Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - HALODRUGSYN (Innovative Strategies towards Halogenated Organic Molecules: From Reaction Design to Application in Drug Synthesis)
Teaser
Current Problem:Molecules that contain halogen substituents such as chlorine, bromine and fluorine are ubiquitous in daily life. They can be found in antibiotic and anticancer natural products, are part of important agrochemicals and blockbuster drugs, and are valuable...
Summary
Current Problem:
Molecules that contain halogen substituents such as chlorine, bromine and fluorine are ubiquitous in daily life. They can be found in antibiotic and anticancer natural products, are part of important agrochemicals and blockbuster drugs, and are valuable building blocks to synthesize functionalized compounds. However, many of the methods used for their production currently suffer from serious drawbacks such as harsh reaction conditions, low functional group tolerance, expensive reagents and precious metal catalysts.
Impact on Society:
We will address these limitations by developing more efficient and practical transformations and showcase their utility by implementing them into the synthesis of biologically active molecules. The ultimate goal is to develop novel drugs to overcome the ever-increasing problem of antibiotic resistance and provide new lead compounds to combat cancer.
Objectives
We will pursue an inexpensive carbon stitching strategy to access halogenated arenes as precursors for natural anti-cancer molecules, antibiotics and biaryl compounds. This method will allow us to accomplish highly modular syntheses of the novel antibiotic salimabromide and the anti-cancer natural product gilvocarcin. In addition, we will create a synthetic platform that is based on the carbon-fluorine bond activation of readily-available trifluoromethyl groups. If successful, this constitutes the first broadly applicable method for the preparation of fluorine containing heteroarenes that are key subunits of pharmaceuticals.
Work performed
Objective 1 – Ring-Expansion Reactions for the Synthesis of Halogenated Arenes
Work Package 1: Synthesis of Halogenated Arenes via Ring-Expansion Reactions
Assembly Line I: Chlorinated Arenes and Synthesis of Salimabromide
Assembly Line II: Axially Chiral Biaryls and Application to the synthesis of ganoapplanin
Assembly Line III: 2-Chloroarenes and Application to the synthesis of the gilvocarcins (type 1) and psammaplysin (type 4)
Additional: investigation of ring-expansion to azepanes, benzimidazoles, pyridines
Objective 2 – Carbon-Fluorine Bond Activation for the Synthesis of Fluorinated Heteroarenes
Fluoroquinolines, Pyridines and Isoquinolines Pyrimidines/Quinazolines and Pyrazines/Quinoxalines and Azepamnes
Final results
1,2-migration/cationic cyclization to give adjacent quaternary stereocenters
Scale-up and Library synthesis - salimabromide
Biaryls - invesigation of the point to axial chirality transfer
Website & more info
More info: https://www.uibk.ac.at/organic/magauer/index.html.en.