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ChemFiles

Vol 2 Supplement

 
Vol . 2, 2002 Supplement
Grubbs' Catalysts & MacMillan's OrganoCatalysts™
Download PDF (641 KB)
Grubbs' Catalysts / MacMillan's OrganoCatalysts™ / Verkade's Superbases / Metal Catalysts and Ligands

Grubbs’ Catalysts

In today’s fast-paced environment, ready access to leading edge developments in catalyst technology by the modern synthetic chemist is a defining competitive advantage. Aldrich is pleased to announce a partnership with Materia, Inc. to offer research quantities of novel organic and organometallic catalysts from Materia's technology portfolio. Materia's olefin metathesis and OrganoCatalyst‘ technologies enable the production of fine chemicals and materials in fewer steps, higher yields, and with fewer byproducts than traditional routes.

Ruthenium-Based Metathesis Catalysts

Olefin metathesis is a synthetically powerful transformation in which a net exchange of olefin substituents occurs. The reaction between substrate and catalyst proceeds via the reversible formation of a metallacyclobutane intermediate. A significant evolution in the development of olefin metathesis catalysts involves the use of ruthenium-based catalysts discovered in the laboratories of Professor Robert Grubbs at Caltech. The synthetic utility of ruthenium-based catalysts is derived from their ability to orchestrate additional metathetical transformations, including Ring-Closing Metathesis (RCM), Ring-Opening Metathesis Polymerization (ROMP), and Acyclic Diene Metathesis Polymerization (ADMET) (Figure 1). These transformations enable the production of novel compounds and high-performance materials for the pharmaceutical and materials science markets.

Pharmaceutical Applications

The application of ruthenium-based olefin metathesis technology to the manufacture of pharmaceutical intermediates is boundless. Perhaps most strikingly, Ring-Closing Metathesis (RCM) enables the efficient production of complex ring systems from simple acyclic precursors using Grubbs’ Catalyst, first generation (1) (Scheme 1).1

RCM using 1 has also been utilized in a key step of the total synthesis of Mevinolin (Scheme 2),2 a compound shown to reduce serum cholesterol levels, and in the synthesis of Ambruticin (Scheme 3),3 an orally active antifungal agent.




A further example illustrates the application of metathesis reactions to peptidomimetics. RCM on acyclic peptides bearing olefin functionalities results in the formation of cyclic species. The olefin generated by metathesis in this case replaces the disulfide linkages found in natural and synthetic peptides. The resulting carbocyclic substructure has a reduced conformational space that often results in an increased affinity for biological receptors, and provides dramatically improved redox stability (Scheme 4).4-7

RCM has also been used in the synthesis of a-substituted and a,a-disubstituted amino acids.8 A comparison of the product yield between catalyst 1 and Grubbs’ Catalyst, second generation (2) is given in Table 1. Calalyst 2 is more active and exhibits excellent functional group tolerance and selectivity. Catalyst concentration also influences overall yields, as demonstrated in the RCM of an ene-ynamide system (Table 2) using Grubbs’ Catalyst, second generation.9

Table 1:

n Catalyst Yield (%)
1 1 92
2 1 74
2 2 87
3 1 57
3 2 83

Table 2:

Run Substrate (mol %) Conditions Time(h) Yielda (%)
1 (R=H) 5 toluene/80 °C 20 22
2   5 toluene/60 °C 20 19 (20)
3   5 CH2CI2/reflux 27 36 (38)
4   10 CH2CI2/reflux 6 85
5   10 CH2CI2/reflux 5 82
6 (R=Me) 10 CH2CI2/reflux 6 61

a The yield in parenthesis is that of the recovered starting material. The reaction was carried out under argon.


Materials Applications

Ruthenium-based metathesis catalysts have shown remarkable utility in the production of fine chemicals on an industrial scale by RCM and Cross Metathesis (CM) reactions. ROMP and ADMET have been used extensively in the field of materials science to produce polymers with unique properties. One such example is the ROMP of dicyclopentadiene (DCPD) to give resins that exhibit remarkable impact and corrosion resistance. DCPD resin is an excellent base resin for a variety of composite products used in areas such as the defense/aerospace industry, sports and recreation, marine, ballistics (Figure 2), and microelectronics.

RCM and Cross Metathesis (CM) can be combined to produce a wide variety of terminally functionalized oligomers or polymers, commonly referred to as telechelic materials (Scheme 5).10,11 These materials are notoriously difficult or impossible to prepare in high yield and selectivity by standard synthetic methods, but have several important and growing applications including the production of multi-block polymers and thermoplastic polyurethanes. 


Figure 2

Ferroelectric liquid crystals (FLC) have been prepared via ADMET polymerization using a derivative of Grubbs’ Catalyst, first generation. The predominant species is the acyclic oligomer with little competition from the RCM cyclic species (Scheme 6).12

Hoveyda-Grubbs' Catalyst

Invented at Boston College, the Hoveyda-Grubbs’ Catalyst (3) shows efficiencies similar to those of Grubbs’ Catalyst second generation, but with a different substrate specificity. The recyclable13 catalyst is unique in catalyzing RCM, ROMP, and CM reactions with highly electron-deficient substrates (Scheme 7).14

09587

Grubbs’ Catalyst,
First Generation


Benzylidenebis-
(tricyclohexylphosphine)-
dichlororuthenium


250mg; 1g; 5g
56,974-7

Grubbs’ Catalyst,
Second Generation


1,3-(Bis(mesityl)-2-
imidazolidinylidene)dichloro-
(phenylmethylene)(tricyclohexyl-
phosphine)ruthenium

500mg; 2g
56,975-5

Hoveyda-Grubbs’
Catalyst


1,3-(Bis(mesityl)-2-
imidazolidinylidene)dichloro-
(o-isopropoxyphenylmethylene)
ruthenium

250mg; 1g; 5g