Olefin Metathesis Reactions Research Articles

The Role of Total Synthesis in Structure Revision and Elucidation of Decanolides (Nonanolides).

Ten-membered lactones are commonly observed structures of natural products. They are mostly fungal metabolites, which often act as plant pathogens, but recently ten-membered lactones were identified as pheromones of frogs and termites. Although modern spectroscopic methods are nowadays routinely used to elucidate the structure of natural products, structural assignments of ten-membered lactones often remain incomplete or are surprisingly often erroneous. Most errors concern the absolute configuration. The examples discussed in this chapter demonstrate that enantioselective total synthesis is not only an efficient tool for corroborating or revising a proposed structure, but that the synthesis of different stereoisomers as references for gas chromatographic investigations can be a vital part of the structure elucidation process if only minute amounts of material are available. As a method of outstanding importance for the synthesis of ten-membered lactones olefin metathesis has emerged. Most of the examples discussed herein use one or more olefin metathesis reactions as key steps.

Insights on alkylidene formation on Mo2C: A potential overlap between direct deoxygenation and olefin metathesis

There is evidence that there is a potential overlap between olefin metathesis and deoxygenation chemistries on molybdenum carbide catalysts. Ketones and aldehydes are known to undergo selective deoxygenation on Mo2C to form surface alkylidenes, and metal alkylidenes are initiator and propagator sites in olefin metathesis reactions. Moreover, a recent report correlated increased olefin metathesis activity with molybdenum carbide or oxycarbide formation on pre-treatment of a supported molybdenum oxide catalyst in methane. Taken together, these three strands prompt a DFT study of the elementary carbonyl bond scission step of selected aldehydes and ketones to form surface alkylidenes on Mo2C. This theoretical study is extended to an analysis of previously reported experimental reflectance infrared data for the interaction of cyclopentanone and acetaldehyde with a polycrystalline bulk hexagonal Mo2C sample.

A molecular endless (74) knot.

Current strategies for the synthesis of molecular knots focus on twisting, folding and/or threading molecular building blocks. Here we report that Zn(II) or Fe(II) ions can be used to weave ligand strands to form a woven 3 × 3 molecular grid. We found that the process requires tetrafluoroborate anions to template the assembly of the interwoven grid by binding within the square cavities formed between the metal-coordinated criss-crossed ligands. The strand ends of the grid can subsequently be joined through within-grid alkene metathesis reactions to form a topologically trivial macrocycle (unknot), a doubly interlocked [2]catenane (Solomon link) and a knot with seven crossings in a 258-atom-long closed loop. This 74 knot topology corresponds to that of an endless knot, which is a basic motif of Celtic interlace, the smallest Chinese knot and one of the eight auspicious symbols of Buddhism and Hinduism. The weaving of molecular strands within a discrete layer by anion-template metal-ion coordination opens the way for the synthesis of other molecular knot topologies and to woven polymer materials.

Design and synthesis of 14 and 15-membered macrocyclic scaffolds exhibiting inhibitory activities of hypoxia-inducible factor 1α

Inspired by the privileged molecular skeletons of 14- and 15-membered antibiotics, we adopted a relatively unexplored synthetic approach that exploits alkaloidal macrocyclic scaffolds to generate modulators of protein–protein interactions (PPIs). As mimetics of hot-spot residues in the α-helices responsible for the transcriptional regulation, three hydrophobic sidechains were displayed on each of the four distinct macrocyclic scaffolds generating diversity of their spatial arrangements. Modular assembly of the building blocks followed by ring-closing olefin metathesis reaction and subsequent hydrogenation allowed concise and divergent synthesis of scaffolds 1–4. The 14-membered alkaloidal macrocycles 2–4 demonstrated similar inhibition of hypoxia-inducible factor (HIF)-1α transcriptional activities (IC50 between 8.7 and 10 µM), and 4 demonstrated the most potent inhibition of cell proliferation in vitro (IC50 = 12 µM against HTC116 colon cancer cell line). A docking model suggested that 4 could mimic the LLxxL motif in HIF-1α, in which the three sidechains are capable of matching the spatial arrangements of the protein hot-spot residues. Unlike most of the stapled peptides, the 14-membered alkaloidal scaffold has a similar size to the α-helix backbone and does not require additional atoms to induce α-helix mimetic structure. These experimental results underscore the potential of alkaloidal macrocyclic scaffolds featuring flexibly customizable skeletal, stereochemical, substitutional, and conformational properties for the development of non-peptidyl PPI modulators targeting α-helix-forming consensus sequences responsible for the transcriptional regulation.

