Absence of the Thorpe-Ingold Effect by gem-Diphenyl Groups in Ring-Closing Enyne Metathesis

In tandem ring-closing metathesis of alkynyl silaketals containing two different tethered olefins, the gem-dimethyl group showed the expected Thorpe-Ingold effect, thereby giving good level of group selectivity. Unexpectedly, however, the corresponding gem-diphenyl group did not show any Thorpe-Ingold effect for the ring-closure reaction.     

Selective formation of dihydropyran derivatives by a tandem domino ring-closing metathesis/cross-metathesis

A ring-closing metathesis (RCM)/cross-metathesis (CM) domino reaction has been applied to esters and unsymmetrical ether prepared from 1,5-hexadien-3-ol. For the first time, dihydropyran derivatives have been obtained via a regioselective cyclization. This reaction was performed in high yield and E stereoselectivity.     

Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

The use of d-mannitol-derived C2-symmetric trienes in tandem metathesis reactions towards valuable lactones

Chiral lactones were synthesized from d-mannitol. C₂-symmetric triene precursors were constructed with a central relay-olefin allowing the key domino ring-closing metathesis to be achieved. It led to the symmetrical cleavage of the substrate and to the formation of 2 mol of the desired 5- or 6-membered lactone. Attempts to form 7-membered lactones thus far only led to 14-membered macrodiolides instead.     

Concise enantioselective synthesis of (−)-lasubine II

An enantioselective synthesis of the quinolizidine alkaloid (−)-lasubine II 1 is reported. Two different pathways to the key intermediate 2 are described. The first case involving a sequence of ring rearrangement metathesis (RRM), simple functional group interconversion operations, followed by a stereoselective cross metathesis (CM) and in the second case a domino ring opening-/ring closing-/cross metathesis step is involved. In both cases, following the metathesis reactions, exclusively the E-isomer was obtained. The final cyclisation towards the quinolizidine skeleton is achieved by an intramolecular Michael reaction. This concept represents the first example of a highly stereoselective RRM-CM combination in the synthesis of a natural product.     

Olefin metathesis polymerization: Some recent developments in the precise polymerizations for synthesis of advanced materials (by ROMP,ADMET)

Recent results for synthesis of end-functionalized polymers (EFP) by using olefin metathesis polymerization have been introduced including basic characteristics in ring-opening metathesis polymerization (ROMP) of cyclic olefins and acyclic diene metathesis (ADMET) polymerization for synthesis of conjugated polymers. Several approaches were demonstrated for synthesis of EFP by living ROMP using molybdenum (exclusive coupling with aldehyde) and ruthenium catalysts (sacrificial ROMP, chain transfer). Cis specific (Z selective) ROMPs were achieved by molybdenum, ruthenium, and vanadium catalysts by the ligand modification. The catalytic synthesis of EFP with high cis selectivity has been achieved by combined ROMP with chain transfer by V(CHSiMe₃)(N-2,6-Cl₂C₆H₃)[OC(CF₃)₃](PMe₃)₂. The ADMET polymerization using molybdenum and ruthenium catalysts afforded defect-free, high molecular weight poly(arylene vinylene)s containing all trans olefinic double bonds. The methods for precise synthesis of EFPs, exhibiting unique optical properties combined with the end groups, were developed. The catalytic one-pot syntheses for EFPs have also been developed.     

Reversible aqueous metathesis reactions for potential application in dynamic combinatorial chemistry

Solutions of heterocycles having an allyl sulfide unit and simple alkenes in 50% t-BuOH/H₂O undergo reversible olefin metathesis reactions with the second generation Hoveyda-Grubbs catalyst. The choice of functional groups is limited by competitive chelation of some heterocycles with the catalyst, and other stereoelectronic effects.     

Total synthesis of haminol A: an analysis of vinylpyridine metathesis reactivity

The total synthesis of haminol A has been completed featuring a masked-alkene metathesis reaction followed by bis-acyloxysulfone elimination to install the 1,3,8-triene subunit. During the course of our synthesis, the metathesis reactivity of 3-vinylpyridine was evaluated and our data suggest the rapid formation of a ruthenium pyridylalkylidene that no longer participates in productive metathesis. A chemotaxis assay using Caenorhabditis elegans demonstrated that haminol A produced an avoidance response from this organism.     

A neutral, water-soluble olefin metathesis catalyst based on an N-heterocyclic carbene ligand

A water-soluble ruthenium-based olefin metathesis catalyst supported by a poly(ethylene glycol) conjugated N-heterocyclic carbene ligand is reported. The catalyst displays greater activity in aqueous ring-opening metathesis polymerization (ROMP) reactions than previously reported water-soluble metathesis catalysts.     

An isomerization-ring-closing metathesis strategy for the synthesis of substituted benzofurans

Twelve substituted benzofurans were synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using ruthenium-mediated C- and O-allyl isomerization followed by ring-closing metathesis.     

Synthesis of a para-quinone macrolactam related to geldanamycin by ring closing metathesis

Model studies conducted with the α,β,γ,δ-unsaturated 3-alkenyl-2,4,5-trimethoxyanilides 11 revealed that a ring closing metathesis (RCM) of these compounds is possible if the ansa chain contains more than 14 atoms. The (Z)-configurated products 12c-e were obtained in good yields (77-87%) and with perfect simple diastereoselectivity. Since the oxidation of the 2,4,5-trimethoxyanilides led predominantly to undesired ortho-quinones such as 15 or to para-azaquinones such as 16 the macrocyclic 2,5-di-iso-propoxy-4-methoxyanilide 22 was prepared. The iso-propyl protecting groups could be selectively cleaved and the intermediate para-hydroquinone oxidized on air to the desired para-quinone 2 (86% yield). The compound shows some key features (macrolactam ring with the same ring size, α,β,γ,δ-unsaturated anilide, para-quinone) of geldanamycin.     

