Alkyne Metathesis Research Articles

Anion Relay Chemistry Enables Stereoselective Carbonyl-Alkyne Metathesis Reactions.

Dithiane chemistry is increasingly advantageous in the development of novel anion relay chemistry (ARC) modes that harness their umpolung properties to address new chemical challenges. Herein, we report the use of an ARC strategy to promote the regioselective carbonyl alkyne metathesis (CAM) of various carbonyl compounds with alkynyl 1,3-dithianes. Notably, this ARC transformation provides a platform for obtaining stereodefined polysubstituted 1,3-dienes.

Water-catalyzed iron-molybdenum carbyne formation in bimetallic acetylene transformation

Transition metal carbyne complexes are of fundamental importance in carbon-carbon bond formation, alkyne metathesis, and alkyne coupling reactions. Most reported iron carbyne complexes are stabilized by incorporating heteroatoms. Here we show the synthesis of bioinspired FeMo heterobimetallic carbyne complexes by the conversion of C2H2 through a diverse series of intermediates. Key reactions discovered include the reduction of a μ-η2:η2-C2H2 ligand with a hydride to produce a vinyl ligand (μ-η1:η2-CH = CH2), tautomerization of the vinyl ligand to a carbyne (μ-CCH3), and protonation of either the vinyl or the carbyne compound to form a hydrido carbyne heterobimetallic complex. Mechanistic studies unveil the pivotal role of H2O as a proton shuttle, facilitating the proton transfer that converts the vinyl group to a bridging carbyne.

Metallacyclobutadienes: Intramolecular Rearrangement from Kinetic to Thermodynamic Isomers.

Metallacyclobutadienes (MCBDs) are key intermediates of alkyne metathesis reactions. There are in principle two isomerization pathway from kinetic to thermodynamic MCBDs, intermolecular and intramolecular. However, systems that simultaneously isolate two kinds of MCBD isomers have not been achieved, thus restricting the mechanistic studies of the isomerization. Here the reactivity of a metallapentalyne that contains an M≡C bond within the aromatic ring, with alkynes to afford a series of MCBD-fused metallapentalenes is studied. In some cases, both kinetic and thermodynamic products are isolated in the same system, which has never been observed in previous MCBD reactions. Furthermore, the isomerization of MCBD-fused metallapentalenes is investigated both experimentally and theoretically, indicating that it is an intramolecular process involving a metallatetrahedrane (MTd) intermediate. This research provides experimental evidence demonstrating that one MCBD can undergo intramolecular rearrangement to transform into another.

Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity

AbstractThe strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy‐directed ruthenium catalyzed trans‐hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non‐natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of any noticeable cytotoxicity. The “northern” allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.

Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity.

The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy-directed ruthenium catalyzed trans-hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non-natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of any noticeable cytotoxicity. The "northern" allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.

A Catalytic Intramolecular Aldehyde–Alkyne Metathesis Approach to Azepino[1,2‐a]indoles

Reported herein is a method for the construction of azepino[1,2‐a]indoles via an intramolecular aldehyde–alkyne metathesis of 1‐(5‐aryl‐4‐pentynyl)indole‐2‐carbaldehydes. This Sc(OTf)3‐catalyzed reaction has several remarkable features, such as ready accessibility of the starting materials, broad substrate scope, operational simplicity, and high yields. The practicality of the process and the synthetic potential of the products were demonstrated with an upscaling experiment and downstream synthetic derivatizations of the obtained products. We have also extended this methodology to synthesize a 6,7‐dihydropyrido[1,2‐a]indole derivative.

Artificial transmembrane channel constructed from shape-persistent covalent organic molecular cages capable of ion and small molecule transport

Shape-persistent arylene ethynylene molecular cages have been investigated as transmembrane channels for ions and small molecules. The molecular cages were obtained starting from tetrayne monomers through alkyne metathesis cyclooligomerization. We found these porphyrin-based rigid molecular cages can insert into the lipid bilayer and efficiently transport ions and small molecules (e.g., calcein). Our study reveals longer hydrophobic alkyl chains on the cage molecule promote the channeling efficiency, while shorter and/or more polar side chains impair such activity. Kinetic analysis shows linear correlation between the rate of proton transport and the concentration of the cage, suggesting the active species is likely a monomeric cage. We found that C70-encapsulated cages are nearly inactive for transmembrane ion transportation, indicating that ions are likely transported through the internal cavity of the cage. Discrete shape-persistent organic cages represent highly stable synthetic ion channels or pores, which could have interesting applications in biomimetic signaling and drug delivery.

