Asymmetric Pentafulvene Carbometalation--Access to Enantiopure Titanocene Dichlorides of Biological Relevance.

Unprecedented asymmetric copper-catalyzed addition of ZnEt2 (ZnBu2) to the exocyclic C=C bond of pentafulvenes C5H4(=CHAr) (Ar=2-MeOPh and related species) results in enantiomerically enriched (up to 93:7 e.r.) cyclopentadienyl ligands (C5H4CHEtAr; abbreviated Cp(R)). Copper catalyst promotion with both chiral phosphoramidite ligands and a phosphate additive is vital in realizing both acceptable enantioselectivities and reaction rates. Enantiomeric Cp(R)2TiCl2 complexes have been prepared; the (S,S) isomer is twice as active towards pancreatic, breast, and colon cancer cell lines as its (R,R) enantiomer at 24 h.