Synthesis of Alkynylated Benzisoxazolines For Copper-Catalyzed Kinetic Resolution

• Kennith Ross, Chemistry, University of Delaware

• Mary Watson, Department of Chemistry and Biochemistry, University of Delaware

Chirality is one of the most important molecular characteristics that influences all living organisms. In particular, chiral amines and chiral nitrogen heterocycles are important foundations in medicinal chemistry. Chiral amines exist naturally within the vast majority of amino acids and synthetically within medicinal drugs such as sertraline, morphine, and ketamine. As a reagent for asymmetric synthesis, alkynes are versatile scaffolds. My graduate student mentor, Alex Melton, has developed a method for a copper catalyzed kinetic resolution of 3-alkynylbenzisoxazolines. Under the optimized reaction conditions, one enantiomer of the starting material undergoes an alkyne insertion into the N-O bond at a faster rate than the other enantiomer. To further test this optimization, I have synthesized substituted benzisoxazolines to evaluate electronic effects in the kinetic resolution. The method resulted in a 39% isolated yield and a high enantiomeric excess (ee) of >99% of 2a in addition to a 47% isolated yield and 15% ee of 3a, the ring-expanded product.  Using an extreme electron-withdrawing derivative of starting material (2h), a 59% NMR yield and 31% ee of 2h and a 2% NMR yield with 10% ee of 3h, the ring-expanded product. The lower yields are indicative of a slower reaction rate with electron withdrawing substituents, however an enantiomeric separation still occurs. Supercritical Fluid Chromatography-Mass Spectrometry (SFC-MS) using a chiral stationary phase and CO2 mobile phase was used to measure ee. 1H, 13C, and 19F NMR data was used to characterize the unknown compounds in addition to IR spectroscopy. The kinetic resolution has demonstrated to be a unique method for the preparation of enantioenriched benzisoxazolines.