Hoveyda, A. H.; Malcolmson, S. J.; Meek, S. J.; Zhugralin, A. R. Catalytic Enantioselective Olefin Metathesis and Natural Product Synthesis. Chiral Metal-Based Complexes that Deliver High Enantioselectivity and More Angew. Chem., Int. Ed. 2010, 49, 34-44.
The ultimate test for the utility and versatility of a new catalyst is its performance in target-oriented synthesis. Despite the enormous progress in olefin metathesis in the past two decades, there is still need for further catalyst development to accomplish reactions with difficult substrates more efficiently. There are still a lot of examples of substrates for natural products synthesis with which the currently existing catalysts are having problems. More stereoselective catalysts are needed for cross metathesis reactions and more efficient catalysts are needed for stubborn ring closing metathesis (RCM) and ring opening metathesis processes that force the use of high catalyst loadings. Part of this mini-review is focused on enantioselective metathesis and presents several examples from the literature where enantioselective metathesis catalysts can make existing synthesis of natural products much more efficient. The examples show that using an effective chiral catalyst instead of starting with enantiopure substrate can simplify and shorten the existing synthesis.
Various examples of chiral Mo- and Ru-catalyzed transformations are presented that not only illustrate the advantages of using chiral metathesis catalysts but also show the shortcomings of the existing catalysts. It is noted that most of the synthetic routes towards natural products were designed to work with existing chiral catalysts. However, a different approach is illustrated by an example from the Hoveyda group. In the synthesis of quebrachamine, the most direct synthesis was chosen and then a new catalyst was developed for the challenging RCM reaction. The newly designed stereogenic-at-Mo catalyst readily delivered the desired tetracyclic diene containing an all-carbon stereogenic center very efficiently and with remarkable selectivity. This example shows how target-oriented synthesis can serve as an indicator of the types of catalysts that remain to be discovered and lead to the design of new more efficient catalysts.
Going beyond its initial focus, an important point which the authors drive home is that a chiral catalyst should not be examined only when an enantioselective reaction is needed. A chiral catalyst might offer reactivity levels that are superior to those furnished by achiral versions and can be relevant to cases other than those where the goal is achieving high enantioselectivity. A couple of examples show how chiral complexes, even in their racemic form, can promote transformations with higher efficiency or with unique types of selectivity (e.g., site- or E/Z-selectivity).