Diene System Research Articles

ChemInform Abstract: Intramolecular Palladium(0)-Catalyzed Coupling of Enol Triflate and Vinylstannane Functions. New Annulation Sequences Leading to Bicyclic Diene Systems.

Abstract A new, concise annulation method leading to the efficient production of structurally novel bicyclic dienes has been developed. The individual synthetic steps that constitute this method, as outlined in general terms in Scheme 1, involve (a) the alkylation of (functionalized) carbonyl compounds with ϵ-iodo-2-trimethylstannyl-1-alkenes (17 → 21), (b) the conversion of the alkylatlon products into the corresponding enol trifluoromethanesulfonates (triflates) (21 → 22), and (c) the palladlum(0)-catalyzed intramolecular coupling of the enol triflate-vinylstannanes to provide the dienes (22 → 23). The generality of the method is demonstrated by the synthesis of functionalized bicyclo(4.3.0]nonane (61, 62, 65, 66), bicyclo[4.4.0]decane (63, 64, 67, 68, 71), bicyclo[5.3.0]decane (70), and bicyclo[5.4.0]undecane (69) derivatives.

ChemInform Abstract: Intramolecular Addition of Hydroxy Group to a Diene System: Oxymercuration-Demercuration and Titanium Tetrachloride-Catalyzed Synthesis of Manoyl Oxides.

ChemInform Abstract: Intramolecular Addition of Hydroxy Group to a Diene System: Oxymercuration-Demercuration and Titanium Tetrachloride-Catalyzed Synthesis of Manoyl Oxides.

ChemInform Abstract: Routes to Derivatives of Strigol (the Witchweed Germination Factor) Modified in the 5-Position.

Abstract The title compounds were prepared using nucleophilic substitution in the 5- position of 5b, 6b, 11a, and 11b or electrophilic addition to the diene system in 4 as key reactions. Methods for configurational assignment at C-5 and C-2′ are discussed.

Total Synthesis of Sporolide B and 9-epi-Sporolide B

The total synthesis of the structurally unique secondary metabolite sporolide B (1b) is described. The total synthesis of 1b was developed on the basis of preliminary studies that revealed the reactivity of an appropriate o-quinone as a diene system toward a number of indene derivatives as dienophiles, first in intermolecular and thence intramolecular settings. Thus, substrates were devised (37 and 75) that underwent exquisite intramolecular [4+2] cycloaddition reactions under thermal conditions to provide primitive sporolide-type structures that were subsequently elaborated to a sporolide model system, 9-epi-sporolide B, and 1b. The requisite indene o-quinone precursor 75 was synthesized through a ruthenium-catalyzed [2+2+2] cycloaddition reaction between a propargylic alcohol and a chloroacetylenic cyclopentenyne, followed by elaboration and silver-promoted oxidation of the resulting chloroindene derivative. In addition to the total synthesis of 1b, this work demonstrated, for the first time, the power of the intramolecular hetero [4+2] cycloaddition reaction in the total synthesis of complex molecules and the application of the ruthenium-catalyzed [2+2+2] cycloaddition reaction to highly substituted indene systems possessing a chlorine residue on the aromatic nucleus.

Reactions of δ-functionalized α-nitrodienes with N-mono- and N,S-binucleophiles

δ-Functionalized α-nitrodienes are polyconjugated electron-deficient systems capable of vigorously reacting with nucleophilic reagents. The results of reactions of 1,4-dinitrodienes with aromatic amines and thiols are determined by nucleophilic attack at the middle or terminal carbon atom of the diene system [1, 2]. In the present communication we report the results of our study on reactions of 1-nitro-4-arylsulfonyldienes I and II with aromatic amines and of 1,4-dinitroand 1-nitro-4-sulfanyldienes III–V with N,S-binucleophiles. Products of addition of 2 equiv of aniline and ethanethiol to 1,4-dintrodienes [1, 2], as well as products of substitution by aromatic thiols, were reported previously.

Synthesys of a Functionalized Tetrahydrofuran Fragment Through Bromination-Cyclization of a Conjugated Diene

Conjugate 1,4-addition of N-bromosuccinimide (NBS) to a diene system, possessing a suitable oxygen functionality, leads to functionalized tetrahydrofuran derivatives, which can be further derivatized into different synthetic targets.

