Acid-Promoted Iso-Nazarov Cyclization of Conjugated trans-Dienones and Dienals for the Synthesis of 2-Cyclopentenones.

The acid-promoted cyclization of all-trans linearly conjugated dienones and dienals constitutes a synthetic strategy for the construction of 2-cyclopentenones.

Biomimetic Domino Knoevenagel/Cycloisomerization Strategy for the Synthesis of Citridone A and Derivatives.

Studies on Knoevenagel condensations between conjugated dienals and 4-hydroxy-2-pyridone/quinolone-type 1,3-dicarbonyl equivalents led to the development of a simple one-pot strategy to access citridone A and related synthetic cyclopenta[b]furopyridones/quinolones. The present work highlights the power of domino cascades in the synthesis of natural product frameworks and may help promote future studies on this promising new class of pyridone alkaloids.

Zanthosimuline and Related Pyranoquinolines as Antifungal Agents for Postharvest Fruit Disease Control.

The natural product zanthosimuline and its 18 analogues were easily prepared from simple starting materials and evaluated in vitro against postharvest fruit fungal pathogens. The panel included Penicillium digitatum, Botrytis cinerea, Monilinia fructicola, and Rhizopus stolonifer; all of them causing relevant economic losses worldwide. The minimum inhibitory concentrations and minimum fungicidal concentrations of each compound were determined, and the main structure-activity relationships were established. The biological activity observed was strongly increased by maintaining the prenyl side chain of zanthosimuline in an N-demethylated derivative. In addition, the compound that is the most active in the in vitro evaluation was tested in freshly harvested peaches exhibiting a promising brown rot control profile, comparable to the commercial agent carbendazim but demonstrating less toxicity against human liver cell lines.

Studies on Biomimetic Singlet Oxygen Oxidations: Application to the Synthesis of the Alkaloid Simulenoline.

The synthesis of the biologically active alkaloid simulenoline, isolated from the roots of Zanthoxylum simulans, is reported. The natural product was assembled from simple commercial reagents via initial domino Knoevenagel/oxa-6π-electrocyclization followed by a one-pot singlet-oxygen ene-reaction/reduction sequence. New insights of singlet oxygen reactivity with olefinic substrates have been revealed.

Domino Self-Sensitized Photooxygenation of Conjugated Dienones for the Synthesis of 1,2,4-Trioxanes.

The photochemical behavior of several dienones was studied under aerobic conditions. 2-Allylidene-1,3-cycloalkanediones prepared via Knoevenagel-type condensation between simple readily available 1,3-dicarbonyl substrates and α,ß-unsaturated aldehydes afforded 1,2,4-trioxane derivatives upon UVA irradiation in the presence of oxygen. This domino self-sensitized photooxygenation cascade of conjugated carbonyl systems proceeds stereoselectively and involves the formation of two new oxa-cycles, three new bonds (two C-O), and three stereocenters.

Iodine-Catalyzed Iso-Nazarov Cyclization of Conjugated Dienals for the Synthesis of 2-Cyclopentenones.

Molecular iodine was identified as an efficient catalyst for the cycloisomerization of conjugated dienals to substituted 2-cyclopentenones. DFT calculations suggested an unexpected concerted character for this cyclization.

[2 + 2 + 2]-Cycloaddition Reactions Using Immobilized Alkynes. A Proof of Concept for an Integral Use of the Outcoming Products in Solid-Phase Synthetic Methodologies.

The transition-metal-catalyzed [2 + 2 + 2]-cycloaddition of alkynes has become a powerful atom-economical strategy for aromatic ring construction. Unfortunately, the control of the stereo-, regio-, and chemoselectivity of these processes is usually challenging, and these reactions can potentially lead to complex unuseful mixtures. While solid-phase chemistry has proven to be a successful tool for decreasing the number of cycloadducts formed and for facilitating the purification step, an integral use of the outcoming products in this complex reaction is described herein. By using an immobilized monoalkyne, the transition-metal-catalyzed [2 + 2 + 2]-cycloaddition with soluble 1,6-diyne-esters led to the simultaneous preparation of soluble and solid-supported phthalides, showing a new way to benefit from solid-phase synthetic methodologies.

Multicomponent Domino Synthesis of Cyclopenta[ b]furan-2-ones.

A stereoselective multicomponent reaction involving Meldrum's acid, a conjugated dienal, and an alcohol is reported. Valuable cyclopenta[ b]furan-2-ones are obtained as products of this straightforward transformation, which is accompanied by the formation of four stereocenters, two new cycles, and four new bonds (two C-C and two C-heteroatom). A reaction mechanism was elaborated involving an initial Knoevenagel condensation followed by cycloisomerization and eventual fragmentation.

NMR and experimental reinvestigation of the condensation reaction between γ-methylene-α,ß-unsaturated aldehydes and propargyl aldehydes.