Synthesis and Alkyne Metathesis Activity of Pincer Rhenium Carbyne Complexes

Synthesis and Alkyne Metathesis Activity of Pincer Rhenium Carbyne Complexes

Rhenium Alkyne Catalysis: Sterics Control the Reactivity.

Metathesis reactions, including alkane, alkene, and alkyne metatheses, have their origins in the fundamental understanding of chemical reactions and the development of specialized catalysts. These reactions stand as transformative pillars in organic chemistry, providing efficient rearrangement of carbon-carbon bonds and enabling synthetic access to diverse and complex compounds. Their impact spans industries such as petrochemicals, pharmaceuticals, and materials science. In this work, we present a detailed mechanistic study of the Re(V) catalyzed alkyne metathesis through density functional theory calculations. Our findings are in agreement with the experimental evidence from Jia and co-workers and unveil critical factors governing catalyst performance. Our work not only enhances our understanding of alkyne metathesis but also contributes to the broader landscape of catalytic processes, facilitating the design of more efficient and selective transformations in organic synthesis.

Total Synthesis of the Guangnanmycin A Alcohol

AbstractGuangnanmycin A is a recently discovered congener of the well‐known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum‐catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium‐catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo‐methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain‐driven thia‐Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Total Synthesis of the Guangnanmycin A Alcohol.

Guangnanmycin A is a recently discovered congener of the well-known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum-catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium-catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo-methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain-driven thia-Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Total Synthesis of the Allenic Macrolide (+)-Archangiumide.

Archangiumide is the first known macrolide natural product comprising an endocyclic allene. For the ring strain that this linear substructure might entail, it was planned to unveil the allene at a very late stage of the projected total synthesis; in actual fact, this was achieved as the last step of the longest linear sequence by using an otherwise globally deprotected substrate. This unconventional timing was made possible by a gold catalyzed rearrangement of a macrocyclic propargyl benzyl ether derivative that uses a -PMB group as latent hydride source to unveil the signature cycloallene; the protecting group therefore gains a strategic role beyond its mere safeguarding function. Although the gold catalyzed reaction per se is stereoablative, the macrocyclic frame of the target was found to impose high selectivity and a stereoconvergent character on the transformation. The required substrate was formed by ring closing alkyne metathesis (RCAM) with the aid of a new air-stable molybdenum alkylidyne catalyst.

Exploring efficient and air-stable d2 Re(v) alkylidyne catalysts: toward room temperature alkyne metathesis.

Transition metal-catalyzed alkyne metathesis has become a useful tool in synthetic chemistry. Well-defined alkyne metathesis catalysts comprise alkylidyne complexes of tungsten, molybdenum and rhenium. Non-d0 Re(v) alkylidyne catalysts exhibit advantages such as remarkable tolerance to air and moisture as well as excellent functional group compatibility. However, the known Re(v) alkylidynes with a pyridine leaving ligand require harsh conditions for activation, resulting in lower catalytic efficiency compared to d0 Mo(vi) and W(vi) alkylidynes. Herein, we report the first non-d0 alkylidyne complex capable of mediating alkyne metathesis at room temperature, namely, the Re(v) aqua alkylidyne complex Re([triple bond, length as m-dash]CCH2Ph)( Ph PO)2(H2O) (14). The aqua complex readily dissociates a water ligand in solution, confirmed by ligand substitution reactions with other σ-donor ligands. The aqua complex can be readily prepared on a large scale, and is stable to air and moisture in the solid state and compatible with a variety of functional groups. The versatile ability of the catalyst has been demonstrated through examples of alkyne cross-metathesis (ACM), ring-closing alkyne metathesis (RCAM), and acyclic diyne metathesis macrocyclization (ADIMAC) reactions. All in all, this work presents a solution for an efficient and air-stable alkyne metathesis catalytic system based on d2 Re(v)-alkylidynes.

