Diene Unit Research Articles

Complete stereochemistry and preliminary structure-activity relationship of rakicidin A, a hypoxia-selective cytotoxin from Micromonospora sp.

The complete stereochemistry of rakicidin A, a hypoxia-selective cytotoxin produced by Micromonospora sp., was unambiguously established by extensive chemical degradation and derivatization studies. During the PGME derivatization-based configurational analysis of 3-hydroxy-2,4,16-trimethylheptadecanoic acid, an irregular Δδ distribution was observed, which necessitated further acylation of the 3-hydroxy group to resolve the inconsistency. A hydrogenated derivative of rakicidin A, its ring-opened product, and two congeners with different alkyl chain lengths were tested for hypoxia-selective cytotoxicity. The results indicated that both the conjugated diene unit and appropriate chain length are essential for the unique activity of rakicidin A.

Synthesis and α‐Glucosidase and α‐Amylase Inhibitory Activity Evaluation of Azido‐ and Aminocyclitols

AbstractFor the synthesis of some azido‐ and aminocyclitols, (3aRS,7aSR)‐1,3,3a,7a‐tetrahydroisobenzofuran was used as the starting material. For further functionalization of the diene unit, the diene was subjected to epoxidation reactions to give mono‐ and bisepoxides depending on the amount of m‐chloroperbenzoic acid used. The ring‐opening of the epoxide functionality with NaN3 resulted in the formation of mono‐ and bisazido cyclitols. The tetrahydrofuran ring was opened in an acid‐catalysed reaction with sulfamic acid. The reduction of azide groups to give amines provided various amino‐ and bisaminocyclitol derivatives. The inhibitory effects of 20 compounds against α‐glucosidase and α‐amylase were tested. The results indicated that some of these compounds seem to have good inhibitory activity against α‐glucosidase, and low inhibitory activity against α‐amylase. Furthermore, it was demonstrated that the number and position of azides, amines, and hydroxy groups appeared to play an important role in determining the inhibitory potency of these compounds.

Regioselectivity in the Cu(I)-catalyzed [4 + 2]-cycloaddition of 2-nitrosopyridine with unsymmetrical dienes.

The thermal (uncatalyzed) and Cu(I)-catalyzed reactions of 2-nitrosopyridine (PyrNO) with the dienes 1,3-pentadiene, E,E-2,4-hexadienol, and 1-phenylbutadiene are investigated experimentally and computationally. The uncatalyzed reactions of the first two dienes occur with low regioselectivity, while the latter proceeds with complete proximal selectivity. Using the M06/6-311+G(d,p)-SDD method, various concerted transition states for the reactions of 2-nitrosopyridine with (E)-1,3-pentadiene and 1-phenylbutadiene were computed. In quantitative agreement with the experimental findings, (a) no energy difference (0.0 kcal/mol) is found between the most stable transition states, endo-prox-anti and endo-dist-anti, in the pentadiene/PyrNO reaction, leading to nearly equal amounts of prox and dist cycloadducts, and (b) the proximal transition state is strongly favored (by 3.7 kcal/mol) over the distal for the highly selective phenylbutadiene/PyrNO reaction. The regioselectivity of the pentadiene/PyrNO reaction is improved markedly (90:10 dist/prox) when catalyzed by Cu(CH3CN)4(+); (diimine)2Cu(+) catalysts increase selectivity for the proximal product (55-65%). Modest effects of the catalyst nature on regioselectivity are observed in the sorbyl alcohol and 1-phenylbutadiene reactions. The relative affinity of an equilibrating set of (diimine)2Cu(+) complexes for the prox and dist cycloadducts, assessed by ESI-MS, is marginally correlated with the prox/dist product regioselectivity produced by the corresponding catalysts. Transition states in the Cu(CH3CN)4(+)- and Cu(diimine)2(+)-catalyzed reactions are located that account for the observed regioselectivities. Coordination effects on the regioselectivity are derived from FMO orbital interactions and the extent of electron transfer between the Cu center and the coordinated nitroso and diene units.

Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-β-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron β-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

Trisequential Photooxygenation Reaction: Application to the Synthesis of Carbasugars

4,5-Dimethylenecyclohex-1-ene was subjected to a photooxygenation reaction to introduce oxygen functionalities. The endoperoxide obtained underwent an ene-reaction to form hydroperoxides with 1,3-diene structures. Further addition of singlet oxygen to the diene units resulted in the formation of tricyclic hydroperoxides having three oxygens in the molecule. Cleavage of the oxygen-oxygen bonds followed by epoxidation of the remaining C-C double bond and concomitant ring-opening reaction furnished the isomeric carbasugars.

