Recent advances in ruthenium-based olefin metathesis.

Ruthenium-based olefin metathesis catalysts, known for their functional group tolerance and broad applicability in organic synthesis and polymer science, continue to evolve as an enabling technology in these areas. A discussion of recent mechanistic investigations is followed by an overview of selected applications.

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.

Formation of macrocycles via ring-closing olefin metathesis.

The enhanced metathesis activity of 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium carbene catalyst 3 significantly increases the feasibility of synthesizing macrocyclic compounds. Catalyst 3 exhibits sufficient activity in RCM to dimerize alpha,beta-unsaturated ester substrates and afford the corresponding head-to-tail (E,E)-dimeric (and trimeric) macrocycles. The dimerization appears to be under thermodynamic control with the product mixture dependent not only on the electronic and steric nature of the substrate but also on concentration.

Enantioselective ruthenium-catalyzed ring-closing metathesis.

[reaction: see text] The first enantioselective ruthenium olefin metathesis catalysts have been prepared, and high enantiomeric excesses (up to 90%) are observed in the desymmetrization of achiral trienes. A model consistent with the stereochemical outcome of the reactions is described and suggests side-on olefin binding and reorganization of the halide ligands.

Ring-closing metathesis of olefinic peptides: design, synthesis, and structural characterization of macrocyclic helical peptides.

Heptapeptides containing residues with terminal olefin-derivatized side chains (3 and 4) have been treated with ruthenium alkylidene 1 and undergone facile ring-closing olefin metathesis (RCM) to give 21- and 23-membered macrocyclic peptides (5 and 6). The primary structures of peptides 3 and 4 were based upon a previously studied heptapeptide (2), which was shown to adopt a predominantly 3(10)-helical conformation in CDCl(3) solution and an alpha-helical conformation in the solid state. Circular dichroism, IR, and solution-phase (1)H NMR studies strongly suggested that acyclic precursors 3 and 4 and the fully saturated macrocyclic products 7 and 8 also adopted helical conformations in apolar organic solvents. Single-crystal X-ray diffraction of cyclic peptide 8 showed it to exist as a right-handed 3(10)-helix up to the fifth residue. Solution-phase NMR structures of both acyclic peptide 4 and cyclic peptide 8 in CD(2)Cl(2) indicated that the acyclic diene assumes a loosely 3(10)-helical conformation, which is considerably rigidified upon macrocyclization. The relative ease of introducing carbon-carbon bonds into peptide secondary structures by RCM and the predicted metabolic stability of these bonds renders olefin metathesis an exceptional methodology for the synthesis of rigidified peptide architectures.

Mechanism and activity of ruthenium olefin metathesis catalysts.

This report details the effects of ligand variation on the mechanism and activity of ruthenium-based olefin metathesis catalysts. A series of ruthenium complexes of the general formula L(PR(3))(X)(2)Ru=CHR(1) have been prepared, and the influence of the substituents L, X, R, and R(1) on the rates of phosphine dissociation and initiation as well as overall activity for olefin metathesis reactions was examined. In all cases, initiation proceeds by dissociative substitution of a phosphine ligand (PR(3)) with an olefinic substrate. All of the ligands L, X, R, and R(1) have a significant impact on initiation rates and on catalyst activity. The origins of the observed substituent effects as well as the implications of these studies for the design and implementation of new olefin metathesis catalysts and substrates are discussed in detail.

Inhibition of cell adhesion to fibronectin by oligopeptide-substituted polynorbornenes.

Polynorbornenes substituted with two different peptide sequences from the RGD-containing integrin cell-binding domain of fibronectin are potent inhibitors of human foreskin fibroblast cell adhesion to fibronectin-coated surfaces. Ring-opening metathesis polymerization (ROMP) using Ru==CHPh(Cl)(2)(PCy(3))(DHIMes) (1) as an initiator produced polymers substituted with GRGDS and PHSRN peptide sequences. The inhibitory activity was quantified for these polymers and compared to the free peptides and GRGES-containing controls. A homopolymer substituted with GRGDS peptides was significantly more active than the free GRGDS peptide (IC(50) of 0.18 +/- 0.03 and 1.33 +/- 0.20 mM respectively), and the copolymer containing both GRGDS and PHSRN is the most potent inhibitor (IC(50) of 0.04 +/- 0.01 mM). These results demonstrate that significant enhancements of observed biological activity can be obtained from polymeric materials containing more than one type of multivalent ligand and that ROMP is a useful method to synthesize such well-defined copolymers.

Novel reactivity of ruthenium alkylidenes in protic solvents: degenerate alkylidene proton exchange.