From the Glovebox to the Benchtop: Air-Stable High Performance Molybdenum Alkylidyne Catalysts for Alkyne Metathesis.

Molybdenum alkylidynes endowed with tripodal silanolate ligands belong to the most active and selective catalysts for alkyne metathesis known to date. This paper describes a new generation that is distinguished by an unprecedented level of stability and practicality without sacrificing the chemical virtues of their predecessors. Specifically, pyridine adducts of type 16 are easy to make on gram scale, can be routinely weighed and handled in air, and stay intact for many months outside the glovebox. When dissolved in toluene, however, spontaneous dissociation of the stabilizing pyridine ligand releases an active species of excellent performance and functional group tolerance. Specifically, a host of polar and apolar groups, various protic sites, and numerous basic functionalities proved compatible. The catalysts are characterized by crystallographic and spectroscopic means, including 95Mo NMR; their activity and stability are benchmarked in detail, and the enabling properties are illustrated by advanced applications to natural product synthesis. For the favorable overall application profile and ease of handling, complexes of this new series are expected to replace earlier catalyst generations and help encourage a more regular use of alkyne metathesis in general.

Ring Expansion Alkyne Metathesis Polymerization.

The synthesis, characterization, and preliminary activity of an unprecedented tethered alkylidyne tungsten complex for ring expansion alkyne metathesis polymerization (REAMP) are reported. The tethered alkylidyne 7 is generated rapidly by combining alkylidyne W(CtBu)(CH2tBu)(O-2,6-i-Pr2C6H3)2 (6) with 1 equiv of an yne-ol proligand (5). Characterized by NMR studies and nuclear Overhauser effect spectroscopy, complex 7 is a dimer. Each metal center contains a tungsten-carbon triple bond tethered to the metal center via an alkoxide ligand. The polymerization of the strained cycloalkyne 3,8-didodecyloxy-5,6-dihydro-11,12-didehydrodibenzo[a,e]-[8]annulene, 8, to generate cyclic polymers was demonstrated. Size exclusion chromatography (SEC) and intrinsic viscosity (η) measurements confirm the polymer's cyclic topology.

Total Synthesis of Njaoamine C by Concurrent Macrocycle Formation.

In conceptual terms, the first total synthesis of the cytotoxic marine natural product njaoamine C differs from all known approaches toward related alkaloids of the manzamine superfamily in that both macrocyclic rings enveloping the diazatricyclic core are concomitantly formed; this goal was reached by double ring closing alkyne metathesis (dRCAM). The success of this maneuver does not merely reflect a favorable preorientation of the four alkyne chains that need to be concatenated in the proper pairwise manner but is also the outcome of dynamic covalent chemistry involving error correction by the chosen "canopy" molybdenum alkylidyne catalyst. The end game downstream of dRCAM capitalizes on the striking chemoselectivity of palladium-catalyzed hydrostannation, which selects for (hetero)arylalkynes even in the presence of sterically much more accessible dialkylalkynes or alkenes; for this preference, the method complements the classical repertoire of hydrometalation and semireduction reactions.

Synthesis of Berkeleylactone A by Ring‐Closing Alkyne Metathesis

AbstractA new route to the macrolactone antibiotic berkeleylactone A was developed. As a key step, a ring‐closing alkyne metathesis (RCAM) of an ester substrate featuring 1‐propynyl termini was used. The carboxylic part of the substrate was easily assembled using alkyne chemistry, like carboxylation of a diyne followed by isomerization of the ynoate section to a dienoate and dihydroxylation of the 4,5‐double bond. The synthesis of the alcohol part of the ester started with opening of (R)‐propylene oxide with an acetylide and was followed by two triple bond migrations. After successful RCAM which formed the C8−C9 bond, the triple bond was selectively hydrogenated to the corresponding alkene before the 4,5‐diol was oxidized to the 5‐hydroxy‐4‐oxo derivative. At this stage, the thioether was formed and the 8,9‐double bond reduced. We also prepared the 8,9‐didehydro analog of berkeleylactone A. However, it turned out that its antimicrobial activity was slightly reduced.

