Research lines

Biologically inspired oxidation catalysis. Nature is a source of inspiration for the development of chemical transformations that stand as unsolved problems in contemporary synthetic chemistry and also for creating sustainable alternatives to methods that are becoming increasingly prohibitive because of society needs to change from a linear to a circular economy. Reaction mechanisms and reagents operating in metalloenzymes can be the starting point guiding the design of small molecule catalysts based in well-defined coordination compounds that retain the main chemical reactivity features of the enzyme while avoiding the size and complexity inherent of the protein scaffold. In parallel, recent years have seen a manipulation of the innate enzymatic reactivity towards transformations that may be chemically considered fundamentally analogous to natural reactions but that are not present in natural systems. For example, formal nitrogen-transfer and carbon transfer reactions via iron-nitrenoid and iron-carbenoid species are not present in nature, but iron oxygenases can be engineered to display such reactivity via hipervalent species that electronically resemble iron-oxo species of heme (P450) and nonheme (TauD) enzymes. This reactivity in turn delineates avenues for the design of novel types of catalysts based in the biologically relevant metals to address these unnatural reactions. These catalysts will differ from those traditionally employed, generally based in precious metals, reinforcing the sustainability benefits of this approach. Furthermore, the singularities of the electronic structures of first row transition metals, which often combine ground states with low lying excited states differing in electronic spin, confer them with reactivity properties that go beyond those attained by the heavier metal counterparts.

Our research interests build on these ideas and target the development of molecular catalysts displaying reactivity of interest in synthetic organic chemistry taking as inspiration motif reactive species and mechanisms operating in metal dependent enzymatic sites. This interest focuses in the following research lines:

Site and enantioselective C(sp3)–H oxidation via catalyst design

One of the long-standing challenges in chemistry is the efficient synthesis of highly added-value chiral molecules from readily available, cheap, and simple hydrocarbon frameworks with minimal waste generation. In this context, given the biological relevance and the high chemical versatility of chiral oxygenated motifs, methods that can enable site and enantioselective C(sp3)–H oxidation are particularly valuable. Despite their interest, these methods remain mostly inaccessible because their realization has to overcome major challenges: the significantly lower reactivity of these bonds compared with most functional groups and he need to control chemo- and stereoselectivity in molecules containing multiple nonactivated nonequivalent C(sp3)–H bonds. Consequently, chiral oxygenated aliphatic frames are still customarily built via the laborious transformation of pre-existing functional groups. Such limitation has resulted in the design of alternative multistep synthetic routes, often involving the use of readily available chiral building blocks deriving from natural sources (i.e., the “chiral pool”), thus restricting the use of simple hydrocarbon scaffolds as starting materials.

Our strategy to address the formidable problems of combining high reactivity with selectivity is the design of chiral catalysts that generate high valent metal-oxo species within highly structured ligand frames. These catalysts, combined with medium effects exerted by the solvent, and judicious use of native functionality as directing groups, or weak interactions by catalyst receptors are used to design site and enantioselective C-H oxidation reactions. At the same time, mechanistic understanding is used to guide catalyst design and to define novel reactions.

Representative publications

L. Vicens, G. Olivo, M. Costas. ACS Catal. 2020, 10, 8611-8631 [doi]
A. Palone, G. Casadevall, S. Ruiz-Barragan, A. Call, S. Osuna, M. Bietti, M. Costas. J. Am. Chem. Soc. 2023, 145, 15742-15753 [doi]
A. Call, G. Capocasa, A. Palone, L. Vicens, E. Aparicio, N. Choukairi Afailal, N. Siakavaras, M. E. López Saló, M. Bietti, M. Costas. J. Am. Chem. Soc. 2023, 145, 18094-18103 [doi]
M. Galeotti, L. Vicens, M. Salamone, M. Costas, M. Bietti. J. Am. Chem. Soc. 2022, 144, 7391-7401 [doi]
M. Borrell, S. Gil-Caballero, M. Bietti, M. Costas. ACS Catal. 2020, 10, 4702-4709 [doi]

Oxidative dearomatization of arenes

Arenes are some of the most abundant feedstock chemicals, produced annually on a million metric ton scale, and finding use in the production of polymers, paints, agrochemicals and pharmaceuticals. Of special interest but largely underdeveloped are reactions where dearomatization occurs concomitantly with introduction of functionality. Oxidative dearomatization reactions are transformations of extraordinary potential in synthesis, but which remain as an unsolved problem outside of biotechnological domains. We aim at addressing this problem by using iron and manganese catalysts employ peroxides (preferentially hydrogen peroxide) as the terminal oxidant. The high electrophilicity of hypervalent iron and manganese oxo species is made instrumental by natural systems in order to overcome the inert character of arenes. By employing biomimetic catalysts that operate via the same type of hypervalent metal-oxo species, we envision to reproduce the desired reactivity under very mild reaction conditions, avoiding or limiting overoxidation reactions.

Representative publications

N. Choukairi Afailal, M. Borrell, M. Cianfanelli, M. Costas. J. Am. Chem. Soc. 2024, 146, 240-249 [doi]

Iron catalyzed carbene transfer reactions

The iron catalyzed carbene/carbenoid transfer to C(sp3)-H bonds has been developed only to a modest extent. Functionalization of strong C−H bonds in both stoichiometric and catalytic fashion have been described but applying harsh reaction conditions. Most importantly, these studies pinpoint to high energetic barriers for the iron mediated C(sp3)−H insertion reactions, which have limited the scope to relatively weak C−H bonds. We have recently developed iron complexes that in combination with a lithium salt activate under mild conditions (room temperature) azoesters, producing iron carbene species that selectively insert into strong C-H bonds (tertiary, secondary and even primary C-H bonds). Our research interest is the development of these catalysts and reactions into enantioselective C-H functionalization tools.

Representative publications

A. Hernán-Gómez, M. Rodríguez, T. Parella, M. Costas. Angew. Chem. Int. Ed. 2019, 58, 13904-13911 [doi]
M. Rodríguez, G. Font, J. Nadal-Moradell, A. Hernán-Gómez, M. Costas. Adv. Synth. Catal. 2020, 362, 5116-5123 [doi]
A. Conde, G. Sabenya, M. Rodríguez, V. Postils, J. M. Luis, M. M. Díaz-Requejo, M. Costas, P. J. Pérez. Angew. Chem. Int. Ed. 2016, 55, 6530-6534 [doi]
V. Postils, M. Rodríguez, G. Sabenya, A. Conde, M. M. Díaz-Requejo, P. J. Pérez, M. Costas, M. Solà, J. M. Luis. ACS Catal. 2018, 8, 4313-4322 [doi]