E-double Bond Research Articles

Targeting phosphoglycerate kinases by tatridin A, a natural sesquiterpenoid endowed with anti-cancer activity, using a proteomic platform.

Tatridin A (TatA) is a germacrane sesquiterpenoid containing one E-double bond and one Z-double bond in its 10-membered ring, which is fused to a 3-methylene-dihydrofuran-2-one moiety. Tatridin A bioactivity has been poorly investigated despite its interesting chemical structure. Here, a functional proteomic platform was adapted to disclose its most reliable targets in leukemia monocytic cells, and phosphoglycerate kinases were recognized as the most affine enzymes. Through a combination of limited proteolysis and molecular docking, it has been discovered that tatridin A interacts with the active domains of phosphoglycerate kinase 1, altering its hinge region, and it can be accountable for tatridin A inhibition potency on enzyme activity. A more detailed tatridin A biological profile showed that it is also fully active against gastric cancer cells, downregulating the mRNA levels of chemokine receptor 4 and β-catenin and inhibiting the invasiveness of living KATO III cells as a direct consequence of phosphoglycerate kinase 1 antagonism.

Enzymatic α-Ketothioester Decarbonylation Occurs in the Assembly Line of Barbamide for Skeleton Editing.

The decarbonylation reaction has been developed significantly in organic chemistry as an effective approach to various synthetic applications, but enzymatic precedents for this reaction are rare. Based on investigations into the hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line of barbamide, we report an on-line α-ketothioester decarbonylation reaction that leads to one-carbon truncation of the elongating skeleton. This enzymatic editing reaction occurs in the first round of lipopeptide extension and modification involving the multienzymes BarE and BarF, which successively house an NRPS module to initiate the biosynthesis and a PKS module to catalyze the first round of chain extension. Starting with processing a leucine-derived α-ketoacyl starter, the ketosynthase domain in BarE displays an unusual dual activity that results in net one-carbon chain elongation. It extrudes carbon monoxide from α-keto-isocaproyl thioester and then mediates decarboxylative condenses of the resultant isovaleryl thioester with malonyl thioester to form a diketide intermediate, followed by BarF-based O-methylation to stabilize the enol form of the β-carbonyl and afford an unusual E-double bond. Biochemical characterization, chemical synthesis, computational analysis, and the experimental outcome of site-directed mutagenesis illustrate the extraordinary catalytic capability of this ketosynthase domain. This work furthers the appreciation of assembly line chemistry and opens the door to new approaches for skeleton editing/engineering of related molecules using synthetic biology approaches.

Total Synthesis of the Antidiabetic (Type 2) Lipid Mediator Protectin DX/PDX.

The first total synthesis of a lipid mediator derived from natural ω-3-fatty acid docosahexaenoic acid (DHA), 10 S,17 S-diHDHA (also referred to as protectin DX/PDX), was achieved in a convergent route (29 steps). The two chiral hydroxyl groups at C-10 and C-17 were derived from readily available ( S)-1,2,4-butanetriol and ( R)-glycidol, respectively. The two stereodefined E-double bonds were generated by a Takai olefination, and the skipped diene side chain was introduced with a stereocontrolled Wittig olefination. Importantly, the sensitive conjugated E, Z, E-triene intermediate was generated by a Boland reduction of the central triple bond of a E, E-dienyne. Overall, this synthetic strategy should allow the preparation of a larger quantity of PDX, which is inaccessible via previously reported biosynthetic approaches.

Radical-Polar Crossover Reactions of Dienylboronate Complexes: Synthesis of Functionalized Allylboronic Esters.

Radical-polar crossover reactions of dienylboronate complexes are applied to the synthesis of functionalized secondary and tertiary allylboronic esters. The transition-metal-free three-component coupling uses readily accessible dienylboronate esters as substrates in combination with various sp3/sp2 carbon nucleophiles and commercial alkyl iodides as radical precursors. In the visible light-initiated radical chain process, two new C–C bonds are formed, and the E-double bond geometry in the product allylboronic esters is controlled with good to excellent selectivity.

Short eight-steps total synthesis of racemic asteriscunolide C

ABSTRACTA concise total synthesis of racemic asteriscunolide C in eight steps has been described starting from neopentane diol involving an efficient Yamaguchi esterification using an aldehyde-acid, intramolecular Horner–Wittig–Emmons olefination, and a late stage ring-closing metathesis to construct the strained 11-membered ring with one Z- and two E-double bonds.

Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists

2-(3-(Naphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid and its 6-hydroxynaphthalen-2-yl analogue are well-known hydroxyl-carboxylic acid (HCA) receptor HCA2 agonists. A series of novel aryl derivatives of 2-amidocyclohex-1-ene carboxylic acid that contained rigidity elements, such as an E-double bond, triple bond, and trans or cis-substituted cyclopropane rings, instead of the saturated ethane linker in the amide part of the molecules were designed and synthesized, and the derivatives’ potency for the activation of HCA1, HCA2, and HCA3 receptors by 3′–5′-cyclic adenosine monophosphate (cAMP) assay were evaluated. The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation.

