Octane Series Research Articles

Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts.

A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.

Activation of C–H bonds of normal alkanes in sulfuric acid solutions of Mn(III)/Mn(II)

One of the most important directions of establishing the mechanisms of activation of C–H bonds, both in saturated and aromatic hydrocarbons in aqueous and sulfuric acid solutions of oxidants, metal complexes and radicals, is to study the kinetics of reactions and the influence of temperature, environment, nature of reagents, etc. The study of mechanisms is important for the development of technologies for processing hydrocarbons into products with high added value. In this work, to determine the nature of limiting stages and mechanisms of reactions of one group of saturated hydrocarbons, normal alkanes, we use the dependences of substrate selectivity (relative rate constants) on their characteristics: ionization potentials, energy and number of primary and secondary C–H bonds. To determine the nature of the limiting stages of reactions of normal alkanes, the correlations between the logarithms of substrate selectivity of alkanes reactions in H2SO4 solutions with one of the most active manganese(III) ions and molecule properties or C–H bond type were studied by the method of correlation analysis. Comparison of the obtained results with quantum-chemically calculated enthalpy changes of different possible variants of the course of this elementary reaction allowed to clarify the mechanism and propose tests to perform the mechanism of the slow limiting stage. It is shown that for alkanes (ethane, pentane, hexane, heptane, octane) the linear dependence with the ionization potential is most accurately performed, the least accurate is the correlation with the number of secondary C–H bonds, which indicates the electron abstraction in the slow limiting stage. For the shorter pentane – octane series, correlation dependences on both the number of secondary C–H bonds and the ionization potentials are performed with almost equal accuracy, which makes it impossible to establish the nature of the slow stage. The results of quantum-chemical calculations of hexane reactions in Mn(III)/Mn(II)–H2SO4 solutions showed that the most favorable are the electron abstraction by manganese(III) and subsequent proton transfer or homolysis of the C–H bond under the action of bisulfate radical, which is likely formed in the oxidation of sulfuric acid by manganese(III).

Stereospecific synthesis of endo-endo-3,7-dioxabicyclo[3.3.0]octane lignans using 1,6-bis(dipropylboryl)-2,4-hexadiene

A general methodology for the stereoselective synthesis of compounds of the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane series was developed. The strategy includes allylboration of aromatic aldehydes with 1,6-bis(dialkylboryl)-2,4-hexadiene, ozonolysis of the thus obtained 1,4-diaryl-2,3-divinyl-1,4-diols, and subsequent intramolecular cyclization. This methodology was used for obtaining the naturally occurring lignans of the furofuran series, viz., diaeudesmin, diayangambin, epiasarinin, epieudesmin, epiyangambin, and asarinin.

ChemInform Abstract: New Condensation Methods in the Synthesis of Bicyclic Bisureas.

For the first time, synthetic approaches to bicyclic bisureas of the octane series bearing three alkyl substituents at nitrogen atoms have been developed.

Synthesis of 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(Pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a Class of Potent Nicotinic Acetylcholine Receptor–Ligands

In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.

The identification of pyrimidine-diazabicyclo[3.3.0]octane derivatives as 5-HT 2C receptor agonists

The 5-HT 2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT 2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT 2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.

New condensation methods in the synthesis of bicyclic bisureas

For the first time, synthetic approaches to bicyclic bisureas of the octane series bearing three alkyl substituents at nitrogen atoms have been developed.

Selective, one‐pot synthesis of 2,3,6‐trisubstituted pyridine and 2‐cyclohexen‐1‐one derivatives from bicyclic ketals

AbstractBoron difluoromethanesulfonate, prepared from 5 equivalents of trimethylsilyl methanesulfonate and 1 equivalent of boron trifluoride etherate, has proved to be an active Lewis acid catalyst for the one‐pot transformation reaction of bicyclic ketals in the 6,8‐dioxabicyclo[3.2.1]octane series to 2,3,6‐trisubstituted pyridine or 2‐cyclohexen‐1‐one selectively, depending on conditions. A 1,5‐diketone was the reaction intermediate for both products. Pyridine was formed selectively by using a nitrile as a solvent or a reagent, but cyclohexenone was prepared in methylene chloride instead of a nitrile.

A novel ketal fragmentation with aluminium iodide

Aluminium iodide, prepared from dry aluminium foil and iodine, in acetonitrile is shown to convert bicyclic ketals in the 6,8-dioxabicyclo[3.2.1]octane series into a cyclohexenone and a substituted pyridine in one step. Details of the structural analysis are discussed. The role of the 1,5-diketone as intermediate for the formation of the cyclohexenone and the pyridine from the bicyclic ketal was secured by subjecting the isolated diketone to various reaction conditions.

A Facile One-Pot Synthesis ofcis1,2-Cyclopentanediol from Bicyclic Ketal

Abstract New method for one-pot preparation of cis 1,2-cyclopentanediols from bicyclic ketals in the 6,8-dioxabicyclo[3.2.1]octane series is described. Bicyclic ketals are refluxed for 1h with AlCl3 (3eq.) in AcOH and further refluxed for 60h after addition of Zn(8eq.) to give cis 1,2-cyclopentanediols in good yield.

Bicyclic Ketals. A Tandem Oxymercuration-Solvomercuration Protocol

Oxymercuration of an enol ether takes place faster than oxymercuration of an isolated alkene. When both functional groups are present in the same molecule, one can use a properly oriented hydroxyl group fixed from the oxymercuration process to participate in a solvomercuration of the second site. This tandem oxymercuration-solvomercuration protocol was applied to the synthesis of two natural products in the 6,8-dioxabicyclo[3.2.1]octane series

Geometrical aspects of complex formation by bicyclic bisureas

Geometrical characteristics of complexes of bicyclic bisureas (BBUs) of the octane series with biological metals (Co, Li, and Zn) have been studied using molecular mechanics. It was established that formation of the complexes [Co(BBU)2-(H2O)2-X2], [Li·BBU·(H2O)3]·X, [Zn·BBU·Cl2·(H2O)], and [Li2·(μ-BBU)2·(H2O)4]·X2 is not sterically hindered.

