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Innovative Strategies towards Halogenated Organic Molecules: From Reaction Design to Application in Drug Synthesis

Periodic Reporting for period 3 - HALODRUGSYN (Innovative Strategies towards Halogenated Organic Molecules: From Reaction Design to Application in Drug Synthesis)

Reporting period: 2019-02-01 to 2020-07-31

Current Problem:
Aromatic 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 based on ring-expansion 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.

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, the anti-cancer natural product gilvocarcin and novel biaryls for chemistry. 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.
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: The synthesis of chlorinated arenes and first synthetic access to salimabromide was accomplished
Assembly Line II: Axially chiral biaryls could be accessed.
Assembly Line III: 2-Chloroarenes were prepared via type 1 expansion and applied to the synthesis of defucogilvocarcin.
Objective 2 – Carbon-Fluorine Bond Activation for the Synthesis of Fluorinated Heteroarenes
A subset of novel fluorinated pyridines and (iso)quinolines was prepared
We developed a novel 1,2-migration/cationic cyclization to provide rapid access to tetrahydronaphthalenes containing adjacent quaternary stereocenters. Detailed investigations of the substrate scope will provide a platform for the generation of novel carbacycles as valuable building blocks for chemistry. The scale-up synthesis of salimabromide will provide sufficient material to support detailed biological studies. The investigated point-to-axial chirality transfer will enable a powerful alternative to previous synthetic methods and expand the pool of valuable biaryl motifs.