Efficient enantioselective synthesis of functionalized tetrahydropyrans by Ru-catalyzed asymmetric ring-opening metathesis/cross-metathesis (AROM/CM)

An efficient method for enantioselective synthesis of highly functionalized pyrans (up to 98% ee) through Ru-catalyzed asymmetric ring-opening metathesis/cross-metathesis is described. Reactions are promoted by a recyclable chiral Ru-chloride or a new chiral Ru-iodide complex; the latter catalyst is less efficient but gives rise to significantly higher levels of enantioselectivity. Catalytic reactions can be performed in undistilled solvent and with a wide range of substrates, including those that contain secondary and tertiary alcohols. Representative regioselective functionalizations that highlight the utility of the catalytic method are also presented.     

A readily available chiral Ag-based N-heterocyclic carbene complex for use in efficient and highly enantioselective Ru-catalyzed olefin metathesis and Cu-catalyzed allylic alkylation reactions

A new chiral bidentate N-heterocyclic carbene (NHC) ligand has been designed and synthesized. The NHC ligand bears a chiral diamine backbone and an achiral biphenol group; upon metal complexation (derived from Ag(I), Ru(II), or Cu(II)), the diamine moiety induces >98% diastereoselectivity such that the biaryl unit coordinates to the metal center to afford the desired complex as a single atropisomer. Because the ligand does not require optically pure biaryl amino alcohols, its synthesis is significantly shorter and simpler than the related first generation ligands bearing a chiral binaphthyl-based amino alcohol. The chiral NHC ligand can be used in the preparation of highly effective Ru- and Cu-based complexes (prepared and used in situ from the Ag(I) carbene) that promote enantioselective olefin metathesis and allylic alkylations with scope that is improved from previously reported protocols. In many cases, transformations promoted by the chiral NHC-based complexes proceed with higher enantioselectivity and reactivity than was observed with previously reported complexes.     

Catalytic asymmetric ring-opening metathesis/cross metathesis (AROM/CM) reactions. Mechanism and application to enantioselective synthesis of functionalized cyclopentanes

Studies regarding the first examples of catalytic asymmetric ring-opening metathesis (AROM) reactions are detailed. This enantioselective cleavage of norbornyl alkenes is followed by an intermolecular cross metathesis with a terminal olefin partner; judicious selection of olefin is required so that oligomerization and dimerization side products are avoided. Results outlined herein suggest that the presence of suitably positioned heteroatom substituents may be critical to reaction efficiency. Mo-catalyzed tandem AROM/CM affords functionalized cyclopentyl dienes in >98% ee and >98% trans olefin selectivity; both secondary and tertiary ether products can be obtained. The examples provided include the catalytic synthesis of an optically pure cyclopentyl epoxide and dimethyl acetal. Mechanistic studies suggest that it is the more substituted benzylidene or silylated alkylidenes that are involved in the catalytic process (vs the corresponding Mo-methylidenes). Although electron rich benzylidenes react more efficiently, the derived electron poor Mo complexes promote AROM/CM transformations as well; alkylidenes that bear a boron substituent are unreactive.     

Enantioselective synthesis of cyclic enol ethers and all-carbon quaternary stereogenic centers through catalytic asymmetric ring-closing metathesis

The first examples of catalytic asymmetric ring-closing metathesis (ARCM) reactions of enol ethers are reported. To identify the most effective catalysts, various chiral Mo- and Ru-based catalysts were screened. Although chiral Ru catalysts (those that do not bear a phosphine ligand) promote ARCM in some cases, such transformations proceed in <10% ee. In contrast, Mo-based alkylidenes give rise to efficient ARCM and deliver the desired products in the optically enriched form. Thus, Mo-catalyzed enantioselective transformations allow access to various five- and six-membered cyclic enol ethers in up to 94% ee from readily available achiral starting materials. The first examples of catalytic ARCM that lead to the formation of all-carbon quaternary stereogenic centers are also disclosed. Mechanistic models that offer a plausible rationale for the identity of major enantiomers as well as the observed levels of enantioselectivity are provided. Representative examples demonstrate that the enol ether moiety and the unreacted alkene of the ARCM products can be discriminated with excellent site selectivity (>98%).     

