In 2000, these researchers independently developed and reported two different examples of asymmetric organocatalysis. List studied the aldol reaction between acetone and a variety of aldehydes, discovering that the amino acid proline is an effective catalyst. The key benefits of proline as a catalyst are that it’s nontoxic, inexpensive and readily available in both enantiomeric forms. MacMillan tested the ability of chiral amines to enantioselectively catalyse the Diels–Alder reaction between α,β-unsaturated aldehydes and dienes. The key idea was that the reversible formation of iminium ions from α,β-unsaturated aldehydes and amines might promote the cycloaddition reaction in a similar way to Lewis acid catalysts. This hypothesis was found to hold true and the enantioselective amine-catalysed Diels–Alder reaction was the result.
Although metal catalysts could be used to carry out similar reactions, the use of a metal often comes with limitations, frequently requiring oxygen- and moisture-free conditions as well as there being potential toxicity issues. Such considerations are particularly restrictive for the application of metal-catalysed methods in large-scale reactions. The research developed by List and MacMillan showed that metals were not required for enantioselective reactions and that small organic compounds could do the same job as large and complex enzymes. Moreover, organocatalysts are typically cheaper to produce compared with their metal or enzyme counterparts, making reactions more cost effective as well as potentially offering a more sustainable metal-free route to some products.
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