Deploying Pictet-Spengler Reactions to Access Constrained Aromatic Amino Acids

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Peptidomimetics are crucial for drug discovery, requiring novel building blocks.
• Conformationally constrained amino acids offer unique structural properties for peptidomimetics.
• Tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives are valuable scaffolds.

Purpose of the Study:

• To develop an efficient synthetic route for unusual, conformationally constrained aromatic amino acids.
• To utilize electrocatalysis, Negishi cross-coupling, and Pictet-Spengler cyclization for Tic residue synthesis.
• To rationalize synthesis ease and energy barriers using computational methods.

Main Methods:

• Electrocatalysis for key bond formations.
• Negishi cross-coupling for C-C bond construction.
• Pictet-Spengler cyclization for ring formation.
• Density Functional Theory (DFT) calculations for energy barrier prediction (ΔG‡).

Main Results:

• Successful synthesis of novel N-Fmoc-protected, conformationally constrained aromatic amino acids.
• Experimental results aligned with DFT predictions for cyclization energy barriers.
• Demonstrated a rational approach to designing and synthesizing constrained amino acids.

Conclusions:

• The combined synthetic strategy provides access to valuable peptidomimetic building blocks.
• DFT calculations are reliable tools for predicting and understanding reaction energetics.
• This work facilitates the design of new peptidomimetics with tailored conformations.