Nitro and Other Electron Withdrawing Group Activated Ruthenium Catalysts for Olefin Metathesis Reactions.

Advanced applications of the Nobel Prize winning olefin metathesis reaction require user‐friendly and highly universal catalysts. From many successful metathesis catalysts, which belong to the two distinct classes of Schrock and Grubbs‐type catalysts, the subclass of chelating‐benzylidene ruthenium complexes (so‐called Hoveyda–Grubbs catalysts) additionally activated by electron‐withdrawing groups (EWGs) provides a highly tunable platform. In the Review, the origin of the EWG‐activation concept and selected applications of the resulting catalysts in target‐oriented synthesis, medicinal chemistry, as well as in the preparation of fine‐chemicals and in materials chemistry is discussed. Based on the examples, some suggestions for end‐users regarding minimization of catalyst loading, selectivity control, and general optimization of the olefin metathesis reaction are provided.

Cationic Group VI Metal Imido Alkylidene N‐Heterocyclic Carbene Nitrile Complexes: Bench‐Stable, Functional‐Group‐Tolerant Olefin Metathesis Catalysts

AbstractDespite their excellent selectivities and activities, Mo‐and W‐based catalysts for olefin metathesis have not gained the same widespread use as Ru‐based systems, mainly due to their inherent air sensitivity. Herein, we describe the synthesis of air‐stable cationic‐at‐metal molybdenum and tungsten imido alkylidene NHC nitrile complexes. They catalyze olefin metathesis reactions of substrates containing functional groups such as (thio‐) esters, (thio‐) ethers and alcohols without the need for prior activation, for example, by a Lewis acid. The presence of a nitrile ligand was found to be essential for their stability towards air, while no decrease in activity and productivity could be observed upon coordination of a nitrile. Variations of the imido and anionic ligand revealed that alkoxide complexes with electron‐withdrawing imido ligands offer the highest reactivities and excellent stability compared to analogous triflate and halide complexes.

4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications.

A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.

Cationic Group VI Metal Imido Alkylidene N-Heterocyclic Carbene Nitrile Complexes: Bench-Stable, Functional-Group-Tolerant Olefin Metathesis Catalysts.

Despite their excellent selectivities and activities, Mo‐and W‐based catalysts for olefin metathesis have not gained the same widespread use as Ru‐based systems, mainly due to their inherent air sensitivity. Herein, we describe the synthesis of air‐stable cationic‐at‐metal molybdenum and tungsten imido alkylidene NHC nitrile complexes. They catalyze olefin metathesis reactions of substrates containing functional groups such as (thio‐) esters, (thio‐) ethers and alcohols without the need for prior activation, for example, by a Lewis acid. The presence of a nitrile ligand was found to be essential for their stability towards air, while no decrease in activity and productivity could be observed upon coordination of a nitrile. Variations of the imido and anionic ligand revealed that alkoxide complexes with electron‐withdrawing imido ligands offer the highest reactivities and excellent stability compared to analogous triflate and halide complexes.

Glycoconjugations of Biomolecules by Chemical Methods.

Bioconjugations under benign aqueous conditions have the most promise to covalently link carbohydrates onto chosen molecular and macromolecular scaffolds. Chemical methodologies relying on C-C and C-heteroatom bond formations are the methods of choice, coupled with the reaction conditions being under aqueous milieu. A number of methods, including metal-mediated, as well as metal-free azide-alkyne cyclo-addition, photocatalyzed thiol-ene reaction, amidation, reductive amination, disulfide bond formation, conjugate addition, nucleophilic addition to vinyl sulfones and vinyl sulfoxides, native chemical ligation, Staudinger ligation, olefin metathesis, and Suzuki-Miyaura cross coupling reactions have been developed, in efforts to conduct glycoconjugation of chosen molecular and biomolecular structures. Within these, many methods require pre-functionalization of the scaffolds, whereas methods that do not require such pre-functionalization continue to be few and far between. The compilation covers synthetic methodology development for carbohydrate conjugation onto biomolecular and biomacromolecular scaffolds. The importance of such glycoconjugations on the functional properties is also covered.