Analysis of Hydroperoxides, Aldehydes and Epoxides by1H Nuclear Magnetic Resonance in Sunflower Oil Oxidized at 70 and 100 °C

A global study of sunflower oil oxidation at two different temperatures (100 and 70 degrees C) with aeration was carried out by (1)H nuclear magnetic resonance ((1)H NMR), paying attention not only to the degradation of the main components but also to the formation of others. The functional groups of compounds monitored simultaneously during the oxidation were, in addition to acyl groups, the following: hydroperoxides, conjugated dienic systems of hydroperoxy acyl groups, aldehydes including the genotoxic and cytotoxic oxygenated alpha,beta-unsaturated aldehydes, and mono- and diepoxides. Chemical shifts of protons of all mentioned groups were given. Differences between both oxidation processes were found from the initial stages to the end. The formation of diepoxides in the oxidation process of edible oils was shown for the first time, as was the influence of temperature on the formation of epoxy acyl groups, some of these latter related to leukotoxin and isoleukotoxin.

Stereocontrolled synthesis of (3Z,5E)-6-aryl-3-methylhexa-3,5-dien-1-ols, intermediates in the synthesis of strobilurin antibiotics

(2E,4E)-5-Aryl-2-(2-benzyloxyethyl)penta-2,4-dien-1-als (aryl is phenyl and 4-methox-yphenyl) were reduced with NaBH4 quantitatively and stereospecifically to the corresponding penta-2(E),4(E)-dien-1-ols. The hydroxymethyl group in the latter was transformed into a methyl one with a stereoselectivity of 92–97%. Debenzylation of the resulting (1E,3Z)-1-aryl-6-benzyloxy-4-methylhexa-1,3-dienes with AlCl3 in the presence of PhNMe2 afforded the target (3Z,5E)-6-aryl-3-methylhexa-3,5-dien-1-ols; the configuration of the C=C bonds in the conjugated aryl diene systems was retained at 95%.

Electrostatic Interaction of Phytochromobilin Synthase and Ferredoxin for Biosynthesis of Phytochrome Chromophore

In plants, phytochromobilin synthase (HY2) synthesize the open chain tetrapyrrole chromophore for light-sensing phytochromes. It catalyzes the double bond reduction of a heme-derived tetrapyrrole intermediate biliverdin IXalpha (BV) at the A-ring diene system. HY2 is a member of ferredoxin-dependent bilin reductases (FDBRs), which require ferredoxins (Fds) as the electron donors for double bond reductions. In this study, we investigated the interaction mechanism of FDBRs and Fds by using HY2 and Fd from Arabidopsis thaliana as model proteins. We found that one of the six Arabidopsis Fds, AtFd2, was the preferred electron donor for HY2. HY2 and AtFd2 formed a heterodimeric complex that was stabilized by chemical cross-linking. Surface-charged residues on HY2 and AtFd2 were important in the protein-protein interaction as well as BV reduction activity of HY2. These surface residues are close to the iron-sulfur center of Fd and the HY2 active site, implying that the interaction promotes direct electron transfer from the Fd to HY2-bound BV. In addition, the C12 propionate group of BV is important for HY2-catalyzed BV reduction. A possible role for this functional group is to mediate the electron transfer by interacting directly with AtFd2. Together, our biochemical data suggest a docking mechanism for HY2:BV and AtFd2.

Modular Total Synthesis of Archazolid A and B

A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.

Contribution to Further Understanding of the Evolution of Sunflower Oil Submitted to Frying Temperature in a Domestic Fryer: Study by1H Nuclear Magnetic Resonance

A study is made of the evolution of the composition of sunflower oil kept over prolonged periods of time at high temperature (190 degrees C) in a domestic fryer. The technique used is (1)H NMR spectroscopy. The degradation rate of linoleic acyl groups is determined in this process, as well as the proportions of monounsaturated, of saturated plus modified acyl groups and the iodine values. Intermediate oxidation compounds having hydroperoxide groups and conjugated dienic systems were not detected; however, some secondary oxidation compounds such as aldehydes are generated very early, among them, the genotoxic and cytotoxic 4-hydroxy-trans-2-alkenals. Both concentrations of each kind of aldehyde at different heating times and changes in their concentration were also determined. Simultaneously, the level of oil degradation corresponding to a content of 25% of polar compounds measured by Viscofrit test was analyzed in function of the (1)H NMR spectra derived data.

