Olefin metathesis has revolutionized the way scientists think about and do chemistry. It offers an easy-to-use tool for the efficient synthesis of complex molecules through the rearrangement of their carbon–carbon double bonds. The reaction's fundamental impact was so significant that it led to the awarding of the 2005 Nobel Prize in Chemistry to Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock.Over the past decade, pharmaceutical companies have become familiar with the reaction. For example, Merck & Co. (Whitehouse Station) efficiently used double ring-closing metathesis to produce the key intermediate in its spiro NK-1 inflammation drug candidate (1). Eisai (Tokyo, Japan) reported using both ring-closing and cross metathesis in a single synthesis in synthesizing its pladienolide (2).
To illustrate, Catalyst A effectively performs desymmetrizing ring-closing metathesis of prochiral trienes and affords enantiomeric excess ranging from 13 to 90%. (8). Catalyst B can deliver high enantioselectivity in asymmetric tandem ring-opening metathesis/cross-metathesis of tricyclic norbornene derivatives (9). Catalyst B, however, is altogether a less active catalyst and requires elevated reaction temperatures and prolonged reaction times. Hoveyda and coworkers subsequently reported analogs of Catalyst B with enhanced catalytic activity using lower catalyst loadings (10, 11). More recently, the Grubbs laboratory developed highly active analogues of Catalyst C (see Catalyst D) that can induce chirality with greater efficiency than Catalyst C (12).
Research is significantly broadening the applicability of olefin metathesis. Pharmaceutical researchers should expect to see developments in the following areas over the short to mid term.
These new catalyst technologies will enable the synthesis of novel pharmaceutical compounds that were previously unattainable.
Richard Pederson, PhD, director of fine chemicals research and development at Materia
1. D.J. Wallace et al., "A Double Ring Closing Metathesis Reaction in the Rapid, Enantioselective Synthesis of NK-1 Receptor Antagonists," Org. Lett. 3 (5) 671-674 (2001).
2. R.M. Kanada et al., "Total Synthesis of the Potent Antitumor Macrolides Pladienolide B and D," Angew. Chem. Int. Ed. 46 (23), 4350-4355 (2007).
3. K.M. Totland et al., "Ring Opening Metathesis Polymerization with Binaphtholate or Biphenolate Complexes of Molybden," Macromolecules 29 (19), 6114-6125 (1996).
4. J.B. Alexander et al., "Catalytic Enantioselective Ring-Closing Metathesis by a Chiral Biphen-Mo Complex," 120 (16) J. Am. Chem. Soc. 120 (16) 4041-4042 (1998).