An Alternative Design for Chiral Brønsted Acid Organocatalysts – CHIRACID

The first works of this project concerned the identification of structures possessing an acid phosphoric function and being able to present a planar chirality. In order to realize this project, the work of both partners were conducted jointly.
PARTNER 1. The Partner 1 realized synthetic studies on the target compounds by using the classic tools of the organic chemistry of synthesis. The developed synthetic routes allowed access to our phosphoric acid targets based on paracyclophane frameworks.
PARTNER 2. The Partner 2 made theoretical studies on target phosphoric acids, to identify quickly the best candidates in term of accessibility.
PARTNER 1. Partner 1 was able to validate the excellent catalytic activity of these new organocatalysts. The products were obtained in good enantioselectivities.
PARTNER 2. Theorical studies performed by Partner 2 led to a new reaction pathway to explain the origin of enantioselctivity for organocatalyzed reduction of nitrogen heterocycles.
Using a collaborative approach and the joint efforts of both partners allowed the project to be carried out.

We have developed a new family of chiral Brønsted acid organocatalysts. These new organocatalysts display planar chiral paracyclophane structures with phosphoric or N-triflyl phosphoramide as acidic function and a 1,1’-ferrocenediyl or a 1,8-biphenylenediyl as tether. These new organocatalysts are very efficient for chiral transformations and may be complementary to other kwon catalysts possessing an axial or central chirality. Moreover, we have used this new chiral scaffold in the field of organometallic chemistry. On one hand, we have prepared metallic organophosphates as catalysts in asymmetric cycloisomerization reactions. On the other hand, we have used also this new chiral scaffold for the preparation of news phosphoramidite ligands for coordination chemistry.

We have developed new chiral Brønsted acid, with planar chirality as organocatalysts. A first family displaying planar chiral paracyclophane structures with phosphoric or N-triflyl phosphoramide as acidic function and a 1,1’-ferrocenediyl have been developed. These new organocatalysts are very efficient for chiral transformations and may be complementary to other kwon catalysts possessing an axial or central chirality.
A second family of organocatalysts displaying planar chiral paracyclophane with 1,8-biphenylenediyl as tether has been also developed. This second family has greater thermal and chemical stabilities. Recently, we have used this new chiral scaffold in the field of organometallic chemistry. On one hand, we have prepared metallic organophosphates as catalysts in asymmetric cycloisomerization reactions. On the other hand, we have used also this new chiral scaffold for the preparation of news phosphoramidite ligands for coordination chemistry.

--> 4 publications in refereed journals:
11) Chemical Communications 2013, 49, 6084-6086. [3,3]Paracyclophanes as Planar Chiral Scaffolds for the Synthesis of New Phosphoric Acids. DOI: 10.1039/c3cc41496e
2) Advanced Synthesis & Catalysis, 2013, 355 (18), 3613-3624. Development of chiral phosphoric acids based on ferrocene-bridged paracyclophane frameworks. DOI: 10.1002/adsc.201300697
3) European Journal of Organic Chemistry, 2014, 4099-4106. Chiral Synthetic Equivalents of 2-Cyanoethyl Tetraisopropylphosphorodiamidite: Application to the Synthesis and Resolution of Chiral Phosphoric Acids. DOI: 10.1002/ejoc.201402203
4) Journal of Organic Chemistry, 2014, 79, 9639-9646. Planar Chiral Phosphoric Acids with Biphenylene-Tethered Paracyclophane Scaffolds: Synthesis, Characterization, and Catalytic Screening. DOI: 10.1021/jo501769t

--> 2 oral communications in international congress :
1) 10th European Workshop on Phosphorus Chemistry 2013 [PhoSciNet Final Conference@EWPC-10]
Regensburg, Allemagne, 18-20 march 2013. [3,3]-Paracyclophanes as Planar Chiral Scaffolds for the Synthesis of New Phosphoric Acids.
2) COST-ORCA (European Cooperation in Science and Technology - Organocatalysis)
ECOST-MEETING-CM0905-180413-028636 Amsterdam, 18-20 april 2013. New Family of Planar-Chiral Phosphoric Acid for Enantioselective Organocatalysis.

--> 5 oral communications in international congress :
1) Journées Modélisation 2013 - ChimieParisTech, 29 au 31 may 2013.
2) JED de Chimie de Paris-Sud Orsay, 18-19 september 2013.
3) Invitation par le Comité d’Organisation des Séminaires du Laboratoire LCOS - UMR 7177 - Strasbourg, 4 october 2013.
4) Réunion ANR mi-parcours. Département R2E. SIMI 7 et 8 (chimie). BLANC / BLANC INTER / JCJC 2011 – Comité de mi-parcours - Paris, 16-18 december 2013.
5) ICSN team workshop, Gif-sur-Yvette, 16 january 2014
6) [RCO-2014], Université Paris Descartes, Paris, 4 april 2014.
7) JED, Paris-Sud Orsay, 01-02 october 2014.

--> 14 poster presentations.

Aim of this project is the development of new families of chiral Brønsted acid organocatalysts. The targeted structures are cyclic phosphoric acids displaying planar chiral molecular scaffolds, i.e. tetrasubstituted ferrocene and paracyclophane units. These acids are expected to be available via simple, straightforward and versatile synthetic approaches, allowing fine modulation of the stereo-electronic properties. Predictive theoretical studies will be applied to catalyst design, based on a ‘structural diversity’ approach.
Thus, our first objective is to find suitable synthetic approaches to small libraries of new, chiral phosphoric acids.
In the second part of our work, we will explore their use in enantioselective organocatalytic reactions, with special attention to challenging processes with high synthetic potential. As representative examples of acid catalyzed processes for which improved chiral catalysts are eagerly sought to date, we could mention here Friedel-Crafts reactions on selected substrates or Nazarov type cyclizations. Setting of efficient enantioselective variants of these reactions will be targeted. During this optimization process, calculations will support catalysts design as well as elucidation of their modes of activation and reaction mechanisms.