Effects of temperature and concentration in some ring closing metathesis reactions

Ring closing metathesis (RCM) has emerged as a powerful tool to construct macrocyclic ring systems. However, the product distribution of monomer and oligomers is often a problem in the formation of medium to large rings. In the course of synthetic studies on the natural product radicicol and its analogs, we have found that the reaction temperature, along with concentration, has significant impact on the outcome of the product ratio. Specifically, carrying out the RCM reaction in refluxing toluene (110°C) at higher dilution affords improved yields of the monomeric macrocycle. Similar observations for another family of macrolactone natural products, the epothilones, are also reported.     

Olefin ring closing metathesis and hydrosilylation reaction in aqueous medium by Grubbs second generation ruthenium catalyst

The Grubbs second generation ruthenium catalyst was shown to catalyze various olefin ring closing metathesis and hydrosilylation reactions in aqueous medium. Reactions proceeded in pure water without any additives or cosolvents, in a short period of time. We found that inhomogeneity of the reaction mixture does not prevent high conversion (70-95%) of the products in both reactions.     

Synthesis of an eight-membered cyclic pseudo-dipeptide using ring closing metathesis

Ring closing metathesis of diallylglycine 6 provided cyclic Z-olefin 7 in 80% yield. The reaction was promoted by substitution of the amide nitrogen with the 2,4-dimethoxybenzyl group allowing for the required cis diallylglycine amide rotamer. Removal of the protecting groups provided cyclic dipeptide 2, a constrained scaffold useful in peptidomimetic research.     

Synthesis of cholaphanes by ring closing metathesis

The synthesis of cholaphanes by ring closing metathesis (RCM) of 3α,7α,12α,24-tetraol allyl derivatives, obtained from cholic acid, was attempted. The reactions of tetraol 3,24-diallyl ether or 3,24-diacrylate were not satisfactory. However, diallyl derivatives of disteroidal 3,3′- or 24,24′-ortho-phthalates reacted smoothly affording cyclic dimers in good yields. In all the reactions studied, the E isomers of the macrocycles were obtained in excess.     

Cationic ruthenium allenylidene complexes as catalysts for ring closing olefin metathesis

A series of well accessible cationic ruthenium allenylidene complexes of the general type [(eta6-arene)(R3P)RuCl(=C=CR'2)]+ X- is described which constitute a new class of pre-catalysts for ring closing olefin metathesis reactions (RCM) and provide an unprecedented example for the involvement of metal allenylidenes in catalysis. They effect the cyclization of various functionalized dienes and enynes with good to excellent yields and show a great tolerance towards an array of functional groups. Systematic variations of their basic structural motif have provided insights into the essential parameters responsible for catalytic activity which can be enhanced further by addition of Lewis or Bronsted acids, by irradiation with UV light, or by the adequate choice of the "non-coordinating" counterion X-. The latter turned out to play a particularly important role in determining the rate and selectivity of the reaction. A similarly pronounced influence is exerted by remote substituents on the allenylidene residue which indicates that this ligand (or a ligand derived thereof) may remain attached to the metal throughout the catalytic process. X-ray crystal structures of the catalytically active allenylidene complexes 3b.PF6 and 15.OTf as well as of the chelate complex 10 required for the preparation of the latter catalyst are reported.     

Synthesis of huperzine B through ring closing metathesis

Huperzine B and its analogues were obtained through ring closing metathesis of N-alkenyl amine to the corresponding tricyclic compounds.     

Synthesis of spirocyclic butenolides by ring closing metathesis

Spirocyclic butenolides were efficiently prepared by a ring closing metathesis strategy.     

Synthesis of bruguierol A employing ring closing metathesis

An expedient synthesis of bruguierol A encompassing a novel 2,3-benzo-8-oxabicyclo[3.2.1]octane ring system is described employing ring closing metathesis to generate the oxa-bridged tricyclic core.     

Synthesis of spiro-pyridones and spiro-quinolones by sequential palladium on carbon-catalyzed allylation and ring closing metathesis reactions

A rapid and efficient strategy for the preparation of spiro-pyridones and spiro-quinolones using sequential Pd(0)/C-catalyzed allylation and ring closing metathesis reactions is described. The developed protocol features a fully regioselective allylation at C3 taking advantage of the unusual reactivity of Pd(0)/C catalyst. Application of the present methodology in nucleoside chemistry has also been investigated.     