Uncovering the origin of Z-configured double bonds in polyketides: intermediate E-double bond formation during borrelidin biosynthesis

The dehydratase domain BorDH3 is assayed with a synthetic surrogate of the predicted tetraketide substrate and shown to be E-selective. Detailed NMR spectroscopic analysis of pre-borrelidin assigns the timing of the E-5 Z-isomerization to the very final steps of borrelidin biosynthesis.

Bioactive polyhydroxylated sterols from the marine sponge Haliclona crassiloba

Four new polyhydroxylated sterols, named halicrasterols A–D (1–4), together with six known analogs (5–10) were isolated from the marine sponge Haliclona crassiloba. Compounds 1 and 2 represented rare examples of steroids featuring 17(20)E-double bonds. The structures of 1–10 were elucidated by spectroscopic analysis and comparison with reported data. This is the first report of a steroid profile for this species. The antimicrobial activities of 1–10 were evaluated against a panel of bacterial and fungal strains in vitro, and compounds 4 and 9 showed moderate activity against some of the Gram-positive strains with MICs ranging from 4 to 32μg/mL.

On the Stereoselectivity of Ring-Opening Metathesis Polymerization (ROMP) of N-Arylpyrrolidine-Fused Cyclobutenes with Molybdenum– and Ruthenium–Alkylidene Catalyst

Ring-opening metathesis polymerization (ROMP) of cyclobutenes fused with N-arylpyrrolidene with Schrock–Hoveyda catalyst containing a racemic biphenolate ligand [Mo(N-2,6-i-Pr2C6H3)(CHCMe2Ph)(biphenolate)] gives polycyclobutenes with homogeneous tacticity and predominantly double bonds in Z-configuration. Reactions of the same substrates with the first-generation Grubbs catalyst [(Cy3P)2Cl2Ru═CHPh] or Schrock molybdenum carbene with monodendate alkoxy ligands [Mo(N-2,6-i-Pr2C6H3)(CHCMe2Ph)(OCMe(CF3)2] yield the corresponding polycyclobutene containing a mixture of Z- and E-double bonds. Upon diimide reduction, all these polycyclobutenes give the same tactic hydrogenated polymers, indicating that the stereochemistry at the asymmetric carbons remains the same in all these reactions. The stereoselectivities of ROMP with cyclobutenes and with norbornenes are compared, and the plausible mechanisms are proposed.

A 12-membered to a strained 11-membered ring: first stereoselective total synthesis of (−)-asteriscunolide C

The first stereoselective total synthesis of (-)-asteriscunolide C has been accomplished in 12 steps in a 16% overall yield. The key step is the conversion of a 12-membered to a strained 11-membered ring with one Z- and two E-double bonds employing a late stage ring-closing metathesis.

C–H Activation and E-Double Bond Formation by Ruthenium Catalysis

C–H Activation and E-Double Bond Formation by Ruthenium Catalysis

Cis, Isotactic Selective ROMP of Norbornenes Fused with N-Arylpyrrolidines. Double Stranded Polynorbornene-Based Ladderphanes with Z-Double Bonds

Upon treatment with a molybdenum-carbene with bidentate substituted biaryl-o,o′-diphenoxide ligand 12, norbornene fused with N-aryl-endo-pyrrolidine 9a undergoes ROMP to give exclusively polynorbornene with cis, isotactic-selectivity. Bis(norbornenes) connected with ferrocene 18 or benzene 20 linkers yield the corresponding double-stranded ladderphanes 19 and 21, respectively with isotactic stereochemistry having all double bonds in Z-configuration. Like the corresponding ladderphanes with E-double bonds, ladderphane 19 also assembles on HOPG to give a highly ordered two-dimensional array as revealed by STM images.

Heteroatom-Substituted Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid

(E)-4-[3'-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic properties-solubility, bioavailability, and toxicity-required improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing its E-double bond with XCH(2) (X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia.

A concise route to the C3–C23 fragment of the macrolide palmerolide A

A concise route to the C3–C23 part of the macrolide palmerolide A was developed. This part features the 7,10,11-trihydroxy sector containing the 8 E-double bond as well as the 14,16-diene subunit. The stereocenter at C-7 originated from a Noyori reduction on alkynone 8. The substrate 16 containing an enyne was obtained via a Claisen rearrangement. The vicinal diol at C10,C11 was created by a Sharpless asymmetric dihydroxylation. After selective protecting group manipulations the propargylic alcohol was reduced with Red-Al to the E-alkylic alcohol 26. The conjugated diene in the fragment 40 resulted from a Stille cross-coupling reaction between the vinylstannane derived from alkyne 30 and the vinyl iodide 39. The latter could conveniently be prepared by an aldol/Wittig strategy.

