Morita Baylis Hillman Adducts Research Articles

Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Preparation of Light‐responsive Unnatural RNA Bases via a Chromogenic Morita‐Baylis‐Hillman Adduct Path

AbstractRNA‐based tools for biological and pharmacological research are raising an increasing interest. Among these, RNA aptamers whose biological activity can be controlled via illumination with specific wavelengths represent an important target. Here, we report on a proof‐of‐principle study supporting the viability of a systematic use of Morita‐Baylis‐Hillman adducts (MBHAs) for the synthesis of light‐responsive RNA building blocks. Accordingly, a specific acetylated MBHA derivative was employed in the functionalization of the four natural RNA bases as well as two unnatural bases (5‐aminomethyl uracil and 5‐methylaminomethyl uracil). The results reveal a highly selective functionalization for both unnatural bases. The conjugation products were then investigated spectroscopically, photochemically and computationally. It is shown that when a single light‐responsive unit is present (i. e. when using 5‐methylaminomethyl uracil), the generated unnatural uracil behaves like a cinnamic‐framework‐based photochemical switch that isomerizes upon illumination through a biomimetic light‐induced intramolecular charge transfer mechanism driving a barrierless and, therefore, ultrafast reaction path.

Chiral Phosphine Ligands of COAP and SKP Switched Regiodivergent Asymmetric Allylic Alkylation of MBH Adducts.

The palladium-catalyzed highly regioselective asymmetric allylic alkylation of 3'-indolyl-3-oxindole derivatives with Morita-Baylis-Hillman (MBH) carbonates was developed to facilely construct chiral 3,3'-bisindole derivatives under mild reaction conditions. The regioselectivity (α/γ) of MBH carbonates was efficiently switched in the presence of chiral oxalamide phosphine or spiroketal-based diphosphine/Pd(0) complexes as a chiral catalyst. A series of multifunctional 3,3'-bisindole derivatives with all-carbon quaternary stereogenic centers were obtained in high yields with good to excellent enantio-, diastereo-, and regioselectivity. The present process is endowed with some salient features such as broad substrate scope, N-protecting group-free, excellent stereoselectivity, as well as adjustable regioselectivity.

Pd/Zn Dual Catalysis for Site-, Enantio-, and Diastereo-Divergent 2-(Alkoxycarbonyl)allylation of α-Hydroxyketones with Morita–Baylis–Hillman Adducts

Pd/Zn Dual Catalysis for Site-, Enantio-, and Diastereo-Divergent 2-(Alkoxycarbonyl)allylation of α-Hydroxyketones with Morita–Baylis–Hillman Adducts

A Facile Access to Green Fluorescent Albumin Derivatives.

A Morita-Baylis-Hillman Adduct (MBHA) derivative bearing a triphenylamine moiety was found to react with human serum albumin (HSA) shifting its emission from the blue to the green-yellow thus leading to green fluorescent albumin (GFA) derivatives and enlarging the platform of probes for aggregation-induced fluorescent-based detection techniques. A possible interaction of MBHA derivative 7 with a lipophilic pocket within the HSA structure was suggested by docking studies. DLS experiments showed that the reaction with HSA induce a conformational change of the protein contributing to the aggregation process of GFA derivatives. The results of investigations on the biological properties suggested that GFA retained the ability of binding drug molecules such as warfarin and diazepam. Finally, cytotoxicity evaluation studies suggested that, although the MBHA derivative 7 at 0.1 μg/mL affected the percentage of cell viability in comparison to the negative control, it cannot be considered cytotoxic, whereas at all the other concentrations≥0.5 μg/mL resulted cytotoxic at different extent.

Aza-[4 + 2] annulations of α-vinyl Morita–Baylis–Hillman adducts for regiodivergent synthesis of exomethylene-bearing azatricyclic compounds

The regiodivergent synthesis of exomethylene-bearing azatricyclic products was achieved via aza-[4 + 2] annulations of cyclic imines with a single C4 synthon, the α-vinyl MBH adduct.