Synthesis and Performance of Acyloxy-diene-Fe(CO)3 Complexes with Variable Chain Lengths as Enzyme-Triggered Carbon Monoxide-Releasing Molecules

Novel η4-acyloxy-cyclohexadiene-Fe(CO)3 complexes (with variable length of the acyloxy chain) were synthesized as potential enzyme-triggered carbon monoxide (CO)-releasing molecules (ET-CORMs). The molecular structure of two complexes was additionally confirmed by X-ray crystallography. The enzyme-triggered CO-releasing activity of the compounds was assessed under physiological conditions (37 °C, 0.1 M phosphate buffer, pH = 7.4) by headspace gas chromatography (GC) and additionally by means of a myoglobin assay (UV). The relative rate of CO release and the amount of liberated CO were found to depend on the length of the acyloxy chain and its position at the diene unit (outer or inner position). Some of the new ET-CORMs exhibited very good biological activity as assessed in different cellular assays (cytotoxicity, protective effect against hypothermia-associated cell damage, and inhibition of TNF-α-mediated VCAM-1 expression).

From natural product to marketed drug: the tiacumicin odyssey

The first members of the tiacumicin family of antibiotics, encompassing more than 40 compounds, were isolated in 1975. Structurally, the core aglycon is an 18-membered macrolactone having two conjugated diene units, one isolated double bond, 5 stereogenic centers and most often, at least one glycosidic linkage. Tiacumicin B, a RNA synthesis inhibitor, is a narrow-spectrum antibiotic against clostridia. For the treatment of Clostridium difficile infection (CDI), it has the same cure rate as vancomycin but with lower relapse rate and was approved by the FDA in May 2011. The aim of this review is to present an overview of the chemistry and biology of tiacumicins since their discovery.

The Formal Total Synthesis of FR252921 – An Immunosuppressant

AbstractThe formal total synthesis of FR252921 is described. The key steps include the preparation of three fragments starting from 1,4‐butanediol, (R)‐malic acid, and prenol, respectively, followed by two consecutive peptide couplings of the three fragments. Other key steps involve an allene‐type rearrangement or enyne isomerization to install the triene moiety, a Seebach methylation, a Julia olefination to construct the trisubstituted diene unit, and an enzymatic resolution strategy to generate the C‐18 stereocenter.

Synthesis of a New 2,3‐Diaminoconduritol with Conduritol F Structure

AbstractA new 2,3‐diaminoconduritol derivative with the conduritol F structure was prepared starting from cyclohexa‐1,4‐diene. Initially, a lactam, prepared by the cycloaddition of chlorosulfonyl isocyanate (CSI) to cyclohexa‐1,4‐diene, was converted into an amino acid. The conversion of the acid functionality into an isocyanate resulted in the formation of an imidazolidinone derivative, formed by an intramolecular cyclization. In the second part of this work, the known anhydride, 3a,4,7,7a‐tetrahydroisobenzofuran‐1,3‐dione was successfully converted into the desired bis(carbamate). The bromination of the double bond in the six‐membered ring followed by a DBU‐induced (DBU = 1,8‐diazabicyclo[5.4.0]undec‐7‐ene) HBr elimination furnished the symmetrical diene. The photooxygenation of the diene unit afforded the bicyclic endoperoxide. The reaction of the endoperoxide with thiourea followed by acetylation resulted in the formation of a syn‐configured diacetate. The deprotection of the urethane and acetate groups gave the new 2,3‐diaminoconduritol with the conduritol F structure.

Synthesis of Bishomoinositols and an Entry for Construction of a Substituted 3-Oxabicyclo[3.3.1]nonane Skeleton

1,3,3a,7a-Tetrahydro-2-benzofuran was used as key compound for the synthesis of various bishomoinositol derivatives. The diene was subjected to an epoxidation reaction for further functionalization of the diene unit. The bisepoxide obtained was submitted to a ring-opening reaction with acid in the presence of water. Various bishomoinositols were synthesized. However, when the reaction was carried out in the presence of acetic anhydride, a substituted 3-oxabicyclo[3.3.1]nonane skeleton was formed. The mechanism of the formation of the products is discussed.

