Diels-Alder Dimerization Research Articles

Enantioselective and Collective Total Syntheses of Xanthanolides.

An enantioselective synthesis of (+)-8-epi-xanthatin hinging on a chiral phosphoric acid catalyzed tandem allylboration/lactonization reaction is reported. With (+)-8-epi-xanthatin as the precursor, the collective synthesis of a series of synthetically challenging xanthanolides was also accomplished. Among them, xanthipungolide, one of the most complex xanthanolide monomers, was accessed through a bioinspired tandem double-bond isomerization/6π electronic cyclization/intramolecular Diels-Alder reaction, and pungiolides A, B, D, E, and L-N, a group of xanthanolide dimers, were assembled through a bioinspired Diels-Alder dimerization followed by late-stage diversification.

Radical Stabilization Algorithm as a Predictive Tool for Novel and Reported Noncanonical Thiele’s Acid Analogues

We recently showed that a simple radical-stabilization algorithm outperformed traditional frontier-molecular orbital methods for rationalizing the outcome of the venerable Thiele’s acid (or ester) Diels–Alder dimerization. In the present Communication, we describe a novel noncanonical Thiele-type dimerization of a cyclopentadiene phosphine oxide, and show that when steric factors are taken into account the ­radical-stabilization method once again correctly rationalizes the regio­chemical outcome for the reaction. We further show that the method appears to be general for all known Thiele- and half-Thiele dimerization events.

DFT Studies of Dimerization Reactions of Boroles.

Boroles undergo dimerization reactions to give Diels-Alder (DA) dimers, bridged-bicyclic (BB) dimers or spiro dimers (SD) depending on the substituents on the borole. We performed DFT calculations to investigate how different substituents at the carbon atoms of the butadiene backbone as well as at the boron atom influence the dimerization reaction pathways. The DFT results show that, in general, both the DA and BB dimers are easily accessible kinetically, and the DA dimers are thermodynamically more stable than the BB dimers. When the substituent-substituent repulsive steric interactions are alleviated to a certain extent, the BB dimers are more stable than the DA dimer, and become accessible. The SD dimers are generally kinetically difficult to obtain. However, we found that aryl substituents promote the formation of the SD dimers.

Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis

AbstractThe total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels–Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non‐enzyme‐mediated) reactivity.

Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis.

The total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels-Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non-enzyme-mediated) reactivity.

Theoretical Prediction on [5]Radialene Sandwich Complexes (CpM)2(C10H10) (Cp = η5-C5H5; M = Fe, Co, Ni): Geometry, Spin States, and Bonding.

[5]Radialene, the missing link for synthesis of radialene family, has been finally obtained via the preparation and decomplexation of the [5]radialene-bis-Fe(CO)3 complex. The stability of [5]radialene complex benefits from the coordination with Fe(CO)3 by losing free 1,3-butadiene structures to avoid polymerization. In light of the similar coordination ability of half-sandwiches CpM(Cp = η5-C5H5; M = Fe, Co, Ni), there is a great possibility that the sandwiched complexes of [5]radialene with CpM are available. Herein, we present the first theoretical prediction on the geometry, spin states and bonding of (CpM)(C10H10) and (CpM)2(C10H10). For M = Fe, Co, Ni, the ground states of (CpM)(C10H10) and (CpM)2(C10H10) are doublet and triplet, singlet and singlet, and doublet and triplet states, where each Fe, Co, and Ni adopts 17, 18, and 19 electron-configuration, respectively. In particular, (CpFe)2(C10H10) and (CpNi)2(C10H10) have considerable open-shell singlet features. Generally the trans isomers of (CpM)2(C10H10) with two CpM fragments on the opposite sides of the [5]radialene plane are apparently more stable than the cis ones with CpM fragments on the same side. However, for the singlet and triplet isomers of (CpNi)2(C10H10) (both cis and trans isomers), the energy differences are relatively small, indicating that these isomers all have the opportunity to exist. Besides, the easy Diels-Alder (DA) dimerization between the [3]dendralene-like fragments of (CpM)(C10H10) suggests the great difficulty in isolating the (CpM)(C10H10) monomer.