Ionic liquid Supported Quinuclidine Catalyzed Morita-Baylis-Hillman Reaction

Abstract: The Morita-Baylis-Hillman (MBH) reaction is an important method for forming carboncarbon bonds between carbonyl-containing compounds and activated olefins. However, the slow reaction rate with electron-rich electrophilic partners has limited its wider use. To overcome this drawback, the effects of pyridinium-based ionic liquids mediated quinuclidine catalytic system for MBH reactions were studied. The method is simple, involving neat and open-flask conditions, and is compatible with a wide range of reagents. We offered general pyridinium-based ionic liquids-mediated quinuclidine catalysis mechanism that is responsible for the observed rate increase. The synthetic versatility of the MBH adducts is demonstrated by the synthesis of important building blocks for the natural product (-)-sitophilure. The authors anticipate that this pyridinium-based ionic liquids-mediated quinuclidine protocol could serve as a general methodology for the MBH reaction. In summary, the study presents a simple and effective method to enhance the reaction rate of the MBH reaction. The authors believe this method has the potential for broader applications and may contribute to developing new synthetic strategies for organic synthesis. We successfully recycled the catalytic system up to 7 runs without losing any catalytic activity.

N-Boc-Amino Acid Mediated Morita-Baylis Hillman reaction of methylphenyl glyoxylate

The organocatalyzed Morita-Baylis Hillman (MBH) reaction of α-keto esters is a challenging carbon-carbon bond-forming reaction. We developed a catalytic system for the MBH reaction of methylphenyl glyoxylate with methyl vinyl ketone in a polar aprotic solvent. We used N-Boc-L-pipecolinic acid as a proton transfer mediator and 4-dimethylaminopyridine as the tertiary amine catalyst. We obtained the MBH adduct with a 66% yield in 48h. We proposed a detailed reaction mechanism involving a transition state that includes the hydrogen transfer by the acid functional group of N-Boc-L-pipecolinic acid.

Palladium-Catalyzed Regioselective Asymmetric Chemodivergent Allylation of Oxazolones with Morita–Baylis–Hillman Adducts

Palladium-Catalyzed Regioselective Asymmetric Chemodivergent Allylation of Oxazolones with Morita–Baylis–Hillman Adducts

Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines.

Substrate-controlled diversity-oriented synthesis of polycyclic frameworks via [4 + 2] and [3 + 2] annulations between ninhydrin-derived Morita-Baylis-Hillman (MBH) adducts and 3,4-dihydroisoquinolines under similar reaction conditions have been developed. The reaction provides diversity-oriented synthesis of a series of novel and structurally complex spiro multi heterocyclic skeletons in good yields (up to 87% and 90%, respectively) with excellent diastereoselectivities (up to >25:1 dr). In particular, the switchable [4 + 2] and [3 + 2] annulation reactions are controlled by tuning the hydroxyl protecting group on the ninhydrin-derived MBH adduct to deliver structural diverse spiro[indene-2,2'-[1,3]oxazino[2,3-a]isoquinoline] and spiro[indene-2,1'-pyrrolo[2,1-a]isoquinoline], respectively. Furthermore, the relative configuration and chemical structure of two kinds of cycloadducts were confirmed through X-ray diffraction analysis.

Biological Activities of Morita-Baylis-Hillman Adducts (MBHA).

The Morita-Baylis-Hillman reaction (MBHR) is considered one of the most powerful and versatile methodologies used for carbon-carbon bond formation. The reaction is defined as the condensation between an electrophilic carbon sp² and the α position of an olefin, carrying an electron-withdrawing group, in the presence of a catalyst. The advantages of the reaction are the high atom economy and mild reaction conditions. Under ideal conditions, this reaction leads to the formation of multifunctional products, called Morita-Baylis-Hillman adducts (MBHA), a class of relevant molecules that exhibit a variety of biological activities. Considering the importance of these compounds, this review brought together several studies regarding the biological activities of MBHA, to point out the use of these molecules as future therapeutic agents. We searched for scientific articles available in the main databases, published between 1999 and 2022, using the descriptors: Morita-Baylis-Hillman adducts, Morita-Baylis-Hillman reaction, biological activity, and biological potentiality. Thirty-five articles showed the variety of biological activities of MBHA, including molluscicidal, antitumor, herbicidal, and fungicidal, antileishmanial, antioxidant, antimalarial, anti-tumor inflammatory, vasorelaxant, antichagasic, antimicrobial, and anti-inflammatory activities. Therefore, these compounds are promising candidates to become drugs for the treatment of a variety of diseases, following further studies to understand the effective mechanisms of action of MBHA.

Synthesis, photophysical and photochemical features of a Morita-Baylis-Hillman adduct derivative bearing a triphenylamine moiety

A new Morita-Baylis-Hillman Adduct (MBHA) derivative 7 was designed and synthesized to obtain a reactive molecule potentially capable of labelling basic amino acid residues. Compound 7 was easily prepared and characterized from the point of view of its photophysical and photochemical features before then to be used in labelling experiments with amino acid.

