Ene-yne Metathesis Research Articles

Stereoconvergent Synthesis of Z-1,3-Disubstituted-1,3-Dienes by Uphill Photocatalysis.

A variety of 1-aryl-1,3-dienes were isomerized from E to Z isomers by photocatalysis using Ru(bpy)3 [PF6 ]2 and blue LED light. Enrichment of the Z-isomer is thought to occur by selective triplet energy transfer from the photocatalyst to the stereoisomeric mixture. The 1,3-diene starting materials are easily made by catalytic ene-yne metathesis (EYM). To access 1,3-diene Z-stereoisomers directly, a one pot procedure was developed. Additional 1,3-dienes were investigated for both isomerization and Z-enrichment. The combination of cross EYM with photocatalysis allows for the stereoconvergent synthesis of Z-1,3-dienes.

Preparation of Dienyl Boronates by Tandem Ene-Yne Metathesis/Dienyl Isomerization: Ready Access to Diene Building Blocks for the Synthesis of Polyenes.

The ene-yne metathesis of alkenyl boronates with terminal alkynes is reported. These challenging metatheses were accomplished using a Grubbs catalyst bearing the cyclic alkyl amino carbene (CAAC) ligand, whereas N-heterocyclic carbene (NHC) derived catalysts gave lower yields. Subsequent dienyl isomerization via a cobalt-catalyzed hydrogen atom transfer (HAT) furnished the more substituted dienyl boronate with high EE/EZ ratios. Finally, the resulting dienyl boronate products were successfully used in Suzuki-Miyaura cross-coupling reactions and in a Diels-Alder cycloaddition.

Styrene-alkyne cross ene-yne metathesis: Catalyst screening and optimization for unbranched terminal alkyne substrates

Cross metathesis between styrenes and unbranched terminal alkynes is reported. Styrene cross metathesis with terminal alkynes that lack branching at the propargylic position are unknown. In general, unbranched terminal alkynes have been problematic in cross metathesis due to competing alkyne oligomerization. A catalyst screen was performed for a variety of Grubbs catalysts to optimize the yield of the desired 1,3‑diene product. This catalyst screen identified two ruthenium carbene complexes that have been rarely used for cross metathesis applications. Additionally, a side product arising from a competing alkene metathesis was minimized by choice of catalyst and through reaction optimization.

Regioselective Cu-Catalyzed Hydroboration of 1,3-Disubstituted-1,3-Dienes: Functionalization of Conjugated Dienes Readily Accessible through Ene–Yne Metathesis

Regioselective Cu-Catalyzed Hydroboration of 1,3-Disubstituted-1,3-Dienes: Functionalization of Conjugated Dienes Readily Accessible through Ene–Yne Metathesis

Total Synthesis of Lyconesidine B: Approach to a Three-Dimensional Tetracyclic Skeleton of Amine-Type Fawcettimine Core and Studies of Asymmetric Synthesis

Abstract Lyconesidine B, isolated from Lycopodium chinense, is characterized by an oxygenated amine core and a trans-fused CD ring with a hydroxymethyl group on the axial position. Because the oxidation level of C13 of this alkaloid is different from other fawcettimine-type alkaloids, we investigated a suitable strategy for its synthesis. As a result, we established a synthetic route to the CD ring decahydroquinoline via cyclopropanation followed by ring-opening and reduction, and the AB ring tetracyclic core by ene-yne metathesis. In the ene-yne metathesis, the use of a quaternary ammonium salt solved the issues of the conformation of the substrate as well as the deactivation of the catalyst. The first total synthesis was achieved by stereoselective derivatization of the tetracyclic skeleton. In addition, we investigated the asymmetric cyclopropanation, which introduces an initial chiral center and was found to be effective for a Ru catalyst with vinyloxazoline-type ligands.

Ene-Yne Metathesis of Allylphosphonates and Allylphosphates: Synthesis of Phosphorus-Containing 1,3-Dienes.

A variety of ene-yne cross metathesis reactions were performed using unsaturated phosphonate and phosphate reagents, affording the corresponding phosphorylated 1,3-diene products in good to excellent yields. These difficult ene-yne metatheses employed a Grubbs catalyst bearing a cyclic amino alkyl carbene ligand. A variety of terminal alkynes of varying substitution underwent the reaction, and different phosphorus-containing alkenes were found to give the conjugated diene products in high yields. The resulting dienes were further transformed by Horner-type Wittig reactions and a Diels-Alder cycloaddition.

