Showing papers on "Metathesis published in 2023"

Enantioselective Total Synthesis of (−)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones

Abstract: Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate- and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a β-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

Water-Accelerated Decomposition of Olefin Metathesis Catalysts

Abstract: Water is ubiquitous in olefin metathesis, at levels ranging from contaminant to cosolvent. It is also non-benign. Water-promoted catalyst decomposition competes with metathesis, even for “robust” ruthenium catalysts. Metathesis is hence typically noncatalytic for demanding reactions in water-rich environments (e.g., chemical biology), a challenge as the Ru decomposition products promote unwanted reactions such as DNA degradation. To date, only the first step of the decomposition cascade is understood: catalyst aquation. Here we demonstrate that the aqua species dramatically accelerate both β-elimination of the metallacyclobutane intermediate and bimolecular decomposition of four-coordinate [RuCl(H2O)n(L)(=CHR)]Cl. Decomposition can be inhibited by blocking aquation and β-elimination.

Total Syntheses of Nominal and Actual Prorocentin

Abstract: The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas a structural relationship cannot be missed and a biosynthetic link was proposed, it is currently unknown whether there is any parallel in the bioactivity profile of these natural products. However, it was insinuated in the past that the structure assigned to prorocentin might need to be revised. Indeed, re-examination of the published spectra cast doubts as to the constitution of the fused/spirotricyclic BCD-ring system in the core. To clarify this issue, a flexible synthesis blueprint was devised that allowed us to obtain the originally proposed structure as well as the most plausible amended structure. The key to success was late-stage gold-catalyzed spirocyclization reactions that furnished the isomeric central segments with excellent selectivity. The lexicon of catalytic transformations used to make the required cyclization precursors comprised a titanium-mediated ester methylenation/metathesis cascade, a rare example of a gold-catalyzed allylic substitution, and chain extensions via organocatalytic asymmetric aldehyde propargylation. A wing sector to be attached to the isomeric cores was obtained by Krische allylation, followed by a superbly selective cobalt-catalyzed oxidative cyclization of the resulting di-unsaturated alcohol with the formation of a 2,5-trans-disubstituted tetrahydrofuran; the remaining terminal alkene was elaborated into an appropriate handle for fragment coupling by platinum-catalyzed asymmetric diboration/oxidation. The assembly of the different building blocks to the envisaged isomeric target compounds proved that the structure of prorocentin needs to be revised as disclosed herein.

The Fluorocarbene Exploit: Enforcing Alternation in Ring-Opening Metathesis Polymerization.

Abstract: Fluoroalkenes are known to be notoriously reluctant substrates for olefin metathesis due to the generation of thermodynamically stable Fischer-type fluorocarbene intermediates, which invariably fail to undergo further reaction. In the present disclosure, we find that fluorine substitution on the sp2 carbon also strictly suppresses homopolymerization of norbornene derivatives (NBEs), and this can be harnessed to achieve alternating ring-opening metathesis polymerization (ROMP) with an appropriately electron-rich comonomer. Dihydrofuran (DHF) is thereby shown to undergo alternating ROMP with fluorinated norbornenes, the perfectly alternating structure of the resulting copolymer having been unambiguously elucidated by 1H, 19F, and 13C NMR analyses. Furthermore, we find that the degradability of the resultant copolymers in acidic media via hydrolysis of enol ether moieties in the backbone can be predictably modulated by the number of fluorine atoms present in the NBE comonomer, affording an opportunity to engage with the desirable physical properties of fluorinated polymers while limiting their attendant environmental degradability issues.

Rapid Aerial Oxidation of Ruthenium-Dithiocatecholate Catalysts: A Challenge to Stereoretentive Olefin Metathesis

Abstract: Ruthenium dithiolene complexes, particularly the dithiocatecholates Ru(S2C6H2-3,6-Cl2)(NHC)(=CHC6H4-2-OiPr) (NHC = H2IPr, H2IMes), are an important class of olefin metathesis catalysts employed for the stereocontrolled assembly of C=C bonds. The poorly understood sensitivity of these catalysts results in unpredictable performance. Here they are shown to resist degradation by amine nucleophiles, in contrast with their dichloride parents; however, they are significantly more oxygen-sensitive. Even as the precatalysts, they decompose within minutes in solution under O2, eliminating the alkylidene ligand as O=CHC6H4-2-OiPr and forming unusual, four-coordinate Ru(IV)-oxo products, Ru(O)(S2C6H2-3,6-Cl2)(NHC). Participation of the latter in O-transfer with PPh3 suggests potential opportunities in catalytic oxidation.

