Solvent- and temperature-dependent functionalisation of enantioenriched aziridines

Area of Science:

• Organic Chemistry
• Stereoselective Synthesis
• Medicinal Chemistry

Background:

• Chiral aziridines are versatile synthetic intermediates.
• Controlling stereochemistry in aziridine functionalization remains a challenge.

Purpose of the Study:

• To develop a highly stereo- and regioselective functionalization method for chiral non-racemic aziridines.
• To explore solvent- and temperature-dependent reactivity for diverse functionalized aziridine synthesis.

Main Methods:

• Lithiation of chiral N-alkyl trans-2,3-diphenylaziridines under varying solvent conditions (toluene vs. THF).
• Temperature-controlled lithiation of a chiral aziridine to generate ortho- and alpha-lithiated species.
• Electrophilic trapping of lithiated intermediates with various electrophiles, including carbonyl compounds.
• Reductive ring-opening of functionalized aziridines.
• X-ray and NMR spectroscopic analysis for stereochemical determination.

Main Results:

• Solvent-dependent generation of distinct chiral aziridinyllithium intermediates from trans-2,3-diphenylaziridines.
• Temperature-dependent generation of ortho- and alpha-lithiated aziridines from a different chiral aziridine.
• Successful synthesis of enantioenriched ortho- and alpha-functionalized aziridines, including chiral hydroxyalkylated derivatives.
• Preparation of chiral amines with quaternary stereogenic centers and chiral aminoalcohols via reductive ring-opening.
• First-time generation of a configurationally stable chiral alpha-lithiated aziridine at 0°C.
• Conversion of ortho-hydroxyalkylated aziridines into chiral aminoalkyl phthalans.

Conclusions:

• The developed method allows for highly stereo- and regioselective functionalization of chiral aziridines.
• Solvent and temperature control offers a powerful strategy for accessing diverse chiral aziridine derivatives and their enantiomers.
• The synthesized functionalized aziridines are valuable building blocks for complex chiral molecules, including pharmaceuticals.