Assessment of Morita-Baylis-Hillman adducts as novel modulators of quorum sensing phenotypes in Chromobacterium CV026 by targeting CviR

This work presents Morita-Baylis-Hillman adducts (MBHA) as new modulators of the violacein biosynthesis in the biosensor strain Chromobacterium CV026. Seven adducts displayed violacein reduction higher than 50±1% when tested at concentrations lower than 625 μM. The most active MBHA inhibited hydrolysis of chitin concomitantly with inhibition of violacein production in CV026, suggesting the disruption of its QS machinery. One MBHA induced the violacein biosynthesis in CV026 in the absence of the cognate AI, also supporting its role as a QS modulator of this QS system. Further, RT-qPCR and competition experiments characterize these two molecules as transcriptional modulators of the QS-regulated operon vioABCDE. Blind docking studies for MBHA showed a strong preference for adducts positioned within the CviR autoinducer-binding domain (AIBD). Our results show MBHA as a promising chemical scaffold for the development of novel QS inhibitors affecting LuxR/LuxI-systems.

Renewable synthesis of novel acrylates from biomass‐derived 5‐substituted‐2‐furaldehydes by Morita‐Baylis‐Hillman reaction

AbstractBiomass‐derived furfurals are becoming increasingly popular as renewable chemical building blocks for synthesizing specialty chemicals. Morita‐Baylis‐Hillman (MBH) reaction is a classic carbon‐carbon bond‐forming transformation between the α‐position of an activated alkene and a carbon electrophile (e. g., aldehyde) using a nucleophilic catalyst, such as a tertiary amine or phosphine. The MBH reaction is highly atom economical, affords excellent yields of adducts under mild reaction conditions, introduces substantial molecular complexity, and enjoys broad substrate scope. In this work, several novel MBH adducts have been synthesized starting from biomass‐derived 5‐substituted‐2‐furaldehydes and acrylates using 1,4‐diazabicyclo[2.2.2]octane (DABCO) as the organocatalyst. This work reports the first systematic study of the MBH reaction of 5‐substituted‐2‐furaldehydes and acrylates. A general synthetic protocol for the high‐yielding synthesis of MBH adducts has been developed. The reactions were performed at room temperature under solvent‐free conditions, and the spectroscopically pure products were produced in good to excellent isolated yields. Moreover, DABCO was recovered from the reaction mixture and successfully recycled.

Comparison between Chemoenzymatic and Bienzymatic Cascades Leading to Morita–Baylis–Hillman Adducts

AbstractChemoenzymatic and bienzymatic cascades offer advantages including increasing diversity of reactions and saving time and operational costs. Herein the oxidation of benzylic alcohols to the corresponding aldehydes coupled with the Morita−Baylis−Hillman (MBH) reactions in biocatalytic compatible potentially ‘green’ conditions has been exemplarily evaluated. One‐pot cascades avoiding the use of reactive aldehyde intermediates are described and compared, including a sequential chemoenzymatic cascade with a variant of galactose oxidase (GOase M3–5) and 1,4‐Diazabicyclo [2.2.2] octane (DABCO), a concurrent dual‐enzyme cascade with GOase M3–5 and a variant of the computationally designed enzyme MBHase (BH32.14), and finally a whole cell biotransformation with the co‐expression modules of the two enzymes. All of the cascades were performed on a diverse range of substrates (12–19 examples), affording moderate to high conversions (up to 93 %) and isolated yields (up to 80 %). The bienzymatic cascades offer optically active products in up to 91 % ee. Key factors affecting the chemoenzymatic and the bienzymatic cascades were highlighted, and the advantages and challenges were compared.

Recent advances in the synthetic applications of Morita-Baylis-Hillman and Rauhut-Currier adducts of nitroalkenes.

The Morita-Baylis-Hillman (MBH) and Rauhut-Currier (RC) adducts of nitroalkenes are important synthetic intermediates in organic synthesis. This review discusses the applications of different MBH and RC adducts of nitroalkenes such as MBH alcohols, acetates, bromides and hydrazinonitroalkenes as well as ketoalkylnitroalkenes in the synthesis of complex molecules including carbocycles and heterocycles. It also covers the mechanistic aspects, including the key intermediates and the reaction pathways. Early reports on MBH and RC reactions of nitroalkenes and applications of the products were covered in previous reviews. The present review covers the reports that appeared in the timeline of 2015-2023.