Cobalt-catalyzed Enantioselective Hydrogenation of Trisubstituted Carbocyclic Olefins: An Access to Chiral Cyclic Amides.

Abstract: The enantioselective hydrogenation of cyclic enamides has been achieved using an earth-abundant cobalt-bisphosphine catalyst. Using CoCl2/(S,S)-Ph-BPE, several trisubstituted carbocyclic enamides were reduced with high activity and excellent enantioselectivity (up to 99%) to the corresponding saturated amides. The methodology can be extended to the synthesis of chiral amines by base hydrolysis of the hydrogenation products. Preliminary mechanistic investigations reveal the presence of a high spin cobalt (II) species in the catalytic cycle. We propose that the hydrogenation of the carbon-carbon double bond proceeds via a sigma-bond-metathesis pathway.

Cesium Heteropolyacid Salts: Synthesis, Characterization and Activity of the Solid and Versatile Heterogeneous Catalysts

Abstract: Keggin-type heteropolyacid cesium salts have been regarded as potential candidates for heterogeneous catalytic reactions. This review describes the success of Keggin-type heteropolyacids cesium salts (Cs-HPA salts) as efficient catalysts in various synthesis processes. The Cs-HPA catalysts can be synthesized as solid salts through the metathesis of a solution containing precursor HPA and another solution containing soluble Cs salt, which will give Cs-HPA salt as a solid precipitate. Alternatively, they can be also obtained from the commercial precursor HPA. In this review, all the routes to prepare the different cesium salts (i.e., saturated, lacunar, metal-doped) were described. These salts can be used in acid-catalyzed reactions (i.e., esterification, etherification, acetalization, dehydration) or oxidative transformations (oxidative esterification, oxidation, epoxidation). All of these reactions were addressed herein. Aspects related to the synthesis and characterization of these catalyst salts were discussed. This review aims to discuss the most pertinent heterogeneous catalytic systems based on Keggin HPA Cs salts. The focus was to correlate the physicochemical properties of these salts with their catalytic activity. Ultimately, the most recent advances achieved in the applications of these Cs-HPA salts as catalysts in the synthesis of industrial interest compounds were discussed. Cesium heteropoly salts are an alternative to the traditional soluble mineral acids as well as to solid-supported catalysts.

Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights.

Abstract: Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however. Here, we present a stereoretentive strategy for CM between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, affording an assortment of E- or Z-trisubstituted alkenyl bromides. The majority of the transformations were catalyzed by two Mo monoaryloxide pyrrolide (MAP) complexes, one purchasable and the other accessible by well-established protocols. Substrates, such as feedstock trisubstituted olefins, can be purchased; the alkenyl bromide reagents are commercially available or can be prepared in two steps in a multigram scale. The catalytic process can be used to generate products that contain polar moieties, such as an amine or an alcohol, or sterically hindered alkenes that are α- or β-branched. The utility of the approach is highlighted by a brief and stereocontrolled synthesis of an unsaturated fragment of phomactin A and a concise total synthesis of ambrein. An unexpected outcome of these investigations was the discovery of a new role for the presence of a small-molecule alkene in an olefin metathesis reaction. DFT studies indicate that this additive swiftly reacts with a short-lived Mo alkylidene and probably helps circumvent the formation of catalytically inactive square pyramidal metallacyclobutanes, enhancing the efficiency of a transformation.

σ-Hole interactions in organometallic catalysts: the case of methyltrioxorhenium(VII).

Abstract: Methyltrioxorhenium(VII) (MTO) is a widely employed catalyst for metathesis, olefination, and most importantly, oxidation reactions. It is often preferred to other oxometal complexes due to its stability in air and higher efficiency. The seminal papers of K. B. Sharpless showed that when pyridine derivatives are used as co-catalysts, MTO-catalyzed olefin epoxidation with H2O2 as oxidant, a particularly useful reaction, is accelerated, with pyridine speeding up catalytic turnover and increasing the lifetime of MTO under the reaction conditions. In this paper, combined experimental and theoretical results show that the occurrence of σ-hole interactions in catalytic systems extends to MTO. Four crystalline adducts between MTO and aliphatic and heteroaromatic bases are obtained, and their X-ray analyses display short Re⋯N/O contacts opposite to both O-Re and C-Re covalent bonds with geometries consistent with σ-hole interactions. Computational analyses support the attractive nature of these close contacts and confirm that their features are typical of σ-hole interactions. The understanding of the nature of Re⋯N/O interactions may help to optimize the ligand-acceleration effect of pyridine in the epoxidation of olefins under MTO catalysis.