Total Synthesis of Lyconesidine B, a Lycopodium Alkaloid with an Oxygenated, Amine-Type Fawcettimine Core.

This report describes the total synthesis of the complex, oxygenated tetracyclic alkaloid, lyconesidine B. The key synthetic challenge involves diastereoselective generation of a decahydroquinoline ring with a quaternary carbon at the angular position via domino cyclopropanation, ring-opening, and reduction. Another crucial step is the domino ene-yne metathesis involving a quaternary ammonium ion, leading to the construction of a decahydroazaazulen framework.

ChemInform Abstract: Hydrazone‐Initiated Reaction Cascades

AbstractReview: [28 refs.

Hydrazone‐Initiated Reaction Cascades

AbstractIn this Focus Review, recently reported cascade reactions that are initiated from hydrazones are described. These cascades are grouped based on the mechanistic characteristics of the reactions paired with the hydrazone‐based transformations. Reactions in which the hydrazone simply acts as a surrogate for a diazo group are not discussed, but rather the focus is maintained on reactions with multiple mechanistically distinct steps. Sigmatropic, ene–yne metathesis, C−H bond insertion, ylide, and cross‐coupling examples are given. The versatility of the hydrazone functional group allows for many transformations, and yet is also compatible with many other transformations. Finally, a discussion of potential future directions for hydrazone‐initiated cascades is presented.

From Resting State to the Steady State: Mechanistic Studies of Ene-Yne Metathesis Promoted by the Hoveyda Complex.

The kinetics of intermolecular ene-yne metathesis (EYM) with the Hoveyda precatalyst (Ru1) has been studied. For 1-hexene metathesis with 2-benzoyloxy-3-butyne, the experimental rate law was determined to be first-order in 1-hexene (0.3-4 M), first-order in initial catalyst concentration, and zero-order for the terminal alkyne. At low catalyst concentrations (0.1 mM), the rate of precatalyst initiation was observed by UV-vis and the alkyne disappearance was observed by in situ FT-IR. Comparison of the rate of precatalyst initiation and the rate of EYM shows that a low, steady-state concentration of active catalyst is rapidly produced. Application of steady-state conditions to the carbene intermediates provided a rate treatment that fit the experimental rate law. Starting from a ruthenium alkylidene complex, competition between 2-isopropoxystyrene and 1-hexene gave a mixture of 2-isopropoxyarylidene and pentylidene species, which were trappable by the Buchner reaction. By varying the relative concentration of these alkenes, 2-isopropoxystyrene was found to be 80 times more effective than 1-hexene in production of their respective Ru complexes. Buchner-trapping of the initiation of Ru1 with excess 1-hexene after 50% loss of Ru1 gave 99% of the Buchner-trapping product derived from precatalyst Ru1. For the initiation process, this shows that there is an alkene-dependent loss of precatalyst Ru1, but this does not directly produce the active catalyst. A faster initiating precatalyst for alkene metathesis gave similar rates of EYM. Buchner-trapping of ene-yne metathesis failed to deliver any products derived from Buchner insertion, consistent with rapid decomposition of carbene intermediates under ene-yne conditions. An internal alkyne, 1,4-diacetoxy-2-butyne, was found to obey a different rate law. Finally, the second-order rate constant for ene-yne metathesis was compared to that previously determined by the Grubbs second-generation carbene complex: Ru1 was found to promote ene-yne metathesis 62 times faster at the same initial precatalyst concentration.

New indenylidene-type metathesis catalysts bearing unsymmetrical N-heterocyclic ligands with mesityl and nitrobenzyl substituents.

New indenylidene-type second generation catalysts bearing modified unsymmetrically substituted N-heterocyclic carbene ligands were synthesized. The complexes contain an N-mesityl and N′-nitrobenzyl substituted NHC ligand. The precursors of free carbenes—imidazolinium salts—were obtained in an easy and environment-friendly way (under aqueous or neat conditions). The new catalysts were prepared by reaction of in situ generated carbenes with a 1st generation indenylidene catalyst, containing pyridine ligands instead of tricyclohexylphosphine. The complexes were tested in RCM, CM, and ene-yne metathesis model reactions in commercial-grade solvents in air. Their activities were compared with that of commercially available indenylidene catalyst. The structures of complexes and their stability were investigated using static DFT calculations with mixed basis set.Graphical abstractElectronic supplementary materialThe online version of this article (doi:10.1007/s00706-016-1697-7) contains supplementary material, which is available to authorized users.