Heptane-soluble ring-closing metathesis catalysts

Terminally vinyl-functionalized polyisobutylene (PIB) oligomers can be easily transformed into end-functionalized PIB-bound Ru metathesis catalysts. The nonpolar catalysts so prepared can be used as solutions in heptane and recycled by a gravity-based extraction after addition of a heptane-immiscible polar solvent. This paper describes the synthesis and the recycling of a PIB-supported second-generation Hoveyda-Grubbs catalyst for Ru-catalyzed ring-closing metathesis and ring-opening metathesis polymerizations.     

Ru complexes bearing bidentate carbenes: from innocent curiosity to uniquely effective catalysts for olefin metathesis

The discovery and development of a new class of Ru-based catalysts for olefin metathesis is described. These catalysts, particularly those that do not bear a phosphine ligand, have been demonstrated to promote unique levels of reactivity in a variety of olefin metathesis reactions. The design and development of supported and chiral optically pure variants of this class of Ru catalysts for use in enantioselective metathesis are discussed as well. All catalysts are air stable, reusable, and can be employed with unpurified solvents.     

Chiral Ru-based complexes for asymmetric olefin metathesis: enhancement of catalyst activity through steric and electronic modifications

Design, synthesis, characterization, and catalytic activity of six enantiomerically pure Ru-based metathesis catalysts are disclosed (3a-3f). The new chiral catalysts were prepared through steric and electronic alterations of the parent catalyst system (3). The present studies indicate that the effect of structural modifications of chiral complex 3 does not always correspond to those of the related achiral complexes. The present findings illustrate that modified Ru complexes (3e and 3f) deliver reactivity levels that are more than 2 orders of magnitude higher than 3. Reactivity and physical data are provided that shed light on the origin of activity differences. Some members of the new generation of chiral Ru catalysts promote asymmetric ring-opening (AROM) and ring-closing (ARCM) metatheses that cannot be effected by the first generation chiral catalyst (3).     

Enantioselective synthesis of cyclic allylboronates by Mo-catalyzed asymmetric ring-closing metathesis (ARCM). A one-pot protocol for net catalytic enantioselective cross metathesis

Mo-catalyzed asymmetric ring-closing metathesis (ARCM) reactions are used to synthesize cyclic allylboronates of high optical purity (89% ee to >98% ee). A one-pot procedure involving formation of allylboronates, Mo-catalyzed ARCM and functionalization of the optically enriched cyclic allylboronates constitutes net asymmetric cross metathesis (ACM). Structural modification of ARCM products include reactions with aldehydes to afford optically enriched compounds that bear quaternary carbon centers with excellent diastereoselectivity. These studies emphasize the significance of the availability of chiral Mo-based complex as a class of chiral metathesis catalysts that frequently complement one another in terms of reactivity and selectivity.     

Catalytic asymmetric olefin metathesis

This paper provides a survey of the first examples of efficient catalytic enantioselective olefin metathesis reactions. Mo-catalyzed asymmetric ring-closing (ARCM) and ring-opening (AROM) reactions allow access to myriad optically enriched compounds that are otherwise difficult to access.     

Catalytic enantioselective total synthesis of (+)-dumetorine by ring-rearrangement metathesis

A concise, enantioselective synthesis of (+)-dumetorine is described, giving the natural product in six steps and a 27% overall yield from a readily available precursor. Among the key steps used, the synthesis entails a high-yielding ring-rearrangement metathesis (RRM), using the commercially available first generation Grubbs catalyst 2 in combination with Ti(Oi-Pr)₄ as a co-catalyst. This constitutes the first enantioselective total synthesis of the alkaloid from a known chiral intermediate, and hence a confirmation of its absolute stereochemistry.     

