Cascade transformations of unsaturated alcohols catalyzed by bifunctional ruthenium complexes

• Applicant: Professor Dr. Edgar Haak
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265182801

Cascade reactions are of special interest in the context of drug discovery. The incorporation of multiple bond-forming events in one process carried out in one pot increases synthetic efficiency significantly and facilitates the generation of various derivatives of intricate molecular structures. Such transformations produce molecular complexity and are thus particularly suitable for the preparation of natural products and analogs as important lead structures in the development of bioactive compounds. Transition metal-catalyzed cascade reactions starting with relatively simple acyclic subunits containing ene and yne fragments provide an atom-economical approach to the one-pot synthesis of complex molecular scaffolds from readily available starting materials. In terms of accessibility propargyl alcohols are particularly noteworthy. They are directly accessible from aldehydes or ketones by acetylide addition. Especially the 1-alkenyl propargyl alcohol motive is a very versatile C5-subunit, since all five carbon atoms are selectively addressable by various transition metal catalysts and a broad range of differently substituted alkynes and α,β-unsaturated aldehydes or ketones are readily available. Due to different functional groups (alkene, alkyne, -OR) several modes of activation can be applied, giving rise to diverse cascade transformations. We discovered that bifunctional (cyclopentadienone)ruthenium(0) complexes and their corresponding imino-derivatives catalyze various addition/cyclization cascades of propargyl alcohols with diverse nucleophiles. The basic coordination site provided by the donor substituted cyclopentadienone ligand and the ligand-metal redox-coupling are crucial for these highly selective transformations. In continuation of our previous research we plan the development of further metal catalyzed cascade processes for the efficient synthesis of polycyclic natural-product-like compounds. The processes are based on ruthenium catalyzed allylation/cycloisomerization-reactions and redox-isomerization/Michael-addition cascades and should also be applied within the total synthesis of bioactive natural products. Asymmetric catalyzed reactions using chiral representatives of the complex series are especially addressed with regard to future applications in the field of natural product and drug synthesis. In addition, options for photocatalytical applications of the developed catalysts should be explored.

• DFG Programme: Research Grants