Morita Baylis Hillman Adducts Research Articles

Domino Sequence of Ketimization and Electrophilic Amination for an Inverse Aza Intramolecular Morita-Baylis-Hillman Adduct.

Morita-Baylis-Hillman (MBH) reaction, typically catalyzed by a Lewis base, is a popular and useful method for C-C bond formation. Unfortunately, it is limited by a slow reaction rate and has sensitivity toward steric and electronic parameters. Despite tremendous efforts, the versatility of the reaction keeps the quest open for new mechanistic and catalytic pathways. Here, we have reported a Bro̷nsted acid-catalyzed, electrophilic amination (Umpolung of imine) as a method for an inverse Aza Intramolecular MBH adduct in the form of 2-acylindole. Umpolung of imine with nitrogen acting as an electrophilic center has been achieved. Interestingly, the reaction was also shown to occur under catalyst-free conditions also. The expected products of ketimine formation, 6π electrocyclization, or quinoline formation were least/not observed. A large number of examples have demonstrated the reaction strength. β-aryl-substituted acrylate and acrylamide (cinnamates and cinnamides), which are extremely sluggish in conventional MBH chemistry, are the highlights of the developed methodology. The annulated product exhibited keto-enol tautomerism, which was proven by 1H NMR integrals. As an application, another tandem reaction in the form of Michael addition on a highly complex amine was carried out to provide spiro-annulated indole.

A Formal [3+3] Annulation of Morita–Baylis–Hillman Ketones to Construct Pyrimidobenzothiazoles

AbstractA calcium triflate-promoted reaction of Morita–Baylis–Hillman (MBH) ketones, derived by the oxidation of MBH adducts, with 2-aminobenzothiazoles resulted in the formation of 4H-pyrimido[2,1-b]benzothiazoles. Formally, the transformation represents a [3+3] annulation and presumably proceeds via an aza-Michael addition followed by an intramolecular condensation. The reaction is completely regioselective and tolerates a wide range of substrates to afford a variety of analogues of the fused heterocycle in good yields.

Atroposelective Arene‐Forming Wittig Reaction by Phosphorus PIII/PV=O Redox Catalysis

AbstractThe Wittig reaction is renowned as exceptionally versatile method for converting a diversity of aldehydes and ketones into alkenes. Recently, strategies for chiral phosphine catalysis under PIII/PV=O redox cycling emerged to render this venerable transformation stereoselective. Herein, we describe that phosphine redox catalysis enables the enantioselective synthesis of pertinent biaryl atropisomers by means of a stereocontrolled arene‐forming Wittig reaction. Key to the process is the release of an endogenous base from readily accessible tert‐butyloxycarbonylated Morita–Baylis–Hillman adducts triggered by catalyst intramolecularization, permitting mild phosphine redox catalysis for atroposelective Wittig reactions. By this strategy, a broad diversity of biaryl atropisomers is obtained with up to 94 : 6 enantioselectivity.

Reactivity of a Morita-Baylis-Hillman adduct derivative bearing a triphenylamine moiety with lysine models.

The reactivity of Morita-Baylis-Hillman Adduct (MBHA) derivative 7 was studied with different primary amine derivatives such as n-butylamine, Na-acetyl-L-lysine methyl ester, and a poly-(L-lysine) derivative as lysine models to obtain information about the possible reactions in complex protein environments. MBHA derivative 7 reacted with n-butylamine or Na-acetyl-L-lysine methyl ester producing monoadducts 9a or 9c, which showed bright emission features in the green region at 526-535 nm with photoluminescence quantum yield values in solutions of 73% and 51%, respectively. Based on these results, MBHA derivative 7 can be considered an interesting new fluorogenic probe potentially useful in the labelling of basic amino acid residues. Furthermore, similar to other MBHA derivatives, compound 7 showed the tendency to produce diadducts especially in polar solvents system where specific interactions between the extended aromatic moieties may play a major role.

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.

Synthesis and molecular docking analysis of MBH adducts' derived amides as potential β-lactamase inhibitors.

Humans suffer from various diseases that require more specific drugs to target them. Among the different potent agents, β-lactamases serve as good antibacterial agents; however, β-lactamases are resistant to such antibiotics. The present study was designed to prepare efficient β-lactamase inhibitor amides (12-15) from inexpensive, easily accessible, and bioactive precursors; Morita Baylis Hillman (MBH) adducts (5-8). The adducts (5-8) were primarily prepared by treating their respective aldehydes with the corresponding acrylate in the presence of an organic Lewis base at ambient temperature. The compounds were characterized using mass spectrometry, FTIR and NMR spectroscopy. Furthermore, in silico studies (using AutoDock Tools and AutoDock Vina programs) on the adduct and corresponding amide product revealed that all MBH adducts (5-8) and their product amides (12-15) are significant inhibitors of β-lactamase. Additionally, among the MBH adducts, adduct 7 showed the highest binding affinity with β-lactamase, whereas amide 15 was identified as a highly potent antibacterial based on its docking score (-8.6). In addition, the absorption, distribution, metabolism, and excretion (ADME) test of the synthesized compounds demonstrated that all compounds showed drug-likeness properties.

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.

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.

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

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.