Metabolic diversity in biohydrogenation of polyunsaturated fatty acids by lactic acid bacteria involving conjugated fatty acid production

Lactobacillus plantarum AKU 1009a effectively transforms linoleic acid to conjugated linoleic acids of cis-9,trans-11-octadecadienoic acid (18:2) and trans-9,trans-11-18:2. The transformation of various polyunsaturated fatty acids by washed cells of L. plantarum AKU 1009a was investigated. Besides linoleic acid, alpha-linolenic acid [cis-9,cis-12,cis-15-octadecatrienoic acid (18:3)], gamma-linolenic acid (cis-6,cis-9,cis-12-18:3), columbinic acid (trans-5,cis-9,cis-12-18:3), and stearidonic acid [cis-6,cis-9,cis-12,cis-15-octadecatetraenoic acid (18:4)] were found to be transformed. The fatty acids transformed by the strain had the common structure of a C18 fatty acid with the cis-9,cis-12 diene system. Three major fatty acids were produced from alpha-linolenic acid, which were identified as cis-9,trans-11,cis-15-18:3, trans-9,trans-11,cis-15-18:3, and trans-10,cis-15-18:2. Four major fatty acids were produced from gamma-linolenic acid, which were identified as cis-6,cis-9,trans-11-18:3, cis-6,trans-9,trans-11-18:3, cis-6,trans-10-18:2, and trans-10-octadecenoic acid. The strain transformed the cis-9,cis-12 diene system of C18 fatty acids into conjugated diene systems of cis-9,trans-11 and trans-9,trans-11. These conjugated dienes were further saturated into the trans-10 monoene system by the strain. The results provide valuable information for understanding the pathway of biohydrogenation by anaerobic bacteria and for establishing microbial processes for the practical production of conjugated fatty acids, especially those produced from alpha-linolenic acid and gamma-linolenic acid.

Synthesis of the C11–C23 Fragment of the Potent Antitumor Agent Dictyostatin (Eur. J. Org. Chem. 10/2009)

AbstractThe cover picture shows the intermolecular interactions between the marine‐derived dictyostatin and the β‐tubulin binding site, as well as some important molecular fragments of the required 15‐step sequence to produce the C11–C23 fragment (highlighted in blue) of dictyostatin in good overall yield. Dictyostatin, an unsaturated 22‐membered macrolactone containing 11 stereocenters, a (Z)‐alkene, and two diene systems, exhibits potent antitumoral activity as a consequence of its reversible and specific binding to the β‐tubulin cavity and modulation of microtubule function. Details of the synthesis and characterization of the C11–C23 fragment are reported in the Short Communication by L. C. Dias et al. on p. 1491 ff. The authors thank Ms. Lívia B. Salum for her contribution to the design of the cover picture.

Graphical Abstract: Eur. J. Org. Chem. 10/2009

AbstractThe cover picture shows the intermolecular interactions between the marine‐derived dictyostatin and the β‐tubulin binding site, as well as some important molecular fragments of the required 15‐step sequence to produce the C11–C23 fragment (highlighted in blue) of dictyostatin in good overall yield. Dictyostatin, an unsaturated 22‐membered macrolactone containing 11 stereocenters, a (Z)‐alkene, and two diene systems, exhibits potent antitumoral activity as a consequence of its reversible and specific binding to the β‐tubulin cavity and modulation of microtubule function. Details of the synthesis and characterization of the C11–C23 fragment are reported in the Short Communication by L. C. Dias et al. on p. 1491 ff. The authors thank Ms. Lívia B. Salum for her contribution to the design of the cover picture.

Timing of the Δ10,12-Δ11,13 Double Bond Migration During Ansamitocin Biosynthesis in Actinosynnema pretiosum

The timing of introduction of the unusually placed Delta(11,13) diene system in ansamitocin (AP) biosynthesis was probed by synthesizing optically active potential tri- and tetraketide intermediates as their SNAC thioesters. An AP-nonproducing mutant Actinosynnema pretiosum was complemented by the R enantiomer of the triketide and by the tetraketide with rearranged double bonds, but not by the tetraketide carrying the double bonds in conjugation to the thioester function. The results show that the double bonds are installed in their final positions during processing of the nascent polyketide on module 3 of the asm PKS and that KS4 of the PKS acts as a gatekeeper which accepts only a tetraketide with shifted double bonds as substrate for further processing.

Study of Very Reactive Tautomeric Phenol Dienones as Dienes in Diels−Alder Reactions

Masked ortho-benzoquinones are very reactive as diene partners in Diels-Alder reactions. Careful exploration of the orbital factors that govern their surprising behavior shows that their LUMO is almost as electron demanding as that of o-benzoquinone itself. Methyl substituents at either end of their diene system influence the activation energy through modification of the reaction pathway being more or less asynchronous.

Stereoselective Synthesis of a 4a,9-Disubstituted Octahydroacridine from Isatin

An efficient method for stereoselective synthesis of a 4a,9-disubstituted octahydroacridine derivative from isatin (2,3-indolinedione) was developed; the method is based on an intramolecular reaction of an N-acyliminium ion with a conjugated diene system.