Synthesis of cycloalkenyl geminal bisphosphonates by ring closing metathesis

Five‐ and six‐membered cycloalkenyl bisphosphonates were obtained by ring closing metathesis (RCM) reactions of diethyl bis(alkenyl)methylene bisphosphonates using ruthenium alkylidene catalysts. The substitution pattern on the double bonds involved in the reaction greatly influences the reaction rate. The synthesis of the starting materials was carried out by dialkylation of tetraethyl methylene bisphosphonate or through a Michael addition of Grignard reagents to tetraethyl vinylidene bisphosphonate followed by alkylation, depending on the structure of the required substrate. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:332–338, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20622     

Synthesis of sulphur-containing heterocycles by ring closing diene metathesis

We have shown that, surprisingly, the Schrock molybdenum alkylidene catalyst 1 can perform ring closing metathesis reactions on substrates containing a sulphide group, converting diallyl sulphide 5 to 2,5-dihydrothiophene 6 with >99 % conversion. By contrast, the ruthenium alkylidene catalyst 2, which is generally more tolerant of functional groups in the substrate, is unreactive towards diallylsulphide. However even the molybdenum catalyst 1 proved unable to catalyse ring closure of tetrathiafulvalene derivative 7.     

Total synthesis of patulolide A through ring closing metathesis

A simple and efficient total synthesis of patulolide A from readily available 7-octen-1-ol is reported by asymmetric synthetic approach. The key reactions involved are asymmetric dihydroxylation using AD-mix-β and Grubbs’ ring-closing metathesis reaction for the synthesis macrocyclic ring system.     

A synthetic entry to 2,3-fused ring indole derivatives by ring-closing metathesis reactions

Six to eight-membered carbocycles and eight-membered azacycles fused to the 2,3-position of the indole ring, representing tricyclic substructures of several indole alkaloids, can be synthesized by RCM reactions from easily accessible dienic precursors.     

Annulated butanolides by ring closing metathesis of diallyltetronic acid derivatives

3,3-Diallyldihydrofuran-2,4-diones 5 with two identical allyl residues were obtained by Tsuji-Trost-type Pd-catalysed allylation of either 4-O-allyltetronates or 3-allyltetronic acids. Allylation of sodium 3-allyltetronate with a second allyl acetate gave mixed derivatives 5 as did the Claisen rearrangement of 4-O-allyl 3-allyltetronates 6 under microwave conditions. Compounds 5 and 6 were converted to butanolides with 3,3-spirocyclopentenyl or 3,4-cycloalkanyl annulation by ring closing metathesis with Grubbs catalysts.     

Synthesis of phosphorus containing medium ring heterocycles by sequential Claisen rearrangement and ring closing metathesis

An efficient method for the synthesis of novel medium ring phosphorus containing heterocycles starting from phenol derivatives by ruthenium catalyzed ring closing metathesis is described. This work deals with a sequential aromatic Claisen-rearrangement, coupling of an allyl/vinyl phosphonate, and ring closing metathesis reaction. All of these reactions were carried out at ambient temperature to afford the medium-sized phosphorus heterocycles in excellent yields.     

Synthesis of chiral macrocyclic sugar-peptide hybrids by ring closing metathesis approach

Furanoside and peptide appended bis-olefins afforded monomeric 12- to 18-membered cyclic olefins fused to furanoside rings via RCM approach using Grubbs’ Catalyst.     

Examination of the olefin-olefin ring closing metathesis to prepare Latrunculin B

Three subunits of the potent actin polymerization inhibitor Latrunculin B were synthesized and assembled using olefin-olefin ring closing metathesis chemistry to close the 14-membered macrocycle. Metathesis reactions of substrates with various remote protecting group patterns were examined and gave 6,7-E-lactones as the preferred products.     

Ring closing enyne metathesis: a powerful tool for the synthesis of heterocycles

The ring closing metathesis (RCM) is a powerful method in organic synthesis for the preparation of cyclic compounds by formation of new carbon-carbon bonds. In the past years a particular subclass of the RCM, the ring closing enyne metathesis (RCEYM), has attracted attention due to its synthetic potential in the generation of ring structures with 1,3-diene moieties, which can subsequently be further functionalised. In this tutorial review mechanistic considerations will be described and the synthetic power of this useful and attractive carbon-carbon bond forming reaction will be illustrated by recent examples of RCEYM applications in the preparation of heterocyclic compounds.     

Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via ring closing metathesis (RCM)

Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.