Sustainable synthesis of SiS2 for solid-state electrolytes by cascaded metathesis

Abstract: Sulfide-based electrolytes containing silicon offer high ionic conductivity and are employed in emerging solid-state batteries that are promising for electric vehicles due to their improved energy density and safety. However, their deployment is constrained by the high cost and low availability of the SiS2 precursor. Here we introduce a green, solution-based synthesis of SiS2 through coupled metathesis reactions. First, the key Li2S precursor is synthesized from the room-temperature reaction between abundant Na2S and LiCl in ethanol. Next, the Li2S is recovered from solution and combined with SiCl4 in ethyl acetate to form a SiS2 solution and regenerate LiCl. The synthesized Li2S and SiS2 are characterized and then combined to form a glassy solid electrolyte with a conductivity of 0.11 mS cm-1 at 30 °C, validating the utility of metathesis-derived metal sulfides to solid electrolyte synthesis. In this cascaded metathesis scheme the expensive components, LiCl and solvents, are recovered and recycled in a circular economy. The cascaded metathesis process can in principle be used to synthesize nearly any metal sulfide of interest to a wide range of applications including energy conversion/storage, catalysis, electronics, and optics.

Chiral Atropisomeric-NHC Catechodithiolate Ruthenium Complexes for Z-Selective Asymmetric Ring-Opening Cross Metathesis of Exo-Norbornenes.

Abstract: A set of 16 chiral ruthenium complexes containing atropisomerically stable N-Heterocyclic Carbene (NHC) ligands was synthesized from prochiral NHC precursors. After a rapid screening in asymmetric ring-opening-cross metathesis (AROCM), the most effective chiral atrop BIAN-NHC Ru-catalyst (up to 97:3 er) was then converted to a Z-selective catechodithiolate complex. The latter proved to be highly efficient in Z-selective AROCM of exo-norbornenes affording valuable trans-cyclopentanes with excellent Z-selectivity (>98%) and high enantioselectivity (up to 96.5:3.5 er).

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis.

Abstract: Catalytic cross-metathesis (CM) reactions that can generate trisubstituted alkenes in high stereoisomeric purity are important but remain limited in scope. Here, CM reactions are introduced that generate Z-trisubstituted α-methyl, α,β-unsaturated, alkyl and aryl esters, thiol esters, and acid fluorides. Transformations are promoted by a Mo bis-aryloxide, a monoaryloxide pyrrolide, or a monoaryloxide chloride complex; air-stable and commercially available paraffin tablets containing a Mo complex may also be used. Alkyl, aryl, and silyl carboxylic esters as well as thiol esters and acid fluoride reagents are either purchasable or can be prepared in one step. Products were obtained in 55-95% yield and in 88:12->98:2 Z/E ratio (typically >95:5). The applicability of the approach is highlighted by a two-step conversion of citronellol to an isomintlactone precursor (1.7 g, 73% yield, and 97:3 Z/E) and a single-step transformation of lanosterol acetate to 3-epi-anwuweizic acid (72% yield and 94:6 Z/E). Included are the outcomes of DFT studies, regarding several initially puzzling catalyst activity trends, providing the following information: (1) it is key that a disubstituted Mo alkylidene, generated by a competing homo-metathesis (HM) pathway, can re-enter the productive CM cycle. (2) Whereas in a CM cycle the formation of a molybdacyclobutane is likely turnover-limiting, the collapse of related metallacycles in a HM cycle is probably rate-determining. It is therefore the relative energy barrier required for these steps that determines whether CM or HM is dominant with a particular complex.

