An Efficient One-Pot Grinding Method for the Synthesis ofOptically Active N-(Chrysenyl) -3-Acetoxy-4-Aryl-2-Azetidin-2-OnesUsing (+)-3-Carene

Introduction: Chiral β-lactams are one of the most promising heterocyclic systems in pharmaceutical chemistry. A mechanochemical, solvent-free approach has been developed to make optically active β-lactam derivatives in an effective and environmentally responsible manner. This study aimed to develop a sustainable and stereoselective method for the synthesis of trans-β-lactams utilising a renewable chiral auxiliary. Methods: This study employed (+)-3-carene as a naturally occurring chiral auxiliary to synthesise enantioselectively trans-(3R,4R)-N-(chrysenyl)-3-acetoxy-4-aryl-2-azetidin-2-ones via a one-pot grinding method. The technique involves a mechanochemical Staudinger [2+2] cycloaddition between polyaromatic imines and a chiral acid chloride made from (+)-3-carene in the presence of triethylamine (TEA). The reaction was performed at room temperature without any solvents. FTIR, 1H NMR, and 13C NMR spectroscopy, along with optical rotation measurements, were used to ensure that the synthetic compounds were appropriately prepared. Results: The reaction proceeds efficiently and provides trans-β-lactam intermediates in good to excellent yields (65-92%). These intermediates are then turned into 3-hydroxy-trans-β-lactams with high stereoselectivity and optical purity. When compared with the grinding-assisted mechanochemical method, standard multistep β-lactam syntheses result in reduced solvent use, fewer reaction steps, and a lower environmental impact. Discussion: Mechanistic rationale under grinding conditions. In the solid state, the ketene generated from chiral acid 3 reacts with the Z-configured imine in an exo approach, leading to a single diastereomer. Grinding facilitates both ketene generation and its reaction with the imine. The steric bulk of the chrysenyl substituent blocks the endo approach, ensuring clean trans selectivity. Conclusion: This is a promising method for the synthesis of optically active trans-( 3R,4R)-N-(chrysenyl)-β-lactams using a solvent-free mechanochemical approach. It provides a quick, easy, and sustainable way to make biologically vital trans-β-lactam frameworks in a stereoselective way.