Organic and Biological Chemistry
Our group focuses its research in organic synthesis, concentrating its efforts in new domino processes and organocatalysis. Our ethos is the design and development of new synthetic methodologies for efficient and sustainable molecular construction programs.
Research lines: Catalysis: the design and development of new sustainable and efficient organocatalytic systems based on the concept of a good nucleophile generates a strong base. Reactivity: the design and development of new synthetic methodologies oriented to the generation of structural diversity. Concept of pluripotent molecular platforms. Complexity: the design and development of new sustainable and efficient domino (cascade) processes for the generation of chemical complexity.
The Organic and Biological Chemistry group profile page on Digital.CSIC.
Our group develops its research using organic synthesis as an innovation axis and organocatalysis and domino chemistry (cascade processes) as vehicles for its development.
We are interested in the design and implementation of new domino methodologies for access to small molecules with chemical and/or biological relevance (new chemical entities), or to structural motifs of certain structural/functional complexity for their pharmacological study (drug discovery and development), for use as prototype of chemical probe (biological chemistry) or simply as molecular building block for use in organic synthesis (fine chemistry).
In recent years we have developed a domino methodology based on the propargyl Claisen rearrangement of propargyl vinyl ethers that has allowed us to access a significant number of molecular skeletons in a fast and instrumentally simple way, and in a way compatible with the protocols of synthesis oriented to diversity. An important aspect of our methodology is its innovative capacity.
In recent years we have developed a programme for the design and implementation of asymmetric and organocatalytic multicomponent reactions (domino reactions with more than two components) in water. As a reason for chirality transfer we use non-covalent chiral catalyst-substrate (or active intermediate) interactions compatible with the presence of water.
All our molecules are tested for biological activity and especially for antitumour activity.
We have developed catalytic systems based on the principle a good nucleophile generates a strong base. The use of this concept allows for the in situ generation of a catalytic amount of a strong base, precluding the necessity of preforming the base in a previous reaction step to preserve...
PhD & MSc. Thesis
Nueva Metodología para la Construcción Molecular Modular y Orientada a la Diversidad
1,4-Diinos terciarios activados. Nuevas plataformas para la generación de complejidad y diversidad estructural
Síntesis Estereoselectiva de Moléculas Bioactivas a Partir de Carbohidratos
Nuevas Metodologías Sintéticas Orientadas a la Diversidad
Master en Biomedicina, Especialidad en Diseño y Desarrollo Preclínico de Fármacos
1-4-DIÍNOS ACTIVADOS: PLATAFORMAS PARA LA GENERACIÓN DE DIVERSIDAD
Master de Investigación en Química. Intensificación Química Orgánica
Nuevas Metodologías Sintéticas Orientadas a la Diversidad
Éteres propargílicos vinílicos: plataformas para la generación de diversidad estructural
Reconocimiento Molecular: Diseño y Síntesis de una Nueva Familia de Módulos Estructurales. Síntesis Radicalaria de Carbociclos en Medios no Reductivos. Síntesis Formal de la (+)-Preusina: Un Nuevo Acceso A Pirrolidinas Quirales
Reacciones Multicomponente en Agua
Máster de Investigación en Química. Intensificación Química Orgánica
Productos naturales y sintéticos con actividades anticancerígenas, anticolesterolémicas y como revertidores de multiresistencia de fármacos
Antonio González González
- 19 January 2021
- 24 April 2020
- 20 December 2018
- 20 September 2018
Stereodiversified Modular Synthesis of Non‐planar Five‐Membered Cyclic N‐Hydroxylamidines: Reactivity Study and Application to the Synthesis of Cyclic Amidines
|A modular, stereodiversified and scalable synthesis of 5‐membered cyclic N‐hydroxylamidines endowed with three contiguous stereogenic centres is reported. The synthesis utilizes 2‐cyano‐3‐aryl‐4‐nitro‐alkynoates as key building blocks, which are provided by a novel 3‐component Knoevenagel ‐Michael addition manifold carried out as an aqueous emulsion (on water). The key building blocks are obtained as separable mixtures of two series of diastereomers: 2,3,4‐syn,syn and 2,3,4‐syn,anti. Both series were separately transformed into the corresponding 5‐membered 3,4,5‐trisubstituted N‐hydroxylamidines by a tandem hydrogenation cyclization reaction (stereodiversification phase). These N‐hydroxylamidines are functionalized at C3‐methinic position of the ring (alpha to the amidine function) by a robust and unprecedented N‐amidinoxyl radical‐mediated auto‐oxidation process (hydroxylation), or by a diastereoselective enamine‐based C−C bond forming manifold (creation of an all‐carbon quaternary centre). The outcome of the latter is biased by the relative disposition of substituents in the ring, affording C3‐quaternized 5‐membered cyclic N‐hydroxylamidines or 2,9‐diazabicyclo[4.3.0]non‐1‐en motives. Finally, the Ti(III)‐reduction of these quaternized N‐hydroxylamidines generates the corresponding amidines in excellent yields.|
Prieto-Ramírez, Mary Cruz; Fernández, Israel; Da Silva, Ivan; González-Platas, Javier; Armas, Pedro de; García-Tellado, Fernando
Synthesis and Utility of 2,2-Dimethyl-2 H-pyrans: Dienes for Sequential Diels-Alder/Retro-Diels-Alder Reactions
The practical use of 2,2-dimethyl-2H-pyrans as electron-rich dienes in sequential Diels−Alder/retro-Diels−Alder (DA/rDA) domino processes to generate aromatic platforms has been demonstrated. Different polysubstituted alkyl 2-naphthoates have been synthesized by the DA/rDA reaction of benzynes and 2,2-dimethyl-2H-pyrans. The use of other activated alkynes allows the access of substituted alkyl benzoate derivatives.
