innoVative DNA-hybrid asymmetric CatalYSis – D-CYSIV

In this multidisciplinary project, we seek to take advantage of the three-dimensional structure of nucleic acids to create a chiral environment around an active metal complex and provide new tools in the field of asymmetric catalysis. To fully realize this project, we will 1) develop new anchoring systems able to change the microenvironment provided by existing anchoring modes, 2) pilot innovative and sustainable catalytic systems easy to handle and with a broad scope, 3) develop recyclable DNA catalysts and 4) perform ordered multistep syntheses in a one pot fashion by changing the toplogy of the DNA.
The first part of the project, which involves the synthesis and catalytic evaluation of a minor groove binder anchorage strategy, will be undertaken at ESPCI ParisTech within Dr Arseniyadis’ Team. Meanwhile, the affinity evaluation of theses new minor groove binder-type ligands using specific AT and GC-rich sequences will be done at the University Montpellier 2 by Pr Smietana and his Team.

Finally, the third and probably the most challenging part of the project will be to order multistep syntheses in a one-pot fashion using a compartimentalization strategy and apply for the first time DNA-based asymmetric catalysis to the synthesis of a structurally complex natural product. This task will be handled jointly by the three Team. Hence, the Smietana Team that will design and synthesise specific oligonucleotides capable of interacting with various catalytic systems through different anchorage strategies, the Arseniyadis Team will develop new multi-catalytic processes, while the Poupon Team will apply them to the biomimetic synthesis of various natural products.

In accordance with our work plan, the start of the project consisted in synthesizing a new family of ligands derived from Hoechst 33258, known to bind firmly to the minor groove of DNA (Milestone 1). Many derivatives, carrying both the Hoechst 33258 core structure and a chelating part, have thus been synthesized. Spectroscopic data coupled with the results obtained in asymmetric catalysis showed a strong correlation between DNA affinity and enantioselectivity. Moreover, a comparative study has demonstrated that these derivatives are highly selective for the AATT sequences, providing for the first time a real possibility of compartmentalisation in hybrid DNA catalysis.
Moreover, we have also explored the structural diversity proposed by RNA and we have shown for the first time that the different catalytic methodologies developed until then with DNA are perfectly applicable to RNA thus enabling a significant extension of the domain of nucleic acid-based catalysis.

In addition, several studies are under way to determine the structural parameters governing the stereoselectivity of DNA-catalyzed reactions.

In the coming months, in addition to the end of the study of structural parameters, our work will focus mainly on the development of new reactions catalyzed by DNA and in particular on cycloadditions and electrocyclization reactions (milestones 3a and 3b). These new reactions will allow us to start the last part of this project, which will consist in applying these different tools to the synthesis of natural molecules. Bio-inspired strategies mimicking biosynthetic pathways will be particularly sought after.

1. N. Duchemin, E. Benedetti, L. Bethge, S. Vonhoff, S. Klussmann, J-J. Vasseur, J. Cossy, M. Smietana,* S. Arseniyadis*
Expanding Biohybrid-mediated Asymmetric Catalysis into the Realm of RNA,
Chemical Communications, 2016, 52, 8604
2. K. Amirbekyan, N. Duchemin, E. Benedetti, R. Joseph, A. Colon, S. A. Markarian, L. Bethge, S. Vonhoff, S. Klussmann, J. Cossy, J.-J. Vasseur, S. Arseniyadis,* M. Smietana,*
Design, Synthesis and Binding Affinity Evaluation of New Hoechst 33258 Derivatives for the Development of Sequence-specific Catalysts for DNA-based Asymmetric Catalysis,
ACS Catalysis, 2016, 6, 3096.
3. N. Duchemin, I. Heath-Apostolopoulos, M. Smietana*, S. Arseniyadis,*
A decade of DNA-hybrid catalysis: from innovation to comprehension.
Organic and Biomolecular Chemistry, 2017 (in Press)
4. S. Arseniyadis,* N. Duchemin, I. Heath-Apostolopoulos, M. Smietana*
Catalyse asymétrique innovante à base d’ADN
l’Actualité Chimique 2017, 417, 17.

The challenge in DNA-based asymmetric catalysis (DAC) is to perform a reaction in the vicinity of the helix, which provides the chiral information to the activated complex and enables chiral discrimination. By analogy with hybrid metalloenzymes, DNA-based asymmetric catalysts incorporate a small-molecule catalyst anchored in a covalent, dative, or non covalent yet kinetically stable fashion to DNA. Obviously, to ensure that the chiral information solely originates from the DNA itself, the catalyst is chosen non chiral.
While still in its infancy, many challenges lie ahead. First, the reactions still need to be run in aqueous media due to the poor solubility and stability of DNA in typical organic solvents, thus limiting the number and type of reactions that can be envisioned. Second, there are some important temperature-limitations that need to be respected in order to avoid either DNA denaturation or water freeze. Third, all the strategies reported so far that involve other metals than Cu need post-synthetic transformations. Finally, compartmentalization has never been achieved to date thus preventing multi-catalytic processes to be performed in a one-pot fashion.
The use of specific ligands with defined binding modes will help us understand the key mechanisms that induce the selectivity and thus allow a great step forward toward the development of programmable cascade reactions. Hence, in this multidisciplinary project, we seek to take advantage of the three-dimensional structure of nucleic acids to create a chiral environment around an active metal catalyst.
To fully realize the potential of DNA-based asymmetric catalysis and to translate the chirality of nucleic acid sequences into small molecules requires the development of improved synthesis and encoding strategies. In this project we ambition to 1) develop new anchoring systems able to change the microenvironment provided by existing anchoring modes, 2) pilot innovative and sustainable catalytic systems easy to handle and with a broad scope, 3) perform ordered multistep syntheses in a one pot fashion by changing the toplogy of the DNA and 4) apply for the first time DNA-based asymmetric catalysis to the synthesis of complex natural products. Hence, by fine-tuning the DNA structural motifs and anchoring modes, we aim to provide new DNA derived biocatalysts capable of achieving multiple synthetic transformations in a one pot fashion with high levels of enantioselection. Our approach has the advantage of being highly modular, allowing to combine a variety of complementary single-stranded DNAs to generate original DNA based catalysts. Additionally, the straightforward assembly allows for rapid optimization studies. Finally, this collaboration between three very complementary teams will be a great opportunity to make new discoveries in the field of DNA-based asymmetric catalysis and allow French groups to be competitive in an international level.