PID2020-115294GB-I0

It is of crucial importance that innovation in synthetic chemistry be employed throughout the entirety of the drug discovery process. The existing synthetic arsenal allows access to the chemical space, thereby facilitating a more comprehensive exploration of it and the identification of potential lead drug candidates. In this context, developing domino processes, particularly in an asymmetric manner, is a general approach to enhancing synthetic efficiency and accessing molecules exhibiting structural diversity. These processes, which meet many of the criteria of green chemistry and are particularly suited to the generation of molecular and stereochemical complexity from accessible starting materials, are the basis of this project. The initial objective is the implementation of asymmetrical tandem protocols for the synthesis of polycyclic pyrroles. This heterocycle is an essential structural motif in numerous biologically active molecules and drugs. Its incorporation in organic molecules increases the probabilities of discovering biologically useful compounds. Two asymmetric tandem processes have been designed for this purpose. The first is modified cycloaromatisation/Pictet Spengler, and the second is intramolecular cycloaromatisation/aza-Friedel Crafts of the appropriate substrates, generating polycyclic pirroles with quaternary stereocentres. Secondly, the objective is to design new asymmetric tandem reactions initiated by a vinylogous Mannich reaction. The vinylogous donors will be 1,1-dicyanoalkenes and allyl metal sulfoxides, while the acceptors will be conjugated fluorinated imines. The initial addition of the Mannich type will generate a source of nucleophile nitrogen that can react in an intramolecular manner with an electrophile present in the intermediate, namely the conjugated malononitrile and vinyl sulfoxide, respectively. This will result in the formation of polycyclic nitrogen heterocycles accompanied by the simultaneous generation of several stereocentres. The third objective of this proposal is to develop enantioselective catalytic domino processes initiated by an intramolecular aza-Michael reaction. The use of N-heterocyclic carbenes or chiral isothioureas as catalysts will generate the corresponding unsaturated alfa,beta-unsaturated acylazoliums intermediates that will initiate the intramolecular tandem aza-Michael/conjugated intramolecular/lactonisation process, resulting in tetracyclic tetrahydropyrroloquinolines. An illustrative example of an emerging technique as a synthetic methodology is photoredox catalysis, which allows for the use of visible light to carry out synthetic transformations of molecules that are not accessible through other methods. This technique will be employed to asses the intramolecular aza-Michael/intramolecular conjugated addition sequence in the presence of a chiral nickel catalyst that will act simultaneously as a photosensitiser and chiral catalyst. Finally, we intend to use some chiral nitrogen heterocycles to form complex transition metals as potential agents of DNA recognition, which will allow us to obtain selective and effective metal-nucleases. The experiments will enable us to comprehend the fundamental mechanisms of interaction of the complexes with DNA and to carry out a rational design of new complexes with antitumor activity.

reacciones tándem, síntesis asimétrica, síntesis total, organocatálisis, química de fluor, heterociclos

Ministerio de Ciencia e Innovación (MICIN)

• AGE - Knowledge Generation Projects