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

Angew Chem Int Ed Engl. 2015 Nov 16;54(47):14179-82. doi: 10.1002/anie.201508034. Epub 2015 Oct 12.

Abstract

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.

Keywords: CC coupling; asymmetric catalysis; carbometalation; copper; ligand effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Catalysis
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Copper / chemistry
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Organometallic Compounds
  • Copper
  • titanocene dichloride