Diels–Alder adducts from Celastraceae species

Celastraceae species are a rich source of adducts whose biosynthesis has been hypothesized as involving a Diels–Alder reaction. The co-occurrence of these natural terpenoids adducts with their corresponding precursors, and the reported regio- and stereoisomers support that their biosynthesis may occur via a Diels–Alderase. Triterpene dimers, composed of a quinonemethide and a phenolic nor-triterpene, are the most numerous group of adducts and are all restricted to the Celastraceae family. This review covers natural Diels–Alder adducts from Celastraceae species, providing an overview of the reported terpenoid adducts classified by their monomer nature. In addition, synthetic efforts on the chemical feasibility of the biosynthetic Diels–Alder reactions involved and the biological activities of these metabolites are discussed.     

Synthesis of polysubstituted β-amino cyclohexane carboxylic acids via Diels–Alder reaction using Ni(II)-complex stabilized β-alanine derived dienes

This paper describes the design and synthesis of a new class of β-alanine derived dienes stabilized by Ni(II)-complex. Preliminary study of their Diels–Alder cycloaddition reactions with several types of dienophiles demonstrates their significant synthetic potential for the preparation of various polyfunctional β-aminocyclohexane carboxylic acids.     

DABCO-based chiral ionic liquids as recoverable and reusable organocatalyst for asymmetric Diels–Alder reaction

New DABCO-based chiral ionic liquids were synthesized and evaluated in asymmetric Diels–Alder reaction of cyclopentadiene with α,β-unsaturated aldehydes or 4-phenyl-3-buten-2-one. Chiral ionic liquid of modified MacMillan catalyst having a DABCO cation and hexafluorophosphate anion acts as organocatalyst (5 mol%) for the Diels–Alder reaction of crotonaldehyde and cyclopentadiene producing 98% of the product and 87% ee (endo) in CH₃CN/H₂O (95/5) at 25°C in 2 h. The scope and limitations of the catalysis were also studied by using cyclopentadiene and α,β-unsaturated aldehydes, and the Diels–Alder products were obtained in 18%–92% yields with 68%–93% ee. The catalyst was recycled and reused up to 6 cycles with a slight drop in ee and conversion of the product.     

Bioactive constituents of Morus wittiorum

From the stem bark of Morus wittiorum, one new Diels–Alder type adduct wittiorumin G (1) and three new 2-arylbenzofuran derivatives wittifurans P–R (2–4) along with five known Diels–Alder type adducts albafuran C, sorocein A, mulberrofuran E, mulberrofuran F and mulberrofuran O were isolated. Their structures were determined on the basis of spectroscopic analysis. Compounds 2–4 and two known compounds sorocein A and mulberrofuran F were evaluated for their antioxidant activity in a Fe²⁺/cysteine-induced microsomal lipid peroxidation assay and cytotoxicity against five human cancer cell lines respectively.     

Total synthesis of (±)-elegansidiol, (±)-farnesiferol B,and (±)-farnesiferol D

The racemic total synthesis of elegansidiol, farnesiferol B, and farnesiferol D has been obtained following a Diels–Alder approach. Gillman addition, cross metathesis reaction are the other key steps involved in the target synthesis.     

Kuwanon W,a natural Diels—Alder type adduct from the root bark of Morus lhou

A natural Diels—Alder type adduct, named kuwanon W, was isolated from ethyl acetate extracts of the root bark of cultivated mulberry tree, and its structure was determined on the basis of spectral and chemical evidence. Kuwanon W is regarded biogenetically as a Diels—Alder adduct of a chalcone derivative and dehydroprenyl-flavone.     

Effect of the cross-linker on the general performance and temperature dependent behaviour of a molecularly imprinted polymer catalyst of a Diels–Alder reaction

Here we present a series of molecularly imprinted polymers capable of catalysing the Diels–Alder reaction between benzyl 1,3-butadienylcarbamate (1) and N,N-dimethyl acrylamide (2). The polymer systems studied here demonstrated an unusual cross-linker and temperature dependent behaviour, namely that polymer catalysis of the Diels–Alder reaction was lower at elevated temperature, in contrast to the solution reaction. Furthermore, not only was the catalytic activity significantly influenced by the choice of cross-linker, but in a similar fashion also the extent of the temperature effect, indicating a close relationship between catalysis and the observed inhibition. Molecular dynamics simulations of both the polymer systems studied were used to provide insight into the molecular background of transition state stabilisation, and differences in properties of the systems based on different cross-linkers.     

