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.
