58944-42-6

A series of (+)-2,2-disubstituted oxiranes bearing an alkene or alkyne functional group were resolved by bacterial epoxide hydrolases with excellent selectivities. The presence of a carbon-carbon double or triple bond furnished a highly flexible system fo

The invention relates to novel compounds for use as inhibitors of NLRP3 inflammasone production, wherein such compounds are as defined by compounds of formula (I) and wherein the integers R1, R2 and R3 are defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of a disease or disorder that is associated with NLRP3 inflammasome activity.

We report the first total synthesis of samroiyotmycin A (1), a C2-symmetric 20-membered anti-malarial macrodiolide isolated from Streptomyces sp. The convergent synthetic strategy orchestrates bisalkyne fragment-assembly using an unprecedented Sch?llkopf-type condensation on a substituted β-lactone and an ambitious late-stage one-pot alkyne cross metathesis–ring-closing metathesis (ACM–RCAM) reaction. The demanding alkyne metathesis sequence is achieved using the latest generation of molybdenum alkylidynes endowed with a tripodal silanolate ligand framework. Subsequent conversion to the required E-alkenes uses contemporary hydrometallation chemistry catalysed by tetrameric cluster [{Cp*RuCl}4].

Pd(0)-systems modified with SPINOL-derived phosphoramidate ligands promote highly enantioselective aza-Heck cyclizations of alkenyl N-(tosyloxy)carbamates. The method provides versatile access to challenging N-heterocycles and represents the broadest scope enantioselective aza-Heck protocol developed to date.

Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring-formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with β- or γ-dicarbonyl systems. These processes embrace a variant of metallacycle-mediated annulation chemistry where initial alkyne-carbonyl coupling is followed by a second, now intramolecular, stereoselective C-C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring.

Lactones are known to react with the reagent generated in situ from CCl4 and PPh3 in a Wittig-type fashion to give gem-dichloro-olefin derivatives. Such compounds are now shown to undergo reductive alkylation on treatment with organolithium reagents RLi to furnish acetylene derivatives bearing the substituent R at their termini (R=Me, n-, sec-, tert-alkyl, silyl); the reaction can be catalyzed with either Cu(acac)2 or Fe(acac)3/1,2-diaminobenzene. Two alkynol derivatives prepared in this way from readily accessible lactone precursors served as the key building blocks for the total syntheses of the cytotoxic marine macrolides tulearin A (1) and C (2). The assembly of these fragile targets hinged upon ring closing alkyne metathesis (RCAM) followed by a formal trans-reduction of the resulting cycloalkynes via trans-hydrosilylation/protodesilylation.

Macrolide lactones, the so called cucujolides derived from unsaturated fatty acids, are aggregation pheromones of cucujid grain beetles. Thirty years ago, Oehlschlarger etaal. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4) and the respective 12-olide (7) attract the sawtoothed grain beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5) increases the response synergistically. The frass of this beetle is attractive for its parasitoid Cephalonomia tarsalis, which potentially can be used for pest control. A GC/MS analysis of attractive frass showed the presence of 5, together with an unknown isomer. CucujolideaV was tentatively identified also in the femoral glands, pheromone-releasing structures, of the Madagascan mantelline frog Spinomantis aglavei. Therefore, a new route to synthesize doubly unsaturated macrolides allowing the flexible attachment of the side chain was developed. A straightforward method to obtain Zaconfigured macrolides involves ring-closing alkyne metathesis (RCAM) followed by Lindlar-catalyzed hydrogenation. This methodology was extended to homoconjugated diene macrolides by using RCAM after introduction of one Zaconfigured double bond in the precursor by Wittig reaction. A tungsten benzylidyne complex was used as the catalyst in the RCAM reaction, which afforded the products in high yield at room temperature. With the synthetic material at hand, the unknown isomer was identified as the new natural product (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX (8). Furthermore, the route also allowed the synthesis of cucujolideaV in good yield. The natural products were identified by the synthesis of enantiomerically pure or enriched material and gas chromatography on chiral phases. The new macrolide (R)-8 proved to be biologically active, attracting female O.asurinamensis, but no males. The synthetic material allowed the identification of (R)-5 in both the beetle and the frog. Attractive synthesis: Females of the sawtoothed grain beetle Oryzaephilus surinamensis are attracted to the new macrolide (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX, prepared by using a combination of Wittig reaction and ring-closing alkyne metathesis (RCAM; see scheme). The synthetic approach also allows the synthesis of the similar cucujolideaV, used by both the beetle and the mantellid frog Spinomantis aglavei.

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With the help of the smaller brother: Although alkyne metathesis will always be the little brother of alkene metathesis, it allows problems to be solved that are currently beyond reach of the more famous sibling. This notion is exemplified by the tulearin macrolides, which could only be selectively forged by ring-closing alkyne metathesis (RCAM)/transreduction using the latest generation of alkyne metathesis catalysts.

The present invention refers to methyl-substituted double-unsaturated macrocyclic lactones comprising 14 to 17 ring atoms of formula (I) wherein n and m are independently selected from 1, 2, 3 and 4 with the proviso that 3 ≤ n + m ≤ 6. The invention relates furthermore to their use as odorant and fragrance composition comprising them.

