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Organo-Catalytic Nanoparticles for Organic Synthesis

Periodic Reporting for period 1 - OCN4OS (Organo-Catalytic Nanoparticles for Organic Synthesis)

Reporting period: 2015-06-01 to 2017-05-31

The objective of this proposal is the development of a platform of recyclable organocatalysts that could be employed in the preparation of drugs or intermediates thereof. In order to achieve this objective the proposal brings together 3 partners with complementary skills: an expert in Phase Transfer Catalysis, Organo-Catalysis and synthesis (RCSI), an expert in development of DNA based catalysis and DNA elaboration (University of Nottingham) and an expert in the manufacture of polymer bound biomolecules and drug intermediates (Kemotech). The relevance of the platform will be demonstrated by the their application to the preparation of unnatural aminoacids, intermediates of synthesis for active pharmaceutical ingredient Pregabalin, a new estrogen-b-receptor modulator and anti-HIV Efavirenz. Organocatalysis has witnessed a terrific development in the last 14 years with thousands of potentially useful transformations being reported. However, for this field to impact on commercial industrial applications, these species must be recoverable and recyclable. Synthesis through organic catalysts offers several advantages over classic metal ligand transformation, including cost efficiency and sustainability. Metals such as Rh, Ru, Pt, Pd are depleted at high rate and syntheses relied upon their use are destined to lose competivity. On the other side, organocatalysts have a limited turn over (typically 10-100) compared to metal catalysts (100-1000) and sometimes their synthesis may require few steps. In this scenario, a platform of recoverable polymer bound organocatalysts would offer several advantages: firstly, should they be reused, their turn over will be immediately expanded; secondly, they will impact on the cost efficiency of the syntheses to which they are applied; thirdly, the issue of metal contamination of pharmaceutical active ingredient, a common problem experienced by drug manufacturers, will be avoided. At present, there are some examples of chiral organocatalysts supported on PEG via covalent bond, namely the Jacobsen and the Takemoto’s thioureas. In addition, there are few examples of chincona based phase transfer catalysts that were equally linked via covalent bonds to dendrimers or PEG. In these examples, a particle of PEG is usually preformed and loaded with the catalysts. In this strategy, a linkage had to be carefully designed in order to allow enough spacing between the large PEG particle and the organocatalyst, this being a required condition for the catalyst to be accessible by the reagents. In addition, the resulting polymeric catalysts may have scarce homogeneity. Itsuno has demonstrated that it was possible to pre-form a quaternary ammonium sulfonate-styrene salt, which was then submitted to polymerisation. The advantage of this method, in which the catalyst is present as a monomer, is to allow the catalyst controlling the polymerization process and develop a particle in which the catalyst is homogeneously distributed. The method is also very practical and controllable. It should be noted that the ammonium-sulfonate ionic bond is among the strongest of this type and that extreme conditions (concentrated inorganic acids) are required to displace the ammonium species from the sulfonated polymer.
The recent past has witnessed many reports in which organic catalysts (organocatalysts) have been employed to generate compounds in high enantiopurity. However, the small turnover number that organocatalysts often display and the cost associated to their preparation have impeded their application for large scale manufacture. In this context, the development of a platform of solid supported (i.e. recoverable) catalysts will cast the way for the commercial exploitation of organoacatalysis by the industrial community. We have selected four commonly used organic catalysts, namely Chincona based phase transfer catalyst, an aminothiourea prototype, an hydroxythiourea prototype and a DNA template. We have planned to join the resin and the catalysts via a non-covalent ionic interaction (sulfonate-ammonium salt). This choice has been made to allow a close proximity between the resin and the catalysts, yet assuring the large particle would have limited influence on the catalyst turnover. We have then devised a strategy to develop polystyrene mono-disperse nanoparticles possessing specific sizes, that can be manufactured via practical and cheap protocol. In addition we have designed a set of specific styrene monomers incorporating a chiral sulfonate moiety, which we have demonstrated to enhance the enantioselectivity of resin bound phase transfer catalysts. Therefore the project had involved the following WPs.

In WP1, a number of monomeric salts were made by combining phase transfer catalysts and chiral styrene sulfonates. In order for this to be achieved, a method for the reduction of ketosulfonates to sultanates (i.e. deoxygenation) has been developed.


In the following WP2-3, the monomeric salts prepared in WP1 were polymerised to give mono-disperse nanoparticles, which synthetic relevance will be then validates in the preparation of a -estrogen receptor modulator intermediate and unnatural -aminoacids

In WP4-5 the preparation of modified bifunctional catalysts incorporating a sulfonate moiety, their inclusion in polystyrene nanoparticles was attempted. In particular the introduction of a sultanate moiety on those catalyst was proved impossible and it will be suggested to use a different method of ligation, perhaps a thiol one addition.

WP7-8 which dealt with the preparation and synthetic use of resin bound DNAs was only attempted .
The study carried out through this project have demonstrated the following:

- Salts of quaternary ammonium salts with chiral sulfonates are equally good catalysts, as the conventional bromides or chlorides, although they impart a different level of enantioselectivity to the reactions they are employed in.

- The introduction of a sultanate salts in some organocatalysts is not a feasible method for their binding on a solid support: future studies must involve other methods such as thiol-ene reaction.