Síntesi de peptidomimètics i pseudopèptids de conformació restringida

Research lines

Multicomponent Reactions based on N- and O-heterocycles

The goals in this field consist in the study of new reactivity pathways for nitrogen and oxygen heterocycles, and their use in efficient, preparative processes. In this respect, multicomponent reactions (MCRs) display the most wanted features of an ideal synthesis (fast, convergent, atom-economy, bond forming efficiency, molecular diversity, etc.). Our main goal is to develop new MCRs dealing with the participation of these heterocyclic systems, as they are the natural precursors of structural types frequently found in natural products and bioactive compounds (piperidines, pyrans, tetrahydrofurans, etc.). In this way we want to prepare new scaffolds, with many diversity points, which may be further manipulated, thus speeding the process of S.A.R. in the search of drug candidates, and eventually amenable for High Throughput Synthesis (automated solid-phase protocols).

The chemistry of dihydropyridines and pyridinium salts presents many interesting aspects which constitute basic research projects with varied and attractive applications. For instance, the couple NADH/NAD + (a 1,4-dihydropyridine and a pyridinium salt, respectively) are the cofactors of many oxidoreductases, and have elicited an enormous interest in Bioorganic Chemistry. In Medicinal Chemistry, dihydropyridines constitute a relevant class of compounds as antihypertensive agents (calcium channel blockers, nifedipine is the archetype of this family). Finally, these heterocyclic systems play an important role in organic synthesis, as key intermediates in the preparation of complex, polysubstituted piperidine rings, structures present in many natural products and bioactive compounds.

In the past years research on these heterocycles was focused on the non conventional redox chemistry. We have developed non-biomimetic oxidacion and reduction reactions, in which bond formation is observed. These productive processes are founded on the additions upon the enaminic moiety of the dihydropyridines, to generate, in an oxidative manner, covalent bonds with electronegative atoms (in comparison, the biomimetic process merely involves electron transfer, no new connectivity is generated). In this way we have prepared diversely substitutes tetrahydropyridines (incorporation of O, N, S, X, P, -based substituents). In a complementary manner, we have studied the non-biomimetic reduction of pyridinium salts. In this context, the bond formation is the result of the trapping of the intermediate radical, produced in the electron transfer upon the pyridinium salt, by addition to activated olefins. The process implies a reversal of the polarity ( umpolung ) in azinium salts, and allows the attachment of functionalized alkyl chains at the g -position, in an aqueous solvent. We wondered if we could further expand the synthetic usefulness of these heterocycles by promoting their participation in MCRs.

These are the structural types accessible through these methodologies

The fist MCR studied involved the interaction of the enamine moiety present in DHP's in front of imines (generated in situ by condensation of an aniline with an aldehyde), in a Lewis acid catalyzed process, allows a one-pot access to benzonaphthyridine structures. The biomimetic reduction of the carbonyl and the imine intermediate by the dihydropyridine was not observed, and a productive transformation occurred instead.

This variation of the Povarov reaction is general and extremely versatile. We have screened all the components of this process, and also by interference in the stepwise reaction mechanism, we have introduced additional components. Solid-phase methodology was also developed.

We have extended this studies to the reactivity of enol ethers, and recently we described a 4CR, in which an enol ether, an amine, an aldehyde an alcohol react to form an adduct. This process follows the same mechanistic pathway than the previous one, and involves the interaction of the imine with the electron rich double bond to generate a cationic intermediate which is then trapped by the alcohol (the final nucleophilic species, so-called terminator).

The new reaction is very general and allows a broad range of combinations with different amines, carbonyl derivatives, enol ethers (including glycals) and terminators. Experiments are underway to improve the stereoselectivity of the process, aiming to reach the “ one MCR, one compound” status.

Another line of research is the participation of heterocyclic structures in the Ugi- and Passerini- chemistries, which would allow a range of interesting transformations. The key step in the reaction mechanism is the formation of the cationic intermediates ready to react with the isocyanides.

In our approach, we would generate these structures by interaction of suitable electrophilic species with dihydropyidines, enol ethers and azines. In this way we have access to a wide collection of carbamoylated heterocycles through these MCRs.

The scaffolds developed so far cover different regions in the chemical space and it is expected that they will display specific biological activities. We are currently exploring their activity profile through a chemical genomics approach.