The condensation reaction between a γ-methylene-α,ß-unsaturated aldehyde and phenylpropargyl aldehyde was revisited and, guided by extensive DFT calculations of NMR shifts, was found to afford a deconjugative aldol condensation product. In this manner, a simple protocol for the preparation of valuable cross-conjugated oxatrienes was uncovered.

The iso-Nazarov reaction.

The construction of five-membered rings is essential in organic chemistry. In this context, pentannulation reactions that provide a straightforward access to cyclopentenones are of particular interest, as these structures are not only embedded in important molecules such as some prostaglandins, but also serve as versatile building blocks in organic synthesis. This review documents the acid-promoted cycloisomerization of conjugated dienals and linearly-conjugated dienones for the construction of cyclopentenones, a transformation that has been largely eclipsed by the well-known Nazarov reaction, i.e. the acid-promoted cycloisomerization of cross-conjugated ketones.

Pericyclic Cascade toward Isochromenes: Application to the Synthesis of Alkaloid Benzosimuline.

The synthesis of biologically active alkaloid benzosimuline, isolated from the shrub Zanthoxylum simulans, is reported. Key transformation involves an oxa-6π electrocyclic ring-opening/hetero-Diels-Alder pericyclic cascade. Although the last aromatization step proved to be cumbersome, this work unfolds a unique route to access interesting molecules from simple precursors.

Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings.

The UVA (350 nm) irradiation of an α-pyran in the presence of oxygen led to the unexpected formation of a tetraoxygenated compound whose structure could not be unambiguously determined on the basis of conventional (1)H-(13)C correlated experiments. 1,1-ADEQUATE (adequate double quantum transfer experiment) and 1,n-ADEQUATE combined with computer-assisted structure elucidation software led to two structural possibilities involving the formation of either an epoxide or an oxetane. Residual dipolar couplings allowed not only the identification of the compound as a spiroepoxide but also the determination of its relative configuration. To account for its formation, we propose a bisepoxide intermediate that, as opposed to most α,ß-epoxyketones under irradiation, undergoes O-Cß cleavage probably due to the presence of an extra oxygen substituent in the ß position. 1,2-Acyl migration would then proceed stereoselectively to the final product obtained as a single diastereomer.

Cycloisomerization of Conjugated Trienones and Isomeric 2H-Pyrans: Unified Strategy toward Cyclopenta[b]furans.

Conjugated trienones and isomeric 2H-pyrans were found to engage in a novel cycloisomerization cascade toward cyclopenta[b]furan derivatives. Knoevenagel chemistry and pericyclic reactions meet again to expand the polyene-carbonyl manifold.

An interrupted vinylogous iso-Nazarov reaction: cycloisomerization of conjugated trienones to cyclopenta[b]furan derivatives.

Iron(III) chloride-catalyzed cyclopentannulation of π-conjugated 1,3-dicarbonyl compounds is described. An interrupted vinylogous iso-Nazarov reaction of trienones was established in which cyclopenta[b]furan derivatives are obtained as single diastereomers.

One-pot organocatalytic tandem aldol/polycyclization reactions between 1,3-dicarbonyl compounds and α,ß,γ,δ-unsaturated aldehydes for the straightforward assembly of cyclopenta[b]furan-type derivatives: new insight into the Knoevenagel reaction.

A new cascade pathway viable for Knoevenagel chemistry that involves the coupling between 1,3-dicarbonyl systems and α,ß,γ,δ-unsaturated aldehydes has been developed. The process comprises the combination of a classic aldol-type condensation and a rare spontaneous metal-free cycloisomerization, representing a convergent and innovative approach for the stereoselective synthesis of cyclopenta[b]furan-type derivatives. The scope and limitations with respect to both reaction partners and mechanistic features were investigated. Meaningfully, our study provides valuable guidance concerning the structural and electronic effects controlling the reactivity of conjugated polyene carbonyl systems.

Unprecedented stereoselective synthesis of cyclopenta[b]benzofuran derivatives and their characterisation assisted by aligned media NMR and 13C chemical shift ab initio predictions.

A new approach to the synthesis of cyclopenta[b]benzofuran derivatives via reaction of 1,3-dicarbonyl compounds with α,ß,γ,δ-unsaturated aldehydes is described. The constitution and configuration of the new products have been firmly established by means of residual dipolar couplings (RDCs) and ab initio (13)C NMR chemical shift predictions.

New strategy for the construction of epoxy-bridged tetrahydropyran frameworks from trioxane precursors: application to a concise synthesis of a Riesling acetal.

A simple one-pot method to prepare dioxabicyclo[2.2.1] heptane derivatives, from readily available 1,2,4-trioxane frameworks, under catalytic hydrogenation conditions over a platinum surface is reported. The overall transformation involves the hydrogenation of the double bond and a ring contraction rearrangement that presumably proceeds via a hydrogenolytic cleavage of the O-O bond and subsequent intramolecular ketalization. The strategy was successfully applied to the synthesis of a Riesling acetal.