Synthesis of 6H-Dibenzo[b,d]pyran-6-ones Using the Inverse Electron Demand Diels–Alder Reaction

A set of coumarin-fused electron-deficient 1,3-dienes was synthesized, which differ in the nature of the electron-withdrawing group (EWG) at the terminus of the diene unit and (when EWG = CO(2)Me) the nature and position of substituents. These dienes reacted with the enamine derived from cyclopentanone and pyrrolidine to afford the corresponding cyclopenteno-fused 6H-dibenzo[b,d]pyran-6-ones, most likely via a domino inverse electron demand Diels-Alder (IEDDA)/elimination/transfer hydrogenation sequence. The parent diene (EWG = CO(2)Me, no substituents) was reacted with a range of electron-rich dienophiles (mostly enamines) to afford the corresponding 6H-dibenzo[b,d]pyran-6-ones or their nondehydrogenated precursors, which were aromatized upon treatment with a suitable oxidant. The enamines could either be synthesized prior to the reaction or generated in situ. The syntheses of 30 dibenzopyranones are reported.

Stereoselective synthesis of optically active dihydrofurans and dihydropyrans via a ring closing metathesis reaction

A ring closing metathesis reaction of dienes and a ring closing enyne metathesis reaction derived from allyl, homoallyl and homopropargyl alcohol backbones are described. 2-Heteroaryl substituted allyl, homoallyl and homopropargyl alcohols have been easily and efficiently resolved through enzymatic resolution with high ee (93–99%) and known stereochemistry. Enantiomerically enriched dienes derived from allyl and homoallyl alcohols afforded the corresponding enantiomerically enriched dihydrofuran and dihydropyran derivatives, respectively, with chemical yields which varied between 72% and 88%. On the other hand, enantiomerically enriched enynes derived from homoallyl and homopropargyl alcohols gave the corresponding optically active dihydropyrans with conjugated diene units with chemical yields between 70% and 80%. A subsequent Diels–Alder reaction of the dihydropyran derivatives with a diene unit with tetracyanoethylene resulted in the formation of a diastereomeric dihydroisochromene ring system as the sole product.

Stereoselective Synthesis ofE,Z-Configured 1,3-Dienes by Ring-Closing Metathesis. Application to the Total Synthesis of Lactimidomycin

Strategic positioning of a silyl group on the diene unit of a diene-ene substrate allows rigorous regio- and stereocontrol to be exerted during metathesis-based macrocyclization reactions. The versatility of this concise approach to E,Z-configured 1,3-dienes of ring sizes of 12 or larger is demonstrated by an application to the total synthesis of lactimidomycin, a potent translation and cell-migration inhibitor.

Analysis of 5-ethylidene-2-norbornene in ethylene-propylene-diene terpolymer using pyrolysis-GC/MS

Ethylene-propylene-diene terpolymer (EPDM) having 5-ethylidene-2-norbornene (ENB) as a diene unit was pyrolyzed and the pyrolysis products were analyzed using gas chromatography/mass spectrometry (GC/MS) to develop a method for identification and quantitation of ENB. Pyrolysis products formed from ENB units were determined by comparing pyrolysis products of EPDMs with different ENB contents. Principal pyrolysis products generated from ENB units were benzene, toluene and 4-ethylidene-1-cyclopentene. Relative peak intensities of benzene and toluene increased as the pyrolysis temperature increased, whereas that of 4-ethylidene-1-cyclopentene decreased. The differences in peak intensity ratios of the ENB-derived pyrolysis products/propylene between EPDM and EPM (ENB content = 0 wt%) linearly increased as the ENB content of EPDM increased. ENB content in EPDM can be determined using the linear relationship between the difference in the peak intensity ratios and the ENB content.

Synthesis of poly(styrene-co-diene)-block-polyglycidol. Self-association and stabilization of aggregates

A series of amphiphilic poly(styrene(S)-co-diene(D))-b-polyglycidol(G) block copolymers have been synthesized from a parent hydrophobic PS block. The block has been previously functionalized with double bonds of randomly distributed diene units (isoprene (I) or butadiene (B)). Hydrophilic PG blocks of different lengths have been introduced into the above prepolymers. Polymer aggregates of different size and shape have been obtained by dissolving the copolymers in organic and mixed organic/water solutions. The formation of nano- and microsized particles has been revealed by light scattering and microscopic studies. A protocol for preparation of aggregates of a tailored core/shell structure has been demonstrated. Stabilization of particles of the desired morphology with ongoing participation of double bonds in the diene units has been achieved by irradiation with UV light directly in solution.

Domino Pd‐Catalyzed Heck Cyclization and Bismuth‐Catalyzed Hydroamination: Formal Synthesis of Elacomine and Isoelacomine

The formal synthesis of hemiterpene spirooxindole alkaloids elacomine (1) and isoelacomine (2) is described. Heck reaction of protected iodoanilines with 5,6-dihydro-2H-pyran-2-one or six-membered unsaturated lactams was investigated. The coupling product was readily converted to a carbamoyl chloride with an incorporated diene unit. The spiro(pyrrolidine-3,3'-oxindole) skeleton, which corresponds to the carbon skeleton of 1 and 2, was efficiently constructed from this intermediate by using a domino palladium-catalyzed Heck reaction and bismuth-catalyzed hydroamination. An isolated byproduct of the reaction could also be converted to the spirooxindole skeleton.

