Mechanistic insights into an enantioselective synthetic strategy for 1,3-disubstituted planar chiral ferrocenes†

Direct construction of 1,3-disubstituted planar chiral ferrocenes (PCFs) is a challenging task. Herein, we have computationally investigated an enantioselective synthetic strategy for 1,3-disubstituted PCFs using density functional theory (DFT) methods to explore its principal characteristics and find plausible solutions to mechanistic issues. A cooperative palladium/norbornene (NBE)-catalyzed enantioselective relay remote C–H bond activation mechanism is established. The obtained results indicate that the total free energy barrier of the conversion process is 31.8 kcal mol⁻¹, which is reasonable under the studied reaction conditions. The rate-determining step consists of a combination of β-carbon elimination and protodepalladation. Calculations of multiple ortho-C–H activation pathways indicate that the acetate-assisted direct C–H activation is the most kinetically favorable route. Meanwhile, computations of a competitive side reaction pathway confirm that the faster the extrusion of the NBE group, the lower the formation probability of the ortho-substituted by-product. Furthermore, in the protodepalladation step, the acidic ligand (s)-Boc-L-Val-OH (L) most likely acts as a proton donor. Enantioselectivity calculations reveal that the high NBE olefin insertion barrier prevents the formation of the R_p isomer and is most likely responsible for the enantioselectivity of this transformation. The findings of the present work can deepen the understanding of PCF construction strategies and pave the way for the synthesis of 1,3-disubstituted PCFs.