Acetylide Coupling Research Articles

Synthesis and antiproliferative effect of the proposed stereoisomer of the marine sponge metabolite halisphingosine A.

The first synthesis of the proposed natural stereoisomer of halisphingosine A, a metabolite of the marine sponge Haliclona tubifera, was accomplished in 11 steps including an enantioselective Henry reaction, a Weinreb amide - acetylide coupling, and stereoselective reductions of the resulting ynone to afford the R,Z-configured allyl alcohol moiety. The synthetic product differed from the natural isolate in some 13C-NMR data. It showed antiproliferative activity at clinically relevant concentrations against six tumour cell lines including such lacking functional tumor suppressor gene p53.

First Total Synthesis of ω-Phenyl Δ6 Fatty Acids and their Leishmanicidal and Anticancer Properties.

The first total synthesis of ω-phenyl Δ6 fatty acids (FA) and their cytotoxicity (A549) and leishmanicidal (L. infantum) activities are described. The novel 16-phenyl-6-hexadecynoic acid (1) and the known 16-phenylhexadecanoic acid (2) were synthesized in 7-8 steps with overall yields of 46 % and 41 %, respectively. The syntheses of the unprecedented 10-phenyl-6-decynoic acid (3), 10-cyclohexyl-6-decynoic acid (4) and 10-(4-methoxyphenyl)-6-decynoic acid (5) was also performed in 3 steps with 73-76 % overall yields. The use of lithium acetylide coupling enabled the 4-step synthesis of 10-phenyl-6Z-decenoic acid (6) with a 100 % cis-stereochemistry. The cytotoxicity of these novel FA was determined against A549 cells and L. infantum promastigotes and amastigotes. Among the ω-phenylated FA, the best cytotoxicity towards A549 was displayed by 1, with an IC50 of 18 ± 1 μM. On the other hand, among the C10 acids, the ω-cyclohexyl acid 4 presented the best cytotoxicity (IC50 = 40 ± 2 μM) towards A549. Based on caspase-3/7 studies neither of the FA induced apoptosis in A549, thus implying other mechanisms of cell death. The antileishmanial studies were performed with the top Leishmania donovani topoisomerase IB (LdTopIB) inhibitors, namely 1 and 2 (EC50 between 14 and 36 μM, respectively), acids that did not stabilize the cleavage complexes between LdTopIB and DNA. Acids 1 and 2 displayed cytotoxicity towards L. infantum amastigotes (IC50 = 3-6 μM) and L. infantum promastigotes (IC50 = 60- 70 μM), but low toxicity towards murine splenocytes. Our results identified 1 as the optimum ω- phenylated acid of the series.

2-Methoxylated FA Display Unusual Antibacterial Activity Towards Clinical Isolates of Methicillin-Resistant Staphylococcus aureus (CIMRSA) and Escherichia coli.

The naturally occurring (6Z)-(±)-2-methoxy-6-hexadecenoic acid (1) and (6Z)-(±)-2-methoxy-6-octadecenoic acid (2) were synthesized in 7-8 steps with 38 and 13% overall yields, respectively, by using an acetylide coupling approach, which made it possible to obtain a 100% cis-stereochemistry for the double bonds. In a similar fashion, the acetylenic analogs (±)-2-methoxy-6-hexadecynoic acid (3) and (±)-2-methoxy-6-octadecynoic acid (4) were also synthesized in 6-7 steps with 48 and 16% overall yields, respectively. The antibacterial activity of acids 1-4 was determined against clinical isolates of methicillin-resistant Staphylococcus aureus (ClMRSA) and Escherichia coli. Among the series of compounds, acid 4 was the most active bactericide towards CIMRSA displaying IC50s (half maximal inhibitory concentrations) between 17 and 37μg/mL, in sharp contrast to the 6-octadecynoic acid, which was not bactericidal at all. On the other hand, acids 1 and 3 were the only acids that displayed antibacterial activity towards E. coli, but 1 stood out as the best candidate with an IC50 of 21μg/mL. The critical micelle concentrations (CMCs) of acids 1-4 were also determined. The C18 acids 2 and 4 displayed a five-fold lower CMC (15-20μg/mL) than the C16 analogs 1 and 3 (70-100μg/mL), indicating that 4 exerts its antibacterial activity in a micellar state. None of the studied acids were inhibitory towards S. aureus DNA gyrase discounting this type of enzyme inhibition as a possible antibacterial mechanism. It was concluded that the combination of α-methoxylation and C-6 unsaturation increases the bactericidal activity of the C16 and C18 FA towards the studied bacterial strains. Acids 1 and 4 stand out as viable candidates to be used against E. coli and CIMRSA, respectively.

Synthesis of the Pentacyclic Core of Citreamicin η.