Farnesyl Diphosphate Synthase: The Art of Compromise between Substrate Selectivity and Stereoselectivity

Farnesyl diphosphate (FPP) synthase catalyzes the consecutive head-to-tail condensations of isopentenyl diphosphate (IPP, C5) with dimethylallyl diphosphate (DMAPP, C5) and geranyl diphosphate (GPP, C10) to give (E,E)-FPP (C15). The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E-double bonds during each addition of a five-carbon isoprene unit. Analysis of the C10 and C15 products from incubations with avian FPP synthase reveals that small amounts of neryl diphosphate (Z-C10) and (Z,E)-FPP are formed along with the E-isomers during the C5 --> C10 and C10 --> C15 reactions. Similar results were obtained for FPP synthase from Escherichia coli, Artemisia tridentata (sage brush), Pyrococcus furiosus, and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E. coli FPP synthase. When (R)-[2-2H]IPP was a substrate for chain elongation, no deuterium was found in the chain elongation products. In contrast, the deuterium in (S)-[2-2H]IPP was incorporated into all of the products. Thus, the pro-R hydrogen at C2 of IPP is lost when the E- and Z-double bond isomers are formed. The synthesis of Z-double bond isomers by FPP synthase during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site.

Transition Metal-Catalyzed Intramolecular Enyne Cyclization Reaction

This review summarizes the recent developments in transition metal-catalyzed 1,n-enyne cyclization reactions that have been reported in the literature from January 1, 2002 to April 30, 2005. The cyclizations described herein include four parts according the reaction mechanism, i. e. cyclization initiated by oxidative cyclometallation; by activation of the triple bond to form a vinyl metal species; by electrophilic activation of the triple bond; and by activation of the double bond. Enyne cyclizations that do not follow the above reaction mechanism are not included. Keywords: E-double bond, electrophilic activation, five-membered ring products, cycloisomerization, phosphine l igands

Thrombomodulin induction in cultured human endothelial cells by 9- cis-locked retinoic acid analogues

9- cis-Retinoic acid (RA) analogues devised to lock the 9- cis double bond by ring formation were synthesized using two stereoselective carbon–carbon bond formation reactions as key steps. The palladium-mediated Suzuki reaction was adopted to construct a 7 E-double bond (RA numbering) and the Horner–Emmons olefination was employed for stereoselective 11 E-double bond (RA numbering) formation. The synthesized 9- cis-RA analogues that are locked by five-membered ring systems (cyclopentene, dihydrofuran, and dihydrothiophene) were shown to have comparable thrombomodulin induction activities to that of 9- cis RA. Conformational analysis of these compounds showed their similarity to 9- cis RA in the spatial orientation of the side chain and the terminal carboxy group.

Tandem Au‐Catalyzed 3,3‐Rearrangement—[2 + 2] Cycloadditions of Propargylic Esters: Expeditious Access to Highly Functionalized 2,3‐Indoline‐Fused Cyclobutanes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Farnesyl Diphosphate Synthase. A Paradigm for Understanding Structure and Function Relationships in E-polyprenyl Diphosphate Synthases

The chain elongation reaction catalyzed by polyprenyl diphosphate synthases is the fundamental building reaction in the isoprenoid pathway. During chain elongation, the hydrocarbon moiety in an allylic isoprenoid diphosphate is added to the carbon–carbon double bond of isopentenyl diphosphate (IPP). The chain elongation enzymes can be divided into two genetically different families depending on whether the stereochemistry of the newly formed double bond during each cycle of chain elongation is E or Z. Farnesyl diphosphate (FPP) synthase, a member of the E-double bond family, is the best studied of the chain elongation enzymes and serves as a paradigm for understanding the reactions catalyzed by E-polyprenyl diphosphate synthases. The mechanism for chain elongation is a stereoselective electrophilic alkylation of the carbon–carbon double bond in IPP by the allylic substrate. X-ray structures of avian and E. coli FPP synthases have provided important insights about the mechanism for chain elongation and a structural basis for understanding the stereochemistry of the reaction.

Tandem Au-Catalyzed 3,3-Rearrangement−[2 + 2] Cycloadditions of Propargylic Esters: Expeditious Access to Highly Functionalized 2,3-Indoline-Fused Cyclobutanes

The treatment of readily available propargylic indole-3-acetates with a catalytic amount of AuCl(PPh3)/AgSbF6 leads to tandem activations of the propargylic esters and the in situ generated allenylic esters, resulting in expeditious access to highly functionalized cyclobutanes with fused 2,3-indoline and gamma-lactone rings and an exocyclic E-double bond through sequential 3,3-rearrangement and [2 + 2] cyclization.