₃₅NO₄S
• Molecular Weight: 613.76
• Protein Sequence: X
• CAS Registry Number: 201531-88-6
• EC Number: 635-229-0
• SMILES: CC(C)([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C3=CC=CC=C13)SC(C4=CC=CC=C4)(C5=CC=CC=C5)C6=CC=CC=C6

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 768.8±60.0 °C 760 mmHg (Calc.)^*
• Flash point: 418.8±32.9 °C (Calc.)^*
• Index of refraction: 1.643 (Calc.)^*
• Alpha: 33 ° (c=1 in methanol) (Expl.)

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335-H413
• Safety Statements: P261-P305+P351+P338

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413

chemBlink Chemical Story

Two methyl groups beside sulfur can change more than an amino acid's name. In peptide research, replacing cysteine with penicillamine introduces extra steric bulk near a potential disulfide bond. Fmoc-S-trityl-L-penicillamine, CAS 201531-88-6, provides that residue in a protected form for synthesis. It is a tool for building the experiment, while the resulting peptide is the material whose structure and activity must be tested.

Penicillamine is beta,beta-dimethylcysteine: its side-chain carbon bears two methyl groups and sulfur. In this reagent, the amino nitrogen carries Fmoc and sulfur carries trityl, a triphenylmethyl group. Neither temporary group should be confused with the two methyl groups that define the penicillamine skeleton. The carboxyl group remains available for peptide assembly.

The L designation also matters. Penicillamine has stereochemical forms, and findings about a different enantiomer cannot automatically be assigned to this L building block. In particular, the pharmaceutical history of free D-penicillamine does not establish a therapeutic use for an Fmoc- and trityl-protected L derivative. Stereochemistry, protection state, and incorporation into a peptide each define a different chemical situation.

Once the appropriate protection is removed, penicillamine sulfur can participate in a disulfide. The two neighboring methyl groups change the environment around that sulfur compared with cysteine. This makes Pen substitution a way to explore how a disulfide-linked scaffold responds to local steric changes. It does not establish that every substitution increases stability, preserves folding, or improves binding.

A 2021 study by Gajewiak and colleagues investigated selected penicillamine substitutions in analogues of the conotoxin RgIA. Its experimental section specifically identifies Fmoc-Pen(Trt)-OH among the building blocks. The work links this protected residue to a concrete peptide-design application, while keeping the biological findings attached to the tested peptide analogues rather than the starting reagent.

The distinction between a selected substitution and a general replacement rule is central. A residue at one position can contribute differently from the same residue at another. Changing the steric environment near a bridge can influence local geometry and the relationships among distant parts of a small peptide. A sequence that tolerates one Pen residue need not tolerate substitution at every cysteine position.

Protection strategy remains a separate source of control. In disulfide-rich peptide synthesis, trityl-protected sulfur can be combined with differently protected sulfur sites so that particular bridges are addressed in sequence. The permanent steric effect comes from the penicillamine skeleton, whereas the temporary masking comes from trityl. Removing trityl does not undo the two methyl groups, and retaining them is often the point of choosing the residue.

Analytical and functional measurements answer complementary questions. Chemical analysis must establish the intended peptide and its bridge arrangement, while biological assays test how that characterized molecule behaves in the selected system. A promising experimental peptide is not the same as a clinically established treatment, and neither finding transfers automatically to the protected monomer.

The beta carbon itself does not acquire a new stereocenter from having two methyl groups, because those two substituents are identical. The defined amino-acid stereochemistry still concerns the alpha center, another reason to read the structural assignment rather than infer it from added bulk.

This building block illustrates how small structural edits can become precise research questions. The chemistry supplies a controlled change near sulfur; the sequence and experiment determine its consequences. Its significance is the ability to make a defined comparison within a peptide scaffold, rather than a universal claim about the benefits of adding methyl groups.

References:
1. Bachem. Fmoc-Pen(Trt)-OH, product 4019778; CAS 201531-88-6. https://shop.bachem.com/product/4019778/
2. Gajewiak J et al. Selective Penicillamine Substitution Enables Development of a Potent Analgesic Peptide that Acts Through a Non-Opioid Based Mechanism. Journal of Medicinal Chemistry (2021). https://doi.org/10.1021/acs.jmedchem.1c00512

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