McMurry Olefination Research Articles

Synthesis of the Altertoxin I Framework

AbstractRoutes to the framework of perylenequinone‐derived mycotoxins of the biphenyl type are described. 1,2,11,12‐Tetrahydroperylenequinone is most suitably prepared in seven steps starting with 3‐hydroxyacetophenone. Key steps are an Ullmann coupling, pinacol‐type cyclization, bromination, enolate reaction, and intramolecular Friedel‐Crafts cyclization. A second approach starting with 1,5‐dihydroxynaphthalene yields the respective decarbonylated core. Key steps of this 5‐step sequence are again an Ullmann coupling and a McMurry olefination. The cleavage of the preferentially utilized hexyl protecting group could be achieved with boron bromide.

Total Synthesis of Panaginsene.

The total synthesis of panaginsene has been accomplished in 11 linear steps starting from methyl 3,3-dimethyl-5-oxocyclopent-1-ene-1-carboxylate. The key steps are a Sharpless asymmetric epoxidation and Ti(III)-mediated reductive epoxide opening-radical cyclization to construct the chiral quaternary carbon stereocenter followed by a very challenging HWE olefination reaction on an 1,3-keto aldehyde and a late stage McMurry olefination using low valent titanium to construct the highly constrained angular tetrasubstituted olefin in a five-membered ring.

Dual-mode coupling copolymerization of aryl dialdehyde and alkynylaldehyde monomers via Concurrent McMurry olefination and alkyne [2+2+2] cycloaddition trimerization reactions mediated by a low-valent titanium reagent

The application of a low-valent titanium reagent recently developed in our group, Ti(O-i-Pr)4/Me3SiCl/Mg, to the McMurry coupling polymerization of aryl dialdehyde monomers and [2 + 2 + 2] cycloaddition polymerization of aromatic diyne monomers is described. Furthermore, on the basis of these reactions, a low-valent titanium-mediated dual-mode coupling copolymerization of aryl dialdehyde and alkynylaldehyde monomers via concurrent McMurry olefination and alkyne cyclotrimerization reactions is proposed.

Treatment of breast cancer with engineered novel pH-sensitive triaryl-(Z)-olefin niosomes containing hydrogel: an in vitro and in vivo study

Triaryl-(Z)-olefin (TZO) was synthesized as a Tamoxifen (TMX) analogue for breast cancer treatment to avoid developing the resistance and toxicity of TMX. TZO was synthesized using McMurry olefination reaction and has anti-cancer activity better than TMX by two folds. In this paper, in situ pH-sensitive TZO-loaded noisome hydrogel was prepared for delivering and targeting TZO to its site of activity. Equi-molar of cholesterol and span 60 was used to prepare TZO-loaded niosomes using the Hand Shaking Method. The central composite experimental design was used to prepare differently in situ pH-sensitive TZO-loaded niosomes formulae. The formulae were done by incorporated TZO-loaded niosomes into different concentrations of chitosan and Glyceryl monooleate (GCM). Increasing the chitosan and GCM concentrations resulted in significantly increasing the viscosity and significantly decreasing the release of TZO from different formulae. The formula composed of (0.61% w/v) of chitosan and (0.23% w/v) of GCM was chosen as an optimum formula to evaluate the efficacy of TZO using Ehrlich carcinoma mice model. A significant anti-tumour effect was shown in comparison with TMX. Briefly, in situ pH-sensitive TZO-loaded niosomes could be an effective treatment for breast cancer.

ChemInform Abstract: Design, Synthesis and Biological Evaluation of Novel Triaryl (Z)‐Olefins as Tamoxifen Analogues.

AbstractThe title compounds (V) are obtained by a McMurry olefination reaction.

Design, synthesis and biological evaluation of novel triaryl (Z)-olefins as tamoxifen analogues

Tamoxifen (TAM) is used for the treatment and prevention of estrogen receptor positive breast cancer. However, the limited activity, toxicity and the development of resistance raised the current need for new potent nontoxic antiestrogen. Six novel TAM analogues 5a–f were synthesized using McMurry olefination reaction. Replacement of the dimethylamino group in TAM by piperidino, piperazino or N-methyl piperazino, substituting the phenyl ring with florine atom at p-position and changing the ethyl group by methyl, afforded compounds showing comparable activity to TAM (1). Compounds 5c and 5e showed significant increase in antiproliferative activity in two breast cancer cell lines (MCF-7 and MDA-MB-231) compared to tamoxifen, while other compounds showed similar activity. The increased anticancer activity of compounds 5c and 5e was attributed to their ability to induce ER-independent cell death.