Chemo- and regio-selective synthesis of hexacyclic indeno-fused coumarins via domino Diels–Alder dimerization/Baeyer–Villiger oxidation

2-Arylindenones have been employed into two parallel chemoselective synthetic transformations. In one path, molecular oxygen was incorporated into the reaction intermediate, leading to hexacyclic benzo indeno-fused coumarins via domino head-to-head Diels–Alder dimerization/Baeyer–Villiger oxidation. On the other hand, under catalyst-free and solvent-free thermal conditions, hexacyclic indeno-fused dihydronaphthalenes were achieved through head-to-head Diels–Alder dimerization of 2/3-arylindenones. Atmospheric oxygen serves as efficient oxidant during dehydrogenative aromatization and Baeyer–Villiger rearrangement.

Gas‐Phase Synthesis of 1‐Silacyclopenta‐2,4‐diene

AbstractSilole (1‐silacyclopenta‐2,4‐diene) was synthesized for the first time by the bimolecular reaction of the simplest silicon‐bearing radical, silylidyne (SiH), with 1,3‐butadiene (C4H6) in the gas phase under single‐collision conditions. The absence of consecutive collisions of the primary reaction product prevents successive reactions of the silole by Diels–Alder dimerization, thus enabling the clean gas‐phase synthesis of this hitherto elusive cyclic species from acyclic precursors in a single‐collision event. Our method opens up a versatile and unconventional path to access a previously rather obscure class of organosilicon molecules (substituted siloles), which have been difficult to access through classical synthetic methods.

Gas-Phase Synthesis of 1-Silacyclopenta-2,4-diene.

Silole (1-silacyclopenta-2,4-diene) was synthesized for the first time by the bimolecular reaction of the simplest silicon-bearing radical, silylidyne (SiH), with 1,3-butadiene (C4 H6 ) in the gas phase under single-collision conditions. The absence of consecutive collisions of the primary reaction product prevents successive reactions of the silole by Diels-Alder dimerization, thus enabling the clean gas-phase synthesis of this hitherto elusive cyclic species from acyclic precursors in a single-collision event. Our method opens up a versatile and unconventional path to access a previously rather obscure class of organosilicon molecules (substituted siloles), which have been difficult to access through classical synthetic methods.

Revisiting the mechanistic origins of Thiele's ester dimerization: probing the reliability of predictive models for cycloadditions.

The Diels-Alder dimerization of cyclopentadiene carboxylic acid (or ester) affords only three products out of a total of 36 possible regioisomers. In this Communication, we compare two competing conceptual models for their ability to rationalize the selective formation of these three compounds. We find that calculated ΔHf values and orbital energy levels are sufficient to describe gross reactivity for the system, but that orbital coefficient arguments (and frontier molecular orbital theory in general) do not reliably predict the regioisomeric outcome for the reaction. By contrast, Deslongchamps' radical stabilization logic (a consequence of the bent bond model of reactivity) correctly predicts all three Diels-Alder products. We anticipate that these data will stimulate broader consideration of radical stabilization effects as a predictive tool for cycloaddition chemistry.

Mechanism for covalent dimerization of pyridine: [4+2] dimerization, an MP2 investigation

The Diels⿿Alder (DA) covalent dimerization mechanisms of pyridine were studied at the MP2/6-311G(d,p) level. Involvement of N atom in DA reaction causes high barrier height, otherwise the barrier heights are low. The two most stable DI dimers formed by intermolecular DA reaction (b-γDI and b-γ⿲DI) and the two most stable DII dimers formed by further intramolecular DA reaction (c-γDII and c-γ⿲DII) were located with relative energy of 26.6 and 26.1kcal/mol, and 32.1 and 31.6kcal/mol, respectively, higher than two moles of pyridines. Theoretical results suggested that DA dimerization of pyridine is slightly easier than that of benzene.

Expansion of Thiele's Acid Chemistry in Pursuit of a Suite of Conformationally Constrained Scaffolds.

