Intramolecular Diels-Alder reaction of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans followed by nucleophilic 1,2-rearrangement of the phosphinyl group

The base-catalyzed intramolecular Diels-Alder reactions of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans 2a-e gave the tetrahydrofuran ring annulated o-diphenylphosphinophenols 3a-e in 70-80% yields, a novel reaction involving an intramolecular Diels-Alder reaction of furan diene with allenyl ether dienophile followed by a nucleophilic 1,2-rearrangement of the diphenylphosphinyl group.     

Synthetic studies on the preparation of oxygenated spongiane diterpenes from carvone

The paper describes a new diastereoselective approach to oxygenated spongiane diterpenes functionally related to natural dorisenones. The strategy followed for the preparation of the spongiane framework, a B→AB→ABC→ABCD approach, is based on the preparation of epoxydecalone 11 (AB rings) from R-(−)-carvone, followed by an intramolecular Diels-Alder reaction for the construction of the C ring (compound 26). Further manipulation of the Diels-Alder adduct functionality allows the completion of the spongiane framework and the elaboration of several oxygenated spongiane-type compounds. The structures of two compounds 27 and 31, has been established by single-crystal X-ray crystallography.     

Synthetic studies on (-)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (1)

Construction of the ABCD ring system of (-)-FR182877 via the highly diastereoselective intramolecular Diels-Alder (IMDA) reaction is described. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.     

An intramolecular [4+3]-cycloaddition approach to rameswaralide inspired by biosynthesis speculation

A concise synthesis of the polycycle 27, which incorporates the 5,5,7-tricyclic ring core of rameswaralide 1, using a biogenetically inspired acid-catalysed [4+3]-cycloaddition approach starting from the furanobutenolide 26 is described, namely, 26→28/29→27. Under thermal conditions, the same furanobutenolide 26 gives the alternative polycyclic compound 35, resulting from a [4+2]-cycloaddition involving the furan as dienophile.     

[60]Fullerene adducts with 9-substituted anthracenes: mechanochemical preparation and retro Diels-Alder reaction

Three 9-substituted anthracene derivatives, that is, 9-hydroxymethylanthracene (2), 9-methoxymethylanthracene (3) and bis(9-anthrylmethyl) adipate (6), were chosen as the model compounds to evaluate the reactivity in their Diels-Alder reactions with [60]fullerene and in retro Diels-Alder reactions of the formed cycloadducts. Corresponding adducts 4, 5 and 7 were prepared in high yields under solvent-free conditions using high-speed vibration milling technique. In order to determine thermal stabilities of adducts 4, 5 and 7, their dissociations in the temperature range of 40-65 °C were investigated. Fitting the dissociation rates and temperatures to the Arrhenius equation gives the activation energies of 25.8, 21.8 and 24.9 kcal/mol for compounds 4, 5 and 7, respectively.     

Synthesis of the novel conjugated ω,ω′-diaryl/heteroaryl hexatriene system with the central double bond in a heteroaromatic ring: photochemical transformations of 2,3-divinylfuran derivatives

New β,β′-aryl/heteroaryl 2,3-divinylfuran derivatives (9a-d) in which a hexatriene system is a part of heteroaromatic ring have been synthesized and their photochemical properties were investigated. The primary process observed was the isomerization to trans,trans-isomers 9a-d followed by photochemical rearrangement of the furan ring giving the phototransposition products (I-IV). Stilbenes (20, 21) and phenanthrenes (22, 25, and 26), formed as secondary products from the competitive intermolecular cycloadditions, were also observed.     

Synthesis and highly selective Diels-Alder cycloadditions of the new dienes N-substituted 2,3,5,6-tetrahydrobenzoxazol-2-ones

The synthesis of the new dienes N-substituted 2,3,4,5-tetrahydrobenzoxazol-2-ones 8a-8c is described, through a one-step convergent process from 1,2-cyclohexanedione (7a) and the corresponding isocyanates 2a-2c. The presence of electron-donor substituents in the aryl ring of the isocyanate gave rise to the exclusive formation of the captodative olefins 10. Diene 8a proved to be reactive and stereoselective in Diels-Alder additions with a cyclic olefin. The reaction with acetylenic dienophiles yielded the 2,3-dihydrobenzoxazol-2-ones 21 and 24, as the products of sequential [4+2] cycloaddition and retro-Diels-Alder reactions. Methyl vinyl ketone (22) underwent regio- and stereoselective tandem Diels-Alder and Michael additions to give propellane 29a. Evidence of an endo π-pyramidalization of the central double bond of adduct 19 would rationalize the exo stereoselection in the formation of 29a. The regioselectivity in these reactions has been rationalized in terms of FMO theory by ab initio calculations.     

