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Novel Organocatalysts for Asymmetric Addition of Me3SiCF3 to Carbonyl Compounds

Final Report Summary - CHIRCAT (Novel organocatalysts for asymmetric addition of Me3SiCF3 to carbonyl compounds)

Summary overview of results:

The 24-month Intra-European Fellowship (IEF) research has produced four distinct results in the area of asymmetric synthesis:

(1) The first part of the work was conducted in collaboration with Dr Ilya Lyapkalo from the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic. A new family of chiral zwitterionic phosphorous-containing heterocycles (zPHCs) was designed, synthesised, characterised and studied. These structures were exploited successfully to determine the optical purity of chiral carboxylic acids by nuclear magnetic resonance (NMR) spectroscopy. This can be exploited by research scientists to rapidly assess the proportion of enantiomeric compounds, which is particularly important for drug discovery. The results from this work have been submitted to a peer-reviewed journal; parts of the work were also presented (by the IEF fellow) in 2012 at the international conference on Catalysis in Organic Synthesis ICCOS-2012, Moscow, Russia.

(2) Based on observations gather in the first part of the project, a novel family of chiral 2-oxopyrimidinium salts was designed and utilised successfully as catalysts for asymmetric Michael reactions, producing valuable molecules of extremely high yield and optical purity. The synthetic utility of the methodology was demonstrated by the synthesis of an analogue of (S)-nicotine. The results of this work have been submitted for publication to a peer-reviewed journal.

(3) Asymmetric synthesis of levonantradol, a molecule with highly potent analgesic and antiemetic properties, has been achieved, for the first time, in this project. This allowed the structure of this interesting molecular to be determined by a combination of NMR experiments and density functional theory (DFT) calculations. This will have important implications in the understanding of its biological activity, and the subsequent development of equally or more potent analogues with better physiological profile. The results of this work have been submitted for publication to a peer-reviewed journal; parts of the work were presented in 2012 at the international conference on Challenges in Bioorganic & Organic Medicinal Chemistry: 13th Tetrahedron Symposium, Amsterdam, the Netherlands.

(4) The detailed synthesis of Pd(OTf)2·2H2O, which was used as a precursor for the preparation of two different types of chiral dicationic palladium complexes for the preparation of optically active amino acid derivatives, which are valuable synthetic intermediates for the synthesis of biologically active molecules and peptidomimetics. These catalysts were also used to prepare levonantradol in the previous project (#3). The developed protocol was published in a peer-reviewed journal (Nat. Prot., 2012, 7, 1765-1773).

Conclusions:

The work programme has delivered results in four distinct areas of asymmetric synthesis:

(1) the development of an analytical tool for the determination of optical purity of chiral intermediates / products;
(2) the development of a new 'first-in-class' catalyst for the asymmetric Michael reaction, and to demonstrate that it can be used in the preparation of potentially biologically interesting molecules;
(3) the first successful total synthesis of a potent analgesic molecule, and the determination of its structure for further biological evaluation; and
(4) the disclosure of a synthetic protocol for the preparation of a class of useful palladium catalysts for asymmetric catalysis.

Socio-economic impact:

Catalysis is a key underpinning technology for many challenges posed by the modern society, from energy futures, renewable feedstocks, climate / environmental remediation, to the production of materials necessary to sustain and improve the quality of life. The CHIRCAT project on asymmetric synthesis delivers direct impact in the synthesis of optically active molecules. In the shorter-term (3 - 5 years), this will enable medicinal chemists to discover new ways of making new molecular entities, which may be used in the combat against diseases, improving the well-being of mankind. By delivering more efficient and selective processes, chemists can also start to make molecules in a shorter time, and generates less waste in the process. In the longer term (> 10 years), the research will provide sustainable manufacturing routes to reduce the demand for critical raw materials, delivering processes with minimal environmental footprint. This will have an important impact on the quality of life, particularly for the population of industrialised nations.