Tejedor, David; Díaz-Díaz, Abián; Diana-Rivero, Raquel; Delgado-Hernández, Samuel; García-Tellado, Fernando
Integrative Pericyclic Cascade: An Atom Economic, Multi C−C Bond‐Forming Strategy for the Construction of Molecular Complexity
An all‐pericyclic manifold is developed for the construction of topologically diverse, structurally complex and natural product‐like polycyclic chemotypes. The manifold uses readily accessible tertiary propargyl vinyl ethers as substrates and imidazole as a catalyst to form up to two new rings, three new C−C bonds, six stereogenic centers and one transannular oxo‐bridge. The manifold is efficient, scalable and instrumentally simple to perform and entails a propargyl Claisen rearrangement–[1,3]H shift, an oxa‐6π‐electrocyclization, and an intramolecular Diels–Alder reaction.
Tejedor, David; Delgado-Hernández, Samuel; Peyrac, Jesús; González-Platas, Javier; García-Tellado, Fernando
Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity-Oriented Synthesis
During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4–O–C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB′ three-component reaction for PVEs; A2BB′ four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, β,γ-unsaturated esters and acids, and fused polycycles. They can be transformed into more elaborated molecular skeletons by the use of chemical handles generated in their own domino reactions or by appending different functionalities to the pluripotent molecular platform (secondary reactivity principles).
Tejedor, David; López-Tosco, Sara ; Méndez-Abt, Gabriela; Cotos, Leandro; García-Tellado, Fernando
Microwave-Assisted Organocatalyzed Rearrangement of Propargyl Vinyl Ethers to Salicylaldehyde Derivatives: An Experimental and Theoretical Study
The microwave‐assisted imidazole‐catalyzed transformation of propargyl vinyl ethers (PVEs) into multisubstituted salicylaldehydes is described. The reaction is instrumentally simple, scalable, and tolerates a diverse degree of substitution at the propargylic position of the starting PVE. The generated salicylaldehyde motifs incorporate a broad range of topologies, spanning from simple aromatic monocycles to complex fused polycyclic systems. The reaction is highly regioselective and takes place under symmetry‐breaking conditions. The preparative power of this reaction was demonstrated in the first total synthesis of morintrifolin B, a benzophenone metabolite isolated from the small tree Morinda citrifolia L. A DFT study of the reaction was performed with full agreement between calculated values and experimental results. The theoretically calculated values support a domino mechanism comprising a propargyl Claisen rearrangement, a [1,3]‐H shift, a [1,7]‐H shift (enolization), a 6π electrocyclization, and an aromatization reaction.
Tejedor, David; Cotos, Leandro ; Márquez-Arce, Daniel; Odriozola-Gimeno, Mikel; Torrent-Sucarrat, Miquel; Cossío, Fernando P.; García-Tellado, Fernando
Water-compatible hydrogen-bond activation: A scalable and organocatalytic model for the stereoselective multicomponent aza-henry reaction
A study was conducted to demonstrate that H-bond based asymmetric organocatalysis can be performed under the so-called in the presence of water conditions. Nitroalkane, catalyst, dimethylcyclohexylamine, benzaldehyde and aniline were mixed to a 0°C cooled and vigorously stirred aqueous solution of NaOAc/AcOH saturated with NaCl. The organic residues were taken into dichloromethane and decanted off. The combined organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel) using a mixture of hexanes/ethyl acetate. From a synthetic point of view, the reaction furnishes enantioenriched b-nitroamines decorated with aromatic or aliphatic substituents at the amine center and a different set of alkyl chains or rings attached to the carbon bearing the nitro functionality. Importantly, the reaction can be scaled up without losing yield and stereoselectivity and with full recovery of the catalyst.
Cruz-Acosta, Fabio; Armas, Pedro de; García-Tellado, Fernando