Novel stereoselective molecularly imprinted polymers via ring-opening metathesis polymerisation

Stereoselective molecularly imprinted polymers (MIPs) have been synthesised via ring-opening metathesis polymerisation, in essentially, quantitative yield. A covalent imprinting strategy was followed during the network formation of the chiral sorbent. Recognition of the substrate however involved non-covalent interactions; a combination of hydrogen bonding and the chiral environment presented by the imprinted cavities. The enantiomeric excess achievable with these new MIPs is solvent dependent and stereoselectivities of up to 20% e.e. (separation factor α=2.2) were found in batch equilibrations.     

Highly Efficient Route to Functionalized Tetrahydrocarbazoles Using a Tandem Cross‐Metathesis/Intramolecular‐Hydroarylation Sequence

The scope of the novel ruthenium‐catalyzed tandem cross‐metathesis/intramolecular‐hydroarylation sequence is described. This methodology offers a practical and efficient synthesis of structurally diverse and complex tetrahydrocarbazoles in good to excellent yields (up to 98 %). Moreover, preliminary efforts towards the development of an enantioselective version of the current process by sequential catalysis with ruthenium complex and chiral amine are presented, with high yields and enantioselectivities (up to 88 % yield and 91 % ee).     

Exploring new synthetic strategies in the development of a chemically activated Ru-based olefin metathesis catalyst

The objective of this work was to develop an industrially relevant olefin metathesis initiator, which circumvents the expensive, patent protected, often cumbersome preparative routes via Grubbs benzylidene complexes. Upon coordination of a Schiff base ligand to a second-generation ruthenium allenylidene complex, the formation of three catalyst isomers was observed. The major isomer was successfully isolated, and tested in a few olefin metathesis reactions. Acids such as HCl and HSiCl(3) were found to boost the metathesis reaction but the in situ formation of a neutral Ru carbyne complex restricted the catalytic capacity. Using the Lewis acid PhSiCl(3), the formation of a carbyne species was avoided, and turnover numbers up to 30,000 were reached in the ring-opening metathesis polymerisation of cycloocta-1,5-diene.     

Synthesis,structure, and activity of enhanced initiators for olefin metathesis

A series of ruthenium olefin metathesis catalysts of the general structure (H(2)IMes)(PR(3))(Cl)(2)Ru=CHPh (H(2)IMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) have been prepared; these complexes are readily accessible in two steps from commercially available (H(2)IMes)(PCy(3))(Cl)(2)Ru=CHPh. Their phosphine dissociation rate constants (k(1)), relative rates of phosphine reassociation, and relative reaction rates in ring-opening metathesis polymerization (ROMP) and ring-closing metathesis (RCM) have been investigated. The rates of phosphine dissociation (initiation) from these complexes increase with decreasing phosphine donor strength. Complexes containing a triarylphosphine exhibit dramatically improved initiation relative to (H(2)IMes)(PCy(3))(Cl)(2)Ru=CHPh. Conversely, phosphine reassociation shows no direct correlation with phosphine electronics. In general, increased phosphine dissociation leads to faster olefin metathesis reaction rates, which is of direct significance to both organic and polymer metathesis processes.     

Asymmetric catalysts for stereocontrolled olefin metathesis reactions

Since the discovery of metathesis as an instrument to reorganize olefinic double bonds, substantial progress has been attained, establishing this method as a versatile and efficient tool for C-C-bond formation. In the last decade fundamental achievements were accomplished in the field of chiral Ru- and Mo-based olefin metathesis, providing an asymmetric access to structures, which are difficult to obtain by alternative routes. The reader is taken behind the scenes of catalyst development, important areas of application are described up to the current state of research; this tutorial review deals with the question, how metathesis is connected to enantioselective synthesis.     

Decomposition of a key intermediate in ruthenium-catalyzed olefin metathesis reactions

Dinuclear ruthenium complex, with a bridging carbide and a hydride ligand, and methyltricyclohexylphosphonium chloride result from thermal decomposition of olefin metathesis catalyst, (IMesH2)(PCy3)(Cl)2Ru=CH2. Involvement of dissociated phosphine in the decomposition is proposed. The dinuclear complex has catalytic olefin isomerization activity, which can be responsible for competing isomerization processes in certain olefin metathesis reactions.     