Ion-Functionalized Silver(I) Carboxylates: Synthesis and Application in Ru-Catalyzed Olefin Metathesis Reaction

The Grubbs–Hoveyda catalysts have a wide range of applications in catalyzed formation of the carbon-carbon double bonds. In this study, several imidazolium- functionalized or pyridinium-functionalized silver carboxylates have been prepared, and their reaction with Grubbs–Hoveyda 2nd generation (G–H 2nd) catalyst leads a new type of processes. Activity and selectivity of the catalysts have been preliminarily evaluated using cross olefin metathesis reactions.

Synthesis of New of Norbornene–1,5-Bis(hexenyl)hexamethyltrisiloxane Copolymers via Olefin Metathesis Reaction

New copolymers of norbornene and 1,5-bis(hexenyl-5)-1,1,3,3,5,5-hexamethyltrisiloxane containing flexible siloxane and rigid norbornene fragments in the main chain are synthesized. Synthesis is carried out using three types of olefin metathesis reactions: the ring-opening metathesis polymerization of norbornene, the metathesis of nonconjugated diene 1,5-bis(hexenyl-5)-1,1,3,3,5,5-hexamethyltrisiloxane, and the interchain macromolecular cross-metathesis between polynorbornene and siloxane-containing polyene. The latter reaction is studied for the first time. With its help, new statistical multiblock copolymers of norbornene and 1,5-bis(hexenyl-5)-1,1,3,3,5,5-hexamethyltrisiloxane with different average block lengths are obtained and characterized by 1H and 13C NMR and IR spectroscopy. The effect of the copolymer structure on their thermal properties is investigated.

Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product (–)‐Haliclonin A†

Summary of main observation and conclusionWe describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate addition to forge the challenging all‐carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule; and (3) as a C1N1 building block to form the 3‐azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel organocatalytic asymmetric conjugate addition of nitromethane to 3‐alkenyl cyclohex‐2‐enone, and the first Pd‐promoted intramolecular coupling of a thiocarbamate moiety onto an electron‐deficient alkene (enone) to form the 3‐azabicyclo[3,3,1]nonane core. The synthesis also features a SmI2‐mediated intermolecular reductive coupling of an enone with an aldehyde, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocycles, and an unprecedented direct transformation of enol into enone.

Multifactor Control of Vinyl Monomer Sequence, Molecular Weight, and Tacticity via Iterative Radical Additions and Olefin Metathesis Reactions.

Monomer sequence control in terms of a single monomer unit, particularly in vinyl polymers, is one of the largest challenges in polymer chemistry. Furthermore, multifactor control of monomer sequence, molecular weight, and stereoregularity is an ultimate goal. In this work, we propose a strategy to prepare C-C main-chain sequence-regulated polymers with controlled molecular weights from vinyl monomers via a combination of iterative atom transfer radical additions and olefin metathesis reactions. This strategy enabled the synthesis of sequence-regulated polymers with exact styrene-acrylate-styrene sequences in the C-C main chains, controlled molecular weights of up to 104, and stereoregularities varying with syndiotacticity, isotacticity, and heterotacticity. The utility of this strategy is further demonstrated by formation of block copolymers consisting of sequence-regulated vinyl polymer segments by combining living ROMP of norbornene derivatives.

