Computational Modeling of Metal Catalyzed Reactions for the Prediction and Improvement of Enantioselectivity

Asymmetric synthesis is an important area of modern organic chemistry as many biologically important molecules contain chiral centers, but the choice of ligand is often based on high throughput screening or simply trial and error. A virtual screening method can greatly increase the speed of the ligand screening process by calculating expected enantiomeric excesses. The Q2MM method was utilized to develop molecular mechanics parameters for such a method. The rhodium catalyzed asymmetric hydrogenation of enamides to generate amino acid products and derivatives is a widely used method to generate unnatural amino acids. The B3LYP/LACVP** calculated potential energy surfaces for the hydrogenations of varied substrates while utilizing a common ligand indicate a mechanistic change based on substrate. This has a significant impact on the origins of enantioselectivity as the first hydride transfer to the substrate is calculated to be irreversible for all substrates, independent of whether it occurs at the Ì_å± or Ì_å_ carbon of the olefin. Utilizing the Q2MM method, new molecular mechanics parameters are derived to model two important transition structures and an intermediate ground state structure in the hydrogenation of dehydro-Ì_å±-amino acids and corresponding derivatives. The new parameters are based on structures calculated at the B3LYP/LACVP** level of theory and added to the MM3* force field. The new parameters were tested against a test set of 47 points of experimental data utilizing a wide range of bis-phosphine ligands, with good agreement between theory and experiment. Data points with large quantitative errors still give good qualitative results, and reasons for these errors are discussed. A second reaction studied was the silver catalyzed intramolecular hydroamination of alkynes, which is an effective method for the rapid construction of nitrogen heterocycles. The chiral ligands in the library are derived from a phenanthroline scaffold. As before, new MM3* parameters were developed to describe the transition state and subsequent screening of a selection of chiral ligands against a common, symmetric aminodiyne. Preliminary synthesis of an aminodiyne substrate was also performed for experimental verification of the predictions.