Genepolide, a Sesterpene γ-Lactone with a Novel Carbon Skeleton from Mountain Wormwood (Artemisia umbelliformis)

The sesterpene gamma-lactone genepolide (5) has been isolated from a Swiss horticultural variety of mountain wormwood (Artemisia umbelliformis) developed as a thujones-free alternative to native Western Alps wormwoods for the production of liqueurs. Genepolide is the formal Diels-Alder adduct of the exomethylene-gamma-lactone costunolide (2) and the diene myrcene (6), two poorly reactive partners in cycloaddition reactions, and its structure was elucidated through a combination of spectroscopic methods. An investigation on the thermal stability of mixtures of 2 and 6, as well as considerations on the sensitivity of 2 to Brønsted and Lewis acids, suggests that 5 is a genuine natural product and that the Swiss chemotype of A. umbelliformis contains Diels-Alderase enzymatic activity that is lacking in native mountain wormwoods from Western Alps. Remarkable differences in thermal and acid-catalyzed reactions of the cyclodecadiene moiety of 2 and 5 suggest that quaternarization at C-11 has far-reaching effects on the reactivity of their homoconjugated medium-sized diene system. The wide occurrence of this structural motif in sesquiterpenoids makes this issue worth a systematic investigation.

Total synthesis of (-)-pseudolaric acid B.

We report a full account of our work toward the total synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon (pinaceae). Compound 1a is an antifungal and antifertility agent. Furthermore, its capacity for inhibiting tubulin polymerization makes it a potential lead for cancer therapy. Herein, we describe the use of a Ru- or Rh-catalyzed [5 + 2] intramolecular cycloaddition reaction of an alkyne and a vinylcyclopropane for the construction of the polyhydroazulene core of the molecule. Our first unsuccessful strategy for the introduction of the quaternary center based on an epoxide opening with cyanide led to the discovery of a new TBAF-mediated isomerization of a 1,4-diene to a 1,3-diene and a vinylogous eliminative opening of an epoxide to form a dienol. Our second strategy, based on the cyclization of an alkoxycarbonyl radical upon a diene system, succeeded in forming the quaternary center. Detailed studies showed the dependence of this underutilized approach for the synthesis of lactones on substrate structure and reaction conditions. In the late stage of the synthesis, the unique capacity of cerium organometallic reagents to add to a sensitive, sterically hindered ketone was demonstrated. The easy formation of an oxo-bridged derivative was the major hurdle to the completion of the synthesis and showcased the intriguing reactivity of the complex core of the pseudolaric acids.

Phycoerythrobilin Synthase (PebS) of a Marine Virus: CRYSTAL STRUCTURES OF THE BILIVERDIN COMPLEX AND THE SUBSTRATE-FREE FORM

The reddish purple open chain tetrapyrrole pigment phycoerythrobilin (PEB; A(lambdamax) approximately 550 nm) is an essential chromophore of the light-harvesting phycobiliproteins of most cyanobacteria, red algae, and cryptomonads. The enzyme phycoerythrobilin synthase (PebS), recently discovered in a marine virus infecting oceanic cyanobacteria of the genus Prochlorococcus (cyanophage PSSM-2), is a new member of the ferredoxin-dependent bilin reductase (FDBR) family. In a formal four-electron reduction, the substrate biliverdin IXalpha is reduced to yield 3Z-PEB, a reaction that commonly requires the action of two individual FDBRs. The first reaction catalyzed by PebS is the reduction of the 15,16-methine bridge of the biliverdin IXalpha tetrapyrrole system. This reaction is exclusive to PEB biosynthetic enzymes. The second reduction site is the A-ring 2,3,3(1),3(2)-diene system, the most common target of FDBRs. Here, we present the first crystal structures of a PEB biosynthetic enzyme. Structures of the substrate complex were solved at 1.8- and 2.1-A resolution and of the substrate-free form at 1.55-A resolution. The overall folding revealed an alpha/beta/alpha-sandwich with similarity to the structure of phycocyanobilin:ferredoxin oxidoreductase (PcyA). The substrate-binding site is located between the central beta-sheet and C-terminal alpha-helices. Eight refined molecules with bound substrate, from two different crystal forms, revealed a high flexibility of the substrate-binding pocket. The substrate was found to be either in a planar porphyrin-like conformation or in a helical conformation and is coordinated by a conserved aspartate/asparagine pair from the beta-sheet side. From the alpha-helix side, a conserved highly flexible aspartate/proline pair is involved in substrate binding and presumably catalysis.