The Non-Covalent Interactions index: From biology to chemical reactivity and solid-state

Abstract: The Non-Covalent Interaction (NCI) index has become a versatile tool for analyzing the presence and strength of localized and delocalized interactions in systems of interest to diverse areas such as biochemistry, reactivity, and solid state. Furthermore, it can be applied to promolecular, ab initio or even experimental electron densities, making it an even more flexible method. In this chapter, we demonstrate some of these NCI capacities by employing it in three representative cases: (a) Interaction between the spike protein of some early variants of the SARS-CoV-2 virus with selected potential inhibitors. (b) The ring-opening metathesis polymerization of two norbornene derivatives, mediated by a ruthenium-alkylidene catalyst. (c) Effect of π-electron delocalization in the structural and electronic changes on the noncovalent interactions in two quinone crystals. These cases are illustrative of the application of NCI to study ligand-protein interactions, the interplay of inter and intramolecular forces in reaction pathways, and crystal packing, respectively. Moreover, we show the suitability of using different methods for obtaining the electron density in each example.

Facile Approach for the Synthesis of Performance-Advantaged Degradable Bio-Based Thermoset via Ring-Opening Metathesis Polymerization from Epoxidized Soybean Oil

Abstract: Design and synthesis of polymeric materials from sustainable feedstocks can partly mitigate environmental polymer pollution, and hence, it has received constant attention. This work aims to synthesize a degradable bio-based thermoset via ring-opening metathesis polymerization (ROMP) from epoxidized soybean oil (ESO). ESO was converted to norbornene-functionalized ESO first, and then, this functionalized ESO was rapidly generated to a thermoset via ROMP. The ESO-based thermoset exhibits promising thermal properties and mechanical performance, is available for fabrication of composites, and can be fully degraded into small molecules and oligomeric species under aqueous NaOH or KOH. Moreover, the functionalized ESO can copolymerize with norbornene to form partially degradable copolymers. This approach can be used to synthesize degradable vegetable oil-based thermosets for various applications and for environmental sustainability.

The Suzuki-Miyaura Cross-Coupling-Claisen Rearrangement-Cross-Metathesis Approach to Prenylated Isoflavones.

Abstract: Isoflavones were synthesized via Suzuki-Miyaura coupling of 3-iodochromones and para-methoxybenzene- and para-phenolboronic acid. In our hands, conditions commonly used for similar cross couplings turned out to be unsuccessful or difficult to reproduce, for example, due to the unplanned partial cleavage of MOM-protecting groups. Using Pd(dba)2 as a precatalyst and tricyclohexylphosphine as an activating ligand, reliable cross-coupling conditions were identified. In all cases, notably higher yields of isoflavones were obtained with para-phenolboronic acid than with para-methoxybenzene boronic acid. This observation and the commercial availability of para-phenolboronic acid suggest that for the synthesis of the important 3'-prenyl- or 3',5'-diprenylisoflavone substitution pattern a synthetic route that introduces the prenyl substituents after the Pd-catalyzed cross-coupling step, thereby avoiding laborious and protecting-group-intensive multistep syntheses of C-prenylated arene boronic acids, is advantageous.

Low-Coordinate Mixed Ligand NacNac Complexes of Rare Earth Metals

Abstract: We report the synthesis and characterization of two types of new mixed-ligand rare earth complexes: tetracoordinate (NacNacMes)Ln(BIANdipp) (Ln = Dy (1), Er (2) and Y (3)) and pentacoordinate (NacNacMes)Ln(APdipp)(THF) (Ln = Dy (4), Er (5) and Y (6)). The first three compounds were prepared by the reaction of [(BIANDipp)LnI] with potassium β-diketiminate. The salt metathesis of β-diketiminato-supported rare earth dichlorides (NacNacMes)LnCl2(THF)2 with sodium o-amidophenolate results in compounds 4–6. The crystal structures of complexes 1–6 were determined by single-crystal analysis. The combination of bulky monoanionic N-mesityl-substituted β-diketiminates with sterically hindered redox-active ligands led to the very low coordination numbers of rare earths and strong distortion of the chelate ligands.

