Application of Palladium-Catalyzed Asymmetric Conjugate Addition Reactions of Arylboron Nucleophiles to α,β-Unsaturated Electrophiles as a Key-Step in Complex Bioactive Molecule Synthesis

• Applicant: Dr. Irina Geibel
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399223652

The development of new synthetic methods is often driven by the demand for drugs with better efficacy and fewer side effects. Recently, attention has shifted toward chiral molecules with quaternary stereocenters, which are bound to four non-equivalent carbon substituents. The three-dimensionality offers a number of superior properties that established, achiral “flat” molecules cannot deliver. However, broadly applicable strategies to access such asymmetric compounds are relatively rare and the synthetic challenges associated with building quaternary stereocenters have largely prevented their implementation in drug discovery. Within the top pharmaceuticals, none have quaternary stereocenters build by chemical synthesis. However, biosynthetic natural starting materials with pre-built quaternary stereocenters are used. The status quo shows a strong dichotomy between the unexploited, promising potential of chiral compounds and the paucity of synthetic methods available for the construction of quaternary stereocenters and consequently the lack of their applications in drug discovery. The objective of the research stay is the application of a new palladium-catalyzed enantioselective conjugate addition reaction as a key step for the synthesis of complex bioactive molecules. It is planned to develop a general approach to tricyclic terpenoids that relies on fragment coupling conjugate addition of arylboronic acids to β-substituted cyclic enones followed by central ring completion. Importantly, the conjugate addition adducts will have enough functionality to address the final structural tailoring needed for multiple terpenoid families. The central ring completion will be pursued by the development of an innovative 2-C bis-electrophilic cyclization - this should allow the synthesis of tricyclic motifs in a general sense. To exemplify this general approach, the application of this strategy to the preparation of antimicrobial abietane derivatives pisiferol and carnosol is planned. Furthermore, the potential significance to the development of medicinal therapeutics is highlighted by the anti-cancer and anti-inflammatory properties of carnosol. Concurrent with this program of target-driven synthesis is a dedicated effort directed toward the development of new techniques and reaction methods that are useful for a range of applications and gain access to novel, medicinally relevant structures.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Brian M. Stoltz, Ph.D.