Two Ene-Yne Metathesis Approaches to the Total Synthesis of Amphidinolide P.

The total synthesis of amphidinolide P was achieved through two different ene-yne metathesis approaches. In each approach, the metathesis step was performed at late stages in the synthesis with all other functionality present. By forging two successful pathways to the synthesis of 1, some of the strengths and weaknesses of metathesis-intensive synthetic strategies were identified.

Alkyl group-tagged ruthenium indenylidene complexes: Synthesis, characterization and metathesis activity

We report on the synthesis of ruthenium indenylidene catalysts [RuCl2(3-R-1-indenylidene)(PCy3)2 in which R is iso-propyl (7a), tert-butyl (7b) or cyclohexyl (7c)]. The obtained alkyl tagged indenylidene catalysts were analyzed by means of IR, elemental analysis, NMR and single crystal X-Ray diffraction analysis. Furthermore, the catalytic performance of these new complexes was examined in different metathesis reactions: ring-closing metathesis (RCM), ring-closing ene-yne metathesis (RCEYM), ring-opening metathesis polymerization (ROMP) and cross metathesis (CM), exhibiting a comparable activity in comparison with the commercially available catalyst 3a.

ChemInform Abstract: Access to Functionalized α‐Trifluoromethyl‐α‐aminophosphonates via Intermolecular Ene—Yne Metathesis.

An efficient approach to a new family of highly functionalized P analogues of α-trifluoromethyl-substituted phenylalanine and its homologues using ruthenium-catalyzed intermolecular ene–yne metathesis as a key step of the reaction sequence has been developed. The method includes cross metathesis of α-alkynyl-α-trifluoromethyl-α-aminophosphonates with alkenes under catalysis by second-generation Grubbs carbene complex to afford the corresponding aminophosphonates with 1,3-diene backbone followed by one-pot Diels–Alder reaction–aromatization step.

ChemInform Abstract: Toward the Synthesis of Amphidinolide P: Optimization of a Model Ene—Yne Metathesis Fragment Coupling.

Abstract Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

Access to Functionalized α-Trifluoromethyl-α-aminophosphonates via Intermolecular Ene–Yne Metathesis

An efficient approach to a new family of highly functionalized P analogues of α-trifluoromethyl-substituted phenylalanine and its homologues using ruthenium-catalyzed intermolecular ene–yne metathesis as a key step of the reaction sequence has been developed. The method includes cross metathesis of α-alkynyl-α-trifluoromethyl-α-aminophosphonates with alkenes under catalysis by second-generation Grubbs carbene complex to afford the corresponding aminophosphonates with 1,3-diene backbone followed by one-pot Diels–Alder reaction–aromatization step.

Toward the synthesis of amphidinolide P: optimization of a model ene–yne metathesis fragment coupling

Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

Inhibitory Effect of Ethylene in Ene–Yne Metathesis: The Case for Ruthenacyclobutane Resting States

Reaction kinetics and mechanistic studies for ethylene-internal alkyne metathesis promoted by the phosphine-free initiator Ru1 (Piers's catalyst) is described. The kinetic order of reactants and catalyst was determined. The effect of ethylene was studied at different solution concentrations using ethylene gas mixtures applied at constant pressure. Unlike earlier studies with the second-generation Grubbs complex, ethylene was found to show an inverse first-order rate dependence. Under catalytic conditions, a ruthenacyclobutane intermediate was observed by proton NMR spectroscopy at low temperature. Combined with the kinetic study, these data suggest a catalytic cycle involving a reactive L(n)Ru═CH2 species in equilibrium with ethylene to form a ruthenacyclobutane, a catalyst resting state. Rates were determined for a variety of internal alkynes of varying substitution. Also, at low ethylene pressures, preparative syntheses of several 2,3-disubstituted 1,3-butadienes were achieved. Using the kinetic method, several phosphine-free inhibitors were examined for their ability to promote ethylene-alkyne metathesis and to guide selection of the optimal catalyst.

Removal of Ruthenium Using a Silica Gel Supported Reagent

A solid-supported isocyanide ligand was developed to destroy active metathesis catalysts and to remove ruthenium byproducts from metathesis reactions. This method was able to significantly reduce the concentration of residual ruthenium from the organic products of several alkene and ene-yne metathesis reactions, under a variety of different conditions.

ChemInform Abstract: Recent Synthetic Strategies to Access Seven‐Membered Carbocycles in Natural Product Synthesis

AbstractReview: ca. 150 refs.