The citreamicins comprise a novel class of polycyclic xanthone natural products that have not yet yielded to total synthesis. A concise 11-step synthesis of the pentacyclic core of citreamicin η is now reported that features the use of a general approach for the synthesis of 1,4-dioxygenated xanthones. The synthesis also showcases improved techniques for effecting regioselective bromination of certain substituted phenols and coupling of acetylides with hindered ketones.

Catalytic domino amination and oxidative coupling of gold acetylides and isolation of key vinylene digold intermediates as a new class of ditopic N-heterocyclic carbene complexes.

A catalytic domino amination and oxidative coupling of in situ prepared gold acetylides has been developed for the synthesis of abnormal NHC (aNHC) gold complexes, and key vinylene digold intermediates are isolated and structurally characterized.

Enantioselective Total Synthesis of Mandelalide A and Isomandelalide A: Discovery of a Cytotoxic Ring-Expanded Isomer.

The total synthesis of mandelalide A and its ring-expanded macrolide isomer isomandelalide A has been achieved. Unexpected high levels of cytotoxicity were observed with the ring-expanded isomandelalide A with a rank order of potency: mandelalide A > isomandelalide A > mandelalide B. Key aspects of the synthesis include Ag-catalyzed cyclizations (AgCC's) to construct both the THF and THP rings present in the macrocycle, diastereoselective Sharpless dihydroylation of a cis-enyne, and lithium acetylide coupling with a chiral epoxide.

Selective Synthesis of [2]- and [3]Catenane Tuned by Ring Size and Concentration

The syntheses of [2]- and [3]catenanes by olefin metathesis and oxidative acetylide coupling have been studied in detail. Pseudorotaxanes that were obtained by mixing crown ether and ammonium salts containing two terminal reactive end-groups were converted to [2]- and [3]catenane. Their yields were influenced not only by the chain length of the ammonium salts but also by the concentration of the crown ether and the ammonium salts. The strain energies of [2]catenane were responsible for the formation of [2]catenane.

Total synthesis of (+)-pentamethylsalvianolic acid C

The total synthesis of a methylated analogue of (+)-Salvianolic acid C has been achieved. Key aspects of the synthetic route include an economical Cu(I) acetylide coupling, unique carboxyl activation conditions via microwave irradiation and a novel lipase catalysed kinetic resolution of a racemic mixture of secondary alcohol Danshensu. The preparation of this methylated analogue will not only improve the bioavailability, but also enable access to new and wider bioactivity applications for (+)-Salvianolic acid C.

ChemInform Abstract: Construction of Cyclopentanol Derivatives via Three‐Component Coupling of Silyl Glyoxylates, Acetylides, and Nitroalkenes.

The three-component coupling of Mg acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective Kuwajima–Reich/vinylogous Michael cascade that provides tetrasubstituted si...

Construction of cyclopentanol derivatives via three-component coupling of silyl glyoxylates, acetylides, and nitroalkenes.

The three-component coupling of Mg acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective Kuwajima-Reich/vinylogous Michael cascade that provides tetrasubstituted silyloxyallene products. The regio- and diastereoselectivity were studied using DFT calculations. These silyloxyallenes were converted to cyclopentenols and cyclopentitols via a unique Lewis acid assisted Henry cyclization. The alkene functionality present in the cyclopentanol products can be elaborated using diastereoselective ketohydroxylation reactions.

Construction of Cyclopentanol Derivatives via Three-Component Coupling of Silyl Glyoxylates, Acetylides, and Nitroalkenes

Construction of Cyclopentanol Derivatives via Three-Component Coupling of Silyl Glyoxylates, Acetylides, and Nitroalkenes

Synthesis of the C7-26 Fragment of Amphidinolides G and H

A new approach to the synthesis of the C7-26 fragment of amphidinolides G and H was developed. In the sequence, the C7-18 portion of this fragment was synthesized using an acetylide coupling protocol, while an Evans alkylation and Sharpless asymmetric dihydroxylation were employed as key steps in construction of the C19-26 subfragment. Finally, both of these units were joined by utilizing an aldol coupling reaction to produce the target C7-26 fragment in good yield.

ChemInform Abstract: Formation of N‐Sulfonylamidines by Copper‐Catalyzed Coupling of Sulfonyl Azides, Terminal Alkynes, and Trialkylamines.

AbstractThe three‐component reaction involves coupling of copper acetylides with azides to give ketimine intermediates which are trapped by trialkylamines to yield the title compounds.