Exploration of a proposed biomimetic synthetic route to plumarellide. Development of a facile transannular Diels-Alder reaction from a macrocyclic enedione leading to a new 5,6,7-tricyclic ring system

A concise synthesis of the macrocyclic vinylbutenolide 19 is described, based on a facile RCM reaction of the substrates 16/18. Treatment of 19 with TFA containing water led to the 5,6,7-tricyclic compound 27, in a single step, in >90% yield, rather than to the alternative ring system 23 found in plumarellide (1). A rationale for the formation of 27 is presented, involving initial acid-catalysed hydrolysis of the furanmethanol intermediate 20 to the furanoxonium ion 21, which is next hydrolysed to the enol ether cyclic hemiketal 22. The intermediate 22 undergoes rapid tautomerisation and isomerisation producing enedione 24, which then takes part in a transannular Diels-Alder cyclisation to 26. Dehydration of 26 finally produces the tricyclic compound 27.     

The second generation synthesis of (+)-pseudodeflectusin

The second generation synthesis of (+)-pseudodeflectusin (1), a potential antitumor agent, has been achieved. The key synthetic step is the cascade reaction involving Diels-Alder reaction, lactonization, and decarboxylation to give cycloadduct 6 with complete regioselectivity in good yield. We found that NaH is the best base to facilitate the Diels-Alder reaction of hydroxypyrone 7 with alkyne 8. The present synthetic route enables the total synthesis of (+)-1 in only five-steps from the known compounds 7 and 8.     

Velutabularins A-J, phragmalin-type limonoids with novel cyclic moiety from Chukrasia tabularis var. velutina

Velutabularins A-J, ten novel phragmalin-type limonoids, were isolated from the stem bark of Chukrasia tabularis var. velutina. In structures of 1-6, the tetrahydrofuran ring from dehydration of OH-15 and OH-17, ring C and 13/14/18-cyclopropanyl moiety formed an unprecedented 8-oxatricyclo[4,3,1^1,6]decane. Compounds 7-10 are derivates of 1-6 opening the tetrahydrofuran ring. All of these compounds possess a novel C-16/C-30 δ-lactone ring, which were reported in phragmalins rarely. The structures of these novel compounds were elucidated based on extensive 1D and 2D spectroscopic analysis. The absolute configuration of 5 and 9 were determined by the calculated electronic circular dichroism (ECD) method. The anti-inflammatory activities of major compounds (2, 4, 5, 9) were evaluated for inhibitory activity against lipopolysaccharide (LPS) induced nitric oxide (NO) production in macrophage (RAW264.7) cell line.     

Chemoenzymatic total syntheses of the linear triquinane-type natural products (+)-hirsutic acid and (−)-complicatic acid from toluene

Total syntheses of title natural products, 1 and 2, have been achieved using the cis-1,2-dihydrocatechol 7 as starting material. Compound 7 is readily obtained in large quantity and enantiomerically pure form through the whole-cell biotransformation of toluene using the genetically engineered micro-organism Escherichia coli JM109 (pDTG601) that over-expresses the enzyme toluene dioxygenase (TDO). Three key chemical steps were employed in these syntheses, the first of which was a high-pressure-promoted Diels-Alder cycloaddition reaction between diene 8 and cyclopentenone to give adduct 9. The second key step was the photochemically promoted oxa-di-π-methane rearrangement of the bicyclo[2.2.2]octenone derivative, 18, of 9 to give 20 while the third key step was the reductive cleavage of the last compound so as to afford the linear triquinane 22. Elaboration of compound 22 to targets 1 and 2 followed conventional and/or established procedures. Single-crystal X-ray analyses were carried out on compounds 10-13, 15, 18, 24, and 34.     

Sulfolenoporphyrins: synthons for refunctionalization of porphyrins

Using sulfolenopyrroles (4) and (11) methods are developed for the synthesis of opp- (15,18,19) and adj- (25) bis-sulfolenoporphyrins; such compounds are useful building blocks for the refunctionalization of the porphyrin system, and readily undergo Diels-Alder cycloaddition reactions.     

Synthesis of the FG ring fragment of pectenotoxins 1-9

The synthesis of the FG ring fragment common to pectenotoxins 1-9 is reported. The successful, convergent synthesis relied on high yielding routes to access two key intermediates; aldehyde 1 and phosphonium salt 2. A Z-selective Wittig reaction gave access to advanced linear precursor 3, which was converted to FG ring fragment 4 using two sequential cyclization reactions.     