Selective synthesis of chiral dioxabicyclo[4.4.0]decane and dioxabicyclo[5.3.0]decane from 3,4-bisallyloxy-but-1-yne derivatives via ruthenium-catalyzed en-yn-ene metathesis

We prepared a series of chiral 3,4-bisallyloxy-but-1-ynes having syn and anti configurations. Treatment of these substrates with Grubbs catalyst Cl2(PCy3)2Ru=CHPh (3 mol %) preferably gave chiral dioxabicyclo[4.4.0]decane (yields > 55%) in addition to dioxabicyclo[5.3.0]decane in minor proportions. On substitution of the 4-allyloxy group of these substrates with a 4-but-2-enyloxy group, the metathesis reactions produced only dioxabicyclo[5.3.0]decane in the presence of Grubbs ruthenium-imidazolidene carbene catalyst.     

Substituent effects and the mechanism of alkene metathesis catalyzed by ruthenium dichloride catalysts

Density functional theory calculations are reported concerning the dissociative mechanism for alkene metathesis by ruthenium dichloride catalysts, including both bisphosphine and diaminocarbene/phosphine complexes. The calculations use a hierarchy of models, ranging from [(L)(PH(3))Ru(Cl)(2)(CH(2))](L=PH(3) or diaminocarbene) through the larger [(L)(PMe(3))Ru(Cl)(2)(CHPh)] to the "real"[(L)(PCy(3))Ru(Cl)(2)(CHPh)]. Calculations show that the rate-limiting step for metathesis is either ring closing from an alkene complex to form a ruthena-cyclobutane, or ring-opening of the latter intermediate to form an isomeric alkene complex. The higher efficiency of the diaminocarbene based catalysts is due to the stabilization of the formal +iv oxidation state of the ruthenium centre in the metallacycle. This effect is partly masked in the smaller model systems due to a previously unnoticed stereoelectronic effect. The calculations do not reproduce the experimental observation whereby the initiation step, phosphine dissociation, is more energetically demanding and hence slower for the diaminocarbene-containing catalyst system than for the bisphosphine. Further calculations on the corresponding bond energies using a variety of DFT and hybrid DFT/molecular mechanics methods all find instead a larger phosphine dissociation energy for the bisphosphine catalyst. This reversed order of binding energies would in fact be the one expected based on the stronger trans influence of the diaminocarbene ligand. The discrepancy with experiment is small and could have a number of causes which are discussed here.     

Ruthenium(II) dipyridoquinoxaline-norbornene: synthesis, properties, crystal structure, and use as a ROMP monomer

The synthesis, X-ray structure, and electrochemical and photophysical characterization of [Ru(phen)(2)dpq-n][PF(6)](2) (phen = phenanthroline, dpq-n = dipyridoquinoxaline-norbornene) are described. This complex contains a Ru(phen)(3)(2+) moiety in close conjugation with a norbornene unit and is the first example of a Ru(II) diimine complex capable of undergoing ring-opening metathesis polymerization. Luminescence studies of this complex showed an increase in quantum efficiency in polar solvents and in water. Preliminary ring-opening metathesis polymerization studies, carried out at low monomer-to-initiator ratio, showed the formation of an oligomeric mixture composed mainly of the dimer of this complex. This dimer exhibits photophysical and redox properties similar to those of the monomer, indicating that the Ru(phen)(3)(2+) moiety remains intact during the polymerization.     

Enantioselective synthesis of hydroxylated pyrrolidines via Sharpless epoxidation and olefin metathesis

The enantioselective synthesis of polyhydroxylated pyrrolidines from enantiomerically pure 2,3-epoxy-pent-4-en-1-ol 5 is described herein. The epoxy alcohol, readily available in any configuration by Sharpless epoxidation, was submitted to regioselective C-3 ring-opening with allyl amine, Boc-protection and ring-closing metathesis to yield dehydropyrrole derivative 7. From this key intermediate, 1,4-dideoxy-1,4-imino-d-ribitol (+)-3 and 1,4-dideoxy-1,4-imino-d-allitol (+)-4 were prepared in high yields. The enantiomers of these compounds can be obtained by the same sequence starting from an epoxy alcohol with the opposite configuration.