First expedient syntheses of naturally occuring protoilludane type sesquiterpenes and analogues; Application of innovative and unprecedented routes for the formation of cyclobutenes, alkylidenecyclobutanes and unsaturated four-membered heterocycles

• Applicant: Professor Dr. Dorian Didier
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 357443029

• Final Report Year: 2021

Final Report Abstract

The funding of this proposal has allowed us to set up new methods for the construction of four-membered ring structures and create novel libraries of building blocks for drug discovery, fulfilling one of our objectives. However, despite our efforts to gain access to natural products, the synthesis of protoilludanes failed. We are now continuing working on this topic and hope to find solutions to complete this challenge. Besides, our investigations led to the unexpected discovery of an interesting ring contraction reaction, efficiently producing biologically relevant cyclopropylketone motifs. We have demonstrated the synthesis, characterization and functionalization of three categories of building blocks: cyclobutenes, azetines and thietes, and applied them in further synthetic steps and rearrangement that proved to selectively increase molecular complexity. We are now at the stage of making these molecules useful in pharmaceutical and protein engineering projects by designing new methods of implementation (such as the development of small ring amino acids). More than opening new synthetic routes, it also gave us the opportunity to discover new strategies in organometallic and organoboron chemistry. For example, Zweifel olefinations were employed to functionalize azetine structures and enabled us to reconsider different aspects of this reaction and improve it by inventing new organocerium species. This has allowed to set up a new line of projects in our research group, recently founded by the Heisenberg fellowship.

Publications

• Methods for the Synthesis of Substituted Azetines. Org. Lett. 2017, 19, 5681–5684
  A. N. Baumann, M. Eisold, A. Music, G. Haas, Y. M. Kiw, D. Didier
  
• Stereoselective Access to Alkylidenecyclobutanes through γ-Selective Cross-Coupling Strategies. Org. Lett. 2017, 19, 4046–4049
  M. Eisold, D. Didier
  
• Stereoselective Sequence toward Biologically Active Fused Alkylidenecyclobutanes. Org. Lett. 2017, 19, 2114–2117
  A. N. Baumann, M. Eisold, D. Didier
  
• Unsaturated Four-Membered Rings: Efficient Strategies for the Construction of Cyclobutenes and Alkylidenecyclobutanes. Chem. Eur. J. 2017, 23, 1634-1644
  M. Eisold, A. N. Baumann. G. M. Kiefl, S. T. Emmerling, D. Didier
  
• Chemodivergent and Stereoselective Access to Fused Isoxazoline Azetidines and Thietanes through [3+2]-Cycloadditions. Org. Lett. 2018, 20, 6736–6740
  A. N. Baumann, F. Reiners, T. Juli, D. Didier
  
• One-pot Preparation of Stable Organoboronate Reagents for the Functionalization of Unsaturated Fourand Five-Membered Carbo- and Heterocycles. Synthesis 2018, 50, 3149-3160
  A. N. Baumann, M. Eisold, A. Music, D. Didier
  
• Oxidative Ring Contraction of Cyclobutenes – A General Approach to Cyclopropylketones and Mechanistic Insights. J. Org. Chem. 2018, 83, 4905–4921
  A. N. Baumann, F. Schüppel, M. Eisold, A. Kreppel, R. de Vivie-Riedle, D. Didier
  
• Parallel Approaches for the Functionalization of Thietes: -Metalation versus C-H Activation. Org. Lett. 2018, 20, 4654–4658
  M. Eisold, F. Reiners, A. Müller-Deku, D. Didier
  
• Regiodivergent Stereoselective Access to Fused Alkylideneazetidines. J. Org. Chem. 2018, 83, 783–792
  A. Music, A. N. Baumann, M. Eisold, D. Didier
  
• Thiete Dioxides as Templates Towards Twisted Scaffolds and Macrocyclic Structures. Chem. Eur. J. 2020, 26, 6029-6035
  A. N. Baumann, F. Reiners, A. F. Siegle, P. Mayer, O. Trapp, D. Didier