Weakening C−O Bonds: Ti(III), a New Reagent for Alcohol Deoxygenation and Carbonyl Coupling Olefination

Investigations detailed herein, including density functional theory (DFT) calculations, demonstrate that the formation of either alkoxy- or hydroxy-Ti(III) complexes considerably decreases the energy of activation for C-O bond homolysis. As a consequence of this observation, we described two new synthetic applications of Nugent's reagent in organic chemistry. The first of these applications is an one-step methodology for deoxygenation-reduction of alcohols, including benzylic and allylic alcohols and 1,2-dihydroxy compounds. Additionally, we have also proved that Ti(III) is capable of mediating carbonyl coupling-olefination. In this sense, and despite the fact that for over 35 years it has been widely accepted that either Ti(II) or Ti(0) was the active species in the reductive process of the McMurry reaction, the mechanistic evidence presented proves the involvement of Ti(III) pinacolates in the deoxygenation step of the herein described Nugent's reagent-mediated McMurry olefination. This observation sheds some light on probably one of the mechanistically more complex transformations in organic chemistry. Finally, we have also proved that both of these processes can be performed catalytically in Cp(2)TiCl(2) by using trimethylsilyl chloride (TMSCl) as the final oxygen trap.

Unsaturated Strained Cyclophanes Based on Dibenz[a,j]anthracene by an Intramolecular McMurry Olefination

A new type of rigid conjugated unsaturated strained cyclophane derivative containing dibenz[a,j]anthracene units was facilely synthesized through an intramolecular McMurry reaction without intermolecular dimerization products in good yields. The photophysical properties of these cyclophane derivatives in dilute solution were investigated, and molecular modeling was employed to study their electronic properties.

Bis(ether) derivatives of tetrakis(2-hydroxyphenyl)ethene — Direct synthesis of (E)- and (Z)-bis(2-hydroxyphenyl)-bis(2-methoxyphenyl)ethene via the McMurry olefination reaction

The direct synthesis of sterically hindered, partially etherified derivatives of tetrakis(2-hydroxyphenyl)ethene is reported by using the McMurry reductive olefination reaction on a range of differentially substituted 2,2′-dialkoxy benzophenone substrates. Three orthogonal protection strategies are demonstrated, incorporating β-silylethyl, 3-butenyl, and tert-butyl protecting groups, respectively, into the starting benzophenones. The latter proved most efficient, with both the McMurry coupling and deprotection steps occurring concomitantly under the McMurry conditions to directly yield the desired bis(2-hydroxyphenyl)-bis(2-methoxyphenyl)ethene as a 1:1 mixture of E- and Z-diastereoisomers.Key words: preorganized polyaryloxide ligands, McMurry olefination, titanium trichloride, supramolecular chemistry, tetrakis(2-hydroxyphenyl)ethene, 2,2′-disubstituted benzophenone.

Synthesis and biological evaluation of acyclic triaryl ( Z)-olefins possessing a 3,5-di- tert-butyl-4-hydroxyphenyl pharmacophore: Dual inhibitors of cyclooxygenases and lipoxygenases

A new class of regioisomeric acyclic triaryl ( Z)-olefins possessing a 3,5-di- tert-butyl-4-hydroxyphenyl (DTBHP) 5-lipoxygenase (5-LOX) pharmacophore that is vicinal to a para-methanesulfonylphenyl cyclooxygenase-2 (COX-2) pharmacophore were designed for evaluation as selective COX-2 and/or 5-LOX inhibitors. The target compounds were synthesized via a highly stereoselective McMurry olefination cross-coupling reaction. This key synthetic step afforded a ( Z):( E) olefinic mixture with a predominance for the ( Z)-olefin stereoisomer. Structure–activity studies for the ( Z)-1-(3,5-di- tert-butyl-4-hydroxyphenyl)-2-(4-methanesulfonylphenyl)-1-phenylalk-1-ene regioisomers showed that COX-1 inhibition decreased, COX-2 inhibition increased, and the COX-2 selectivity index (SI) increased as the chain length of the alkyl substituent attached to the olefinic double bond was increased (Et → n-butyl → n-heptyl). In this group of compounds, inhibition of both 5-LOX and 15-LOX was dependent upon the length of the alkyl substituent with the hex-1-ene compound 9c having a n-butyl substituent exhibiting potent inhibition of both 5-LOX (IC 50 = 0.3 μM) and 15-LOX (IC 50 = 0.8 μM) relative to the inactive (IC 50 > 10 μM) Et and n-heptyl analogs. Compound 9c is of particular interest since it also exhibits a dual inhibitory activity against the COX (COX-1 IC 50 = 3.0 μM, and COX-2 IC 50 = 0.36 μM, COX-2 SI = 8.3) isozymes. A comparison of the relative inhibitory activities of the two groups of regioisomers investigated shows that the regioisomers in which the alkyl substituent is attached to the same olefinic carbon atom (C-2) as the para-methanesulfonylphenyl moiety generally exhibit a greater potency with respect to COX-2 inhibition. The 4-hydroxy substituent in the 3,5-di- tert-butyl-4-hydroxyphenyl moiety is essential for COX and LOX inhibition since 3,5-di- tert-butyl-4-acetoxyphenyl derivatives were inactive inhibitors. These structure–activity data indicate acyclic triaryl ( Z)-olefins constitute a suitable template for the design of dual COX-2/LOX inhibitors.

