Molecular Sciences

Sustainable Metal Catalysis

The work carried out by the Sustainable Metal Catalysis research group is focused on the development of new application methodologies in organic synthesis within the context of sustainable catalysis. It seeks to develop new methodological processes within a more sustainable chemical context. These synthetic methodologies are applied in the synthesis of natural products, derivatives or fragments thereof. All the products generated, both in the development of new methodologies and in the synthesis of natural products, are submitted to biological evaluation in real time.

The Sustainable Metal Catalysis group profile page on Digital.CSIC.

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Presentacion
Presentation

In our group we have initiated a line of research within the Institute of Natural Products and Agrobiology based on sustainable metal catalysis. We are looking for the development of new methodological processes within a more sustainable chemical context. Likewise, these synthetic methodologies are applied in the synthesis of natural products, derivatives or fragments of these.

All the products generated, both in the development of new methodologies and in the synthesis of natural products, are submitted to biological evaluation in real time. This project is carried out together with the research group of Professor Víctor S. Martín of the University Institute of Bio-Organics of the University of La Laguna.

The research group is focused on the development of new application methodologies in organic synthesis within the context of sustainable catalysis. One of the possibilities in this field is the search for complexes, capable of exerting a catalytic action, in which the metallic atom has a greater availability, and which is also environmentally neutral.

This is the field of sustainable metal catalysis, in which a specific group of metals plays a leading role, such as calcium, magnesium, manganese, iron, cobalt, nickel, copper, zinc and molybdenum. The developed methodologies are used in the synthesis of oxa- and azazycles of different sizes (from small rings to medium size rings). Subsequently, the methodologies developed in the synthesis of both natural and analogous products with possible biological activity are applied. These heterocycles have been obtained using the Prins cycle as a central reaction and Fe(III) salts as a sustainable metallic catalyst.

The interest and use of Fe(III) salts as catalysts in organic chemistry has grown exponentially in recent years. There has been a great demand for methods that are chemically more sustainable and environmentally benign. The use of these Fe(III) salts is characterized by their low cost and low pollutant character.

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Fig1

Synthesis of six-member oxacicles

First, the synthesis of differently substituted tetrahydropyrans and dihydropyrans was carried out using stoichiometric amounts of iron. We observe that the salts of Fe(III) catalyze the classical Prins reaction, using both homoalyl alcohols and homoalyl tosylamines. Subsequently these...

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Fig.3

Synthesis of five-member oxacicles

Excellent cycling between 2-hydroxy homoalyl tosyl amine and aldehydes in the presence of iron(III) salts has been achieved to give very good yield 3-alkyl-1-tosyl pyrrolidines.

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Fig.4

Synthesis of seven-member oxacicles

The cycling of prins between bis-homoalyl alcohols and aldehydes catalyzed by Fe(III) salts has shown an excellent selectivity in the formation of seven-member oxacicles (oxepanes) cis-2,7-disubstituted.

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Fig.5

Toll type 4 receptor chemistry programming: Design, synthesis and biological studies of prostate cancer vaccines

The immune system is an essential element in the defence of the organism against microbial infections, as well as in the control and surveillance of malignant neoplasms. Immune cells scan different tissues in order to eliminate possible malignant cells before they become tumours. Immune cells...

Catálisis sostenible. Síntesis de azaciclos de tamaño medio (TFM)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Daniel Alejandro Cruz Perdomo

Tipo:Máster y TFG

Formación de enlaces C-C usando ácidos de Lewis. Aplicaciones de los haluros de Fe(III). (DEA)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Pedro Oswaldo Miranda Chinea

Tipo:Máster y TFG

Aplicación de las Sales de Fe (III) en la formación de enlaces C-C. Síntesis de anillos piránicos via reacción de Prins. Estudios sintéticos de éteres bioactivos de origen marino

Año:2019
Director del trabajo:

Víctor S. Martín, M. A. Ramírez y Juan I. Padrón

Estudiante:

Pedro Oswaldo Miranda Chinea

Tipo:Tesis doctoral

Síntesis de oxaciclos de tamaño medio (TFM)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Juan Miguel López Soria

Tipo:Máster y TFG

La ciclación de Prins y la hidrobromación regioselectiva de alquenos bajo el paradigma de la catálisis metálica sostenible

Año:2019
Director del trabajo:

Juan I. Padrón y Víctor S. Martín

Estudiante:

Daniel Alejandro Cruz Perdomo

Tipo:Tesis doctoral

Estudios Estereoquímicos de Sacáridos en disolución

Año:2019
Director del trabajo:

Juan I. Padrón y Jesús T. Vázquez

Estudiante:

Alfredo Röen Martín

Tipo:Tesis doctoral

Aplicación de la ciclación de Prins en la síntesis de Tetrahidropiranos fusionados (DEA)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Sixto Pérez Moreno

