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Overcoming the Selectivity Challenge in Chemistry and Chemical Biology via Innovative Tethering Strategies

Periodic Reporting for period 4 - SeleCHEM (Overcoming the Selectivity Challenge in Chemistry and Chemical Biology via Innovative Tethering Strategies)

Reporting period: 2023-07-01 to 2023-12-31

In the last two centuries, synthetic organic chemistry has undergone an unprecedented revolution. The ability to understand and modify the molecular structure of matter has changed our life in many areas, such as medicine, agriculture or commodity materials. These major successes gave the impression that synthetic chemistry is a mature field. However, this impression is completely misleading, as current synthetic methods still lack the selectivity needed for the modification of complex molecules. Both selecting between different reactive groups and functionalizing inert bonds in their presence represent formidable challenges. Nevertheless, we need to solve this challenge if we want to discover better drugs, agrochemicals and materials.
In this project, we propose to develop highly selective “molecular tethers” for the functionalization of both natural/synthetic organic compounds and biomolecules. The envisioned tethers are bifunctional small organic molecules having three fundamental properties:
1) A selective “biting end”, which is able to react with only one position, even on complex molecules.
2) A “functional end”, whose reactivity can be revealed “at will” to bring modification.
3) Being traceless, meaning that they can be removed easily once the desired functionalization has been achieved.

The use of this tethering strategy enabled us to reach the two main objectives of the project:
1) The selective functionalization of biomolecules based on the reactivity of hypervalent iodine reagents.
2) The development of tethers derived from electron-deficient carbonyl compounds for the modification of inert bonds in oxygen- and nitrogen-rich building blocks.

The main impact of this project was in fundamental synthetic organic chemistry, as it contributed to overcoming major selectivity hurdles in the functionalization of complex molecules. It will therefore result in faster progress in all the fields depending on synthetic molecules, such as medicine, agriculture or materials.
Reaching our first objective resulted in a more efficient functionalization of biomolecules, allowing us to soften the boundaries between synthetic chemistry and biology. This can lead to major progress in our understanding of living systems and our ability to modify them. It can also lead to the discovery of new peptide-based bioactive compounds, which are among the fastest growing class of drugs nowadays.
The second objectives enabled the synthesis of enantiopure building blocks based on a new strategy of the "catalytically formed chiral auxiliaries". The obtained multi-functionalized compounds are of high interest for medicinal chemistry.
During the project, the two major objectives could be reached:

1) New method to functionalize biomolecules, in particular proteins: in a team work with biologists, we were able to develop reagents able to selectively modify a single amino acid residue in proteins. Our "hypervalent iodine reagents" displayed unique reactivity and selectivity, and allow for example to introduce fluorescent molecules into proteins to study the biology of the cell. We can also use these reagents to identify the target of bioactive compounds, such as natural products and drugs, a process essential to develop new medication. Another application we developed in collaboration is the selective modification of antibodies, which opens the way for drug-antibody conjugates, with the potential for cures with less side effects. We were able to use our reagents to stabilize bioactive peptide, demonstrating increased binding affinity towards important targets for cancer therapy. The introduction of hypervalent iodine reagents on peptides enable completely new types of bioorthogonal chemistry. This enabled us to synthesize cyclic peptides using very mild catalytic conditions, either using light-activation or commercially available non-toxic gold catalysts. Promising applications of the synthetized compounds as protein inhibitors or as dyes for cell imaging have already been identified.

2) The selective functionalization of alkynes (carbon carbon triple bonds) using commercially available tethering molecules and a palladium catalyst. This reaction gives access to amino alcohols, essential structural elements, especially for medicinal chemistry. Indeed, more than 300'000 amino alcohols have already been reported. They can be found in more than 2000 natural products and 80 FDA approved drugs. The enantioselective selective synthesis of such essential building blocks is already an important result for the SeleCHEM project. From the fundamental point of view, we introduced a new strategy in asymmetric synthesis: the catalytic generation of chiral auxiliaries. This new method combines the advantages of two classical approaches in the field (chiral auxiliary control and enantioselective catalysis), resulting in the best compromise between efficiency and generality.

Our research has therefore contributed to a more selective chemistry (SeleCHEM) for both the modification of small synthetic compounds and large biomolecules. We have disseminated our results already through 19 peer-reviewed publications, which are easily accessible from our project website, more than 25 presentations in conferences, and social media (twitter (no "X") and Linkedin.
Our achievement in the functionalization of biomolecules certainly went far beyond the state of the art in the field. This was the first application of hypervalent iodine reagents for the functionalization of peptides and proteins. The reaction displayed kinetics and selectivity equal or better when compared to current golden standards. Our new method for peptides stapling is comparable to the best reported approaches, and has the advantage to use easy to access non-toxic reagents and do not require protection of the amino acids side chains or termini. The developments in the last two years of the project introducing new hypervalent iodine reagents based building blocks into peptides are truly exciting, resulting in particular in two new unprecedented methods for peptide macrocyclization. The chemistry involved was fully bioorthogonal, which set the basis for applications in more complex settings such as proteins or even living cells.

Concerning the tethered functionalization of small molecules, our main breakthrough is different from our original plan. It resulted from the unexpected perfect diastereoselectivity induced by the installed tether, which motivated us to develop the concept of catalytically formed chiral auxiliaries. This started indeed an unexpected direction within our project, which enable us to develop a new approach for the selective installation of stereocenters in organic molecules, especially in highly substituted systems that were difficult to synthesize before. The obtained building blocks are of high interest, especially for medicinal chemistry.
project abstract