Metathesis Of Substrates Research Articles

Syntheses of 9‐Vinylated Benzotropolones by a Sequence of Acylation, Ring‐Closing Enyne Metathesis, and Oxidation

AbstractPrevious studies from our group revealed that 6,7‐benzannulated nona‐1,8‐diene‐5‐ones of a variety of substitution patterns undergo ring‐closing diene metatheses in the presence of the Grubbs‐II catalyst; the benzocycloheptadienones formed thereby gave benzotropolones in between one and four follow‐up steps. The present study discloses that exemplary 6,7‐benzannulated non‐1‐en‐8‐yn‐5‐ones undergo ring‐closing enyne metatheses in the presence of the Grubbs‐II catalyst; the vinylated benzocycloheptadienones formed thereby gave 9‐vinylbenzotropolones in four steps: silyl enol ether formation, Rubottom‐type oxidation, desilylation, and Dess‐Martin oxidation. The metathesis substrates were synthesized either from (ortho‐bromoaryl)ethynes with an unsubstituted sp‐carbon by a Br→Li exchange and an acylation with an H2C=CH‐containing Weinreb amide; or, they were synthesized from (ortho‐bromoaryl)ethynes with a trimethylsilylated sp‐carbon by a Br→Li→ZnHal exchange, an acylation with an H2C=CH‐containing thioester, and a desilylation.

Toward E-selective Olefin Metathesis: Computational Design and Experimental Realization of Ruthenium Thio-Indolate Catalysts

The selective transformation of 1-alkenes into E-olefins is a long-standing challenge in olefin metathesis. Density functional theory (DFT) calculations predict high E-selectivity for catalysts incorporating a bidentate, dianionic thio-indolate ligand within a RuXX’(NHC)(py)(= CHR) platform (NHC = N-heterocyclic carbene; py = pyridine). Such complexes are predicted to yield E-olefins by favoring anti-disposed substituents in the transition state expected to be rate-determining: specifically, that for cycloreversion of the metallacyclobutane intermediate. Three pyridine-stabilized catalysts Ru21a-c were synthesized, in which the thio-indolate ligand bears a H, Me, or Ph substituent at the C2 position, and the NHC ligand is the unsaturated imidazoline-2-ylidene Me2IMes (which bears N-mesityl groups and methyl groups on the C4,5 backbone). Single-crystal X-ray diffraction analysis of Ru21c confirms the ligand orientation required for E-selective metathesis, with the thio-indolate sulfur atom binding cis to the NHC, and the indolate nitrogen atom trans to the NHC. However, whereas the new complexes mediated metathetic exchange of their 2-thienylmethylidene ligand in the presence of the common metathesis substrates styrene and allylbenzene, no corresponding self-metathesis products were obtained. Only small amounts of 2-butene (73% (Z)-2-butene) were obtained in self-metathesis of propene using Ru21a. Detailed DFT analysis of this process revealed that product release is surprisingly slow, limiting the reaction rate and explaining the low metathesis activity. With the barrier to dissociation of (Z)-2-butene being lower than that of (E)-2-butene, the calculations also account for the observed Z-selectivity of Ru21a. These findings provide guidelines for catalyst redesign in pursuit of the ambitious goal of E-selective 1-alkene metathesis.Graphic abstract

The Influence of Various N-Heterocyclic Carbene Ligands on Activity of Nitro-Activated Olefin Metathesis Catalysts.

A set of nitro-activated ruthenium-based Hoveyda-Grubbs type olefin metathesis catalysts bearing sterically modified N-hetero-cyclic carbene (NHC) ligands have been obtained, characterised and studied in a set of model metathesis reactions. It was found that catalysts bearing standard SIMes and SIPr ligands (4a and 4b) gave the best results in metathesis of substrates with more accessible C–C double bonds. At the same time, catalysts bearing engineered naphthyl-substituted NHC ligands (4d–e) exhibited high activity towards formation of tetrasubstituted C–C double bonds, the reaction which was traditionally Achilles’ heel of the nitro-activated Hoveyda–Grubbs catalyst.

