Azapeptide Atropisomers From Late-Stage N-Alkylations

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Late-stage functionalization is crucial for peptide modification.
• Azapeptides and azapeptoids offer unique structural and chemical properties.
• Understanding reaction compatibility and conformational properties is essential for their application.

Purpose of the Study:

• To evaluate the compatibility of various protected amino acid side chains during late-stage N-alkylation of azapeptides.
• To characterize the atropisomeric properties, specifically N-N rotational energy barriers, of azapeptoid and N1,N2-dialkylated azapeptide products.

Main Methods:

• Solid-phase synthesis of azapeptides.
• Late-stage N-alkylation reactions.
• Variable temperature Nuclear Magnetic Resonance (NMR) spectroscopy.
• Dynamic High-Performance Liquid Chromatography (HPLC).

Main Results:

• Most protected amino acid side chains demonstrated compatibility with late-stage N-alkylation conditions on resin.
• Methionine was identified as an exception, showing incompatibility.
• N-N rotational energy barriers were determined: 15-16 kcal/mol for azapeptoids and 20-24 kcal/mol for N1,N2-dialkylated azapeptides.

Conclusions:

• Late-stage N-alkylation is a viable strategy for modifying azapeptides, with broad side-chain compatibility.
• The study provides quantitative insights into the conformational stability of azapeptoid and azapeptide derivatives.
• These findings are valuable for the rational design and synthesis of novel peptide-based therapeutics and materials.