Developing highly active and enantioselective ligands for the asymmetric hydrogenation of ketones has consistently attracted significant attention from scientists. A series of novel tetradentate sulfur-containing ligands, termed as f-thiophamidol, were successfully designed and synthesized which exhibited excellent performance in the asymmetric hydrogenation of simple ketones (up to 99% yield, 99% ee) and α-substituted β-keto sulfonamides (up to 99% yield, 99% ee, 99:1 dr). The subsequent successful gram-scale experiments with high TON demonstrated the immense potential application value of this system in synthesizing drug molecules.