Vanessa M. Marx

Highly Active Ruthenium Metathesis Catalysts Exhibiting Unprecedented Activity and Z-Selectivity

A novel chelated ruthenium-based metathesis catalyst bearing an N-2,6-diisopropylphenyl group is reported and displays near-perfect selectivity for the Z-olefin (>95%), as well as unparalleled TONs of up to 7400, in a variety of homodimerization and industrially relevant metathesis reactions. This derivative and other new catalytically active species were synthesized using an improved method employing sodium carboxylates to induce the salt metathesis and C-H activation of these chelated complexes. All of these new ruthenium-based catalysts are highly Z-selective in the homodimerization of terminal olefins.

Stereoselective access to Z and E macrocycles by ruthenium-catalyzed Z-selective ring-closing metathesis and ethenolysis.

The first report of Z-selective macrocyclizations using a ruthenium-based metathesis catalyst is described. The selectivity for Z macrocycles is consistently high for a diverse set of substrates with a variety of functional groups and ring sizes. The same catalyst was also employed for the Z-selective ethenolysis of a mixture of E and Z macrocycles, providing the pure E isomer. Notably, an ethylene pressure of only 1 atm was required. These methodologies were successfully applied to the construction of several olfactory macrocycles as well as the formal total synthesis of the cytotoxic alkaloid motuporamine C.

Concise Syntheses of Insect Pheromones Using Z‐Selective Cross Metathesis

Very short synthetic routes to nine cis-olefin-containing pheromones containing a variety of functionality, including an unconjugated (E,Z) diene, are reported. These lepidopteran pheromones are used extensively for pest control, and were easily prepared using ruthenium-based Z-selective cross metathesis, highlighting the advantages of this method over less efficient ways to form Z olefins.

Cyclic alkyl amino carbene (CAAC) ruthenium complexes as remarkably active catalysts for ethenolysis.

An expanded family of ruthenium-based metathesis catalysts bearing cyclic alkyl amino carbene (CAAC) ligands was prepared. These catalysts exhibited exceptional activity in the ethenolysis of the seed-oil derivative methyl oleate. In many cases, catalyst turnover numbers (TONs) of more than 100,000 were achieved, at a catalyst loading of only 3 ppm. Remarkably, the most active catalyst system was able to achieve a TON of 340,000, at a catalyst loading of only 1 ppm. This is the first time a series of metathesis catalysts has exhibited such high performance in cross-metathesis reactions employing ethylene gas, with activities sufficient to render ethenolysis applicable to the industrial-scale production of linear α-olefins (LAOs) and other terminal-olefin products.

Synthesis of Highly Cis, Syndiotactic Polymers via Ring-Opening Metathesis Polymerization Using Ruthenium Metathesis Catalysts

The first example of ruthenium-mediated ring-opening metathesis polymerization generating highly cis, highly tactic polymers is reported. While the cis content varied from 62 to >95% depending on the monomer structure, many of the polymers synthesized displayed high tacticity (>95%). Polymerization of an enantiomerically pure 2,3-dicarboalkoxynorbornadiene revealed a syndiotactic microstructure.

Ru-based Z-selective metathesis catalysts with modified cyclometalated carbene ligands

A series of cyclometalated Z-selective ruthenium olefin metathesis catalysts with alterations to the N-heterocyclic carbene (NHC) ligand were prepared. X-Ray crystal structures of several new catalysts were obtained, elucidating the structural features of this class of cyclometalated complexes. The metathesis activity of each stable complex was evaluated, and one catalyst, bearing geminal dimethyl backbone substitution, was found to be comparable to our best Z-selective metathesis catalyst to date.

Probing Stereoselectivity in Ring-Opening Metathesis Polymerization Mediated by Cyclometalated Ruthenium-Based Catalysts: A Combined Experimental and Computational Study

The microstructures of polymers produced by ring-opening metathesis polymerization (ROMP) with cyclometalated Ru-carbene metathesis catalysts were investigated. A strong bias for a cis,syndiotactic microstructure with minimal head-to-tail bias was observed. In instances where trans errors were introduced, it was determined that these regions were also syndiotactic. Furthermore, hypothetical reaction intermediates and transition structures were analyzed computationally. Combined experimental and computational data support a reaction mechanism in which cis,syndio-selectivity is a result of stereogenic metal control, while microstructural errors are predominantly due to alkylidene isomerization via rotation about the Ru═C double bond.

Targeted microbubbles: a novel application for the treatment of kidney stones

Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randalls plaques, which also contain hydroxyapatite crystals, can also be targeted to pre‐emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high‐risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine.

Cyclometalated Ruthenium Alkylidene Complexes: A Powerful Family of Z-Selective Olefin Metathesis Catalysts

The past 5 years have witnessed an enormous growth in the field of Z-selective olefin metathesis. The development of a new class of cyclometalated ruthenium-based catalysts has extended the utility of olefin metathesis to the synthesis of useful Z-olefin-containing small molecules, polymers, and natural products. This review highlights the recent advances in the area of Z-selective olefin metathesis employing cyclometalated ruthenium alkylidene catalysts, with particular focus on its applications and mechanistic basis. A deeper understanding of structure–activity relationships should aid in the future design of even more active and selective olefin metathesis catalysts.