The double-unsaturated macrocyclic lactones (4E,8Z)-12- methyloxacyclotetradeca-4,8-dien-2-one and its 7a-homologue (4E,9Z)-13- methyloxacyclopentadeca-4,9-dien-2-one, designed as new potent musk odorants by molecular modeling, were synthesized by ring-closing alkyne metathesis in the presence of 10 mol% of Schrock's alkylidyne catalyst, and subsequent Lindlar hydrogenation. Demethylation of citronellol, induced by nitrous acid, afforded the 3-methyloct-6-yn-1-ol building block. The substrates for the alkyne metathesis were prepared by Steglich esterification of citronellol with the 3E-configured non-3-en-7-ynoic and dec-3-en-8-ynoic acids, accessible by β,γ-selective Knoevenagel condensation from the corresponding alkynals hept-5-ynal and oct-6-ynal, which were synthesized by Eschenmoser-Ohloff fragmentation of the epoxide of 2-methylcyclohex-2-enone, and methylation of hex-5-yn-1-ol, respectively. Both target structures, (4E,8Z)-12-methyloxacyclotetradeca-4,8-dien-2-one and its 7a-homologue, emanated most pleasant and powerful musk odors. Georg Thieme Verlag Stuttgart.

A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied. The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides 5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation, which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent nucleofugacity of the triflate moiety is channeled through the σ-bond framework of 1, providing direct access to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 → 6 or 8), is also illustrated.

Cyclic vinylogous triflate hemiacetals can serve as 'synthetic equivalents' for alkynyl aldehydes: treatment of a vinylogous triflate hemiacetal with excess amounts of Grignard reagents produces acyclic alkynyl alcohols in good to high yields. This transf

We report here, an effective methodology for the preparation of 8,11-dimethylene-bicyclo[5.3.1]undecan-2-one. The key steps in these reactions were chloromethylation, cationic-alkyne cyclization and anionic fragmentation sequence.

Liquid-crystalline and light-emitting poly(2-alkyne)s and poly(-phenyl-1-alkyne)s containing biphenyl (Biph) cores, alkyl spacers, and alkoxy tails (-{RC=C[(CH2)m-OCO-Biph-OC7H 15]}n-, where R, m = CH

The Pd(0)-mediated rapid coupling (trapping) reaction of methyl iodide with an excess amount of alkynyltributyl-stannane has been developed with the aim to incorporate a short-lived 11C-labeled methyl group into biologically active organic compounds with a 1-propynyl structural unit.

Trifluoroacetylperrhenate promotes the hydroxyl-directed syn-oxidative cyclization of trishomoallylic alcohols. The cyclization reaction is highly stereospecific and stereoselective, providing a novel and efficient synthesis of trans-2,6-disubstituted tetrahydropyranyl alcohols.

The cyclisation of the alkynylhydroxylamines 2, 13, 14, 19, 27, 34, 39, 46 and 47 to give five-, six- and seven-membered cyclic nitrones is described.A concerted intramolecular ene-like pathway is proposed for the addition of the N-O-H group across the tr

Oxidative cyclization of δ,ε- and ε,ζ-unsaturated enol silyl ethers 4a and 4b with cupric triflate and cuprous oxide or ceric ammonium nitrate and sodium bicarbonate in acetonitrile provides the tricyclic ketones 5a and 5b stereoselectively.These cyclizat

The ω-silyloxypropargyltrimethylsilanes regiospecifically react with aliphatic and aromatic aldehydes to lead to vinylidene oxigen-containing heterocycles, such as 3-vinylidene oxolanes, oxanes, oxepanes and oxocanes.

The reaction of carbene-chromium complexes with alkynes provides a direct route to naphthoquinone derivatives and is the key step in a new approach to the isochromanone antibiotics exemplified by deoxyfrenolicin (1) and nanaomycin A (2).While the regioselectivity of intermolecular addition of the appropriate unsymmetrical disubstituted alkyne is unfavourable, two successful approaches have been developed.Allylacetylene reacts with methoxy-(o-methoxyphenyl)methylidene-Cr(CO)5 with high regioselectivity.Bromination, lithiation, and reaction with acetaldehyde produced the desired precursor.Alkoxypalladation led to pyran ring formation and introduction of the acetate side chain.Following earlier procedures, nanaomycin A (2) was produced.A more convergent alternative involved intramolecular cycloaddition of an alkyne with the alkylidene-chromium unit.A series of model cyclizations established the tether to hold the alkyne in place for cyclization and allows easy removal at a later stage.Deoxyfrenolicin (1) was produced in a highly convergent and efficient process.

Three triflates were solvolyzed at various temperatures in water-alcohol mixtures, in TFE-water mixtures, in TFA, in TFIP, in HFIP, and in 100% TFE in the presence of various buffers and the resulting products were determined. The three reactants were also solvolyzed in a standard mixture (1:100:100 equals triflate:TFE:Na//2CO//3) at various temperatures, and the yields of products were compared. The solvolysis products were shown to be under kinetic control.

Ligands have been synthesized containing two vicinal dioxime functions joined by a carbon chain to which is attached in the centre a bromomethyl or chloromethyl group (20, 22, 25).These ligands, upon reaction with cobalt(II) chloride in the presence of pyridine and sodium borohydride afforded bridged intramolecularly alkylated cobaloximes.When the vicinal dioxime functions are separated by a chain of nine carbon atoms mainly dimeric complexes are formed.Two of these, 26 and 27, were isolated and characterized by spectroscopic methods and their structures were established by X-ray crystallography.Ligands containing eleven or thirteen carbon atoms between the dioxime functions afforded mainly monomeric cobaloximes with cis configuration, e. g. 28.The trans-monomeric complex 30 was produced along with the cis isomer when the number of carbon atoms in the bridge was raised to fifteen.