Development of a Robust Ring-Closing Metathesis Reaction in the Synthesis of SB-462795, a Cathepsin K Inhibitor

Wang, Huan; Goodman, Steven N.; Dai, Qunying; Stockdale, Gregory W.; Clark, William M.

doi:10.1021/op700288p

Cited by 60 publications

(38 citation statements)

References 13 publications

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“…However, supported catalysts have a few drawbacks, some of which are high catalyst loadings, low turnover numbers and tedious synthetic procedures. There have also been numerous attempts to reduce the ruthenium content in metathesis products by homogeneous work-up techniques-chromatography 21 , chemical transformations 22 , scavenging ruthenium residues using phosphines 23 (more than 10 equiv.) or 50 equiv.…”

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confidence: 99%

Catalytic living ring-opening metathesis polymerization

Nagarkar

Kilbinger

2015

Nature Chem

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In living ring-opening metathesis polymerization (ROMP), a transition-metal-carbene complex polymerizes ring-strained olefins with very good control of the molecular weight of the resulting polymers. Because one molecule of the initiator is required for each polymer chain, however, this type of polymerization is expensive for widespread use. We have now designed a chain-transfer agent (CTA) capable of reducing the required amount of metal complex while still maintaining full control over the living polymerization process. This new method introduces a degenerative transfer process to ROMP. We demonstrate that substituted cyclohexene rings are good CTAs, and thereby preserve the 'living' character of the polymerization using catalytic quantities of the metal complex. The resulting polymers show characteristics of a living polymerization, namely narrow molecular-weight distribution, controlled molecular weights and block copolymer formation. This new technique provides access to well-defined polymers for industrial, biomedical and academic use at a fraction of the current costs and significantly reduced levels of residual ruthenium catalyst. In olefin metathesis reactions, olefinic bonds are rearranged with the help of a transition-metal catalyst 1,2 . In the early days following the discovery of this reaction, ill-defined catalysts 3 were used to carry out this transformation. After Herisson and Chauvin 4 had proposed a reaction mechanism, the olefin metathesis reaction was better understood and soon gained much popularity. Typical catalysts used for olefin metathesis reactions include those based on ruthenium (developed mainly by the Grubbs group 5 ), tungsten and molybdenum (developed mainly by the Schrock group 6 ). Owing to the low oxophilicity of ruthenium compared to those of molybdenum and tungsten, the ruthenium metathesis catalysts (commonly known as Grubbs' catalysts) are more tolerant towards many polar functional groups and residual impurities, as well as to water 7 . Therefore, these catalysts are the catalysts of choice in highly functional organic chemistry transformations as well as for the majority of metathesis polymerizations carried out today. Catalysts G1 (first generation) and G3 (third generation) are the most widely used ruthenium initiators for ring-opening metathesis polymerization (ROMP). In comparison to the G1 initiator, the third-generation catalyst G3 exhibits very fast initiation and propagation rates, and thereby gives polymers with very narrow dispersities and an excellent control over their molecular weights. Owing to its superior stability as well as the favourable polymerization kinetics, the third-generation Grubbs' catalyst G3 was used for this work. ROMP is a polymerization technique that uses the metathesis of cyclic olefins to synthesize linear polymers. Depending on the structure of the monomer, such polymerizations can be controlled perfectly to give polymers with a narrow molecular weight distribution and a controlled average molecular weight. Ring-strained monomers, li...

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confidence: 99%

Catalytic living ring-opening metathesis polymerization

Nagarkar

Kilbinger

2015

Nature Chem

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“…[11][12][13][14][15] ForRumetathesis catalysts,both Brønsted and Lewis base functionalities are now known to be problematic ( Figure 3; see also Section 2.4). [11][12][13][14][15] ForRumetathesis catalysts,both Brønsted and Lewis base functionalities are now known to be problematic ( Figure 3; see also Section 2.4).…”

Section: Impact Of Impuritiesmentioning

confidence: 99%

“…[28] Process robustness was agreater challenge.Aphosphine-free catalyst (HII)was found to be essential at the discovery stage.O ns cale-up, however, the catalyst loadings required for complete conversion varied dramatically from batch to batch. [14] An impurity profile analysis (spiking with potential poisons,accompanied by multivariate analysis), revealed that 13 and 14 (Figure 11 c) were principally responsible.Urea 13 is ab yproduct of sulfonamide installation;a mide 14 forms during aqueous workup prior to RCM. Considered as potential culprits were DBU and phosphazene base (Figure 3), and ar ange of basic sideproducts containing as econdary amine or urea functionality.…”

Section: Cathepsin Inhibitorsmentioning

confidence: 99%

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

2016

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“…While increased temperatures have previously shown to improve metathesis efficiency,6c,9 temperatures above 55°C decreased assay consistency and resulted in solvent losses. To minimize introducing experimental errors into the system, all assays were carried out at 50 °C which was the best compromise between fast reaction rates and solvent loss.…”

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Low Catalyst Loadings in Olefin Metathesis: Synthesis of Nitrogen Heterocycles by Ring-Closing Metathesis

et al. 2010

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A series of ruthenium catalysts have been screened under ring closing metathesis (RCM) conditions to produce five-, six-, and seven-membered carbamate-protected cyclic amines. Many of these catalysts demonstrated excellent RCM activity and yields with as low as 500 ppm catalyst loadings. RCM of the five-membered carbamate-series could be run neat, the six-membered carbamate-series could be run at 1.0 M concentrations and the seven-membered carbamate-series worked best at 0.2 M to 0.05 M concentrations.

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Development of a Robust Ring-Closing Metathesis Reaction in the Synthesis of SB-462795, a Cathepsin K Inhibitor

Cited by 60 publications

References 13 publications

Catalytic living ring-opening metathesis polymerization

Catalytic living ring-opening metathesis polymerization

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

Low Catalyst Loadings in Olefin Metathesis: Synthesis of Nitrogen Heterocycles by Ring-Closing Metathesis

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