DFT Calculation-Assisted Virtual Screening to Refine Chiral Phosphoric Acid-Catalyzed Allylboration Enabling Organocatalytic Synthesis of Tetrafibricin C21–C40 Fragment

The development of asymmetric reactions for the total synthesis of natural products often requires extensive trial-and-error approaches owing to the complexity of substrates. In this manuscript, we demonstrated a DFT calculation-assisted virtual screening strategy that significantly streamlines this process, transitioning from an empirical to a more rational approach. Our in silico virtual screening strategy efficiently identified novel catalyst candidates for challenging chiral phosphoric acid-catalyzed enantioselective allylborations, drastically reducing experimental effort and costs. This strategy led to the discovery of previously underexplored 9-anthryl-substituted chiral phosphoric acids as optimal catalysts for the enantioselective allylboration of functionalized alkyl aldehydes, thereby eliminating the need to prepare multiple complex catalysts by trial and error. Importantly, our strategy enabled the efficient and catalytic construction of all six stereogenic centers within the tetrafibricin C21–C40 fragment in good total yield with excellent stereoselectivity. The present work highlights the utility of strategically leveraging the DFT calculation-assisted virtual screening for the discovery of suitable catalysts, paving the way for efficient and sustainable synthesis of complex molecules.