The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the oxazoline-directed, Pd(II)-catalyzed sp(3) C-H bond iodination and acetoxylation reactions as reported in previous publications has been studied and explained on the basis of experimental and computational investigations. The characterization of a trinuclear chiral C-H insertion intermediate by X-ray paved the way for further investigations into C-H insertion step through the lens of stereochemistry. Computational investigations on reactivities and diastereoselectivities of C-H activation of t-Bu- and i-Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical predictions with DFT calculations revealed that C-H activation occurs at the monomeric Pd center and that the most preferred transition state for C-H activation contains two sterically bulky t-Bu substituents in anti-positions due to steric repulsion and that this transition state leads to the major diastereomer, which is consistent with the structure of the newly characterized C-H insertion intermediate. The structural information about the transition state also suggests that a minimum dihedral angle between C-H bonds and Pd-OAc bonds is crucial for C-H bond cleavage. We have also utilized density functional theory (DFT) to calculate the energies of various potential intermediates and transition states with t-Bu- and i-Pr-substituted oxazolines and suggested a possible explanation for the substantial difference in reactivity between the t-Bu- and i-Pr-substituted oxazolines.