Synthesis of 2′-O,3′-O bicyclic adenosine analogues using ring closing metathesis

The synthesis of 2′-O,3′-O bicyclic adenosine derivatives is presented as the first examples of a new family of 13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene intermediate using Grubbs’ catalyst. The Z and E isomers were purified and characterised.     

Toward the synthesis of amphidinolide P: optimization of a model ene–yne metathesis fragment coupling

Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.     

Synthesis of the floresolide B hydroquinone lactone core using ring-closing metathesis

The hydroquinone lactone core of the floresolides was synthesized through a ring-closing metathesis (RCM) approach. Optimal RCM efficiency was obtained at higher reaction concentration. An unexpected Lewis acid-promoted rearrangement of the hydroquinone and other observations relevant to on-going total synthesis efforts are discussed.     

Boron trifluoride–etherate in fluorinated alcohols: A powerful promoter system for intramolecular alkyne–aldehyde metathesis of o-(3-arylpropargyloxy)benzaldehydes

Boron trifluoride–etherate (BF₃·OEt₂) in 2,2,2‐trifluoroethanol (TFE) was found to be a highly efficient promoter system for the intramolecular alkyne–aldehyde metathesis of o-(3-arylpropargyloxy)benzaldehydes. The reaction produces the corresponding 3-aroyl-2H-chromenes in excellent yields under metal-free conditions.     

Asymmetric synthesis of cyclic β-amino acids and cyclic amines via sequential diastereoselective conjugate addition and ring closing metathesis

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters followed by ring closing metathesis is used to afford efficiently a range of substituted cyclic β-amino esters in high d.e. Alternatively, conjugate addition to α,β-unsaturated Weinreb amides, functional group conversion and ring closing metathesis affords cyclic amines in high d.e. The further application of this methodology to the synthesis of a range of carbocyclic β-amino esters via conjugate addition, enolate alkylation and ring closing metathesis is also described. Application of this methodology affords, after deprotection, (S)-homoproline, (S)-homopipecolic acid, (S)-coniine and (1S,2S)-trans-pentacin.     

Expeditious convergent procedure for the preparation of bis(POC) prodrugs of new (E)-4-phosphono-but-2-en-1-yl nucleosides

A series of unsaturated acyclonucleoside bis(POC) prodrugs of E configuration were synthesized through an expeditious, highly efficient and stereoselective one-step procedure from corresponding bis(POC)allylphosphonate through Ru catalyzed cross-coupling metathesis reaction. The [RuCl₂(PCy₃)(SIPr)(Indenylidene)] and [RuCl₂(PCy₃)(IMes)(benzylidene)] catalysts were employed; the unsaturated ANP were used bore C5-halovinyl uracil, C5-dihalovinyluracil or furanopyrimidine motifs. The chemical cleavage of biolabile (POC) group is a useful pathway to acid phosphonate derivatives.     

Diastereoselective synthesis of highly substituted polycyclic scaffolds via a one-pot four-step tandem catalytic process

A rapid and diastereoselective synthesis of highly substituted aminobicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes from alkyne derived allylic alcohols has been developed using a one-pot multi-bond forming tandem catalytic process. Overman rearrangement of the allylic trichloroacetimidates was followed by a ring closing enyne metathesis/cross metathesis sequence of reactions, in which both steps were catalysed by Grubbs second generation catalyst. The resulting exo-diene was then subjected to a hydrogen bonding directed Diels–Alder reaction forming an endo-adduct as a single diastereomer. Variation of the cross metathesis partner and dienophile allowed examination of the scope of this one-pot process and the preparation of a diverse series of highly substituted polycyclic scaffolds.     

Ruthenium olefin metathesis catalysts with modified styrene ethers: influence of steric and electronic effects

A series of olefin metathesis catalysts with modified isopropoxybenzylidene ligands were synthesised, and the effects of ligands on the rate of metathesis investigated. Increased steric hinderance ortho to the isopropoxy group enhanced reaction rates. In the case of N-heterocyclic carbene complexes, decreasing electron density at both the chelating oxygen atom and the RuC bond accelerated reaction rates appreciably. Catalysts containing a tricyclohexylphosphane ligand, followed the same trend with regard to benzylidene electrophilicity, while higher electron density at oxygen enhanced reaction rates.     

Asymmetric synthesis of passifloricin A: a correction in structure

The structure reported in the literature for the pharmacologically active, natural lactone passifloricin A (δ-lactone of 2Z,5R*S*,7R*,9S*,11S*-tetrahydroxyhexacos-2-enoic acid) is incorrect not only as regards stereochemical issues, but also in the placement of one of the hydroxyl groups of the side chain. By means of an unambiguous synthesis, passifloricin A is shown to be the δ-lactone of 2Z,5R,7S,9S,12S-tetrahydroxyhexacos-2-enoic acid. All of the stereogenic centres were created with the aid of Brown's asymmetric allylation methodology. The lactone ring was made via ring-closing metathesis.