Cross Metathesis

By: William Sommer, ChemFiles Colume 9 Article 6

Cross metathesis has become an invaluable method for the preparation of olefins.1 While cross metathesis is typically conducted under mild conditions and is tolerant of a variety of functionalities, the chemo- and stereoselectivity of the reaction were more difficult to predict.2 However, due to advances in catalyst design and reaction understanding, predictability has improved.

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Synthesis of Glabrescol

In 2000, Corey and coworkers utilized cross metathesis to synthesize a series of stereoisomers of glabrescol.3 Glabrescol is the biosynthetic precursor to steroids and triterpenoids. Upon preparation of the original structure proposed for glabrescol, it was realized the wrong structure for the natural product was reported. Corey and coworkers utilized a cross metathesis dimerization approach, which allowed for the preparation of the various isomers of glabrescol in a single step and ultimately lead to the correct structure assignment for glabrescol (Scheme 1).

Scheme 1

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Cross Metathesis Reaction of Hindered Substrates

Exploiting the ability of the o-tolyl-NHC Hoveyda-Grubbs catalyst to react with hindered substrates, the Grubbs group recently reported a series of cross metathesis reactions between terminal olefins.4 Reduction in steric bulk contained on the NHC ligand resulted in successful coupling of sterically-hindered substrates (Scheme 2). The authors reported that this catalyst outperformed the Hoveyda-Grubbs catalyst (2nd Generation) in all cases studied. A variety of disubstituted olefins were prepared in good yields using 5 mol % of the catalyst.

Scheme 2

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Exploiting Grubbs Catalysts with Novel Reactivity

The Howell group recently reported the first synthesis of tetrasubstituted olefins using cross metathesis during the course of investigating the synthesis of a-alkylidene-ß-lactams, which serve as building blocks for the preparation of ß-lactam antibiotics. The Hoveyda-Grubbs catalyst (2nd Generation) outperformed the Grubbs catalyst (2nd Generation) in cross metathesis and portion-wise catalyst addition led to increased product yields.5 Using variable catalyst loadings, the desired tetrasubstituted olefin was generated in good yields (Scheme 3).

Scheme 3

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Enyne Metathesis

Enyne metathesis has emerged as a powerful method for the synthesis of conjugated dienes.6 Botta and coworkers utilized a similar approach, where the olefin was replaced with an enol ether. Reaction between the alkyne and the enol ether generated the ß-substituted crotonaldehydes in good yields. The reaction is conducted in the presence of the Grubbs catalyst (2nd Generation), an aqueous solution of CuSO4, and under microwave conditions. Irradiation under microwave conditions (3 X 10 minutes) is followed by the addition of iodine to provide the desired crotonaldehydes in good yields (Scheme 4).7

Scheme 4

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Ring-Opening Metathesis Polymerization(ROMP)

ROMP has become an important reaction for the formation of well defined polymers. Ziegler and Natta's early studies on ethylene and polypropylene polymerization lead to extensive research efforts on the investigation of transition metal catalyzed polymerization and its mechanism, which ultimately lead to the development of ROMP.8 In 1992, the Grubbs group reported the synthesis of the first well defined ruthenium alkylidene, paving the way to a new generation of highly functional group tolerant ROMP catalysts.9 These catalysts are also utilized in living ROMP, allowing control of the molecular weight, a low polydispersity, and clean polymer end-capping. These advantages made ROMP the method of choice for the synthesis of complex polymeric architectures. Norbornene's strained bicyclic structure makes it an ideal monomer for ROMP and polymerization using the Grubbs family of catalysts leads to high reaction control. Furthermore, the monomer can be readily functionalized, which many groups have exploited to synthesize polynorbornene side chain functionalities such as catalysts, biological reagents, hydrogen bonding units or trapping molecules. This living character also allows for the introduction of two monomers resulting in the formation of alternative, block or random copolymers. These copolymers can impart a wide range of properties to the bulk polymer.

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Synthesis of Brush-like Polymers via ROMP

Recently, Cheng and coworkers reported the synthesis of brush-like polymers, by which the main polymer chain was prepared using ROMP followed by polymerization of peptide units on the amine side chain with N-carboxyanhydrides. These new materials may extend the application of brush-like polymers to include new ranges of properties. In this report, the authors use the Grubbs catalyst (3rd Generation) to polymerize the norbornene monomers. Excellent polydispersity of the polymer was reported with PDI ranges of 1.03 to 1.15 (Scheme 1).10

Scheme 1

Materials

     

References

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  2. Chatterjee, A. K. et al.J. Am. Chem. Soc. 2003, 125, 11360.
    1. Xiong, Z. et al. J. Am. Chem. Soc. 2000, 122, 4831.
    2. Xiong, Z. et al. J. Am. Chem. Soc. 2000, 122, 9328.
  3. Stewart, I. C. et al. Org. Lett. 2008, 10, 441.
  4. Liang, Y.et al. Tetrahedron Lett. 2009, 50, 1020.
  5. Diver, S. T. et al. Chem. Rev. 2004, 104, 1317.
  6. Castagnolo, D. et al. J. Org. Chem. 2009, 74, 3172.
    1. Ziegler, H. et al. Angew. Chem. 1955, 67, 541.
    2. Natta, G. Angew. Chem. 1956,68, 393.
  7. Nguyen, S. T. et al. J. Am. Chem. Soc. 1992, 114, 3974.
  8. Lu, H. et al. J. Am. Chem. Soc.,2009, 131, 13582.

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