First total synthesis and antileishmanial activity of (Z)-16-methyl-11-heptadecenoic acid, a new marine fatty acid from the sponge Dragmaxia undata

The first total synthesis for the (Z)-16-methyl-11-heptadecenoic acid, a novel fatty acid from the sponge Dragmaxia undata, was accomplished in seven steps and in a 44% overall yield. The use of (trimethylsilyl)acetylene was key in the synthesis. Based on a previous developed strategy in our laboratory the best synthetic route towards the title compound was first acetylide coupling of (trimethylsilyl)acetylene to the long-chain protected 10-bromo-1-decanol followed by a second acetylide coupling to the short-chain 1-bromo-4-methylpentane, which resulted in higher yields. Complete spectral data is also presented for the first time for this recently discovered fatty acid and the cis double bond stereochemistry of the natural acid was established. The title compound displayed antiprotozoal activity against Leishmania donovani (IC50=165.5±23.4μM) and inhibited the leishmania DNA topoisomerase IB enzyme (LdTopIB) with an IC50=62.3±0.7μM.

First total synthesis and antiprotozoal activity of ( Z)-17-methyl-13-octadecenoic acid, a new marine fatty acid from the sponge Polymastia penicillus

The first total synthesis for the ( Z)-17-methyl-13-octadecenoic acid was accomplished in seven steps and in a 45% overall yield. The use of (trimethylsilyl)acetylene was key in the synthesis. Based on a previous developed strategy in our laboratory the best synthetic route towards the title compound was first acetylide coupling of (trimethylsilyl)acetylene to the long-chain protected 12-bromo-1-dodecanol followed by a second acetylide coupling to the short-chain 3-methyl-1-bromobutane, which resulted in higher yields. Complete spectral data is also presented for the first time for this recently discovered fatty acid. The title compound displayed antiprotozoal activity against Leishmania donovani (EC 50 = 19.8 μg/ml) and inhibited the leishmania DNA topoisomerase IB at concentrations of 50 μM.

Sluggish σ-Bond Formation between sp-Hybridized Carbons: Acetylide Coupling on Ag(111)

Chemisorbed methylacetylide intermediates were generated on clean Ag(111) to study the mechanism and kinetics of C−C σ-bond formation between sp-hybridized carbon centers. Following the adsorption of propynyl iodide (C3H3I) at 110 K, surface heating led to the cleavage of the C−I bond at 200 K, and the resulting surface Cα⋮Cβ−CH3 species were tilted and coordinated to the surface via a metal−carbon σ-bond with weak π-interactions, confirmed by reflection absorption infrared spectroscopy and theoretical calculations. Temperature programmed reaction (TPR) showed that a Csp−Csp coupling reaction occurred at ∼500 K to afford 2,4-hexadiyne through head-to-head dimerization involving Cα carbons. We attribute the relatively slow acetylide−acetylide coupling rate against those from vinyl−vinyl (Csp2−Csp2) and alkyl−alkyl (Csp3−Csp3) couplings to the stronger metal−carbon (M−Cα) bond strength as well as the anionic character bestowed upon the adsorbed acetylides, which all correlate with the increased s-character ...

First total syntheses of ( Z)-15-methyl-10-hexadecenoic acid and the ( Z)-13-methyl-8-tetradecenoic acid

The first total syntheses for the ( Z)-15-methyl-10-hexadecenoic acid and the ( Z)-13-methyl-8-tetradecenoic acid were accomplished in seven steps and in 31–32% overall yields. The (trimethylsilyl)acetylene was the key reagent in both syntheses. It is proposed that the best synthetic strategy towards monounsaturated iso methyl-branched fatty acids with double bonds close to the ω end of the acyl chain is first acetylide coupling of (trimethylsilyl)acetylene to a long-chain bifunctional bromoalkane followed by a second acetylide coupling to a short-chain iso bromoalkane, since higher yields are thus obtained. Spectral data is also presented for the first time for these two unusual fatty acids with potential as biomarkers and as topoisomerase I inhibitors.

Furanyl spiroketals: thermodynamic control of remote asymmetry

( E, E)-2-Alkyl-8-furanyl-1,7-dioxa-spiro[5.5]undecanes ( 1a– i) have been prepared in good yield and with very high diastereoselectivity from lactones ( 2a– e) and alkynes ( 3a, b) using lithium acetylide coupling, hydrogenation, desilylation and acid catalysed cyclisation/equilibration.

Catalytic Decarboxylative sp—sp3 Coupling.

A palladium-catalyzed 1,4-enyne synthesis was developed based the decarboxylative coupling of acetylides with allyl electrophiles. Stereochemical studies have implicated palladium−allyl−acetylides as intermediates. Thus, decarboxylative metalation was established as an environmentally benign alternative to transmetalation from alkynyl tin reagents.

Catalytic Decarboxylative sp−sp3 Coupling

A palladium-catalyzed 1,4-enyne synthesis was developed based the decarboxylative coupling of acetylides with allyl electrophiles. Stereochemical studies have implicated palladium-allyl-acetylides as intermediates. Thus, decarboxylative metalation was established as an environmentally benign alternative to transmetalation from alkynyl tin reagents.