Directed evolution of artificial metalloenzymes for in vivo metathesis

The field of biocatalysis has advanced from harnessing natural enzymes to using directed evolution to obtain new biocatalysts with tailor-made functions. Several tools have recently been developed to expand the natural enzymatic repertoire with abiotic reactions. For example, artificial metalloenzymes, which combine the versatile reaction scope of transition metals with the beneficial catalytic features of enzymes, offer an attractive means to engineer new reactions. Three complementary strategies exist: repurposing natural metalloenzymes for abiotic transformations; in silico metalloenzyme (re-)design; and incorporation of abiotic cofactors into proteins. The third strategy offers the opportunity to design a wide variety of artificial metalloenzymes for non-natural reactions. However, many metal cofactors are inhibited by cellular components and therefore require purification of the scaffold protein. This limits the throughput of genetic optimization schemes applied to artificial metalloenzymes and their applicability in vivo to expand natural metabolism. Here we report the compartmentalization and in vivo evolution of an artificial metalloenzyme for olefin metathesis, which represents an archetypal organometallic reaction without equivalent in nature. Building on previous work on an artificial metallohydrolase, we exploit the periplasm of Escherichia coli as a reaction compartment for the 'metathase' because it offers an auspicious environment for artificial metalloenzymes, mainly owing to low concentrations of inhibitors such as glutathione, which has recently been identified as a major inhibitor. This strategy facilitated the assembly of a functional metathase in vivo and its directed evolution with substantially increased throughput compared to conventional approaches that rely on purified protein variants. The evolved metathase compares favourably with commercial catalysts, shows activity for different metathesis substrates and can be further evolved in different directions by adjusting the workflow. Our results represent the systematic implementation and evolution of an artificial metalloenzyme that catalyses an abiotic reaction in vivo, with potential applications in, for example, non-natural metabolism.

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks

A range of metathesis substrates was assembled from triplets of unsaturated building blocks. The approach involved the iterative attachment of a propagating and a terminating building block to a fluorous-tagged initiating building block. Metathesis cascade chemistry was used to “reprogram” the molecular scaffolds. Remarkably, in one case, a cyclopropanation reaction competed with the expected metathesis cascade process. Finally, it was demonstrated that the metathesis products could be derivatised to yield the final products. At each stage, purification was facilitated by the presence of a fluorous-tagged protecting group.

Olefin Cross-Metathesis on Proteins: Investigation of Allylic Chalcogen Effects and Guiding Principles in Metathesis Partner Selection

Olefin metathesis has recently emerged as a viable reaction for chemical protein modification. The scope and limitations of olefin metathesis in bioconjugation, however, remain unclear. Herein we report an assessment of various factors that contribute to productive cross-metathesis on protein substrates. Sterics, substrate scope, and linker selection are all considered. It was discovered during this investigation that allyl chalcogenides generally enhance the rate of alkene metathesis reactions. Allyl selenides were found to be exceptionally reactive olefin metathesis substrates, enabling a broad range of protein modifications not previously possible. The principles considered in this report are important not only for expanding the repertoire of bioconjugation but also for the application of olefin metathesis in general synthetic endeavors.

Synthesis of Small Molecules with High Scaffold Diversity: Exploitation of Metathesis Cascades in Combination with Inter‐ and Intramolecular Diels–Alder Reactions

Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules. Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter- and intramolecular Diels-Alder reactions, when used in conjunction with metathesis cascades, can extend the range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to "reprogram" the molecular scaffolds. In many cases, the metathesis products were 1,3-dienes, which were potential substrates for either inter- or intramolecular Diels-Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a "safety-catch" linker that we have developed. It was demonstrated that, in certain cases, Diels-Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.

A fluorous-tagged "safety catch" linker for preparing heterocycles by ring-closing metathesis.