Approaches to 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans via asymmetric synthesis of dihydro- and tetrahydro-furan derivatives

Cyclisation of chiral non-racemic phenylsulphonylvinyl epoxy ethers, produced using the Sharpless epoxidation reaction, has been used to prepare a series of enantiomerically enriched 2-aryl-4-(α-hydroxybenzyl)-4,5-dihydrofuran derivatives. Reduction of these compounds using triethylsilane and BF3–diethyl ether gave the corresponding tetrahydrofuran derivatives stereoselectively. Attempts to convert either the dihydro- or tetrahydro-furan derivatives into lignans belonging to the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane series have so far proved unsuccessful.

ChemInform Abstract: Synthesis of Side‐Chain Unsaturated endo‐ and exo‐Brevicomins. Representatives of Pheromone Analogues in the Dioxabicyclo(3.2.1)octane Series.

ChemInformVolume 20, Issue 15 Heterocyclic Compounds ChemInform Abstract: Synthesis of Side-Chain Unsaturated endo- and exo-Brevicomins. Representatives of Pheromone Analogues in the Dioxabicyclo(3.2.1)octane Series. S. WERSHOFEN, S. WERSHOFEN Inst. Org. Chem., RWTH, D-5100 AachenSearch for more papers by this authorH.-D. SCHARF, H.-D. SCHARF Inst. Org. Chem., RWTH, D-5100 AachenSearch for more papers by this author S. WERSHOFEN, S. WERSHOFEN Inst. Org. Chem., RWTH, D-5100 AachenSearch for more papers by this authorH.-D. SCHARF, H.-D. SCHARF Inst. Org. Chem., RWTH, D-5100 AachenSearch for more papers by this author First published: April 11, 1989 https://doi.org/10.1002/chin.198915174Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume20, Issue15April 11, 1989 RelatedInformation

Synthesis of Side-Chain Unsaturatedendo- andexo-Brevicomins. Representatives of Pheromone Analogs in the Dioxabicyclo[3.2.1]octane Series

Synthesis of Side-Chain Unsaturated<i>endo</i>- and<i>exo</i>-Brevicomins. Representatives of Pheromone Analogs in the Dioxabicyclo[3.2.1]octane Series

A novel bicyclic ketal fragmentation reaction

Bicyclic ketals of the 6,8-dioxabicyclo[3.2.1]octane series are specifically cleaved to give δ, ε-unsaturated ketones by treatment of the ketal with acetyl iodide.

A new general synthetic route to bridged carboxylic ortho esters

Acylation of the readily available 3-methyl-3-hydroxymethyl oxetane ( 2 ) leads to the corresponding oxetane esters ( 3 ) which rearrange smoothly in the presence of boron trifluoride etherate in methylene chloride at −15° to form ortho esters of the 2, 6, 7-trioxabicyclo[2.2.2]octane series ( 4 ).

Crystal structures of two lactones of the bicyclo[2,2,2]octane series

The crystal structures of two γ-lactones of the bicyclo[2,2,2]octane series, endo-3-carboxy-exo-5- iodobicyclo[2,2,2]octane-2,6-carbolactone (2; R = CO2H) and exo-3-methoxycarbonyl-endo-5-acetoxybicyclo[2,2,2] octane-2,6-carbolactone (7b), have been determined by direct methods from three-dimensional X-ray data and refined by least-squares to final residuals of 0.033 (2; R = CO2H) and 0.036 (7b) for 1918 and 630 'observed' reflections respectively. Crystals for (2; R = CO2H) are monoclinic, space group P21/c with Z 8 in a cell of dimensions a 7.192(2), b 23.785(8), c 13.199(5) �, β 105.35(2)�, while (7b) crystallizes in the orthorhombic space group P212121 with Z 4 in a cell of dimensions a 13.347(7), b 11.839(7), c 8.227(11) �.

1H and 13C NMR study of the effects exerted by an oxirane ring in the epoxybicyclo‐[2.2.2]octane series

AbstractThe 1H and 13C NMR spectra of 2,3‐disubstituted exo‐5,6‐ and endo‐5,6‐bicyclo[2.2.2]octanes, and the corresponding alkanes, have been investigated to determine the effects exerted by an oxirane ring. The 1H NMR study showed that the anti protons, H‐7a and H‐8a, are significantly shielded and the syn protons, H‐7s and H‐8s, are deshielded, although to a smaller extent, by the exo‐oxirane. An endo‐oxirane has practically no effect on the same protons. The stereochemistry of epoxybicyclo[2.2.2]octanes is, thus, easily deduced from 1H NMR data. The 13C NMR study of the epoxy compounds provided an estimate of the value of α, β, γ syn and γ anti effects (to the epoxide oxygen) of an oxirane ring. In these rigid bicyclic molecules, of known geometry, the γ syn and the γ anti effects are of the same value, even though the dihedral angles are very different (0° and 120°).

The chemistry of bicyclic bisureas. 4. Reduction of bicyclic bisureas and their O-alkyl derivatives

1. When LiAlH4, is allowed to react with unsubstituted, di-, and tetra-N-alkylated bicyclic bisureas (BBU) of the octane and nonane series, reduction takes place only in the case of tetra-N-alkyl BBU, reduction of one or both carbonyl groups taking place according to the structure of the BBU. 2. Reaction of non-N-alkylated O-alkyl BBU with nucleophilic reagents results in deprotonation with the formation of bicyclic isoureas.