Mechanistic Investigation of Organolanthanide-Mediated Hydroamination of Conjugated Aminodienes: A Comprehensive Computational Assessment of Various Routes for Diene Activation

The present computational mechanistic study comprehensively explores alternative scenarios for activation of the amine-linked diene C=C linkage toward C-N ring closure in intramolecular hydroamination of a prototypical aminodiene by a well-characterised lanthanocene-amido catalyst. Firstly, the non-insertive mechanism by Scott featuring ring closure with concomitant amino proton delivery onto the diene unit has been explored and key features have been defined. This scenario has been compared with the classical stepwise insertion mechanism that involves rapid substrate association/dissociation equilibria for the 3t-S1 resting state and also for azacycle intermediates 4s, 4a, facile and reversible exocyclic migratory diene insertion into the La-N(amido) σ-bond, linked to turnover-limiting La-C azacycle aminolysis. The Ln-N σ-bond insertive mechanism prevails for the examined intramolecular hydroamination of (4E,6)-heptadienylamine 1t by [Cp*(2)La-CH(TMS)(2)] starting material 2.The following aspects are in support of this mechanism: 1) the derived rate law is consistent with the observed empirical rate law; 2) the assessed effective barrier for turnover-limiting aminolysis does agree remarkably well with empirically determined Eyring parameters; 3) the ring-ether double-bond selectivity is consistently elucidated. This study reveals that the non-insertive mechanism is not achievable for the particular lanthanocene-amido catalyst and furthermore cannot account for the observed product spectrum. Notwithstanding of these findings, the non-insertive mechanism cannot be discarded a priori for intramolecular aminodiene hydroamination. Spatial demands around the lanthanide centre influence the two mechanisms differently. The Ln-N σ-bond insertive mechanism critically relies on a sufficiently accessible lanthanide and enhanced encumbrance renders cyclisation and aminolysis steps less accessible kinetically. It contrasts with the non-insertive mechanism, where greater lanthanide protection has a rather modest influence. The present study indicates that the non-insertive mechanism would prevail if the lanthanide centre were to be protected effectively against C=C bond approach. Notably, a different product spectrum would be expected for aminodiene hydroamination following the insertive or non-insertive route.

Cobalt‐Mediated Radical Coupling (CMRC): An Unusual Route to Midchain‐Functionalized Symmetrical Macromolecules

Cobalt-mediated radical coupling (CMRC) is a straightforward approach to the synthesis of symmetrical macromolecules that relies on the addition of 1,3-diene compounds onto polymer precursors preformed by cobalt-mediated radical polymerization (CMRP). Mechanistic features that make this process so efficient for radical polymer coupling are reported here. The mechanism was established on the basis of NMR spectroscopy and MALDI-MS analyses of the coupling product and corroborated by DFT calculations. A key feature of CMRC is the preferential insertion of two diene units in the middle of the chain of the coupling product mainly according to a trans-1,4-addition pathway. The large tolerance of CMRC towards the diene structure is demonstrated and the impact of this new coupling method on macromolecular engineering is discussed, especially for midchain functionalization of polymers. It is worth noting that the interest in CMRC goes beyond the field of polymer chemistry, since it constitutes a novel carbon-carbon bond formation method that could be applied to small organic molecules.

Total Synthesis of the Anti-Apoptotic Agents Iso- and Bongkrekic Acids

The first convergent total synthesis of isobongkrekic acid is reported involving three different stereospecific palladium cross-couplings for the formation of the diene units. Access to bongkrekic acid by this route is also demonstrated. These syntheses involve the formation of several potentially general building blocks.

Influence of Appended Groups on the Formation of 16-Membered Macrolactone Core Related to the Plecomacrolides via Diene-Ene Ring-Closing Metathesis

A 1,3-diene-ene ring-closing metathesis (RCM) strategy was investigated for assembling the 16-membered macrolactone core of the plecomacrolides. It was found that the desired (10E,12E)-diene unit could be constructed from the fully functionalized C13-C17 homoallyl alcohol fragment and the C1-C12 acid fragment possessing one E double bond at C2-C3 or C3-C4. The functional groups at C2 and C3 resulted in preferential formation of the undesired (12Z)-macrolactone, while additional appended groups at C6-C8 furnished the (12Z)-macrolactone as the sole RCM product.