A fluorous-tagged “safety catch” linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitiates the purification of metathesis substrates, the removal of the catalyst, the functionalization of the products, and the release of only metathesis products. The synthesis of a range of heterocycles is described.

Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds

Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds

End Capping Ring-Opening Olefin Metathesis Polymerization Polymers with Vinyl Lactones

The selective placement of a functional group at the chain end of a ring-opening metathesis polymer using ruthenium carbene initiators has been a significant limitation. Here we demonstrate a highly effective and facile end-capping technique for ROMP with living ruthenium carbene chain ends using single-turnover olefin metathesis substrates. Vinylene carbonate and 3H-furanone are introduced as functionalization and termination agents for the ruthenium-initiated ring-opening metathesis polymerization. This leads directly to the formation of functional polymer end groups without further chemical transformation steps. Aldehyde and carboxylic acid end groups can be introduced by this new method which involves the decomposition of acyl carbenes to ruthenium carbides. The high degrees of chain-end functionality obtained are supported by (1)H NMR spectroscopy, MALDI-ToF mass spectrometry, and end-group derivatization.

Olefin Metathesis of Amine‐Containing Systems: Beyond the Current Consensus

AbstractOlefin metathesis is one of the most powerful synthetic tool to access amine‐containing heterocycles and alkaloids. A major drawback associated with the use of amines concerns their ability to coordinate to metal‐alkylidene complexes and to interfere unproductively with catalytic activity. Based on literature precedents, it has been established as a “dogma” that efficient metathesis reactions are suppressed in the presence of basic amines and that such substrates must invariably be deactivated by conversion of the amines to the corresponding carbamates or ammonium salts. However, an increasing number of examples of amine‐containing compounds that are good substrates for metathesis is being reported in the literature. How can this “non‐classical” reactivity be rationalized and exploited? The purpose of this review is to provide an overview of successful metathesis reactions performed with amine‐containing compounds in order to allow some guidelines to be formulated. A special emphasis is placed on the different parameters that may influence the outcome of the reaction such as steric effects, amine basicity, and the nature of the catalyst.

Metathesis of heteroatom-substituted olefins and alkynes: Current scope and limitations

The use of vinyl- or alkynyl derivatives of the type C C–X or C C–X (where X is an heteroatom) as substrates for metathesis increases further this reaction’s versatility. Selected examples illustrating recent progress in this area of research are presented. Current scope and future potential developments are discussed.

Metathesis of Structurally Preorganized Bivalent Carbohydrates. Synthesis of Macrocyclic and Oligomeric Scaffolds

[reaction: see text] Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary structure depends on whether secondary or tertiary amides are present, and this influences the course of the metathesis reaction leading to novel multivalent scaffolding. Molecular modeling suggests that a very rigid macrocyclic scaffold has potential for the development of alpha-helix peptidomimetics.

A Sequential Claisen/Ring‐Closing Metathesis Approach to the Synthesis of Spirocyclic Cyclopentanes and Cyclohexanes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A sequential Claisen/ring-closing metathesis approach to the synthesis of spirocyclic cyclopentanes and cyclohexanes

A new method for the formation of spirocycles is described using a sequential Ireland–Claisen/Metathesis strategy to construct spirocyclic systems. Optimization of the Ireland–Claisen conditions provides the key metathesis substrates. The metathesis reactions were highly regioselective by virtue of steric hindrance in the substrate olefins.

Structure/property relationship of Schrock-type alkylidene complexes based on tungsten and molybdenum

The structure/property relationship of Schrock-type alkylidene complexes with tungsten and molybdenum as central atoms was investigated. Terminal and, E and Z internal olefins as well as double bond substituted and unsubstituted unsaturated polymers served as metathesis substrates. According to the results obtained, it is possible to choose the optimal catalyst depending on the metathesis substrate and temperature, the central atom plays a decisive role. Examples concerning equilibrium polymerization demonstrate the practical utilization.