A novel organometallic transformation is reported in which the alkylidene protons of water-soluble ruthenium alkylidenes 1 and 2 undergo nondestructive, degenerate exchange with solvent-derived deuterons in perdeuterated protic solvents such as D(2)O and CD(3)OD. Deuterated alkylidene complex (1-D) was isolated from a solution of alkylidene 1 in D(2)O, and the new alkylidene was fully characterized by (1)H, (2)H, (13)C, and (31)P NMR spectroscopy and fast-atom bombardment mass spectroscopy (FAB-MS). The rate of alkylidene proton exchange for this transformation was found to correlate with the bulk dielectric constant of the solvent or solvent mixtures employed. The data support a mechanism for proton exchange involving the dissociation of a chloride ion from the ruthenium metal center. The rate of alkylidene H/D exchange for alkylidene 2 was faster than the rate of exchange for alkylidene 1, demonstrating that relative rates of exchange are influenced by the electron densities at the metal centers of these complexes. Several additional ruthenium alkylidenes were found to undergo analogous alkylidene H/D exchange reactions, including parent alkylidene (Cy(3)P)(2)Cl(2)Ru=CHPh (3) in CD(2)Cl(2)/CD(3)OD mixtures. These data suggest that this novel reactivity may be general for an entire class of ruthenium alkylidenes provided that protic species are available in solution and that the dielectric constant of the reaction medium is sufficiently high to ionize the halide ligands.

Post implantation adjustable intraocular lenses.

To eliminate persistent refractive errors after cataract and phakic IOL surgery, photosensitive silicone IOLs have been developed. These IOL formulations enable precise laser adjustment of IOL power to correct spherical and toric errors post-operatively, after wound and IOL stabilization. Initial experience with these laser adjustable IOLs indicate excellent biocompatability and adjustability of more than five diopters.

The development of L2X2Ru=CHR olefin metathesis catalysts: an organometallic success story.

In recent years, the olefin metathesis reaction has attracted widespread attention as a versatile carbon-carbon bond-forming method. Many new applications have become possible because of major advances in catalyst design. State-of-the-art ruthenium catalysts are not only highly active but also compatible with most functional groups and easy to use. This Account traces the ideas and discoveries that were instrumental in the development of these catalysts, with particular emphasis on (PCy3)2Cl2Ru=CHPh and its derivatives. The discussion includes an analysis of trends in catalyst activity, a description of catalysts coordinated with N-heterocyclic carbene ligands, and an overview of ongoing work to improve the activity, stability, and selectivity of this family of L2X2Ru=CHR complexes.

In situ preparation of a highly active N-heterocyclic carbene-coordinated olefin metathesis catalyst.

Highly active N-heterocyclic carbene-coordinated catalysts may be synthesized and used in situ, without requiring prior isolation of the catalyst. Activation of this in situ catalyst with ethereal HCl dramatically reduces the reaction times required for high conversions. A variety of alpha,beta-unsaturated carbonyl-containing substrates participate readily in cross and ring-closing metathesis reactions using this preparation.

The pharmacology of a new nitric oxide donor: B-NOD.

We describe here a new compound, B-NOD, which, in vitro and in situ, releases nitric oxide (NO). Its activity in situ persists for more than 7 h, it does not cause a fall in blood pressure or an increase in heart rate and can be orally administered. It increases cyclic guanosine monophosphate (cGMP) and prevents platelet aggregation. In vitro, its release of NO is augmented by the presence of living cells (blood platelets). B-NOD may be useful in a number of clinical conditions in which prolonged release of NO without hemodynamic effects are desirable. A combination of aspirin with B-NOD could be formulated in which the individual concentrations of aspirin and B-NOD may be useful in the long-term treatment of coronary artery disease and in clinical situations in which long-term release of NO may be beneficial.

Stereoselectivity of macrocyclic ring-closing olefin metathesis.

[reaction: see text] Macrocyclic ring-closing olefin metathesis using ruthenium catalyst 3 was performed to produce a 14-membered lactone. The E/Z ratio of lactone was high regardless of the R group (auxiliary) or the initial alkene stereochemistry. A kinetic study demonstrates that the high E/Z ratio is due to secondary metathesis reactions that isomerize the product to the thermodynamic E/Z ratio.

Synthesis of trisubstituted alkenes via olefin cross-metathesis.

[formula: see text] Trisubstituted alkenes have been prepared for the first time via intermolecular olefin cross-metathesis, using 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ruthenium alkylidene complexes 3a,b in good yields with moderate E selectivity. In addition, protected alcohols near the geminal disubstituted olefin improve reactivity for cross-metathesis.

Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands.

[formula: see text] A new family of 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene-substituted ruthenium-based complexes 9a-c has been prepared starting from RuCl2(=CHPh)(PCy3)2 2. These air- and water-tolerant complexes were shown to exhibit an increased ring-closing metathesis activity at elevated temperature when compared to that of the parent complex 2 and the previously developed complex 3. In many instances the activity of these complexes also rivaled or exceeded that of the alkoxy-imido molybdenum complex 1. Catalyst loadings of as low as 0.05 mol% could be used.