Metathesis of Classical and Functionalized Olefins Catalyzed by Silica‐Supported Single‐Site Well‐Defined W and Mo Pre‐catalysts

AbstractOlefin metathesis of α‐olefins (C6, C8, C10), α, β‐unsaturated ester, α, β‐ unsaturated acetate and cross‐metathesis of 1‐octene and ethyl 6‐heptenoate were carried out using well‐defined [(≡Si−O−)W(CH3)5] and [(≡Si−O−)Mo(≡CtBu)(CH2tBu)2] pre‐catalysts. During the reaction, it was observed that irrespective of the chain length, linear α‐olefins are almost showing similar TON. We observed that Mo pre‐catalyst performs better with TONs between 700 and 1478 as compared to W with TONs between 213 and 962 at room temperature. Both pre‐catalysts performed equally at 70 °C, with almost similar activity as well as TON (≈1700). We also carried out self‐metathesis of functionalized olefins using both silica‐supported W and Mo pre‐catalysts. It was observed that W pre‐catalyst performs much better than Mo pre‐catalyst for functionalized olefin metathesis reaction in our conditions. Additionally, we noticed that W pre‐catalyst provides selective metathesis product, whereas Mo pre‐catalyst gives a range of products due to the isomerization of the olefinic bond.

Impact of Ethylene on Efficiency and Stereocontrol in Olefin Metathesis: When to Add It, When to Remove It, and When to Avoid It

AbstractEthylene is the byproduct of olefin metathesis reactions that involve one or more terminal alkenes. Its volatility is one reason why many cross‐metathesis or ring‐closing metathesis processes, which are reversible transformations, are efficient. However, because ethylene can be converted to a methylidene complex, which is a highly reactive but relatively unstable species, its concentration can impact olefin metathesis in other ways. In some cases, introducing excess ethylene can increase reaction rate owing to faster catalyst initiation. Ethylene and a derived methylidene complex can also advantageously inhibit substrate or product homocoupling, and/or divert a less selective pathway. In other instances, a methylidene's low stability and high activity may lead to erosion of efficiency and/or kinetic selectivity, making it preferable that ethylene is removed while being generated. If methylidene decomposition is so fast that there is little or no product formation, it is best that ethylene and methylidene complex formation is avoided altogether. This is accomplished by the use of di‐ or trisubstituted alkenes in stereoretentive processes, which includes adopting methylene capping strategy. Here, we analyze the different scenarios through which ethylene and the involvement of methylidene complexes can be manipulated and managed so that an olefin metathesis reaction may occur more efficiently and/or more stereoselectively.

Impact of Ethylene on Efficiency and Stereocontrol in Olefin Metathesis: When to Add It, When to Remove It, and When to Avoid It.

Ethylene is the byproduct of olefin metathesis reactions that involve one or more terminal alkenes. Its volatility is one reason why many cross-metathesis or ring-closing metathesis processes, which are reversible transformations, are efficient. However, because ethylene can be converted to a methylidene complex, which is a highly reactive but relatively unstable species, its concentration can impact olefin metathesis in other ways. In some cases, introducing excess ethylene can increase reaction rate owing to faster catalyst initiation. Ethylene and a derived methylidene complex can also advantageously inhibit substrate or product homocoupling, and/or divert a less selective pathway. In other instances, a methylidene's low stability and high activity may lead to erosion of efficiency and/or kinetic selectivity, making it preferable that ethylene is removed while being generated. If methylidene decomposition is so fast that there is little or no product formation, it is best that ethylene and methylidene complex formation is avoided altogether. This is accomplished by the use of di- or trisubstituted alkenes in stereoretentive processes, which includes adopting methylene capping strategy. Here, we analyze the different scenarios through which ethylene and the involvement of methylidene complexes can be manipulated and managed so that an olefin metathesis reaction may occur more efficiently and/or more stereoselectively.

Asymmetric "Clip-Cycle" Synthesis of Pyrrolidines and Spiropyrrolidines.

The development of an asymmetric "clip-cycle" synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by "clipping" them to thioacrylate via an alkene metathesis reaction. Enantioselective intramolecular aza-Michael cyclization onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reaction accommodated a range of substitutions to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ketone and oxoester-containing substrates. DFT studies supported the aza-Michael cyclization as the rate- and stereochemistry-determining step and correctly predicted the formation of the major enantiomer. The catalytic asymmetric syntheses of N-methylpyrrolidine alkaloids (R)-irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties, were achieved using the "clip-cycle" methodology.

Light-Activated Olefin Metathesis: Catalyst Development, Synthesis, and Applications.

