Z-selective catalysts

Recent efforts have achieved Z-selective ruthenium carbene catalysts, providing a catalyst solution to a general problem in stereoselective alkene synthesis Diastereoselectivity in Olefin Metathesis Development of Z-Selective Ru Catalysts Vol 1, Chapter 3 Grubbs, Handbook of Metathesis, 2nd Edition, Volume 2, Chapter 7. As this is a relatively new field, mechanistic studies are 

Further evaluation of these new Z-selective catalysts showed that, for the bidentate anionic hgand complexes, initiation rates similar to the second-generation Grubbs-Hoveyda complex 3a could be achieved through modification of the complex s electronic and steric environment. Solvent was shown to play a role in overall reaction yields, but its effects were shown to be related to catalyst decomposition, not the precatalyst initiation. 

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The stereoselectivity of olefin formation is crucial to the utility of CM. To date, a general metathesis catalyst capable of effecting diastereomeric control over a broad range of substrates has yet to be realized. Of particular interest is the development of a Z-selective catalyst, as Z olefins are a prevalent structural motif within both natural products and pharmaceutical agents.Current examples of Z-selective olefin CM have proved to be substrate dependent. These include the CM of enynes with alkenes, acrylonitrile the CM reaction... 

Catalyst Structure and Cis-Trans Selectivity in Ruthenium-based Olefin Metathesis 33 2.4 Z-selective Ru-based metathesis catalysts 2.4.1 Thiophenolate-based Z-selective catalysts... 

Figure 14 Model for selectivity in thiophenolate-based Z-selective catalysts...

Figure 77 Targeted monopivalate Z-selective catalyst 48 and unexpected product 49...

To date, three distinct strategies have been utilized to impose a preference for i yn-metal-lacycles in Ru-based olefin metathesis catalysts, resulting in three families of Z-selective catalysts. Promising initial reactivity has been observed with both thiophenolate- and dithiolate-based catalysts and both frameworks offer many opportunities for further tuning of activity and Z-selectivity. The cyclometallated catalysts have been further developed and have demonstrated high activity and Z-selectivity for a wide variety of substrates. However, in all cases, further improvements will be necessary to achieve Z-selective metathesis across the broad substrate scope demonstrated by previous generations of Ru-based catalysts. 

Scheme 3.2 The preparation of Z-selective catalysts using a large ligand strategy...

Figure 3.1 The effect of the X-ligand on measured initiation rate constants, catalyst activity, and Z selectivity. Catalysts 7 and 10 were found to have the best activity and Z selectivity (Dipp = 2,6-di-isopropylphenyl).

It is worth noting that the performance of other Ru-based, Z-selective catalysts was also found to depend on the nature of the X-type ligand. For example, the... 

Z-selective catalysts (see Section 7.3, Chapter 3, and see Grubbs, Handbook of Metathesis, 2nd Edition, Volume 2, chapter 7). 

Using the Gmbbs second-generation catalyst, the product of cross-metathesis is the f-isomer. Some specialized Z-selective catalysts have been designed (Scheme 8.92). ° ... 

Accordingly, considerable effort has been dedicated to the development of olefin metathesis catalysts exhibiting kinetic selectivity. As a result, a number of Z-selective tungsten-, molybdenum-, and ruthenium-based olefin metathesis catalysts have been recently developed (For Mo- and W-based Z-selective catalysts [24-41], For Ru-based Z-selective catalysts [42-45], For cyclometalated Ru-based Z-selective catalysts [46-58]). Many of these systems exhibit consistently high levels of activity and selectivity across a broad range of substrates. Herein, we will focus specifically on the cyclometalated ruthenium-based catalysts developed in our laboratory [46-58]. This chapter is intended to provide a comprehensive summary of the evolution of these cyclometalated ruthenium catalysts, from their initial serendipitous discovery to their recent applications in Z-selective olefin metathesis transformations. Current mechanistic hypotheses and limitations, as well as future directions, will also be discussed. 

The abovementioned cyclometalated ruthenium catalysts have been applied in a number of Z-selective olefin metathesis reactions [46-58]. Of these catalysts, 10 remains the state of the art with respect to a general Z-selective catalyst for CM (Sect. 3.1) and mRCM (Sect. 3.3). The potential of 10 remains to be fully evaluated in more specialized transformations such as AROCM (Sect. 3.2), Z-selective ethenolysis (Sect. 3.5), or ROMP (Sect. 3.4). 

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