Rios Group

Organocatalytic synthesis of fluorine compounds. Development of
new methodologies for the enantioselective introduction of fluorine
building blocks via CH activation of sp3 carbon

CSP3OCF is a research project which meets a major technological need: The need to develop new sustainable, green and catalytic technologies for the synthesis of fluorine containing compounds using catalytic systems.

B.1.1.1 the importance of catalysis in the synthesis of fluorinated compounds in Organic Chemistry.
Sustainable development is an overarching objective of the European Union: we need to ensure that our present development does not compromise the ability of future generations to meet their needs. For these reason the development of catalytic methodologies that minimize the waste generated and the energy used in chemical reactions is of great importance. Concretely, Catalysis and its application in organic synthesis underpin the basic science of drug discovery. From isolation and characterization of natural compounds to the synthesis of libraries of new molecules, of derivatives of natural products for biological essays, or modifications of natural products to improve their metabolic properties, catalytic methodologies play a huge role (is one of the research areas highlighted by research policy of EU). However, despite the huge advances reported so far, organic synthesis is still limited in its ability to reproduce the complexity of natural products or metabolites with interesting biological activities. The synthesis of these natural products often represents huge efforts, requiring multiple steps, with the subsequent purifications, just to obtain few milligrams of the final compound. These limitations result in cumbersome big scale syntheses to implement in industry. For these reasons the development of new efficient methodologies that simplify the purification, conditions and avoid the use of protecting groups are highly desirable.
The importance of fluorinated compounds is demonstrated that of the top 30 best-selling pharmaceuticals compounds (US sales 2008),2a 10 have at least one fluorine atom. This fact illustrates the impact of organic fluorine chemistry in the development of high end of the market, health care products. The success of Fluorination to improve molecular properties has been convincingly demonstrated in a wide range of applications. In many cases, the small and highly electronegative (EN) fluorine atom is introduced following a particular rationale, based on our understanding of the effects of fluorination.1 In the life sciences area, well-known effects include enhancement of metabolic stability, conformational stabilisation, and modifications of functional group (FG) reactivity, acid/base properties, enhance binding interactions, increase CNS penetration or lipophilicity. Importantly, these effects cannot be considered individually as usually a number of properties are influenced simultaneously.2 For example, fluorination of amines in order to increase their metabolic stability also leads to a decrease in pKa(H), an increase in their lipophilicity, and may induce strong conformational effects. For this reason, the development of new enantioselective methodologies that will deliver b-fluoroamines a common moiety in drug candidates will be of great interest not only for academia but also for chemical industry.

B.1.1.2 Benefits of the development of new suistainable methodologies for the synthesis of Fluorine compounds
As previously stated the introductions of fluorine atoms in organic compounds modify the properties of these compounds. The first example of the beneficious introduction of fluorine atoms in pharmaceuticals was reported by Fried and Sabo in 1954. They show that the introduction of a fluorine atom to the 9a position of cortisol, improved its therapeutic index as an anti-inflammatory by an order of magnitude. Almost 20% of new licensed chemical entities licenced on the market contains at least one fluorine atom. These reasons made the research in new methodologies to introduce fluorines inorganic compounds highly interesting.
Another bigger concern for organic chemists should be the generation of waste in organic reactions, and the development of suistanables and green methodologies. Recently, organocatalysis have emerged as one of the most used GREEN technology. Organocatalysis presents several advantages as:

The catalytic enantioselective activation of a Csp3-H bond to form a new C-C bond provides a potent strategic approach for the synthesis of numerous complex chiral molecules, and is at the forefront of current chemical research. This reaction is more atom economical and environmentally friendly than other cross-coupling reactions, and can be considered as a complementary strategy to the existing direct C-H bonds activations. In the last decade, Csp3-H activation has become one of the most attractive approaches for the synthesis of organic compounds. The advantages of Csp3-H activation rely in the possibility to activate C-H bonds such as R2CHNR2 or R2CHOR.
For these reasons the development of New Green technologies based in the use of organocatalysis for the introduction of fluorine atoms in organic compounds through Csp3-H activation should benefit the development of new suistanable processes for the synthesis of interesting pharmaceutical compounds.

For recent reviews of C H activation, see: a) “C H Activation”:Topics in Current Chemistry (Eds.: J. Q. Yu, Z. Shi), Springer,Berlin, 2010; b) K. Godula, D. Sames, Science 2006, 312, 67; c) R. G. Bergman, Nature 2007, 446, 391; d) K. R. Campos, Chem. Soc. Rev. 2007, 36, 1069; e) J. C. Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2008, 41, 1013; f) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed. 2009, 48, 5094; g) S.-I. Murahashi, D. Zhang, Chem. Soc. Rev. 2008, 37, 1490.