New Tetrakis(4‐aminophenyl)ethenes: Synthesis and Electrochemical Investigations.

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.

Synthesis of Sterically Hindered Ortho-Substituted Tetraphenylethenes. Electronic Effects in the McMurry Olefination Reaction

[reaction: see text] Contrary to literature consensus, the McMurry olefination reaction can be extended to the direct synthesis of sterically encumbered tetrakis(2-substituted) tetraphenylethenes from the corresponding 2,2'-disubstituted benzophenones. The reaction exploits previously unrecognized substrate-based electronic effects that dominate over otherwise controlling steric considerations and provides highly efficient access to derivatives of tetrakis(2-hydroxyphenyl)ethene, a novel preorganized ligand system for polymetallic coordination chemistry and catalysis.

New tetrakis(4-aminophenyl)ethenes: synthesis and electrochemical investigations

Four novel functional conjugated tetraarylamines containing a tetraphenylenecore were synthesized via Ni-catalyzed aryl amination followed by McMurry olefination. Their electrochemical properties were studied by cyclic voltammetry, coulometry, and electrolysis monitored by UV–vis spectroscopy, and discussed with regard to those of the known tetrakis(dimethylaminophenyl)ethane.

Stilbenophane Analogues of Deoxycombretastatin A-4

A new family of polyoxygenated stilbenophanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. By means of the McMurry olefination process, compounds derived from diethyleneglycol and 1,6-hexanediol were obtained, whereas Grubbs' catalyst failed in producing the ring-closing metathesis to this kind of macrocyclic products.

Methylsulfonyl and Hydroxyl Substituents Induce Z‐Stereocontrol in the McMurry Olefination Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Design of Acyclic Triaryl Olefins: A New Class of Potent and Selective Cyclooxygenase‐2 (COX‐2) Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Influence of the Nature of Low Valent Titanium Reagents in McMurry Olefination: Stereoselective Synthesis of Symmetrical and Unsymmetrical Hydroxystilbenes

Intramolecular reductive deoxygenation of ethylenedioxy tethered symmetrical and unsymmetrical aromatic bis(ketone) ethers with the low-valent titanium (LVT) reagent (TiCl4-Zn-DME) yielded the corresponding cyclic stilbenes with excellent Z-selectivity. On the other hand, coupling of the aldehydic tethered ethers proceeded with high E-selectivity with the LVT reagent (TiCl3 / Li / KCl (2.0 eq.) / THF). Dealkylation of the cyclic stilbenes furnished the geometrically pure hydroxystilbenes.

Design of acyclic triaryl olefins: a new class of potent and selective cyclooxygenase-2 (COX-2) inhibitors

A new class of acyclic 1,1-diphenyl-2-(4-methylsulfonylphenyl)-2-alkyl-1-ethenes were synthesized, via a short two-step McMurry olefination reaction and then oxidation of the thiomethyl intermediate using Oxone®, in 62–76% yield. The title compounds possess identical C-1 phenyl substituents which precludes the possibility of ( Z)- and ( E)-stereoisomers. 1,1-Diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene exhibited highly potent (IC 50=0.014 μM) and selective COX-2 (Selectivity Index >7142) inhibitory activity.

Methylsulfonyl and Hydroxyl Substituents InduceZ-Stereocontrol in the McMurry Olefination Reaction

Aryl ketones possessing methylsulfonyl and hydroxyl substituents, that induce stereocontrol, selectively afford Z-olefins using a Zn-TiCl 4 catalyzed McMurry reaction.

Highly active salted low-valent titanium reagents for various SET induced reactions

External addition of inorganic salts (Group I and II metal halides) to the preformed low-valent titanium reagent A (TiCl 3–Li–THF) dramatically enhanced its activity. The new reagents were used to carry out various SET reactions including McMurry's olefination at a faster rate even at ambient temperature.