2005 Nobel Prize Award Winning Metathesis Catalyst Technology!

Chemfiles Volume 6 Article 1

Sigma-Aldrich would like to congratulate Robert Grubbs, Richard Schrock, and Yves Chauvin on their research achievements leading to the 2005 Nobel Prize Award in chemistry! Metathesis catalyst technology has enriched the areas of drug discovery, flavors/ fragrances, and polymers while leading scientists to discover new disconnections in synthetic organic chemistry. Through our partnership with Materia, Inc., we are proud to be the exclusive provider of Grubbs’ metathesis catalysts for the research market.

Olefin metathesis is an efficient and powerful reaction for the formation of carbon–carbon bonds, via a net exchange of olefin substituents.1 The reaction between substrate and active catalyst proceeds through the reversible formation of a metallacyclobutane intermediate. A significant evolution in the development of olefin metathesis catalysts involves the utilization of ruthenium-based catalysts discovered in the Grubbs’ research group at Caltech. Grubbs’ first-generation catalyst, Cl2(PCy3)2Ru=CHPh, pushed metathesis to the organic synthetic community due to its air and moisture stability and functional group tolerance.2 The broad synthetic utility of ruthenium-based catalysts is derived from their capacity to orchestrate key metathetical transformations (Scheme 26), including Ring-Opening Metathesis Polymerization (ROMP), Ring-Closing Metathesis (RCM), and Acyclic Diene Metathesis Polymerization (ADMET). These transformations enable the production of novel compounds, often of pharmacological importance, and high-performance materials science products.


Scheme 26.

Recently, Grubbs and co-workers examined the ROMP of 1,5‑cyclooctadiene (COD) to afford linear polybutadiene that contains an exclusive 1,4-regioisomeric backbone (Scheme 27).3 The ROMP reaction readily advances by adding the second generation catalyst 17 into a methylene chloride solution consisting of the monomer at 40 ºC. The related 1,5,9-trans-cis-transcyclododecatriene (CDT) monomer, which is commercially available, also provides 1,4‑polybutadiene via ROMP.


Scheme 27.

Grubbs’ utilized Ru alkylidene catalyst (18) in a seminal article covering the selective and quantitative Ring Closing Metathesis (RCM) of neighboring vinyl substituents in 1,2-polydienes to generate polycycloolefins (Scheme 28).4 Specifically atactic 1,2-polybutadiene undergoes greater than 97% cyclization of the α,ω-dienes. The authors then hydrogenated the polycycloolefin unsaturated backbone to yield atactic poly(methylene-1,3-cyclopentane), whose structure was confirmed by NMR analysis of the known material. It should be noted that this methylene-based ruthenium catalyst would be expected to represent the active species in metathesis processes involving first generation catalyst, (PCy3)2Cl2Ru=CHPh, via transmutation with another terminal olefin.


Scheme 28.

Metathesis catalyst (IMes)(PCy3)Cl2Ru=CHPh (17) has been shown to facilitate “one-pot” tandem catalytic metathesis-hydrogenation processes.5 After the RCM reaction is complete by NMR, the reaction container can be pressurized with hydrogen and then heated to 70 °C. The Grubbs research team performed this “one-pot” tandem protocol to obtain (R)-(−)-Muscone in an expeditious fashion and in good (56% overall) yield (Scheme 29). This methodology has also been extended to include the cross metathesis of vinylketones with aryl olefins, followed by subsequent regiospecific hydrogenation.


Scheme 29.

RCM has been successively applied to the ring-expansion of bis-vinyl ketones with cycloolefins.6 This novel reaction process utilizes the Grubbs’ second generation catalyst 17 and creates a functionalgroup compatible route for the synthesis of macrocycles of various ring sizes (Scheme 30). Interestingly, the same metathesis catalyst reacts with α,β-unsaturated carbonyl compounds under certain conditions to generate active enoic carbene catalysts.7 Grubbs and co-workers have reported the production of enoic carbenes in this manner and their efficient catalytic cross-metathesis reactions (Scheme 31). Furthermore, ring-opening of cyclohexene was achieved and applied in the cross metathesis of a vast array of unsaturated ketones. This in situ generated enoic carbene complex, stabilized by electron-deficient groups, effectively catalyzes the crosscoupling of gem-disubstituted olefins and the ROMP of cyclohexene, the latter of which was previously unattainable by standard ROMP conditions.


Scheme 30.


Scheme 31.

Ruthenium-based olefin metathesis technology has found a privileged status as the driving force behind the manufacture of countless pharmaceutical intermediates and natural products. Perhaps most strikingly, Ring-Closing Metathesis enables the expeditious creation of complex ring architectures from simple acyclic precursors using Grubbs’ catalysts. Amos Smith, III and co-workers successfully completed the total synthesis of (−)-Kendomycin,8 a novel polyketide that boasts potent endothelin antagonist activity,9 via a decisive RCM reaction to form the macrocycle (Scheme 32). Alcohol 19 was exposed to the second generation Grubbs’ catalyst 17 to yield macrocycle (+)-20 as a single isomer,10 with the configuration of the C(13,14) olefin confirmed unambiguously by X-ray analysis to be Z. This article details the first example of a 16-membered ring closure by RCM, in which the substrate bears a sterically encumbered olefin.


Scheme 32.

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References

  1. (a) Grubbs, R. H. et al. Acc. Chem. Res. 1995, 28, 446. (b) Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 109, 2124. (c) Grubbs, R. H. et al. Tetrahedron 1998, 54, 4413. (d) Blechert, S. Pure Appl. Chem. 1999, 71, 1393. (e) Furstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3013.
  2. Zuercher, W. J. et al. J. Org. Chem. 1998, 63, 4291.
  3. Grubbs, R. H. et al. J. Am. Chem. Soc. 2003, 125, 8424.
  4. Grubbs, R. H. et al. J. Am. Chem. Soc. 1996, 118, 229.
  5. Grubbs, R. H. et al. J. Am. Chem. Soc. 2001, 123, 11312.
  6. Grubbs, R. H. et al. J. Am. Chem. Soc. 2002, 124, 3224.
  7. Grubbs, R. H. et al. J. Am. Chem. Soc. 2001, 123, 10417.
  8. Smith, A. B. III et al. J. Am. Chem. Soc. 2005, 127, 6948.
  9. Ishimaru, T. et al. Japan Patents 08231551 [A2960910] and 08231552, 1996; Chem. Abstr. 1997, 126, 6553; Chem. Abstr. 1996, 125, 326518.
  10. (a) Grubbs, R. H. et al. Acc. Chem. Res. 2001, 34, 18. (b) Grubbs, R. H. et al. J. Org. Chem. 2001, 66, 7155.

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