Chemistry and Biology of Biosynthetic Diels-Alder Reactions

Nature's repertoire of biosynthetic transformations has recently been recognized to include the Diels–Alder cycloaddition reaction. Evidence now exists that there are enzymes that mediate the Diels–Alder reaction in secondary metabolic biosynthetic pathways. 2002 marked the 100th anniversary of Alder's birth and 75 years since the discovery of the Diels–Alder reaction. It would appear that living systems discovered and made use of this ubiquitously useful ring‐forming reaction eons ago for the construction of complex natural products. In this Review an overview is given of all of the known classes of natural products (polyketides, isoprenoids, phenylpropanoids, alkaloids) that have been speculated to arise by a biological Diels–Alder reaction. Do they or don't they? A Diels–Alder cycloaddition has been assumed to occur in the biosynthesis of numerous natural products, for example, lovastatin (see scheme). The existence of enzymes that catalyze these reactions (Diels–Alderases) was until recently not know for certainty, even when biosynthetic investigations and the biommetic total syntheses in some cases suggested it to be so.