Karl Anker Jørgensen and Søren Bertelsen from Aarhus University, Denmark, talk about impressive achievements in organocatalysis

Asymmetric synthesis has been the focus of a number of organic chemists for many years. Now, constructing stereogenic carbon atoms is a fundamental part of organic chemistry, not least in life science, where strict regulations regarding stereogenic pharmaceuticals, for example, make stereoselective synthesis highly interesting. As such, methods for constructing and/or manipulating stereocentres are central tools in the organic chemist's toolbox.

Traditionally, stereocentres have been obtained and transformed from natural sources, but asymmetric catalysis has allowed us to construct non-racemic stereocentres de novo using substoichiometric catalyst amounts. Clearly, designing and understanding the catalysts' mechanisms are highly important. 

Enzymes and metals have played central roles in asymmetric catalysis and are still considered the best for a number of transformations. Recently, though, organocatalysis has entered the scene, promising easy procedures to synthesise valuable optically active intermediates. Organocatalysis complements established procedures involving metal or enzyme catalysts, but it allows a greater substrate scope than most enzymes and avoids the use of metals, which can be difficult to remove from products.

 

Holding all the cards - the versatility of organocatalysis

 

A privileged organocatalyst family is the secondary amines. Stereoselective carbonyl compound transformations by secondary amine catalysts have been known for several decades, but the interest in their use exploded less than a decade ago when they efficiently catalysed aldol and [4+2]-cycloaddition reactions. In particular, the naturally occurring amino acid proline has proven to be a highly privileged structure. It is able to catalyse reactions with amazing results considering the simplicity of its structure. The usual substrates for many of these reactions are carbonyl compounds, such as aldehydes or ketones. They are easy to transform, making versatile products for further reactions, and the secondary amines have shown great potential as carbonyl compound activators.

Organocatalysts have impressed us with their ability to promote stereoselective incorporation of non-metallic elements into an -C-H bond relative to the carbonyl compound. Several studies have focused on elucidating the underlying mechanism, but what about other synthetic challenges?

A close interplay between experimental and theoretical chemists has led them to develop new catalysts designed to address specific synthetic problems. Whereas proline, and more recently, other chiral secondary amines, have shown unsurpassed generality in the -functionalisation of carbonyl compounds, organocatalysts are also being developed for stereoselective -functionalisation. Most non-metallic (and non-halogenic) compounds can now, routinely, be incorporated into the -position with high stereoselectivities and good yields. Understanding the active mechanisms has been crucial in developing these transformations.

Recently, chemists have developed two new activation methods to allow for unprecedented transformations. The first was -functionalisation - on inspecting the mechanism, the possibility of an umpolung (a reversal of polarity when a functional group is modified) was realised. Consequently, it is now possible to perform stereoselective C-H to C-N or C-C bond transformations in the remote -position relative to the carbonyl. The other novel activation method employs radicals in mechanisms related to the -functionalisations. Using these new methodologies, the previously elusive organocatalytic stereoselective -alkylation of aldehydes has now been achieved.

Organocatalysts' complementary activation methods, then, open new vistas for one-pot, cascade or tandem reactions leading to highly complex products using simple procedures. Their versatility allows for intricate reaction protocols that lead to multiple activations of specifically designed molecules. One eminent example is the facile total synthesis of Oseltamivir, an antiviral drug to treat influenza, using a one-pot procedure. Various other applications of amino catalysts further underline the importance of this relatively new research field. Organocatalysis, we believe, will remain a highly competitive field, providing us with unexpected and fascinating new discoveries.

Read more in Søren Bertelsen and Karl Anker Jørgensen's tutorial review 'Organocatalysis - after the gold rush'  in issue 8, 2009 of Chemical Society Reviews.

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