Molybdenum Alkylidyne Silyloxy N‐Heterocyclic Carbene Complexes – Highly Active Alkyne Metathesis Catalysts that can be Handled in Air

AbstractA series of molybdenum alkylidyne silyloxy N‐heterocyclic carbene (NHC) complexes of the general formula [Mo(≡C(R))(OSiPh3)3(NHC)] (R=tBu, 4‐methoxyphenyl, 2,4,6‐trimethylphenyl; NHC = 1,3‐diisopropylimidazol‐2‐ylidene, 1,3‐dicyclohexylimidazol‐2‐ylidene, 1,3‐dicyclohexyl‐4,5‐dihydroimidazol‐2‐ylidene, 1,3‐dimethylimidazol‐2‐ylidene, 1,3‐dimethyl‐4,5‐dichloroimidazol‐2‐ylidene) was synthesized. Single crystal X‐ray analyses revealed that with increasing steric demand of the alkylidyne group, enhanced air‐stability of the complexes in the solid‐state is achieved with the most stable complex (R=2,4,6‐trimethylphenyl, NHC = 1,3‐diisopropylimidazol‐2‐ylidene) being stable in air for 24 h without showing signs of decomposition in 1H NMR. In contrast to previously reported air‐stable molybdenum‐based complexes, the novel catalysts proved to be highly active in alkyne metathesis, allowing for turnover numbers (TONs) of up to 6000 without further activation, and tolerant towards several functional groups such as tosyl, ether, ester, thioether and nitro moieties. Their air stability allows for facile handling of the catalysts in air and even after exposure to ambient atmosphere for one week, the most stable representative still displayed high productivity in alkyne metathesis.

Ultrahigh strength and negative thermal expansion and low thermal conductivity in graphyne nanosheets confirmed by machine-learning interatomic potentials

After several decades of experimental endeavors, most recently large-area γ-graphyne layered materials have been synthesized via a reversible dynamic alkyne metathesis approach (Nature Synthesis (2022) 1, 449–454). Motivated by the aforementioned accomplishment and highly appealing physics of the nanoporous sp–sp2-hybridized carbon allotropes, herein we explore the thermal and mechanical properties of six different graphyne lattices, via machine-learning interatomic potentials (MLIPs). To this aim, by employing a computationally efficient passive-training approach, the thermal and mechanical properties are evaluated with ab-initio level of accuracy using the classical molecular dynamics simulations. Analysis of mechanical properties at room temperature reveal that graphyne nanosheets depending on the atomic structure and loading direction can show remarkably high ultimate tensile strengths up to around 90 GPa. The graphyne nanomembranes are however predicted to show by around two orders of magnitude suppressed lattice thermal conductivity than graphene. Graphyne nanoporous networks are also predicted to show ultrahigh negative thermal expansion coefficients, one order of magnitude higher than that of the graphene. The presented MLIP-based results provide a critical vision on the structure and thermo-mechanical property relationships in sp–sp2-hybridized graphyne allotropes, which can be useful for the design of novel nanodevices using this important class of nanomaterials.

Promoting productive metathesis pathway and tuning activity of multidentate molybdenum catalysts in alkyne metathesis: A theoretical perspective

Molybdenum alkylidyne complexes, including those containing monodentate or multidentate ligands, can catalyze CC bond formation via alkyne metathesis, which is of great importance to organic synthesis and materials chemistry. Herein, to understand the catalyst working mechanism and explore the key parameters determining the catalyst performance, alkyne metathesis catalyzed by molybdenum-based multidentate complexes was systematically investigated using density functional theory calculations. By comparing the desired cross metathesis and undesired polymerization pathways in multidentate and monodentate catalytic systems, the former shows significantly higher activation barrier for alkyne polymerization, resulting in the shutdown of ring-expansion by-product formation. Furthermore, the calculations show that the multidentate ligands taking trigonal-pyramidal geometry play two roles: (1) occupying one of substrate coordination sites to inhibit the polymerization pathway, thus promoting the desired productive pathway; (2) changing the electronic and steric environment to tune catalytic activity. It is worth noting that the metallacyclobutadiene complex with hither plane feature may play a key role in determining the activity of the catalysts. This work thus provides a guiding principle toward high-performance multidentate catalysts for alkyne metathesis.