Highly Efficient Olefin-Metathesis Catalysts - Pharmaceutical Technology

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Highly Efficient Olefin-Metathesis Catalysts
The authors describe the Piers' catalysts and detail latest progress in olefin-metathesis catalyst technology.


Pharmaceutical Technology



Figure 1 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Olefin metathesis provides an efficient method for the construction of carbon-carbon double bonds. Significant progress in catalyst development and applications has been made during the past 15 years (1–5). One recent advancement in olefin-metathesis catalysts has been reported by the group of Prof. Warren E. Piers with their synthesis of novel 4-coordinate metathesis catalysts possessing an open coordination site trans to the phosphine or the N -heterocyclic carbene ligand (see Figure 1) (6, 7). These novel, 4-coordinate metathesis catalysts directly mimic the active 14-electron olefin-metathesis catalytic species and negate any prior ligand dissociation step that is necessary with the original 5-coordinate Grubbs- and Hoveyda-type catalysts. Piers' catalysts are active at low temperatures, which makes them particularly useful in inhibiting double-bond migrations (8–12). These new catalysts have contributed to the increasing importance of olefin metathesis as highly functional-group tolerant and as a user-friendly synthetic methodology.

Olefin metathesis in pharmaceutical applications


Figure 2 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
In recent years, olefin metathesis has been increasingly used by the pharmaceutical industry to synthesize biologically active molecules. Notably, K.C. Nicolaou's group described the syntheses of a variety of complex biologically active molecules using olefin metathesis as the key step (5, 13). Merck reported the synthesis of a NK-1 inflammation drug candidate in which double ring-closing metathesis (RCM) was used to build a key spirocyclic intermediate (see Figure 2) (14). Eisai reported the use of both RCM and cross metathesis (CM) in the synthesis of pladienolide (see Figure 3) (15). Eisai showed that cross-metathesis was successful when the traditional Julia–Kocienski coupling failed to produce the desired product


Figure 3 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
This article describes the latest progress in olefin-metathesis catalyst technology for applications in both the pharmaceutical and fine-chemical industries and highlights the discovery and use of the new 4-coordinate, 14-electron Piers' olefin-metathesis catalysts.

Olefin-metathesis catalysts


Figure 4 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
During the past 15 years, major progress has been made in advancing ruthenium olefin-metathesis catalysts. The majority of these new metathesis catalysts were based on ligand modification of well-defined and widely employed Grubbs and Hoveyda ruthenium catalysts (see Catalysts 3, 4, 5, Figure 4) (16–18). Most recently, metathesis catalysts (see Catalysts 6 and 7, Figure 5) were developed to address the need for the highly efficient synthesis of hindered olefins, particularly for RCM reactions forming tetrasubstituted cycloalkenes (see Figure 5) (19, 20).


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