ConspectusThe most important means for tuning and improving a catalyst’s properties is the delicate exchange of the ligand shell around the central metal atom. Perhaps for no other organometallic-catalyzed reaction is this statement more valid than for ruthenium-based olefin metathesis. Indeed, even the simple exchange of an oxygen atom for a sulfur atom in a chelated ruthenium benzylidene about a decade ago resulted in the development of extremely stable, photoactive catalysts. This Account presents our perspective on the development of dormant olefin metathesis catalysts that can be activated by external stimuli and, more specifically, the use of light as an attractive inducing agent.The insight gained from a deeper understanding of the properties of cis-dichlororuthenium benzylidenes opened the doorway for the systematic development of new and efficient light-activated olefin metathesis catalysts and catalytic chromatic-orthogonal synthetic schemes. Following this, ways to disrupt the ligand-to-metal bond to accelerate the isomerization process that produced the active precatalyst were actively pursued. Thus, we summarize herein the original thermal activation experiments and how they brought about the discoveries of photoactivation in the sulfur-chelated benzylidene family of catalysts. The specific wavelengths of light that were used to dissociate the sulfur–ruthenium bond allowed us to develop noncommutative catalytic chromatic-orthogonal processes and to combine other photochemical reactions with photoinduced olefin metathesis, including using external light-absorbing molecules as “sunscreens” to achieve novel selectivities. Alteration of the ligand sphere, including modifications of the N-heterocyclic carbene (NHC) ligand and the introduction of cyclic alkyl amino carbene (CAAC) ligands, produced more efficient light-induced activity and special chemical selectivity. The use of electron-rich sulfoxides and, more prominently, phosphites as the agents that induce latency widened the spectrum of light-induced olefin metathesis reactions even further by expanding the colors of light that may now be used to activate the catalysts, which can be used in applications such as stereolithography and 3D printing of tough metathesis-derived polymers.

Iron-Catalyzed Carbonyl–Alkyne and Carbonyl–Olefin Metathesis Reactions

Construction of carbon–carbon bonds is one of the most important tools for the synthesis of complex organic molecules. Among multiple possibilities are the carbonyl–alkyne and carbonyl–olefin metathesis reactions, which are used to form new carbon–carbon bonds between carbonyl derivatives and unsaturated organic compounds. As many different approaches have already been established and offer reliable access to C=C bond formation via carbonyl–alkyne and carbonyl–olefin metathesis, focus is now shifting towards cost efficiency, sustainability and environmentally friendly metal catalysts. Iron, which is earth-abundant and considered as an eco-friendly and inexpensive option in comparison to traditional metal catalysts, fulfils these requirements. Hence, the focus of this review is on recent advances in the iron-catalyzed carbonyl–alkyne, carbonyl–olefin and related C–O/C–O metathesis reactions. The still large research potential for ecologically and economically attractive and sustainable iron-based catalysts is demonstrated.

Superelectrophilic aluminium(iii)–ion pairs promote a distinct reaction path for carbonyl–olefin ring-closing metathesis

Catalytic carbonyl–olefin metathesis reactions represent powerful synthetic strategies for alkene formation. Successful approaches for carbonyl–olefin ring-closing, ring-opening and cross metathesis have been developed in recent years, but current limitations hamper the generality of these transformations. Stronger, more efficient catalytic systems are needed to further broaden the scope of these transformations while they prevent undesired reaction pathways. Here we report the development of an aluminium-based heterobimetallic ion pair as a superior catalyst that promotes carbonyl–olefin ring-closing metathesis via a distinct reaction mechanism and allows access to six- and seven-membered rings, which suffer from low yields and poor conversion under previously reported conditions. Mechanistic investigations support a distinct reaction profile in which two productive reaction pathways competitively form metathesis products. These insights are expected to have important implications in the catalyst design and development for carbonyl–olefin metathesis and enable future advances to ultimately expand the synthetic utility of these transformations. Carbonyl–olefin metathesis reactions are a valuable tool in synthetic chemistry, but there are still some limitations in scope. Now, a catalyst system allows the activation of previously unreactive substrates for such a reaction by aluminium(iii)–ion pairs acting as Lewis acidic superelectrophiles.