What's Next In: Ingredients

API Synthesis

Catalysis plays a critical role in the synthesis of active pharmaceutical ingredients (APIs). It provides a way to improve yield, achieve desired stereoselectivity, improve reaction conditions, and synthesize increasingly complex APIs. Recent advances in catalyzed-olefin metathesis reveal its value and promise in the pharmaceutical industry.

(IMAGE: PHOTOS.COM/MELISSA MCEVOY)

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).

A recent challenge has been the pharmaceutical industry's interest in asymmetric catalysis. For these reactions, Schrock's chiral molybdenum catalysts provide the most impressive examples of enantioselective ring-closing metathesis products (3–7). Chiral ruthenium metathesis catalysts such as complexes A and B (see Figure 1), developed by the Grubbs and Hoveyda groups, respectively afford appreciable enantiomeric excess (see Figure 1) (8,9).

Figure 1. Examples of chiral ruthenium olefin metathesis catalysts.(Source: Materia)

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.

• More active and enantioselective metathesis catalysts

• More efficient metathesis catalysts with turnover numbers of >250,000

• Trans-selective metathesis catalysts

• Cis-selective metathesis catalysts

• More active immobilized metathesis catalysts

• More active and longer-lived ethenolysis metathesis catalysts

• Tandem olefin metathesis reactions (with carbon-carbon forming, oxidation, reduction, or rearrangement chemistries)

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

References

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).

5. S.S. Zhu et al., "Chiral Mo-Binol Complexes: Activity, Synthesis, and Structure. Efficient Enantioselective Six-Membered Ring Synthesis through Catalytic Metathesis," J. Am. Chem. Soc. 121 (36), 8251-8259 (1999).

6. R.R. Schrock and A.H. Hoveyda, "Molybdenum and Tungsten Imido Alkylidene Complexes as Efficient Olefin-Metathesis Catalysts," Angew. Chem., Int. Ed. 42 (38), 4592-4633 (2003).

7. A.H. Hoveyda and R.R. Schrock, "Catalytic Asymmetric Olefin Metathesis," Chem. Eur. J. 7 (5 ), 945-950 (2001).

8. T.J. Seiders, D.W. Ward, and R.H. Grubbs, "Enantioselective Ruthenium-Catalyzed Ring-Closing Metathesis," Org. Lett. 3 (20) 3225-3228 (2001).

9. J.J. Van Veldhuizen. "A Recyclable Chiral Ru Catalyst for Enantioselective Olefin Metathesis. Efficient Catalytic Asymmetric Ring-Opening/Cross Metathesis in Air," J. Am. Chem. Soc. 124 (18), 4954-4955 (2002).

10. J.J. Van Veldhuizen et al., "Chiral Ru-Based Complexes for Asymmetric Olefin Metathesis: Enhancement of Catalyst Activity through Steric and Electronic Modification," J. Am. Chem. Soc. 125 (41), 12502-12508 (2003).

11. D.G. Gillingham et al., "Efficient Enantioselective Synthesis of Functionalized Tetrahydropyrans by Ru-Catalyzed Asymmetric Ring-Opening Metathesis/Cross-Metathesis (AROM/CM)," J. Am. Chem. Soc. 126 (6), 12288-12290 (2004).

12. T.W. Funk, J.M. Berlin, and R.H. Grubbs, "A Highly Active Palladium Catalyst for Intermolecular Hydroamination. Factors that Control Reactivity and Additions of Functionalized Anilines to Dienes and Vinylarenes," J. Am. Chem. Soc. 128 (6), 1840-1846 (2006).

Industry experts give their predictions for the next 30 years.