Here we report asymmetric and divergent mono and sequential hydrofunctionalization reactions of 1,3-enyne-containing amide substrates under the cooperative catalysis of Pd(0)/chiral phosphoric acid (CPA). By utilizing Pd(0) π-Lewis base-promoted protonation and tuning the modulation of both the ligand and the CPA, this protocol enables precise control over single and sequential hydrofunctionalization pathways. Specifically, the combination of Pd/PPhos and 3,3′-(SiPh₃)₂-BINOL-derived CPA halts the reaction at the initial hydroalkylation stage, delivering the medium ring-sized allenes containing both axial and central chirality, whereas an intramolecular hydroamination reaction is followed to construct complex chiral polycyclic skeletons by switching to an assembly of Pd/P(2-furyl)₃ and 3,3′-(9-anthryl)₂-BINOL-derived CPA. Furthermore, the latter catalytic system can facilitate the hydroamination reaction of the previously obtained chiral allene products, but furnishing the polycyclic architectures with different diastereoselectivity. This work not only expands the application of cooperative catalytic systems, but also provides a practical strategy for the efficient, modular, and divergent construction of axially chiral medium ring-sized molecules and complex spirocyclic frameworks. Accordingly, for the synthesis of medium ring-sized allene 2, substrate 1 (0.1 mmol), [Pd(cinnamyl)Cl]₂ (0.005 mmol, 2.6 mg), ligand L3 (0.011 mmol, 7.1 mg), and chiral phosphoric acid A4 (0.02 mmol, 17.3 mg) were introduced into an oven-dried Schlenk tube under an argon atmosphere. After dry toluene (0.5 mL) and H₂O (40 μL) were added, the mixture was stirred at 30 °C for 12 h. Alternatively, for the synthesis of polycyclic product 3, substrate 1 (0.1 mmol), cinnamyl(cp)Pd (0.01 mmol, 2.9 mg), ligand L4 (0.02 mmol, 4.6 mg), and chiral phosphoric acid A3 (0.02 mmol, 14.0 mg) were mixed in dry toluene (2.0 mL) under an argon atmosphere and stirred at 40 °C for 48-72 h. The progress of the reaction was monitored by TLC. Upon completion, the mixture was directly purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to afford the desired product 2 or 3, respectively.

Key words: cooperative catalysis, divergent synthesis, asymmetric hydrofunctionalization, π-Lewis base catalysis, medium ring-sized allene