Diisobutylaluminium hydride mediated efficient synthesis of Morita–Baylis–Hilman adducts through α‐functionalization of alkyl propiolates

AbstractGenerally, oxindole derivatives are biologically important molecules and valuable building blocks in organic synthesis. Herein, we report a diisobutylaluminium hydride mediated efficient one‐pot synthesis of oxindole derivatives using N‐substituted isatins with methyl or ethyl propiolates at lower temperature (−78°C) through Morita‐Baylis‐Hillman (MBH) reaction. Within a short reaction time, a wide range of N‐alkyl or N‐aryl 3‐hydroxy oxindole derivatives (MBH adducts) were easily accessed in excellent yields under mild reaction conditions.

A New MBH Adduct as an Efficient Ligand in the Synthesis of Metallodrugs: Characterization, Geometrical Optimization, XRD, Biological Activities, and Molecular Docking Studies

This article reports the synthesis, characterization, geometrical optimization, and biological studies of new MBH-based organometallic compounds of medicinal significance. The ligand (MNHA) was prepared via the Morita-Baylis-Hillman (MBH) synthetic route, from aromatic aldehyde containing multiple functional groups. Metal complexes were prepared in an alkaline medium and under other suitable reaction conditions. Spectral and elemental analyses were used to identify the structural and molecular formulas of each compound. Optimized geometry was determined through density functional theory (DFT) B3LYP and 6-311++ G (d,p) basis set for the MBH adduct, whereas structures of novel complexes were optimized with the semi-empirical PM6 method. Powder XRD analysis furnished the crystal class of complexes, with Co3+, Cr3+, and Mn2+ being cubic, while Ni2+ was hexagonal, and Cu2+ was orthorhombic. Moreover, the ligand, along with Ni2+ and Co3+ complexes, showed profound antibacterial action against S. aureus, E. coli, B. pumilis, and S. typhi. Additionally, all of the complexes were shown to persist in the positive antioxidant potential of the ligand. Contrarily, not a single metal complex conserved the antifungal potentials of the ligand.

Lipase-Catalysed Enzymatic Kinetic Resolution of Aromatic Morita-Baylis-Hillman Derivatives by Hydrolysis and Transesterification.

Acylated Morita-Baylis-Hillman (MBH) adducts were synthesised and subjected to enzymatic kinetic resolution (EKR) by hydrolysis employing various lipase enzymes: from P. fluorescens, P. cepacia (PCL), C. antarctica A (CAL-A), C. antarctica B (CAL-B) and Novozyme 435. In a number of instances enantiopure Morita-Baylis-Hillman acetates or butyrates and their corresponding hydrolysed MBH adducts were obtained with ee values of >90 %, at ca. 50 % conversion, corresponding to enantiomeric ratio (E) values of >200. Enantioselective transesterification reactions on MBH adducts was achieved using acyl anhydrides in THF or the greener organic solvent 2-MeTHF in the presence of CAL-A. This is the first report of successful lipase-catalysed EKR of aromatic MBH adducts by transesterification in organic medium.

Synthesis, Characterization, Biological Activities and Ab-initio Study of Transition Metal Complexes of [Methyl 2-((4-chlorophenyl)(hydroxy)methyle) Acrylate

Taking cognizance of the medicinal significance and diverse functions of synthetic Morita-Baylis-Hillman adducts (MBHA), the title ligand was synthesized and purified through column chromatography. Cr+3, Mn+2, Co+3, Ni+2, Cu+2 complexes of the ligand were synthesized under basic conditions, subjected to characterization through spectral analyses and verified with the IR spectrum that was generated computationally by the DFT B3LYP method, with 6-311++ G (d,p) basis set and Hartree Fock (HF) B3LYP method in conjunction with 3-21G(d,p) basis set. Powder XRD helped to testify crystals of the complexes. Moreover, the antibacterial, and antioxidant characteristics of MBHA and its complexes were also established. All of them were found to be active antioxidants. The antibacterial activities, examined against S. aureus, E. coli, B. pumilis and S. typhi have revealed that its Cobalt complex has an excellent potential to act against all of them. Hence, these compounds maybe having potentialities for the discovery of new, cheaper and efficient drugs against various infectious diseases. The study also uncovers the first example of utilization of MBHA towards metal complex formation.