Tipo:Máster y TFG

Desarrollo de nuevas metodologías catalizadas por sales de hierro(III) y su aplicación en la síntesis de oxa-y azaciclos

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Sixto J. Pérez Moreno

Tipo:Tesis doctoral

Síntesis de trans-pirrolidinas y trans-prolinas a través de hidroaminación intramolecular catalizada por sales de hierro (III). (TFM)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

María Victoria Sinka

Tipo:Máster y TFG

Cloruro de Fe(III) en la formación de enlaces C-C aplicado a la sínteis de tetrahidrofuranos (DEA)

Año:2019
Director del trabajo:

Juan I. Padrón y Víctor S. Martín

Estudiante:

Martín Alejandro Purino

Tipo:Máster y TFG

Desarrollo y estudios mecanísticos de nuevos procesos catalizados por sales de Fe(III)

Año:2019
Director del trabajo:

Juan I. Padrón y Víctor S. Martín

Estudiante:

Martín Alejandro Purino

Tipo:Tesis doctoral

Aproximación a la síntesis de alcaloides pirrolidínicos mediante el uso de las sales de hierro (TFG)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Juan Daniel Cabrera García

Tipo:Máster y TFG

Desarrollo de nuevas metodologías en la formación de enlaces Carbono-Carbono empleando sales de Hierro (III) y su aplicación en la síntesis de aza-ciclos (DEA)

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Rubén Marrero Carballo

Tipo:Máster y TFG

Desarrollo de nuevas metodologías en la formación de enlaces carbono-carbono empleando sales de Hierro (III) y su aplicación en la síntesis de aza-ciclos

Año:2019
Director del trabajo:

Víctor S. Martín y Juan I. Padrón

Estudiante:

Rubén Marrero Carballo

Tipo:Tesis doctoral
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MEC

Química sostenible: de moléculas pequeñas a sistemas funcionales complejos

Investigador principal:

Juan I. Padrón

Víctor S. Martín

Estado:

En Ejecución

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acisii

Síntesis de oxocenos presentes en la ciguatoxina por procesos benignos con el medioambiente

Investigador principal:

Juan I. Padrón

Víctor S. Martín

Estado:

En Ejecución

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MEC

Síntesis orgánica bajo el paradigma de la sostenibilidad

Investigador principal:

Víctor S. Martín

Estado:

Finalizado

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7

Programación química de receptores Toll tipo 4: Diseño, síntesis y estudios biológicos de vacunas contra el cáncer de próstata

Los TLR constituyen un elemento clave del sistema inmunitario, ya que se expresan en células inmunitarias innatas y ayudan a reconocer los patógenos invasores. En…

Investigador principal:

Juan I. Padrón

Estado:

Finalizado

Proyecto de investigación

Generación de diversidad esqueletal en lupanos como herramienta en la búsqueda de nuevos agentes anticancerosos

Investigador principal:

Rubén Marrero Carballo

Juan I. Padrón Peña

Estado:

Finalizado

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MEC

Síntesis de nuevas entidades químicas para cartografiar la bioactividad en el espacio químico

Investigador principal:

Víctor S. Martín García

Estado:

Finalizado

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Gobierno de Canarias

Diseño, síntesis y evaluación citotóxica de nuevos antitumorales basados en farmacóforos de piranos y aza-ciclos

Investigador principal:

Juan I. Padrón

Estado:

Finalizado

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MEC

Desarrollo de nuevos procesos catalíticos dirigidos a la síntesis de moléculas bioactivas

Investigador principal:

Víctor S. Martín García

Estado:

Finalizado

Proyecto de investigación

Diseño, síntesis y evaluación citotóxica de nuevos antitumorales basados en farmacóforos de piranos y aza-ciclos. Proyectos Intramurales (CSIC)

Investigador principal:

Juan I. Padrón

Estado:

Finalizado

Selected Publications

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Iron-Catalyzed Prins-Peterson

Iron-Catalyzed Prins-Peterson Reaction for the Direct Synthesis of δ4-2,7-Disubstituted Oxepenes

A direct iron(III)-catalyzed Prins-Peterson reaction involving α-substituted γ-triphenylsilyl bis-homoallylic alcohols and aldehydes is described. Thus, cis--2,7-disubstituted oxepenes were synthesized in a diastereoselective reaction using sustainable catalytic conditions (3-5 mol %). This highly productive process is the result of a cascade of three chemical events with the concomitant formation of a C-O bond, a C-C bond, and a endocyclic double bond, through a Prins cyclization followed by a Peterson-type elimination. This tandem reaction is chemoselective vs the classical Prins cyclization.

Cruz, Daniel A.; Sinka, Victoria; Martín, Víctor S.; Padrón, Juan I.