The Diels-Alder dimer of cyclopentadiene carboxylate, Thiele's acid has conformational properties that make it attractive as a molecular scaffold for applications in supramolecular and biological chemistry. However, a lack of known reaction methodology for derivatives of Thiele's acid (or the corresponding esters) has hampered its utilization in these fields. We describe an improved preparation of Thiele's esters and survey the chemistry of these versatile intermediates. As part of this effort, we also describe the synthesis of a suite of Thiele's acid (or ester) analogues spanning a broad range of cleft angles.

Singlet oxygen addition to cyclo-1,3-hexadienes from natural sources and from organocatalytic enal dimerization

The photoxygenation reactions of the natural monote rpene aldehyde safranal (1) and its reduction product safranol ( 4) were studied and the endoperoxide 5 from safranol was isolated and characterized by single crystal X-ray analysis. A dyade synthesis using DCC coupling of safranol with artesunic acid delivered the reactive substrate 7 for 1,3-diene photooxygenation. Singlet oxygen reaction of the substrate 7 enabled the synthesis of the trioxane-endoperoxide dyade 8. The diastereoisomeric 1,3-cyclohexadienes 10 were obtained from the proline-catalyzed Diels-Alder dimerization of the Michael aldehyde 9. From the singlet oxygen addition with the diastereoisomeric substrates 10 , only the kinetically preferred cis-endoperoxide 11 was formed.

STAUDINGER AND RUZICKA'S ALTERED PYRETHROLONE: THE CYCLOPENTADIENONE DIMERS DERIVED FROM PYRETHRIN I

The reaction of pyrethrin I (1) with sodium hydroxide in ethanol produced the cyclopentadienone 29 which rapidly underwent Diels-Alder dimerisation to give two cyclopentadienone dimers which were isolated in 30 and 38% yield, respectively. A combination of one-dimensional and two-dimensional NMR spectroscopic studies allowed determination of the structure and stereochemistry of the higher and lower Rf dimers as being 26 and 27, respectively. The dimers are formed by cycloaddition reactions of the least substituted alkene of the cyclopentadienone, and via both possible regioisomeric endo transition states.

Total Synthesis of Ramonanins A–D

AbstractThe first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5‐diaryl‐3,4‐dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels–Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6‐31G(d) and M06‐2X/6‐31G(d) model chemistries.

Total synthesis of ramonanins A-D.

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels-Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6-31G(d) and M06-2X/6-31G(d) model chemistries.

Biosynthetic origins of the epoxyquinone skeleton in epoxyquinols A and B.

The biosynthetic origins of epoxyquinols A (1) and B (2) produced by an unidentified fungus have attracted considerable interest because these compounds could be assembled from a biosynthetic precursor, epoxycyclohexenone aldehyde (3), via an electrocyclization/intermolecular Diels-Alder dimerization cascade reaction. Furthermore, very little is known about the biosynthetic origins of naturally occurring epoxyquinone moieties. We herein describe the incorporation of (13)C at specific positions within the structure of a shunt product, epoxycyclohexenone (4), using stable isotope feeding experiments with sodium [1-(13)C]-acetate and sodium [1,2-(13)C2]-acetate. The results of these experiments strongly suggest that the epoxyquinone skeleton is assembled by a polyketide synthase.

ChemInform Abstract: Remarkable Switch of Regioselectivity in Diels—Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles.

AbstractA remarkable switch of reactivity of the Diels—Alder dimerization of indole substituted butadienes is discovered.

ChemInform Abstract: Diastereoselective Synthesis of a Highly Functionalized Cyclohexene Embedded with a Quaternary Stereogenic Centre by Self Diels—Alder Dimerization of a [3]Dendralene Attached to a (‐)‐Menthol Auxiliary.

AbstractPhosphonate (I) is olefinated in a Horner‐Wadsworth‐Emmons reaction by para‐bromobenzaldehyde followed by a highly diastereoselective and spontaneous Diels—Alder dimerization.

Synthesis of dipyrrolo[3,4-a:3,4-c]carbazoles: new kinase inhibitors

Two dipyrrolo[3,4-a:3,4-c]carbazole stereoisomers were unexpectedly obtained by Diels–Alder dimerization of 3-indolylmaleimide. Three dimensional structures of both stereoisomers were confirmed by X-ray analysis. Moreover compound 4 inhibits protein kinases in vitro, especially Pim-3, in the sub-micromolar range.