Computational study of one-step polar Diels–Alder reactions using the NEB method for the minimum energy paths search

The Nudged Elastic Band (NEB) method is an algorithm to search the minimum energy path (MEP), which has been successfully applied for studying several processes that involve solid-state models; however, it has not been widely tested in discrete molecular systems. Performing density functional theory calculations, this method was employed in NWChem to find the MEP of reactions between cyclopentadiene and cyano-substituted ethylenes. Results suggest that the reaction mechanism is concerted in all systems. Also, kinetics and thermodynamics analysis were done: With respect to experimental data, energetic parameters are computed better at the M06-2X/6-31++G** level; entropy and frequency factors were poorly predicted. This is a simple methodology, where the NEB method is evaluated to find the MEP in some prototypical Diels–Alder reactions.     

Synthesis of 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives and their screening for antimicrobial and antioxidant properties

Novel 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives have been synthesized using boron trifluoride diethyl etherate catalyzed Diels–Alder reaction. This method presents considerable synthetic advantages in terms of high atom economy, mild reaction condition and good yields. The synthesized compounds have been screened for their antibacterial and antioxidant activities.     

Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution and selected adduct transformations

The Diels–Alder cycloaddition of nitroethylene to some androsta-14,16-dien-17-yl acetates has been studied. The addition occurs stereoselectively, giving predominantly head-to-head-adduct. 14β-Cyanomethyl steroids were obtained via the reductive cleavage reaction of bridged nitro compounds. The structures of the new compounds have been fully characterized by 2D NMR and tandem mass-spectrometry methods.     

Synthese d'un acide gras cyclohexenique disubstitute: L'acide (propyl-2′ cyclohexen-4′ yl-1′)-9 nonanoïque

(Propyl-2′ cyclohexen-4′ yl-1′)-9 nonanoïc acid was synthesized through a succession of the following reactions: condensation, according to Kondakof, of methyl undecylenate and propionyl chloride; condensation, according to Diels Alder, between the resulting aliphatic ketone and butadiene; reduction of the disubstituted cyclohexenyl ketone, according to Hutchins.The compounds formed at each step of the synthesis were studied and characterized.     

Protein tyrosine phosphatase 1B inhibitors isolated from Morus bombycis

Bioassay-guided fractionation of the chloroform-soluble fraction of Morus bombycis, using an in vitro PTP1B inhibitory assay led to the identification of three 2-arylbenzofurans, albafuran A (1), mulberrofuran W (2) and mulberrofuran D (6), along with three chalcone-derived Diels–Alder products, kuwanon J (3), kuwanon R (4), and kuwanon V (5). Compounds 1–6 showed remarkable inhibitory activity against PTP1B with IC₅₀ values ranging from 2.7 to 13.8 μM. Inhibition kinetics were analyzed by Lineweaver–Burk plots, which suggested that compounds 1–6 inhibited PTP1B in a mixed-type manner. The present results indicate that the respective lipophilic and hydroxyl groups of 2-arylbenzofurans and chalcone-derived Diels–Alder products play an important role in inhibition of PTP1B.     

Anti-leishmanial evaluation of C2-aryl quinolines: Mechanistic insight on bioenergetics and sterol biosynthetic pathway of Leishmania braziliensis

A series of diverse simple C2-aryl quinolines was synthesized de novo via a straightforward synthesis based on the acid-catalyzed multicomponent imino Diels–Alder reactions. Seven selected quinolines were evaluated at different stages of Leishmania braziliensis parasite. Among them, the 6-ethyl-2-phenylquinoline 5f was able to inhibit the growth of promastigotes of this parasite without affecting the mammalian cells viability and decreasing the number of intracellular L. braziliensis amastigotes on BMDM macrophages. The mechanism of action studied for the selected compound consisted in: (1) alteration of parasite bioenergetics, by disrupting mitochondrial electrochemical potential and alkalinization of acidocalcisomes, and (2) inhibition of ergosterol biosynthetic pathway in promastigote forms. These results validate the efficiency of quinoline molecules as leishmanicide compounds.     

Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives by a one-pot dynamic kinetic resolution/intramolecular Diels–Alder reaction: Total synthesis of (−)-himbacine

One-pot sequential reactions using the acyl moieties installed by enzymatic dynamic kinetic resolution of alcohols have been little investigated. In this work, the acryloyl moiety installed via the lipase/oxovanadium combo-catalyzed dynamic kinetic resolution of a racemic dienol [4-(cyclohex-1-en-1-yl)but-3-en-2-ol or 1-(cyclohex-1-en-1-yl)but-2-en-1-ol] with a (Z)-3-(phenylsulfonyl)acrylate underwent an intramolecular Diels–Alder reaction in a one-pot procedure to produce an optically active naphtho[2,3-c]furan-1(3H)-one derivative (98% ee). This method was successfully applied to the asymmetric total synthesis of (?)-himbacine.     

