Mascareñas / López / Gulías

Our current research program deals with two main topics:

Synthesis and catalysis: discovery and development of innovative catalytic methodologies.

Chemical biology and biomedicine: a) synthesis of molecular systems to interfere with and/or sense biological processes, b) development of novel biomedical tools; c) merging metal catalysis with cell biology.

Along recent years we have made many advances in fundamental science in both topics. As a result, between 2000 and 2020 we have published many articles in high profile journals, including 3 in Nature Comm., 23 in Angewandte Chemie, 23 in the J. Am. Chem. Soc., 15 in Chem. Sci. and 7 in ACS Catalysis. In addition, we have increased our tech transfer activities, as demonstrated by the presentation of up to 21 patent applications.

Part of the recent results are aligned with the project METBIOCAT, funded with an ERC ADVANCED GRANT (2014-2020). Further information at our website: http://www.metbiocat.eu.

Prof. José L. Mascareñas, Dr. Fernando López and Dr. Moisés Gulías

Modern organic synthesis is more than getting to the target at any cost. Therefore, a great part of our efforts in this topic are focused on the invention of unconventional annulation strategies based on transition metal catalysts, which allow to transform simple and readily accessible substances into cyclic, target-relevant products. We have paid an increased emphasis on reactions that activate otherwise inert C-C and C-H bonds, owing to their innovative and synthetic potential, and on the discovery of enantioselective variants. Some representative examples:

1. Carbophilic metal catalysis: Access to relevant carbo- and heterocyclic structures (F. López and J. L. Mascareñas)

We have demonstrated the potential of platinum and gold catalysts for promoting novel annulations using allenes as key reaction partners, to produce substituted cyclohexanes, cyclobutanes, 5,7-bicyclic systems, 2,6-disubstituted tetrahydropyrans, highly substituted piperidines or aza-bridged medium-sized carbocycles (e.g. tropanes).

J. Am. Chem. Soc., 2018, 140, 16821 (See also: Acc. Chem. Res., 2019, 52, 465, Chem Sci., 2020, 11, 4209-4220, Angew. Chem. Int. Ed., 2020, 59, 20049-20054)

We also applied one of methods for a highly efficient, versatile and enantioselective synthesis of Englerin A, a complex natural product that has attracted great interest as antitumoral agent.

Angew. Chem. Int. Ed., 2016, 55, 14359

2. C-C bond activation: Metal catalyzed annulations with strained cyclic systems (F. López and J. L. Mascareñas)

A long-standing research line in the group dealing with the activation of alkylidencyclopropanes. Recently, we have developed novel palladium and cobalt- catalyzed enantioselective cycloadditions using alkylidenecyclopropanes as three-carbon partners, to build 5,5 and 5,7-bibyblic systems with high ee’s.

ACS Catalysis, 2018, 8, 6100  (See also: Angew. Chem. Int. Ed., 2010, 49, 9886 and Chem. Eur. J., 2014, 20, 10255); ACS Catal., 2020, 10, 7710-7718; Angew. Chem. Int. Ed., 2021, early view

3. Cyclizations based on metal catalyzed C-H activations (F. López, M. Gulías and J. L. Mascareñas)

We have discovered iridium-catalyzed intramolecular hydroalkenylation processes that allow the formation of synthetically relevant cyclic structures bearing quaternary carbon stereocenters. The method has been extended to the hydrocarbonation of alkynes.

Angew. Chem. Int. Ed., 2017, 56, 9541-9545. ACS Catal., 2018, 8, 7397–7402

4. Formal cycloadditions based on C-H activation reactions (M. Gulías and J. L. Mascareñas)

We have invented a number of methodologies to assemble biorelevant heterocyclic scaffolds through formal cycloadditions that involve a metal catalyzed C-H activation step. We have also discovered asymmetric variants, which is one of the emerging topics in the area.

     Angew. Chem. Int. Ed., 2019, 58, 1700     Angew. Chem. Int. Ed., 2018, 57, 8255      J. Am. Chem. Soc., 2014, 136, 834 and J. Am. Chem. Chem. Soc., 2014, 136, 7607           J. Am. Chem. Soc., 2019, 141, 1862    Angew. Chem. Int. Ed., 2015, 54, 2374

Angew. Chem. Int. Ed., 2020, 59, 9149-9154

Intramural collaborations:

CiQUS PI Prof. Eugenio Vázquez: development of new metal-based alternatives to bind DNA, RNA and proteins (Chem. Sci., 2019, 10, 8668-8674)

CiQUS PI Dr. Javier Montenegro: development of tactics to control the cellular uptake of anions (Chem. Sci., 2019, 10, 8930-8938)

2. Transition metal catalysis at the interphase with cell biology (J. L. Mascareñas and F. López)

Under the umbrella of the ERC Adv Grant MetBioCat we are demonstrating that transition metal complexes can achieve catalytic transformations in biological media and even inside live cells.

In this sense, we have for instance described a reaction involving a carbon–carbon bond cyclization using a gold catalyst. The process is highly bioorthogonal, biocompatible, and can be efficiently carried out inside living mammalian cells, representing a significant addition to the toolbox of life compatible transformations. Additionally, a significant accomplishment was to demonstrate that this gold-promoted reaction can be coupled to another metal-promoted process, namely, a ruthenium promoted deallylation, both in a bioorthogonal and mutually orthogonal manner.

Nature Commun., 2018, 9, 1913

In one of our later studies, we developed hydride-transfer catalytic processes, promoted by Ru(IV) complexes, inside live cells. This has led to the first metal-catalyzed isomerization reaction described in the literature for “in cellulo” settings. This work revealed that typical intermediates of catalytic organometallic reactions, including ruthenium-hydride complexes, can survive the crowded atmosphere of cell lysates or even living cells.

More recently, also using ruthenium catalysts, we have shown for the first time the viability of performing (2+2+2) multicomponent alkyne cycloaromatizations inside live mammalian cells. Using this procedure we have, for instance, generated intracellular products that otherwise cannot be delivered to the cell (i.e. anthraquinone AIEgens).

J. Am. Chem. Soc., 2019, 141, 5125-5129                      Angew. Chem. Int. Ed., 2020, 59, 17628-17633

We have also invented a new azide-alkyne click cycloaddition reaction, mediated by a ruthenium catalyst, which is biocompatible and biorthogonal, and mutually compatible with the classical CuAAC (RuAtAC).

Angew. Chem. Int. Ed., 2017, 56, 10766

Intramural collaborations:

CiQUS PI Dr. Pablo del Pino: exploring new catalytic nanomaterials in living settings (Cell Rep. Phys. Sci., 2020, 1, 100076)