Influence of the Norbornene Anchor Group in Ru-Mediated Ring-Opening Metathesis Polymerization: Synthesis of Linear Polymers

Abstract: Ring-opening metathesis polymerization (ROMP) mediated by Grubbs’ first-generation catalyst [G1, (PCy3)2(Cl)2RuCHPh] and Grubbs’ third-generation catalyst [G3, (H2IMes)(Cl)2(pyr)2RuCHPh] can exhibit living characteristics for some monomer classes, most commonly substituted norbornenes. Here, we studied how various anchor groups, the series of atoms connecting the polymerizable norbornene unit to a functional group, affect livingness in ROMP in a series of small-molecule exo-norbornene monomers. We first designed and calculated the HOMO energy of 61 monomers using density functional theory methods, finding that these energies spanned a range of 25 kcal/mol. We then performed kinetics experiments using 1H NMR spectroscopy to measure the propagation rate constant (kp,obs) under identical conditions for eight selected monomers with different anchor groups across the range of HOMO energies. We observed a positive correlation between the HOMO energy or the HOMO/LUMO energy gap and measured kp,obs values for both catalysts, revealing a 30-fold and a 10-fold variation in kp,obs values across the series for G1 and G3, respectively. Interestingly, we observed a plateau for the three monomers with the highest HOMO energies for G3 catalyst, suggesting that above a certain level, the HOMO energy no longer influenced the rate-determining step under the conditions studied here. Chelation studies revealed that only one of the eight monomers showed measurable binding of electron-rich groups on the monomer to the catalyst, but with no apparent effect on kp. Finally, we utilized 1H NMR spectroscopy to measure the rate of catalyst decomposition in the presence of each monomer, a key termination pathway in ROMP. Ultimately, we determined that the anchor group did not substantially affect catalyst decomposition, a proxy for the termination rate constant (kt). In sum, these combined computational and experimental studies collectively demonstrate that livingness in ROMP of exo-norbornene monomers using G1 and G3 catalysts, as measured by relative kp/kt ratios, is primarily controlled by the kp of the anchor group, which is correlated with the HOMO energy.

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

Abstract: The involvement of 1,3-dipolar cycloaddition (1,3-DP), double bond migration, metathesis, and nitrile oxide (including in situ-generated nitrile oxide) as dipoles, together with the C=C bond containing dipolarophiles, in the syntheses of 2-isoxazolines is presented. Methods for synthesizing isoxazolines (other than 1,3-DP cycloaddition) were also presented briefly. Various methods of nitrile oxide preparation, especially in situ-generated procedures, are presented. Special attention was paid to the application of various combinations of 1,3-DP cycloaddition with double bond migration (DBM) and with alkene metathesis (AM) in the syntheses of trisubstituted isoxazolines. Allyl compounds of the type QCH2CH=CH2 (Q = ArO, ArS, Ar, and others) play the role of dipolarophile precursors in the combinations of DPC mentioned, DBM and AM. Mechanistic aspects of cycloadditions, i.e., concerted or stepwise reaction mechanism and their regio- and stereoselectivity are also discussed from experimental and theoretical points of view. Side reactions accompanying cycloaddition, especially nitrile oxide dimerization, are considered. 2-Isoxazoline applications in organic synthesis and their biological activity, broad utility in medicine, agriculture, and other fields were also raised. Some remaining challenges in the field of 1,3-DP cycloaddition in the syntheses of isoxazolines are finally discussed.

Synthesis of High-Purity Li2S Nanocrystals via Metathesis for Solid-State Electrolyte Applications

Abstract: Li2S is the key precursor for synthesizing thio-LISICON electrolytes employed in solid state batteries. However, conventional synthesis techniques such as carbothermal reduction of Li2SO4 aren’t suitable for the generation of...

Synthesis of polynorbornadienes by ring-opening metathesis polymerization and their saturated derivatives bearing various ester groups and carboxyl groups

Abstract: Various symmetric and non-symmetric polynorbornadienes having a variety of ester groups and carboxyl groups were synthesized by ring-opening metathesis polymerization (ROMP) with Grubbs' third generation catalyst (G3 or [Ru]-III catalyst) in a controlled living manner from half-esters prepared by the selective monohydrolysis of symmetric diesters that we previously reported. The half-esters thus obtained can be directly submitted to ROMP with the G3 catalyst, leading to mostly the trans structure and narrow polydispersity indexes. The subsequent hydrogenation yielded saturated polymers, improving the thermostabilities according to the T5d results. Our selective monohydrolysis reactions combined with ROMP initiated by the G3 catalyst have proven to be an efficient tool for the production of a variety of homopolymers with well-controlled structures in a living manner.