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

Periodic Reporting for period 4 - HALODRUGSYN (Innovative Strategies towards Halogenated Organic Molecules: From Reaction Design to Application in Drug Synthesis)

Berichtszeitraum: 2020-08-01 bis 2022-01-31

Aromatic molecules that contain halogen substituents such as chlorine, bromine and fluorine are ubiquitous in daily life. They can be found in bioactive (e.g. antibiotic and anticancer) natural products, are part of important agrochemicals and blockbuster drugs, and consitute 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 thus preventing access to these molecules. By developing novel ring-expansion reactions we wanted to address this issue. The application of these reactions to the synthesis of bioactive natural products reveals the enormous potential for organic synthesis. By removing the limitations of current methods, we will have access to more efficient, sustainable and practical transformations to rapidly produce biologically active molecules. The ultimate goal is to facilitate the development of novel drugs to overcome for instance the ever-increasing problem of antibiotic resistance and provide new lead compounds to combat cancer. For this purpose, we pursued an inexpensive carbon stitching strategy to access halogenated arenes as precursors for natural anti-cancer molecules, antibiotics and biaryl compounds. This method allowed us to accomplish highly modular syntheses of the novel antibiotic salimabromide, anti-cancer gilvocarcin natural products such as defucogilvocarcin M and novel biaryl motifs for chemistry. In addition, we have obtained crucial insights into the carbon-fluorine bond activation of readily-available trifluoromethyl groups. The scientific community has now access to more efficient synthetic methods and chemical syntheses of valuable molecules that have previously eluded their large scale production. We are now capable of studying these molecules in full detail and of developing even more powerful tools to make chemical synthesis even more sustainable and powerful.
The research team was able to accomplish several breakthroughs for the project. We were able to accomplish and scale up the first total synthesis of salimabromide. This molecule has been isolated only once in minute quantitates (0.5 mg) and has eluded its synthesis as well as re-isolation since then. The devleoped synthetic sequence is robust enough to be conducted on multi-gram scale, enables deep-seated structural modifications and set the foundation for structure-activity-relationship studies. The optimized route enabled us to prepare 296 mg of salimabromide in a single batch. During these studies, we discovered a powerful method for the construction of vicinal all-carbon stereocenters from readily available neopentylic epoxides. The developed transformation benefits from mild reaction conditions proceeding in a temperature range from 0 to 23 °C. Systematic variation of the terminating (hetero)arene and selected modifications of the remote substitution pattern provided a wealth of structurally unique, previously unknown tetralin and chromane systems. Investigation of the migration tendencies of various substituents revealed an unusual disproportionation pathway for which we performed computational studies to support the putative reaction mechanism. In collaborative work with Prof. Werz (University of Jena) salimabromide was found to display a novel stimulating priming effect on lipid mediator formation, being cell type/stimulus specific and not cytotoxic. The ring-expansion of chlorinated/brominated cyclopropanes proceeds under mild conditions employing simple 1-indanones of which more than 60 substrates are readily available from commercial suppliers. The method is robust enough to allow for rapid access to structurally diverse analogs as demonstrated in the synthesis of the natural product defucogilvocarcin M. While investigating several methods to accomplish oxidation of a crucial defucogilvocarcin precursor, we also discovered a (transition)-metal free conditions to selectively oxidize the benzylic position of isochromanes. In addition, we discovered a unique dearomatization of halogenated naphthols that warrants further investigations. The investigated point-to-axial chirality transfer enabled synthesis of an enantiomerically enriched biaryl for the first time. Based on these studies, we realized a general synthetic entry to Ganoderma natural products. The developed strategy enabled access to the applanatumols, meroapplanin, lingzhilactone and lingzhiol. The successful application of a rare photo-Fries reaction and the incorporation of a recently disclosed photoredox catalyzed process highlights the potential of photochemistry for natural product synthesis. The realization of the decarboxylative oxidation process has also implications for the biosynthesis of these natural products. We were also able to synthesize the oxepin core of psammaplysin and provided an overview about synthetic methods to access this fascinating motif. In this context, we also obtained detailed insights in the behaviour of substituted oxepins. The envisioned C–F activation of work package 2 provided several key insights but turned out to be highly limited to a small subset of substrates. We therefore shifted our focus on the advancement of work package 1. The results of the project were described in eight high-impact publications, presented on more than 35 occasions to the scientific community - 10 selected presentations: University of Oxford, GDCh-Wissenschaftsforum, Basler Chemische Gesellschaft, Bayer Crop Science, University of Cologne, Firmenich, MIT, SCRIPPS BiCoastal Seminar, Caltech, UCSD). The result and impact of our research were also shared with the public, for instance via press releases, the Wissensdurst Festival and most recently via an OEAW Young Science talk. The research team has been very successful and all previous team members have received offers from academia and industry.
We developed a novel 1,2-migration/cationic cyclization to provide rapid access to adjacent quaternary stereocenters. Detailed investigations of the substrate scope have provided a platform for the generation of novel carbacycles as valuable building blocks for chemistry. The scale-up synthesis of salimabromide has provided sufficient material to support detailed biological studies. The investigated point-to-axial chirality transfer has enabled for the first time an alternative to previous synthetic methods and expands the pool of valuable biaryl motifs. The implementation of a photoredox catalyzed oxidative decarboxylation sequence followed by an intramolecular Friedel–Crafts reaction provided rapid access to lingzhiol. The successful application of a classic, yet rare photo-Fries reaction and the incorporation of a recently developed photoredox catalyzed process highlights the potential of photochemistry for complex molecule synthesis. The realization of the decarboxylative oxidation process has also implications for the biosynthesis of Ganoderma meroterpenoids. We believe that a related process might be also operative in nature and therefore implications to the biosynthesis. We are convinced that the results of this proejct will catch the attention of many chemists and will attract a high number of scientists, especially those who focus on synthetic methodology and natural product synthesis.
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