Journal of Organic Chemistry 83: 12632-12647 (2018)
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Direct Access to 2,3,4,6-Tetrasubstituted

Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem SN2′–Prins Cyclization

A new, direct, and diastereoselective synthesis of activated 2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans is described. In this reaction, iron(III) catalyzed an SN2′–Prins cyclization tandem process leading to the creation of three new stereocenters in one single step. These activated tetrahydro-2H-pyran units are easily derivatizable through CuAAC conjugations in order to generate multifunctionalized complex molecules. DFT calculations support the in situ SN2′ reaction as a preliminary step in the Prins cyclization.

Scoccia, Jimena; Pérez, Sixto J.; Sinka, Victoria; Cruz, Daniel A.; López-Soria, Juan M.; Fernández, Israel; Martín, Víctor S.; Miranda, Pedro O. ; Padrón, Juan I.

Organic Letters 19(18): 4834-4837 (2017)
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Enantiodivergent Synthesis of (+)- and (-)-Pyrrolidine 197B

Enantiodivergent Synthesis of (+)- and (-)-Pyrrolidine 197B: Synthesis of trans-2,5-Disubstituted Pyrrolidines by Intramolecular Hydroamination

A highly efficient, diastereoselective, iron(III)‐catalyzed intramolecular hydroamination/cyclization reaction involving α‐substituted amino alkenes is described. Thus, enantiopure trans‐2,5‐disubstituted pyrrolidines and trans‐5‐substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l‐α‐amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)‐ and (−)‐pyrrolidine 197B alkaloids from l‐glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation.

Pérez, Sixto J.; Purino, Martín; Cruz, Daniel A.; López-Soria, Juan M.; Carballo, Ruben M.; Ramírez, Miguel A.; Fernández, Israel; Martín, Víctor S.; Padrón, Juan I.

Chemistry-A European Journal 22(43): 15529-15535 (2016)
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Prins Cyclization Catalyzed by a Fe(III)/TMS System: the Oxocarbenium Ion Pathway versus the [2+2] Cycloaddition

The different factors that control the alkene Prins cyclization catalyzed by iron(III) salts have been explored by means of a joint experimental–computational study. The iron(III) salt/trimethylsilyl halide system has proved to be an excellent promoter in the synthesis of crossed all‐cis disubstituted tetrahydropyrans, minimizing the formation of products derived from side‐chain exchange. In this iron(III)‐catalyzed Prins cyclization reaction between homoallylic alcohols and non‐activated alkenes, two mechanistic pathways can be envisaged, namely the classical oxocarbenium route and the alternative [2+2] cycloaddition‐based pathway. It is found that the [2+2] pathway is disfavored for those alcohols having non‐activated and non‐substituted alkenes. In these cases, the classical pathway, via the key oxocarbenium ion, is preferred. In addition, the final product distribution strongly depends upon the nature of the substituent adjacent to the hydroxy group in the homoallylic alcohol, which can favor or hamper a side 2‐oxonia‐Cope rearrangement.

Pérez, Sixto J.; Purino, Martín; Miranda, Pedro O.; Martín, Víctor S.; Fernández, Israel; Padrón, Juan I.

Chemistry - A European Journal 21(43): 15211-15217 (2015)
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Iron Catalyzed

Iron(III) Catalyzed Direct Synthesis of cis-2,7-Disubstituted Oxepanes. The Shortest Total Synthesis of (+)-Isolaurepan

Prins cyclization of bis-homoallylic alcohols with aldehydes catalyzed by iron(III) salts shows excellent cis selectivity and yields to form 2,7-disubstituted oxepanes. The iron(III) is able to catalyze this process with unactivated olefins. This cyclization was used as the key step in the shortest total synthesis of (+)-isolaurepan.

Purino, Martín A.; Ramírez, Miguel A.; Daranas, Antonio: Martín, Víctor; Padrón, Juan I.

Organic Letteer 14(23): 5904-5907 (2012)
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A new catalytic prins

A New Catalytic Prins Cyclization Leading to Oxa- and Azacycles

A new Prins cyclization process that builds up one carbon−carbon bond, one heteroatom-carbon bond, and one halogen-carbon bond, (in an oxa- and azacycle) relies on an iron catalyst system formed from Fe(acac)3 and trimethylsilyl halide. The method displays a broad substrate scope and is economical, environmentally friendly, and experimentally simple. This catalytic method permits the construction of chloro, bromo and iodo heterocycles, by the suitable combination of iron(III) source, the corresponding trimethylsilyl halide and the solvent, in high yields.

Miranda, Pedro O.; Carballo, Ruben M.; Martín, Víctor S.; Padrón, Juan I.

Organic Letters 11(2): 357-360 (2009)

Collaborations

Dr. I. Fernández
Departamento de Química Orgánica I, Facultad de Ciencias Químicas
Universidad Complutense de Madrid, 28040 Madrid (Spain)
E-mail: israel [at] quim.ucm.es


Dr. R. M. Carballo
Laboratorio de Química Farmacéutica, Facultad de Química
Universidad Autónoma de Yucatán, C/41, nº421x26 y 28
97150 Mérida, Yucatan (México)