Asymmetric Diels-Alder reaction involving chiral benzimidazoles as organocatalysts

(S)‐(−)‐2‐(α‐hydroxyethyl)‐benzimidazole and (S)‐(+)‐2‐(α‐hydroxybenzyl)‐benzimidazole work as chiral Brønsted bases (BBs) in Diels–Alder reaction between anthrone and maleimides under mild reaction condition. These chiral BBs cause asymmetric induction. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Synthesis of quinoline derivatives for fluorescent imaging certain bacteria

Highly fluorescent quinoline derivatives were synthesized using Sc(OTf)₃ catalyzed imino Diels–Alder reaction. Both the aromatic and their analogous tetradehydroquinoline derivatives were explored for the detection of bacteria using fluorescent imaging studies. Surprisingly the aromatic quinoline derivatives show a remarkable fluorescent response that can be useful in the detection of both gram positive and gram negative bacteria even at a concentration in the range of 0.078 mM.     

Design and synthesis of dual active neovibsanin derivatives based on a chemical structure merging method

A hybrid compound consisting of neovibsanin and trans-banglene was designed according to a structure merging method and synthesized via a sequence of key steps including a Diels–Alder cycloaddition, stereoselective alkynylation, and intramolecular oxa-Michael addition reaction. The biological activity of the synthetized acetal compound and its hemiacetal analogue was investigated in PC12 cells. These studies revealed that the designed hybrid compounds displayed neuritogenic activity. Furthermore, a relatively strong neurite outgrowth promoting activity was observed in the presence of NGF. These results suggest that the designed hybrid compound exhibited a dual activity.     

Cooperativity of chirality in homogeneous catalysis: The gold(I)-catalyzed aldol reaction and the vanadium(IV)-catalyzed hetero Diels–Alder cycloaddition

The notion of internal (or intramolecular) cooperativity of chirality is reviewed on the basis of various examples of diastereoisomeric ferrocenylphosphine ligands used in the gold(I)-catalyzed aldol reaction. It was found that the stereochemical outcome of this reaction strongly depends on the specific combination of the absolute configuration of the different stereogenic centers present in the ligand. Thus, individual chirotopic segments in these ligand molecules can act either in a cooperative or noncooperative manner in determining both diastereo-and enantioselectivity. Furthermore, several examples of application of the strategy of double stereodifferentiation (external, or intermolecular cooperativity of chirality) in the gold(I)-catalyzed aldol reaction and the vanadium(IV)-catalyzed hetero Diels–Alder condensation are presented. Based on our work it is apparent that, whether the diastereoselectivity of these two reactions is controlled by the catalyst or by a chiral substrate, cannot be predicted and very much depends on the nature of every individual reactant. Thus, it was found that in both reactions the chiral aldehyde substrate usually has a strong impact on the diastereoselectivity, leading to interesting patterns of double asymmetric induction. On the other hand, chiral isocyanoacetate and chiral-activated dienes, respectively, showed little or no effect on the stereochemical outcome of the reactions.     

Synthesis and evaluation as potential anticancer agents of novel tetracyclic indenoquinoline derivatives

We report the synthesis and evaluation as potential anticancer agents of a series of tetracyclic indenoquinolines. The compounds, which are obtained through the photoisomerization of Diels–Alder adducts formed between purpurogallin derivatives and nitrosobenzene, have in vitro antiproliferative activities in the μM to nM range against breast (MCF-7), lung epithelial (A-549), and cervical (HeLa) adenocarcinoma cells. The cytotoxicities of several of the novel tetracycles are comparable to or better than that of camptothecin. A strong correlation between the activity of the compounds and their aromaticity and planarity was observed, suggesting a mode of action similar to that of topoisomerase poisons.     

Comparison of a Molecular and an Immobilized Gadolinium(III)‐tris[(1R,4S)‐3‐heptafluorobutanoyl‐camphor] as Catalyst in the Asymmetric Danishefsky‐Hetero‐Diels‐Alder‐Reaction

On‐column reaction gas chromatography combines the power of separation and rapid analysis of reactants and reaction products with screening of reactions in a single step. Not only conversions but the reaction rates at various temperatures can be obtained from single measurements, making this approach superior to the time‐consuming measurements typically performed in reaction progress analysis. However, this approach has only been used in the investigation of interconversion processes, rearrangement reactions, and only a few examples of higher‐order reactions are known. Here we present the screening of immobilized gadolinium(III)‐tris[(1R,4S)‐3‐heptafluorobutanoyl‐camphor] in the Danishefsky‐hetero‐Diels‐Alder‐reaction by enantioselective on‐column reaction gas chromatography utilizing cryogenic focusing to achieve catalytic conversions in this higher‐order reaction and subsequent separation of the enantiomeric product mixture to determine the enantiomeric ratio. The results obtained by this approach could be transferred to the conventional batch reaction at a larger scale, demonstrating that on‐column reaction chromatography provides reliable results in the screening of enantioselective reactions. Chirality 26:243–248, 2014. © 2014 Wiley Periodicals, Inc.