Exceptional molecular architectures via cycloadditions to pyrenequinones

The thermal reaction of phencyclone (2) with a 1:1 mixture of 1,8-pyrenequinone (4) and 1,6-pyrenequinone (5) yields 2:1 adducts only of compounds 2 and 4. The observed polycyclic aromatic hydrocarbon 8 is formed via double Diels-Alder addition of 2 to 4, and the polycyclic ketone 9 arises from a combination of Diels-Alder and hetero-Diels-Alder reactions of 2 and 4. In contrast, Lewis acid-catalyzed reactions of 2, 4, and 5 give 2:1 adducts only of 2 and 5. The chief product, polycyclic diketone 10, is derived from a double hetero-Diels-Alder addition of 2 to 5. X-ray analysis of compound 8 shows it to be an exceptionally large polycyclic aromatic arch, and the X-ray structure of 10 reveals it to be a chiral molecular tweezer.     

Synthesis of furan 4′-thio-C-nucleosides, their methylsulfonium and sulfoxide derivatives. Evaluation as glycosidase inhibitors

A series of furan C-nucleosides having a sulfur atom in the sugar ring were synthesised. The α and β anomers of 3-ethoxycarbonyl-2-methyl-5-(4′-thio-d-erythrofuranosyl)furans 10 and 11 were obtained by acid treatment of (4′-S-acetyl-4′-thio-d-arabino-tetritol-1-yl)furan 9. Oxidation of 10 with m-chloroperbenzoic acid gave sulfoxide 12 as one epimer at the sulfur atom whereas 11 was transformed into sulfoxide 13 as an epimeric mixture. S-Methylation of 10 and 11 with methyl triflate led to sulfonium salts 14 and 15. The prepared compounds were found to be moderate inhibitors of α-l-fucosidase.     

Syntheses of oxygenated spongiane diterpenes from carvone. Synthesis of dorisenone C

The synthesis of dorisenone C, a representative member of the spongiane-type diterpene family, is described. The synthesis follows a B→AB→ABC→ABCD approach and is based on the initial preparation of the previously known hydroxy-aldehyde 14 (AB rings) from R-(−)-carvone, followed by an intramolecular Diels-Alder reaction between an oxygenated diene moiety and an acetylenic dienophile for the construction of the C ring (compound 22), and adequate manipulation of the Diels-Alder adduct functionality for completion of the spongiane framework.     

Multicomponent synthesis of epoxy-tetrahydronaphthyridine and structural diversification by subsequent fragmentation

Three-component reaction of an α-isocyanoacetamide 7, an homoallylamine 8 and an aldehyde 9 in methanol at room temperature provides oxa-bridged tricycle 4 in good to excellent yield as a mixture of two separable diastereoisomers. In this one-pot multicomponent process, one C-N, one C-O and three C-C bonds are formed with concomitant creation of five asymmetric centers and three rings. Fragmentation of epoxy-tetrahydronaphthyridine 4 affords differentially substituted 5,6,7,8-tetrahydro-1,7-naphthyridine (5, 6) depending on the reaction conditions, providing thus additional structural diversity. A one-pot three-component synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridine (6) from 7, 8 and 9 is also documented.     

Bicyclo[2.2.2]octene-based molecular spacers. Construction of U-shaped syn-facial etheno-bridged polyhydrononacenyl frameworks

Based on the methodology of repetitive Diels-Alder reactions, the rack- and U-shaped polycyclic compounds 15b, 17b, 19, 20, and 21 were constructed utilizing 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene (TDCp), p-benzoquinone, and norbornadiene as starting materials. These spacer molecules are composed of nine linearly syn-fused polyhydrobenzene rings (i.e., polyhydrononacene), in which all the etheno-bridge double bonds are arranged on the same side of the carbon skeletons. Upon irradiation with an ordinary tungsten lamp, 17b and 21 underwent [2+2]photocyclization to form quadruple- and double-caged compounds 18 and 22, respectively. The structure of 20 was analyzed by X-ray crystallography and found to have U-shaped framework.     

Synthesis of BCD tricyclic analogues of the novel cardiac glycoside rhodexin A

A concise synthesis of novel cardiac glycoside analogues of rhodexin A, 14 and 24, having the BCD tricyclic system is described. The key constructive step is an inverse-electron demand Diels-Alder reaction of the silyl enol ether 4 and the 2-acetyldiene, 7 and 15.     

A simple synthesis of cytotoxic endoperoxide lactones

A series of dihydrobenzofuran-2-one 3 have been submitted to various dienophiles: whereas maleic anhydride led only to the adducts 4a,b, singlet oxygen gave the expected new endoperoxide lactones 5a-d, 6 and 7a,b, three of them showing interesting cytotoxicity towards various cancer cell lines.